Studies Toward the Total Synthesis of Stenine
Current researcher: Weidong Zhang
Nucleophilic carbenes have recently emerged as powerful 1,1-dipole equivalents for the
construction of functionalized hydroindolone derivatives via a novel [4+1] cycloaddition
with vinyl isocyanates in our laboratory. This methodology has been successfully used in
the total synthesis of several alkaloids, such as tazettine and mesembrine.
Currently, we are investigating the total synthesis of stenine (1), a member of Stemona
alkaloids which are isolated from the root extracts of Stemona species of plants. Our
synthetic strategy involves the assembly of hydroindolone 4 by using [4+1] cycloaddition
of vinyl isocyanate 2 and bis(alkylthio)carbene 3. Another key transformation of our
approach is to install the 7-membered ring moiety of the azepinoindole on highly
functionalized hydroindolone via a 7-endo trig radical cyclization (5→6). Current efforts
are directed toward preparing advanced intermediate 5 and further elaborating it to
stenine (1).
O
O
NR2
R'O
+
R''S
SR''
[4+1]
H
R'O
NR2
(SR'')2
O
N C
O
N
3
SR''
R''S
2
4
O
H SR''
SR''
O
7-endo trig
O
N
X
5
O
O
H SR''
SR''
O
H
O
H
6
H
O
H
N
H
N
Stenine (1)
Novel Reactions of Nucleophilic Carbenes with Vinyl
Isocyanates and Vinyl Ketenes
Current researcher: Zhengqiang Wang
My research in Professor Rigby’s Group has been focused on the chemistry of vinyl
isocyanates. As 1,4-dipole equivalents, these adducts have a high propensity to cyclize
with a variety of electron rich 1,2- or 1,1-dipoles to afford different core structures for
many alkaloids families (Scheme 1).
Scheme 1
X
X
O
N
H
O
NCO
[4 + 2]
N
[ 4 + 1]
X
X
Reactions between Vinyl Isocyanates and Nucleophilic Diaminocarbenes
An interesting feature about this new [4+1] cycloaddition reaction is that, although two
equivalents of carbene precursor was employed, only one equivalent of carbene was
found to be incorporated in the final product (Scheme 2). No N-H insertion was observed,
which is in sharp contrast to the case of dialkoxy or dithio carbenes reactions. A
hydantion compound obtained in some cases, which was derived from an intermolecular
attack of the initially formed zwitterionic intermediate on the second molecule of vinyl
isocyanate.
Scheme 2
NHPh
PhN
+
RN
NR
O
NCO
N
H
Reactions between Vinyl Ketenes and Nucleophilic Carbenes
With the success of vinyl isocyanates as powerful building blocks in alkaloids synthesis,
we became interested in looking into other possible 1,4-dipole equivalents for an efficient
[4+1] cycloaddition reaction. Vinyl ketenes, which are structurally reminiscent to vinyl
isocyanates, seem to be good candidates in this context. The chemistry of silyl-stabilized
vinyl ketenes has been well established by Danheiser.
Scheme 3
R1
O
C
R1
X
X
∆
+
R2
X
X
R2
X = O, S, N
R
O
R3
3
The reaction was found to proceed with excellent yields. As depicted in Scheme 3, this
new transformation provides an effective entry into functionalized five-membered
carbocycles. Simple post-cyclization manipulations turned out to be valid in producing
cyclopentenone ring structures (Scheme 4), which may find applications in the synthesis
of various natural products.
Scheme 4
R1
O
TSOH.H2O
acetone / CH2Cl2
R2
0
R3
oC
R1
O
X
X
R2
R1
Raney-Ni
0 oC
O
R2
R3
R3
X = SR
X = NRR'
Studies towards the Total Synthesis of Camptothecin and Nothapodytine B
Due to their interesting biological activities, Camptothecin and natural products of its
family have drawn tremendous amount of interest in synthetic community. Many total
syntheses of camptothecin and a few of Nothapodytine B have been reported. Based on
the chemistry of our group, a [4+2] cycloadition reaction between a vinyl isocyanate and
an enamine quickly constructs a highly substituted pyridone system. Hence, our strategy
towards the total synthesis of Camptothecin and Nothapodytine B is straightforward as
shown in Scheme 5.
Scheme 5
O
OR
N
N
HO
Camptothecin
N
+
O
N
C
O
O
O
HO
O
O
OR
N
N
N
+
N
Nothapodytine B
O
C
O
O
Research is currently underway towards the total synthesis of these two molecules.
