Klebsiella pneumoniae (NBRC 3319) mediated asymmetric reduction of α-substituted β-oxo esters and its application to the enantioiselective synthesis of small-ring carbocycle derivatives

Article abstract of DOI:10.1002/ejoc.201101695

Ketoreductases from Klebsiella pneumoniae (NBRC 3319) selectively reduce several 2-substituted ethyl 3-oxobutyrates to yield the corresponding syn-β-hydroxy esters with remarkable stereocontrol (de > 99%, ee > 99%). The enantiopure hydroxy oxo esters were

Full text of DOI:10.1002/ejoc.201101695

FULL PAPER
DOI: 10.1002/ejoc.201101695
Klebsiella pneumoniae (NBRC 3319) Mediated Asymmetric Reduction of
α-Substituted β-Oxo Esters and Its Application to the Enantioiselective
Synthesis of Small-Ring Carbocycle Derivatives
Rajib Bhuniya,[a] Tridib Mahapatra,[a] and Samik Nanda*[a]
Keywords: Ketoreductases / Biotransformations / Small ring systems / Asymmetric synthesis
Ketoreductases from Klebsiella pneumoniae (NBRC 3319) se-
lectively reduce several 2-substituted ethyl 3-oxobutyrates to
yield the corresponding syn-β-hydroxy esters with remark-
able stereocontrol (de Ͼ 99%, ee Ͼ 99%). The enantiopure
hydroxy oxo esters were synthetically manipulated to access
new small-ring carbocycles.
catalysts can be accumulated inexpensively within
a
Introduction
shorttime. Several recombinant ketoreductase strains are
also available, which require an efficient cofactor recycling
system.
Optically pure secondary alcohol functionalities are pres-
ent in many biologically active natural products and active
pharmaceutical ingredients. They can be efficiently synthe-
sised in numerous ways. Asymmetric reduction of a prochi-
ral carbonyl group by chemical[1] or biocatalytic routes[2]
constitute two efficient methods to access these compounds.
Kinetic resolution is an alternative synthetic strategy (enan-
tioselective oxidation of racemic alcohols[3] or acyl transfer
by hydrolases),[4] which has been employed for the synthesis
of enantiopure secondary alcohols. However, the yield of
the resolution process is limited to 50% in favour of one
enantiomer. Enantioselective deracemisation,[5] dynamic ki-
netic resolution with in situ racemisation[6] of the slow-re-
acting enantiomer and deracemisation by stereoinversion[7]
are strategies that have been used to overcome the 50%
yield limitation. The asymmetric reduction of a prochiral
carbonyl compound by ketoreductases is unique in that it
can yield 100% of one stereoisomer. There has been phe-
nomenal growth in asymmetric bioreduction processes for
the synthesis of enantiopure secondary alcohols by various
microbial and plant ketoreductases in the last two dec-
ades.[8] Crude whole cells of several microbial ketoreduct-
ases (growing or resting cells of different ketoreductase-pro-
ducing microorganisms) often lead to enantiopure second-
ary alcohols as products with a commendable range of en-
antio- and diastereoselectivities and yields (high space–time
yield).[9] As the cells are self-replicating and require simple
2-Substituted β-oxo esters are good substrates for several
ketoreductase enzymes, and numerous studies have demon-
strated the successful application of this class of enzymes
to yield β-hydroxy esters in a stereocontrolled way.[8,10] In a
preliminary report by Miya et al.,[11] ketoreductases from
Klebsiella pneumoniae stereoselectively reduced different es-
ters of 2-methyl-3-oxobutanoic acids to yield the corre-
sponding β-hydroxy esters [ee = 99%, diastereomeric excess,
de = 99% in favour of (3R,4S) stereoisomers]. Enantiopure
β-hydroxy esters are useful intermediates for the synthesis
of the corresponding hydroxy acids, aldehydes and other
useful small organic molecules. We are interested in the de-
velopment of efficient chemoenzymatic processes to synthe-
sise small organic molecules in an asymmetric fashion. As
the substrate spectrum of the ketoreductase from Klebsiella
pneumoniae has not been explored, we targeted the use of
different 2-substituted β-oxo esters as potential substrates
for the enzyme to synthesise β-hydroxy esters in an enantio-
pure fashion. We intend to use the enzymatically synthe-
sised β-hydroxy esters for the effective construction of use-
ful molecules such as oxetanes, β-lactones, carbohydrate
mimics and functionalised cyclopentane and cyclohexane
frameworks (Scheme 1).
Results and Discussion
nutrients for their growth, huge amounts of whole-cell bio-
In an earlier stage of our work, we prepared different 2-
substituted β-oxo esters by a standard method.[12] A se-
lected strain of Klebsiella pneumoniae, which contains keto-
reductases of proven high activity, was obtained from
NBRC, Japan, and stored in glycerol (50% v/v) at –20 °C.
Klebsiella pneumoniae cells were grown in YM glucose me-
[a] Department of Chemistry, Indian Institute of Technology,
Kharagpur 721302, India
Fax: +91-3222-282252
E-mail: snanda@chem.iitkgp.ernet.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101695.
Eur. J. Org. Chem. 2012, 1597–1602
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1597

R. Bhuniya, T. Mahapatra, S. Nanda
FULL PAPER
Scheme 1. Klebsiella pneumoniae (NBRC 3319) mediated synthesis of various 2-substitited β-hydroxy esters and proposed synthetic manip-
ulations.
