Organocatalytic asymmetric oxy-Michael addition to a γ-hydroxy- α,β-unsaturated thioester via hemiacetal intermediates

Article abstract of DOI:10.1039/c2cc31602a

We report an asymmetric oxy-Michael addition to a γ-hydroxy-α, β-unsaturated thioester via hemiacetal intermediates in the presence of Cinchona-alkaloid-thiourea-based bifunctional organocatalysts. This method provides a novel enantioselective route to β-hydroxy carboxyl compounds, which in turn can be used to synthesize valuable chiral building blocks.

Full text of DOI:10.1039/c2cc31602a

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Chemical Communications
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Volume 48 | Number 42 | 25 May 2012 | Pages 5045–5200
ISSN 1359-7345
COMMUNICATION
Keisuke Asano, Seijiro Matsubara et al.
Organocatalytic asymmetric oxy-Michael addition to a γ-hydroxy-α,β-unsaturated thioester via hemiacetal
intermediates

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Cite this: Chem. Commun., 2012, 48, 5076–5078
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COMMUNICATION
Organocatalytic asymmetric oxy-Michael addition to a c-hydroxy-a,
b-unsaturated thioester via hemiacetal intermediateswz
Takaaki Okamura, Keisuke Asano* and Seijiro Matsubara*
Received 3rd March 2012, Accepted 23rd March 2012
DOI: 10.1039/c2cc31602a
We report an asymmetric oxy-Michael addition to a c-hydroxy-
a,b-unsaturated thioester via hemiacetal intermediates in the
presence of Cinchona-alkaloid-thiourea-based bifunctional organo-
catalysts. This method provides a novel enantioselective route to
b-hydroxy carboxyl compounds, which in turn can be used to
synthesize valuable chiral building blocks.
aldehydes have been used as substrates, and there are very few
demonstrations of asymmetric oxy-Michael addition to a
higher-oxidation-state substrate such as an a,b-unsaturated
carboxylic acid derivative,10a,13 which can be an alternative to
the acetate aldol reaction.14
We recently reported intramolecular oxy-Michael addition
reactions mediated by Cinchona-alkaloid-thiourea-based
bifunctional organocatalysts.15 By our protocol, enantioselective
oxy-Michael addition to g-hydroxy-a,b-unsaturated ketones via
hemiacetal intermediates was realized, and 1,3-dioxolanes
bearing an easily removable acetal functionality were obtained
(Scheme 1).15a Although the diastereoselectivity of this reaction
was only moderate, the absolute configurations at the b-positions
of the carbonyl group were consistent in both diastereomers;
further, this reaction proceeded with high enantioselectivity.
Therefore, we sought to apply the abovementioned method to
reactions in which carboxylic acid derivatives were used as
substrates. Herein, we present a novel asymmetric oxy-Michael
addition to a g-hydroxy-a,b-unsaturated carboxylic acid derivative
via a hemiacetal intermediate in the presence of bifunctional
organocatalysts derived from Cinchona alkaloids.6,16
b-Hydroxy carbonyl compounds are important synthetic inter-
mediates, and they exist as structural motifs in a variety of
natural products; hence, considerable efforts have been devoted
to their stereoselective synthesis.1 One of the most notable methods
for the enantioselective synthesis of b-hydroxy carbonyls, besides
the aldol reaction2 and the hydrogenation of b-ketoesters,3 is
the conjugate addition of oxygen-centred nucleophiles to
a,b-unsaturated substrates.4 Direct hydration of a,b-unsaturated
substrates by the conjugate addition of water is challenging
because of the low nucleophilicity of water, high reaction
reversibility, and the difficulty involved in efficient stereochemical
control.5 Nevertheless, several protocols for stereoselective formal
hydration using O-nucleophiles bearing a removable group have
been developed.6–11 Catalytic enantioselective reactions involving
the conjugate addition of benzyl alcohol8 or allyl alcohol9 suffer
from drawbacks similar to those observed when using water as
the nucleophile. However, the use of an oxime10a–c or hydrogen
peroxide10d as a water surrogate is advantageous because of its
high nucleophilicity; the labile N–O or O–O bond facilitates the
subsequent reductive cleavage, leading to free b-hydroxy
products. Another efficient route is intramolecularization12
using boronic acid hemiesters generated in situ from g-hydroxy-
a,b-unsaturated ketones and boronic acids; the hemiester
undergoes intramolecular oxy-Michael addition to form a
dioxaborolane, which then affords the corresponding optically
active b,g-dihydroxy ketone upon oxidative hydration.11 However,
in most of the reported examples, a,b-unsaturated ketones or
Initially, we employed the optimized conditions reported in our
previous work of the reaction with g-hydroxy-a,b-unsaturated
ketones as substrates (Table 1).15a The reaction of g-hydroxy-
a,b-unsaturated ester 1a with cyclohexanecarboxaldehyde (2a)
in the presence of quinidine-based bifunctional catalyst 4a
(Fig. 1) did not proceed at all, presumably because of the poor
electrophilicity of the substrate (Table 1, entry 1). Phenyl ester
1b afforded the desired products, albeit in very low yield
(Table 1, entry 2). In order to increase the electrophilicity of
the substrate, we used some thioesters as substrates (Table 1,
entries 3–6).17 Thioester 1c afforded the corresponding product
Department of Material Chemistry, Graduate School of Engineering,
Kyoto University, Kyotodaigaku-Katsura, Nishikyo, Kyoto 615-8510,
Japan. E-mail: keisuke.asano@t03kr913mk.mbox.media.kyoto-u.ac.jp,
matsubar@orgrxn.mbox.media.kyoto-u.ac.jp; Fax: +81 75 383 2438;
