Catalytic asymmetric conjugate addition of simple alkyl thiols to α,β-unsaturated N-acylated oxazolidin-2-ones with bifunctional catalysts

Full text of DOI:10.1021/ja8085092

Published on Web 12/29/2008
Catalytic Asymmetric Conjugate Addition of Simple Alkyl Thiols to
r,ꢀ-Unsaturated N-Acylated Oxazolidin-2-ones with Bifunctional Catalysts
Yan Liu, Bingfeng Sun, Baomin Wang, Matthew Wakem, and Li Deng*
Department of Chemistry, Brandeis UniVersity, Waltham, Massachusetts 02454-9110
Received September 25, 2008; E-mail: Deng@brandeis.edu
Optically active chiral thiols and sulfides have seen broad
applications as biologically interesting compounds,1 ligands for
metallic catalysts,2 organic catalysts3 and chiral auxiliaries.4 The
asymmetric conjugate additions with sulfur-nucleophile, or sulfa-
Michael additions, constitute a direct and versatile approach toward
optically active chiral sulfur compounds. This strategy is particularly
valuable, since enantioselective nucleophilic additions to a
carbon-sulfur double bond, unlike those to carbonyls and imines,
are not synthetically viable.5 Accordingly considerable efforts have
been devoted to the development of catalytic enantioselective sulfa-
Michael reactions.
Several effective chiral metallic and organic catalysts have been
developed for conjugate additions of aryl thiols to various Michael
acceptors.6 However, the development of effective catalysts for
asymmetric sulfa-Michael reactions involving the less active but
synthetically more useful simple alkyl thiols remains a significant
challenge.7 To date only iminium catalysis by chiral secondary
amines has afforded high enantioselectivity for conjugate additions
of simple alkyl thiols to R,ꢀ-unsaturated aldehydes and ketones.8
Although providing a significant breakthrough in the asymmetric
synthesis of optically active sulfur compounds, due to the sensitive
nature of thiols and sulfides toward oxidations, these reactions do
not provide straightforward access to valuable chiral sulfur com-
pounds such as ꢀ-mercapto acid derivatives,9 which contain
functionalities of higher oxidation state. Currently, such thiol
compounds are only accessible by chiral auxiliary-directed conju-
gate additions.10 Herein we report the use of acid-base bifunctional
catalysts to realize a highly enantioselective sulfa-Michael reaction
of simple alkyl thiols to R,ꢀ-unsaturated N-acylated oxazolidin-2-
ones, an R,ꢀ-unsaturated carboxylic acid derivative. Being comple-
mentary in scope to existing catalytic asymmetric sulfa-Michael
reactions of alkyl thiols, this reaction provides a uniquely valuable
method for the enantioselective synthesis of chiral sulfur compounds.
Cinchona alkaloids have a venerable history in the development
of enantioselective catalytic sulfa-Michael reactions.11 However,
it is until recently that a modified cinchona alkaloid was found to
afford a useful level of enantioselectivity for asymmetric conjugate
additions with aryl thiols.6c Later acid-base bifunctional catalysis
by cinchona alkaloids has also been extended to a sulfa-Michael
reaction of aryl thiols to R,ꢀ-unsaturated carboxylic acid deriva-
tives.12 However, our attempts to identify an effective catalyst from
literature-reported cinchona alkaloid catalysts for the addition of
benzyl thiol (6a) to R,ꢀ-unsaturated N-acylated oxazolidin-2-one
5a were unsuccessful. As summarized in Table 1, natural cinchona
alkaloids such as quinidine failed to promote the conjugate addition
(entry 1, Table 1). Other bifunctional cinchona alkaloids such as
the 6′-OH cinchona alkaoids 2 and 9-thiourea cinchona alkaloid 3
afforded only modest enantioselectivity for the addition of 6a to
5a, although both have been shown to be highly effective catalysts
for the promotion of numerous asymmetric conjugate additions
involving a wide range of donors and acceptors.13-15
Figure 1. Cinchona alkaloids 1-4.
Table 1. Conjugated Addition of 6a to 5a with Cinchona Alkaloidsa
entry
catalyst
time (h)
conv (%)b
ee (%)c
1
2
3
4
5
6
7
8
1
24
24
24
24
24
24
5
5
5
5
5
0
5
11
40
15
N.D.
47
40
44
49
45
68
73
70
80
84
85
2a
2b
2c
2d
3
4a
4b
4c
4d
4e
4f
95
>99
>99
>99
>99
>99
>99
9
10
11
12
5
a See Supporting Information (SI) for details. b Conversion
determined by 1H NMR. c Ee determined by HPLC (column OD)
analysis (see SI).
We noticed that the acidity of the hydrogen bond donor motifs
in cinchona alkaloids 1-3 has a significant impact on their catalytic
activity (entries 1-6, Table 1). The activity of the catalyst improves
as the acidity of the hydrogen bond donor increases. Although the
enantioselectivities obtained with cinchona alkaloids 1-3 were not
promising, results from our initial studies suggested that further
investigations should focus on cinchona alkaloids bearing a strong
hydrogen bond donor and a readily tunable handle. Thus we began
to synthesize and screen various 6′-thiourea cinchona alkaloids 4,
although such catalysts had never been shown to be effective
catalysts for asymmetric conjugate addition reactions.16 Indeed, the
6′-thiourea cinchona alkaloids 4 afforded considerably better activity
than that by catalysts 1-3 (entries 7-12 vs 1-6). Furthermore,
the structure of the 9-substituent was found to have a considerable
9
418 J. AM. CHEM. SOC. 2009, 131, 418–419
10.1021/ja8085092 CCC: $40.75
2009 American Chemical Society