Scheme 2. Exclusive formation of syn-β-hydroxy oxo esters by Klebsiella pneumoniae.
dium in a 500 mL conical flask for 24 h. The substrates (2- 10, the absolute configuration was assigned by chemical
substituted β-oxo esters) were directly added to the growing analogy.
cells in an orbital incubator shaker at 30 °C. The product
formation was monitored periodically by TLC. It usually
took 2–5 d for quantitative conversion, and the products
were extracted with organic solvents and purified by stan-
dard techniques (chromatography). The product distribu-
tion lies exclusively in favour of syn-β-hydroxy oxo esters
(2R,3S), which was confirmed by comparing the optical ro-
Table 1. Klebsiella pneumoniae (NBRC 3319) mediated synthesis of
various 2-substituted β-hydroxy esters.
1
tations and H NMR spectroscopic data (Scheme 2).
It was observed that ketoreductase from Klebsiella pneu-
moniae tolerate a large number of substrates and yield the
corresponding syn-β-hydroxy esters with excellent chemical
and optical yield. The space–time yield of the ketoreduction
was optimised up to 40 g/L for almost all substrates [except
R = Bn, PMB (p-methoxybenzyl)]. Thus, when 2-substi-
tuted β-oxo esters (40 g, ca. 0.2 mol) were directly added to
the growing cells of Klebsiella pneumoniae (1 L flask) and
the solution was incubated in an incubator shaker for 48–
120 h (Table 1), quantitative conversion was achieved. The
alcohol products were obtained as a single diastereomer in
each case (Table 1). The absolute configuration of the β-
hydroxy esters was established by comparison of optical ro-
tations and 1H NMR spectroscopic data with that of
R
Yield [%][a] Time [h][b] ee [%] de [%]
Me
Et (1)
90
78
82
80
75
76
88
86
88
68
70
81
48
72
90
100
100
100
90
Ͼ 99
Ͼ 99
Ͼ 99
Ͼ 99
Ͼ 99
Ͼ 99
Ͼ 99
Ͼ 99
Ͼ 99
Ͼ 99
Ͼ 99
Ͼ 99
Ͼ 99
Ͼ 99
Ͼ 99
Ͼ 99
Ͼ 99
Ͼ 99
Ͼ 99
Ͼ 99
Ͼ 99
Ͼ 99
Ͼ 99
Ͼ 99
nPr (2)
nBu (3)
iBu (4)
nC6H13 (5)
Allyl (6)
3-Butenyl (7)
4-Pentenyl (8)
Benzyl (9)
4-Methoxybenzyl (10)
Propargyl (11)
96
100
120
120
80
[a] Isolated yield. [b] Time after the introduction of the substrates
into growing cultures of K. Pneumoniae at which TLC indicated
known compounds (1–3, 6, 9 and 11).[13] For 4, 5, 7, 8 and complete consumption of the substrate.
1598
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 1597–1602

Asymmetric Reduction of α-Substituted β-Oxo Esters
We intend to explore the synthetic potential of the en-
The enantiopure triols 24 and 25 can serve as potential
antio-enriched β-hydroxy esters obtained by biotransforma- precursors for 5Ј-methylaristeromycin and related ana-
tions for the synthesis of functionalised cyclopentane and logues.[16] The structure of 21 was confirmed unambigu-
cyclohexane scaffolds (Scheme 1). Compounds 7 and 8 were ously by single-crystal X-ray analysis of the corresponding
exploited for the synthesis of optically pure small-ring car- bis(para-nitrobenzoate) derivative. The ORTEP representa-
bocycles from biocatalytically derived β-hydroxy esters. The tion of this structure can be found in the Supporting Infor-
free secondary hydroxy group was protected as its tert- mation. This demonstrates the excellent diastereo- and
butyldiphenylsilyl (TBDPS) ether (12 and 13) by treatment enantioselectivity obtained in the initial bioreduction step.
with imidazole and TBDPSCl. Selective reduction of the
ester functionality was achieved by treatment with diiso-
butylaluminium hydride (DIBAL-H, 1 equiv. at –78 °C) to
Conclusions
afford the corresponding aldehydes 14 and 15 in good yield.
We have described an easy, efficient and reliable synthetic
Wittig olefination of the aldehydes with methyltri-
strategy for the construction of functionalised small-ring
phenylphosphonium iodide at 0 °C afforded the corre-
carbocycles by applying ketoreductases from Klebsiella
sponding olefins 16 and 17 in good yield. Ring-closing me-
tathesis with Grubbs second-generation catalyst (G-II)[14]
afforded functionalised cyclopentene and cyclohexene de-
rivatives 18 and 19, respectively. The asymmetric dihydrox-
ylation of 18 and 19 under Sharpless conditions[15] afforded
the respective diols 20 and 21 (with minor diastereomers 22
and 23). Deprotection of the TBDPS group with tetrabut-
ylammonium fluoride (TBAF)/tetrahydrofuran (THF) af-
forded the enantiopure triols 24 and 25 in good yield
(Scheme 3).
pneumoniae. Further work towards the development of the
synthetic potential of Klebsiella pneumoniae is in progress.
Experimental Section
General Information: Unless otherwise stated, materials were ob-
tained from commercial suppliers and used without further purifi-
cation. THF and diethyl ether were distilled from sodium benzo-
phenone ketyl. N,N-Dimethylformamide (DMF) and dimethyl sulf-
oxide (DMSO) were distilled from calcium hydride. The microbial
ketoreductase strain from K. Pneumoniae (NBRC 3319) was ob-
tained from NBRC, Japan, and maintained in a petri dish as well
as in glycerol slants. Bioreductions were performed in an incubator
shaker at 35 °C. Reactions were monitored by TLC carried out
with 0.25 mm silica gel plates (Merck) with UV light, ethanolic
anisaldehyde and phosphomolybdic acid/heat as developing agents.
Yields refer to chromatographically and spectroscopically homo-
geneous materials unless otherwise stated. NMR spectra were re-
corded with Bruker 200 and 400 MHz spectrometers at 25 °C in
CDCl3 by using Me4Si as the internal standard. 13C NMR spectra
were recorded with a complete proton-decoupling environment.
