SELECTIVE MONOHYDROLYSIS OF SYMMETRIC DIESTERS
IN MAINLY AQUEOUS MEDIA
by
Hanjoung Cho, M.S.
A Dissertation
In
CHEMISTRY
Submitted to the Graduate Faculty
of Texas Tech University in
Partial Fulfillment of
the Requirements for
the Degree of
DOCTOR OF PHILOSOPHY
Approved
Satomi Niwayama
Chairperson of the committee
Guigen Li
Michael F. Mayer
Fred Hartmeister
Dean of the Graduate School
December, 2010
Copyright 2010, Hanjoung Cho
Texas Tech University, Hanjoung Cho, December 2010
ACKNOWLEDGEMENTS
I would like to show my gratitude to my research advisor, Dr. Satomi Niwayama,
for her constant support. This dissertation would not have been possible unless I have met
her at Texas Tech University. She is one of the kindest persons who I have met in my life.
I am very thankful to her for giving me the selective monohydrolysis project which was
firstly reported by her.
I want to thank to Dr. Guigen Li and Dr. Michael F. Mayer for their serving on my
committee members and providing me scientific guidance and advice. I really appreciate
Dr. Mayer for providing me a lot of suggestions and chemical information in the area of
organic chemistry.
I owe my deepest gratitude to my family for their love, support and encouragement
throughout my entire life. I am very happy to start to share my life with Shi Ra Kim
(wife), Suah Cho (daughter), and Sumin Cho (daughter) in Lubbock. I really appreciate
them to support me everything and drive me toward a higher goal in our life. Lastly, I
dedicate this dissertation to my father, Sun-Ho Cho. I will always remember his previous
support in my future life.
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Texas Tech University, Hanjoung Cho, December 2010
TABLE OF CONTENTS
ACKNOWLEDGEMENT ................................................................................................ ii
ABSTRACT ..................................................................................................................... vii
LIST OF TABLES ........................................................................................................... ix
LIST OF FIGURES ......................................................................................................... xi
LIST OF SCHEMES ..................................................................................................... xiii
CHAPTER
1.
INTRODUCTION .................................................................................................. 1
1.1.
1.2.
Water-mediated organic reactions ....................................................................... 3
1.1.1.
Brønsted acid catalysis in water .................................................................3
1.1.2.
Lewis acid catalysis in water ......................................................................4
1.1.3.
Micellar catalysis ........................................................................................6
1.1.4.
Water soluble chiral auxiliaries ..................................................................7
1.1.5.
Nucleophilic substitution ............................................................................8
Hydrolysis of esters...............................................................................................8
1.2.1.
Saponification (ester hydrolysis with basic catalysis) ................................9
1.3.
Structural properties of ester groups .................................................................. 10
1.4.
Desymmetrization in organic synthesis ............................................................. 13
1.4.1.
Diastereoselective anhydride opening reactions ......................................13
1.4.2.
Enzymatic desymmetrization reactions of esters .....................................14
1.4.3.
The scope of selective monohydrolysis of symmetric diesters ................15
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Texas Tech University, Hanjoung Cho, December 2010
1.5.
1.6.
2.
The theoretical background for computational calculation ............................... 16
1.5.1.
Schrödinger equation ................................................................................16
1.5.2.
Atomic units (au or a.u.) ...........................................................................17
1.5.3.
Basis sets ..................................................................................................18
1.5.4.
Density functional theory (DFT) ..............................................................19
References .......................................................................................................... 21
HIGHLY
EFFICIENT
SELECTIVE
MONOHYDROLYSIS
OF
DIALKYL MALONATES AND THEIR DERIVATIVES .............................. 24
2.1.
Introduction ........................................................................................................ 24
2.2.
Monohydrolysis of dimethyl malonate with possible alkali bases .................... 29
2.3.
Monohydrolysis of dialkyl malonate and their derivatives................................ 31
2.4.
Scale-up monohydrolysis of dimethyl malonate 1 and diethyl malonate 3 ....... 37
2.5.
Conclusion ......................................................................................................... 44
2.6.
Experimental section .......................................................................................... 44
2.7.
References .......................................................................................................... 55
3.
REMOTE EXO/ENDO SELECTIVITY IN SELECTIVE
MONOHYDROLYSIS OF DIALKYL BICYCLO[2.2.1]HEPTANE-2,3DICARBOXYLATE DERIVATIVES ................................................................ 57
3.1.
Introduction ........................................................................................................ 57
3.2.
The selective monohydrolysis of (exo,endo)-dimethyl- and
diethylbicyclo[2.2.1] hept-5-ene-2,3-dicarboxylate 1a and 1b ......................... 61
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3.3.
The selective monohydrolysis of (exo, endo)-dimethyl- and
diethylbicyclo[2.2.1] heptane-2,3-dicarboxylate 4a and 4b .............................. 66
3.4.
The selective monohydrolysis of acetonide protected (exo,endo)-dimethyland diethylbicyclo[2.2.1] hept-5-ene-2,3-dicarboxylate 7a and 7b ................... 71
3.5.
The selective monohydrolysis of steric hindered bicyclic diesters on C5–C6
bond.................................................................................................................... 73
3.6.
Conclusion ......................................................................................................... 77
3.7.
Experimental section .......................................................................................... 78
3.8.
References .......................................................................................................... 98
4.
THE CONFORMATIONAL ANALYSIS OF SYMMETRIC DIESTERS
BY THEORETICAL CALCULATIONS ........................................................ 100
4.1.
Introduction ...................................................................................................... 100
4.2.
Calculation method .......................................................................................... 102
4.3.
Conformational studies on dimethyl maleate 1 ............................................... 105
4.4.
Conformational studies of dimethyl bicyclo[2.2.1]hepta-2-ene diester 2........ 111
4.5.
Conformational studies on dimethyl succinate 3 ............................................. 117
4.6.
Conclusion ....................................................................................................... 120
4.7.
References ........................................................................................................ 121
5.
ASYMMETRIC MONOHYDROLYSIS OF SYMMETRIC DIESTERS
WITH CHIRAL IONIC LIQUIDS ................................................................... 123
5.1.
Introduction ...................................................................................................... 123
5.2.
Monohydrolysis of a symmetric diester in ionic liquids .................................. 125
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5.3.
Asymmetric monohydrolysis in chiral ionic liquids ........................................ 126
5.4.
The scope for asymmetric monohydrolysis with chiral ionic liquids .............. 127
5.5.
Experimental section ........................................................................................ 128
5.6.
References ........................................................................................................ 132
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ABSTRACT
As water possesses many ideal characteristics for a reaction medium such as
accessibility, environmental safety, and low cost, the development of organic reactions in
aqueous media has been of central importance in recent organic chemistry. Since many
organic compounds have limited solubility in water, efficient water-mediated reactions
with high selectivities and reactivities are still somewhat rare, and hence there is a need
for organic methodological development in mainly water media. The desymmetrization
of meso compounds is a powerful concept with regards to both asymmetric and
nonasymmetric synthesis. Half-esters produced by desymmetrization of symmetric
diesters are especially versatile building blocks in organic synthesis. In this dissertation,
the syntheses of various half-esters from the corresponding diesters via monohydrolysis,
which is a desymmetrization reaction, in mainly water media are discussed.
The highly selective monohydrolysis of dialkyl malonates and their derivatives are
discussed. In the second chapter, the reactions are practical, yielding the corresponding
half-esters in high yields in a straightforward manner without inducing decarboxylation.
The hydrophobicity of diester substrates was found to be one of the factors which could
determine the selectivity in monohydrolysis reactions. The high exo-facial selectivity
observed in the selective monohydrolysis of a series of near-symmetric diesters is
described in the third chapter. The selectivities were found to be specific, although the
reaction center in these reactions is one covalent bond distant from the norbornane or
norbornene ring, where the difference of the environment between the exo face and endo
face is expected to be negligible. In addition to these experimental studies, the
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conformational studies in symmetric diesters showed electronic interaction between the
two carbonyl groups via computational calculations in the fourth chapter. The stable
structures of symmetric diesters with attractive interaction on the two carbonyl groups are
presented. This conformational preference is expected to contribute to the high
selectivities in the monohydrolysis of symmetric diesters. The asymmetric
monohydrolysis of symmetric diester is also investigated with chiral ionic liquids in the
last chapter. Since the reactivity of selective monohydrolysis of symmetric diesters with
an alkali base could be affected on the choice of co-solvents, the chiral ionic liquids can
influence the chirality of half-ester by selective monohydrolysis. The studies to improve
the enantiomeric excesses of half-esters by the modification of substrates and chiral ionic
liquids are underway.
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LIST OF TABLES
2.1
Selective monohydrolysis of dimethyl malonate 1 ............................................... 30
2.2
Selective monohydrolysis of dialkyl malonate derivatives .................................. 32
2.3
The reaction rate constant in the monohydrolysis of bicyclic diester 11 with
different co-solvent ............................................................................................... 36
2.4
Practical scale-up monohydrolysis of 0.12 mole of dimethyl malonate 1 ............ 39
2.5
Practical scale-up monohydrolysis in 0.08 mole diethyl malonate 3.................... 41
3.1
Selective monohydrolysis of bicyclic diester 1a and 1b ...................................... 62
3.2
Selective monohydrolysis of dimethyl and diethyl bicyclo[2.2.1] heptane-2,3dicarboxylate 4a and 4b ........................................................................................ 67
3.3
Selective monohydrolysis of acetonide-protected diesters 7a and 7b .................. 72
3.4
Selective monohydrolysis of diesters 10a and 10b............................................... 74
4.1
Electronic energies of possible structures of dimethyl maleate 1 at the level of
the B3LYP/6-31G(d)//B3LYP/6-31G(d) and MP2/6-31G(d)//B3LYP/631G(d) ................................................................................................................. 107
4.2
Electronic energies with selected dihedral angles (deg) on the B3LYP/631G(d)//B3LYP/6-31G(d) and MP2/6-31G(d)//B3LYP/631G(d) optimized
structures of dimethyl maleate 1 ......................................................................... 109
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Texas Tech University, Hanjoung Cho, December 2010
4.3
Electronic energies of possible structures of bicyclic diester 2 at the level of
the B3LYP/6-31G(d)//B3LYP/6-31G(d) and MP2/6-31G(d)//B3LYP/631G(d) ................................................................................................................. 113
4.4
Electronic energies with selected dihedral angles (deg) on the B3LYP/631G(d)//B3LYP/6-31G(d) and MP2/6-31G(d)//B3LYP/631G(d) optimized
structures of bicyclic diester 2 ............................................................................ 115
4.5
Selected dihedral angles (deg) of dimethyl succinate 3 at the level of
B3LYP/6-31G(d) ................................................................................................ 119
4.6
Electronic energies of possible structures of dimethyl succinate 3 at the level
of the B3LYP/6-31G(d)//B3LYP/6-31G(d) and MP2/6-31G(d)//B3LYP/631G(d) ................................................................................................................. 119
5.1
Selective monohydrolysis of bicyclic diester with ionic liquids ........................ 126
5.2
Asymmetric monohydrolysis of bicyclic diester 1 under chiral ionic liquid 2 ... 127
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LIST OF FIGURES
1.1
Equilibrium in ester conformations…… .............................................................. 11
1.2
Geometry of methyl formate …… ........................................................................ 12
2.1
Examples of biologically important molecules which are synthesized from
monomethyl or monoethyl malonate ................................................................... 25
2.2
Potential micelle intermediate of monohydrolysis of general symmetric
diesters ................................................................................................................. 35
3.1
HPLC chromatogram for mixture of monomethyl half-esters 2a and 3a ............. 64
3.2
1
H NMR spectra of the mixture of monomethyl ester (top), endo-hydrolyzed
monomethyl ester (middle), and exo-hydrolyzed monomethyl ester (bottom)..... 65
3.3
1
H NMR spectra of the mixture of monomethyl ester (top), endo-hydrolyzed
monomethyl ester (middle), and exo-hydrolyzed monomethyl ester (bottom) .... 70
3.4
X-ray crystal structure of half-ester 11a ............................................................... 75
4.1
Possible electrostatic interactions between two carbonyl groups ....................... 101
4.2
Structures of diesters which are investigated by theoretical methods ................ 102
4.3
Possible conformations of an ester functional group .......................................... 103
4.4
Two important dihedral angles (, ) in dimethyl maleate 1, bicyclic diester 2,
and dimethyl succinate 3 ..................................................................................... 103
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4.5
Optimized structures of dimethyl maleate 1 at the selected dihedral angles by
the B3LYP/6-31G(d) level .................................................................................. 106
4.6
Potential energy curve for φ (C3=C2–C1=O2) torsion at  (C2=C3–C4=O3) =
0° in dimethyl maleate 1 calculated at the MP2/6-31G(d)//B3LYP/6-31G(d)
level ..................................................................................................................... 109
4.7
The fully optimized structure of dimethyl maleate 1 by B3LYP/6-31G(d)
calculations (top and side view) .......................................................................... 110
4.8
Optimized structures of bicyclic diesters 2 at the selected dihedral angles by
the B3LYP/6-31G(d) level .................................................................................. 112
4.9
Potential energy curve for φ (C3=C2–C1=O2) torsion at  (C2=C3–C4=O3) = 0°
in bicyclic diester 2 calculated at the MP2/6-31G(d)//B3LYP/6-31G(d) level .. 114
4.10
Geometric optimized structure of dimethyl bicyclo[2.2.1]hept-2-ene
dicarboxylate 2 by B3LYP/6-31G(d) at the lowest energy ................................ 115
4.11
The X-ray crystal structure of bicyclic diester 2 ................................................. 117
4.12
The optimized structure of dimethyl succinate 3 at the level of B3LYP/631G(d) ................................................................................................................ 118
4.13
Geometric optimized structures of dimethyl succinate 3 by B3LYP/6-31G(d) 120
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LIST OF SCHEMES
1.1
Brønsted acid-catalyzed Mannich reaction in aqueous media ................................ 4
1.2
Lewis acid-catalyzed aldol reaction in aqueous media ........................................... 4
1.3
Ytterbium triflate-catalyzed Diels-Alder reaction in an aqueous medium ............. 5
1.4
Enantioselective Diels-Alder reaction in water ...................................................... 5
1.5
Asymmetric Michael reaction in water ................................................................... 6
1.6
Surfactant-aided Lewis acid-catalyzed aldol reactions in water ............................. 7
1.7
Diastereoselective Diels-Alder reaction with a water soluble chiral auxiliary ....... 7
1.8
Ring opening reactions of oxiranes in water........................................................... 8
1.9
General scheme of ester hydrolysis under conditions............................................. 9
1.10
Mechanism of ester hydrolysis under basic conditions ........................................ 10
1.11
Saponification of trimyristin with sodium hydroxide ........................................... 10
1.12
Diastereoselective alcoholysis of meso cyclic anhydrides.................................... 13
1.13
Enantioselective hydrolysis of esters with Pig liver esterase................................ 14
1.14
A hydrolytic desymmetrization of dimethyl diesters ............................................ 15
2.1
Classical methods for preparing monomethyl malonate 2 .................................... 26
2.2
Classical methods for preparing monoethyl malonate 3a ..................................... 26
2.3
General scheme for selective monohydrolysis of symmetric diester.................... 28
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3.1
Reduction of 2-norbornanone by sodium borohydride ......................................... 58
3.2
Monohydrolysis of exo,endo-dimethyl- and diethylbicyclo[2.2.1]hept-5-ene2,3-dicarboxylates, 1a and 1b ............................................................................... 59
3.3
Synthesis of (exo,endo)-dimethyl- and diethylbicyclo[2.2.1]hept-5-ene-2,3dicarboxylate 1a and 1b ........................................................................................ 61
3.4
The preparation of dialkyl bicyclo[2.2.1] heptane-2,3-dicarboxylate 4a and 4b
by hydrogenation with palladium on carbon ........................................................ 66
3.5
The preparation of authentic half-esters 5a and 6a with HPLC and followed
by hydrogenation of 2a and 3a ............................................................................. 69
3.6
Synthesis of acetonide-protected bicyclic diesters 7a and 7b .............................. 71
3.7
Synthesis of dialkyl diesters 10a and 10b............................................................. 73
4.1
Selective monohydrolysis of dimethyl maleate and dimethyl fumarate ............. 101
5.1
Enantioselective methanolysis of the bicyclic meso anhydride 1 with
catalyst 3 ............................................................................................................. 124
5.2
Enantioselective hydrolysis of ester with enzyme in a chiral ionic liquid .......... 125
5.3
Proposed asymmetric monohydrolysis of symmetric diesters with chiral ionic
liquids.................................................................................................................. 128
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CHAPTER 1
INTRODUCTION
Water is among the most abundant molecules on the earth and the general solvent
in which chemistry of the life processes typically occurs. Water has many ideal
characteristics as a reaction medium, for example, easy accessibility, safe and convenient
use, and low environmental toxicity;1,2 furthermore, it is recently known to enhance the
rates and efficiencies of a wide variety of organic reactions.3,4
Organic reactions in water media can comprise ideal green chemistry. Among
diverse synthetic transformations, desymmetrization of symmetric compounds is one of
the most cost-effective reactions because the starting symmetric compounds are typically
available commercially at low cost or are produced easily on a large scale from
inexpensive precursors. Water-mediated desymmetrization of symmetric organic
compounds has the potential to be a greener reaction process of remarkable synthetic
value.
The reactions of esters have been known for long, and the hydrolysis of esters is
one of the most frequently used transformations in contemporary organic synthesis. Ester
hydrolysis is usually catalyzed by acids or bases. The catalytic action of alkali in
hydrolysis was studied by Scheele as early as 1792.5
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Monohydrolysis of symmetric diesters produces half-esters, which are highly
versatile building blocks in organic synthesis and have considerable commercial value.
Because the two ester groups in the symmetric diesters are equivalent, it is challenging to
distinguish these ester groups chemically. Classical saponification6 usually produces
complex mixtures of dicarboxylic acids, half-esters, and the starting diesters, which may
be difficult to separate. As a result, saponification yields a large amount of undesirable,
dirty waste. The most common method for effective monohydrolysis uses enzymes,
which provide, however, no basis for predicting the yield or enantioselectivity. Ringopening reactions of cyclic acid anhydrides require hazardous organic solvents.7
This dissertation is focused on the development of monohydrolysis of various
symmetric diesters and conformational analysis of symmetric diesters with computational
calculations. The first chapter discusses water-mediated organic reactions with brief
introductions about structural properties of the ester group, general examples about
hydrolysis of ester groups, and theoretical background for computational calculations.
The second chapter describes the monohydrolysis of dialkyl malonates and their
derivatives and practical-scale monohydrolysis of those substrates. The third chapter
involves exo/endo selective monohydrolysis of dialkyl bicyclic diesters using an alkali
base in water with co-solvents. The fourth chapter shows the conformational study of
symmetric diesters such as dimethyl maleate and dimethyl succinate with computational
calculations. The last chapter presents the asymmetric monohydrolysis of symmetric
diesters with chiral ionic liquids.
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To our knowledge, the selective monohydrolysis that we have studied here is
among the first examples of water-mediated reactions that are applied to
desymmetrization. Since desymmetrization in water is extremely green and practical,
with mild and safe conditions, and requires only inexpensive reagents, its synthetic utility,
particularly in process chemistry, is expected.
1.1. Water-mediated organic reactions
As water is an attractive solvent in many ways, performing the reaction in the
water medium is now of great interest. Water is also one of the most inexpensive solvents
used in organic synthesis. The most obvious potential advantages of water as a solvent
are cost, safety, and environmental concerns. Therefore, water is now regarded as one of
the most favorable solvents in academic laboratories as well as in industry.
This section introduces nonasymmetric and asymmetric organic reactions in
aqueous media. While there are numerous examples of organic reactions in water, acidcatalysis, micellar catalyst, water-soluble chiral auxiliaries, and nucleophilic substitution
in water are discussed in the following subsections.
1.1.1. Brønsted acid catalysis in water
Compared with Lewis acids such as titanium chloride and aluminum chloride,
Brønsted acids can be stable toward water and oxygen. A potential synthetic advantage of
water over organic solvents in Brønsted acid-catalyzed reactions is that the
nucleophilicity of the corresponding base, which can lead to undesired side reactions,
may be of less concern due to extensive solvation and diffusion of charge by hydrogenbonding water molecules. One example is that HBF4-catalyzed Mannich-type reactions in
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silyl enol ethers with aromatic aldehydes derived from activated imines afford the
corresponding β-amino ketones (Scheme 1.1).8
Scheme. 1.1 Brønsted acid-catalyzed Mannich reaction in aqueous media
1.1.2. Lewis acid catalysis in water
Lewis acid catalysis is widely used in modern organic synthesis. However, as
many of the common Lewis acids are highly reactive toward water, their use in organic
synthesis is restricted to strictly anhydrous conditions. To develop the concepts of Lewis
acid catalysis to water-based organic reactions, it is required that metal species retain
Lewis-acid activity, even in pure water. One of the classes of metal salts which are
tolerant in water are lanthanide triflates. Lanthanide triflates were found to be catalysts in
aldol reactions of formaldehyde in aqueous media (Scheme 1.2).9 In this reaction, a
commercially available aqueous formaldehyde solution was used as the source of the
electrophile. This invaluable finding introduced the concept of Lewis acid catalysis in
aqueous media to many organic chemists.
Scheme 1.2 Lewis acid-catalyzed aldol reaction in aqueous media
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Diels-Alder reactions can be catalyzed by ytterbium triflate in aqueous media
(Scheme 1.3). After the reaction, the catalyst was quantitatively recovered from the
aqueous layer and reused several times without loss of acitivity.10
Scheme 1.3 Ytterbium triflate-catalyzed Diels-Alder reaction in an aqueous medium
One of the reported asymmetric reactions with an acid catalyst in water is the
Diels-Alder reaction. The first reported enantioselective Diels-Alder reaction in water
used the combination of a copper salt and an amino acid, especially N-α-methyl-Ltryptophan (Scheme 1.4).11
Scheme 1.4 Enantioselective Diels-Alder reaction in water
Another example is an asymmetric Michael reaction in water. While several
excellent chiral catalysts for asymmetric Michael reactions have been developed in
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organic solvents, examples in water are limited. It was found that the combination of
BINAP derivatives and silver salts made good catalysts for asymmetric Michael reactions
in water. (Scheme 1.5)12
Scheme. 1.5 Asymmetric Michael reaction in water
1.1.3. Micellar catalysis
In an early stage of developing organic reactions in aqueous systems, aldol
reactions with rare earth triflates in THF-water or ethanol-water13 provided successful
results. On the other hand, when the reactions were performed in pure water, the
corresponding aldol products were obtained in low yields.14 This result was probably
because solubility of organic substrates was low and decomposition of silyl enol ethers
occurred faster than the desired aldol reactions in water. Micellar catalysis in water was
conceived to address this issue.15 The concept is based on the idea that organic
compounds can exist in an emulsion which can be formed by using a surfactant in water.
One of the examples which demonstrated the effect of a surfactant-aided Lewis acid on
aldol reactions is shown Scheme 1.6.
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Surfactant
None
SDS
Triton X-100
CTAB
Time
(h)
4
4
60
4
Yield
(%)
3
88
89
Trace
Scheme 1.6 Surfactant-aided Lewis acid-catalyzed aldol reactions in water
1.1.4. Water soluble chiral auxiliaries
Attachment of a water-soluble auxiliary is one way of solubilizing hydrophobic
compounds. Furthermore, if the attached auxiliary has a chiral nature, asymmetric
induction may be achieved. For example, Diels-Alder reactions of dienes with an
attached carbohydrate at the anomeric position proceeded faster and with higher endo/exo
selectivity in water than the corresponding reactions of dienes attached to a peracetylate
carbohydrate in toluene. One example is shown in Scheme 1.7.16
Scheme 1.7 Diastereoselective Diels-Alder reaction with a water soluble chiral auxiliary
Although the asymmetric induction was low (20% de), separation of the
diastereomers and hydrolytic cleavage of the sugar moiety produced enantiomerically
pure compounds. It is noteworthy that in these reactions diastereofacial preferences were
determined by the anomeric configuration of the sugar.16
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1.1.5. Nucleophilic substitution
Substitutions of SN2 type are frequently used for carbon–carbon or carbon–
heteroatom bond formation. Since the competitive hydrolysis of the electrophile in water
and SN2-type reactions being slower in aqueous conditions than in a polar aprotic solvent,
little attention has been devoted to the development of such reactions in water.
One of the nucleophilic substitutions in water is ring opening of oxiranes. The ring
opening of α,β-epoxycarboxylic acids by bromide and iodide ions has been effectively
achieved in water in a highly regio- and stereoselective manner.17 The indium chloride
catalyzed iodolysis of trans-β-iodohydrins in 88–95% yields, whereas the iodolysis at pH
4.0 without any added Lewis acid gave the anti-β-hydroxy-α-iodocarboxylic acids
(Scheme 1.8).
Scheme 1.8 Ring opening reactions of oxiranes in water
1.2. Hydrolysis of esters
Hydrolysis of esters and amides are very common in either acidic or basic solution.
Their hydrolysis occurs when the nucleophile attacks the carbon of the carbonyl group of
the amide or ester. In an aqueous base, hydroxyl ions are better nucleophiles than dipoles
such as water. The products for both hydrolysis are compounds with carboxylic acids.
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1.2.1. Saponification (ester hydrolysis with basic catalysis)
The most widely used hydrolysis of ester is alkaline hydrolysis, which makes use
of base and an alcohol. Hydrolysis of an ester in base, saponification, is an essentially
irreversible reaction (Scheme 1.9).
Scheme 1.9 General scheme of ester hydrolysis under basic conditions
Because it is irreversible, the hydrolysis of an ester in basic conditions often gives
better yields of carboxylic acid and alcohol than acidic hydrolysis of an ester. Because
the reaction occurs in base, the product of saponification is the carboxylate salt. The free
acid is generated when the solution is acidified. Ester hydrolysis in basic conditions has
been generally useful for hydrolysis of a single ester into a carboxylic acid on a large
scale at low cost.
The mechanism of saponification is based on the nucleophilic acyl substitution.
First an orthoester anion can be formed by attack of a hydroxide nucleophile at the
carbonyl carbon, breaking the π bond and creating the tetrahedral intermediate. The
reformation of the C and O double bond results in the loss of the leaving group the
alkoxide, RO. The formation of alkoxide anion generates carboxylate. As the alkoxide
groups deprotonate the carboxylic acid as bases, proton transfer between carboxylic acid
and alkoxide quickly generates carboxylate.
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Scheme 1.10 Mechanism of ester hydrolysis under basic conditions
The basic hydrolysis of a fat or oil provides the carboxylic acid called a fatty acid;
it generally has a long, unbranched hydrocarbon chain. The saponification means "the
making of soap". Soaps are synthesized by the saponification of fats. For example, the
hydrolysis of trimyristin in alkali base forms glycerol and sodium trimyristate which is
classical soap (Scheme 1.11).18
Scheme 1.11 Saponification of trimyristin with sodium hydroxide
1.3. Structural properties of ester groups
Esters, one of the most useful classes of organic compounds, are prepared from
carboxylic acids. While a carboxylic acid has the –COOH group, an ester group contains
any alkyl or aryl group instead of the hydrogen. The carbonyl carbon atom in an ester
group is hybridized (sp2 state) with three planar σ-bonding orbitals to the carbonyl
oxygen, carboalkoxy oxygen, and R group. The carbonyl bond is formed by overlapping
10
Texas Tech University, Hanjoung Cho, December 2010
of two atomic orbitals between the carbon and the oxygen. One is the atomic orbital in
the sp2 hybridized carbon and another is a p orbital of the oxygen atom forming the π
bond with the carbon p orbital. The π electrons are not equally shared due to the greater
electronegativity of the oxygen atom. Equally important to the structure of the carbonyl
group are the nonbonding electrons of the oxygen atom, the 2s2 and 2p2 electrons. These
electrons belong to two lone-pair orbitals (each doubly filled and nonbonding) in a plane
at a right angle to the π bond between the lone-pair orbitals and the carbon-oxygen σ
bond.19
In principle, an ester structure might exist in either conformation of Z (trans) or E
(cis) structures. The conformations of an ester group are shown in methyl20 and ethyl
formate.21
Figure 1.1 Equilibrium in ester conformations
As the E–Z energy difference in methyl formate (R = H, R' = CH3) is so large as to
be difficult to measure, the amount of E isomer of methyl formate is negligible at room
temperature. From the temperature dependence of the absorbance ratio, ΔHE–Z was found
to be 4.75±0.19 kcal/mol favoring the Z conformer.22
The geometry of methyl formate is shown in Figure 1.2.20 The C–O–C angle
(114.8°) is much larger than that in ethers (111.5°), and the H–C=O angle (124.8°) is
remarkably large. The acyl oxygen single bond, 1.334Å is considerably shorter than the
11
Texas Tech University, Hanjoung Cho, December 2010
alkoxy oxygen bond, 1.437Å . This difference suggests overlap of one of the p orbitals on
the alkyl oxygen with C=O bond. As a result, the H–C–O–C framework is planar and the
barrier to rotation about the C–O bond is high. Surprisingly, the C=O bond is not
lengthened; its length of 1.200Å is actually slightly shorter than those usually found in
aldehydes and ketones, which are around 1.220Å . The reasons why the Z conformer of
methyl formate is more stable than E are complex. The following factors may contribute:
(a) H/CH3 steric repulsion in the E conformer. This factor is probably small in formates
but important in alkyl esters where the repulsion is of R/CH3 type. (b) Electrostatic
attraction between oxygen and H3Cδ+ in the Z conformer. (c) n–σ* overlap in the Z
conformer.23
One of the unshared pairs on the alkyl oxygen is in the R–C–O–R' plane of the
ester function and antiperiplanar to the C=O bond. While this pair is not involved in the
p-π overlap, which contributes to the planarity of the ester group, it is properly disposed
for overlap with the σ* orbital of the C=O bond, thus stabilizing the Z conformation in a
manner similar to that involved in the anomeric effect.
Figure 1.2 Geometry of methyl formate
12
Texas Tech University, Hanjoung Cho, December 2010
1.4. Desymmetrization in organic synthesis
Desymmetrization of meso compounds is proven to be a powerful synthetic tool in
asymmetric or non-asymmetric modern organic synthesis. In this section,
diastereoselective anhydride opening reactions for preparing half-esters and enzymatic
desymmetrization are discussed.
1.4.1. Diastereoselective anhydride opening reactions
Desymmetrization of a cyclic anhydride by nucleophiles such as alcohols, diols,
and hydroxyacids can offer the half-ester and was explored by Cohen in the mid-1950s
for the first time.24 This reaction of a meso or prochiral cyclic anhydride with a chiral
alcohol produces the corresponding half-ester as two diastereomers. The
diastereoselective desymmetrization was studied with metal salts of chiral diols and
chiral amino alcohols. Taguchi reported that modest to excellent selectivities could be
achieved for the ring opening of both meso succinic anhydrides and prochiral 3substituted glutaric anhydrides using the monosodium salt of a diol (Scheme 1.12).25
Scheme 1.12 Diastereoselective alcoholysis of meso cyclic anhydrides
However, ring opening reactions of cyclic anhydride requires dry conditions and
cannot produce compounds which contained trans C=C double bond due to ring strain.
Therefore, other organic reaction methodology for preparing half-esters is essential.
13
Texas Tech University, Hanjoung Cho, December 2010
1.4.2. Enzymatic desymmetrization reactions of esters
Enzymes have been widely used in synthesis to make useful organic compounds
effectively, and are now considered efficient complements to metal catalysts.26 Catalysis
of the nucleophilic reactions of esters by various enzymes is widespread and varied.
Especially, various lipases and esterases have been used for the hydrolysis of esters.
Several lipases or esterases have been widely used for broad substrate specificities,
activities, and chemo-, regio- and enantioselectivities. For example, useful chiral acids
can be obtained through the resolution of meso esters by pig liver esterase-catalyzed
hydrolysis (Scheme 1.13).27
Scheme 1.13 Enantioselective hydrolysis of esters with pig liver esterase
PLE-catalyzed hydrolytic desymmetrizations of some other meso and prochiral
acyl donors have proven to be highly enantioselective. Thus, both the product and its
enantiomer have been synthesized through a chemoenzymatic approach in which chirality
was introduced by means of a hydrolytic desymmetrization of prochiral dimethyl diesters
(Scheme 1.14).28
14
Texas Tech University, Hanjoung Cho, December 2010
Scheme 1.14 A hydrolytic desymmetrization of dimethyl diesters
The obtained monoesters are useful chiral synthons for the preparation of both
pharmaceuticals and natural products. However, the enzymatic monohydrolyses have the
limitation of prediction of the yield and enantioselectivity and the lack of commercial
availability. Using a particular enzyme, no systematic studies have been performed for
the synthesis of racemic or achiral monoesters.
1.4.3. The scope of selective monohydrolysis of symmetric diesters
The desymmetrization reactions in mainly aqueous media were not reported to date.
In particular, a limited number of the desymmetrization reactions via the hydrolysis of
symmetric diesters were reported. Two methods for preparing half-esters were widely
used. One of the reported examples is the monosaponification of symmetric diesters in
base and alcohol. However, the reactivity of monosaponification of symmetric diesters
has a statistical maximum of 50% yield, and the separation of the half-ester is difficult.
The other examples are enzymatic monohydrolysis of symmetric diesters which are
shown in the previous section. However, the prediction for reactivity and selectivity is
limited due to the lack of systematic investigations of enzymatic reactions. Therefore, the
studies in non-enzymatic monohydrolysis of symmetric diesters and the development of
preparing half-ester is essential. Furthermore, since water as a reaction medium has some
benefits such as easy accessibility and environmental safety, water-mediated
15
Texas Tech University, Hanjoung Cho, December 2010
desymmetrization such as the monohydrolysis of symmetric diesters have become
important in modern organic synthesis.
1.5. The theoretical background for computational calculation
The properties of atomic and molecular systems can be predicted by ab initio
molecular orbital theory. It is based upon the fundamental equations of quantum
mechanics and uses a variety of mathematical transformation and approximation methods
to solve the basic equations. As we discussed the theoretical results at Chapter 4, this
section provides an introductory overview of the theory dealing with electronic properties
of molecules.
1.5.1. Schrödinger equation
The following Schrödinger equation (1) is the equation for a single particle;
In the equation, Ψ (r, t) is the wave function, i is imaginary unit, m is the mass of the
particle, h is Planck’s constant, and V(r) is the potential energy of the particle in the force
field. The square value of Ψ (r, t) is the probability amplitude for the particle to be found
at position r at time t. For the equation of many particles, the wave function contains a
certain time as well as positions for all particles. As a boundary condition of molecule is
applied to the Schrödinger equation with potential energy, the solution to the equation
can provide the wave function and energy of the molecule. The energy is obtained by
solving the equation and each wave function represents a stationary point, e.g. orbital.
The Schrödinger equation can be transformed to relatively simple differential equation.
16
Texas Tech University, Hanjoung Cho, December 2010
The wave function, Ψ (r, t), is converted through separation of two variables, time and
distance, as follows;
Since the potential energy is only a function of position, not time, the time
independent Schrödinger equation can be generated without time function and equation
(3) is mainly used for theoretical calculations of molecules:
E is the energy of particles, r is the position of particle, and H is the Hamiltonian
operator:
The solutions of equation (3) generate the stationary states and energy values and
the state with lowest energy is the ground state of the molecule.
1.5.2. Atomic units (au or a.u.)
The fundamental equations of quantum chemistry are usually expressed in units
designed to simplify their form by eliminating fundamental constants. The atomic unit of
length is the Bohr radius:
Coordinates can be transformed to bohrs by dividing them by a0. Energies are
measured in hartree, defined as the Coulomb repulsion between two electrons separated
by 1 a0 (1 bohr):
17
Texas Tech University, Hanjoung Cho, December 2010
The unit of mass in atomic units is the electron mass as is specified in terms of
electron mass units such as me = 1. For example, the electronic energy of the hydrogen
atom in the ground state is simply
with atomic units. Atomic units are
commonly used in the Gaussian program package.29
1.5.3. Basis sets
A basis set is a set of functions used to create the molecular orbitals for theoretical
calculation. The molecular orbitals are expressed as linear combinations of a pre-defined
set of one-electron functions known as basis functions. These basis functions are usually
centered on the atomic nuclei and so bear some resemblance to atomic orbitals. However,
the actual mathematical treatment is more general than this, and any set of appropriately
defined functions may be used. An individual molecular orbital is defined as:
The coefficients cμi are known as the molecular orbital expansion coefficients. The
basis functions xμ are also chosen to be normalized. Gaussian and other ab initio
electronic structure programs use gaussian-type atomic functions as basis functions.
Gaussian functions have the general form:
α is a constant determining the size of the function. Here are three representative
Gaussian functions for s, py and dxy orbitals, respectively.
18
Texas Tech University, Hanjoung Cho, December 2010
Linear combinations of primitive gaussian like these are used to from the actual
basis functions.
Basis sets have minimal basis set, split valence basis set, polarized basis set, and
diffuse function. The most common minimal basis set is STO-nG. For example, STO-3G,
three primitive gaussian orbitals are fitted to a single Slater-type orbital (STO).
Split valence basis sets, such as 3-21G and 6-31G(d), have two (or more) size of
basis function for each valence orbital. Split valence basis sets allow orbitals to change
size, but not to change shape. Polarized basis sets remove this limitation by adding
orbitals with angular momentum beyond what is required for the ground state to the
description of each atom. Diffuse functions are large-size versions of s- and p-type
functions and are important for systems where electrons are relatively far from the
nucleus such as molecules with lone pairs, anions, or excited states. The basis sets with
diffuse functions are denoted with a plus sign such as 6-31+G(d) or 6-31++G(d).
1.5.4. Density functional theory (DFT)
Density functional theory (DFT) is one of the quantum mechanical theories used in
physics and chemistry. DFT is usually used to investigate the electronic structure of
19
Texas Tech University, Hanjoung Cho, December 2010
atoms, molecules, and condensed phases in the ground state. With this theory, the
properties of a many-electron system can be determined by using functionals which in
this case is the spatially dependent electron density.
DFT has been very popular for calculations in solid state physics since the 1970s.
In many cases the results of DFT calculations for solid-state systems agreed quite
satisfactorily with experimental data. Also, the computational costs were relatively low
when compared to traditional ways which were based on the complicated many-electron
wavefunction, such as Hartree-Fock theory. However, DFT was not considered accurate
enough for calculations in quantum chemistry until the 1990s, when the approximations
used in the theory were greatly refined to better model the exchange and correlation
interactions. DFT is now a leading method for electronic structure calculations in
chemistry and solid-state physics.
Following the work of Kohn and Sham, the approximate functional employed by
current DFT methods partition the electronic energy into several terms;
Ex[P] and Ec[P] are exchange and correlation functional with density matrix [P]
respectively. Ex[P] can be expressed the integral of function with electron density.
20
Texas Tech University, Hanjoung Cho, December 2010
1.6. References
1.
Anastas, P.T.; Williamson, T. C. Green Chemistry: Frontiers in Benign Chemical
Syntheses and Processes, Oxford University Press, 1998.
2.
Matlack, A. S. Introduction to Green Chemistry, Marcel Dekker, New York, 2001.
3.
Li, C. J.; Chan, T. H. Organic Reactions in Aqueous Media, Wiley, New York,
1997.
4.
Grieco, P. A. Organic Synthesis in Water, Blackie, London, 1998.
5.
Bender, M. L. Chem. Rev. 1960, 60, 53.
6.
(a) Corey, E. J. J. Am. Chem. Soc. 1952, 74, 5897. (b) Vecchi, A.; Melone, G. J.
Org. Chem. 1959, 24, 109. (c) Strube, R. E. Organic Synthesis; Wiley & Sons: New
York, 1963; Collect. Vol. IV, p 417. (d) Robertson, A.; Sandrock, W. F. J. Chem.
Soc. 1933, 1617.
7.
(a) Hiratake, J.; Yamamoto, Y.; Oda, J. J. Chem. Soc., Chem. Commun. 1985, 1717.
(b) Hiratake, J.; Inagaki, M.; Yamamoto, Y.; Oda, J. J. Chem. Soc., Perkin Trans. 1
1987, 1053. (c) Kawakami, Y.; Hiratake, J.; Yamamoto, Y.; Oda, J. J. Chem. Soc.,
Chem. Commun. 1984, 779. (d) Theisen, P. D.; Heathcock, C. H. J. Org. Chem.
1993, 58, 142.
8.
(a) Akiyama, T.; Takaya, J.; Kagoshima, H. Synlett 1999, 1045. (b) Akiyama, T.;
Takaya, J.; Kagoshima, H. Adv. Synth. Catal. 2002, 344, 338.
9.
Kobayashi, S. Chem. Lett. 1991, 2187.
10.
Kobayashi, S.; Hachiya, I.; Takahori, T.; Araki, M.; Ishitani, H. Tetrahedron Lett.
1992, 33, 6815.
11.
(a) Otto, S.; Boccaletti, G.; Engberts, J. B. F. N. J. Am. Chem. Soc. 1998, 120, 4238.
(b) Otto, S.; Engberts, J. B. F. N. J . Am. Chem. Soc. 1999, 121, 6798.
12.
Kobayashi, S.; Kakumoto, K.; Mori, Y.; Manabe, K. Isr. J. Chem. 2001, 41, 247.
13.
Kobayashi, S.; Hachiya, I.; Oyamada, H. Bull. Chem. Soc. Jpn. 1994, 67, 2342.
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14.
(a) Kobayashi, S.; Hachiya, I. J. Org. Chem. 1994, 59, 3590. (b) Lubineau, A. J.
Org. Chem. 1986, 51, 2142. (c) Kobayashi, S.; Nagayama, S.; Busujima, T. Chem.
Lett. 1997, 959.
15.
(a) Kobayashi, S.; Wakabayashi, T.; Oyamada, H. Chem. Lett. 1997, 831. (b)
Kobayashi, S.; Wakabayashi, T.; Nagayama, S.; Oyamada, H. Tetrahedron Lett.
1997, 38, 4559.
16.
(a) Lubineau, A.; Auge, J.; Bellanger, N.; Caillebourdin, S. J. Chem. Soc., Perkin
Trans. 1 1992, 1631. (b) Lubineau, A.; Auge, J.; Bellanger, N.; Caillebourdin, S.
Tetrahedron Lett. 1990, 31, 4147.
17.
Amantini, D.; Fringuelli, F.; Pizzo, F.; Vaccaro, L. J. Org. Chem. 2001, 66, 4463.
18.
Beal, G. D.; Clarke, H. T.; Taylor, E. R. Organic Syntheses, Coll. Vol. 1, p. 379
1941; Vol. 6, p. 66 1926.
19.
Cook, D. J. Am. Chem. Soc. 1958, 80, 49.
20.
Curl, R. F. J. Chem. Phys. 1959, 30, 1529.
21.
Riveros, J. M.; Wilson, E. B. J. Chem. Phys. 1967, 46, 4605.
22.
(a) Blom, C. E.; Günthard, H. H. Chem. Phys. Lett. 1981, 84, 267. (b) Ruschin, S.;
Bauer, S. H. J. Phys. Chem. 1980, 84, 3061.
23.
Kirby, A. J. The Anomeric Effect and Related Stereoelectronic Effects at Oxygen,
Springer, New York, 1983.
24.
Altschul, R.; Bernstein, P.; Cohen, S. G. J. Am. Chem. Soc. 1956, 78, 5091.
25.
Suda, Y.; Yago, S.; Shiro, M.; Taguchi, T. Chem. Lett. 1992, 389.
26.
(a) Fessner, W. D. Biocatalysis from Discovery to Application, Springer, Berlin,
2000. (b) Drauz, K.; Waldmann, H. Enzyme Catalysis in Organic Synthesis: A
Comprehensive Handbook, Wiley-VCH Verlag GmbH, Weinheim, Germany, 2002.
27.
(a) Sabbioni, G.; Jones, J. B. J. Org. Chem. 1987, 52, 4565. (b) Kobayashi, S.;
Kamiyama, K.; Iimori, T.; Ohno, M. Tetrahedron Lett. 1984, 25, 2557.
22
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28.
Honda, T.; Koizumi, T.; Komatsuzaki, Y.; Yamashita, R.; Kanai, K.; Nagase, H.
Tetrahedron: Asymmetry 1999, 10, 2703.
29.
Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A.; Stratmann, R. E.; Burant,
J. C.; Dapprich, S.; Millam, J. M.; Daniels, A. D.; Kudin, K. N.; Strain, M. C.;
Farkas, O.; Tomasi, J.; Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli,
C.; Adamo, C.; Clifford, S.; Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.;
Morokuma, K.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.;
Cioslowski, J.; Ortiz, J. V.; Baboul, A. G.; Stefanov, B. B.; Liu, G.; Liashenko, A.;
Piskorz, P.; Komaromi, I.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; AlLaham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.;
Johnson, B.; Chen, W.; Wong, M. W.; Andres, J. L.; Gonzalez, C.; Head-Gordon,
M.; Replogle, E. S.; Pople, J. A. GAUSSIAN 98, Revision A. 3. Gaussian,
Pittsburgh, PA, 1998.
23
Texas Tech University, Hanjoung Cho, December 2010
CHAPTER 2
HIGHLY EFFICIENT SELECTIVE MONOHYDROLYSIS OF DIALKYL
MALONATES AND THEIR DERIVATIVES*
2.1. Introduction
Half-esters are widely used in organic synthesis as very important building blocks.
In particular, half-esters of malonic acid and its derivatives have been applied to the
synthesis of a variety of significant pharmaceuticals and natural products.1 Several
examples in which monomethyl malonic acid and monoethyl malonic acid are used as
starting compounds in organic synthesis are shown in Figure 2. 1.
Half-esters of malonic acid and their derivatives are still difficult to obtain because
of potential decarboxylation. A limited number of examples of selective
monosaponification have been reported starting from diethyl malonate, dimethyl
malonate,2 or their derivatives.3
* (a) Niwayama, S.; Cho, H.; Lin, C. Tetrahedron Lett. 2008, 49, 4434. (b) Niwayama, S.; Cho, H. Chem. Pharm. Bull. 2009, 57, 508.
24
Texas Tech University, Hanjoung Cho, December 2010
Figure 2.1 Examples of biologically important molecules which are synthesized from
monomethyl or monoethyl malonate
For the production of monomethyl malonate, some modified procedures have been
reported that apply 4-nitro-3-oxobutyrate,4 Meldrum’s acid,5 carboxylic acid,6 or
enzymes.7 The transformation from 4-nitro-3-oxobutyrate produce rather modest yields
of the corresponding half-esters and the commercial applicability of the reported
enzymatic hydrolysis is limited. In the case of conversion of Meldrum’s acid, isolated
yields of the half-esters are not reported and Meldrum’s acid is more costly than dimethyl
malonate 1.
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Texas Tech University, Hanjoung Cho, December 2010
Scheme 2.1 Classical methods for preparing monomethyl malonate
A limited number of procedures for synthesis of monoethyl malonate 3a are
reported as well as monomethyl malonate 2, as shown in Scheme 2.2.
Scheme 2.2 Classical methods for preparing monoethyl malonate 3a
Two classical methods for preparing monoethyl malonate are reported. Those are
monosaponification of diethyl malonate and ring opening alcoholysis with cyclic
anhydride and alcohol. The efficiency for both transformations is modest. For the case of
26
Texas Tech University, Hanjoung Cho, December 2010
ring opening reactions, as the malonic anhydride is not commercially available, the
ozonolysis of the diketene is used for preparation of the malonic anhydride.3h
Even though half-esters of malonic acids and their derivatives are widely used as
synthetic building blocks, their commercial accessibility is still limited and they are quite
expensive, and they are more generally available as the corresponding potassium salts. In
particular, monomethyl malonate 2 became commercially available since 2008, but is
expensive, or the purities are typically less than 99%, such as 96%. Therefore,
development of a more efficient synthetic method for monoalkyl malonate on a large
scale is essential.
One possible approach for monohydrolysis on a large scale is monosaponification
of symmetric diesters. However, successful distinction of the two identical ester groups
remains challenging. In fact, monosaponification typically produces a mixture of the
starting diester, the corresponding half-ester, and the diacid together with the use of one
equivalent of a base. Since half-esters of malonic acid have the potential of
decarboxylation, the synthesis of half-esters of malonic acid is still difficult especially on
a large scale. Only a limited number of examples of monosaponification of dimethyl or
diethyl malonate have been reported on a large scale,2 but a long time and more than one
reaction step might be required. To scale up modified procedures applying Meldrum’s
acid,5 it should conquer the drawbacks about cost for Meldrum’s acid and purification
and isolation of monoalkyl malonate should be considered. Another scale-up method is
the enzymatic monohydrolysis of dialkyl malonate. However, the reported enzymatic
monohydrolysis of dialkyl malonates used an enzyme which is not commercially
27
Texas Tech University, Hanjoung Cho, December 2010
available.6 Other methods by monoesterification of malonic acid are also reported, but the
yields are rather modest.7
However, by applying the selective monohydrolysis of symmetric diesters
Niwayama reported before8, we have been able to obtain a series of half-esters of malonic
acid derivatives in high yields in a straightforward manner.