Tel: +81 75 383 2440
w This article is part of the joint ChemComm–Organic & Biomolecular
Chemistry ‘Organocatalysis’ web themed issue.
z Electronic supplementary information (ESI) available: Experimental
procedures, analytical and spectroscopic data for synthetic compounds,
copies of NMR and HPLC spectra. See DOI: 10.1039/c2cc31602a
Scheme 1 Oxy-Michael addition via hemiacetal intermediates to
g-hydroxy-a,b-unsaturated ketones via hemiacetal intermediates.
c
5076 Chem. Commun., 2012, 48, 5076–5078
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Table 1 Optimization of substratesa,b
Table 3 Optimization of aldehydes and ketones 2a,b
Entry R1
R2
2
Yieldc (%) ee (%) (3,30) dr (3/30)
1
2
3
4
5
6
7
8d
Cy
Et
i-Pr
t-Bu
CF3
H
H
H
H
Ph
2a 90
2b 99
2c 99
2d 73
96, 81
95, 88
96, 87
99, 97
69, 72
N. D.
99
4.4
3.4
3.8
3.5
1.1
—
Entry
1
Yieldc,d (%)
ee (%) (3, 30)
dr (3/30)
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
0 (97)
—
—
2e
99
o5
13 (87)
18 (69)
7 (o1)
62 (38)
28 (60)
96, 84
94, 61
97, 87
97, 84
93, 85
3.0
3.6
3.7
4.3
4.0
CH3 CH3 2f
–(CH2)5–
H
2g 31
2h 86
—
—
H
72
a
Reactions were run using 1e (0.25 mmol), 2 (0.5 mmol), and 4a
b
(0.025 mmol) in CPME (0.5 mL). CPME = cyclopentyl methyl ether.
a
Reactions were run using 1 (0.25 mmol), 2a (0.25 mmol), and 4a
b
(0.025 mmol) in CPME (0.5 mL). CPME = cyclopentyl methyl ether.
c
d
Isolated yields. Reaction was run using aqueous formaldehyde
c
Isolated yields. d Values in parentheses show the starting material recovery.
(37% solution, 0.5 mmol).
the amount of 2a, concentration, and reaction time helped
improve the yield to a practical level with only a slight decrease
in the enantioselectivity (Table 2, entry 5). Catalyst screening
showed that 4c (Fig. 1) efficiently catalyzes the reaction to
afford opposite enantiomers of the products in good yield and
with high enantioselectivity (Table 2, entry 8).
Using the optimized reaction conditions and 4a as a catalyst, we
subsequently investigated the reactions of some other aldehydes
and ketones 2 (Table 3).18 Although aryl aldehydes were much less
reactive,19 some aliphatic aldehydes 2b–2d gave the corresponding
products in high yields and with good enantioselectivities (Table 3,
entries 2–4). Pivalaldehyde (2d) proved to be a good counter-
part and gave excellent enantioselectivity for both diastereomers
(Table 3, entry 4). An electron-deficient ketone such as 2e could
also be employed in the reaction; however, the enantioselectivity
was only moderate in this case (Table 3, entry 5). Although the
use of a symmetric ketone or aldehyde would circumvent the
generation of diastereomers, the reaction using acetone (2f) was
sluggish (Table 3, entry 6), and the yield obtained from cyclo-
hexanone (2g) was low despite the excellent enantioselectivity
(Table 3, entry 7). On the other hand, aqueous formaldehyde
(2h) afforded the product in acceptable yield, but the enantio-
selectivity was unsatisfactory, probably because of the presence
of water (Table 3, entry 8).
Fig. 1 Bifunctional organocatalysts derived from Cinchona alkaloids.
in higher yield than did the abovementioned esters (Table 1,
entry 3). Benzenethiol ester 1d also gave the desired products
in low yield, but when thioesters bearing bulkier aryl groups
were employed, side reactions were suppressed to a great extent.
2,6-Dimethylbenzenethiol ester 1e was identified as the best
substrate in terms of the product yield (Table 1, entries 4–6).
We next optimized the reaction conditions using 1e as the
substrate (Table 2). After screening a number of solvents, we
found that cyclopentyl methyl ether (CPME) was the optimum
solvent in terms of both yield and stereoselectivity (Table 2,
entries 1–5). Further modification of other conditions such as
Table 2 Optimization of reaction conditionsa,b
To demonstrate the utility of the proposed method, we extended
the optimized reaction to the asymmetric syntheses of some
b-hydroxy carboxyl compounds (Scheme 2). Oxy-Michael addition
to 1e using 2d as the source of an oxygen-centred nucleophile in the
presence of 13 mol % 4a on the 2 mmol scale afforded the products
3ed and 3ed0 in 3.8 : 1 diastereomeric ratio, with excellent enantio-
selectivity. Subsequent treatment of the diastereomixture of 3ed
and 3ed0 with titanium tetrachloride led to the generation of a free
b,g-dihydroxy product 5 with high optical purity while keeping the
thioester group intact. Alternatively, treatment of the diastereo-
mixture with p-toluenesulfonic acid in aqueous medium gave
b-hydroxy-g-butyrolactone 6, a versatile chiral synthetic
intermediate20 that could be transformed into (L)-carnitine
(7), an important bioactive agent, via a reported procedure.21
Taking advantage of the thioester functionality, we carried
out functional group transformations of 3ed, and found that
Entry Catalyst Solvent Yieldc,d (%) ee (%) (3ea, 3ea0) dr (3ea/3ea0)
1
2
3
4
4a
4a
4a
4a
4a
4a
4b
4c
4d
CPME 62 (38)
THF
Et2O
Benzene 60 (o1)
CH2Cl2 43 (1)
CPME 90 (8)
CPME 89 (1)
CPME 90 (6)
CPME 90 (6)
97, 84
96, 76
97, 87
94, 84
95, 73
96, 81
95, 74
–94, –59
–91, –47
4.3
4.3
3.9
3.4
4.1
4.4
3.5
4.2
4.1
20 (78)
65 (12)
5
6e
7e
8e
9e
a
Reactions were run using 1e (0.25 mmol), 2a (0.25 mmol), and the
b
catalyst (0.025 mmol) in the solvent (0.5 mL). CPME = cyclopentyl
c
methyl ether. Isolated yields. Values in parentheses show the starting
e
material recovery. Reactions were run using 0.50 mmol of 2a in
0.25 mL of CPME for 48 h.
d
c
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Chem. Commun., 2012, 48, 5076–5078 5077

