The baker's yeast reduction of the β-keto aldehydes in the presence of a sulfur compound

Article abstract of DOI:10.1055/s-1999-2824

Improved enantio- and diastereoselectivity was achieved in the baker's yeast reduction of β-keto aldehyde derivatives using a sulfur compound as an additive. The resulting enantiomerically pure diol was transformed into serricornin, a sex pheromone of the cigarette beetle.

Full text of DOI:10.1055/s-1999-2824

1298
LETTER
The Baker’s Yeast Reduction of the b-Keto Aldehydes in the Presence of a
Sulfur Compound
Ryuuichirou Hayakawa, Makoto Shimizu*
Department of Chemistry for Materials, Mie University, Tsu, Mie 514-8507, Japan
Received 19 May 1999
duction could be improved using a sulfur compound as an
Abstract: Improved enantio- and diastereoselectivity was achieved
additive.8 We are interested in the generality of this meth-
in the baker’s yeast reduction of b-keto aldehyde derivatives using
od. On the other hand, the baker’s yeast reduction of a-
substituted b-keto aldehydes has not been reported al-
though the resulting chiral 2-substituted-1,3-diol deriva-
tives are useful intermediates. Now we wish to report an
efficient method of the bakers' yeast reduction of a-substi-
tuted b-keto aldehyde derivatives using a sulfur com-
pound. The b-keto aldehydes as substrates were prepared
from the corresponding ketones by formylation.9 The b-
keto aldehydes as substrates were prepared from the cor-
responding ketones by formylation.9 In a typical proce-
dure of the baker’s yeast reduction, a suspension of 3.1 g
of dry baker’s yeast (S. I. Lesaffre) in 21 mL of phosphate
buffer (pH 7.0) was stirred for 0.5 h at ambient tempera-
ture. To the resulting suspension a sulfur compound was
added. After 0.5 h stirring, 2.1 mL of an ethanol solution
of 3-formyltetrahydrothiopyran-4-one 1b (100 mg, 0.69
mmol) was added to the suspension of bakers’ yeast. After
24 h stirring, Celite and ethyl acetate were added to the re-
action mixture, and the whole mixture was stirred for 0.5
h. The resulting mixture was filtered through a Celite pad.
The filtrate was extracted with ethyl acetate (5 x 50 mL).
The combined organic extracts were dried over anhydrous
Na2SO4 and concentrated in vacuo. The residue was puri-
fied by flash chromatography. The results are summarized
in Table 1.
a sulfur compound as an additive. The resulting enantiomerically
pure diol was transformed into serricornin, a sex pheromone of the
cigarette beetle.
Key words: a-substituted-b-keto aldehyde, baker’s yeast, sulfur
compound, chiral 1,3-diol, serricornin
The baker’s yeast reduction of a carbonyl compound is
one of the most useful methods for the preparation of the
optically active alcohols.1 Especially the baker’s yeast re-
duction of b-keto esters has been widely investigated be-
cause of its synthetic utility. However, there have been
numerous examples that afforded unsatisfactory results,
low chemical yield, and/or low selectivity, mainly be-
cause of the participation of multiple enzymes with differ-
ent enantioselectivity.1 A number of methods have been
reported for the improvement of the enantioselectivity of
the baker’s yeast reduction of b-keto ester derivatives, in-
volving some modification of the substrate,2 addition of
an additive as a selective inhibitor of reductase,3 addition
of an inorganic salt,4 immobilization of baker’s yeast,5
thermal treatment of yeast cells,6 or use of an organic sol-
vent .7 However, the rate of reduction and chemical yield
usually decreased in such cases. We have found that the
reactivity and enantioselectivity of the baker’s yeast re-
O
OH
OH
Baker's Yeast
Sulfur-Compound
EtOH
O
OH
R1
R1
R1
R1
OH
OH
OH
H
R2
R2
syn-3
R2
anti-3
R2
Buffer (pH 7.0)
2
1a ; R1 = Me, R2 = Me
1b ; R1, R2 = CH2SCH2
Table 1 The Baker’s Yeast Reduction of b-Keto Aldehyde Derivatives
Synlett 1999, No. 8, 1298–1300 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
The Baker’s Yeast Reduction of the b-Keto Aldehydes in the Presence of a Sulfur Compound
1299
The baker’s yeast reduction of 2-methyl-3-oxopentanal
1a gave (S)-2-methyl-3-oxopentanol 2a with 36% ee. The
