6-Membered Rings
Ways of constructing 6-membered ring
1. Diels-Alder reaction
2. O-Quinodimethanes
3. Intramolecular ene reaction
4. Cation olefin cyclization
5. Robinson annulation
6. Ring closing metathesis
7. Enyne metathesis
09/04/12 CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Pericyclic Reactions
Ø  Pericyclic reaction involves a cyclic redistribution of bonding electrons
through a concerted process (i.e, without intermediates)
CycloaddiEon Group transfer Sigmatropic Pericyclic reactions
Ene Chelotropic CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Cycloaddition Reactions
Ø  Cycloaddition reactions results in the formation of a new ring
Ø  Designated as [A+B]
A and B refers to number of atoms containing ∏ electrons
Ø  Three important classifications of cycloaddition reactions
(i) Diels-Alder reaction
(ii) 1,3-Dipolar cycloaddition
(iii) [2+2] Cycloaddition
CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Diels-Alder Reaction
Discovered by Professor Otto Diels and his student Kurt Alder in 1928
and received Nobel prize in 1950
Otto Diels (1876-1952)
Kurt Alder (1902-1958)
“We explicitly reserve for ourselves the application of the
reaction developed by us to the solution of such problems”
CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Diels-Alder Reaction
Ø  Reaction
Ø  Highly
between a conjugated diene and dienophile
effective method for the formation of cyclohexane ring
+
diene
dienophile
CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Diels-Alder Reaction Classification
Ø  Normal [4+2]
Diene is electron-rich
Dienophile is electron-poor
Ø  Inverse electron-demand [4+2]
Diene is electron-poor
Dienophile is electron-rich
Ø  Hetero [4+2]
Hetero atom can be a part of Diene or
Dienophile or both
CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Requirements of Diene
Ø  Diene can be open chain or cyclic
Ø  Diene should be electron rich and reactivity enhanced
by electron donating group substituents
Open chain diene can assume two conformations
s-cis
(reactive conformation)
Two double bonds
are cis to each other
s-trans
(unreactive conformation)
Two double bonds
are trans to each other
CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Requirements of Diene
Ø  The diene must adopt an s-cis conformation to be
reactive
Ø  Cyclic dienes which adopt s-cis conformation are very
reactive
Ø  Cyclic dienes which are permanently in s-trans
conformation are unreactive in Diels-Alder reaction
CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Requirements of Dienophile
Ø  Dienophile can be open chain or cyclic
Ø  Dienophile should be electron deficient and reactivity
enhanced by electron withdrawing substituents
CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Stereochemistry of D-A Reaction
Ø  Diels-Alder reaction is stereospecific
Ø  Relative stereochemical relationship of diene and dienophile is
reproduced in the product
Ø  Diels-Alder reaction occurs due to the overlapping of P-orbitals
of diene and dienophile lying perpendicular to the plane
of carbon atoms
Ø  Hence, a given diene possess two faces namely top face
and bottom face
Ø  Dienophile can approach either of the faces and lead
to racemic mixture
CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Stereochemistry of Diels-Alder Reaction
Stereochemistry of both diene and dienophile retained in the product
Reaction controls the relative stereochemistry at four contiguous
centers
top face
H
H
H
H
H
H
H
H
H
H
H
H
H
H
bottom face
H
H
H
CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan H
H
H
Stereochemistry of Diene
Rule of thumb:
Given the bottom face approach of dienophile: -  inside substituents of diene will become β- configuration
the product
in
-  outside substituents of diene will become α-configuration in
the product
outside
substituents
Inside
substituents
+
CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Stereochemistry of Diene
Me
Me
H
+
H
H
Me
H
CO2Me
CO2Me
Me
MeO2C
MeO2C
H
H Me
H
CO2Me
Me
Me
CO2Me
CO2Me
H Me
CO2Me
CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Stereochemistry of Dienophile
Given the bottom face approach of dienophile Substituents on
dienophile can take two different orientations with respect to
the plane of the diene called endo or exo
Ph
Ph
H
H
H
H
Ph
Ph
“endo”
“exo”
OHC
CHO
Ph
Ph
H
H
H
Ph
OHC
H
Ph
CHO
CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Stereochemistry of Dienophile
Ph
Ph
H
endo
approach
H
H
H
Ph
Ph
OHC
OHC
Ph
H
H
Ph
CHO
Ph
Ph
H
OHC
CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Stereochemistry of Dienophile
Ph
Ph
exo
approach
H
H
H
H
Ph
Ph
CHO
CHO
Ph
H
H
CHO
Ph
Ph
Ph
CHO
H
CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Alder’s endo Rule
endo mode of addition is usually preferred to exo addition due to
secondary orbital overlap between the dienophile’s activating substituent
and the diene.