Earlier, the highly efficient selective monohydrolysis of symmetric diesters in
aqueous NaOH and THF media was reported by Niwayama’s group. Monoalkyl ester can
be prepared in high yield through this reaction methodology (Scheme 2.3).8
Scheme 2.3 General scheme for selective monohydrolysis of symmetric diester
The selectivity for cyclic 1,2-diesters with the two ester groups was found to be
particularly high due to close proximity, even with the use of almost 2 equivalent of the
base, producing the corresponding half-esters in near-quantitative yields. We assumed
that electrostatic attractive interaction between the two closely located carbonyl groups
may play a role in the high selectivity. These possible electrostatic attractions will be
discussed in Chapter IV with theoretical calculations. We have been expanding the scope
of this reaction to others as well as 1,1-diesters which do not contain such an ideal
conformation. In this chapter, the development of an organic reaction methodology to
synthesize half-esters of dialkyl malonates and their derivatives and practical scale-up of
monohydrolysis of those substrates will be discussed.
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Texas Tech University, Hanjoung Cho, December 2010
2.2. Monohydrolysis of dimethyl malonate with possible alkali bases
When the selective monohydrolysis of dimethyl malonate was performed with the
same conditions we reported before,8 only 22% of the corresponding half-ester was
obtained. We have reasoned out the lack of selectivity of monohydrolysis of dimethyl
malonate. Those are the expected decarboxylation, and overuse of the base, as well as
lack of the ideal conformation of the starting diesters. Therefore we reduced the amount
of the base. We also altered the type of base to maximize the reaction conditions.
First of all, the optimal amount of the base was examined for monohydrolysis of
dimethyl malonate 2. Since overuse of base might cause decarboxylation, we started the
equivalent of the base from 1.2, 1.0, or 0.8 equivalents and investigated the yield of the
half-ester. After the monohydrolysis of dimethyl malonate in THF/aqueous media was
performed with the possible type of base, equivalent, and reaction times, the isolated
yields of monomethyl malonate are shown in the following in Table 2.1.
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Texas Tech University, Hanjoung Cho, December 2010
Table 2.1 Selective monohydrolysis of dimethyl malonate 1
a
Entry
Base
Equivalent
Time
Half-ester (%)
1
LiOH
0.8
1h
61 (13)
2
NaOH
0.8
0.5 h
62 (3)
3
KOH
0.8
1h
84
4
LiOH
1.0
1h
80 (10)
5
NaOH
1.0
1h
82 (10)
6
KOH
1.0
1h
83 (3)
7
LiOH
1.2
1h
75 (10)
8
NaOH
1.2
1h
83 (5)
9
KOH
1.2
1h
74
Isolated yield of the half-ester. The recovered diester is shown in parentheses (%).
From these results, we found that the reactivity was slightly different with the type
of alkali base used. The monohydrolysis of dimethyl malonate with the use of KOH is
more efficient than with the use of NaOH. For use of LiOH, the selectivity and reactivity
of monohydrolysis was slightly decreased for the applied equivalent of base. This
tendency was well consistent with the reference comparing the selectivity of the
monohydrolysis of dimethyl glutarate with LiOH, NaOH, KOH, and CsOH.9 The
30
Texas Tech University, Hanjoung Cho, December 2010
electropostitive character of the counter cations (K+>Na+>Li+) might be associated with
these selectivities for monohydrolysis of acyclic and symmetric diesters.10 From these
results we might assume that counter cations are participating in the initial stage of the
reaction where the discrimination is about to occur in order to bring the two identical
ester groups into close proximity by electrostatic effect. These electrostatic effects should
play a more important role in such acyclic systems than in rigid cyclic systems. The
enhanced size and "softness" of the counter cations are also expected to provide
advantages for the affinity in general.
The isolated yields of the half-ester and diester in these monohydrolyses indicated
that a small amount of diacid (malonic acid) perhaps formed. However, malonic acid was
not completely extracted during the work-up procedures due to its solubility in water.
This monohydrolysis appears to allow the highly practical synthesis of monomethyl
malonate 2 with a reaction time of only about 1 h, which illustrates the synthetic utility of
this monohydrolysis.
2.3. Monohydrolysis of dialkyl malonate and their derivatives
Based on the condition of the monohydrolysis of dimethyl malonate, we next
expanded this monohydrolysis reaction, into a wider range of dialkyl malonates and their
derivatives using aqueous NaOH or KOH as a base. The isolated yields, reaction
conditions, the type of base, and equivalent of base for monohydrolysis of dialkyl
malonates and their derivatives are summarized in Table 2.2. Most of these diesters such
as dimethyl malonate, diethyl malonate, and diethyl phenylmalonate, are commercially
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Texas Tech University, Hanjoung Cho, December 2010
available, and commercially unavailable diesters were prepared by the standard Fischer
esterification which is the reaction between an acid and an alcohol under acidic
conditions with specific glassware (Dean-Stark11 apparatus) assistance.12
Table 2.2 Selective monohydrolysis of dialkyl malonate derivatives
Base
Equivalent
Time
Half-estera (%)
1
KOH
0.8
1h
90
2
NaOH
1.0
1h
86 (3)
3
KOH
0.8
1h
91 (8)
4
NaOH
1.0
0.5 h
92 (8)
5
KOH
1.2
1.5 h
94 (2)
6
NaOH
1.2
1.5 h
93 (6)
7
KOH
1.2
1.5 h
96 (2)
8
NaOH
1.2
1.5 h
96 (4)
Entry
Diester
32
Texas Tech University, Hanjoung Cho, December 2010
a
b
9
KOH
1.2
1.75 h
97 (3)
10
NaOH
1.2
1.75 h
98 (2)
11
KOH
1.2
1h
95 (5)
12
NaOH
1.2
1h
95 (5)
13
KOH
1.2
5h
94 (4)
14
NaOH
1.2
5h
86 (13)
15
KOH
0.8
33 h
68 (29)
16b
KOH
0.8
33 h
77 (22)
17b
NaOH
0.8
33 h
68 (32)
Isolated yield of the half-ester. The recovered diester is shown in parentheses (%).
Acetonitrile was used instead of THF as a co-solvent
A yellowish reaction mixture of diester, half-ester and diacid was found in the
classical monosaponification, whereas mainly half-esters, starting diesters, and in rare
cases diacids, if existing, were isolated in all cases in our monohydrolysis. In some cases
in Table 2.2, small amounts of the diacids have been found based on the percentage of the
yield of the half-ester and recovered diester. However, since these acids are soluble in
water and in the aqueous layer in the work-up procedure, the diacids were not isolated
and purified by column chromatography. According to sharp elemental analysis data, all
of the half-esters were obtained with excellent purity. No decarboxylated products were
33
Texas Tech University, Hanjoung Cho, December 2010
found in any of the monohydrolysis reactions we tried. Overall, the reactivity of
monohydrolysis of these substrates tends to be higher with KOH than with NaOH. In the
aspect of selectivity, the monohydrolysis in KOH is slightly more selective than in NaOH
for dialkyl malonates and their derivatives. This tendency may be best illustrated in the
monohydrolysis of diethyl phenyl malonate (entry 13 and 14 in Table 2.2), which showed
enhanced reactivity and selectivity with the use of KOH, compared to the results we
previously published with the use of NaOH for monohydrolysis of the same diester.8
Interestingly, an increase in the hydrophobicity of the molecules also seems to
improve the selectivity. For example, for the case of monohydrolysis of dialkyl malonate
1, 3, and 4 (Table 2.1 and entries 1–4 in Table 2.2), as the alkyl groups in the diester
increase hydrophobicity, the isolated yields of the half-ester also increase. Furthermore
the yields of half-esters become even higher when the additional methyl or phenyl group
is introduced at C–2 position. One of our hypotheses in this monohydrolysis reaction is
that upon the monohydrolysis of the two identical ester groups, inter- and/or
intramolecular hydrophobic attractive interactions within the remaining portion of the
molecule may play an important role for this high selectivity, as aggregates may be
protected from further hydrolysis. One of the possible intermediates is a micelle
intermediate shown in Figure 2.2. The substrates after monohydrolysis can be divided
into two portions. One is carboxylate and the other is an ester group. The carboxylate
portion is hydrophilic as to be exposed into water whereas the relatively hydrophobic
ester group might aggregate with organic solvent. We are investigating further
34
Texas Tech University, Hanjoung Cho, December 2010
mechanistic hypotheses to detect potential intermediates with assistance of
physicochemical techniques.
Figure 2.2 Potential micelle intermediate of monohydrolysis of general symmetric
diesters
Therefore, this tendency may explain such hydrophobic effects. We have found
one exception in the case of dipropyl phenylmalonate 10. This exception for selective
monohydrolysis might be explained by the extended period of the reaction time, which
also sometimes allowed isolation of a visible amount of the corresponding diacid. In
order to improve the reactivity for monohydrolysis of dipropyl phenylmalonate 10, we
applied another slightly aprotic and polar solvent that is more soluble in water, i.e.,
acetonitrile, instead of THF as a co-solvent. The acetonitrile as a co-solvent in
monohydrolysis helped increase the reaction rate to some extent, increasing the yield of
the half-ester by about 10%. Earlier, Niwayama’s group studied the influence of the cosolvent in the monohydrolysis of dimethyl bicyclic diester 11 and found that a slightly
35
Texas Tech University, Hanjoung Cho, December 2010
polar aprotic solvent with a small degree of solubility with water appears to be an
effective co-solvent (Table 2.3).13
According to our previous report, the reaction rate constant in the monohydrolysis
with acetonitrile as a co-solvent is slightly greater than that with THF. This tendency was
also found in the monohydrolysis of dipropyl phenylmalonate 10. When THF was used as
a co-solvent, the isolated yield was 68% for 33 hours of reaction time (entry 15 in Table
2.2). The reaction rate in the monohydrolysis of dipropyl phenylmalonate 10 in
acetonitrile or THF has the same tendency as that of dimethyl bicyclic diester 11. It may
also be possible that introduction of several bulky groups prohibited adoption of a
preferable conformation for this selectivity.
Table 2.3 The reaction rate constant in the monohydrolysis of bicyclic diester 11 with
different co-solvent
Co-solventa
Yieldb (%)
Reaction rate constant
(L mol–1s–1)
THF
>99 (0)
4.70±0.02×10–2
CH3CN
>99 (0)
4.85±0.40×10–2
Methanol
90(0.8)
3.73±0.50×10–2
Ethanol
86 (0)
3.48±0.06×10–2
2-propanol
88(0.8)
3.29±0.02×10–2
CH2Cl2
9 (89)
8.60±0.27×10–4
a. Isolated yield of half-ester. Recovered diester is shown in parentheses.
b. The same conditions reported in Ref. 8.
36
Texas Tech University, Hanjoung Cho, December 2010
2.4. Scale-up monohydrolysis of dimethyl malonate 1 and diethyl malonate 3
In this section, we plan to discuss a large-scale synthesis of monomethyl malonate
2 and monoethyl malonate 3a. In our previous study, we have found a selective
monohydrolysis of a series of symmetric diesters with the use of aqueous NaOH or KOH
and a co-solvent such as tetrahydrofuran (THF) or acetonitrile at 0 °C. Since water is
mainly used as solvent, this monohydrolysis is practical, mild, and environmentally
benign, and has been of interest in process chemistry, exhibiting the potential of scaling
up.
As mentioned in the previous section, we recently modified the conditions of this
reaction and applied them to monohydrolysis of a series of dialkyl malonates and their
derivatives on the scale of 1.2 mmol.14
We have found that the isolated yields of half-esters are over 80% to near
quantitative. Based on the previous result on the mmol scale of the selective
monohydrolysis of dialkyl malonate, we examined the possibility of scaling up this
reaction, mainly focusing on monomethyl malonate 2 and monoethyl malonate 3a, which
are among the most commonly applied synthetic building blocks in organic synthesis.
In scaling up the reaction, we first examined the reaction parameters, such as the
co-solvent, types of base, the equivalents of the base, and the reaction duration. As we
already knew the conditions on the 1.2 mmol scale monohydrolysis of dimethyl malonate
1 and diethyl malonate 3 from previous studies, we needed to consider a co-solvent with
relatively polar aprotic solvents, such as THF, acetonitrile, and dimethyl sulfoxide
(DMSO) because the co-solvent can assist to improve the selectivity and accelerate the
37
Texas Tech University, Hanjoung Cho, December 2010
reaction time.13 For the selection of aqueous alkali bases, we had found that KOH tended
to be more reactive and selective than NaOH, but LiOH was less reactive and less
selective for this selective monohydrolysis reaction.9 Therefore we first optimized these
reaction parameters with THF and acetonitrile as a co-solvent, which are volatile upon
work-up and therefore more suitable than DMSO as a co-solvent. Aqueous KOH and
NaOH were used as the base because of their relative reactivity in the monohydrolysis of
dimethyl malonate 1 and diethyl malonate 3.
Initially, the monohydrolysis of dimethyl malonate 1 in a 0.12 mole scale reaction
(158.30 g)of dimethyl malonate 1 was investigated to probe reaction conditions. Since on
the large scale, a far greater amount of solvent and a far larger reaction vessel are
required, the concentration on this larger scale was 200 times greater than what we
reported earlier.14 In the case of the monohydrolysis of diethyl malonate 3 with the same
concentration, the isolated yield of monoethyl malonate 3a was unfortunately reduced by
10%. This lower yield in high concentration may be explained by the hydrophobicity of
the monocarboxylate. As the monoethyl malonate 3a had somewhat reduced solubility in
the reaction media, possibly due to the increased hydrophobicity, the yield could be
reduced in relatively small portion of organic solvent. Therefore we applied 50 times
more concentrated conditions than what we had reported earlier8 for 0.08 mole (128.66 g)
of diethyl malonate 3.
The results for monohydrolysis of dimethyl malonate 1 are summarized in Table
2.4 and Table 2.5 for that of diethyl malonate 3. The formed half-esters were purified by
distillation under reduced pressure instead of flash column chromatography. The
38
Texas Tech University, Hanjoung Cho, December 2010
reactions were monitored by TLC with staining solution and stopped when the
consumption or near-consumption of the starting diesters was observed.
Table 2.4 Practical scale-up monohydrolysis of 0.12 mole of dimethyl malonate 1
Entry
Base
Equivalent
Co-solvent
Time
Half-ester
(%)b
Diacid (%)
1
NaOH
0.8
THF
1h
67.1 (24.5)
0.0
2
NaOH
1.0
THF
1h
81.9 (7.0)
2.7
3
NaOH
1.2
THF
1h
67.4 (1.7)
8.3
4
NaOH
0.8
CH3CN
1h
69.0 (23.9)
0.0
5
NaOH
1.0
CH3CN
1h
82.1 (6.6)
4.4
6
NaOH
1.2
CH3CN
1h
71.3 (0.0)
15.8
7
KOH
0.8
THF
1h
75.0 (20.9)
1.5
8
KOH
1.0
THF
1h
83.1 (3.4)
4.3
9
KOH
1.2
THF
1h
72.4 (0.0)
17.2
10
KOH
0.8
CH3CN
1h
75.7 (16.3)
1.9
11
KOH
1.0
CH3CN
1h
84.5 (0.0)
4.3
12
KOH
1.2
CH3CN
1h
69.1 (0.0)
17.1
13
KOH
1.0
None
2h
79.6 (1.9)
4.4
14
KOH
1.2
None
1.5 h
76.0 (0.0)
9.8
a
b
The ratio between co-solvent and water is 1 : 10. Isolated yield of the half-ester. The
recovered diester is shown in parentheses (%).
39
Texas Tech University, Hanjoung Cho, December 2010
While diacid (malonic acid) could not be isolated on the previous 1.2 mmol scale
of monohydrolysis of dimethyl malonate 1, a small amount of diacid (malonic acid) was
extracted upon work-up but a larger portion of the formed diacid remained in the aqueous
layer. The formed diacid (malonic acid) in the practical large scale could conveniently
remain in the glassware after the distillation under reduced pressure.
From these results, the highest yield of monomethyl malonate 2 was found when
1.0 equivalent of aqueous KOH and acetonitrile was used as a co-solvent. Furthermore,
for monohydrolysis of dimethyl malonate 1, the similar reactivity and selectivity was
shown when one equivalent of aqueous base (NaOH or KOH) with either THF or
acetonitrile was used.
40
Texas Tech University, Hanjoung Cho, December 2010
Table 2.5 Practical scale-up monohydrolysis in 0.08 mole diethyl malonate 3
Entry
Base
Equivalent
Co-solvent
Time
Half-ester (%)b
Diacid (%)
1
NaOH
0.8
THF
1h
46.9 (27.4)
7.0
2
NaOH
1.0
THF
1h
55.4 (13.0)
14.3
3
NaOH
1.2
THF
1h
60.9 (1.9)
16.4
4
NaOH
1.2
THF
0.5 h
74.1 (0.2)
10.0
5
NaOH
1.0
CH3CN
1h
76.0 (6.6)
4.1
6
NaOH
1.2
CH3CN
0.5 h
67.0 (4.4)
12.4
7
KOH
1.0
THF
1h
75.0 (4.4)
4.6
8
KOH
1.2
THF
0.5 h
76.9 (0.7)
8.3
9
KOH
1.0
CH3CN
1h
81.0 (1.4)
1.4
10
KOH
1.2
CH3CN
0.5 h
63.4 (1.9)
17.5
11
KOH
1.0
None
4h
42.2 (16.4)
29.8
12
KOH
1.2
None
6h
35.6 (6.9)
36.6
a
The ratio between co-solvent and water is 1 : 10. b Isolated yield of the half-ester. The
recovered diester is shown in parentheses (%).
Under trials for monohydrolysis of either dimethyl malonate 1 or diethyl malonate
3 with 0.8 equivalents of base, we found that 0.8 equivalents of the base was not enough
to maximize the yield. Therefore for monohydrolysis of ethyl malonate 3 (Table 2.5), we
41
Texas Tech University, Hanjoung Cho, December 2010
applied only 1.0 and 1.2 equivalents of NaOH and KOH for the monohydrolysis. For
monohydrolysis of diethyl malonate 3, the optimal conditions were clearly when 1.0
equivalent of aqueous KOH and acetonitrile was used and this condition was the same as
those for monohydrolyses of dimethyl malonate 1. Compared with the small scale
transformation of dialkyl malonates, which did not show critical differences by the choice
of co-solvent, the type of base, or its equivalent, the reactivity and selectivity had a
significant difference depending on such reaction conditions. For example, the efficacy of
the co-solvent, THF or acetonitrile was not very different for the monohydrolysis of
dimethyl malonate 1 in 1.2 mmol scale but it became more apparent in these large-scale
reactions. As the solubility of the diesters or monocarboxylate is increased and they are
more efficiently dispersed in the reaction mixture, the reactivity and selectivity was
increased in the monohydrolysis reactions, which was expected from our previous
studies.13
Therefore, based on these preliminary investigations, we applied these optimal
reaction conditions into a large-scale monohydrolysis of dimethyl malonate 1 and diethyl
malonate 3. The scale in the monohydrolysis of 1.2 mol (158.30 g) for dimethyl malonate
1 and 0.8 mol (128.66 g) for diethyl malonate 3 was executed with acetonitrile and water
as solvent. Since the reaction temperature is an important factor,15 the reactions were
carried out in a cold room maintained at 0~4 °C. After the reaction mixture was worked
up, the half-ester was collected by distillation instead of flash column chromatography.
The isolated yields were 81% (114.77 g) for monomethyl malonate 2 and 82%
(87.073 g) for monoethyl malonate 3a by these procedures. As the boiling point of the
42
Texas Tech University, Hanjoung Cho, December 2010
diester and the corresponding half-ester are quite different in both cases, the distillation
was selected for isolation of product. In addition to straightforward separation of
recovered diester and half-ester, the small amount of diacid (malonic acid) remained
behind in the distillation. Therefore, the separation by distillation under the reduced
pressure on these larger scales was found to be an efficient way to isolate pure
monomethyl malonate 2 and monoethyl malonate 3a compared the separation via column
chromatography on a smaller scale monohydrolysis.
Monomethyl malonate 2 and monoethyl malonate 3a can be obtained in high
yields by one step within a reaction duration of only about one hour even on this large
scale. While the reported selective monosaponification2 typically requires two steps, this
reaction can readily be achieved in only one step. The total amount of time required for
the entire procedure is only half a day, as opposed to the previously reported large-scale
selective monosaponification,2 which takes more than one day. According to the
elemental analysis, the prepared monomethyl malonate 2 and monoethyl malonate 3a by
this method are close to the accepted tolerance of ±0.4% error, indicating that these halfesters have a purity of nearly 100%. The entire procedure requires mainly water and a
small portion of acetonitrile, and produces no hazardous by-products, highlighting the
greenness of this reaction. Under comparable conditions on a 0.12 mol-scale reaction
with a duration of 1 h, we have also obtained the half-esters of dimethyl methyl malonate
5 and diethyl methyl malonate 6 in 90% and 83% yields, respectively.
43
Texas Tech University, Hanjoung Cho, December 2010
2.5. Conclusion
The selective monohydrolysis of dialkyl malonates and their derivatives were
investigated with THF or acetonitrile as a co-solvent at 0 °C. We have found that this
reaction, with around 1 equivalent of aqueous KOH or NaOH, to selectively
monohydrolyze a series of dialkyl malonates and their derivatives. The isolated yields of
half-esters here are among the highest reported. All of the half-esters prepared here
showed excellent purity and are quite stable over a long period of time. We also found
that the hydrophobicity of the starting diesters also affected the selectivity of the
monohydrolysis of symmetric diesters. As the hydrophobicity of the diesters increased,
the selectivity generally increased and the reactivity slightly decreased.
In addition to laboratory scale monohydrolysis of a series of dialkyl malonates and
their derivatives, a large scale synthesis of monomethyl malonate 2 and monoethyl
malonate 3a was studied with applying the selective monohydrolysis of symmetric
diester which we reported previously.
2.6. Experimental section
General experimental conditions
All the solvents, unless otherwise stated, were used without further purification.
Melting points were measured on an electrothermal capillary instrument (MEL-TEMP® )
and were uncorrected. NMR spectra were recorded on a Varian Unity Plus 300 or a
Varian Mercury Plus 300 spectrometer at 300 and 125 MHz for 1H and 13C, respectively.
Trimethylsilane (TMS, δ = 0) or the residual solvent peak (CDCl3, δ = 7.24) was used as
44
Texas Tech University, Hanjoung Cho, December 2010
a shift reference for 1H NMR spectra and the chemical shift for the solvent peak (CDCl3,
δ = 77.00) served as a reference for 13C NMR spectra. IR spectra were recorded on a
Nicolet IR100 FT-IR spectrometer. Elemental analyses were performed with CHN
combustion analyses on TC and IR detection by Columbia Analytical Services INC
(Tuscan, AZ). Thin layer chromatography (TLC) was performed using precoated
aluminum backed TLC plates, silica gel 60, F254 (EMD Chemicals). Flash silica
chromatography was performed with Silica Gel, 230–400 mesh.
Monomethyl malonate, 2
Dimethyl malonate, 1 (159 mg, 1.20 mmol) was dissolved in 2 mL of THF, and 20
mL of water was added. The reaction mixture was cooled to 0 oC in an ice-water bath.
To this mixture was added the indicated equivalent of a 0.25 M aqueous NaOH, KOH or
LiOH solution dropwise with stirring. The reaction mixture was stirred for 30 minutes to
one hour, and acidified with 1 M HCl at 0 oC, saturated with NaCl, extracted with ethyl
acetate (X4), and dried over Na2SO4. This extract was concentrated in vacuo and purified
by silica gel column chromatography with hexane:ethyl acetate (3:1) and then ethyl
acetate as typical eluents to afford monomethyl malonate 2.
45
Texas Tech University, Hanjoung Cho, December 2010
Oil. 1H NMR (300 MHz, CDCl3) δ = 3.39 (2H, s), 3.70 (3H, s), 11.19 (1H, br. s);
13
C NMR (75 MHz, CDCl3) δ = 40.50, 52.50, 167.03, 171.46; IR (neat, cm-1) 1741, 1746,
2960-3185; Anal. Calcd for C4H6O4: C, 40.68; H, 5.12. Found: C, 40.51; H, 5.34.
Monoethyl malonate 3a
Diethyl malonate, 3 (192 mg, 1.2 mmol) was dissolved in 2 mL of THF, and 20
mL of water was added. The reaction mixture was cooled to 0 oC in an ice-water bath.
To this mixture was added the indicated equivalent of a 0.25 M aqueous NaOH, or KOH
solution dropwise with stirring. The reaction mixture was stirred for one hour, and
acidified with 1 M HCl at 0 oC, saturated with NaCl, extracted with ethyl acetate (X4),
and dried over Na2SO4. This extract was concentrated in vacuo and purified by silica gel
column chromatography with hexane:ethyl acetate (3:1) and then ethyl acetate as typical
eluents to afford monoethyl malonate 3a.