Studies Toward the Total Synthesis of Ingenol
Current Researchers: Dr. Olivier Mirguet, Hoon Bae
Ingenol (1), the ester of which is a known tumor promoter isolated from the genus
Euphorbia in 1968, still remains a formidable challenge to the synthetic organic
community. We are currently investigating the total synthesis of this interesting
diterpene. Our plan entails the use of an intramolecular [6+4] cycloaddition of dienetropone 2 to construct the A, B and C rings of 1. This cycloaddition strategy not only
forms two key C-C bonds, but also establishes three new stereocenters. Thus far, we have
prepared tricycle 3 and elaborated it to the advanced intermediate 4 using novel reactions
developed in our labs. Further studies have been initiated on an asymmetric version of the
[6+4] cycloaddition reaction. Thus, an optically enriched tricycle 3 has been obtained.
Intensive efforts are now being directed to elaborate intermediate 4 to ingenol (1).
O
O
[6+4]
cycloaddition
H
H
2
3
steps
O
O
H
H
OR
HO HO
HO
Ingenol, 1
OH
O
RO
OR
4
Synthetic Application of 1,1-dioxo-2,7-dihydrothiepin:
Studies Toward Total Synthesis of Leukotrienes
Current researcher: Bryan Forrest
Extrusion of sulfur dioxide from 1,1-dioxo-2,7-dihydrothiepin 1 gives 1,3,5-hexatriene
with a geometrically defined (Z) double bond about carbons three and four (eq. 1).
O
O
S
∆ or light
(eq.1)
3
4
1
Alkylation of 1 alpha to the sulfone with aldehydes, primary alkyl triflates and acid
chlorides followed by chelotropic extrusion provides various 1-substituted E,Z,E trienes
(eq. 2).
O
O
S
1
n-BuLi
THF : HMPA
O
O
S
OH
∆ or light
HO
(eq. 2)
-SO2
then
BF3.OEt2
O
50%
79%
The E,Z,E triene function is present in a number of important natural products, included
are the leukotrienes. Some members of the leukotriene family are potent mediators of
immediate hypersensitivity reactions and inflammation. A retrosynthetic scheme for total
synthesis of (5S, 12R)-dihydroxy-6,8,10,14-eicosatetraeneoic acid 2 a member of the
leukotriene family is outlined in Scheme 1. The synthesis utilizes 1 as a template for
synthesis of the triene portion of the molecule and a metal-mediated [6+2] cycloaddition
to establish the necessary carbon-carbon bonds at the two and seven positions of 1. Key
to the success of this synthesis will be the feasibility of a regioselective ozonolysis of the
tetrasubstituted double bond in the cycloadduct.
Scheme 1
HO
O
S
OH
HO
CO2H
O
CO2H
3
H
H
C5H11
OH
2
O
O
O
O O
O
S
O
CO2Me
H
H
H
O
S
O O
CO2Me
O
[6+2]
O
S
CO2Me
H
3
O
Cr(CO)3
O
In a model study chromium complex 3 and alkyne 4 were irradiated for 7hrs and
cycloadduct 5 was isolated in 59% yield (eq. 3).
O
O
S
Cr(CO)3
3
TMS
TMS
4
hv
uranium filter
Cl
Cl
S
OO
5
59%
(eq. 3)
Cr (0)-Mediated Multi-Component Higher Order
Cycloaddition Reactions
Current researcher: Zeeshan Kamal
A few years ago Cr (0)-mediated three-component triene/alkyne cycloaddition reaction
was discovered and reported by the Rigby group. This reaction creates 5 new C-C bonds
and 6 stereocenters from readily available starting materials (Scheme 1).
R
R
X
+
2H
R
X
hv
Cr(CO)3
Scheme 1
My job in the Rigby’s group is to widen the scope of this reaction by accomplishing
tandem (6+2+2) cycoaddition with an alkyne and an alkene respectively (Scheme 2). This
method will generate 5 new C-C bonds and 8 stereocenters.
R2
X
+
R2
R1
R1
X
hv
Cr(CO)3
Cr(CO)3
R2
CO2R3
hv
R1
X
R3O2C
Scheme 2
The use of enynes as trieneophiles will further increase the flexibility and utility of this
reaction by forming 5 carbocyclic rings, further functional group and structural
manipulations will lead towards the total synthesis of triquinane type natural products
(Scheme 3).
