S-Methylidene agents: preparation of chiral non-racemic heterocycles

Article abstract of DOI:10.1016/j.tet.2008.10.019

Reaction of sulfur ylide with aldehyde, imine, and ketone functionality affords the desired three-membered heterocycle in excellent yield. The sulfur ylide is generated in situ upon decarboxylation of carboxymethylsulfonium betaine functionality. Of the seven carboxymethylsulfonium betaine derivatives surveyed, the highest level of conversion of π-acceptor to heterocycle was obtained with the one having S-methyl and S-phenyl functionality bound to a thioacetate derivative. Methylene aziridinations and epoxidations involving the decarboxylation of carboxymethylsulfonium betaine functionality complements existing technologies with the advantages of the reaction protocol, levels of conversion, and scope. While moderate levels of diastereocontrol were observed in the aziridination of imine functionality, the four oxiranes resolved using Jacobsen's Co(II)-salen complex were obtained in both high yield and enantioselectivity. The isolated chiral non-racemic oxiranes constitute the formal synthesis of chelonin B and combretastatin starting from 3-bromo-4-methoxybenzaldehyde and 3,4,5-trimethoxybenzaldehyde, respectively.

Full text of DOI:10.1016/j.tet.2008.10.019

Tetrahedron 65 (2009) 70–76
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
S-Methylidene agents: preparation of chiral non-racemic heterocycles
,
a
a
a
David C. Forbes a , Sampada V. Bettigeri , Samit A. Patrawala , Susanna C. Pischek ,
*
Michael C. Standen b
,
*
a Department of Chemistry, University of South Alabama, Mobile, AL 36688, USA
b Synthetech, Albany, OR 97321, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Reaction of sulfur ylide with aldehyde, imine, and ketone functionality affords the desired three-mem-
bered heterocycle in excellent yield. The sulfur ylide is generated in situ upon decarboxylation of car-
boxymethylsulfonium betaine functionality. Of the seven carboxymethylsulfonium betaine derivatives
Received 24 July 2008
Received in revised form 30 September
2008
Accepted 9 October 2008
Available online 14 October 2008
surveyed, the highest level of conversion of p-acceptor to heterocycle was obtained with the one having
S-methyl and S-phenyl functionality bound to a thioacetate derivative. Methylene aziridinations and
epoxidations involving the decarboxylation of carboxymethylsulfonium betaine functionality comple-
ments existing technologies with the advantages of the reaction protocol, levels of conversion, and scope.
While moderate levels of diastereocontrol were observed in the aziridination of imine functionality, the
four oxiranes resolved using Jacobsen’s Co(II)–salen complex were obtained in both high yield and
enantioselectivity. The isolated chiral non-racemic oxiranes constitute the formal synthesis of chelonin B
and combretastatin starting from 3-bromo-4-methoxybenzaldehyde and 3,4,5-trimethoxybenzaldehyde,
respectively.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
(Scheme 1).5 Important to note is that the process does not re-
quire the use of strong and often pyrophoric bases such as butyl
In the context of alkylidene transfer agents, a method, which
offers the direct and stereospecific assembly of small ring carbo-
and heterocyclic building blocks represents an extremely attrac-
tive synthetic transformation.1 The crescendo being the synthesis
of terminal (monosubstituted) three-membered rings of high
lithium or sodium hydride, does not require expensive metal
catalysts, and is compatible with ecologically benign solvent sys-
tems. The key step in our process is the decarboxylation of the
carboxymethyl betaine functionality, which generates the requi-
site sulfur ylide ii in situ.