Oil. 1H NMR (300 MHz, CDCl3) δ = 1.25 (3H, t, J = 7.2), 3.39 (2H, s), 4.19 (2H,
q, J = 7.2), 10.67 (1H, br. s); 13C NMR (75 MHz, CDCl3) δ = 13.84, 40.90, 61.85, 166.69,
171.77; IR (neat, cm-1) 1736, 1741, 2914-3182; Anal. Calcd for C5H8O4: C, 45.46; H,
6.10. Found: C, 45.83; H, 6.30.
46
Texas Tech University, Hanjoung Cho, December 2010
Monopropyl malonate 4a
Dipropyl malonate 4 (226 mg, 1.2 mmol) was dissolved in 2 mL of THF, and 20
mL of water was added. The reaction mixture was cooled to 0 oC in an ice-water bath.
To this mixture was added the indicated equivalent of a 0.25 M aqueous NaOH, or KOH
solution dropwise with stirring. The reaction mixture was stirred for 30 minutes to one
hour, and acidified with 1 M HCl at 0 oC, saturated with NaCl, extracted with ethyl
acetate (X4), and dried over Na2SO4. This extract was concentrated in vacuo and purified
by silica gel column chromatography with hexane:ethyl acetate (3:1) and then ethyl
acetate as typical eluents to afford monopropyl malonate 4a.
Oil. 1H NMR (300 MHz, CDCl3) δ = 0.93 (3H, t, J = 7.7), 1.66 (2H, m), 3.42 (2H,
s), 4.11 (2H, q, J = 7.2), 10.14 (1H, br. s); 13C NMR (75 MHz, CDCl3) δ = 10.13, 21.69,
40.89, 67.42, 166.81, 171.75; IR (neat, cm-1) 1723, 1740, 2883-3181; Anal. Calcd for
C6H10O4: C, 49.31; H, 6.90. Found: C, 49.43; H, 7.14.
Monomethyl methylmalonate 5a
47
Texas Tech University, Hanjoung Cho, December 2010
Dimethyl methylmalonate, 5 (175 mg, 1.2 mmol) was dissolved in 2 mL of THF,
and 20 mL of water was added. The reaction mixture was cooled to 0 oC in an ice-water
bath. To this mixture was added the 1.2 equivalents of a 0.25 M aqueous NaOH, or KOH
solution dropwise with stirring. The reaction mixture was stirred for 1.5 hours, and
acidified with 1 M HCl at 0 oC, saturated with NaCl, extracted with ethyl acetate (X4),
and dried over Na2SO4. This extract was concentrated in vacuo and purified by silica gel
column chromatography with hexane:ethyl acetate (3:1) and then ethyl acetate as typical
eluents to afford monomethyl methylmalonate, 5a.
Oil. 1H NMR (300 MHz, CDCl3) δ = 1.43 (3H, d, J = 7.2), 3.48(1H, q, J = 7.2),
3.74 (3H, s), 9.42 (1H, br.s); 13C NMR (75 MHz, CDCl3) δ = 13.08, 45.48, 52.39, 170.16,
175.38; IR (neat, cm-1) 1721, 1739, 2956-3202; Anal. Calcd for C5H8O4: C, 45.46; H,
6.10. Found: C, 45.65; H, 5.94.
Monoethyl methylmalonate, 6a
Diethyl methylmalonate, 6 (209 mg, 1.2 mmol) was dissolved in 2 mL of THF,
and 20 mL of water was added. The reaction mixture was cooled to 0 oC in an ice-water
bath. To this mixture was added the 1.2 equivalents of a 0.25 M aqueous NaOH, or KOH
solution dropwise with stirring. The reaction mixture was stirred for 1.5 hours, and
acidified with 1 M HCl at 0 oC, saturated with NaCl, extracted with ethyl acetate (X4),
48
Texas Tech University, Hanjoung Cho, December 2010
and dried over Na2SO4. This extract was concentrated in vacuo and purified by silica gel
column chromatography with hexane:ethyl acetate (3:1) and then ethyl acetate as typical
eluents to afford monoethyl methylmalonate, 6a.
Oil. 1H NMR (300 MHz, CDCl3) δ = 1.22 (3H, t, J = 7.2), 1.40 (3H, d, J = 7.5),
3.44 (1H, q, J = 7.2), 4.19 (2H, q, J = 7.2), 11.21 (1H, br, s); 13C NMR (75 MHz, CDCl3)
δ = 13.44, 13.90, 45.93, 61.69, 169.83, 176.00; IR (neat, cm-1) 1722, 1735, 2946-3200;
Anal. Calcd for C6H10O4: C, 49.31; H, 6.90. Found: C, 49.68; H, 6.75.
Monopropyl methylmalonate 7a
Dipropyl methylmalonate 7 (243 mg, 1.2 mmol) was dissolved in 2 mL of THF,
and 20 mL of water was added. The reaction mixture was cooled to 0 oC in an ice-water
bath. To this mixture was added the 1.2 equivalents of a 0.25 M aqueous NaOH, or KOH
solution dropwise with stirring. The reaction mixture was stirred for one hour and 45
minutes, and acidified with 1 M HCl at 0 oC, saturated with NaCl, extracted with ethyl
acetate (X4), and dried over Na2SO4. This extract was concentrated in vacuo and purified
by silica gel column chromatography with hexane:ethyl acetate (3:1) and then ethyl
acetate as typical eluents to afford monopropyl methylmalonate, 7a.
Oil. 1H NMR (300 MHz, CDCl3) δ = 0.92 (3H, t, J = 7.5), 1.43 (3H, d, J = 7.2),
1.65 (2H, m), 3.47 (1H, q, J = 7.2), 4.10 (2H, q, J = 7.2), 10.62 (1H, br, s); 13C NMR (75
49
Texas Tech University, Hanjoung Cho, December 2010
MHz, CDCl3) δ = 10.17, 13.51, 21.77, 45.94, 67.24, 169.93, 175.96; IR (neat, cm-1) 1717,
1739, 2883-2971; Anal. Calcd for C7H12O4: C, 52.49; H, 7.55. Found: C, 52.74; H, 7.49.
Monomethyl phenylmalonate 8a
Dimethyl phenylmalonate 8 (250 mg, 1.2 mmol) was dissolved in 2 mL of THF,
and 20 mL of water was added. The reaction mixture was cooled to 0 oC in an ice-water
bath. To this mixture was added the 1.2 equivalents of a 0.25 M aqueous NaOH, or KOH
solution dropwise with stirring. The reaction mixture was stirred for one hour, and
acidified with 1 M HCl at 0 oC, saturated with NaCl, extracted with ethyl acetate (X4),
and dried over Na2SO4. This extract was concentrated in vacuo and purified by silica gel
column chromatography with hexane:ethyl acetate (3:1) and then ethyl acetate as typical
eluents to afford monomethyl phenylmalonate, 8a.
White solid; m.p. 92-93 oC; 1H NMR (300 MHz, CDCl3) δ = 3.75(3H, s), 4.65 (2H,
s), 7.35 (5H, m), 8.99 (1H, br. s); 13C NMR (75 MHz, CDCl3) δ = 53.06, 57.33, 128.55,
128.77, 129.15, 131.96, 168.59, 173.24; IR (neat, cm-1) 1717, 1740, 2956-3212; Anal.
Calcd for C10H10O4: C, 61.85; H, 5.19. Found: C, 61.92; H, 5.40.
50
Texas Tech University, Hanjoung Cho, December 2010
Monoethyl phenylmalonate 9a
Dimethyl phenylmalonate 9 (284 mg, 1.2 mmol) was dissolved in 2 mL of THF,
and 20 mL of water was added. The reaction mixture was cooled to 0 oC in an ice-water
bath. To this mixture was added the 1.2 equivalents of a 0.25 M aqueous NaOH, or KOH
solution dropwise with stirring. The reaction mixture was stirred for five hours, and
acidified with 1 M HCl at 0 oC, saturated with NaCl, extracted with ethyl acetate (X4),
and dried over Na2SO4. This extract was concentrated in vacuo and purified by silica gel
column chromatography with hexane:ethyl acetate (3:1) and then ethyl acetate as typical
eluents to afford monoethyl phenylmalonate, 9a.
White solid; m.p. 74 oC (lit 76-77 oC)3a; 1H NMR (300MHz, CDCl3) δ = 1.25 (3H,
t, J = 7.2), 4.21 (2H, q, J = 7.2), 4.63 (1H, s), 7.37 (5H, m), 10.16 (1H, br. s); 13C NMR
(75 MHz, CDCl3) δ = 13.81, 57.51, 62.10, 128.39, 128.62, 129.13, 132.01, 167.95,
173.84; IR (neat, cm-1) 1717, 1737, 2941-3190; Anal. Calcd for C11H12O4: C, 63.45; H,
5.81. Found: C, 63.30; H, 5.80.
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Texas Tech University, Hanjoung Cho, December 2010
Monopropyl phenylmalonate 10a
Dipropyl phenylmalonate 10 (317 mg, 1.2 mmol) was dissolved in 2 mL of
acetonitrile, and 20 mL of water was added. The reaction mixture was cooled to 0 oC in
an ice-water bath in a cold room maintained around at 4 oC. To this mixture was added
the 0.8 equivalents of a 0.25 M aqueous NaOH, or KOH solution dropwise with stirring.
The reaction mixture was stirred for 33 hours in a cold room maintained at around 4 oC,
and acidified with 1 M HCl at 0 oC, saturated with NaCl, extracted with ethyl acetate
(X4), and dried over Na2SO4. This extract was concentrated in vacuo and purified by
silica gel column chromatography with hexane:ethyl acetate (3:1) and then ethyl acetate
as typical eluents to afford monopropyl phenylmalonate, 10a.
Oil. 1H NMR (300 MHz, CDCl3) δ = 0.87 (3H, t, J = 7.5), 1.64 (2H, m, J = 7.2),
4.12 (2H, m), 4.64 (1H, s), 7.35 (5H, m), 10.02 (1H, br. s); 13C NMR (75 MHz, CDCl3) δ
= 10.16, 21.74, 57.47, 67.72, 128.48, 128.73, 129.12, 132.21, 168.41, 173.07; IR (neat,
cm-1) 1717, 1736, 2881-3067; Anal. Calcd for C12H14O4: C, 64.85; H, 6.35. Found: C,
65.17; H, 6.61.
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Texas Tech University, Hanjoung Cho, December 2010
Scale-up monohydrolysis of dimethyl malonate 1
In a 1 L-sized one-necked flask, equipped with a magnetic stirrer, was placed
158.30 g (1.2 mol) of dimethyl malonate, 1, and 10 mL of acetonitrile was added to
dissolve this dimethyl malonate, 1. After the solution was stirred for one minute, the
reaction mixture was cooled to 0 oC with an ice-water bath in a cold room maintained at
0-4 oC. To this mixture, 100 mL of water was added and the mixture was stirred for 30
minutes. To this reaction mixture was added 240 mL of 5 M aqueous KOH (1.2 mol)
solution dropwise with continuous stirring for a period of 15 minutes with an addition
funnel. When this addition was completed, the reaction mixture was stirred for one
additional hour while covered with a stopper and immersed in the ice-water bath in the
cold room maintained at 0-4 oC. The reaction was monitored by TLC using a staining
solution prepared with bromocresol green (40 mg) dissolved in ethanol (100 mL, 200
proof).
The reaction mixture was acidified with 150 mL of 12 M aqueous HCl solution in
the ice-water bath, saturated with NaCl, and extracted with five 500 mL portions of ethyl
acetate with a 1 L separatory funnel. The extract was washed with 500 mL of a saturated
aqueous NaCl solution. The ethyl acetate extract was dried over approximately 100 g of
anhydrous sodium sulfate. After the drying agent was removed by gravity filtration, the
ethyl acetate solution was concentrated by a rotary evaporator and distilled under a
reduced pressure at 2.5 mm Hg. The fraction showing a boiling point of 91-92 oC was
collected to yield monomethyl malonate, 2, as a colorless oil. The yield of monomethyl
malonate 2 was 114.77 g (81%).12
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Texas Tech University, Hanjoung Cho, December 2010
1
H NMR (300 MHz, CDCl3) δ = 3.47 (2H, s), 3.78 (3H, s), 10.88 (1H, br. s); 13C
NMR (75 MHz, CDCl3) δ = 40.52, 52.51, 167.09, 171.33; IR (neat, cm-1) 1724, 1741,
2960-3533; Anal. Calcd for C4H6O4: C, 40.68; H, 5.12. Found: C, 40.29; H, 5.27.
Scale-up monohydrolysis of diethyl malonate 3
In a 1 L-sized one-necked flask, equipped with a magnetic stirrer, was placed
128.66 g (0.8 mol) of diethyl malonate, 3, and 30 mL of acetonitrile was added to
dissolve this diethyl malonate, 3. After the solution was stirred for one minute, the
reaction mixture was cooled to 0 oC with an ice-water bath in a cold room maintained at
0-4 oC. To this mixture, 300 mL of water was added and the mixture was stirred for 30
minutes. To this reaction mixture was added 160 mL of 5 M aqueous KOH (0.8 mol)
solution dropwise with continuous stirring for a period of 15 minutes with an addition
funnel. When this addition was completed, the reaction mixture was stirred for one
additional hour while covered with a stopper and immersed in the ice-water bath in the
cold room maintained at 0-4 oC. The reaction was monitored by TLC using a staining
solution prepared with bromocresol green (40 mg) dissolved in ethanol (100 mL, 200
proof).
The reaction mixture was acidified with 120 mL of 12 M aqueous HCl solution in
the ice-water bath, saturated with NaCl, and extracted with five 500 mL portions of ethyl
acetate with a 1 L separatory funnel. The extract was washed with 500 mL of a saturated
aqueous NaCl solution. The ethyl acetate extract was dried over approximately 100 g of
anhydrous sodium sulfate. After the drying agent was removed by gravity filtration, the
ethyl acetate solution was concentrated by a rotary evaporator and distilled under a
54
Texas Tech University, Hanjoung Cho, December 2010
reduced pressure at 2.5 mm Hg. The fraction showing a boiling point of 79-81 oC was
collected to yield monoethyl malonate, 3a, as a colorless oil. The yield of monoethyl
malonate 3a was 87.073 g (82%).13
1
H NMR (300 MHz, CDCl3) δ = 1.30 (3H, t, J = 7.2), 3.44 (2H, s), 4.24 (2H, q,
J=7.2), 10.21 (1H, br. s); 13C NMR (75 MHz, CDCl3) δ = 13.78, 40.88, 61.80, 166.64,
171.76; IR (neat, cm-1) 1722, 1741, 2946-3523; Anal. Calcd for C5H8O4: C, 45.46; H,
6.10. Found: C, 45.76; H, 6.20.
2.7. References
1.
(a) Bulychev, A.; Bellettini, J. R.; O’Brien, M.; Crocker, P. J.; Samama, J.-P.;
Miller, M. J.; Mobashery, S. Tetrahedron 2000, 56, 5719. (b) Bihovsky, R.;
Pendrak, I. Bioorg. Med. Chem. Lett. 1996, 6, 1541. (c) Horikawa, M.; Shirahama,
H. Synlett 1996, 95. (d) Keum, G.; Hwang, C. H.; Kang, S. B.; Kim, Y.; Lee, E. J.
Am. Chem. Soc. 2005, 127, 10396. (e) Kim, H.-J.; Lindsey, J. J. Org. Chem. 2005,
70, 5475. (f) Knoelker, H.-J.; Wolpert, M. Tetrahedron Lett. 1997, 38, 533. (g)
Marcaccini, S.; Pepino, R.; Pozo, M. C.; Basurto, S.; Garcia-Valverde, M.; Torroba,
T. Tetrahedron Lett. 2004, 45, 3999. (h) List, B.; Doehring, A.; Fonseca, M. T. H.;
Job, A.; Torres, R. R. Tetrahedron 2006, 62, 476. (i) Balasubramanian, T.; Lindsey,
J. S. Tetrahedron 1999, 55, 6771. (j) Hudson, R. D. A.; Osborne, S. A.; Stephenson,
G. R. Synlett 1996, 845. (k) Ashton, M. J.; Hills, S. J.; Newton, C. G.; Taylor, J. B.;
Tondu, S. C. D. Heterocycles 1989, 28, 1014. (l) Williams, D. R.; Kammler, D. C.;
Goundy, R. F. Heterocycles 2006, 67, 555.
2.
(a) Strube, R. E. Organic Synthesis; Wiley: New York, NY, 1963; Collect. Vol. 4,
417. (b) Grakauskas, V.; Guest, A. M. J. Org. Chem. 1978, 43, 3485. (c)
Hutchinson, C. R.; Nakane, M.; Gollman, H.; Knutson, P. L. Organic Synthesis;
Wiley: New York, NY, 1990; Collect. Vol. 7, 323.
3.
For example, (a) Corey, E. J. J. Am. Chem. Soc. 1952 74, 5897. (b) Vecchi, A.;
Melone, G. J. J. Org. Chem. 1959, 24, 109. (c) Westermann, J.; Schneider, M.;
Platzek, J.; Petrov, O. Org. Process Res. Dev. 2007, 11, 200. (d) de Meijere, A.;
Ernst, K.; Zuck, B.; Brandl, M.; Kozhushkow, S. I.; Tamm, M.; Yufit, D. S.;
55
Texas Tech University, Hanjoung Cho, December 2010
Howard, J. A. K.; Labahn, T. Eur. J. Org. Chem. 1999, 11, 3105. (e) De Kimpe, N.;
Boeykens, M.; Tehrani, K. A. J. Org. Chem. 1994, 59, 8215. (f) Robertson, A.;
Sandrock, W. F. J. Chem. Soc. 1933, 1617. (g) Eaton, P. E.; Nordari, N.;
Tsanaktsidis, J.; Upadhyaya, S. P. Synthesis 1995, 501. (h) Perrin, C. L.; Arrhenius,
T. J. Am. Chem. Soc. 1978, 100, 5249.
4.
Duthaler, R. Helv. Chim. Acta 1983, 66, 1475.
5.
(a) Rigo, B.; Fasseur, D.; Cauliez, P.; Couturier, D. Tetrahedron Lett. 1989, 30,
3073. (b) Junek, H.; Ziegler, E.; Herzog, U.; Kroboth, H. Synthesis 1976, 332.
6.
Krapcho, A. P.; Jahngen, E. G. E., Jr.; Kashdan, D. S. Tetrahedron Lett. 1974, 15,
2721.
7.
Ozaki, E.; Uragaki, T.; Sakashita, K.; Sakimae, A. Chem. Lett. 1995, 539.
8.
Niwayama, S. J. Org. Chem. 2000, 65, 5834.
9.
Niwayama, S.; Rimkus, A. Bull. Chem. Soc. Jpn. 2005, 78, 498.
10.
(a) Nagle, J. K. J. Am. Chem. Soc. 1990, 112, 4741. (b) Allen, L. C. J. Am. Chem.
Soc. 1989, 111, 9003. (c) Luo, Y.-R.; Benson, S. W. Acc. Chem. Res. 1992, 25, 375.
11.
Dean, E. W.; Stark, D. D. Ind. Eng. Chem. 1920, 12, 486.
12.
Fischer, E.; Speier, A. Chem. Ber. 1895, 28, 3252.
13.
Niwayama, S.; Wang, H.; Hiraga, Y.; Clayton, J. C. Tetrahedron Lett. 2007, 48,
8508.
14.
Niwayama, S.; Cho, H.; Lin, C. Tetrahedron Lett. 2008, 49, 4434.
15.
Niwayama, S. J. Synth. Org. Chem., Jpn., 2008, 66, 983.
56
Texas Tech University, Hanjoung Cho, December 2010
CHAPTER 3
REMOTE EXO/ENDO SELECTIVITY IN SELECTIVE MONOHYDROLYSIS
OF DIALKYL BICYCLO[2.2.1]HEPTANE-2,3-DICARBOXYLATE
DERIVATIVES*
3.1. Introduction
Functional bicyclic compounds, namely : norbornene, norbornadiene, or
norbornanone system have been well studied in general and show high exo-facial
selectivity in the electrophilic, nucleophilic, or cyclic additions. In order to explain this
exo-facial selectivity, many research groups have reported extensive studies from
theoretical and experimental points of view. The preferred exo-facial reactivity can be
explained in the categories of (1) steric effects where the ethano bridge is larger than the
methano bridge,1 (2) a torsional effect that is relieved by exo attack but increased by endo
attack in the transition state,2 (3) pyramidalization of the sp2 carbons toward the endo
directions leading to the favored attack on the convex face of the pyramidalized sp2
carbons,3 and (4) nonequivalent orbital extension caused by the mixing of σ orbitals and
π orbitals, inducing higher exo reactivity.4 Since norbornene, norbornadiene, or
norbornanone and their derivatives are versatile synthetic building blocks for further
synthesis, the high exo selectivity has been applied to development of a variety of useful
*
Niwayama, S.; Cho, H.; Zabet-Moghaddam, M.; Whittlesey, B. R. J. Org. Chem. 2010, 75, 3775.
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Texas Tech University, Hanjoung Cho, December 2010
stereospecific or stereoselective reactions in organic synthesis such as epoxidation and
hydroboration. For example, the exo/endo selectivity in the reduction of 2-norbornanone
by sodium borohydride is shown Scheme 3.1.
Scheme 3.1 Reduction of 2-norbornanone by sodium borohydride
However, for the sp2 carbons that are one covalent bond away from the norbornane
skeleton, such exo/endo-facial selectivities have not been systematically studied. The
reason which we can consider is that the differences of the reported steric effects are
anticipated to be too small, and the torsional effects considered within the norbornane
ring are not expected. Among well-known reactions of bicyclic compounds, electrophilic
additions to 2-methylenenorbornene are still known to show the predominant exo
selectivity due to the fact that the C2 carbon is part of the norbornane ring. The DielsAlder reactions toward isodicyclopentadiene, showing the bottom-face selectivity with a
variety of dienophiles, are interesting expectations in which the new bond forms on the
sp2 carbons next to the C2 and C3 sp2 carbons of the norbornane ring.5 For these
reactions, as the olefinic ends are still within the strained norbornane ring, the selectivity
is explained by the out-of-plane bending of groups at C2 and C3 on the ring, although it
appears that the steric bulkiness of the dienophile also affects the selectivity.6 Therefore,
the only studies reported as remote exo/endo-facial selectivity away from the norbornane
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Texas Tech University, Hanjoung Cho, December 2010
or norbornene ring were enzyme-catalyzed reactions, for which the mechanisms of
selectivity are not understood.7
Niwayama and Hiraga previously observed unusually prominent exo-facial
selectivity on the sp2 carbons that are one covalent bond distant from the norbornene ring
in the selective monohydrolysis reactions we reported earlier.8 Niwayama and Hiraga
have investigated selective monohydrolysis of (exo, exo), (endo, endo), and (exo, endo)dimethyl and diethyl esters attached to the norbornene skeleton and observed enhanced
reactivity on hydrolysis of the exo esters in all cases, perhaps due to the mild reaction
conditions. Therefore the observed prominent exo-facial monohydrolysis of various
diesters will be discussed in this chapter.
Niwayama and Hiraga found that this reaction can recognize slight steric
differences and can also selectively hydrolyze one of the two ester groups in near
symmetrical diesters, and therefore, these reactions can selectively monohydrolyze the
ester group of the exo position in exo,endo-dimethyl- and diethylbicyclo[2.2.1]hept-5ene-2,3-dicarboxylates, 1a and 1b (Scheme 3.2).8, 9
Scheme 3.2 Monohydrolysis of exo,endo-dimethyl- and diethylbicyclo[2.2.1]hept-5-ene2,3-dicarboxylates, 1a and 1b8
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Texas Tech University, Hanjoung Cho, December 2010
Initially, reactions with THF as a co-solvent, 10 times the volume of water, and
aqueous NaOH solution, were used for the selective monohydrolysis reaction. This
practical reaction was found to monohydrolyze all the diesters thus far tried, forming a
reaction mixture that lead to straightforward purification, unlike the classical
saponification. In addition to the monohydrolysis for various symmetric diesters, we also
studied solvent effects, types of base, and steric effects and found conditions that improve
the selectivity and reactivity. For the case of co-solvent effect, polar aprotic solvents such
as THF, acetonitrile, or dimethyl sulfoxide are in general appropriate for an accelerated
reaction rate and higher selectivity, while protic solvents such as alcohols are not as
effective.10 As for bases, aqueous KOH is often more effective than aqueous NaOH as a
base, perhaps due to the enhanced electropositive character of the countercation, while
LiOH tends to be inferior to NaOH.11
Currently, we assume that this high selectivity for monohydrolysis might be from
aggregation of the monocarboxylate intermediate. After one of the ester groups is
monohydrolyzed, the intermediary monocarboxylate in water may form aggregates in
which the remaining hydrophobic portions point inside and the hydrophilic CO2- groups
point outside, thus prohibiting further hydrolysis. In this hypothesis, co-solvent may
affect the aggregate formation via interaction with the ester group that was not
hydrolyzed. Solvent effects we have observed thus far are consistent with this hypothesis.