absolute stereochemistry was determined by its derivati-
zation to the dibenzoate derivative of the corresponding
diol derivative, and comparison of the retention time of
HPLC (Daicel chiralcel OD) with the known dibenzoate
derived from diol 3. Improved enantioselectivity was ob-
tained using a sulfur compound with up to 73% ee. The
use of L-cysteine as an additive was the most effective in
the reduction of 2-methyl-3-oxopentanal 1a, although the
result was not completely satisfactory. Therefore the bak-
er’s yeast reduction of 3-formyltetrahydrothiopyran-4-
one 1b was next investigated, because it has been known
that introduction of a sulfur atom to the substrate im-
proves the enantioselectivity and the sulfur can be re-
moved via either a reductive or oxidative process.10 The
corresponding diol derivative 3 was obtained in the bak-
er’s yeast reduction of 3-formyltetrahydrothiopyran-4-
one 1b, while the reduction of 2-methyl-3-oxopentanal 1a
gave the corresponding 3-oxoalkanol derivative 2. The
difference in the reactivity may be due to the bulkiness of
the substrate. A similar example has been reported in the
baker’s yeast reduction of the b-keto ester derivatives.
The reduction of 3-methoxycarbonyltetrahydrothiopyran-
4-one gave the reduced product, while reduction of meth-
yl 2-methyl-3-oxopentanoate did not proceed.11 The syn-
selectivity was improved using a sulfur compound such as
L-cysteine or DMSO with a ratio of 90 : 10 or 88 : 12, re-
spectively. The relative configuration was determined by
O
O
OH
Me2C(OMe)2
2N HCl
Y. 98%
OH
3
CSA / acetone
S
4
S
5
Y. 91%
OTBDMS
OTBDMS
OTs
I
NaI
1. TsCl / Py
2. TBDMSOTf
iPr2NEt
NaHCO3
S
S
6
acetone
5
CH2Cl2
Y. 98% (2 sreps)
Y. 98%
NMe2
OH
S
O
OH
O
N
1. LDA,
2. 2N HCl, EtOH
S
syn-7
Y. 27% (2 steps)
anti-7
Y. 43% (2 steps)
OH
O
Raney-Ni (W-2)
EtOH, reflux
Ac2O
Py
Y. 41%
Y. 85%
serricornin 8
OAc
O
[α]D23 = -18.1 (c 0.21, n-hexane)
lit. [α]D23 = -17.7 (c 0.155, n-hexane)
1
500 MHz H NMR analysis of the crude product of the
corresponding acetonide derivative 4.12 Improved enanti-
oselectivity was also obtained using a sulfur compound. In summary, improved enantio- and diastereoselectivity
The best enantioselectivity of syn-3a was achieved using in the baker’s yeast reduction of b-keto aldehyde deriva-
DMSO as an additive in up to >99% ee. The absolute ste- tives was achieved using a sulfur compound as an addi-
reochemistry was established by its derivatization to ser- tive. Previously, the baker’s yeast reduction of b-keto
ricornin acetate, and comparison of the optical rotation.
aldehyde derivatives has not been reported. The homo-
chiral diol was transformed into serricornin in enantio-
merically pure form in short steps and high yield,
demonstrating the synthetic usefulness of the use of a sul-
fur compound as an additive in the baker’s yeast reduc-
tion.
The enantiomerically pure 1,3-diol derivative 3 was trans-
formed into serricornin. Serricornin is a sex pheromone
produced by the female cigarette beetle (Lasioderma ser-
ricorne F.), which is a serious pest of cured tobacco
leaves.13 The diastereomeric mixture of the diol derivative
3 was separated with flash chromatography after the trans-
formation into the acetonide derivative 4. Selective tosy-
lation of the primary hydroxy group of the diastereo- and
enantiomerically pure diol syn-3, followed by the protec-
tion of the secondary hydroxy group with TBDMS and io-
dination of the tosylate gave the iodide derivative 6 in
high yield. Alkylation of the hydrazone with the iodide 6
followed by hydrolysis for construction of the skeleton of
serricornin gave a separable diastereomeric mixture of the
coupling product 7. The anti-isomer of the alkylated prod-
uct anti-7 was reduced with Raney-nickel (W-2) to give
serricornin 8. The absolute stereochemistry was estab-
lished by comparison of the optical rotation of serricornin
acetate 9.13b
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R. Hayakawa, M. Shimizu
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Synlett 1999, No. 8, 1298–1300 ISSN 0936-5214 © Thieme Stuttgart · New York