C O M M U N I C A T I O N S
influence on the enantioselectivity of 4. Our catalyst screening and
tuning studies led to the discovery that 4f, a cinchona alkaloid not
yet reported in the literature, could afford promising enantioselec-
tivity at room temperature (entry 12). By lowering the reaction
temperature to -20 °C, the 4f-catalyzed reaction of 6a and 5a
generated the corresponding 1,4-adduct 7a in 94% ee and nearly
quantitative yield (entry 1, Table 2).
In summary we have developed an unprecedented catalytic
enantioselective conjugate addition of simple alkyl thiols 6 to R,ꢀ-
unsaturated N-acylated oxazolidin-2-ones 5. The reaction allows
employment of a wide range of alkyl thiols while tolerates a
considerable degree of variations of the Michael acceptor. Conse-
quently, the current reaction provides a useful catalytic method for
the synthesis of optically active chiral sulfur compounds that are
otherwise difficult to prepare by asymmetric catalysis. Notably, the
current study also revealed that, upon suitable tuning, the 6′-thiourea
cinchona alkaloids 4 could afford efficient catalysis for asymmetric
conjugate additions that cannot be promoted in comparable ef-
ficiency with existing catalysts.
We were pleased to find that the high efficiency demonstrated
by 4f for the model reaction could be sustained for reactionsem-
Table 2. Conjugated Addition of 6 to 5 with 4fa
Acknowledgment. We are grateful for financial support from
the NIH (GM-61591). We acknowledge Brandeis University Mass
Spectrometry Facility (BUMS) for MS analysis.
entry
R
R′
t (°C) yield (%)b ee (%)c
Supporting Information Available: Experimental procedures and
characterization of the products. This material is available free of charge
via the Internet at http://pubs.acs.org.
1
2
3
4
5
6
7
8
Me (5a)
Me (5a)
Me (5a)
Me (5a)
Me (5a)
Me (5a)
Me (5a)
Me (5a)
Bn (6a)
-20
-20
-20
-20
98
99
99
98
97
95
92
91
96
97
98
96
98
96
97
99
95
93
84
94
91
94
93
96
92
93d
92
92
90
94
94
91
93
93
95
94
93
87
94
93
92
96
4-ClBn (6b)
4-OMeBn (6c)
C6H5CH2CH2 (6d)
TBSOCH2CH2 (6e) -20
TESOCH2CH2 (6f) -20
TMSCH2CH2 (6g)
i-Bu (6h)
Cyclopentyl (6i)
Allyl (6j)
4-OMeBn (6c)
4-OMeBn (6c)
4-OMeBn (6c)
4-OMeBn (6c)
4-OMeBn (6c)
4-OMeBn (6c)
4-OMeBn (6c)
Allyl (6j)
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ploying a broad range of alkyl thiols. As summarized in Table 2 (entries
1-10), in the presence of 4f, reactions with alkyl thiols containing
either an aromatic or simple aliphatic group consistently proceeded in
excellent enantioselectivity. Even secondary thiols, either acyclic (6h)
or cyclic (6i), could be applied in the reaction. The presence of various
functional groups in the alkyl thiols is well tolerated by the catalyst.
Importantly, the catalyst also demonstrated a considerable latitude in
accommodating steric as well as electronic variations of the ꢀ-sub-
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reaction accommodates both a ꢀ-alkyl and -aryl substituent and
afforded a similarly high enantioselectivity for γ-branched or -un-
branched Michael acceptors (entry 13 vs 12). As demonstrated in the
conversion of the 1,4-adduct 7l to a ꢀ-mercapto ester (9), this new
catalytic enantioselective reaction provided a facile entry into chiral
sulfur compounds bearing a functional group of high oxidation state
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Scheme 1. Asymmetric Synthesis of ꢀ-Mercapto Ester 9
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