Initially, the selectivity of monohydrolysis was observed to be especially high
when the two ester groups were located in close proximity to each other and the
stereochemistry was cis. Another possible reason for high selectivity can be explained by
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Texas Tech University, Hanjoung Cho, December 2010
the potential reasons based on the electrostatic attractive interaction between the two
carbonyl groups due to their close location before formation of the potential aggregate
above.9, 12 However, applying the conditions we found later based on the information
obtained from these basic studies, we have also been successful in selectively
monohydrolyzing linear diesters13 or those with trans stereochemistry.
3.2. The selective monohydrolysis of (exo,endo)-dimethyl- and diethylbicyclo[2.2.1]
hept-5-ene-2,3-dicarboxylate 1a and 1b
Previously, we have reported and found the selectivity in monohydrolysis of
exo,endo-dimethyl- and diethylbicyclo[2.2.1]hept-5-ene-2,3-dicarboxylate, 1a and 1b.8 In
order to improve the reaction, we investigated selective monohydrolysis of those diesters
with various conditions.
(exo,endo)-Dimethyl- and diethylbicyclo[2.2.1]hept-5-ene-2,3-dicarboxylate, 1a
and 1b were prepared by Diels–Alder reactions between cyclopentadiene and dimethyl
and diethyl fumarate at room temperature.14 (Scheme 3.3)
Scheme 3.3 Synthesis of (exo,endo)-dimethyl- and diethylbicyclo[2.2.1]hept-5-ene-2,3dicarboxylate 1a and 1b
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Texas Tech University, Hanjoung Cho, December 2010
For monohydrolysis of dimethyl and diethylbicyclo[2.2.1]hept-5-ene-dicarboxylate
1a and 1b, we have investigated the reactivity and selectivity with the type of base, cosolvent, and the amount of base and the results are shown in Table 3.1.
Table 3.1 Selective monohydrolysis of bicyclic diester 1a and 1b
a
Entry
Diester
Co-solvent
Base
Base
(equiv)
Time
(h)
Yielda
(%)
Ratio
(2:3)
1
1a
THF
LiOH
1.2
1
77 (22)
82:18
2
1a
THF
NaOH
1.2
1
93 (4)
80:20
3
1a
THF
KOH
1.2
1
97 (2)
82:18
4
1a
THF
CsOH
1.2
1
87 (11)
80:20
5
1b
THF
KOH
1.7
7
91 (2)
87:13
6
1b
CH3CN
KOH
1.7
7.5
96 (0)
87:13
7
1b
CH3CN
KOH
1.2
6
65 (34)
86:14
Isolated yield of the mixture of the half-esters. The recovered diester is shown in
parentheses (%).
In order to confirm the selectivity and reactivity with the type of bases, the
monohydrolysis of dimethyl diester 1a with aqueous LiOH, NaOH, and KOH was
investigated (entries 1, 2, and 3). We found that all of these bases preferred to hydrolyze
the carbomethoxy in exo position rather than in the endo position and the reactivity of the
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Texas Tech University, Hanjoung Cho, December 2010
monohydrolysis with aqueous KOH was the highest among those of aqueous bases. This
result where the reactivity of monohydrolysis of symmetric diesters increased with the
use of aqueous KOH compared with the use of NaOH or LiOH is also consistent with the
results we reported earlier.11, 13 Therefore, the monohydrolysis of diethyl diester 1b was
performed with aqueous KOH instead of the other alkali bases.
The amount of the base was also slightly reduced because of the stereochemistry of
the starting diester, which appears to have helped improve the yield for this particular
diester. Also, more time was required for selective monohydrolysis of diethyl ester than
the corresponding dimethyl ester due to the increased hydrophobicity. As we found the
co-solvent effect for the monohydrolysis of dialkyl malonate in the previous chapter,10
acetonitrile was applied to the monohydrolysis of diethyl diester as a co-solvent instead
of THF. The results with two aprotic polar co-solvents were shown in entries 5 and 6
(Table 3.1). Since the ethyl group is more hydrophobic than a methyl group, more base
was required in the monohydrolysis of diethyl diesters 1b and the result showed that the
yield of the half-ester significantly was 96% in 7.5 h, while we found that the use of 1.7
equivalent of base is preferable to 1.2 equivalent. Furthermore, the selectivity in the
monohydrolysis of diethyl diester 1b is higher than that of the monohydrolysis of
dimethyl diester 1a. The ratio between exo-hydrolyzed half-ester and endo-hydrolyzed
ester is 82 : 18 for the monohydrolysis of dimethyl diester 1a (entry 3) and 87 : 13 for the
monohydrolysis of diethyl diester 1b (entry 6). These ratios for exo-carboxylic acid and
endo-carboxylic acid are comparable to those we reported earlier,8 while the yields
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Texas Tech University, Hanjoung Cho, December 2010
improved significantly, without production of the corresponding diacid despite the fact
that the stereochemistry of these diesters is trans.
The relative intensities of the integral curves of the methyl or ethyl signal in the
reaction mixture of the 1H NMR spectra were used for analysis of the product ratios of 2a
and 3a and 2b and 3b. In addition to comparison of 1H NMR spectra, we also confirmed
the ratio with the assistance of HPLC instrumentation. For example, the chromatogram of
the mixture of monomethyl half-esters is shown in Figure 3.1. The component at 9.15
min (red colored line) indicated endo-hydrolyzed half-ester and component at 9.81 min
was exo-hydrolyzed half-ester. Each half-ester was separated and isolated with HPLC and
structures were confirmed by the 1H and 13C NMR spectra with our previous reports.
Figure 3.1 HPLC chromatogram for mixture of monomethyl half-esters 2a and 3a
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Texas Tech University, Hanjoung Cho, December 2010
We compared the 1H NMR spectra of the mixture of monomethyl and monoethyl diesters
with those of pure corresponding half-esters. Each spectrum is shown in Figure 3.2.
Based on these spectra, we determined the ratio of the exo-hydrolyzed half-ester to the
endo-hydrolyzed half-ester.
Figure 3.2 1H NMR spectra of the mixture of monomethyl ester (top), endo-hydrolyzed
monomethyl ester (middle), and exo-hydrolyzed monomethyl ester (bottom)
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Texas Tech University, Hanjoung Cho, December 2010
3.3. The selective monohydrolysis of (exo, endo)-dimethyl- and diethylbicyclo[2.2.1]
heptane-2,3-dicarboxylate 4a and 4b
In this section, selective monohydrolysis of structural variants of the C5–C6
positions will be discussed. Since the reaction center is not on the norbornene ring, we
hypothesize that this remote exo-facial selectivity was induced by the difference of the
steric bulkiness of the methano bridge and the ethano bridge on C5-C6 carbons.
Diesters 4a and 4b were prepared by hydrogenation with palladium on carbon of
diesters 1a and 1b, respectively. (Scheme 3.4)
Scheme 3.4 The preparation of dialkyl bicyclo[2.2.1] heptane-2,3-dicarboxylate 4a and
4b by hydrogenation with palladium on carbon
The selective monohydrolyses of these diesters were performed, and the results are
summarized in Table 3.2.
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Texas Tech University, Hanjoung Cho, December 2010
Table 3.2 Selective monohydrolysis of dimethyl and diethyl bicyclo[2.2.1] heptane-2,3,dicarboxylate 4a and 4b
Entry
Diester
Cosolvent
Base
Base
(equiv)
Time
(h)
Yielda
(%)
Ratio
(5:6)
1
4a
THF
LiOH
1.7
2.5
96 (4)
97:3
2
4a
THF
NaOH
1.7
2
>99
91:9
3
4a
THF
KOH
1.7
2
>99
95:5
4
4a
THF
CsOH
1.7
2
>99
92:8
5
4b
CH3CN
KOH
2.0
12
73 (17)
96:4
6
4b
DMSO
KOH
1.7
11
91 (0)
97:3
a
Isolated yield of the mixture of the half-esters. The recovered diester is shown in
parentheses (%).
From these results, this exo-selectivity in the monohydrolysis of diesters 4a and 4b
was found to be higher than those of olefinic diesters 1a and 1b, in which the double
bond in 1a and 1b was hydrogenated to introduce two additional hydrogens on the C5-C6
positions. The exo selectivities in monohydrolysis are increased by more than 10% for
both diesters 4a and 4b. Interestingly, a similar enhancement was found in the addition of
ethyl bromoacetate to 2-norbornenone (90% exo) versus 2-norbornanone (100% exo) in
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Texas Tech University, Hanjoung Cho, December 2010
the Reformatsky reaction.15 The enhanced extent is close to 10% but in our selective
monohydrolysis, the nucleophile, OH-, is far smaller than ethyl bromoacetate and thus
may appear less influenced by the steric environment, especially in this remote position.
It is also noteworthy that sodium borohydride reduction of the carbonyl of 2norbornenone and 2-norbornanone showed slightly enhanced exo-selectivity in the
reduction of 2-norbornenone (95% exo) than of 2-norbornanone (86% exo). The reasons
are perhaps due to the enhanced ring strain by introduction of the olefinic bond within the
ring and the small size of the nucleophile, H- in this case,16 although the extent of the
enhancement of the selectivity is again comparable to our results in 4a and 4b. For
monohydrolysis of diethyl ester 4b, the solvent effect we studied earlier again contributed
to the increase in reactivity, as DMSO is a polar aprotic solvent, and improved the yield
of this selective monohydrolysis of 4b (run 6).9b,10
To separate the mixture of half-esters 5a, 6a, 5b, and 6b, HPLC was applied.
However, as pure half-esters were not isolated by HPLC, an alternative method was used
for producing the authentic samples of half-esters 5a, 6a, 5b, and 6b. As we already
isolated pure half-esters 2a, 3a, 2b, and 3b above, those isolated half-esters were
hydrogenated for preparing authentic half-esters 5a, 6a, 5b, and 6b (Scheme 3.5).
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Scheme 3.5 The preparation of authentic half-esters 5a and 6a with HPLC and followed
by hydrogenation of 2a and 3a
The structures of these half-esters, 5a, 6a, 5b, and 6b, were determined by the
matching of 1H and 13C NMR spectral data of the authentic 5a, 6a, 5b, and 6b,
synthesized by hydrogenation of the purified major and minor half-esters 2a, 3a, 2b, and
3b above. 1H NMR spectra of the mixture of monomethyl ester 5a and 6a, major halfester 5a, minor half-ester 6a, are shown Figure 3.3.
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Figure 3.3 1H NMR spectra of the mixture of monomethyl ester (top), endo-hydrolyzed
monomethyl ester (middle), and exo-hydrolyzed monomethyl ester (bottom)
From these results, we have found that these remote exo-facial selectivities can be
enhanced by steric hindrance at the C5–C6 bridges, and it was obvious that the most
significant factor that governs these remote exo-facial selectivities is the steric hindrance
by the C5-C6 bridges compared to the C7 bridge. Based on these results, more exclusive
selectivity was found with further modification of the C5–C6 bridge.
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3.4. The selective monohydrolysis of acetonide protected (exo,endo)-dimethyl- and
diethylbicyclo[2.2.1] hept-5-ene-2,3-dicarboxylate 7a and 7b
In this section, we have examined the monohydrolysis of bicyclic diesters which
was modified by the acetonide group at the exo positions. These diesters 7a and 7b, in
which the exo positions of the C5-C6 positions are blocked by bulkier 1,2-Oisopropylidene. For preparation of these diesters, we used osmium-catalyzed
dihydroxylation of 1a and 1b and subsequent protection of the formed diol as acetonides
under acidic conditions (Scheme 3.6).17
Scheme 3.6 Synthesis of acetonide-protected bicyclic diesters 7a and 7b
The selective monohydrolysis was conducted on these prepared diesters with the
use of aqueous KOH. The results are summarized in Table 3.3.
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Table 3.3 Selective monohydrolysis of acetonide-protected diesters 7a and 7b
Base
Base
(equiv)
Time
(h)
Yielda
(%)
Ratio
(8:9)
Entry
Diester
Cosolvent
1
7a
THF
KOH
1.7
3
83 (5)
98:2
2
7a
CH3CN
KOH
1.7
3
87 (4)
98:2
3
7a
DMSO
KOH
1.7
3
89 (3)
98:2
4
7b
DMSO
KOH
1.7
6
92 (3)
98:2
a
Isolated yield of the half-ester. The recovered diester is shown in parentheses (%).
Since these half-esters have the enhanced steric hindrance on the exo direction of
the C5–C6 bond, the ratios for half-esters 8 : 9 are 98:2 for both the methyl and ethyl
esters, showing higher exo-facial selectivity than monohydrolysis of 4a or 4b. We also
found the co-solvent effects and again confirmed that the polar aprotic solvent, CH3CN or
DMSO, in particular DMSO, improved the yield (entry 3). Therefore, only DMSO was
applied to selective monohydrolysis of diethyl ester 7b, which led to high yields of the
half-esters (entry 4).
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3.5. The selective monohydrolysis of steric hindered bicyclic diesters on C5–C6 bond
In Section 3.4, we have investigated the steric effect of the exo positions of the
C5–C6 bond with acetonide protected diesters. In this section, the steric effect of the endo
position of the C5–C6 would be considered by modification of bicyclic compounds in
this section. Initially, we expected that blocking the endo position would most effectively
lead to the high exo selectivity due to bulky steric hindrance on the endo locations. To
study our expectation, we synthesized endo,endo-dimethyl-substituted diesters 10a and
10b by the Diels-Alder reaction of 2,3-dimethylcyclopentadiene prepared in situ18 with
dimethyl fumarate and subsequent hydrogenation (Scheme 3.7). Both the structures of
dimethyl and diethyl diesters and intermediates were confirmed by 1H and 13C NMR
spectra and high-resolution mass spectroscopy.
Scheme 3.7 Synthesis of dialkyl diesters 10a and 10b
The selective monohydrolysis of both of these dimethyl and diethyl esters were
conducted with the use of aqueous KOH, and co-solvent with water at 0 °C, and the
results are shown in Table 3.4.
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Table 3.4 Selective monohydrolysis of diesters 10a and 10b
Time
Ratio
(11:12)
Entry
Diester
1
10a
THF
KOH
1.7
9h
63 (26)
100:0
2
10a
CH3CN
KOH
1.7
9h
99
100:0
3
10a
DMSO
KOH
1.7
8h
49
100:0
4
10b
DMSO
KOH
1.7
1d
79 (18)
100:0
5
10b
DMSO
KOH
2.5
2d
79 (16)
100:0
a
Base
Base
(equiv)
Yielda
(%)
Cosolvent
Isolated yield of the half-ester. The recovered diester is shown in parentheses (%).
When the selectivity of monohydrolysis in these diesters was compared with
diesters in previous sections, interestingly, the only exo-hydrolyzed half-esters were
found in the monohydrolysis of dimethyl and diethyl diesters 10a and 10b. Compared to
the selectivity in the monohydrolysis of acetonide protected diesters 10a and 10b, even
though the methyl groups are far smaller than the O-isopropylidene, only the ester groups
on the exo position were hydrolyzed exclusively for both dimethyl and diethyl esters,
demonstrating the importance of the steric effects toward the endo directions. The
structure was confirmed by X-ray crystal analysis of the half-ester 11a and its crystal
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Texas Tech University, Hanjoung Cho, December 2010
structure is shown in Figure 3.4. Therefore, we conclude that the most critical factor
appears to be the steric effect that blocked approach of the nucleophile OH- from the
endo direction on the C5-C6 bridge.
Figure 3.4 X-ray crystal structure of half-ester 11a
From these results in Table 3.4, we also demonstrated effects of the co-solvent,
indicating that polar aprotic solvents improve the reactivity and selectivity. Acetonitrile
as a co-solvent can enhance reactivity of the monohydrolysis of diesters for the
monohydrolysis of dialkyl malonates,13 and the monohydrolysis with DMSO as cosolvent was the most efficient solvent in these reactions as well. In particular, the yield of
the half-ester for the methyl ester 11a was near-quantitative (entry 2 and entry 3).
Since the effects of substituents on C5 and/or C6 position of norbornene, or
norbornanone have been understood as too remote even for the reactions that occur on the
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bicyclic ring, there have been very few systematic studies reported about the effects of
substituents on such positions and the reported selectivities are rather complicated. One
of the reported results is the addition of bromine to several 5,6-disubstituted
norbornenes.19 The initial bromonium cation is expected to form on the exo position, but
the second bromide ion can have possible attack either from the endo or exo face,
forming trans- by endo-facial attack or cis-dibromide by exo-facial attack, respectively.
Interestingly, it appears that the selectivity toward formation of the cis-dibromide/transdibromide from cis-exo,exo-5,6-dicyanonorbornene in acetic acid is not necessarily high
(11% cis, 89% trans). Bromination of trans-5,6-dichloro- or –dicyanonorbornene is
reported to form a considerable extent of the trans dibromide depending on the reaction
conditions (33-100%), even though these functional groups are not as bulky as Oisopropylidene. Although the cis-endo,endo-5,6-dichloro- or –dicyanonorbornenes appear
to retard the reaction rate of bromination more than the corresponding trans- or cisexo,exo-5,6-dichloro- or -dicyanonorbornene, the order of reaction rate for epoxidation
on the same norbornene derivatives appears to be the opposite, while that for addition of
diazomethane was the same.20 Therefore, our reaction demonstrates unique examples for
distinguishing the exo and endo selectivity by the C5 and C6 functional groups in a
straightforward manner.
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3.6. Conclusion
In this chapter, we have investigated the predominately exo-facial monohydrolysis
of various bicyclic diesters. While the exo-/endo-facial selectivities are shown as
negligible for the carbons that are one covalent bond distant from the norbornane ring, we
have demonstrated that such specific carbons can be successfully distinguished by our
selective monohydrolysis reaction with high exo-facial selectivity. We have shown that
the selectivity is controllable in a predictable manner based on the steric effect on the
C5-C6 ethano bridge. In particular, introduction of the smallest alkyl groups, methyl
groups, on the endo positions of the C5-C6 bonds leads to the exclusive exo selectivity.
These results are the first examples of systematic studies of remote exo-facial
selectivities that occur one covalent bond away from the norbornyl system. Since
norbornyl systems with various endo and exo functional groups are often applied to
synthesis of polymers with different physical properties,21 our new finding is expected to
expand the scope of exo/endo-facial selectivity observed in the norbornyl systems with
the use of this selective monohydrolysis reaction, in particular on dimethyl and diethyl
esters.
In addition, it has become more apparent that a polar aprotic co-solvent
significantly improves the reactivity and selectivity of the selective monohydrolysis of
diesters, confirming results of our previous studies about the influence of co-solvents in
the monohydrolyses of other diesters. This solvent effect is expected to improve yields of
half-esters by selective monohydrolysis of other diesters.
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3.7. Experimental section
General experimental conditions
All solvents, unless otherwise stated, were used without further purification.
Melting points were measured on an electrothermal capillary instrument (MEL-TEMP® )
and were uncorrected. NMR spectra were recorded on a Varian Unity Plus 300 or a
Varian Mercury Plus 300 spectrometer at 300 and 125 MHz for 1H and 13C, respectively.
Trimethylsilane (TMS, δ = 0) or the residual solvent peak (CDCl3, δ = 7.24) used as a
shift reference for 1H NMR spectra, and chemical shift for solvent peak (CDCl3, δ =
77.00) served as a reference for 13C NMR spectra. IR spectra were recorded on a Nicolet
IR100 FT-IR spectrometer. Elemental analyses were performed with CHN combustion
analyses on TC and IR detection by Columbia Analytical ServicesINC (Tuscan, AZ). High
resolution mass spectrometry was performed with MALDI-TOF/TOF (Matrix-assisted
laser desorption/ionization Time-of-flight) instrument which was equipped in
Experimental Sciences at Texas Tech University. Single crystal X-ray crystallographic
analysis was performed on a Rigaku SCX mini diffractometer equipped with a TEC-50
cryostream and employing Mo-Kα (λ =0.71073 Å ) irradiation from a sealed X-ray source.
High-performance liquid chromatography (HPLC) system has Waters 600E pump and
Waters 2996 Photodiode Array Detector. The HPLC grade solvent was used and the ratio
was 98 : 2 of hexane : 2-propanol. The equipped column was Intersil SIL-100 purchased
from GL Science and its dimension is 4.6 mm i.d. × 250 mm. The flow rate was 2.0
mL/min and detection wavelength was 215 nm. Thin layer chromatography (TLC) was
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Texas Tech University, Hanjoung Cho, December 2010
performed using precoated aluminum backed TLC plates, silica gel 60, F254 (EMD
Chemicals). Flash silica chromatography was performed with Silica Gel, 230–400mesh.
Synthetic procedure and additional information of compounds
Synthesis of diester 1a
Diester 1a was synthesized by Diels-Alder reaction of dicyclopentadiene and
dimethyl fumarate as reported previously. Dimethyl fumarate (15.0 g, 104 mmol) was
dissolved in dry CH2Cl2 (50 mL) under nitrogen atmosphere at 0 °C. To this solution
was added cyclopentadiene (20.623 g, 312 mmol) dropwise. The colorless solution was
stirred for 2 hours at room temperature under nitrogen atmosphere. After the solution
was concentrated and purified by distillation under reduced pressure, diester 1a was
obtained with the isolated yield of 61.3% at 99–100 °C.
Colorless liquid, 1H NMR (300 MHz, CDCl3) δ = 1.39 (1H, dq, J = 1.6, 8.9 Hz),
1.55 (1H, d, J = 8.9 Hz), 2.61 (1H, dd, J = 1.6, 4.6 Hz), 3.05 (1H, m), 3.20 (1H, m), 3.31
(1H, t, J = 4.0 Hz), 3.57 (3H, s), 3.64 (3H, s), 6.00 (1H, dd, J = 2.8, 5.7 Hz), 6.20 (1H, dd,
J = 3.2, 5.6 Hz); 13C NMR (75 MHz, CDCl3) δ = 45.5, 46.9, 47.2, 47.5, 47.7, 51.7, 51.9,
135.0, 137.4, 173.5, 174.7; HRMS calcd for C11H15O4 [M+H]+: 211.0970, found
211.0978.
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Texas Tech University, Hanjoung Cho, December 2010
Monohydrolysis of diester 1a (entry 3 in Table 3.1)
Dimethyl bicyclic diester 1a (252 mg, 1.2 mmol) was dissolved in 2 mL of THF,
and 20 mL of water was added. The reaction mixture was cooled to 0 oC in an ice-water
bath. To this mixture was added 0.25 M KOH aqueous solution (5.76 mL, 1.20
equivalent) dropwise with stirring. The reaction mixture was stirred for 1 hours, and
acidified with 1 M HCl at 0 °C, saturated with NaCl, extracted with ethyl acetate (×4),
and dried over sodium sulfate. This extract was concentrated in vacuo and purified by
silica gel column chromatography with hexane:ethyl acetate (3:1) and then ethyl acetate
as typical eluents to afford mixture (2a + 2b) of half-esters with 97% isolated yield and
ratio of 82 : 18 (2a : 2b) determined by integral comparison in chemical shift δ 3.71 and δ
3.64 in 300 MHz 1H NMR.
endo-Monomethyl bicyclo[2.2.1]hept-5-ene carboxylic acid 2a
White solid, 1H NMR (300 MHz, CDCl3) δ = 1.47 (1H, dq, J = 1.6, 8.9 Hz), 1.60 (1H, br,
J = 8.9 Hz), 2.71 (1H, dd, J = 1.5, 4.7 Hz), 3.19 (1H, m), 3.26 (1H, m), 3.36 (1H, t, J =
4.0 Hz), 3.64 (3H, s), 6.07 (1H, dd, J = 2.8, 5.7 Hz), 6.28 (1H, dd, J = 3.2, 5.6 Hz), 11.41
(1H, br); 13C NMR (75MHz, CDCl3) δ = 45.6, 47.1, 47.4, 47.6, 47.8, 51.9, 135.3, 137.5,
173.6, 179.0; IR (neat, cm-1): 1696, 1724, 2950-3000; mp 121-122 °C; HR-EIMS calcd
for C10H12O4 : 196.0736, found 196.0892.
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Texas Tech University, Hanjoung Cho, December 2010
exo-Monomethyl bicyclo[2.2.1]hept-5-ene carboxylic acid 2b
Colorless oil, 1H NMR (300 MHz, CDCl3) δ = 1.47 (1H, dq, J = 1.6, 8.9 Hz), 1.61 (1H,
br, J = 8.9 Hz), 2.65 (1H, dd, J = 1.6, 4.4 Hz), 3.13 (1H, m), 3.28 (1H, m), 3.41 (1H, t, J
= 4.0Hz), 3.71 (3H, s), 6.12 (1H, dd, J = 2.9, 5.6 Hz), 6.28 (1H, dd, J = 3.2, 5.6 Hz),
11.41 (1H, br); 13C NMR (75 MHz, CDCl3) δ = 45.6, 47.1, 47.4, 47.6, 47.8, 51.9, 135.3,
137.5, 173.6, 179.0; IR (neat, cm-1): 1696, 1724, 2950-3000; HR-EIMS calcd for
C10H12O4 : 196.0736, found 196.0735.