H
H
H
H
H
H
secondary
orbital interaction
H
H
H
secondary orbital overlap
(endo)
no secondary
orbital interaction
H
H
H
no secondary orbital overlap
(exo)
CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Regiochemistry of Diels-Alder Reaction
For a monosubstituted diene, outcome of the product depends on the
carbon atom where it is substituted
Consider two classical cases, where the electron donating substituent
could be present at carbon 1 or carbon 2
1-substituted diene
2-substituted diene
CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Regiochemistry of Diels-Alder Reaction
Ø  1-substituted diene react to give mainly [1,2]product
[1,2]-product
[1,3]-product
CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Regiochemistry of Diels-Alder Reaction
Regioselectivity for the preference of [1,2]-product can be explained
by considering the polarization of diene and dienophile
Connect the electron rich center of diene to electron deficient center
of dienophile
electron rich electron deficient center
center
CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Regiochemistry of Diels-Alder Reaction
2-substituted diene react to give mainly [1,4]- substituted product
[1,4]-­‐product
[1,3]-­‐product
electron rich center
electron deficient center
CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Problem solving approach for D-A Reaction
First locate the diene and dienophile
consider bottom face approach of dienophile
Look for stereochemistry of diene substituents in the
product
(Inside substituents – β and outside substituents –α )
Look for stereochemistry of dienophile substituent (exo vs endo)
Regioselectivity if both diene and dienophile are unsymmetrical
CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Problem solving approach for Diels-Alder Reaction
H Me
H
Me
H
+
CO2Me
Me
H
CO2Me
Me H
OMe
OMe
CO2Me
CO2Me
+
OMe
CO2Me
CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Problem solving approach for D-A Reaction
OMe
OMe
CO2Me
CO2Me
+
TMSO
Danishefsky’s diene
TMSO
OMe
TMSO
CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan CO2Me
Problem solving approach for D-A Reaction
CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Problem solving approach for D-A Reaction
CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Synthetic equivalence in D-A Reaction
Synthetic utility of DAR can be enhanced by the use of masked
functionality
As ketenes can not be used as such in DAR, ketene equivalents with
masked functionality provide an alternative choice
Commonly employed ketene equivalents are, α-Chloro acrylonitrile
and Nitro ethylene
α-Chloro acrylonitrile
Nitro ethylene
CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Synthetic equivalence in D-A Reaction
O2N
O
O
+
C
Cl
CH2
CN
NO2
NO2
+
Nef reaction
O
Cl
Cl
CN
CN
KOH, DMSO
+
CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Synthetic equivalence in D-A Reaction
Commonly employed ethylene equivalent, Vinyl sulfone
CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Synthetic equivalence in D-A Reaction
Commonly employed acetylene equivalent, Vinyl sulfoxide
SOPh
SOPh
SOPh
CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Synthetic equivalence in D-A Reaction
Commonly employed allene equivalent, Vinyl phosphonium salt
CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Chiral Auxiliary
A chiral auxiliary is a homochiral group that is temporarily directly
attached to an achiral substrate (R-X).
The modified substrate undergoes a diastereoselective reaction
Finally, the chiral auxiliary is cleaved and recovered to give a
product (R-Y*) bearing a new stereogenic centre (or in some cases
several stereogenic centres).
e.g.
CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Chiral Auxiliary
Requirements for a Chiral Auxiliary
The diastereoselective step to give R-Y*-Aux* must proceed with
very good stereocontrol
Cleavage of R-Y*-Aux* must occur under mild conditions and with no
racemization
The auxiliary Aux* ideally should be low cost
Both enantiomers of the auxiliary should be available CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Commonly Used Chiral Auxiliaries
Evan’s oxazolidinone
Corey’s 8-phenylmenthol Oppolzer’s sultam
CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Chiral Auxiliary: Corey’s 8-phenylmenthol
Asymmetric Diels Alder Reaction:
+
+
+
CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Chiral Auxiliary: Corey’s 8-phenylmenthol
Asymmetric Diels Alder Reaction:
+
+
or
+
Chiral Auxiliary: Evan’s Oxazolidinone
Asymmetric Diels Alder Reaction:
CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Intramolecular Diels-Alder Reaction (IMDA)
Type I IMDA : Dienophile is attached to C-1 atom of diene
results in the formation of fused bicyclic system
Fused bicyclic system
CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Intramolecular Diels-Alder Reaction (IMDA)
Type II IMDA:
Dienophile is attached to C-2 atom of diene
Type II IMDA generally results in the formation of bridged bicyclic
system, provided the ring formed other than six member should be
minimum seven member ring
Bridged bicyclic system
CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan IMDA – Type I Examples
CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan IMDA – Type I Examples
CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan IMDA – Type II Examples
CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Hetero Diels-Alder Reaction
Hetero diene: Hetero atom is part of the diene
CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Hetero Diels-Alder Reaction
Ø Hetero Dienophile
Hetero atom is part of the dienophile
CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Inverse electron demand D-A Reaction
Ø  Inverse electron-demand [4+2]
Diene is electron-poor
Dienophile is electron-rich
CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Inverse electron demand D-A Reaction
CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Ortho-Quinodimethanes
R
benzocyclobutane
R
R
R
o-quinodimethane
LDA, then
S
O2
SO2
O2S
I
O
BF3-OEt2
O
O
O
O
O
2
09/04/12 CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan O
Ortho-Quinodimethanes
O
OTMS
O
MgBr
LiNH2, NH3, THF
CuI, TMS-Cl
I
O
O
Me3Si
SiMe3
170 oC
Me3Si
CpCo(CO)2
Me3Si
Me3Si
O
H
Me3Si
H
Me3Si
09/04/12 Me3Si
H
O
1) CF3CO2H
CCl4, -30 oC
H
2) Pb(O2CCF3)4
H
HO
CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Estrone
H
Ortho-Quinodimethanes
O
O
HN
155 oC
HN
H
Me
O
N
O
155 oC
Me
N
O
O
Me
O
N
O
N
OMe
155 oC
N
Me
O
Me
N
O
N
OMe
Me
N
180 oC
N
NH
09/04/12 CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Photoenolization
R
R
O
hν
O
OH
H
H
R
R
R
MeO2C
R
OH
CO2Me
R
R
CO2Me
CO2Me
H2O
CO2Me
CO2Me
R
R
R
R
O
O
O
O
OH O
R
OH
hν
O
H
R
09/04/12 R
CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan R
O
Intramolecular Ene Reactions
O
H
SnCl4
CHO
H
Me2AlCl
BnO
H
OH
OH
OBn
CHO
Binaphthol
CHO
09/04/12 Me2Zn
OH
CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Polyene Cyclization
Terpene Biosynthesis
09/04/12 monoterpenes
C10
geraniol
sesquiterpenes
C15
farnesol
diterpenes
C20
geranylgeraniol
steroids
C30
squalene
CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Terpene Biosynthesis
Isoprene-basic building block
PP = pyrophospate
O
O
OPP
isopentyl-PP
isoprene unit
O P O P OH
O
O
OPP
OPP
OPP
geraniol-PP (C10)
09/04/12 farnesyl-PP (C15)
squalene (C30)
geranylgeraniol-PP (C20)
α-cedrane
O
camphor
HO2C
CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan abietic acid
Terpene Biosynthesis
OPP
H
α-terpinol
α-terpine
H
OH
α-pinene
09/04/12 CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan camphor
Terpene Biosynthesis
Biosynthesis of cedrane
OPP
H
H
cedrane
09/04/12 CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Terpene Biosynthesis
Stork-Eschenmoser Hypothesis - olefin geometry is preserved in the
cyclization reaction
trans olefin leads to trans fused ring junction
Me
Me
Me
Me
Me
Me
R
R
Me
Me
H
09/04/12 H
H
H
CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Terpene Biosynthesis
OPP
OPP
H
H+
H
OPP
H
H
H
H+
H
H
09/04/12 H
HO2C
CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan H
abietic acid
Terpene Biosynthesis
squalene
squalene
epoxidase
H
H+
squalene
cyclase
H
H
HO
O
H
H
H
HO
H
H
protosterol
H
H
H
H
H
H
H
H
HO
H
09/04/12 HO
H
lanosterol
H
HO
CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan cholesterol
Polyene cyclization
SnCl4
CH3NO2, 0 oC
H
8%
H
H
HO
δ-Amyrin
O
E. E. van Tamelen
OH
CHO
MeO
09/04/12 SnCl4
PhH, rt
38%
H
H
MeO
CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Polyene cyclization
H
SnCl4
pentane
H
27%
O
O
HO
O
H
W. S. Johnson
H
CO2Me
OPO(OEt)2
CO2Me
2. NaCl
09/04/12 O
1. Hg(O2CCF3)2
ClHg
H
CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan Robinson Annulation
O
acid or base
(thermodynamic
conditions)
O
O
Unfavorable equilibrium for the Michael addition under kinetic conditions
O
O
base
(kinetic conditions)
O
O
Vinyl silane can shift the equilibrium towards Michael addition product
O
Me3Si
O
09/04/12 base
(kinetic condition)
Me3Si
O
O
CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan O
Robinson Annulation
OR
OR
a) MeLi
b)
Me3SiO
O
O
O
O
H
Me3Si
O
O
c) MeONa
O
Methyl vinyl ketone equivalents
I
mCPBA
+
O
Me3Si
O
Me3Si
Me3Si
H+
O
09/04/12 O
O
O
CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan O
Robinson Annulation
I
+
O
O
O
O
O
O
O
Intramolecular aldol condensation of 1,5-diketones
O
O
R'
base
H2O
R
09/04/12 R'
R
O
CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan 09/04/12 CH-­‐588 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan