Highly stereoselective methylene transfers onto butanediacetal-protected chiral non-racemic sulfinyl imines using S-ylide technology

Article abstract of DOI:10.1039/b822779a

Diastereomeric ratios of >95: 5 were obtained when performing methylene transfers onto imines originating from d-mannitol and (S)-(-)-2-methyl-2-propane sulfinamide or ascorbic acid and (R)-(-)-2-methyl-2-propane sulfinamide.

Full text of DOI:10.1039/b822779a

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Highly stereoselective methylene transfers onto butanediacetal-protected
chiral non-racemic sulfinyl imines using S-ylide technologyw
David C. Forbes,* Sampada V. Bettigeri and Susanna C. Pischek
Received (in College Park, MD, USA) 18th December 2008, Accepted 12th February 2009
First published as an Advance Article on the web 9th March 2009
DOI: 10.1039/b822779a
Diastereomeric ratios of 495 : 5 were obtained when performing
methylene transfers onto imines originating from D-mannitol and
(S)-(À)-2-methyl-2-propane sulfinamide or ascorbic acid and
(R)-(À)-2-methyl-2-propane sulfinamide.
Previously communicated from our laboratory was a novel
protocol for the preparation of methylphenylsulfonium
Scheme 2
methylide ii (Scheme 1).1 When prepared in situ, this sulfur
functionality, a drop in the diastereomeric ratio was observed
ylide has been shown to effectively trap aldehydes and ketones
when going from electron-deficient to electron-releasing
to form terminal epoxides and imines to form terminal
aryl-substituted imines.
aziridines.2
The ease by which sulfur ylide ii is generated is one key
When working at reaction temperatures below that of
refluxing THF, a moderate increase in stereoselection was
observed. This was, however, at the expense of percent
advantage of our method over other existing technologies.3
Generation of the sulfur ylide occurs upon decarboxylation of
conversion and still below the level of diastereocontrol
carboxylmethyl betaine functionality. The process does not
reported when working with the less stabilized dimethyl-
require the use of strong and often pyrophoric bases such as
sulfonium methylide under identical reaction conditions
butyl lithium or sodium hydride, does not require expensive
(dr = 93 : 7 with dimethylsulfonium methylide (84% isolated
metal catalysts, and is compatible with ecologically benign
yield at room temperature) and dr = 90 : 10 with methylphenyl-
solvent systems. However, the ‘ease by which the sulfur ylide is
sulfonium methylide ii (50% conversion at room temperature)).
generated’ as stated above does come at a price. That is,
In our search for alternative protocols for S-ylide generation
while proficient when considering both scope and levels of
that might be capable of sustaining highly stereoselective
conversion, the shortcomings of a protocol which relies on
refluxing THF for complete conversion of p-acceptor to
heterocycle are notable when considering asymmetry.
methylene transfers, we were intrigued by reports from Michel
and Ley using butane-2,3-diacetals as chiral building blocks.4
Butane-2,3-diacetals have not only been shown to be
Our entry into stereoselective methylene transfers began
effective substitutes for glyceraldehyde acetonide but highly
with the use of chiral non-racemic sulfinyl imines (Scheme 2).2b
stereodiscriminating. This might be best illustrated when
Reaction of thioacetate derivative 1 with a series of
aryl-substituted chiral non-racemic sulfinyl imines afforded
considering organometallic additions onto butanediacetal-
protected glyceraldehyde 2 (Scheme 3).4a
the corresponding aziridines in high yield and good
As our system ideally operates in warm THF and does not
stereoselection. A total of seven systems were examined
involve a chiral non-racemic sulfide promoter, the combina-
which consisted of both electron-deficient and electron-
tion of the above stereodirecting elements, tert-butylsulfinyl
releasing aryl-substituted chiral non-racemic imines. Upon
imine and butane-2,3-diacetal, posed an interesting question
in situ generation of the sulfur ylide via the thermally
involving stereoselective cycloadditions onto a p-acceptor.
induced decarboxylation of carboxymethylsulfonium betaine
Efforts to address the match/mismatch paradigm with
methylene transfers have been made and reported herein are
our findings in the stereoselective assembly of heterocylic
building blocks of aziridine functionality.