Synthesis of diester 4a
To the mixture of 10 % Pd-C (4 mg) in ethanol (10 mL), diester 1a (1.5 g, 7 mmol)
was added at room temperature. After the reaction mixture was stirred under H2
atmosphere for 12 hours, the crude product was filtered with Celite and the solvent was
removed under reduced pressure. Pure diester 4a (1.365 g, 90 %) was obtained by
fractional distillation at 89–90 °C under reduced pressure (~2 mm Hg).
Colorless oil. 1H NMR (300 MHz, CDCl3) δ = 1.54–1.21 (6H, m), 2.51 (1H, d, J =
3.6 Hz), 2.57, (1H, s), 2.76 (1H, d, J = 5.1 Hz), 3.15 (1H, t, J = 3.3 Hz), 3.62 (3H, s), 3.64
(3H, s); 13C NMR (75 MHz, CDCl3) δ = 24.2, 28.7, 38.0, 40.1, 41.6, 48.5, 49.3, 51.7,
51.8, 173.8, 175.0; IR (neat, cm-1) 1725, 2879, 2969; C11H16O4 HRMS calcd for
C11H16O4Na [M+Na]+: 235.0946, found 235.0934.
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Texas Tech University, Hanjoung Cho, December 2010
Monohydrolysis of diester 4a (entry 3 in Table 3.2)
Dimethyl bicyclic diester 4a (255 mg, 1.2 mmol) was dissolved in 2 mL of THF,
and 20 mL of water was added. The reaction mixture was cooled to 0 oC in an ice-water
bath. To this mixture was added 0.25 M KOH aqueous solution (8 mL, 1.67equivalent)
dropwise with stirring. The reaction mixture was stirred for 2 hours, and acidified with 1
M HCl at 0 °C, saturated with NaCl, extracted with ethyl acetate (×4), and dried over
sodium sulfate. This extract was concentrated in vacuo and purified by silica gel column
chromatography with hexane:ethyl acetate (3:1) and then ethyl acetate as typical eluents
to afford mixture (5a + 6a) of half-esters with 99% isolated yield and ratio of 95 : 5 (5a :
6a) determined by integral comparison in chemical shift δ 3.71 and δ 3.69 in 300MHz 1H
NMR spectrum.
endo-Monomethyl bicyclo[2.2.1]heptane carboxylic acid 2a
White solid. 1H NMR (300 MHz, CDCl3) δ = 1.60–1.22 (6H, m), 2.62 (2H, t, J = 1.5 Hz),
2.85 (1H, d, J = 5.4 Hz), 3.17 (1H, t, J = 4.5 Hz), 3.69 (3H, s), 11.60 (1H, br); 13C NMR
(75 MHz, CDCl3) δ = 24.20, 28.84, 38.17, 40.15, 41.65, 48.39, 49.35, 51.91, 173.80,
178.77; IR (neat, cm-1): 1693, 1704, 2880-3550; mp 81-82 °C; HRMS Calcd for
C10H14O4Na [M+Na]+: 221.0790. Found: 221.0801.
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Texas Tech University, Hanjoung Cho, December 2010
exo-Monomethyl bicyclo[2.2.1]heptane carboxylic acid 2b
White solid. 1H NMR (300 MHz, CDCl3) δ = 1.61–1.23 (6H, m), 2.57 (1H, t, J = 3.6 Hz),
2.67 (1H, s), 2.76 (1H, d, J = 5.1 Hz), 3.25 (1H, t, J = 4.5 Hz), 3.67 (3H, s), 11.60 (1H,
br); 13C NMR (75 MHz, CDCl3) δ = 24.18, 28.81, 38.16, 40.13, 41.65, 48.43, 49.11,
52.08, 174.97, 177.44; IR (neat, cm-1): 1698, 1720, 2880-3500; mp 79 °C; HRMS Calcd
for C10H14O4Na [M+Na]+: 221.0790. Found: 221.0780.
3. Synthesis of diester 7a
To a solution of diester 1a (1.3 g, 6.0 mmol) in acetone/H2O (9:1, 100 mL), 4methylmorpholine N-oxide monohydrate (1.1 g, 9.0 mmol) and osmium tetroxide (0.15
mmol, 2.5 mol%) were added at 0 °C. The mixture was stirred for 1 hour at room
temperature and a saturated aqueous solution of NaHCO3 was added. The crude product
was extracted with ethyl acetate and dried over anhydrous sodium sulfate. After the
mixture was concentrated under reduced pressure, the crude product was purified by
column chromatography on silica gel (CH2Cl2: MeOH = 40 : 1, then 20 : 1).
Next, a solution of crude compound 13a (1.0 g) in anhydrous acetone (40 mL)
containing 2,2-dimethoxypropane (2.5 mL) and p-toluenesulfonic acid monohydrate (96
mg) was stirred at room temperature for 30 min. Then, a saturated aqueous solution of
NaHCO3 was added, and the crude product was extracted with ethyl acetate, dried over
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Texas Tech University, Hanjoung Cho, December 2010
sodium sulfate, concentrated under reduced pressure, and purified by column
chromatography on silica gel (ethyl acetate : hexane, 9:1) to afford protected diester 7a
(1.01 g, 89%) as a white solid.
White solid. 1H NMR (300 MHz, CDCl3) δ = 1.27 (3H, s), 1.37 (1H, d, J = 12.3
Hz), 1.43 (3H, s), 1.80 (1H, d, J = 12.3 Hz), 2.60 (1H, s), 2.67 (2H, d, J = 5.1 Hz), 3.23
(1H, t, J = 5.1 Hz), 3.71 (3H, s), 3.72 (3H, s), 4.01 (1H, d, J = 5.4 Hz), 4.15 (1H, d, J =
5.4 Hz); 13C NMR (75 MHz, CDCl3) δ = 24.0, 25.3, 31.3, 43.3, 43.5, 45.1, 45.1, 52.1,
52.2, 78.2, 80.9, 109.4, 172.7, 173.9; IR (neat, cm-1) 1735, 2954, 2989; mp 82 °C; HRMS
calcd for C14H21O6 [M+H]+: 285.1338, found 285.1324.
Monohydrolysis of diester 7a (entry 2 in Table 3.3)
Dimethyl bicyclic diester 7a (171 mg, 0.6 mmol) was dissolved in 1 mL of CH3CN,
and 10 mL of water was added. The reaction mixture was cooled to 0oC in an ice-water
bath. To this mixture was added 0.25 M KOH aqueous solution (4 mL, 1.67 equivalent)
dropwise with stirring. The reaction mixture was stirred for 2 hours, and acidified with 1
M HCl at 0 oC, saturated with NaCl, extracted with ethyl acetate (×4), and dried over
sodium sulfate. This extract was concentrated in vacuo and purified by silica gel column
chromatography with hexane:ethyl acetate (3:1) and then ethyl acetate as typical eluents
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Texas Tech University, Hanjoung Cho, December 2010
to afford mixture (8a + 9a) of half-esters with 87% isolated yield and ratio of 98 : 2 (8a :
9a) determined by integral comparison in chemical shift δ 3.16-3.23 and δ 3.25-3.29 in
500MHz 1H NMR spectrum.
endo-Monomethyl acetonide protected bicyclic carboxylic acid 8a
Colorless oil. 1H NMR (300 MHz, CDCl3) δ = 1.26 (3H, s), 1.36 (1H, d, J = 11.1 Hz),
1.42 (3H, s), 1.80 (1H, d, J = 11.1 Hz), 2.65 (2H, s), 2.70 (1H, d, J = 4.5 Hz), 3.19 (1H, t,
J = 5.1 Hz), 3.71 (3H, s), 4.01 (1H, d, J = 5.1 Hz), 4.15 (1H, d J = 5.1 Hz), 7.82 (1H, br);
13
C NMR (75 MHz, CDCl3) δ = 24.09, 25.33, 31.49, 43.35, 43.35, 45.07, 45.18, 52.26,
78.25, 80.89, 109.57, 172.70, 177.44; IR (neat, cm-1): 1700, 1733, 2937-3389; HRMS
Calcd for C13H18O6Na [M+Na]+: 293.1001. Found: 293.1003.
Synthesis of diester 15a and 10a
To a mixture of magnesium (0.450 g) in dry ether (20 mL), 3.0 g of methyl iodide
was added at room temperature to prepare the Grignard reagent under nitrogen. After
one hour of stirring, 2-methyl-2-cyclopentanone 14 (1.5 g, 15.6 mmol) was added to this
mixture in an ice-water bath. The mixture was stirred for 1.5 hours in the ice-water bath,
and was quenched with a cold saturated ammonium chloride solution. This crude product
was extracted with ether (x 3) and dried with sodium sulfate. After concentration of the
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Texas Tech University, Hanjoung Cho, December 2010
reaction mixture, the crude tertiary alcohol was used for the subsequent Diels-Alder
reaction without further purification. To an ether solution (75 mL) of this alcohol were
added p-toluenesulfonic acid (~30 mg) and dimethyl fumarate (2.25 g, 1 equivalent) at
0 °C. After being stirred for 3 hours at 0 °C and for 12 hours at room temperature under
nitrogen, the solution was washed with saturated aqueous sodium bicarbonate solution
and brine, and dried over sodium sulfate. After removal of the ether, compound 15a
(1.731 g, 46.6%) was isolated by silica gel chromatography (hexane/ethyl acetate = 10/1).
For hydrogenation, 10% Pd/C (10% of the weight) was added to the solution of
compound 15a in methanol (5 mL), and the reaction mixture was stirred under hydrogen
atmosphere. After being stirred for 3 days at 55 °C, the mixture was filtered with Celite
and the solvent was removed with a rotary evaporator. Diester 10a (92%) was isolated
by column chromatography with eluents of hexane/ethyl acetate.
Diester 15a
Colorless oil. 1H NMR (300 MHz, CDCl3) δ = 1.45 (1H, m), 1.51 (1H, m), 1.54
(3H, d, J = 1.2 Hz), 1.68 (3H, d, J = 0.9 Hz), 2.76 (1H, dd, J = 4.8 Hz, 1.5 Hz), 2.83 (1H,
d, J = 1.5 Hz), 3.01 (1H, q, J = 1.8 Hz), 3.37 (1H, t, J = 4.2 Hz), 3.65 (3H, s), 3.70 (3H, s);
13
C NMR (75 MHz, CDCl3) δ = 11.5, 12.9, 45.8, 46.6, 49.2, 51.4, 51.8, 51.3, 52.8, 135.3,
137.7, 173.6, 175.2; IR (neat, cm-1) 1436, 1731, 2953; HRMS calcd for C13H19O4
[M+H]+: 239.1283, found 239.1290.
Diester 10a
Colorless oil. 1H NMR (300 MHz, CDCl3) δ = 0.73 (3H, d, J = 7.5 Hz), 0.92 (3H,
d, J = 7.5 Hz), 1.41 (1H, dd, J = 10.2 Hz, 1.5 Hz), 1.53 (1H, dt, J = 10.2 Hz, 1.8 Hz), 2.11
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Texas Tech University, Hanjoung Cho, December 2010
(2H, m), 2.37 (1H, d, J = 2.1 Hz), 2.61 (1H, m), 3.17 (2H, m), 3.64 (3H, s), 3.65 (3H, s);
13
C NMR (300 MHz, CDCl3) δ = 11.2, 11.7, 34.9, 35.0, 39.6, 40.4, 46.5, 47.0, 48.6, 51.5,
52.0, 174.5, 176.0; IR (neat, cm-1) 1730, 2955; HRMS calcd for C13H20O4Na[M+Na]+:
263.1259, found 263.1248.
Monohydrolysis of diester 10a (entry 2 in Table 3.4)
(exo,endo)-Dimethyl bicyclo[2.2.1]hepta-5,6-(endo,endo)-dimethyl diester 10a
(144 mg, 0.6 mmol) was dissolved in 1 mL of CH3CN, and 10 mL of water was added.
The reaction mixture was cooled to 0 oC in an ice-water bath. To this mixture was added
0.25 M KOH aqueous solution (4 mL, 1.67 equivalent) dropwise with stirring. The
reaction mixture was stirred for 9 hours, and acidified with 1 M HCl at 0 oC, saturated
with NaCl, extracted with ethyl acetate (×4), and dried over sodium sulfate. This extract
was concentrated in vacuo and purified by silica gel column chromatography with
hexane:ethyl acetate (3:1) and then ethyl acetate as typical eluents to afford its half-esters
11a with 99% isolated yield.
endo-Monomethyl bicyclo[2.2.1]hepta-5,6-(endo,endo)-dimethyl carboxylic acid 11a
White solid. 1H NMR (300 MHz, CDCl3) δ = 0.73 (3H, d, J = 7.5 Hz), 0.93 (3H, d,
J = 6.9 Hz), 1.42 (1H, dd, J = 9.9 Hz, 1.5 Hz), 1.53 (1H, dt, J = 9.9 Hz, 1.8 Hz), 2.13 (2H,
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Texas Tech University, Hanjoung Cho, December 2010
m), 2.46 (1H, d, J = 2.4 Hz), 2.62 (1H, m), 3.11 (1H, m), 3.12 (1H, dd, J = 6.6 Hz, 1.5
Hz), 3.68 (3H, s); 13C NMR (75 MHz, CDCl3) δ =11.25, 11.76, 34.85, 35.05, 39.70,
40.57, 46.51, 46.95, 48.61, 51.63, 174.47, 181.27; IR (neat, cm-1): 1704, 1714, 2850-3400;
mp 75-76 °C; Anal. Calcd for C12H18O4: C, 63.70; H, 8.02. Found: C, 63.74; H,7.58.
Crystal data for 11a : C12H18O4; M = 226.26; a = 6.9411(8) Å , b = 9.2660(11) Å , c
= 10.4142(12) Å ; V = 603.26(12) Å 3; Z = 2; T = 293(2) K; μ = 0.093 mm-1; 6897
measured reflns, 2643 unique reflns; R = 0.0504, Rw = 0.1428.
Synthesis of diester 1b
Diester 1b was synthesized by a Diels-Alder reaction of cyclopentadiene and
diethyl fumarate as reported previously. Diethyl fumarate (15.0 g, 87 mmol) was
dissolved in dry CH2Cl2 (25 mL) under a nitrogen atmosphere at 0 °C. To this solution
was added cyclopentadiene (17.276 g, 261 mmol) dropwise. The colorless solution was
stirred for 12 hours at room temperature under a nitrogen atmosphere. After the solution
was concentrated under reduced pressure and purified by column chromatography with
hexane/ethyl acetate (4:1), the diethyl diester 1b was obtained with the isolated yield of
74%.
Colorless liquid, 1H NMR (300 MHz, CDCl3) δ = 1.21, (3H, t, J = 7.2 Hz), 1.24
(3H, t, J = 7.2 Hz), 1.41 (1H, dq, J = 1.6, 8.9 Hz), 1.58 (1H, br, J = 8.9 Hz), 2.64 (1H, dd,
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J = 1.6, 4.6 Hz), 3.07 (1H, m), 3.22 (1H, m), 3.34 (1H, t, J = 4.0 Hz), 4.06 (2H, q, J = 7.2
Hz), 4.12 (2H, q, J = 7.2 Hz), 6.03 (1H, dd, J = 2.8, 5.7 Hz), 6.24 (1H, dd, J = 3.2, 5.6
Hz); 13C NMR (75 MHz, CDCl3) δ = 14.1, 14.1, 45.5, 47.0, 47.1, 47.6, 47.7, 60.3, 60.6,
134.9, 137.4, 173.1, 174.3; HRMS calcd for C13H19O4 [M+H]+: 239.1283, found
239.1271
Monohydrolysis of diester 1b (entry 6 in Table 3.1)
Diethyl bicyclic diester 1b (286 mg, 1.2 mmol) was dissolved in 2 mL of
acetonitrile, and 20 mL of water was added. The reaction mixture was cooled to 0 oC in
an ice-water bath. To this mixture was added 0.25 M KOH aqueous solution (8 mL, 1.67
equivalent) dropwise with stirring. The reaction mixture was stirred for 7.5 hours, and
acidified with 1 M HCl at 0 oC, saturated with NaCl, extracted with ethyl acetate (×4),
and dried over sodium sulfate. This extract was concentrated in vacuo and purified by
silica gel column chromatography with hexane:ethyl acetate (3:1) and then ethyl acetate
as typical eluents to afford the mixture (2b + 3b) of half-esters with 96% isolated yield
and ratio of 87 : 13 (2b : 3b) determined by integral comparison in chemical shift δ 2.63
and δ 2.71 in 300 MHz 1H NMR spectrum.
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endo-Monoethyl bicyclo[2.2.1]hept-5-ene carboxylic acid 2b
Colorless oil, 1H NMR (300 MHz, CDCl3) δ = 1.21 (3H, t, J = 7.0 Hz), 1.46 (1H,
dd, J = 1.6 Hz, 8.9 Hz), 1.60 (1H, br, J = 8.9 Hz), 2.71 (1H, dd, J = 1.5 Hz, 4.5 Hz), 3.18
(1H, m), 3.26 (1H, m), 3.40 (1H, t, J = 4.0 Hz), 4.08 (2H, m), 6.06 (1H, dd, J = 2.8 Hz,
5.7 Hz), 6.28 (1H, dd, J = 3.2 Hz, 5.6 Hz), 11.0 (1H, br); 13C NMR (75 MHz, CDCl3) δ =
14.2, 45.6, 47.2, 47.3, 47.7, 47.9, 60.7, 135.2, 137.5, 173.1, 180.5; IR (neat, cm-1): 1704,
1732, 2950-3000; HRMS calcd for C11H14O4: 210.0892, found 210.0892.
exdo-Monoethyl bicyclo[2.2.1]hept-5-ene carboxylic acid 3b
Colorless oil, 1H NMR (300 MHz, CDCl3) δ = 1.26 (3H, t, J = 7.0 Hz), 1.45 (1H,
dd, J = 1.6 Hz, 8.7 Hz), 1.59 (1H, br, J = 8.7 Hz), 2.63 (1H, dd, J = 1.6 Hz, 4.4 Hz), 3.11
(1H, m), 3.28 (1H, m), 3.43 (1H, t, J = 4.0 Hz), 4.15 (2H, q, J = 7.1 Hz), 6.12 (1H, dd, J
= 2.9 Hz, 5.6 Hz), 6.28 (1H, dd, J = 3.2 Hz, 5.6 Hz), 11.0 (1H, br); 13C NMR (75 MHz,
CDCl3) δ = 14.2, 45.6, 47.3, 47.4, 47.6, 47.7, 61.0, 135.2, 137.8, 174.2, 177.9; IR (neat,
cm-1): 1704, 1732, 2950-3000; HRMS calcd for C11H14O4: 210.0892, found 210.0892.
Synthesis of diester 4b
To the mixture of 10% Pd-C (500 mg) in methanol (30 mL), diester 1b (5.0 g, 21
mmol) was added at 55 °C. After the reaction mixture was stirred under a H2 atmosphere
for 24 hours, the crude product was filtered through Celite, and the solvent was removed
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under reduced pressure. Diester 4b (4.692 g, 93 %) was obtained by silica gel column
chromatography with an eluent of hexane/ethyl acetate.
Colorless oil. 1H NMR (300 MHz, CDCl3) δ = 1.23-1.62 (12H, m), 2.57 (1H, s),
2.64 (1H, s), 2.81 (1H, d, J = 4.8 Hz), 3.20 (1H, m), 4.09-4.19 (4H, m); 13C NMR (75
MHz, CDCl3) δ = 14.1, 14.2, 24.1, 28.7, 37.9, 40.1, 41.8, 48.6, 49.2, 60.4, 60.5, 173.4,
174.6; IR (neat, cm-1) 1729, 2878, 2974; HRMS calcd for C13H21O4 [M+H]+: 241.1439,
found 241.1445.
Monohydrolysis of diester 4b (entry 6 in Table 3.2)
Diethyl bicyclic diester 4b (288 mg, 1.2 mmol) was dissolved in 2 mL of DMSO,
and 20 mL of water was added. The reaction mixture was cooled to 0 oC in an ice-water
bath. To this mixture was added 0.25 M KOH aqueous solution (8 mL, 1.67 equivalent)
dropwise with stirring. The reaction mixture was stirred for 11 hours, and acidified with
1 M HCl at 0 oC, saturated with NaCl, extracted with ethyl acetate (×4), and dried over
sodium sulfate. This extract was concentrated in vacuo and purified by silica gel column
chromatography with hexane:ethyl acetate (3:1) and then ethyl acetate as typical eluents
to afford the mixture (5b +6b) of half-esters with 91% isolated yield and ratio of 97 : 3
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(5b : 6b) determined by integral comparison in chemical shift δ 3.24 and δ 3.14 in 300
MHz 1H NMR spectrum.
endo-Monoethyl bicyclo[2.2.1]heptane carboxylic acid 5b
Colorless oil. 1H NMR (300 MHz, CDCl3) δ = 1.60–1.23 (10H, m), 2.62 (2H, t, J =
1.5 Hz), 2.86 (1H, d, J = 5.1 Hz), 3.15 (1H, t, J = 0.9 Hz), 4.10 (2H, q, J = 7.2 Hz); 13C
NMR (75 MHz, CDCl3) δ = 14.30, 24.10, 28.81, 38.18, 40.15, 41.62, 48.27, 49.44, 60.73,
173.36, 178.74; IR (neat, cm-1): 1695, 1730, 2880-3400; HRMS Calcd for
C11H16O4Na[M+Na]+ : 235.0946. Found: 235.0935.
exo-Monoethyl bicyclo[2.2.1]heptane carboxylic acid 6b
Colorless oil. 1H NMR (300 MHz, CDCl3) δ = 1.60–1.23 (10H, m), 2.55 (2H, t, J =
1.5 Hz), 2.72 (1H, d, J = 5.1 Hz), 3.24 (1H, t, J = 0.9 Hz), 4.15 (2H, q, J = 7.2 Hz); 13C
NMR (75 MHz, CDCl3) δ = 14.30, 24.25, 28.81, 38.18, 40.15, 41.80, 48.49, 49.44, 60.78,
174.54, 179.72; IR (neat, cm-1): 1695, 1730, 2880-3400; HRMS Calcd for
C11H16O4Na[M+Na]+ : 235.0946. Found: 235.0935.
Synthesis of 7b
To a solution of diester 1b (2.0 g, 8.4 mmol) in acetone/H2O (9:1, 100 mL), 4methylmorpholine N-oxide monohydrate (1.48 g, 12.6 mmol) and osmium tetroxide (0.17
mmol, 2.0 mol%) were added at 0 °C. The mixture was stirred for 1 hour at room
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temperature and a saturated aqueous solution of NaHCO3 was added. Then, the crude
product was extracted with ethyl acetate and dried over anhydrous sodium sulfate. After
the mixture was concentrated under reduced pressure, the crude product was purified by
column chromatography on silica gel (CH2Cl2 : MeOH = 40 : 1 then 20 : 1).
A solution of crude compound 13b (1.6 g) in anhydrous acetone (50 mL)
containing 2,2-dimethoxypropane (3.45 mL) and p-toluenesulfonic acid monohydrate
(140 mg) was stirred at room temperature for 30 min. Then, a saturated aqueous solution
of NaHCO3 was added, and the crude product was extracted with ethyl acetate, dried over
sodium sulfate, concentrated under reduced pressure, and purified by column
chromatography on silica gel (ethyl acetate : hexane, 9:1) to afford diester 7b (1.724 g,
95 %) as a white solid.
White solid. 1H NMR (300 MHz, CDCl3) δ = 1.21 (9H, m), 1.30 (1H, d, J = 12.3
Hz), 1.37 (3H, s), 1.72 (1H, d, J = 12.3 Hz), 2.53 (1H, s), 2.67 (2H, d, J = 5.1 Hz), 3.17
(1H, t, J = 5.1 Hz), 3.98 (1H, d, J = 5.1 Hz), 4.13 (5H, m); 13C NMR (75 MHz, CDCl3) δ
= 14.1, 14.1, 24.0, 25.3, 31.3, 43.4, 43.5, 45.1, 45.2, 60.9, 61.0, 78.2, 80.9, 109.3, 172.3,
173.5; IR (neat, cm-1) 1729, 2937, 2985; mp 42-43 °C; HRMS calcd for C16H24O6Na
[M+Na]+: 335.1470, found 335.1459.