stereoselectivity starting from a large variety of
p
-acceptors
While very satisfied with the chemistry, our methylene transfer
technology has yet to reach its full potential when considering
catalysis, scope, and asymmetry. Efforts to address the latter two,
(Fig. 1).2
Nucleophilic alkylidene transfer agents have been shown to be
extremely useful for the introduction of functionality into organic
molecules.3 Of the many methods available, the sulfur ylide ap-
proach offers the most advantages when considering scope, atom
efficiency, and facility for stereocontrol. This method typically
involves a stepwise sequence of (1) alkylation of a dialkyl sulfide
to form a sulfonium salt and (2) treatment of the sulfonium salt
with strong base to form the ylide.4 While highly enantio- and
diastereoenriched systems can be prepared, limitations exist. The
strength of our process involving the decarboxylation of
carboxymethylsulfonium betaines is the trapping of aldehydes to
form terminal epoxides and imines to form terminal aziridines
addition to other
p-acceptors and asymmetry, have been made
and reported herein are our findings in the stereoselective as-
sembly of heterocyclic building blocks of aziridine and oxirane
functionality.
O
R
O
R
RN
R
RN
R
CH2
H2C
R
H2C
R
* Corresponding authors.
E-mail addresses: dforbes@jaguar1.usouthal.edu(D.C. Forbes), mikes@synthetech.
com (M.C. Standen).
Figure 1. Formation of terminal three-membered rings.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.10.019

D.C. Forbes et al. / Tetrahedron 65 (2009) 70–76
71
O
O
CH2
OH
CH3
O
THF
Cs2CO3
reflux
OTf
X
R
X
S
S
R
S
CH3
CH3
1
ii
X = O, NR
CH3
i
CO2
S
Scheme 1.
2. Background
formation when working with sulfonium salts 2a–c we proposed
that at higher temperatures (refluxing THF), the decarboxylation
rate is high providing relatively high levels of ylide that can be
trapped by carbonyl compounds, particularly the more electro-
philic (electron deficient) ones. As the electrophilicity of the car-
bonyl compound decreases, the forward rate of epoxidation slows
down and fails to compete effectively with ylide fragmentation and
other side reactions. The data obtained clearly documented the
need to recognize the factors associated with decarboxylation rates
and competing side reactions when working with sulfur ylides as
alkylidene transfer agents.
2.1. Carboxylmethyl betaines
Previous communications from our lab focused on the process of
generating nucleophilic alkylidene transfer agents using sulfur
ylide technologies.5a,b To date, we have prepared and studied a total
of seven sulfonium salts (Chart 1). While the preparation of each
system started with the sulfenylation of either iodoacetic acid or
bromoacetic acid,6 the efficacy of each salt to perform the role of
alkylidene transfer agent varied greatly.
O
O
O
O
OH
CH3
OH
CH3
OH
I
OH
CH3
S
S
S
S
R
X
OTf
OTf
R
1
2
3
4
(a) R = NO2
(b) R = CN
(c) R = OCH3
(a) R = (CH2)7CH3; X = Br
(b) R = CH3; X = I
Chart 1.
As previously reported, added stability of the sulfur ylide and
a more facile rate of decarboxylation resulted when switching from
alkyl to aryl functionality.7 Sulfur ylide intermediate ii is best de-
scribed as a semi-stabilized ylide when compared to thioacetate
scaffolds consisting of not alkyl aryl substitution but alkyl alkyl
substitution on sulfur. While traditional points of stabilization
would focus on the alkylidene carbon, attachments onto the sulfur
moiety and even solvation of the intermediate itself have also been
shown to improve the half-lives of sulfur ylides. The disappoint-
ingly low yields observed with the less electrophilic (electron rich)
aldehydes were largely attributed to the instability of the S-ylide
when working with alkyl, alkyl functionality bound to the thio-
acetate derivative (sulfonium salts 3 and 4).8,9
2.3. Asymmetry: chiral non-racemic imines
In our search for alternative mild protocols for S-ylide genera-
tion, which might be capable of sustaining asymmetric methylene
transfers, we were intrigued by reports from Stockman and co-
workers using sulfinyl imines as chiral non-racemic
p-acceptors in
methylene transfer processes (Scheme 2).10 Using methylidene
agents derived from trimethylsulfonium iodide, a series of ali-
phatic, aromatic, and heterocyclic tert-butylsulfinyl aziridines were
prepared. The Corey–Chaykovsky reaction of chiral non-racemic
sulfinyl imines resulted in yields ranging from 63% to 84% and di-
astereomeric ratios as high as 98:2. Reaction times ranging be-
tween 3 h and 10 h using NaH as base, DMSO as solvent at 20 ꢀC led
to the highest levels of conversion and diastereoselectivity.