Methylphenylsulfonium methylide ii is best described as a
semi-stabilized ylide. While traditional points of stabilization
would focus on the alkylidene carbon, attachments onto the
sulfur moiety and even solvation of the intermediate itself have
Scheme 1
Department of Chemistry, University of South Alabama, Mobile,
AL 36688, USA. E-mail: dforbes@jaguar1.usouthal.edu;
Fax: +1 251 460 7359; Tel: +1 251 460 7423
w Electronic supplementary information (ESI) available: Experimental
and spectral data in the preparation of compounds 4 and 5,
the corresponding aziridines and control reactions. See DOI:
10.1039/b822779a
Scheme 3
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Table
glyceraldehyde
1
Methylene transfers onto butanediacetal-protected
Entry
1
Imine
Yield (%)a
92
drb
495 : 5
Scheme 4
2
3
88
89
78 : 22
79 : 21
also been shown to improve the half-lives of sulfur ylides.5
Accordingly, when used in excess quantities, extremely clean
methylene transfers have been documented onto a host of
p-acceptors. With a proven technology at hand, our attention
has now shifted toward stereoselective transformations. For
this study, our study began with the preparation of both
enantiomeric lines of BDA-protected sulfinyl imines.
Scheme 4 illustrates the preparation of one of the four systems
we examined.
4
94
495 : 5
a
b
Isolated chromatographically pure material. Determined by 1H
NMR (crude reaction mixture).
Starting from D-mannitol, butane-2,3-diacetal glyceraldehyde
3 was prepared in two steps using the experimental procedures
of Michel and Ley.4 Condensation of (S)-(À)-2-methyl-2-
propane sulfinamide with aldehyde 3 resulted in the synthesis
of imine 4 in excellent yield. Using (R)-(À)-2-methyl-2-
propane sulfinamide and aldehyde 3, the diastereomeric
isomer of 4 was prepared in again excellent yield. For ent-3,
ascorbic acid started the synthetic sequence and was prepared
following published reports.4 Once obtained (ent-3) identical
reaction conditions were used to prepare both diastereomers
(RS and SS). With all four systems at hand, we next examined
methylene transfers using sulfur ylides generated by the
decarboxylation of carboxymethyl betaine functionality. The
data from the study are presented in Table 1.
495 : 5 (entries 1 and 4, Table 1) has been achieved. Epimeric
changes to either the butanediacetal-protected diol or the
sulfinyl imine resulted in a drop of diastereoselectivity. While
the levels of conversion were on par when examining all
four butanediacetal-protected chiral non-racemic sulfinyl
imines, this series using both enantiomeric lines poses an
interesting question when considering the source of
asymmetry. Accordingly, a series of control reactions were
examined. The data from this study are presented in Table 2.
As previously reported by Stockman and co-workers,
reaction of sulfur ylides (dimethylsulfonium methylide) onto
cyclohexyl derivatives of tert-butylsulfinyl imine 6 resulted in
high levels of diastereocontrol (495 : 5).6 Warmer reaction
temperatures, not surprisingly, resulted in lower levels of
diastereocontrol using sulfonium salt 1 and imine 6 (61 : 39,
entry 1). Interestingly when switching from a semi-stabilized
ylide (ii) to dimethylsulfonium methylide using as p-acceptor
imine 4, an inextrictable crude reaction mixture was
obtained (entry 2). This reaction was repeated multiple times
at temperatures as low as 0 1C. While starting material was
consumed with each reaction, no evidence of aziridine
(nor oxirane when working with aldehyde 3) was observed
All reactions reported here were clean as judged by NMR
analysis of the crude reaction mixture. The analysis revealed
no by-products other than desired product with minor
diastereomer. This was validated based upon the isolated
yields obtained. Using as a baseline the data obtained when
performing methylene transfers with methylphenylsulfonium
methylide ii onto aryl-substituted chiral non-racemic sulfinyl
imines (dr ranging from 66 : 34 to 87 : 13),2b we were excited to
see such high levels of diastereoselectivity when working with
imine 4 (entry 1). The high isolated yield and 495 : 5
diastereomeric ratio was confirmed when working with ent-4
(entry 4). While entries 2 and 3 reveal slightly lower levels of
stereodiscrimination, these data points support not only the
trend within this enantiomeric series (5 and ent-5) but a
match/mismatch paradigm when performing methylene
transfers. Perhaps more significant with this study is the level
of diastereocontrol observed using the reaction conditions of
refluxing THF.
1
using dimethylsulfonium methylide based upon the H NMR
analysis. When working with a modified sulfinyl imine
7 (4-methylphenyl, entry 3) or butane-2,3-diacetal-protected
glyceraldehyde 3 itself (entry 4), lower levels of diastereo-
selectivity were observed.