Optical rotations were measured with a JASCO P1020 digital pola-
rimeter. Elemental analysis was performed with a Perkin–Elmer
CHN analyzer (2400, series II). Mass spectral analyses were per-
formed at IACS, Kolkata, India. CCDC-833927 contains the sup-
plementary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Synthesis of Ethyl 2-Acetylhex-5-enoate: The β-oxo ester was syn-
thesised from ethyl acetoacetate and 4-iodo-1-butene by a standard
procedure.[12] 1H NMR (200 MHz, CDCl3): δ = 5.8–5.6 (m, 1 H),
5.03–4.88 (m, 2 H), 4.16 (q, J = 7.0 Hz, 2 H), 3.41 (t, J = 7.2 Hz,
1 H), 2.12 (s, 3 H), 2.03–1.89 (m, 4 H), 1.23 (t, J = 7.0 Hz, 3 H)
ppm. 13C NMR (50 MHz, CDCl3): δ = 202.9, 169.6, 136.9, 115.9,
61.2, 58.8, 31.3, 28.9, 27.0, 14.0 ppm.
Ethyl 2-Acetylhept-5-enoate: 1H NMR (200 MHz, CDCl3): δ =
5.84–5.64 (m, 1 H), 5.03–4.91 (m, 2 H), 4.23–4.09 (m, 2 H), 3.38
(m, 1 H), 2.2 (s, 3 H), 1.89–1.71 (m, 4 H), 1.44–1.28 (m, 2 H), 1.22
(m, 3 H) ppm. 13C NMR (50 MHz, CDCl3): 203.1, 169.8, 137.9,
115.0, 61.3, 59.7, 33.3, 28.7, 27.5, 26.6, 14.1 ppm.
Growing Conditions for Microbial Ketoreductases from Klebsiella
pneumoniae (NBRC 3319): The dried cells obtained from the cul-
ture collection were moistened with rehydration fluid [peptone
(10 g), yeast extract (2 g), MgSO4·7H2O (1 g), distilled water (1 L),
pH = 7.0]. The rehydrated cells were streaked into several Petri
Scheme 3. Synthesis of small-ring carbocycles. Reagents and condi-
tions: (a) K. Pneumoniae; (b) imidazole, TBDPS-Cl, 25 °C; (c)
DIBAL-H (1 equiv.), CH2Cl2, –78 °C; (d) lithium bis(trimetylsilyl)-
amide (LHMDS), MePh3P+I–, 0 °C; (e) G-II, CH2Cl2, 25 °C; (f)
AD-mix-β, MeSO2NH2, tBuOH/H2O (4:1); (g) TBAF/THF, 25 °C.
Eur. J. Org. Chem. 2012, 1597–1602
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1599

R. Bhuniya, T. Mahapatra, S. Nanda
FULL PAPER
dishes [containing the same components with additional agar
(15.0 g/L)] and incubated at 25 °C in an incubator for 24 h. For
the biotransformations with NBRC 3319, a liquid medium [glucose
(40.0 g), meat extract (5.0 g), NaCl (5.0 g), peptone (10.0 g),
CaCO3 (40.0 g), distilled water (1 L)] was prepared without agar,
and cells of K. pneumoniae were transferred to this medium through
an inoculating loop. The cells were incubated in an incubator
shaker for 48 h, and the parent β-oxo ester was directly added to
the growing culture medium. The reaction was monitored occasion-
ally by TLC. After completion of the reaction, the product was
isolated by extraction with EtOAc. It was purified by silica gel
chromatography to afford the product alcohol.
[α]2D9 = –12.6 (c = 0.5, MeOH). HRMS (ESI): calcd. for C26H36O3-
SiNa [M + Na]+ 447.2331; found 447.2337.
Synthesis of (R)-2-[(S)-1-(tert-Butyldiphenylsilanyloxy)ethyl]hex-5-
enal (14): Compound 12 (610 mg, 1.44 mmol) was dissolved in an-
hydrous CH2Cl2 (10 mL) and cooled to –78 °C, DIBAL-H (1 m
solution in CH2Cl2, 1.5 mL, 1.44 mmol) was added slowly to the
reaction mixture, and the solution was stirred for 1.5 h. After com-
pletion of the reaction indicated by TLC, it was quenched with a
saturated solution of sodium/potassium tartarate solution, and the
layers were separated. The aqueous layer was extracted with
CH2Cl2 (20 mL). The organic layers were combined, dried with
MgSO4, filtered, and the solvent was removed in vacuo. The crude
residue was purified by flash column chromatography (EtOAc/hex-
ane, 1:40) to afford 14 (276 mg, 82%). 1H NMR (200 MHz,
CDCl3): δ = 9.92 (d, J = 1.6 Hz, 1 H), 7.7–7.66 (m, 4 H), 7.42–
7.36 (m, 6 H), 5.79–5.57 (m, 1 H), 4.97–4.9 (m, 2 H), 4.23–4.11 (m,
1
Ethyl (R)-2-[(S)-1-Hydroxyethyl]-4-methylpentanoate (4): H NMR
(200 MHz, CDCl3): δ = 4.15 (q, J = 7.0 Hz, 2 H), 3.95–3.89 (m, 1
H), 2.57 (br., 1 H, OH), 2.50–2.41 (m, 1 H), 1.71–1.44 (m, 3 H),
1.28 (t, J = 7.0 Hz, 3 H), 1.17 (d, J = 6.8 Hz, 3 H), 0.89 (s, 3 H),
0.86 (s, 3 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 175.8, 68.5,
60.5, 50.1, 36.2, 26.3, 23.4, 21.7, 20.2, 14.2 ppm. [α]2D9 = +17.4 (c =
1.0, MeOH). C10H20O3 (188.27): calcd. C 63.80, H 10.71; found C
63.72, H 10.76. HRMS (ESI): calcd. for C10H20O3Na [M + Na]+
211.1310; found 211.1316.