2.2. Rates of decarboxylation
Table 1
Based upon our kinetic studies, when adjusting the electronic
environment about the sulfur atom, a significant change in the rate
of decarboxylation of the betaine was observed (Table 1).5b This
unfortunately resulted in a detrimental effect when considering
mass throughput of aldehyde to oxirane. That is, all three sulfonium
salts (2a–c) were ineffective at improving the levels of conversion
from aldehyde to oxirane when compared to the results obtained
with sulfonium salt 1.
Rates of decarboxylationa
CH3
S
CH3
S
H
triethylamine
(3 equiv)
H
CH3
40 °C
CD3CN
R
O
OH
R
OTf
a
OTf
Use of strong electron deficient groups resulted in half-lives for
sulfonium salts 2a and 2b in less than a minute and a half as
compared to just over 13 min for sulfonium salt 1 under identical
reaction conditions. When switching to an electron releasing aryl
substituent at position 4 of the aromatic ring, the half-life of sul-
fonium salt (2c) exceeded 1 h. To explain the drop in epoxide
Entry
Sulfonium salt
t1/2 (min)
1
2
3
4
1 (R¼H)
13.3
1.2
1.3
2a (R¼NO2)
2b (R¼CN)
2c (R¼OCH3)
85.6
a
Reactions monitored by 1H NMR.

72
D.C. Forbes et al. / Tetrahedron 65 (2009) 70–76
non-racemic aziridines, cyclopropanes, and epoxides based on the
O
S
O
generation of S-ylides.1 Aggarwal and co-workers via reaction of
chiral sulfides with rhodium metallocarbenes have reported on
a range of substituted heterocycles, which can be generated in high
yield and with excellent control of both absolute and relative ste-
reochemistry. The same author has as well demonstrated a similar
catalytic cycle using Simmons–Smith reagents (Et2Zn/ClCH2I) as
S-ylide precursors to perform asymmetric methylene transfers
(Scheme 3).11
H3C
H3C
H3C
NaH
S
H3C
H3C
N
R
(CH3)3S
I
+
N
DMSO
20 °C / 3-10h
(63-84%)
R
CH3
major
(dr 88:12 - 98:2)
R = aliphatic, aromatic, and heterocyclic
Scheme 2.
Our entry into stereoselective methylene transfer processes
began with an aziridination study using our decarboxylation
technology (Table 2).5c We chose to test a series of aryl substituted
chiral non-racemic tert-butylsulfinyl imines against our sulfonium
salt 1.
O
H
O
R2S
CH2Cl2
(54%)
Et2Zn
R2S =
ICH2Cl
O
+
+
ee = 47% (S)
O
Table 2
Methylene aziridinations using sulfonium salt 1
N
N
S
S
O
H3C
H3C
H3C
O
N
O
S
THF
S
OH
CH3
H3C
H3C
Cs CO
S
+
N
Ar
2
3
Ar
Scheme 3.
5
reflux
12h
CH3
OTf
(major)
1
A second example involving an asymmetric methylene epoxi-
dation was reported two years later by Goodman and co-workers
Entry
Imine
Yielda (%)
drb
(Scheme 4).12 Using a
D-mannitol derived chiral non-racemic sul-
fide, levels of enantiocontrol reached 57% in the formation of sty-
rene oxide starting from benzaldehyde (54% yield). This is the
highest level of enantiocontrol achieved to date when discussing
methylene epoxidations.
