Asymmetric vinylogous aldol reaction of silyloxy furans with a chiral organic salt

Article abstract of DOI:10.1021/ja103331t

Despite their synthetic significance there is a general lack of asymmetric vinylogous aldol reactions that tolerate variations of both the silyloxy furans and aldehydes. We have developed a new chiral organic catalyst based on a carboxylate-ammonium salt prepared from a thiourea-amine and a carboxylic acid. This new catalyst enabled us to develop an efficient asymmetric vinylogous aldol reaction of unprecedented scope with respect to both 2-trimethylsilyloxy furans and aldehydes.

Full text of DOI:10.1021/ja103331t

Published on Web 06/29/2010
Asymmetric Vinylogous Aldol Reaction of Silyloxy Furans with a Chiral
Organic Salt
Ravi P. Singh, Bruce M. Foxman, and Li Deng*
Department of Chemistry, Brandeis UniVersity, Waltham, Massachusetts 02454-9110
Received April 20, 2010; E-mail: deng@brandeis.edu
Scheme 1. Plausible Catalytic Cycle for Vinylogous Aldol Reaction
Abstract: Despite their synthetic significance there is a general
lack of asymmetric vinylogous aldol reactions that tolerate
variations of both the silyloxy furans and aldehydes. We have
developed a new chiral organic catalyst based on a carboxylate-
ammonium salt prepared from a thiourea-amine and a carboxylic
acid. This new catalyst enabled us to develop an efficient
asymmetric vinylogous aldol reaction of unprecedented scope
with respect to both 2-trimethylsilyloxy furans and aldehydes.
Chiral butenolides are a common structural subunit in natural
products1 and provide valuable chiral building blocks for the
asymmetric synthesis of biologically active compounds.2 Owing
to their synthetic significance, the development of efficient catalytic
methods for the generation of optically active butenolides has
attracted considerable attention.3 In particular asymmetric vinylo-
gous aldol reactions of 2-silyloxy furan and prochiral carbonyl
compounds have been investigated with both chiral metal and
organic catalysts.4 Significant progress has also been made in the
promotion of catalytic asymmetric vinylogous aldol reactions
between dihydrofuranone and aldehydes.5 Nonetheless, the develop-
ment of such asymmetric vinylogous aldol reactions that afford useful
levels of enantioselectivity and diastereoselectivity with both aryl and
alkyl aldehydes still represents a challenging task. Moreover there is
a general lack of catalytic methods that tolerate variations of both the
silyloxy furans and aldehydes. For example, there are only two
examples of anti-selective, highly enantioselective vinylogous aldol
reactions of silyloxy furans and aliphatic aldehydes, which are achieved
with a chiral Cu-bisoxazoline complex and chiral phase transfer
catalyst, respectively.4b,g However, the former affords useful enanti-
oselectivity and diastereoselectivity for only benzyloxyacetaldehyde
while the latter for only the 4-methyl-2-trimethylsilyloxy furan. Herein,
we report the design and development of a chiral organic catalyst
system that effectively promotes anti-selective asymmetric vinylogous
aldol reactions of various 2-trimethylsilyloxyfurans with aryl, alkenyl,
and alkyl aldehydes.
Earlier we reported a highly enantioselective addition of TMSCN
to R-acetal ketones with cinchona alkaloids as monofunctional chiral
Lewis base catalysts.6 Recently, modified cinchona alkaloids bearing
various hydrogen bond donors have been shown by us and others to
be efficient bifunctional chiral organic catalysts with a broad range of
asymmetric reactions, including 1,2-additions to carbonyls.7 These
precedents prompted us to explore 6′-OH, 6′- and 9-thiourea cinchona
alkaloids as bifunctional catalysts for the vinylogous aldol reactions
of 2-trimethylsilyloxyfuran (6a) and benzaldehyde (5A). As sum-
marized in Table 1 quinine and 6′-OH cinchona alkaloids Q-1 gave
very poor conversion (entries 1 and 2). On the other hand, the thiourea
catalysts Q-2 and Q-3 were found to be more active. However, even
the better catalyst Q-3 provided only modest enantioselectivity.
We recently determined the structure by X-ray crystallography
of a carboxylate ammonium salt Q-4a, which was derived from a
solution of Q-3 and m-chlorobenzoic acid in methanol (Scheme
1). As expected the quinuclidine nitrogen was protonated. Interest-
Table 1. Vinylogous Aldol Reaction with Cinchona Alkaloids
T
(°C)
%
Convb
drb
(anti/syn)
% ee
(anti)c
T
(°C)
%
Convb
drb
(anti/syn)
% ee
(anti)c
entry
Catalyst
entry
Catalyst
1
2
3
4
Quinine
Q-1
Q-2
23
23
23
23
∼8
∼5
86
ND
ND
59:41
63:37
-
-
-26
73
5
6
Q-4a
Q-4b
Q-4c
Q-4c
23
23
23
64
68
77
96
74:26
69:31
81:19
95:5
79
70
88
95
7
Q-3
54
8d
-20
a Unless noted, reactions were performed with 0.1 mmol of 5A and 0.15 mmol of 6a in 0.2 mL of CH2Cl2 with 10 mol % of catalyst. b Determined
by 1H NMR analysis. c Determined by HPLC analysis. d Reaction was performed in 0.1 mL of Et2O/CH2Cl2 (1/1) for 96 h.
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9558 J. AM. CHEM. SOC. 2010, 132, 9558–9560
10.1021/ja103331t  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Reactions of 5 and 6a with Q-4c (QD-4c)
Figure 1. Structure of cinchona alkaloid catalysts.
IV. In this proposed catalytic cycle the carboxylate is postulated
to serve a dual role: activating the silyloxy furan 6a and facilitating
the silyl transfer from 6a to the aldolate product. It should be noted
that the second function was also speculated to be responsible for
the beneficial effect of the carboxylate ligand on asymmetric aldol9
and vinylogous aldol reactions10 mediated by metal-based chiral
Lewis acids.
We were pleased to find that the salt Q-4a, prepared by simply
mixing Q-3 and m-chlorobenzoic acid in a 1:1 ratio, furnished
improved activity and selectivity over those by Q-3 under identical
conditions (entry 4 vs 5, Table 1). Upon investigation of various
carboxylic acids we found the reaction occurred in a highly
diastereo- and enantioselective fashion with the trifluoroacetic acid
derived salt Q-4c (Table 1, entry 7). A further improved reaction
was achieved at -20 °C in Et2O/CH2Cl2 (1:1), affording the anti-
adduct 7Aa in 95/5 dr and 95% ee.
Under the optimized conditions the Q-4c catalyzed reactions of
6a and various aldehydes (5A-P) were investigated. Aryl and
heteroaryl aldehydes (5A-K) were converted into the correspond-
ing anti-adduct 7 in 84/16 to 95/5 dr, 91-95% ee, and 71-94%
yield (Table 2). Useful diastereoselectivity and enantioselectivity
could be attained with alkenyl (5L) and, most significantly, alkyl
aldehydes (5M-P). These results constitute significant progress
for asymmetric vinylogous aldol reactions of silyloxy furans and
this class of synthetically useful but highly challenging aldehydes.
We also investigated the reaction with various substituted 2-trim-
ethylsilyloxy furans (6b-e) (Table 3). Remarkably, the catalyst
4c even afforded useful selectivity for reactions of sterically
hindered 5-substituted-2-trimethylsilyloxy furans 6c-e, which
generate chiral adducts bearing adjacent tertiary-quaternary centers.
In summary, we have developed a readily accessible and efficient
organic catalyst based on a carboxylate ammonium salt prepared
by mixing a thiourea-amine and a carboxylic acid. This new catalyst
enabled us to develop an efficient asymmetric vinylogous aldol
reaction of 2-trimethylsilyloxy furans and aldehydes of unprec-
a Unless noted, reactions were performed with 0.25 mmol of 5, 0.37
mmol of 6a, and 10 mol % of Q-4c in 0.25 mL of solvent. b Unless
noted, isolated yield of vinylogous aldol adduct 7 with ratio of anti/syn
diastereomers indicated. c Determined by 1H NMR analysis of crude
reaction mixture. d Determined by HPLC analysis. e The results in
parentheses were obtained with QD-4c; see Supporting Information (SI)
for details. f The absolute configuration of the aldol adduct anti-7Ea was
established by X-ray crystallographic analysis (see SI). g Isolated yield
of pure anti-7. h Reaction was run with 1.25 mmol of 5M and 0.25
mmol of 6a and 10 mol % of Q-4c in 0.25 mL of solvent. i Reaction
was performed with 20 mol % of Q-4c.
ingly, the carboxylate was found to bind to the thiourea moiety
through hydrogen-bonding interactions8 instead of forming a tight
ion pair with the quinuclidinium cation. We envisaged a catalytic
cycle for a Q-4a-promoted vinylogous aldol reaction (Scheme 1).
Presumably, the hydrogen-bonded carboxylate could react with
silyloxy furan 6a to form the corresponding trimethylsilylester and
the 2-furoxy anion while releasing a thiourea-NH that could serve
as a hydrogen bond donor to activate aldehyde 5A (Intermediates
I and II). With the 2-furoxy anion and aldehyde 5A interacting
with the protonated quinuclidine and thiourea-NH, respectively, the
reaction between the two reactants might proceed in a highly
diastereoselective and enantioselective fashion (Intermediate III).
Importantly, the silyl transfer step should be facile in light of the
proximity of the trimethylsilylester and the aldolate in intermediate
Table 3. Reaction with Substituted 2-Silyloxy Furan
entrya
5
R
6
R1
R2
T(°C)
yieldb (%)
drc
% eed (major)
1
2
3f
4
5
5A
5N
5A
5A
5A
Ph
6b
6b
6c
6d
6e
Me
Me
Me
H
H
H
0
0
rt
-10
-10
75
62
77
65
70
93:7e
80:20e
95:5g
95:5g
96:4g
94
87
85
81
84
PhCH2CH2
Ph
Ph
Ph
Me
CH3CH2
CH2CHdCH2
H
a Unless noted, reactions were run with 0.1 mmol of aldehyde, 0.15 mmol of 6, and 10 mol % of Q-4c in 0.1 mL of Et2O. b Isolated yield of
c
vinylogous aldol adduct 7 with ratio of anti/syn diastereomers indicated in the SI. Determined by H NMR analysis of crude reaction mixture. d ee of
major diastereomer as determined by HPLC analysis. e Ratio of anti/syn diasteromers. f Reaction was run with 10 mol % of QD-4c (see SI). g Anti/syn
diastereomers not determined.
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C O M M U N I C A T I O N S
edented scope with respect to both reactants.11 As a broad range
of both chiral amine-ureas and carboxylic acids are readily available,
such chiral salts provide a new class of easily tunable chiral
catalysts. Finally, the cooperative and multifunctional catalysis by
these chiral salts designed for the promotion of the asymmetric
vinylogous aldol reactions should in principle be applicable to a
range of other asymmetric reactions.
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Acknowledgment. This paper is dedicated to Professor Eric
N. Jacobsen on the occasion of his 50th birthday. We are grateful
for the generous financial support from National Institutes of Health
(GM-61591).
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.
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