1 H), 2.46–2.41 (m, 1 H), 2.05–1.89 (m, 4 H), 1.12 (12 H) ppm. 13
C
NMR (50 MHz, CDCl3): δ = 205.4, 137.9, 136.0, 135.6, 134.4,
130.1, 129.9, 129.5, 127.9, 127.7, 115.4, 70.0, 57.9, 31.7, 21.1, 23.9,
20.5, 19.4 ppm. [α]2D9 = –5.8 (c = 0.5, MeOH).
Synthesis of tert-Butyl[(1S,2S)-1-methyl-2-vinylhex-5-enyloxy]di-
phenylsilane (16): To a suspension of methyltriphenylphosphonium
iodide (700 mg, 1.73 mmol) in dry THF (20 mL) was added
LHMDS (1.8 mL, 1.73 mmol) at 0 °C. The bright yellow mixture
was kept at 0 °C for 15 min. A solution of 14 (220 mg, 0.58 mmol)
in THF (5 mL) was added to the reaction mixture at –5 °C, and
the reaction mixture was allowed to attain room temperature. After
1.5 h, the reaction was quenched by addition of water, and the lay-
ers were separated. The aqueous layer was extracted with Et2O
(3ϫ15 mL). The organic layers were combined, dried with MgSO4,
filtered, and the solvent was removed in vacuo. The crude residue
was purified by flash column chromatography (EtOAc/hexane,
1:40) to afford 16 (85%). 1H NMR (200 MHz, CDCl3): δ = 7.8–
7.63 (m, 4 H), 7.46–7.4 (m, 6 H), 5.89–5.66 (m, 2 H), 5.18–4.9 (m,
4 H), 3.93–3.82 (m, 2 H), 2.23–2.0 (m, 3 H), 1.7–1.62 (m, 1 H),
1.45–1.34 (m, 1 H), 1.14 (s, 9 H), 1.08 (d, J = 7.0 Hz, 3 H) ppm.
13C NMR (50 MHz, CDCl3): δ = 139.1, 138.9, 137.0, 136.0, 134.5,
134.3, 129.6, 129.4, 127.6, 127.4, 116.3, 114.3, 72.2, 50.8, 31.4, 29.2,
27.1, 20.1, 19.4 ppm. [α]2D9 = –18.3 (c = 1.2, MeOH). HRMS (ESI):
calcd. for C25H34OSiNa [M + Na]+ 401.2277; found 401.2270.
Ethyl (R)-2-[(S)-1-Hydroxyethyl]octanoate (5): 1H NMR
(200 MHz, CDCl3): δ = 4.19 (q, J = 7.0 Hz, 2 H), 3.92 (m, 1 H),
2.35 (m, 2 H), 1.27–1.16 (m, 8 H), 1.14 (d, J = 6.8 Hz, 3 H), 0.83
(t, J = 7.0 Hz, 3 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 175.3,
68.2, 60.4, 52.2, 31.6, 29.2, 27.6, 27.3, 22.5, 20.2, 14.2, 14.0 ppm.
[α]2D9 = +14.8 (c = 0.25, MeOH). C12H24O3 (216.32): calcd. C 66.63,
H 11.18; found C 66.62, H 11.16. HRMS (ESI): calcd. for
C12H24O3Na [M + Na]+ 239.1623; found 239.1618.
Ethyl (R)-2-[(S)-1-Hydroxyethyl]hex-5-enoate (7): 1H NMR
(200 MHz, CDCl3): δ = 5.9–5.7 (m, 1 H), 5.09–4.97 (m, 2 H), 4.22
(q, J = 7.2 Hz, 2 H), 4.04–3.92 (m, 1 H), 2.49–2.39 (m, 1 H), 2.19–
2.01 (m, 2 H), 1.84–1.7 (m, 2 H), 1.33 (t, J = 7.2 Hz, 3 H), 1.2 (d,
J = 6.4 Hz, 3 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 174.9,
137.6, 115.2, 68.2, 60.4, 51.8, 31.6, 26.7, 20.3, 14.2 ppm. [α]2D9
=
+17.4 (c = 0.5, MeOH). C10H18O3 (186.25): calcd. C 64.49, H 9.74;
found C 64.52, H 9.76. HRMS (ESI): calcd. for C10H18O3Na [M
+ Na]+ 209.1154; found 209.1148.
Ethyl (2R,3S)-3-Hydroxy-2-(4-methoxybenzyl)butanoate (10): 1H
NMR (200 MHz, CDCl3): δ = 7.1 (d, J = 6.8 Hz, 2 H), 6.78 (d, J
= 6.8 Hz, 2 H), 4.09–4.01 (m, 3 H), 3.76 (s, 3 H), 2.93 (d, J =
7.6 Hz, 2 H), 2.74–2.66 (m, 1 H), 2.6 (br., 1 H, OH), 1.22 (d, J =
6.8 Hz, 3 H), 1.08 (d, J = 7.0 Hz, 3 H) ppm. 13C NMR (50 MHz,
CDCl3): δ = 174.4, 158.1, 131.1, 129.8, 113.8, 68.0, 60.5, 55.2, 54.6,
32.8, 20.4, 14.0 ppm. [α]2D9 = +37.1 (c = 1.1, MeOH). C14H20O4
(252.31): calcd. C 66.65, H 7.99; found C 66.72, H 7.96. HRMS
(ESI): calcd. for C14H20O4Na [M + Na]+ 275.1259; found 275.1265.