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Monohydrolysis of diester 7b (entry 4 in Table 3.3)
Diethyl acetonide protected bicyclic diester 7b (187 mg, 0.6 mmol) was dissolved
in 1 mL of DMSO, and 10 mL of water was added. The reaction mixture was cooled to 0
o
C in an ice-water bath. To this mixture was added 0.25 M KOH aqueous solution (4 mL,
1.67 equivalent) dropwise with stirring. The reaction mixture was stirred for 6 hours, and
acidified with 1 M HCl at 0 oC, saturated with NaCl, extracted with ethyl acetate (×4),
and dried over sodium sulfate. This extract was concentrated in vacuo and purified by
silica gel column chromatography with hexane:ethyl acetate (3:1) and then ethyl acetate
as typical eluents to afford mixture (8b + 9b) of half-esters with 92% isolated yield and
ratio of 98 : 2 (8b : 9b) was determined by integral comparison in chemical shift δ 3.16
and δ 3.26 in the 300 MHz 1H NMR spectrum.
endo-Monoethyl acetonide protected bicyclic carboxylic acid 8b
White solid. 1H NMR (300 MHz, CDCl3) δ = 1.29–1.24 (6H, m), 1.35 (1H, m, J =
11.1 Hz), 1.42 (3H, s), 1.81 (1H, d, J = 11.1 Hz), 2.65 (2H, s), 2.71 (1H, d, J = 0.9 Hz),
3.17 (1H, t, J = 5.1 Hz), 4.02 (1H, d, J = 5.4 Hz), 4.19–4.12 (3H, m); 13C NMR (75 MHz,
CDCl3) δ = 14.20, 24.08, 25.32, 31.53, 43.39, 43.43, 45.09, 45.30, 61.23, 78.21, 80.91,
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109.54, 172.20, 178.52; IR (neat, cm-1): 1720, 1730, 2935-3473; mp 64-66 °C; HRMS
Calcd for C14H20O6Na[M+Na]+: 307.1158. Found: 307.1143.
Synthesis of diester 10b and 15b
To a mixture of magnesium (0.28 g) in dry ether (40 mL), methyl iodide (1.90 g)
was added at room temperature under nitrogen to prepare the Grignard reagent. After
one hour of stirring, 2-methyl-2-cyclopentanone 14 (1.00 g, 10.4 mmol) was added to this
mixture in an ice-water bath. The mixture was stirred for 1.5 hours in the ice-water bath
and quenched with a cold saturated ammonium chloride solution. This crude product was
extracted with ether (x 3) and dried with sodium sulfate. After concentration of the
reaction mixture, the crude tertiary alcohol was used for the subsequent Diels-Alder
reaction without further purification. To an ether solution (50 mL) of this alcohol, were
added p-toluenesulfonic acid (~20 mg) and dimethyl fumarate (1.80 g, 1 equivalent) at
0 °C. After being stirred for 3 hours at 0 °C and for 12 hours at room temperature under
nitrogen, the solution was washed with saturated aqueous sodium bicarbonate solution
and brine, and dried over sodium sulfate. After removal of the ether, compound 15b
(0.97 g, 35 %) was isolated by silica gel chromatography (hexane/ethyl acetate = 10/1).
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Texas Tech University, Hanjoung Cho, December 2010
For hydrogenation, 10 % Pd/C (10 % of the weight) was added to the solution of
compound 15b in methanol (5 mL), and the reaction mixture was stirred under H2
atmosphere. After being stirred for 1 day at 55 °C, the mixture was filtered through
Celite, and the solvent was removed with rotary evaporator. The product 10b (0.77 g,
76%) was isolated by column chromatography with an eluent of hexane/ethyl acetate.
Diester 15b
Colorless oil. 1H NMR (300 MHz, CDCl3) δ = 1.23 (6H, dt, J = 2.4, 7.2Hz), 1.39
(1H, m), 1.47 (1H, m), 1.51 (3H, d, J = 1.2 Hz), 1.65 (3H, d, J = 0.9 Hz), 2.70 (1H, dd, J
= 4.8, 1.5 Hz), 2.77 (1H, d, J = 1.5 Hz), 2.97 (1H, q, J = 1.8 Hz), 3.32 (1H, t, J = 4.5 Hz),
4.14–4.02 (4H, m); 13C NMR (75 MHz, CDCl3) δ = 11.6, 13.1, 14.1, 14.2, 45.9, 46.8,
49.3, 51.9, 53.0, 60.3, 60.6, 135.4, 137.7, 173.3, 174.9; IR (neat, cm-1) 1446, 1729, 2977;
HRMS calcd for C15H23O4 [M+H]+: 267.1596, found 267.1600.
Diester 10b
Colorless oil. 1H NMR (300 MHz, CDCl3) δ = 0.75 (3H, d, J = 7.2 Hz), 0.93 (3H,
d, J = 7.2 Hz), 1.23 (6H, m), 1.38 (1H, d, J = 9.6 Hz), 1.51 (1H, dt, J = 1.2, 8.1 Hz), 2.10
(2H, m), 2.36 (1H, d, J = 2.1 Hz), 2.61 (1H, s), 3.15 (2H, s), 4.16–4.02 (4H, m); 13C
NMR (75 MHz, CDCl3) δ = 11.3, 12.0, 14.0, 14.2, 35.0, 35.1, 39.6, 40.5, 46.5, 47.1, 48.7,
60.4, 60.6, 174.1, 175.7; IR (neat, cm-1) 1728, 2963; HRMS calcd for C15H25O4 [M+H]+:
269.1753, found 269.1750.
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Monohydrolysis of diester 10b (entry 4 in Table 3.4)
(exo,endo)-Diethyl bicyclo[2.2.1]hepta-5,6-(endo,endo)-dimethyl diester 13 (161
mg, 0.6 mmol) was dissolved in 1 mL of DMSO and 10 mL of water was added. The
reaction mixture was cooled to 0 oC in an ice-water bath. To this mixture was added 0.25
M KOH aqueous solution (6 mL, 2.5 equivalents) dropwise with stirring. The reaction
mixture was stirred for 3 days, and acidified with 1 M HCl at 0 oC, saturated with NaCl,
extracted with ethyl acetate (×4), and dried over sodium sulfate. This extract was
concentrated in vacuo and purified by silica gel column chromatography with
hexane:ethyl acetate (3:1) and then ethyl acetate as typical eluents to afford its half-esters
11b with 79% isolated yield.
endo-monoethyl bicyclo[2.2.1]hepta-5,6-(endo,endo)-dimethyl carboxylic acid 11b
Colorless oil. 1H NMR (300 MHz, CDCl3) δ = 0.75 (3H, d, J = 7.5 Hz), 0.93 (3H,
d, J = 6.9 Hz), 1.27 (3H, m), 1.42 (1H, dd, J = 9.9 Hz, 1.5 Hz), 1.53 (1H, dt, J = 9.9 Hz,
1.8 Hz), 2.13 (2H, m), 2.45 (1H, d, J = 2.4 Hz), 2.63 (1H, s), 3.11 (1H, m), 3.12 (1H, dd,
J = 6.6 Hz, 1.5 Hz), 4.12 (2H, m); 13C NMR (75 MHz, CDCl3) δ = 11.24, 12.02, 14.04,
34.96, 35.07, 39.75, 40.47, 46.47, 47.36, 48.56, 60.60, 174.06, 180.93; IR (neat, cm-1):
1705, 1715, 2932-3400; mp 75-76 °C; Anal. Calcd for C13H20O4: C, 64.98; H, 8.39.
Found: C, 65.24; H,8.49.
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3.8. References
1.
(a) Brown, H. C.; Kawakami, J. H. J. Am. Chem. Soc. 1970, 92, 1990. (b) Brown, H.
C.; Hammar, W. J.; Kawakami, J. H.; Rothberg, I.; Vander Jugt, D. L. J. Am. Chem.
Soc. 1967, 89, 6381. (c) Brown, H. C.; Kawakami, J. H.; Liu, K.-T. J. Am. Chem.
Soc. 1973, 95, 2209.
2.
Schleyer, P. v. R. J. Am. Chem. Soc. 1967, 89, 701.
3.
(a) Rondan, N. G.; Paddon-Row, M. N.; Caramella, P.; Houk, K. N. J. Am. Chem.
Soc. 1981, 103, 2436. (b) Rondan, N. G.; Paddon-Row, M. N.; Caramella, P.;
Mareda, J.; Mueller, P. H.; Houk, K. N. J. Am. Chem. Soc. 1982, 104, 4974.
4.
Inagaki, S.; Fujimoto, H.; Fukui, K. J. Am. Chem. Soc. 1976, 98, 4054.
5.
(a) Sugimoto, T.; Kobuke, Y.; Furukawa, J. J. Org. Chem. 1976, 41, 1457. (b)
Paquette, L. A.; Kravetz, T. M.; Boehm, M. C.; Gleiter, R. J. Org. Chem. 1983, 48,
1250. (c) Subramanyam, R.; Bartlett, P. D.; Iglesias, G. Y. M.; Watson, W. H.;
Galloy, J. J. Org. Chem. 1982, 47, 4491. (d) Avenati, M.; Vogel, P. Helv. Chim.
Acta 1983, 66, 1279.
6.
Brown, F. K.; Houk, K. N. J. Am. Chem. Soc. 1985, 107, 1971.
7.
(a) Klunder, A. J. H.; van Gastel, F. J. C.; Zwanenburg, B. Tetrahedron Lett. 1988,
29, 2697. (b) Van der Eycken, J.; Vandewalle, M.; Heinemann, G.; Laumen, K.;
Schneider, M. P.; Kredel, J.; Sauer, J. J. Chem. Soc., Chem. Commun. 1989, 306.
8.
Niwayama, S.; Hiraga, Y. Tetrahedron Lett. 2003, 44, 8567.
9.
(a) Niwayama, S. J. Org. Chem. 2000, 65, 5834. (b) Niwayama, S. J. Synth. Org.
Chem., Jpn. 2008, 66, 983.
10.
Niwayama, S.; Wang, H.; Hiraga, Y.; Clayton, J. C. Tetrahedron Lett. 2007, 48,
8508.
11.
Niwayama, S.; Rimkus, A. Bull. Chem. Soc. Jpn. 2005, 78, 498.
12.
Cho, H.; Niwayama, S. 238th American Chemical Society National Meeting,
Washington, DC, August 2009, ORGN 516.
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13.
(a) Niwayama, S.; Cho, H.; Lin, C. Tetrahedron Lett. 2008, 49, 4434. (b)
Niwayama, S.; Cho, H. Chem. Pharm. Bull. 2009, 57, 508.
14.
Crag, D. J. Am. Chem. Soc. 1951, 73, 4889.
15.
Lauria, F.; Vecchietti, V.; Logemann, W.; Tosolini, G.; Dradi, E. Tetrahedron 1969,
25, 3989.
16.
Brown, H. C.; Muzzio, J. J. Am. Chem. Soc. 1966, 88, 2811.
17.
Moreno-Vargas, A. J.; Schutz, C.; Scopelliti, R.; Vogel, P. J. Org. Chem. 2003, 68,
5632.
18.
Maruyama, K.; Tamiaki, H. J. Org. Chem. 1986, 51, 602.
19.
(a) Kikkawa, S.; Nomura, M.; Uno, Y.; Matsubara, M.; Yanagida, Y. Bull. Chem.
Soc. Jpn. 1972, 45, 2523. (b) Yanagida, Y.; Shigesato, H.; Nomura, M.; Kikkawa, S.
Bull. Chem. Soc. Jpn. 1974, 47, 677.
20.
(a) Yanagida, Y.; Shigesato, H.; Nomura, M.; Kikkawa, S. Nihon Kagaku Kaishi
1975, 4, 657. (b) Yanagida, Y.; Yokota, T.; Nomura, M.; Kikkawa, S. Nihon
Kagaku Kaishi 1975, 4, 652.
21.
For example, see: (a) Nishihara, Y.; Inoue, Y.; Nakayama, Y.; Shiono, T.; Takagi,
K. Macromolecules 2006, 39, 7458. (b) Delaude, L.;Demonceau, A.; Noels, A. F.
Macromolecules 2003, 36, 1446. (c) Pollino, J. M.; Stubbs, L. P.; Weck, M.
Macromolecules 2003, 36, 2230.
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CHAPTER 4
THE CONFORMATIONAL ANALYSIS OF SYMMETRIC DIESTERS BY
THEORETICAL CALCULATIONS
4.1. Introduction
The ester group is one of the widely used functional groups in synthetic organic
chemistry. For example, the monohydrolysis of symmetric diester using an enzyme is
widely used in organic synthesis.1 Earlier, we have reported nonenzymatic and selective
monohydrolyses of symmetric diesters in THF and water media.2
To date, a limited number of theoretical studies on symmetric molecules including
diamides3, and diesters4 have been reported. These studies, however, have been
performed at the HF level3,4b, focused on folding3a,4a of methylene units which are
connected in two carbonyl groups, i.e., dimethyl succinate, and interacting between
carbonyl group and solvent.4a
In general, the reaction of acyclic molecules proceeds with low stereoselectivity
due to their conformational flexibility. However, when the two carbonyl groups are
located closely, conformational bias such as A or B in Figure 4.1 has been proposed in
some cases.2,5 These electrostatic interactions can provide conformational distinction
between two carbonyl groups, which might allow control of the selectivity of these
reactions.
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Figure 4.1 Possible electrostatic interactions between two carbonyl groups
For example, in our previous research about monohydrolysis of symmetric
diesters,2 the reactivity of monohydrolysis of dimethyl fumarate and dimethyl maleate is
quite different. Since two carbonyl groups are located on the different side in dimethyl
fumarate and dimethyl maleate, we could assume that the reactivity of monohydrolysis of
symmetric diesters might be determined by the conformational difference of the
symmetric diesters (Scheme 4.1).2 This conformational restriction might play an
important role for the difference of the selectivity for monohydrolysis of dimethyl
fumarate and dimethyl maleate.2
Scheme 4.1 Selective monohydrolysis of dimethyl maleate and dimethyl fumarate
Recently, some examples of electrostatic interaction (n→π*interaction) between
two carbonyl groups have been reported.6 Since this interaction has been used in
elucidation of protein structures, the theoretical studies of electrostatic interaction need to
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be extended into symmetric organic diesters in this context. Furthermore, as the
electrostatic interaction between two carbonyl groups might have a key role in the
selectivity in monohydrolysis, the conformational calculations were performed by density
functional theory (DFT) and Møller-Plesset perturbation theory (MP2) levels.7 These
studies could provide insight into molecular and structural parameters and most stable
conformers and their chemical behaviors. In this chapter, the conformational studies with
dimethyl maleate 1, dimethyl bicyclo[2.2.1]hepta-2-ene dicarboxylate 2, and dimethyl
succinate 3 will be discussed.
Figure 4.2 Structures of diesters which are investigated by theoretical methods
4.2. Calculation method
There are two general conformational structures for ester groups. One is the (Z)conformation which allocate the same direction with carbonyl oxygen and carboalkoxy
groups and another is the (E)-conformation which is vice versa. As mentioned in Chapter
1, there are several factors which can stabilize the (Z)-conformation such as the
interaction between the lone pair of oxygen in –OCH3 group and the σ* orbital8 of C=O
and the electrostatic interaction between the local dipole moments9, only the (Z)conformation on both sides of ester groups was considered in all our calculations.
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Figure 4.3 Possible conformations of an ester functional group
Two dihedral angles that were assigned to φ and  on symmetric diesters were
concerned in order to study conformational studies. For dimethyl maleate 1, φ angle
consists of C3=C2–C1=O1 and  angle is the dihedral angle with C2=C3–C4=O3 and same
dihedral angles selected for bicyclic diester 2 and dimethyl succinate 3 as well (Figure
4.4).
Figure 4.4 Two important dihedral angles (, ) in dimethyl maleate 1, bicyclic diester 2,
and dimethyl succinate 3
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For geometric optimization of dimethyl maleate 1 and bicyclic diester 2, seven
possible structures for dimethyl maleate 1 and nine structures of bicyclic diester 2 were
first considered at the level of B3LYP/6-31G(d), respectively. While dimethyl maleate 1
is symmetrical through the C2 mirror plane, the C2 mirror plane does not exist in bicyclic
diester 2. Therefore, more structures of bicyclic diester 2 should be required for energy
comparison. After geometry optimization was performed at certain dihedral angles, we
compared electronic energies for the possible structures of dimethyl maleate 1 and
bicyclic diester 2 at the level of MP2/6-31G(d)//B3LYP/6-31G(d) level. After the stable
geometries were found, the potential energy curve for the φ (C3=C2–C1=O1) dihedral
angle was obtained to gain insight into the conformational behavior at the level of
MP2/6-31G(d)//B3LYP/6-31G(d) while fixing  (C2=C3–C4=O3) dihedral angle to be 0°
and optimizing the geometries at every 10° of dihedral angle φ (C3=C2–C1=O1) for
dimethyl maleate 1 and dimethyl bicyclic diester 2. The full geometric optimizations for
dimethyl succinate 3 was explored by B3LYP/6-31G(d)10 levels based on possible
structures which can be expected and published before at the level of HF calculations.4
Since the molecular size of dimethyl bicyclic diester 2 is larger than dimethyl
maleate 1 and dimethyl succinate 3, initial geometrical parameters were based on X-ray
crystal data which we previously reported.11 All geometrical parameters except two
dihedral angles were fully optimized at the RHF/6-31G(d) and B3LYP/6-31G(d) levels
without any symmetric constraints, and then the single point energy calculation was
performed at the MP2/6-31G(d) levels. The same computational methods which were
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applied to dimethyl maleate 1 were used for obtaining the potential curve with the variant
size of dihedral angle.
We also investigated conformational preferences of dimethyl succinate 3 with the
density functional theory levels. As six stable structures of dimethyl succinate 3 were
reported at the level of HF,4a we expanded these geometries by the density functional
theory level and analyzed the interaction of two carbonyl groups the interaction of two
carbonyl groups in dimethyl succinate 3 with electron density. All calculations have been
performed by using GAUSSIAN 98.12
4.3. Conformational studies on dimethyl maleate 1
We began the geometry optimization of possible conformers of dimethyl maleate
and performed MP2 single point energy calculations with 6-31G(d) basis set. The
optimized structures are shown in Figure 4.5. The electronic interaction between the
carbonyl oxygen and the carbon on the other carbonyl group can exist in structures I and
II and these interactions may stabilize the electronic energy of dimethyl maleate 1. Even
though the steric interference between two carbonyl groups is minimized in structures VI
and VII, the relative electronic energies are higher than those of structures III, IV, and V
where the electrostatic repulsion could exist between two oxygens in both of the carbonyl
groups.
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Structure I
Structure II
Structure III
Structure IV
Structure V
Structure VI
Structure VII
Figure 4.5 Optimized structures of dimethyl maleate 1 at the selected dihedral angles by
the B3LYP/6-31G(d) level
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Table 4.1 Electronic energies of possible structures of dimethyl maleate 1 at the level of
the B3LYP/6-31G(d)//B3LYP/6-31G(d) and MP2/6-31G(d)//B3LYP/6-31G(d)
Electronic energies (hartree)a
a
B3LYP/6-31G(d)//B3LYP/6-31G(d)
MP2/6-31G(d)//B3LYP/6-31G(d)
I
-534.3348811 (0)
-532.7750221 (0)
II
-534.3329586 (1.2)
-532.7732218 (1.1)
III
-534.3309525 (2.5)
-532.7690714 (3.7)
IV
-534.3310388 (2.4)
-532.7683674 (4.2)
V
-534.3288994 (3.8)
-532.7657880 (5.8)
VI
-534.3222878 (7.9)
-532.7636162 (7.2)
VII
-534.3229649 (7.5)
-532.7629878 (7.6)
The values in the parentheses refer to relative electronic energies (kcal/mol).
The total and relative energies of the structures are summarized in Table 4.1. When
one of the carbonyl groups is located at the perpendicular position and the other carbonyl
group is at the planar where the carbonyl oxygen interacts with the carbonyl carbon
(Structure I), the geometry in the Structure I of dimethyl maleate 1 is stable as a point of
an electronic energy. The structures VI and VII which have the least steric hindrance are
destabilized by 8.5 and 8.9 kcal/mol at the MP2/6-31G(d)//B3LYP/6-31G(d) level,
respectively. Therefore, we concluded that the geometries which have electrostatic
attractive interaction, e.g. structures I and II, have the lowest energies among the possible
geometries of dimethyl maleate 1.
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From these results, we concluded that the geometry of dimethyl maleate 1 has the
lowest energy when one of the two carbonyl groups is planar and the other is
perpendicular with respect to the C=C bond. In order to obtain insight into the
conformational behavior, we have performed calculations about the electronic energy
surfaces while the dihedral angle of one of the carbonyl groups changes every 10 degrees.
We calculated at the MP2/6-31G(d)//B3LYP/-31G(d) level the potential energy curve for
the φ dihedral angle (C3=C2–C1=O2) of dimethyl maleate 1 while fixing the other ,
C2=C3–C4=O3 skeleton to be planar (0°) and optimizing the structures at every 10° of the
C3=C2–C1=O2 dihedral angle. The obtained C3=C2–C1=O2 dihedral potential energy
curve is shown in Figure 4.6. One can find that there are two energy minima at the
C3=C2–C1=O2 dihedral angle of –100° and 100°. In Table 4.2, we showed electronic and
relative energies, calculated at the B3LYP/6-31G(d)//B3LYP/6-31G(d) and MP2/631G(d)//B3LYP/6-31G(d) levels.
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Figure 4.6 Potential energy curve for φ (C3=C2–C1=O2) torsion at  (C2=C3–C4=O3) = 0°
in dimethyl maleate 1 calculated at the MP2/6-31G(d)//B3LYP/6-31G(d) level
Table 4.2 Electronic energies with selected dihedral angles (deg) on the B3LYP/631G(d)//B3LYP/6-31G(d) and MP2/6-31G(d)//B3LYP/631G(d) optimized structures of
dimethyl maleate 1
φ
a
Electronic energies (hartree)a
B3LYP/6-31G(d)//B3LYP/6-31G(d)
MP2/6-31G(d)//B3LYP/6-31G(d)
–100
-534.3352406 (0)
-532.7752779 (0)
0
-534.3309525 (2.7)
-532.7690714 (3.5)
100
-534.3352404 (0.00013)
-532.7752860 (-0.0051)
The values in the parentheses refer to relative energies (kcal/mol)
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Based on the geometry of dimethyl maleate 1 at the minimum point (φ = –100°, 
= 0°) at the level of B3LYP/3-61G(d), the fully optimized geometry of dimethyl maleate
1 was found at the level of B3LYP/6-31G(d) and the structure is shown in Figure 4.7. In
the optimized structure, we found that one of the dihedral angles is –111.2° (, C3=C2–
C1=O2) and the other angle is 8.3° (, C2=C3–C4=O3). These dihedral angles show that
one carbonyl group is near to perpendicular (–111.2°) along the plane that consists of C2,
C3, and each carbonyl carbon (C1 or C4) and the other carbonyl group is near to planar
(8.3°) with the same plane. This specific geometry might explain about electrostatic
interaction between the two carbonyl groups which was mentioned before.
In the optimized structure of dimethyl maleate 1, the distance between C1 and O3 is
2.850 Å (Figure 4.7). This distance between the carbonyl carbon and the oxygen suggests
that the carbonyl π* orbital of the perpendicular CO2CH3 group might have the attractive
interaction with the carbonyl oxygen lone pair of the planar CO2CH3 group. The
Mulliken overlap population in parentheses indicates that the bonding interaction should
be in C1 and O3 (Figure 4.7).13
Figure 4.7 The fully optimized structure of dimethyl maleate 1 by B3LYP/6-31G(d)
calculations (top and side view)
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4.4. Conformational studies on dimethyl bicyclo[2.2.1]hepta-2-ene diester 2
In order to compare the conformations of two carbonyl groups in diesters with
bulky groups, we investigated geometries and conformational energies of bicyclic diester
2 that is relatively more rigid and larger than dimethyl maleate 1. In the bicyclic diesters,
the nine geometries were optimized with the two dihedral angles (φ and ) fixed to be
planar and perpendicular with respect to the C=C bond at the level of B3LYP/6-31G(d)
(Figure 4.8).
Structure I
Structure II
Structure III
Structure IV
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Structure V
Structure VI
Structure VII
Structure VIII
Structure IX
Figure 4.8 Optimized structures of bicyclic diesters 2 at the selected dihedral angles by
the B3LYP/6-31G(d) level
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Table 4.3 Electronic energies of possible structures of bicyclic diester 2 at the level of the
B3LYP/6-31G(d)//B3LYP/6-31G(d) and MP2/6-31G(d)//B3LYP/6-31G(d)
Electronic energies (hartree)a
a
B3LYP/6-31G(d)//B3LYP/6-31G(d)
MP2/6-31G(d)//B3LYP/6-31G(d)
I
-995.6532314 (0)
-992.6745922 (0)
II
-995.6527696 (0.29)
-992.6743956 (0.12)
III
-995.6520931 (0.71)
-992.6738775 (0.45)
IV
-995.6523219 (0.57)
-992.6737655 (0.52)
V
-995.6500716 (2.0)
-992.6704069 (2.6)
VI
-995.6485267 (3.0)
-992.6696903 (3.1)
VII
-995.6494152 (2.4)
-992.6694150 (3.3)
VIII
-995.6425988 (6.7)
-992.6646818 (6.2)
IX
-995.6414521 (7.4)
-992.6638061 (6.8)
The values in the parentheses refer to relative energies (kcal/mol)
The total and relative energies to structures of bicyclic diesters are summarized in
Table 4.3. The most stable structure of bicyclic diester 2 (Structure I) has the two
carbonyl groups where one of them is perpendicular and the other is planar with respect
to C=C. This geometry in Structure I is a similar conformation to dimethyl maleate 1.