R
X
+
R
CO2Et
Cr(CO)3
Scheme 3
X
hv
EtO2C
One of a very interesting part of my research is to establish and explore the scope and
utility of (6+2), homo (6+4) cycloaddition of triene with alkyne and a diene respectively
(Scheme 4). This would prove to be a very powerful tool for the total synthesis of
azulene type natural products.
R2
X
+
R2
R1
R1
X
hv
Cr(CO)3
Cr(CO)3
R2
R3
R1
X
Scheme 4
R3
[6+2] Cycloaddition of allenes with
(cycloheptatriene)Cr(CO)3 complex
Current researcher: Dr. Laxmisha, M.S.
Chromium(0)-mediated higher-order cycloaddition reaction has emerged as an important
means for assembling complex ring systems that are often difficult or impossible to make
in other ways. As part of our ongoing interest on the [6+2] cycloaddition of new
trienophiles with (cycloheptatriene)Cr(CO)3 complexes, we recently initiated a project on
the [6+2]cycloaddition of allenes with (cycloheptatriene)Cr(CO)3 complex. Since suitably
substituted allenes can be chiral, this methodology can be employed to obtain chiral [6+2]
cycloadducts.
Some early results from this study are shown below. Irradiation of the chromium
complex 1 with the allenic ester 2 furnished the cycloadduct 3 in 55-60% yield. Identical
results were obtained for this cycloaddition when the reaction was carried out under
thermal conditions. The allene 4 however gave a mixture of cycloadducts 5 and 6, and the
ratio depended on the reaction conditions used. Reaction of diphenylallene with the
chromium complex 1 gave the cycloadduct 7 as a single regioisomer albeit in poor yield.
Extension of this methodology employing axially chiral allenes, to obtain chiral
cycloadducts is currently underway.
CO2Et
CO2Et
2
Cr(CO)3
1
H
hv, hexane
or
∆, nBu2O
55-60%
H
OTHP
3
OTHP
conditions
H
H
+
Cr(CO)3
50-60%
1
5
4
hv, THF
ratio 3:4
3:1
1: 1.8
∆, nBu2O
1: 2
Ph
Ph
Ph
1
H
OTHP
conditions: hv, hexane
Cr(CO)3
H
Ph
H
H
hv, hexane
32%
7
6
Evan’s Oxazolidinone Asymmetric Chemistry on Solidsupport
Current researcher: Dr. Laxmisha, M.S.
Over the past decade polymer supported reactions have been the subject of considerable
study as a result of the increasing significance of combinatorial chemistry and multiple
parallel synthesis. The design of new linkers has been important to the success of this
endeavor since linker diversity allows a broader scope of substrates and reagents to
participate in solid-phase chemistry. In this context, the use of π-(arene)Cr(CO)3
complexes for loading substrates onto solid supports offers attractive opportunities,
because arene-chromium moiety is compatible with most functional groups. Described
below is the projected use of arene-chromium linkers for carrying out Evan’s
oxazolidinone chemistry
O
O
O
O
PPh2
NH
NH
BuLi
cyclooctene, hv
+
Cl
Cr(CO)2
Ph2P
O
Cr(CO)3
O
O
O
O
N
O
NH
O
1. LDA/RX
+
2. LiSEt
R
Cr(CO)2
Ph2P
EtS
Cr(CO)2
Ph2P
A rapid construction of 4-aminopyridones via a [4+2]
cycloaddition of N,N-keteneacetal and vinyl isocyanates.
Current researcher: Dr. Chee-Seng, Lee
Many biological active natural products and other compounds of medicinal interest
possess the pyridone moiety. It’s our interest to explore new strategies for rapid
construction of this important class of compounds.Reaction of vinylisocyanate 1 and
nucleophilic carbene 2 allows one carbon unit addition to the vinylisocyanate to construct
the 5-membered heterocycle 3. Here we disclose the rapid construction of 6-membered
2-amino pyridones 5 via a [4+2] cycloaddition between 2-methylene imidazoline 4 and
vinylisocyanate (Scheme 1).
Scheme 1
Me2N
+ Me2N
N C
O
1
NMe2
NMe2
O
2
3
N
H
HN
+
N C
O
N
N
N
N
H
4
O
5
A variety of substituted and functionalized vinyl isocyanates were used in this study to
probe the utility of this process. We sought to test not only the scope of the reaction but
also the versatility of the reaction in the presence of various functional groups. Acid 6-12
were obtained commercially or through synthesis via literature preparation. (Figure 1).