Synthesis of tert-Butyl{(S)-[(S)-1-cyclopent-2-enyl]ethoxy}diphen-
ylsilane (18): Compound 16 (150 mg, 0.3953 mmol) was dissolved
in anhydrous degassed CH2Cl2 (180 mL). G-II (40 mg, 0.05 mmol)
was added, and the solution was stirred at room temperature for
5 h. The solution was concentrated, and the residue was directly
loaded onto a silica gel column. Flash chromatography with hex-
ane/EtOAc (1:50) afforded 18 (77%). 1H NMR (200 MHz, CDCl3):
δ = 7.78–7.75 (m, 4 H), 7.48–7.38 (m, 6 H), 5.86–5.8 (m, 1 H),
5.71–5.68 (m, 1 H), 3.93–3.81 (m, 1 H), 2.91–2.87 (m, 1 H), 2.36–
2.29 (m, 2 H), 2.01–1.91 (m, 1 H), 1.79–1.62 (m, 1 H), 1.13 (s, 9
H), 1.07 (d, J = 6.0 Hz, 3 H) ppm. 13C NMR (50 MHz, CDCl3): δ
= 136.0, 135.1, 134.5, 132.5, 132.2, 131.5, 129.5, 129.4, 127.5, 127.4,
72.3, 54.0, 32.1, 27.1, 25.4, 20.9, 19.4 ppm. [α]2D9 = –50.2 (c = 0.25,
MeOH). HRMS (ESI): calcd. for C23H30OSiNa [M + Na]+
373.1964; found 373.1958.
Synthesis of Ethyl (R)-2-[(S)-1-(tert-butyldiphenylsilanyloxy)eth-
yl]hex-5-enoate (12): Compound 7 (330 mg, 1.76 mmol) was dis-
solved in anhydrous CH2Cl2 (5 mL) and cooled to 0 °C. Imidazole
(239 mg, 3.51 mmol) and 4-(dimethylamino)pyridine (catalytic)
were added to the reaction mixture followed by TBDPS-Cl
(0.6 mL, 2.1 mmol). The reaction mixture was warmed to room
temperature for 2 h, after which water was added, and the organic
layer was washed with brine and dried with MgSO4. The product
was purified by flash chromatography to afford 12 in 88% yield.
Synthesis of (1S,2R,3S)-3-[(S)-1-(tert-Butyldiphenylsilanyloxy)ethyl-
1H NMR (200 MHz, CDCl3): δ = 7.7–7.62 (m, 4 H), 7.45–7.3 (m, ]cyclopentane-1,2-diol (20): A mixture of tBuOH (4 mL), H2O
6 H), 5.76–5.62 (m, 1 H), 4.98–4.89 (m, 2 H), 4.15–3.98 (m, 3 H),
(1 mL) and AD-mix-β (392 mg) was stirred for 15 min. Methane-
2.54–2.44 (m, 1 H), 2.02–1.9 (m, 2 H), 1.87–1.69 (m, 2 H), 1.22 (t, sulfonamide (41 mg) was added, and stirring was continued for
J = 7.2 Hz, 3 H), 1.08 (12 H) ppm. 13C NMR (50 MHz, CDCl3): 15 min. Compound 18 (95 mg, 0.27 mmol) was added in one por-
δ = 174.1, 137.8, 135.9, 135.6, 134.4, 133.8, 129.6, 129.5, 127.5,
127.4, 115.0, 70.7, 60.1, 52.7, 31.8, 27.7, 26.9, 20.5, 19.3, 14.2 ppm.
tion. The slurry was stirred vigorously at 20 °C for 24 h. Sodium
sulfite (433 mg) was added, and stirring was continued for 1 h. The
1600
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 1597–1602

Asymmetric Reduction of α-Substituted β-Oxo Esters
reaction mixture was extracted with EtOAc. The organic layer was
dried (Na2SO4), and the solvents were evaporated in vacuo. The
diol was purified by flash chromatography (hexane/EtOAc, 5:1) to
afford 20 as the major product and 22 as a minor one (86% yield).
(m, 6 H), 5.89–5.64 (m, 2 H), 5.12–4.94 (m, 4 H), 3.89–3.77 (m, 1
H), 2.13–1.97 (m, 3 H), 1.49–1.37 (m, 4 H), 1.18 (s, 9 H), 1.03 (d,
J = 6.2 Hz, 3 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 139.5,
139.3, 139.0, 136.0, 134.9, 134.4, 129.6, 129.4, 127.5, 127.4, 116.0,
1H NMR (400 MHz, CDCl3): δ = 7.72–7.68 (m, 4 H), 7.46–7.38 114.33, 72.2, 51.3, 33.8, 29.6, 27.1, 26.6, 20.0, 19.4 ppm. [α]2D9
=
(m, 6 H), 4.21 (br. s, 1 H), 4.02–3.97 (m, 2 H), 3.51 (1 H), 2.54 (br.,
1 H), 1.9–1.7 (m, 4 H), 1.22 (d, J = 6.0 Hz, 3 H), 1.1 (s, 9 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 135.9, 134.5, 133.8, 129.8, 129.7,
129.6, 127.8, 127.6, 73.3, 71.6, 69.8, 48.9, 29.9, 27.1, 27.0, 22.8,
20.9 ppm. [α]2D9 = –1.65 (c = 0.2, MeOH). HRMS (ESI): calcd. for
C23H32O3SiNa [M + Na]+ 407.2018; found 407.2026.