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and Y. G. Kim, Tetrahedron: Asymmetry, 2005, 16, 3762; (c) H. Kim,
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Tetrahedron, 1989, 45, 7397; (e) A. Bernardi, S. Cardani, C. Scolastico
and R. Villa, Tetrahedron, 1990, 46, 1987; (f) S. Cardani, C. Scolastico
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Scheme 2 Application of the proposed protocol to asymmetric
syntheses of b-hydroxy carboxyl compounds.
Scheme 3 Transformations of the thioester group of 3ed.
the chiral acetal moiety was unaffected after the transformations
(Scheme 3).15a,22 Reduction of 3ed with lithium aluminium hydride
afforded the corresponding primary alcohol 8 quantitatively
without loss of optical purity. Besides, Liebeskind–Srogl cross
coupling enabled the replacement of the arylthio group of 3ed
to give ketone 9, indicating that these thioester products can
be easily transformed into various chiral ketones.23
In conclusion, we have developed a novel asymmetric oxy-
Michael addition reaction to the a,b-unsaturated carboxylic
acid derivative. The use of a suitable g-hydroxy-a,b-unsaturated
thioester allowed for enantioselective oxygen induction via
hemiacetal formation, and subsequent deacetalization afforded
valuable optically active b-hydroxy carboxyl compounds.
Further studies on the application of this methodology to the
asymmetric syntheses of various chiral materials, including
natural products, are currently underway in our laboratory.
This research was supported financially by the Japanese
Ministry of Education, Culture, Sports, Science and Technology.
K.A. also acknowledges the Japan Society for the Promotion of
Science for Young Scientists for fellowship support.
14 For reviews, see: (a) S. Masamune, W. Choy, J. S. Petersen and
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17 See ESIz for the electrophilicity of thioesters.
18 See ESIz for determination of the configurations of the products.
19 See ESIz for details.
Notes and references
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c
5078 Chem. Commun., 2012, 48, 5076–5078
This journal is The Royal Society of Chemistry 2012