1, a
97
87:13
78:22
O2N
Cl
2, b
3, c
4, d
5, e
6, f
96
94
95
85
93
Cl
77:23
74:26
84:16
80:20
O
O
Cl
O
O
O
S
Et2Zn
ICH2Cl
N
N
N
O
N
Zn
O
ee = 57%
Cl
Cl
CH2Cl2
(56%)
O
H3CO
Scheme 4.
HO
´
The third and final example by Solladie-Cavallo and co-workers
did not utilize a methylene epoxidation, rather they utilized para-
formaldehyde and a chiral non-racemic benzyl substituted sulfo-
nium salt (Scheme 5).13 As a result, extremely high levels of
enantiocontrol have been achieved in the asymmetric preparation
of terminal oxiranes (98%). While only two 2-aryl oxiranes were
reported in this communication, the oxathiane scaffold derived
from (þ)-(R)-pulegone is a clever design in sulfonium salt forma-
tion. That is, the 1,3-heteroatomic disposition within the fused bi-
cycle effectively exploits the differences in lone pair basicity on
sulfur resulting in a highly diastereoenriched sulfur ylide via the
sulfonium salt.
7, g
89
66:34
H3CO
a
Isolated chromatographically pure material.
Determined by 1H NMR (crude reaction mixture).
b
A total of seven derivatives were surveyed. While the isolated
yields were excellent, the diastereoselectivities observed in this
series, which is believed to be under kinetic control ranged from
a low of 66:34 for electron releasing aryl imines to a high of 87:13
with electron withdrawing imines. While significantly higher levels
of diastereocontrol could be obtained with our technology, it was at
the expense of aziridine conversion (dr¼90:10 at 50% conversion
for 5d). Albeit lower levels of diastereocontrol were observed
overall, we were encouraged by the fact that extremely high levels
of conversion were obtained with a process, which does not rely on
DMSO as solvent and strong bases such as NaH or nBuLi.
2.5. Asymmetry: resolutions
Recognizing the shortcomings of a protocol, which relies on
refluxing THF for complete conversion of p-acceptor to heterocycle,
we sought alternative asymmetric processes in the assembly of
chiral non-racemic oxiranes. When considering scope and highly
stereoselective processes yielding terminal oxiranes, the two-step
process starting with an asymmetric dihydroxylation followed by
ring closure to afford the desired oxirane is the method of choice.14
With asymmetric dihydroxylations, a host of monosubstituted
2.4. Asymmetry: chiral non-racemic sulfides
As previously stated, a number of groups have demonstrated
and refined ingenious catalytic asymmetric approaches to chiral

D.C. Forbes et al. / Tetrahedron 65 (2009) 70–76
73
Cl
Cl
H
OH
H
O
H
CH3
CH3
CH3
Cl
Cl
H3C
NaH
(CH2O)
CH3
H3C
O
S
Tf2O
n
O
S
pyridine
CH2Cl2
THF
(73%)
ee = 98% (R)
OTf
Cl
(86%)
Cl
Scheme 5.
alkenes consistently yield chiral non-racemic diols with excep-
tionally high enantioselectivities and conversion. If an even higher
level of enantioenrichment is desired (>99%), options do exist. One
option being the kinetic resolution of chiral racemic materials using
conventional or enzymatic processes.1,15 The first step allows for
the recovery of enantiopure oxirane from diol via a hydrolytic ki-
netic resolution. Once separated, the second step consisting of ring
closure of the diol furnishes the enantiomeric oxirane. Logistically,
one key advantage to this strategy is that when both stereoisomers
are needed, returning to an earlier synthetic step using an epimeric
complex is not needed.
