Baker's yeast reduction of β-hydroxy ketones

Article abstract of DOI:10.1002/ejoc.200901006

Reduction of β-hydroxy ketones to the corresponding 1,3-diols by baker's yeast was investigated, in order to develop methods for simultaneous control over the configurations of multiple stereogenic centres. The reactions were found to be enantiospecific a

Full text of DOI:10.1002/ejoc.200901006

FULL PAPER
DOI: 10.1002/ejoc.200901006
Baker’s Yeast Reduction of β-Hydroxy Ketones
Daniela Acetti,[a] Elisabetta Brenna,*[a] Claudio Fuganti,[a] Francesco G. Gatti,[a] and
Stefano Serra[b]
Keywords: Enzymes / Baker’s yeast / Reduction / Asymmetric synthesis / 1,3-Diols / Ketones
Reduction of β-hydroxy ketones to the corresponding 1,3-
diols by baker’s yeast was investigated, in order to develop
methods for simultaneous control over the configurations of
multiple stereogenic centres. The reactions were found to be
enantiospecific and generally characterised by good dia-
stereoselectivity. Substrates with a substituent at the carbon
atom in the α position were also considered. When the sub-
stituent at the α-carbon atom was part of a ring, higher selec-
tivity was observed.
view. Some biocatalytic reductions have shown potential for
simultaneous control over the configurations of multiple
stereogenic centres with high enantio- and diastereoselectiv-
ity.[8]
We have recently been involved in investigations of
baker’s yeast reductions[9] of syn- and anti-1 (Scheme 1),
which afforded a 1:1 mixture of the enantiomerically pure
diols (1S,2S,R)-anti,anti-2 and (1S,2R,S)-anti,syn-2. This
was quite a novel finding because β-hydroxy ketones are
typically the final products of baker’s yeast reductions of β-
diketones,[5g,10] and in most cases they are not further trans-
formed.
Introduction
Stereoselective reduction of carbonyl moieties is a very
useful tool for the introduction of stereogenic centres into
chiral synthons, which are necessary for the preparation of
natural products and pharmaceuticals.[1] Chemical method-
ologies such as metal hydride reduction, catalytic hydrogen-
ation or hydrogen-transfer reactions,[2] as well as biocata-
lytic approaches using either isolated enzymes or whole-cell
systems[3] have been optimised for transformations of this
kind .
The prerequisites for the ideal reagent or catalyst should
be the following: broad substrate acceptance, predictability
of access to enantiomers and/or diastereoisomers, minimal
environmental burden, and possibly at the lowest cost.[4]
Enzymes are very interesting candidates as choices of ap-
propriate reducing agents, and this has recently prompted a
renewal of interest in the application of baker’s yeast and
isolated ketoreductases in stereoselective reactions.[5]
The chiral molecules that organic chemists are called on
to prepare today show such stereochemical complexity that
the configuration of more than one stereogenic centre often
has to be controlled.[6] The synthesis of configurationally
defined steric sequences such as 1,3-diols or 2-alkyl-1,3-di-
ols, for example, is a challenging task that can be achieved
through highly stereoselective 1,3-diketone or 3-hydroxy
ketone reductions.[7] The concomitant formation of ste-
reogenic centres of precise configuration in one-pot trans-
formations is of great advantage from a synthetic point of
Scheme 1.
Chênevert,[11] for example, described the extraordinary
selectivity of the baker’s yeast reduction of 1-phenylbutane-
1,3-dione to optically pure (S)-3-hydroxy-1-phenylbutan-1-
one. The reaction was found to be unexpectedly chemose-
lective, with only the carbonyl group at the 3-position being
affected, in spite of the fact that baker’s yeast was known
to reduce acetophenone. The reaction was also enantiospec-
ific, with only the (S)-(+) enantiomer of the final hydroxy
ketone being obtained. In 2004[12] the conversion of the hy-
[a] Politecnico di Milano, Dipartimento di Chimica, Materiali, In-
gegneria Chimica,
Via Mancinelli 7, 20131 Milano, Italy
Fax: +39-02-23993180
E-mail: elisabetta.brenna@polimi.it
[b] Istituto CNR per la Chimica del Riconoscimento Molecolare,
Dipartimento di Chimica, Materiali, Ingegneria Chimica, Po-
litecnico di Milano,
droxy ketone
3 (Scheme 2) into (1S,3S)-(–)-syn and
(1R,3S)-(+)-anti diol 4 in a reduction mediated by Sac-
charomyces cerevisiae was described.
Via Mancinelli 7, 20131 Milano, Italy
142
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Baker’s Yeast Reduction of β-Hydroxy Ketones
group not adjacent to the aromatic ring. The results of our
investigation are reported here.