–26.8 (c = 1.0, MeOH). HRMS (ESI): calcd. for C26H36OSiNa [M
+ Na]+ 415.2433; found 415.2429.
tert-Butyl[(S)-(S)-1-cyclohex-2-enylethoxy]diphenylsilane (19): 1H
NMR (200 MHz, CDCl3): δ = 7.73–7.7 (m, 4 H), 7.44–7.36 (m, 6
H), 5.82–5.64 (m, 2 H), 3.86–3.75 (m, 1 H), 2.26 (br., 1 H), 1.98–
1.9 (m, 2 H), 1.76–1.45 (m, 4 H), 1.08 (s, 9 H), 1.02 (d, J = 6.4 Hz,
3 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 136.0, 135.1, 134.5,
129.5, 129.4, 128.8, 128.5, 127.8, 127.5, 127.4, 72.3, 43.4, 27.1, 25.5,
24.8, 21.8, 19.9, 19.5 ppm. [α]2D9 = –72.54 (c = 1.0, MeOH). HRMS
(ESI): calcd. for C24H32OSiNa [M + Na]+ 387.2120; found
387.2126.
Synthesis of (1S,2R,3R)-3-[(S)-1-Hydroxyethyl]cyclopentane-1,2-
diol (24): Compound 20 (85 mg, 0.219 mmol) was dissolved in dry
THF (3 mL), TBAF (1 m in THF, 0.34 mL) was added at 0 °C, and
the reaction mixture was stirred at room temperature for 3 h. THF
was evaporated, water (2 mL) was added, and the reaction mixture
was extracted with EtOAc (2ϫ10 mL). The organic layer was
washed with NaHCO3 and brine and dried (MgSO4). It was puri-
fied by flash chromatography (hexane/EtOAc, 3:1) to afford 24
(38 mg, 90%). 1H NMR (200 MHz, CDCl3): δ = 4.15–4.14 (m, 1
H), 3.93–3.86 (m, 1 H), 3.75–3.72 (m, 1 H), 3.19 (br. s, 3 H, OH),
1.95–1.9 (m, 1 H), 1.88–1.78 (m, 2 H), 1.77–1.71 (m, 1 H), 1.4–1.31
(m, 1 H), 1.28 (d, J = 6.0 Hz, 3 H) ppm. 13C NMR (50 MHz,
(1S,2R,3S)-3-[(S)-1-(tert-Butyldiphenylsilanyloxy)ethyl]cyclohex-
1
ane-1,2-diol (21): H NMR (400 MHz, CDCl3): δ = 7.71–7.68 (m,
4 H), 7.47–7.38 (m, 6 H), 4.0–3.92 (m, 2 H), 3.76–3.73 (m, 1 H),
2.6 (br., 1 H), 2.14–2.08 (m, 1 H), 1.96–1.93 (m, 1 H), 1.62–1.3 (m,
4 H),1.1 (12 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 136.0,
134.2, 133.5, 132.9, 130.2, 130.0, 127.9, 127.8, 74.2, 73.1, 69.0, 42.4,
29.8, 27.1, 26.8, 19.3, 19.2, 17.6 ppm. [α]2D9 = –20.9 (c = 0.5,
MeOH). HRMS (ESI): calcd. for C24H34O3SiNa [M + Na]+
421.2175; found 421.2171.
CDCl3): δ = 75.0, 73.2, 67.5, 49.9, 30.1, 21.3, 20.7 ppm. [α]2D9
=
+16.6 (c = 1, MeOH). HRMS (ESI): calcd. for C7H14O3Na [M +
Na]+ 169.0841; found 169.0837.
(1R,2S,3R)-3-[(S)-1-Hydroxyethyl]cyclopentane-1,2-diol (26): 1H
NMR (200 MHz, CDCl3): δ = 4.27–4.24 (m, 1 H), 4.07–4.05 (m, 2
H), 3.79–3.72 (br. s, 3 H, OH), 2.12–1.58 (m, 5 H), 1.21 (d, J =
6.0 Hz, 3 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 76.1, 74.1,
66.4, 45.8, 30.3, 22.8, 19.3 ppm. [α]2D9 = –32.1 (c = 0.8, MeOH).
HRMS (ESI): calcd. for C7H14O3Na [M + Na]+ 169.0841; found
169.0837.
(1R,2S,3S)-3-[(S)-1-(tert-Butyldiphenylsilanyloxy)ethyl]cyclohex-
ane-1,2-diol (23): H NMR (400 MHz, CDCl3): δ = 7.76–7.7 (m, 4
1
H), 7.49–7.4 (m, 6 H), 4.0–3.9 (m, 2 H), 3.57–3.51 (m, 1 H), 2.0–
1.2 (m, 7 H), 1.1 (s, 9 H), 0.9 (d, J = 6.2 Hz, 3 H) ppm. 13C NMR
(50 MHz, CDCl3): δ = 135.8, 134.2, 133.1, 132.9, 129.9, 129.6,
127.8, 127.5, 75.0, 73.1, 69.1, 44.6, 30.2, 26.9, 26.1, 21.1, 19.2,
18.8 ppm. [α]2D9 = +12.6 (c = 1.0, MeOH).
Ethyl (R)-2-[(S)-1-Hydroxyethyl]hept-6-enoate (8): 1H NMR
(200 MHz, CDCl3): δ = 5.8–5.6 (m, 1 H), 4.96–4.85 (m, 2 H), 4.11
(q, J = 7.2 Hz, 2 H), 3.92 (m, 1 H), 2.34–2.27 (m, 1 H), 2.14–2.04
(m, 2 H), 1.61–1.53 (m, 2 H), 1.37–1.25 (m, 2 H), 1.23 (d, J =
6.8 Hz, 3 H), 0.93 (d, J = 7.0 Hz, 3 H) ppm. 13C NMR (50 MHz,
CDCl3): δ = 171.0, 138.2, 114.6, 68.2, 65.8, 52.4, 33.5, 32.2, 27.0,
20.7, 13.7 ppm. [α]2D9 = 20.3 (c = 0.5, MeOH). C11H20O3 (200.14):
calcd. C 65.97, H 10.07; found C 65.92, H 10.12. HRMS (ESI):
calcd. for C11H20O3Na [M + Na]+ 223.1310; found 223.1315.