reports vary greatly on the efficacy of methylene transfer using
trimethylsulfonium salts onto electron releasing aryl aldehydes.17
One solution toward the fluxional levels of conversion observed has
been to utilize a biphasic system. The advantage with a solvent
partitioned protocol is that the aqueous medium offers a more
hospitable environment for the unstabilized ylide. However, uti-
lizing this approach with the scope of carbonyl derivatives pre-
sented in Tables 2 and 3 would result in hydrolysis of the respective
Table 3
Methylene epoxidations using sulfonium salt 1
O
OH
CH3
R'
R'
THF
3. Results and discussion
O
S
Cs2CO3
reflux
12h
R
R
O
3.1. Methylene epoxidations
OTf
6
1
While the three communications by Aggarwal, Goodman, and
Entry
Carbonyl derivative
Yielda (%)
97
´
Solladie-Cavallo demonstrate elegant strategies in the chemistry of
asymmetric transfers to furnish terminal oxiranes, each has limi-
tations when considering catalysis, scope, levels of enantiocontrol,
and conversion. Coupling hydrolytic kinetic resolutions with a very
effective method capable of furnishing a host of monosubstituted
oxiranes in high yield is an extremely viable strategy toward the
preparation of chiral non-racemic terminal oxiranes. Accordingly,
we chose to test sulfonium salt 1 against the same group of car-
bonyl derivatives used in our initial studies with the anticipation
that the oxiranes generated can be resolved.
O
1, a
O2N
O
2, b
3, c
97
98
Cl
Cl
O
The group of carbonyl derivatives ranged from electron deficient
aryl aldehydes to less reactive ketone substrates. While electron
deficient aryl aldehydes reacted the quickest yielding the desired
oxirane in less than 3 h, electron releasing aryl aldehydes required
reaction times up to 12 h. The data from the study is presented
below in Table 3.
All reactions reported here were clean as judged by GC and NMR
analysis of the crude reaction mixture. The analysis of the crude re-
action mixtures revealed no by-products other than desired product
and based upon the isolated yields, very little unreacted starting
material. A comparison of this data with previous reports from our
lab reveals several interesting trends. While moderate improve-
ments, for comparative purposes, were observed for the electron
deficient aryl aldehydes (entries 1–3), significant improvements
were observed for benzaldehyde (95% (entry 4) versus 77% (Ref. 5b))
and 4-methoxybenzaldehyde (86% (entry 6) versus 25% (Ref. 5b)).
Use of an alkyl aldehyde (95% yield (entry 9)) and ketone (86% yield
(entry 10)) confirms the breadth of this technology.
Three additional electron releasing aryl aldehydes were sur-
veyed (entries 5, 7, and 8). As evident in the isolated yields reported,
excellent levels of conversion were obtained with this class of al-
dehydes, which is a significant achievement in the area of methy-
lene epoxidations.16 Our approach complements existing
technologies toward the preparation of chiral racemic terminal
oxiranes and offers the added advantages of scope, mild reaction
conditions, ease in workup, and levels of conversion using a unified
protocol. While reaction is observed when working with tri-
methylsulfonium salts and a host of aliphatic and aryl aldehydes,
Cl
O
4, d
5, e
6, f
7, g
95
93
86
92
Br
O
H3CO
O
H3CO
O
O
O
H3CO
O
8, h
9, i
91
H3CO
OCH3
H3C
95
86
O
10
CH3
O
10, j
a
Isolated chromatographically pure material.

74
D.C. Forbes et al. / Tetrahedron 65 (2009) 70–76
Using styrene oxide as our benchmark standard (entry 1), we
were successful in the resolution of both electron deficient (entry 2)
and electron releasing (entries 3 and 4) 2-aryl oxiranes. The suc-
cessful resolution of these systems adds to an already impressive
body of work where highly enantioenriched terminal oxiranes have
been isolated using this technology. Using HPLC (Whelk-O 1), we
were unable to observe any of the minor isomer for entries 1–3.