O
CO2H
O
CO2H
O
CO2H
CO2H
CO2H
6
O
7
8
CO2H
CO2H
9
10
11
12
Figure 1. Various vinylacids
All the isocyanates were synthesized directly from the corresponding acids and
diphenylphosphoryl azide. The resulting azide was then refluxed in acetonitrile or
benzene to give the isocyanate, which was either used without purification or quickly
purified through column chromatography. Exposure of vinyl isocyanate to 2-methylene
imidazoline in either benzene or acetonitrile at 0 ºC followed by refluxing for 2 hours
afforded the desired 2-amino pyridone either through column chromatography or simple
filtration (Figure 2). The 6, 7, and 8-fused pyridones 6a, 11a, 12a, were obtained in 6575% yield. The ketal functional group survived through the process. The corresponding
pyridone 9a was obtained in 50% yield. The pyridone 7a derived from perillic acid was
obtained in 60% yield. In contrast to the cyclic vinylisocyanates, the acyclic 2methylpent-1-ene vinylisocyanates gave the corresponding pyridone 8a in only 32%
yield. Most interestingly, we were able to construct pyridone 10a which posseses a
quaternary center at the ring fusion.
6a
H
N
H
N
H
N
N
N
N
N
H
O
11a
O
N
H
12a
H
N
N
N
N
N
H
O
H
N
H
N
O
N
H
7a
O
H
N
N
O
O
O
9a
N
H
O
8a
N
H
N
H
O
10a
O
Figure 2. Pyridones obtained
The generation of this ring fusion quaternary center encouraged us to explore the
possibility of chiral synthesis of this group of pyridones (Scheme 2). Chiral synthesis of
various imidazolines and its application in this [4+2] cycloaddition with vinylisocyanates
is currently under investigation. In conclusion, our results have illustrated the
experimental ease and quick assembly of highly substituted pyridones as potential
templates of several biological active compounds.
Scheme 2
Ph
HN
O
O
+
N
N
O
Ph
Ph
N
O
NCO
10
Ph
N
H
13
14
O
Studies in Synthesis of Vinyl Carbenes and Their
Potential Application in Organic Synthesis
Current researcher: Dr. Chee-Seng Lee, Aarron Proffitt
Syntheses of indoline, pyridone and azepine moieties have attracted many synthetic
interests. In our laboratory, we have successfully demonstrated facile approaches toward
the indoline and pyridone unit. However, Many biological significant natural products
and synthetically interesting molecules possess the azepine moiety. An efficient and easy
synthesis of the azepine unit is required. Herein, we disclose our preliminary studies
toward synthesis of azepines.
Nucleophilic carbenes 2, such as dithiocarbene, dimethoxycarbene and diaminocarbene
react with vinylisocyanate to give the corresponding 5-membered nitrogen heterocycle 3
while 2-methylene imidazoline 4 successfully adds to the vinylisocyanate to give the
desired 6-membered pyridone 5. Here, we set out to investigate the synthesis of
vinylcarbenes 6 and their potential use in constructing azepines 7 (Scheme1).
Scheme 1
X
+
N C
O
X
X
X
O
N
X=OR, SR, NR2
1
2
3
X
X
HN
+
N C
O
N
N
N
4
+
N
5 H
O
X
X
N C
O
N
H
6
O
7
X=OR, SR, NR2
Our approach toward the precursor of vinylcarbene 11 began with the synthesis of the
required hydrazone 9 in 80% yield over 3 steps (Scheme 3). It was then oxidized to the
cyclic o x a d i a z o l i n e 10. Exhausted attempt to convert the corresponding
thioacetyloxadiazoline 10 to the vinyloxadiazoline 11 gave no fruitful result. Treatment
of the thioacetyl-oxadiazoline 10 with various Lewis acids such as BF3•Et2O, TMSOTf,
and organic acids such as p-TsOH and TFA in the presence of excess equivalent of
various nucleophiles such as vinyl, allyl and propagylsilanes failed to produce any
desired product. In most cases, complex mixtures or product decomposition was
observed.
Scheme 3
i. Carbonyldiimidazole
O
ii. H2NNH2 monohydrate
SH
8
Pb(OAc)4
S
iii. Acetone
N
N
PrS
N
O
CH2Cl2
N
9
80%
PrS
AcO
N
H
N
O
95%
11
10
We then turned our attention toward construction of the vinyl equivalent of the
corresponding oxadiazoline (Scheme 4).