(1S,2R,3R)-3-[(S)-1-Hydroxyethyl]cyclohexane-1,2-diol (25): 1H
NMR (200 MHz, CDCl3): δ = 4.11–3.93 (m, 3 H), 2.05–1.35 (m, 7
H), 1.18 (d, J = 6.0 Hz, 3 H) ppm. 13C NMR (50 MHz, CDCl3): δ
= 72.8, 70.2, 69.6, 42.2, 29.6, 26.0, 19.1, 17.8 ppm. [α]2D9 = –16.82
(c = 0.5, MeOH). HRMS (ESI): calcd. for C8H16O3Na [M +
Na]+ 183.0997; found 183.0991.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, 1H and 13C NMR spectra for all
new compounds, X-ray crystal data.
Ethyl (R)-2-[(S)-1-(tert-Butyldiphenylsilanyloxy)ethyl]hept-6-enoate
1
(13): H NMR (200 MHz, CDCl3): δ = 7.72–7.66 (m, 4 H), 7.38–
Acknowledgment
7.34 (m, 6 H), 5.85–5.65 (m, 1 H), 5.02–4.91 (m, 2 H), 4.18–4.07
(m, 2 H), 4.02–3.93 (m, 1 H), 2.55–2.47 (m, 1 H), 2.05–1.94 (m, 2
H), 1.61–1.51 (m, 2 H), 1.38–1.2 (m, 5 H), 1.1 (12 H) ppm. 13C Financial support from the Department of Science and Technology
NMR (50 MHz, CDCl3): δ = 174.6, 138.8, 137.1, 136.3, 134.8,
134.2, 130.0, 129.9, 127.9, 127.8, 115.0, 71.2, 60.4, 53.8, 33.9, 32.5,
28.6, 27.3, 20.9, 19.7, 14.6 ppm. [α]2D9 = –16.4 (c = 0.6, MeOH).
HRMS (ESI): calcd. for C27H38O3SiNa [M + Na]+ 461.2488; found
461.2481.
(DST) India is gratefully acknowledged (Grant: SR/S1/OC-55/
2009, IRPHA for NMR instrument and X-ray diffractometer).
R. B. is thankful to Council of Scientific and Industrial Research
(CSIR) India for a research fellowship. We are thankful to Prof.
Kumar Biradha of IIT Kharagpur for X-ray analysis.
1
(R)-2-[(S)-1-(tert-Butyldiphenylsilanyloxy)ethyl]hept-6-enal (15): H
NMR (200 MHz, CDCl3): δ = 9.92 (d, J = 2.0 Hz, 1 H), 7.71–7.66
(m, 4 H), 7.46–7.36 (m, 6 H), 5.82–5.67 (m, 1 H), 5.02–4.9 (m, 2
H), 4.2–4.09 (m, 1 H), 2.38–2.36 (m, 1 H), 2.03–1.56 (m, 6 H), 1.1
(12 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 205.3, 138.2, 135.8,
133.2, 134.0, 132.6, 129.9, 129.7, 127.8, 127.6, 114.7, 69.8, 58.5,
34.7, 33.6, 31.6, 26.7, 22.7, 14.1 ppm. [α]2D9 = –11.2 (c = 0.5,
MeOH).
[1] a) B. T. Cho, Chem. Soc. Rev. 2009, 38, 443–52; b) M. Node,
J. Pharm. Soc. Jpn. 2002, 122, 71–88; c) W. Martin, H. Jerome,
Curr. Opin. Drug Dis. Development. 2002, 5, 881–891; d) B. T.
Cho, Tetrahedron 2006, 62, 7621–7643; e) New Frontiers in
Asymmetric Catalysis (Eds.: K. Mikami, M. Lautens), Wiley-
Interscience, Hoboken, 2007, p. 1–32; f) T. Ikariya, A. J.
Blacker, Acc. Chem. Res. 2007, 40, 1300–1308.
[2] a) W. Krouti, H. Mang, K. Edegger, K. Faber, Curr. Opin.
Chem. Biol. 2004, 8, 120–126; b) K. Nakamura, T. Matsuda,
Curr. Org. Chem. 2006, 10, 1217–1246; c) S. Kambourakis, J. D.
tert-Butyl[(1S,2S)-1-methyl-2-vinylhept-6-enyloxy]diphenylsilane (17):
1H NMR (200 MHz, CDCl3): δ = 7.76–7.71 (m, 4 H), 7.49–7.37
Eur. J. Org. Chem. 2012, 1597–1602
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1601

R. Bhuniya, T. Mahapatra, S. Nanda
FULL PAPER
Rozzell, Pharma Chem. 2006, 5, 2–5; d) A. Berenguer-Murcia,
R. Fernandez-Lafuente, Curr. Org. Chem. 2010, 14, 1000–1021;
e) H. Groeger, S. Borchert, M. Krausser, H. Werner, Encycl.
[8] a) E. Garcia-Urdiales, I. Alfonso, V. Gotor, Chem. Rev. 2011,
111, 110–180; b) J. C. Moore, D. J. Pollard, B. Kosjek, P. N.
Devine, Acc. Chem. Res. 2007, 40, 1412–1419.
Ind. Biotechnol. 2010, 3, 2094–2110; f) G. A. Cordell, T. L. G. [9] a) K. Nakamura, R. Yamanaka, T. Matsuda, T. Harada, Tetra-
Lemos, F. J. Q. Monte, M. C. de Mattos, J. Nat. Prod. 2007,
70, 478–492.
hedron: Asymmetry 2003, 14, 2659–2681; b) Z. L. Wie, G. Q.