While we were not successful in separating the racemic mixture of
2-(3,4,5-trimethoxyphenyl)oxirane by HPLC (entry 4), our evidence
for the isolation of highly enantioenriched material was furnished
by comparing the specific rotation obtained with the literature
data.21c Additional evidence for the formation of highly enan-
tioenriched material for all four systems includes (1) the analysis of
resolved oxirane using the enantiomeric Co(II)–salen complex and
(2) the efficiency of this process when analyzing the levels of
conversion and specific rotations of isolated diol.22
N
O
N
CH3
CH3
CH3
CH3
Co
H3C
H3C
O
H3C
CH3
CH3
H3C
H3C
CH3
Figure 2. (R,R)-Co(II)–salen complex.
imine and oxirane functionality when working with electron de-
ficient aryl imines and aldehydes.18 Furthermore, self-condensation
reactions when working with enolizable carbonyl derivatives is
a possibility.
3.2. Hydrolytic kinetic resolutions
3.3. Chelonin B and combretastatin
As stated above, while very satisfied with the chemistry, our
approach toward methylene transfers has yet to reach its full po-
tential when considering catalysis, scope, and asymmetry. When
working with chiral non-racemic sulfinyl imines, we, not surpris-
ingly, documented an inverse relationship with temperature and
stereoselectivity.5c Reaction temperatures ranging from room tem-
perature to refluxing THF resulted in diastereoselectivities ranging
from 90% to 65%, respectively. The unacceptably low levels of con-
version observed when operating at room temperature present an
interesting challenge when wanting to pursue an asymmetric pro-
tocol. While we determined to resolve this foreseeable limitation,
options when wanting chiral non-racemic material do exist. One
option being the hydrolytic kinetic resolution of chiral racemic
oxiranes using Jacobsen’s Co(II)–salen complex (Fig. 2).19
Entries 5 and 8 from Table 3 are 2 of 17 examples, which illus-
trate the scope of sulfonium mediated methylene transfers onto
p-acceptors using sulfonium salt 1. Isolated yields of 2-(3-bromo-4-
methoxyphenyl)oxirane and 2-(3,4,5-trimethoxyphenyl)oxirane
starting from 3-bromo-4-methoxybenzaldehyde and 3,4,5-trime-
thoxybenzaldehyde were 93% and 91%, respectively. Both systems
as racemates were successfully resolved. While oxirane 6e (2-(3-
bromo-4-methoxyphenyl)oxirane) was isolated in >99% ee, our
unsuccessful attempts in separating the racemate 2-(3,4,5-trime-
thoxyphenyl)oxirane (6h) by HPLC using the Whelk-O 1 column
resulted in the recording of an 89% ee using data obtained by
a polarimeter. While we have no reason to believe the enantioen-
richment of this material is in excess of 99%, our evidence is based
upon the literature data as shown in Table 4, entry 4.
With both enantiomeric complexes commercially available and
ample literature precedence on the process, we chose to resolve
a series of aryl substituted oxiranes, four in all, using Jacobsen’s
Co(II)–salen complex.20 The data from the study is presented below
in Table 4.
Synthesized oxiranes 6e and 6h as chiral non-racemic materials
are interesting examples, in that they constitute the formal syn-
theses of two systems of biological and medicinal significance
(Fig. 3).
Table 4
Starting from 3-bromo-4-methoxybenzaldehyde, Lawrence and
Bushell prepared (S)-(þ)-chelonin B in less than 10 steps.23 The key
step in the preparation of the marine natural product was an
asymmetric dihydroxylation of the monosubstituted styrene de-
rivative obtained from the Wittig methylenation of 3-bromo-4-
methoxybenzaldehyde. The corresponding diol was next cyclized
to afford chiral non-racemic oxirane in 76% overall yield (three
synthetic transformations) and 96% ee based upon HPLC analysis. A
direct comparison of our approach with theirs has an almost
identical overall yield (78%24 vs 76%) and slight improvement in the
level of enantioenrichment (>99% vs 96%). While a clear dis-
advantage is the mass throughput when considering the resolution,
advantages include the number of synthetic steps needed to obtain
Hydrolytic kinetic resolutions using Co(II)–salen complex21
(R,R) Co(II)
salen complex
O
O
H
H2O:CH3CN:CH2Cl2
Ar
Ar
rt
Entry
1
Oxirane
Recoverya (%) eeb (%)
[a]
D
O
46
45
>99
>99
ꢁ24.0 (ꢁ23.7 (lit.))