Synthesis of the masking
acetylvinyloxadiazoline 12 began with treatment of acrylic acid with PhSH to give the
resulting Michael addition adduct 15 in excellent yield. Acid chloride formation
followed by acylation gave the corresponding hydrazone 17 in good yield. Oxidation of
the hydrazone using Pb(OAc)4 gave the desired oxadiazoline 18 in 36% yield. However,
attempts at conversion of sulphide 18 to the vinylcarbene precursor 19 were not
successful. Currently, other approaches toward the vinylcarbene precursor are under
vigorous exploration.
Scheme 4
PhS
N
O
O
12
O
Et3N, PhSH
OH
THF
75-84%
14
N
13
OH
CH2Cl2
15
85-90%
H2N
O
SOCl2
O
PhS
N
X
N
X
PhS
Cl
Et3N, CH2Cl2
16
76-82%
PhS
O
Pb(OAc)4
N
H
PhS
17
N
CH2Cl2
36%
O
18
N
AcO
N
AcO
N
N
O
19
N
Studies on the Solid-Phase-Synthesis of Cyclic Peptides Using π-Arene Chromium
“Traceless Linkers”
Solid-phase synthesis has become increasingly important in the past few years.
Its ease in purification has attracted many interests especially the pharmaceutical
industry. Recently, our laboratory has developed a convenient and efficient protocol for
construction of π-arene-chromium linker and its usefulness in solid phase synthesis of
small molecules.1
Many cyclic peptides possess significant biological activity and are drugs of
choice for treatment of many diseases. The presence of aromatic amino acids in many of
these peptides prompted us to employ our newly developed π-arene-chromium linker in
the synthesis of complex cyclic peptides. Herein, we disclose our studies in the synthesis
of a cyclic tetrapeptides. Boc-L-phenylalanine methyl ester chromium complex 2 was
prepared from the corresponding Boc-protected amino acid 1 and Cr(CO)6 in 92% yield.
It was then tethered to the polystyrene-based resin to give the polymer-bound compound
3 in 94% yield. Attempt deprotection of the Boc-group using TFA was not successful.
However, upon treatment of the compound 3 with BBr3 , the desired amine 4 was
obtained in 88% yield (Scheme 1).
Scheme 1
Cr(CO)6, Bu2O,
THF, ref., 46 h
OMe
BocHN
86-92%
i. Cyclooctene, PhMe,
(CO)3Cr
hν, 0 oC, 8 min
OMe
BocHN
O
O
1
PhMe, rt, 44 h
2
(CO)2
Cr
PPh2
ii. Polystyrene-PPh2,
94%
CF3COOH,
CH2Cl2, 0 oC
(CO)2
Cr
PPh2
OMe
BocHN
O
3
BBr3, CH2Cl2
-10oC to r.t., 3h
88%
OMe
H2N
O
4
Simultaneously, it was also found that Fmoc reaction conditions are compatible
with the π-arene chromium bond. The Cr(CO)3 precursor 7 was obtained in two steps
starting from the L-phenylalanine methyl ester 5 bearing unprotected N-terminus. It was
then tethered to the resin to give the polymer-bound compound 8 in 91% yield (Scheme
2).
Scheme 2
(CO)3Cr
Cr(CO)6, Bu2O,
THF, ref., 46 h
OMe
H2N
52%
OMe
H2 N
O
Fluorenylmethyl
chloroformate,
KHCO3, AcOEt,
H2O, 0 oC-rt, 40 min
66%
O
5
6
(CO)2
Cr
PPh2
i. Cyclooctene, PhMe,
(CO)3Cr
hν, 0 oC, 8 min
OMe
FmocHN
ii. Polystyrene-PPh2,
O
FmocHN
O
PhMe, rt, 44 h
O
91%
7
8
The ‘traceless’ solid-phase synthesis of a cyclic tetrapeptide using π-arenechromium began in the N to C direction. Compound 4 was coupled with Fmoc-L-valine
to give the peptide 9. Synthesis toward the polymer-bound cyclic tetrapeptide 11 is
currently under vigorous investigation (Scheme 2).
Scheme 3
(CO)2
Cr
PPh2
(CO)2
Cr
PPh2
O
Fmoc-L-valine, HBTU
OMe
H2N
Hunig's base, PhMe, r.t. 8h
O
FmocHN
83%
N
H
4
O
O
9
(CO)2
Cr
PPh2
O
O
HN
O
N
H
O
NH
N
O
HN
10
O
N
H
O
NH
N
O
11