The structures VIII and IX which have the least steric hindrance are destabilized by 6.2
and 6.8 kcal/mol at the MP2/6-31G(d) level, respectively. Therefore, we concluded that
the geometries that have electrostatic attractive interaction, e.g. structures I and II, have
the lowest energies among the possible geometries of bicyclic diesters 2. These
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conformations also show the electrostatic interaction between two carbonyl groups and
have the similar patterns in dimethyl maleate as well 1.
Based on the structure I, we calculated at the MP2/6-31G(d)//B3LYP/6-31G(d)
level the potential energy curve for the φ, C3=C2–C1=O2 dihedral angle of bicyclic diester
2 while fixing the other , C2=C3–C4=O3 angle to be planar and optimizing the structures
at every 10° of the C3=C2–C1=O2 dihedral angle and the potential energy surfaces by
MP2/6-31G(d)//B3LYP/6-31G(d) is shown in Figure 4.9.
Figure 4.9 Potential energy curve for φ (C3=C2–C1=O2) torsion at  (C2=C3–C4=O3) = 0°
in bicyclic diester 2 calculated at the MP2/6-31G(d)//B3LYP/6-31G(d) level
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From the energy potential curve, we found that the energy profile curve was not
symmetrical. Since the bulky groups on C2–C3 are in bicyclic diester 2, the steric
interference with those bulky groups and carbonyl groups might affect these differences.
Table 4.4 Electronic energies with selected dihedral angles (deg) on the B3LYP/631G(d)//B3LYP/6-31G(d) and MP2/6-31G(d)//B3LYP/631G(d) optimized structures of
bicyclic diester 2
Electronic energies (hartree)
φ
a
B3LYP/6-31G(d)//B3LYP/6-31G(d)
MP2/6-31G(d)//B3LYP/6-31G(d)
–60
-995.6519970 (1.4)
-992.6738815 (1.1)
0
-995.6485267 (3.6)
-992.6696903 (3.7)
110
-995.6542023 (0)
-992.6755626 (0)
The values in the parentheses refer to relative energies (kcal/mol)
We used these two dihedral angles to find the optimized structures of bicyclic
diester 2 at the level of B3LYP/6-31G(d). The fully optimized structure is shown in
Figure 4.10.
Figure 4.10 Geometric optimized structure of dimethyl bicyclo[2.2.1]hept-2-ene
dicarboxylate 2 by B3LYP/6-31G(d) at the lowest energy
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To explain the electronic interaction between the two carbonyl groups, the spatial
distance between the carbonyl carbon and one of the oxygens in the other carbonyl group
might be important. The optimized structure of diester 2 has the distance, 3.030 Å for C1–
O3. This distance is slightly longer than that of C1–O3 (2.850 Å ) in dimethyl maleate 1.
These differences might be explained by the bulky groups which connect with alkene
(C2=C3). As the structure of dimethyl maleate 1 has only double bond itself without any
neighboring groups, dimethyl maleate 1 can be flexible for molecular motion. The two
dihedral angles (, ) which might explain the extent of tilting on C2=C3 bond are 117.2°
of φ (C3=C2–C1=O2) and –4.3° of  (C2=C3–C4=O3) for bicyclic diester 2.
We also compared the optimized structure (Figure 4.10) with one of the X-ray
crystal structures which were previously reported.11 Both of the crystal structures have
geometries that include the electrostatic interactions between two carbonyl groups. One
of the X-ray crystal structures are shown in Figure 4.11. The electrostatic interaction
between the carbonyl oxygen and the carbonyl carbon are also found in the X-ray crystal
structure. This reported crystal structure has the similar interaction with the stable
geometry in Figure 4.10. In order to compare the calculated structure with the X-ray
crystal structure, the two dihedral angles and the distance between the oxygen and the
carbon in the different carbonyl groups were analyzed. While two dihedral angles have
117.2° of φ (C3=C2–C1=O2) and –4.3° of  (C2=C3–C4=O3) in the optimized structure of
bicyclic diester 2 at the level of B3LYP/6-31G(d), the crystal structure has 102.5° of φ
(C3=C2–C1=O2) and 13.3° of  (C2=C3–C4=O3), respectively. The distance between O3
and C1 is 3.030 Å in the calculated structure and 3.002 Å in the crystal structure. The
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similarity of geometries between the calculated structure and the crystal structure might
be the evidence for supporting the electronic interaction between the two carbonyl groups
in the diesters.
Figure 4.11 The X-ray crystal structure of bicyclic diester 2
4.5. Conformational studies on dimethyl succinate 3
The optimized structures of dimethyl succinate 3 at the level of B3LYP/6-31G(d)
are shown in Figure 4.12. Six possible structures were obtained and their dihedral angles
and relative electronic energies are summarized in Tables 4.5 and 4.6, respectively.
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Structure I
Structure II
Structure III
Structure IV
Structure V
Structure VI
Figure 4.12 The optimized structure of dimethyl succinate 3 at the level of B3LYP/631G(d)
We found that structure I has the most stable structure among 6 geometries.
Interestingly, structure I has lower energies than structure II which has less steric
hindrance between two carbonyl groups at the level of MP2/6-31G(d), which is
consistent to the previous studies.4a Structure II has an all-trans conformation and is
destabilized by 0.55 kcal/mol with respect to the lowest energy at the MP2/6-31G(d)
level.
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Table 4.5 Selected dihedral angles (deg) of dimethyl succinate 3 at the level of B3LYP/631G(d)
I
II
III
IV
V
VI
C–O1–C1(=O2)–C2
-179.5
-179.8
-179.9
-178.2
179.1
-176.1
O1–C1(=O2)–C2–C3
-168.5
-178.9
-178.5
-168.9
20.6
73.1
68.9
-178.6
62.6
-175.0
59.2
59.7
C2–C3–C4(=O3)–O4
-167.9
-178.8
25.6
52.0
20.7
73.6
C3–C4(=O3)–O4–C
-179.5
-179.8
179.7
178.9
179.1
-176.1
C1(=O2)–C2–C3–C4(=O3)
Table 4.6 Electronic energies of possible structures of dimethyl succinate 3 at the level of
the B3LYP/6-31G(d)//B3LYP/6-31G(d) and MP2/6-31G(d)//B3LYP/6-31G(d)
Electronic energies (hartree)a
B3LYP/6-31G(d) //B3LYP/6-31G(d)
MP2/6-31G(d)// B3LYP/6-31G(d)
a
I
-535.5764577 (0.0)
-533.9860797 (0.0)
II
-535.5756253 (0.5)
-533.9836647 (1.5)
III
-535.5741647 (1.4)
-533.9843036 (1.1)
IV
-535.5738137 (1.7)
-533.9823168 (2.4)
V
-535.5723677 (2.6)
-533.9828189 (2.0)
VI
-535.5717016 (3.0)
-533.9821339 (2.5)
The values in the parentheses refer to relative energies (kcal/mol)
The optimized structure which is showing the lowest energy minimum is shown in
Figure 4.13. The Mulliken overlap population shown in parentheses indicates that there is
a bonding interaction.
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Figure 4.13 Geometric optimized structures of dimethyl succinate 3 by B3LYP/6-31G(d)
There are two possible interactions between the carbonyl carbon and the carbonyl
oxygen. These electrostatic interactions depend on the distance and electronic charges.
We found that the distance of C1–O3 is 3.160 Å and C4–O2 is 3.172 Å and are slightly
longer than those of dimethyl maleate 1 (2.850 Å ) and bicyclic diester 2 (3.030 Å and
3.352 Å ) because the bond length at C2–C3 in dimethyl succinate 3 is longer than at
C2=C3 in diesters 1 and 2.
4.6. Conclusion
We have investigated the conformational bias of two dihedral angles in several
symmetric diesters. The quantum mechanical calculations were performed on dimethyl
maleate 1, dimethyl bicyclic diester 2, and dimethyl succinate 3 all of which have the two
symmetric dimethyl diester groups. The theoretical studies showed that two carbonyl
groups in 1,2-diesters have electrostatic interactions. In the dimethyl maleate and bicyclic
diesters, one of the carbonyl groups at the perpendicular position and the other carbonyl
group is close to planar with respect to the carbon and carbon double bond. Even though
this pattern was not found in the structure of dimethyl succinate 3, the electrostatic
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interaction was also found with a different conformation of carbonyl groups in dimethyl
succinate 3. We found that these theoretical studies of diesters revealed the distinction of
two carbonyl groups in symmetric diesters with electrostatic properties.
4.7. References
1.
(a) Chenevert, R.; Dickman, M. J. Org. Chem. 1996, 61, 3332. (b) Matsumoto, T.;
Konegawa, T.; Yamaguchi, H.; Nakamura, T.; Sugai, T.; Suzuki, K. Synlett 2001,
10, 1650. (c) Lane, J. W.; Halcomb, R. L. J. Org. Chem. 2003, 68, 1348.
2.
Niwayama, S. J. Org. Chem. 2000, 65, 5834.
3.
(a) Navarro, E.; Alemán, C.; Puiggalí, J. J. Am. Chem. Soc. 1995, 117, 7307. (b)
Alemán, C.; Navarro, E.; Puiggali, J. J. Org. Chem. 1995, 60, 6135.
4.
(a) Alemán, C.; Puiggalí, J. J. Org. Chem. 1997, 62, 3076. (b) Akakura, M.; Koga,
N. Bull. Chem. Soc. Jpn. 2002, 75, 1785.
5.
Yamamoto, Y.; Nemoto, H.; Kikuchi, R.; Komatsu, H.; Suzuki, I. J. Am. Chem. Soc.
1990, 112, 8598.
6.
(a) Choudhary, A.; Gandla, D.; Krow, G. R.; Raines, R. T. J. Am. Chem. Soc. 2009,
131, 7244. (b) Hodges, J. A.; Raines, R. T. Org. Lett. 2006, 8, 4695.
7.
Møller, C.; Plesset, M. S. Phys. Rev. 1934, 46, 618.
8.
Hermann, A.; Trautner, F.; Gholivand, K.; von Ahesen, S.; Varetti, E. L.; Della
Vedova, C. O.; Willner, H.; Oberhammer, H. Inorg. Chem. 2001, 40, 3979.
9.
Evanseck, J. D.; Houk, K. N.; Briggs, J. M.; Jorgensen, W. L. J. Am. Chem. Soc.
1994, 116, 10630.
10.
(a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648. (b) Becke, A. D. Phys. Rev. A 1998,
38, 3098.
11.
Niwayama, S.; Inouye, Y.; Eastman, M. Tetrahedron Lett. 1999, 40, 5961.
12.
Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A.; Stratmann, R. E.; Burant,
J. C.; Dapprich, S.; Millam, J. M.; Daniels, A. D.; Kudin, K. N.; Strain, M. C.;
121
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Farkas, O.; Tomasi, J.; Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli,
C.; Adamo, C.; Clifford, S.; Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.;
Morokuma, K.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.;
Cioslowski, J.; Ortiz, J. V.; Baboul, A. G.; Stefanov, B. B.; Liu, G.; Liashenko, A.;
Piskorz, P.; Komaromi, I.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; AlLaham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.;
Johnson, B.; Chen, W.; Wong, M. W.; Andres, J. L.; Gonzalez, C.; Head-Gordon,
M.; Replogle, E. S.; Pople, J. A. GAUSSIAN 98, Revision A. 3. Gaussian,
Pittsburgh, PA, 1998.
13.
Mulliken, R. S. J. Chem. Phys. 1955, 23, 1833.
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CHAPTER 5
ASYMMETRIC MONOHYDROLYSIS OF SYMMETRIC DIESTERS WITH
CHIRAL IONIC LIQUIDS
5.1. Introduction
Enantioselective desymmetrization of meso compounds is a powerful synthetic
means of preparing enantiomerically enriched products, enabling the conversion of cheap
starting materials into more expensive ones. Examples of substrates for enantioselective
desymmetrization reactions include epoxides, aziridines, cyclic anhydrides, and diesters.1
Enzymatic desymmetrization reactions are also powerful tools in the development of
methodologies for the asymmetric synthesis of a variety of natural products.1e
Enantiomerically enriched half-esters of norbornene derivatives are very versatile
building blocks for the synthesis of natural products. To date, only a limited number of
synthetic methods for preparing half-ester of norbonane derivatives with high
enantiomeric excess were reported.2 One of the reported methods was enantioselective
methanolytic desymmetrization of cyclic anhydrides with a bifunctional organocatalyst
(Scheme 5.1).3
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Scheme 5.1 Enantioselective methanolysis of the bicyclic meso anhydride 1 with catalyst
3
The half-ester was obtained with high yield and excellent enantiomeric excess
through the methanolytic desymmetrization of cyclic anhydrides and enzymatic
asymmetric hydrolysis. However, as the methanolytic desymmetrization of cyclic
anhydrides requires high cost and is limited to cis anhydride substrates, and there were no
systematic studies for predicting reactivity or enantioselectivity in enzymatic asymmetric
hydrolysis reactions, the development of asymmetric desymmetrization is essential.
Ionic liquids are low melting organic salts in the liquid state at room temperature.
In recent, ionic liquids have been established as alternatives to organic solvents and as
new reaction media for chemical reactions and separation techniques.4 Since the first
example of a chiral ionic liquid was reported in 1997 by Howarth et al.,5 the research on
chiral ionic liquids grew rapidly.
Chiral solvents have already been used as an inducer of chirality in asymmetric
synthesis.6 However, chiral solvents require high cost and complicated preparation. Thus
chiral ionic liquids have the potential to produce chiral environment and could overcome
some of these complications. The comparable simple synthesis and the possibility for
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Texas Tech University, Hanjoung Cho, December 2010
recycling suggest that chiral ionic liquids could improve the application of chiral solvents
in asymmetric synthesis.
A chiral ionic liquid was also used in the asymmetric hydrolysis of esters. The
enzymatic hydrolysis of phenylalanine methyl ester in aqueous solutions of CILs carrying
anions of chiral α-amino acids is shown in Scheme 5.2.7 The protease activity was
stabilized and moderate to high enzyme enantioselectivities could be observed.
Scheme 5.2 Enantioselective hydrolysis of ester with enzyme in a chiral ionic liquid
Therefore, we are currently investigating the asymmetric monohydrolysis of
symmetric diesters using proline-based chiral ionic liquids.
5.2. Monohydrolysis of a symmetric diester in ionic liquids
Since the reactivity of selective monohydrolysis of symmetric diesters with an
alkali base could be affected by the choice of co-solvents,8 we have initially investigated
the reactivity of monohydrolysis of symmetric diesters with imidazolium-based ionic
liquids 2 and 3 as co-solvents. We found that ionic liquids with chloride and imidazolium
salts showed better reactivity than hexafluorophosphate and imidazolium salt in the
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Texas Tech University, Hanjoung Cho, December 2010
monohydrolysis, perhaps due to high ionic mobility in chloride organic salts rather than
hexafluorophosphate salts.9 Furthermore, we found that ionic liquids can serve as cosolvent in the monohydrolysis of symmetric diesters with aqueous KOH and tetrabutyl
ammonium hydroxide as well. (Table 5.1)
Table 5.1 Selective monohydrolysis of bicyclic diester with ionic liquids
Entry
Ionic
liquid
Time
(h)
Yield
(1a, %)
Recovered diester
(%)
1
2 (0.5 g)
10 mL KOH (1.67 eq.)
3
90.1
8.0
2
2 (1.0 g)
0 mL KOH (1.67 eq.)
6
47.2
48.8
3
3
(0.5 mL)
10 mL
KOH (1.67 eq.)
1
0
95
4
3
(0.5 mL)
0 mL
TBAH (2.0 eq.)
6
26.7
20
water
Base
5.3. Asymmetric monohydrolysis in chiral ionic liquids
The asymmetric monohydrolysis in a chiral ionic liquid (organic salt) are
summarized in Table 5.2. The role of the chiral ionic liquid 2 in asymmetric
monohydrolysis of symmetric diesters was found from entries 1 and 2. The
monohydrolysis without chiral ionic liquid 2 produced half-ester as racemate (entry 1)
and the addition of chiral ionic liquid 2 as solvent induced enantiomeric excess to 2.4 %.
Interestingly, the enantioselectivity enhanced to 14% with the use of aqueous potassium
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Texas Tech University, Hanjoung Cho, December 2010
hydroxide as base instead of organic base, TBAH. These results showed that the ratio of
asymmetric transformation can improve in the aqueous media with alkali base in
selective monohydrolysis.
Table 5.2 Asymmetric monohydrolysis of bicyclic diester 1 under chiral ionic liquid 2
a
Entry
CIL 2
Base
Time
1
0
TBAH
(2.0 eq.)
1h
2
1.67
eq.
3
4
Temp
Solvent
(°C)
Yield
(%)
Diacid Recovered ee
(%) diester (%) (%)a
rt
no
18
82
0
0
TBAH
1.5 h
(2.0 eq.)
0
no
64
36
0
2
1.67
eq.
TBAHb
(1.5 eq.)
2h
rt
no
60
40
0
4
1.67
eq.
aq. KOH
2h
(1.5 eq.)
0
water
100
0
0
14
Enantiomeric excess was analyzed by GC with chiral Cyclosil-B column.
5.4. The scope for asymmetric monohydrolysis with chiral ionic liquids
The preliminary data for asymmetric monohydrolysis in chiral ionic liquids were
established. Even though the moderate enantiomeric excess was obtained with prolinebased chiral ionic liquids, we found that a chiral ionic liquid as solvent could induce
asymmetric transformation for enantioselective monohydrolysis of symmetric diesters.
According to our previous reports,10 the reactivity and selectivity can be determined by
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Texas Tech University, Hanjoung Cho, December 2010
the factor of hydrophobicity of symmetric diesters. For example, diesters with aromatic
groups have the potential to interact with hydrophobic portion of chiral ionic liquid, and
these interactions may induce asymmetric transformation (Scheme 5.3). The development
of asymmetric monohydrolysis by modification of diesters or chiral ionic liquids is
underway.
Scheme 5.3 Proposed asymmetric monohydrolysis of symmetric diesters with chiral ionic
liquids
5.5. Experimental section
All solvents, unless otherwise stated, were used without further purification.
Melting points were measured on an electrothermal capillary instrument (MEL-TEMP® )
and were uncorrected. NMR spectra were recorded on a Varian Unity Plus 300 or a
Varian Mercury Plus 300 spectrometer at 300 and 125 MHz for 1H and 13C, respectively.
Trimethylsilane (TMS, δ = 0) or the residual solvent peak (CDCl3, δ = 7.24) used as a
shift reference for 1H NMR spectra, and chemical shift for solvent peak (CDCl3, δ =
77.00) served as a reference for 13C NMR spectra. IR spectra were recorded on a Nicolet
IR100 FT-IR spectrometer. Gas chromatography (GC) system has Shimadzu GC-17A
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with plotter, C-R8aA. The chiral column, Cyclosil-B, was purchased from Agilent
Technologies. The dimension of this chiral column is 30 m (length), 0.250 mm of ID, and
0.25 μm (film). The enantiomeric excess was measured at 250 °C for injector, 155 °C for
column, and 250 °C for detector. The calibration of enantiomeric excess was pefromed
with racemic half-ester. Thin layer chromatography (TLC) was performed using
precoated aluminum backed TLC plates, silica gel 60, F254 (EMD Chemicals). Flash
silica gel chromatography was performed with Silica Gel, 230–400 mesh.
Synthesis of proline based chiral ionic liquid
To a solution of anhydrous THF (70 mL) and lithium aluminum hydride (39 mL,
1.0 M THF solution), L-proline 1 (2.878 g, 25 mmol) was added in small portions at 0 °C.
The reaction mixture was stirred for one hour at reflux temperature. After this time 20%
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Texas Tech University, Hanjoung Cho, December 2010
KOH (5 mL) was added a dropwise with dropping funnel with ice bath. The mixture was
filtered through Celite and dried overnight with anhydrous sodium sulfate. After volatile
organic solvent was removed under reduced pressure, the crude product was obtained as
99% yield and used without further purification.
To a stirred solution of crude product (2) in dichloromethane (25 mL) and 1 N
NaOH (25 mL) was added dropwise di-t-butyldicarbonate (5.456 g, 25 mmol). After
stirring overnight at room temperature, the organic layer was separated, washed with
water and dried over anhydrous sodium sulfate. Removal of the solvent under reduced
pressure gave 3 as an oil.
N-Boc-L-prolinol 3 (4.5 g, 22 mmol) was dissolved in 50 mL of anhydrous
pyridine, and cooled down to 0 °C for 6 hours. After this time, the reaction mixture was
diluted with ethyl acetate and washed with 1 M HCl, saturated NaHCO3 and, finally,
water. The organic layer was dried with sodium sulfate, filtered and concentrated under
reduced pressure, yielding colorless oil. The product 4 was purified and isolated with
silica column chromatography with hexane/ethyl acetate (3:1) solvent.
Compound 5
Imidazole (313 mg, 4.5 mmol) and NaH (140 mg, 96%, 5.635 mmol) were added
to 15 mL of anhydrous acetonitrile and stirred at room temperature for 0.5 h, then
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Texas Tech University, Hanjoung Cho, December 2010
compound 4 (800 mg, 2.24 mmol) was added. The mixture was heated at reflux for 5 h
under nitrogen atmosphere and then cooled to room temperature. The crude mixture was
concentrated under reduced pressure and diluted with water. The resulted mixture was
extracted with chloroform and the collected organic layer was dried with sodium sulfate.
The residue was purified by flash chromatography on silica gel (EtOAc/Hexane = 5 : 1)
to give coupled product 5 as colorless solid (453 mg, 80%).
[α]Drt = -128.0° (c=1.0, CHCl3); 1H NMR (300 MHz, CDCl3): δ = 1.27-1.28 (1H, m),
1.48 (9H, s), 1.60-1.75 (2H, br), 1.89-1.94 (1H, m), 3.14-3.37 (2H, m), 3.99-4.08 (2H, m),
4.22-4.26 (1H, m), 6.87 (1H, s), 7.04 (1H, s), 7.44 (1H, s); 13C NMR (75 MHz, CDCl3): δ
= 23.3, 28.5, 29.1, 47.0, 48.6, 57.2, 79.8, 119.9, 129.4, 137.7, 162.3.
Compound 7
Under nitrogen, compound 5 (500 mg, 2.0 mmol) and n–butylbromide (548 mg, 4
mmol) were added in 10 mL of anhydrous toluene. The solution was stirred at 70 °C for
24 hours. The solvent was removed under vacuo and the residue was purified by flash
chromatography on silica gel (EtOAc/MeOH = 20 : 1) to afford a pale yellow viscous
liquid 6 (572mg, 93%). The obtained compound 6 in 5 mL of ethyl acetate was
deprotected in 4 M HCl water solution (8mL) and concentrated under vacuum to give the
hydrogen chloride salt, which was subsequently neutralized in saturated NaHCO3
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solution. The aqueous solution was evaporated to dryness in vacuo and the solid residue
was extracted with chloroform and the combined organic layer was dried and
concentrated under reduced pressure to give chiral ionic liquid 7.
[α]Drt = +25.5° (c=1.0, CHCl3); IR (neat, cm–1): 3428, 2961, 1562, 1401, 1083;1H NMR
(300 MHz, CDCl3): δ = 0.88 (3H, t, J= 7.5 Hz), 1.26-1.33 (3H, m), 1.63-1.65 (2H, m),
1.77-1.82 (2H, m), 1.90-1.93 (1H, m), 2.78-2.86 (2H, m), 3.49-3.52 (1H, m), 3.89-3.97
(1H, m), 4.12-4.22 (3H, m), 7.27 (1H, s), 7.47 (1H, s), 8.97 (1H, s); 13C NMR (75 MHz,
CDCl3): δ = 13.3, 19.4, 25.9, 29.0, 31.9, 46.5, 49.7, 54.3, 57.4, 121.5, 123.3, 136.1.
5.6.References
1.
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(a) Song, Y.-M.; Choi, J. S.; Yang, J. W.; Han, H. Tetrahedron Lett. 2004, 45, 3301.
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(a) Rogers, R. D.; Seddon, K. R. Science 2003, 302, 792. (b) Welton, T. Chem. Rev.
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Howarth, J.; Hanlon, K.; Fayne, D.; McCormac, P. Tetrahedron Lett. 1997, 38,
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Seebach, D.; Oei, H. A. Angew. Chem. Int. Ed. Engl. 1975, 14, 634.
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