O
2
3
ꢁ17.2 (þ19.3 (lit. (ent)))
OH
H
Cl
Br
H
N
O
O
NH
H3CO
42
43
>99
ꢁ9.8
H3CO
Br
H3CO
Br
R
chelonin B (R = H)
bromochelonin B (R = Br)
O
H3CO
H3CO
H
O
OCH3
OH
4c
>89d
þ13.8 (þ15.5 (lit.))
H3CO
H3CO
H
OH
H3CO
H3CO
OCH3
OCH3
a
b
c
Isolated chromatographically pure material. Monitored by 1H NMR.
HPLC Regis (R,R)-Whelk-O 1 column.
(S,S) Co(II)–salen complex.
Based upon specific rotation; unable to resolve enantiomers by HPLC.
combretastatin
OCH3
d
Figure 3. Retrosynthetic analyses for chelonin B, bromochelonin B, and combretastatin.

D.C. Forbes et al. / Tetrahedron 65 (2009) 70–76
75
chiral non-racemic oxirane 6e (two vs three), the type and use of
materials needed, and the fact that both enantiomers are available
for further use when performing a hydrolytic kinetic resolution.
An almost identical approach was used in the preparation of
combretastatin.21c Starting from not the bromo methoxy but rather
the trimethoxy derivative of benzaldehyde, ring opening of chiral
non-racemic oxirane 6h with an organometallic reagent (bromine
lithium exchange of an aryl bromide) afforded the secondaryalcohol
in 75% yield. Aside from reporting the specific rotation of oxirane 6h,
the communication reports an enantioenrichment of 97% of the
TBDMS derivative shown in Figure 3 by HPLC analysis. Starting from
3,4,5-trimethoxybenzaldehyde, preparation of the key in-
termediate, chiral non-racemic oxirane 6h, required four synthetic
transformations (Wittig methylenation, asymmetric dihydroxy-
lation, formation of a tosyl derivative, and ring closure). The overall
yield was 88%. A direct comparison again of the two approaches
reveals a lower overall yield (78% vs 88%) and assuming the optical
purity of oxirane 6h obtained upon dihydroxylation of the styrene
derivative is identical to the secondary alcohol, a slight improve-
ment from97% to>99% ee is observed. As was the casewith chelonin
B, the amount of materials needed to prepare oxirane 6h alone far
exceeds that required using methylene transfer technology.
residue was purified using a neutral alumina column (150 mesh,
58 Å) unless specified otherwise. All chemicals used for synthetic
procedures were reagent grade or better.
5.2. Representative procedure for methylene epoxidations
An oven-dried 25 mL round-bottomed flask was equipped with
a stir bar, septum, and water-jacketed condenser. The system was
next charged with aldehyde (1.0 mmol, 1.0 equiv), cesium carbon-
ate (2.0 equiv) and THF (3.0 mL). To this slurry was added a solution
of betaine (2.0 equiv) in THF (2.0 mL) via syringe in two equal
portions at 6 h intervals. The system was externally heated to 80 ꢀC
(sand bath) and the reaction mixture was allowed to stir for a pe-
riod of 12 h. After cooling to room temperature, the reaction mix-
ture was filtered over a pad of Celite, concentrated in vacuo and
then immediately purified by chromatography (neutral alumina
(150 mesh, 58 Å)) using a gradient eluent system of hexanes and
ethyl acetate to afford analytically pure oxirane.