Lin, Z. Y. Li, Bioorg. Med. Chem. 2000, 8, 1129–1137; c) T.
Matsuda, T. Harada, N. Nakajima, T. Itoh, K. Nakamura, J.
Org. Chem. 2000, 65, 157–163.
[3]
a) J. B. Arterburn, Tetrahedron 2001, 57, 9765; b) J. W. Faller,
A. R. Lavoie, Org. Lett. 2001, 3, 3703; c) A. Schmid, F.
Hollmann, B. Bühler, “Oxidation of Alcohols”, in Enzyme Ca-
talysis in Organic Synthesis, vol. 3 (Eds.: K. Drauz, H. Wald-
mann), Wiley-VCH, Weinheim, 2002, p. 991; d) Y. Nishibaya-
shi, A. Yamauchi, G. Onodera, S. Uemura, J. Org. Chem. 2003,
68, 5875; e) S. K. Mandal, M. S. Sigman, J. Org. Chem. 2003,
68, 7535; f) K. Edegger, H. Mang, K. Faber, J. Gross, W. Krou-
til, J. Mol. Catal. A 2006, 251, 66.
[10] a) I. A. Kaluzna, T. Matsuda, A. K. Sewell, J. D. Stewart, J.
Am. Chem. Soc. 2004, 126, 12827–12832; b) K. Faber, Biotrans-
formations in Organic Chemistry, 5th ed., Springer-Verlag,
Berlin, Heidelberg, New York, 2004, p. 179; c) Enzymes in Or-
ganic Synthesis, 2nd ed., vol. III (Eds.: K. Drauz, H. Wald-
mann), Wiley-VCH, Weinheim, 2002, p. 991.
[11] a) H. Miya, M. Kawada, Y. Sugiyama, Biosci. Biotechnol. Bio-
chem. 1996, 60, 95–98; b) H. Miya, M. Kawada, Y. Sugiyama,
Biosci. Biotechnol. Biochem. 1996, 60, 760–764.
[4]
U. T. Bornscheuer, R. J. Kazlauskas, Hydrolases in Organic
Synthesis, 2nd ed., Wiley-VCH, Weinheim, 2006.
[12] H. S. Lee, J. S. Park, B. M. Kim, S. H. Gellman, J. Org. Chem.
2003, 68, 1575–1578.
[5] a) S. R. Wallner, M. Pogorevc, H. Trauthwein, K. Faber, Eng.
Life Sci. 2004, 4, 512; b) M.-C. Gutierrez, R. Furstoss, V. Alp-
hand, Adv. Synth. Catal. 2005, 347, 1051.
[13] a) D. Zhu, C. Mukherjee, J. D. Rozzell, S. Kambourakis, L.
Hua, Tetrahedron 2006, 62, 901–905; b) Y. Kawai, M. Tsujim-
oto, S. Kondo, K. Takanobe, K. Nakamura, A. Ohno, Bull.
Chem. Soc. Jpn. 1994, 67, 524–528; c) B. Pan, J. Gu, Z. Li,
O. P. Ward, Enz. Microb. Technol. 1995, 17, 853–855; d) I. A.
Kaluzna, T. Matsuda, A. K. Sewell, J. D. Stewart, J. Am. Chem.
Soc. 2004, 126, 12827–12832; e) P. Rodriguez, M. Barton, V.
Aldabalde, S. Onetto, P. Panizza, P. Menendez, D. Gonzalez,
S. Rodriguez, J. Mol. Catal. B 2007, 49, 8–11.
[14] M. Scholl, S. Ding, C. W. Lee, R. H. Grubbs, Org. Lett. 1999,
1, 953–956.
[15] L. F. Tietze, T. Eicher, U. Diederichsen, A. Speicher, in Reac-
tions and Syntheses, Wiley-VCH, Weinheim, 2007, p. 211.
[16] a) D. Acetti, E. Brenna, C. Fuganti, F. G. Gatti, L. Malpezzi,
S. Serra, Eur. J. Org. Chem. 2008, 5125–5134; b) W. Ye, S. W.
Schneller, J. Org. Chem. 2006, 71, 8641–8643.
[6] a) H. Pellissier, Tetrahedron 2011, 67, 3769–3802; b) B. Martin-
Matute, J.-E. Bäckvall, Curr. Opin. Chem. Biol. 2007, 11, 226;
c) A. Kamal, M. A. Azhar, T. Krishnaji, M. S. Malik, S.
Azeeza, Coord. Chem. Rev. 2008, 252, 569; d) N. J. Turner,
Curr. Opin. Chem. Biol. 2004, 8, 114; e) N. J. Turner, R. Carr,
“Biocatalytic Routes to Nonracemic Chiral Amines” in Biocat-
alysis in the Pharmaceutical and Biotechnology Industry (Ed.:
R. N. Patel), CRC, Boca Raton, 2007, p. 743; f) F. F. Huerta,
A. B. E. Minidis, J.-E. Bäckvall, Chem. Soc. Rev. 2001, 30, 321–
331.
[7] a) C. V. Voss, C. C. Grubber, W. Kroutil, Synlett 2010, 7, 991–
998; b) A. J. Carnell, Adv. Biochem. Eng./Biotechnol. 1999, 63,
57; c) R. Azerad, D. Buisson, Curr. Opin. Biotechnol. 2000, 11,
565; d) K. Nakamura, T. Matsuda, T. Harada, Chirality 2002,
14, 703; e) C. C. Gruber, I. Lavandera, K. Faber, W. Kroutil,
Adv. Synth. Catal. 2006, 348, 1789.
Received: November 27, 2011
Published Online: January 30, 2012
1602
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 1597–1602