While the present study did not establish the configuration
of the new aziridine stereocenter, the data presented in both
Tables 1 and 2 clearly document the need to have both
stereodiscriminating elements present for high levels of
diastereoselectivity. Even though there is ample precedent for
An increase in the diastereomeric ratio from a previous high
of 87 : 13 when working with aryl-substituted chiral
non-racemic sulfinyl imines (aryl being 4-nitrophenyl) to
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Table 2 Control reactionsa
The chemistry recently reported by Hodgson and
co-workers best illustrates the potential in that regioselective
ring-opening of the terminal aziridine bearing sulfinyl
functionality using PhMgBr in the presence of CuI would
allow for the installation of the benzyl functionality found in
both amprenivir and saquanivir.9 Switching PhMgBr with
thiophenol, an advanced intermediate used in the preparation
of nelfinavir can be realized. That is, the final steps toward the
preparation of N-protected 3-amino-1,2-epoxide 8 would
include deprotection of the aminodiol using HCl in dioxane,4,9
BOC-protection of the amine, and functional group inter-
conversion of the diol to epoxy functionality.8a,10
Yield
(%)b drc
Entry Sulfonium salt p-acceptor
1
81
61 : 39
d
2
3
4
—
In summary, a number of groups have demonstrated and
refined ingenious approaches toward the preparation of
homochiral carbo- and heterocyclic rings using sulfur ylide
technology. While our approach has several shortcomings in
that the decarboxylative process does not operate well at
or below ambient reaction temperatures, high levels of
diastereocontrol can be achieved. Diastereomeric ratios of
80
72
67 : 33
60 : 40
495
: 5 were obtained when performing methylene
transfers onto imines originating from the D-mannitol and
(S)-(À)-2-methyl-2-propane sulfinamide or ascorbic acid and
(R)-(À)-2-methyl-2-propane sulfinamide. Currently we are
active in examining the source of stereocontrol through
computational studies and applying this technology in the
assembly of materials of biological and medicinal importance.
Results from these studies will be reported in due course.
This work was supported in part by NIGMS (NIH NIGMS
1R15GM085936), NSF (CHE 0514004), and the Camille and
Henry Dreyfus Foundation (TH-06-008).
a
b
See ESIw for reaction details. Isolated chromatographically pure
material. Determined by 1H NMR (crude reaction mixture).
d
c
Inextrictable crude reaction mixture (1H NMR).
Fig. 1 Potential applications.
Notes and references
1 D. C. Forbes, S. R. Amin, C. J. Bean and M. C. Standen, J. Org.
Chem., 2006, 71, 8287.
2 (a) D. C. Forbes, S. V. Bettigeri, S. A. Patrawala, S. C. Pischek and
M. C. Standen, Tetrahedron, 2009, 65, 70; (b) D. C. Forbes,
S. V. Bettigeri, S. R. Amin, C. J. Bean, A. M. Law and
R. A. Stockman, Synth. Commun., in press.
3 D. C. Forbes, M. C. Standen and D. L. Lewis, Org. Lett., 2003, 5,
2283.
4 (a) P. Michel and S. V. Ley, Angew. Chem., Int. Ed., 2002, 41, 3898;
(b) P. Michel and S. V. Ley, Synthesis, 2003, 1598; (c) P. Michel
and S. V. Ley, Synthesis, 2004, 147.
highly discriminating additions onto either butanediacetal-
protected glyceraldehyde 24 or tert-butylsulfinamides such as
those present in a-chloroimines,7 our study which operates at
an elevated reaction temperature when compared to the pre-
vious two mandates both when performing stereoselective
methylene transfers onto butanediacetal-protected chiral
non-racemic sulfinyl imines.
We do believe the stereodiscriminating event is addition
onto the imine and not epimerization of the aziridine. Control
reactions which examined a solution of Cs2CO3 and the
aziridine using imine ent-5 did not result in a change of
diastereomeric ratio even after 10 h at reflux (Table 1,
entry 3). Furthermore, stopping the aziridination reaction
prematurely using imine 4 had the same diastereomeric ratio
as its endpoint of 495 : 5.
Synthesized terminal azirdines, both enantiomeric lines,
starting from imines 4 and ent-4 are interesting examples in
that they present a viable scaffold when considering the
assembly of systems of biological and medicinal significance.
Using as an example the three-carbon building block
N-protected 3-amino-1,2-epoxide 8, which is an intermediate
used in the assembly of many HIV protease inhibitors,8 our
approach serves as a viable alternative toward the preparation
of this advanced intermediate (Fig. 1).
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This journal is The Royal Society of Chemistry 2009
1884 | Chem. Commun., 2009, 1882–1884