5.3. Representative procedure for the kinetic resolution of
aryl oxiranes
As for absolute stereochemistry, by virtue of resolving the ra-
cemates into highly enantioenriched oxiranes and diols, both en-
antiomeric lines are generated and thus confirming the formal
synthesis of chelonin B and combretastatin. Research in our group
continues in the areas of (1) understanding the kinetics of the re-
action, (2) increasing the scope using modified sulfonium salts, and
(3) the development of a decarboxylative protocol involving the use
of chiral, non-racemic sulfide promoter. The results from these
studies will be reported in due course.
To a 25 mL round bottom flask with stir bar, was added oxirane
(12.5 mmol), H2O (7.5 mmol), a 1:1 mixture of CH2Cl2 and CH3CN
(0.25 ml), and the colbalt(II) salen complex (0.3 mol %). The reaction
mixture was allowed to stir at room temperature. During that time,
the reaction was monitored by 1H NMR using as markers the di-
agnostic peaks associated with oxirane and diol. Upon observing
50% conversion, the reaction was judged as complete. Workup in-
volved filtering the reaction mixture through a plug of anhydrous
Mg2SO4. The resulting organic solution was then concentrated in
vacuo. Prior to HPLC analysis the reaction mixture was purified by
column chromatography using neutral alumina (hexanes). All HPLC
4. Conclusion
analyses were performed using
a (R,R)-Whelk-O 1 column
A host of existing protocols all demonstrate elegant strategies in
the chemistry of methylene transfers. Each has limitations when
considering scope, levels of enantiocontrol, and conversion. Our
unified two-step approach complements existing protocols with
several key advantages. Methylene transfers starting from a carboxy-
methylsulfonium betaine scaffold allows for the efficient conversion
of both imine and aldehyde functionality to the corresponding
aziridine and oxirane. Coupling hydrolytic kinetic resolutions with
a very effective method capable of furnishing a host of mono-
substituted oxiranes in high yield is an extremely viable strategy
toward the preparation of highlyenantioenriched terminal oxiranes.
(25 cmꢂ4.6 mm, 5 m). The mobile phase was hexanes/IPA at a flow
m
rate ranging between 0.9 mL/min and 1.0 mL/min with a detector
wavelength of 220 nm. Prior to and post each HPLC analysis, runs
using chiral racemic aryl oxiranes were performed. In addition to
HPLC analyses, optical rotations of chiral non-racemic material were
obtained and compared to published values when possible.
Acknowledgements
D.C.F. would like to thank NIGMS (NIH NIGMS 1R15GM085936),
NSF (CHE 0514004), and the Camille and Henry Dreyfus Foundation
(TH-06-008) for partial funding of this research. S.A.P. would like to
acknowledge financial support through the Alabama Space Grant
Scholars Program. S.C.P. and S.A.P. would as well like to acknowl-
edge financial support through the University of South Alabama
(UCUR and University Honors Program).
5. Experimental
5.1. General experimental considerations
1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were
obtained as solutions in CDCl3. Chemical shifts were reported in
Supplementary data
parts per million (ppm) and referenced to
d
d
7.27 (1H NMR) and
77.00 (13C NMR). Infrared spectra were recorded using a FTIR and
Experimental and spectral data in the preparation of com-
pounds 6a–j and resolution of compounds 6a, 6d, 6e, and 6h are
provided. Supplementary data associated with this article can be
found in the online version, at doi:10.1016/j.tet.2008.10.019.
reported in wavenumbers (cmꢁ1). Analytical high pressure liquid
chromatography (HPLC) was performed with a built-in photometric
detector using a (R,R)-Whelk-O 1 column (4.6 mmꢂ25 cm). Sol-
vents for HPLC analyses were of spectroscopic grade and filtered
before use. GC analyses were performed using a ZB-5 with guardian
References and notes
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