Results and Discussion
Scheme 2. Baker’s-yeast-mediated reduction of hydroxy ketone 3 as
The hydroxy ketones 3 and 5–11 were prepared from
readily available, cheap starting materials through aldol
condensations, promoted by catalytic amounts of aqueous
NaOH (40%) in methanol as a solvent. Only rac-8 was ob-
tained by a different route, by ozonolysis of 2-methyloct-1-
en-4-ol. The derivatives rac-9 and rac-10 were each obtained
as a mixture of two racemic diastereoisomers, in a ratio of
0.7:1 for syn-9/anti-9 and of 0.5:1 for syn-10/anti-10. They
were subjected to baker’s yeast fermentation as such with-
out isomer separation. The two diastereoisomers of rac-11
could be separated by column chromatography and sub-
jected separately to enzyme reduction.
in ref.[12]
The importance of simultaneous control over more than
one stereogenic centre through baker’s yeast fermentation
prompted us to investigate this transformation further with
the hydroxy ketones 3 and 5–11 (Scheme 3), including with
substrates containing substituents at their α carbon atoms.
The results of baker’s yeast fermentation of the hydroxy
ketones 3 and 5–11 are summarised in Tables 1 and 2. The
reductions of the carbonyl moieties showed high enantio-
selectivity and always afforded new stereogenic centres of S
configuration. Enantiomeric excesses or optical purity val-
ues in the 95–99% range were observed for the final diols.
The only low value was found for (1S,3S)-syn-14 (ee =
68%).
In our hands, baker’s yeast reduction of the hydroxy
ketone 3 proved to be more stereoselective (de = 70%) than
the transformation described by Taneja et al. (de = 33%).[12]
In the reduction of the β-hydroxy ketones 3 and 5–7 a pref-
Scheme 3. Hydroxy ketones subjected to baker’s yeast fermentation
conditions.
erence for the formation of the anti diols was observed: dia-
1
We envisaged the possibility of employing this enzymatic stereoisomeric excess values, calculated from the H NMR
procedure to obtain synthons for the preparation of suitable spectra of the crude reaction mixtures, ranged from 43%
natural compounds (Scheme 4), including i) prelactone V[13] for anti-/syn-13, to 70–74% for anti-/syn-4 and -14, to
(I), which has a C6 1,3-diol steric sequence in a definite Ͼ99% for anti-12. The reduction of rac-8 gave the corre-
absolute configuration embedded in its structure and can sponding syn and anti diols in nearly 1:1 ratio, with a slight
be prepared by one-carbon homologation of the C5 chiral preference for the syn diol.
fragment obtained by bioreduction of ketone 10, and
In the cases of the α-substituted β-hydroxy ketones 9–
ii) compound with structure of type II containing a C5 1,3- 11 the formation of the anti diols was generally preferred:
diol sequence, a key fragment in the synthesis of amphidin- diastereoisomeric excess values of 56 and 35% were found
olides O and P,[14] that can be prepared from the reduction for the anti diols 16 and 17 (anti diol = syn,anti + anti syn;
products of ketone 10.
syn diol = anti,anti + syn,syn), but Ͼ99% for anti,syn-18,
For all the β-hydroxy ketones employed as starting mate- the only product of anti-11 reduction. In the reduction of
rials in this work (except for the aliphatic compound rac-8) syn-11 nearly equimolar amounts of syn and anti diols were
we intentionally chose the regioisomer with the carbonyl obtained.
Scheme 4. Chiral synthons for natural products.
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D. Acetti, E. Brenna, C. Fuganti, F. G. Gatti, S. Serra
FULL PAPER
Table 1. Baker’s yeast reductions of the β-hydroxy ketones 3 and 5–8 to afford the diols 4 and 12–15.
[a] Percentages of total diols in the crude reaction mixtures calculated from 1H NMR spectra. [b] Ratios between anti and syn diols
1
calculated from the H NMR spectra of the crude reaction mixtures.
In the reduction of rac-9, which was richer in the anti (Scheme 5) in methanol solution in the presence of catalytic
diastereoisomer, the diastereoisomeric distribution of prod- amounts of Pd/C, to give (S)-(+)-19 and (1S,2S)-(+)-20,
ucts was in favour (1.8:1) of those showing the syn arrange- respectively.
ment at the stereogenic centres already present in the start-
ing material, whereas the same ratio (2:1) was maintained
in the reduction of rac-10. When the mixture of syn- and
anti-1 was subjected to the fermentation conditions, only
the anti diastereoisomer was transformed.
The diols obtained from the baker’s yeast reductions
were separated from the reaction mixtures by column
chromatography and characterised. The absolute configura-
tions of the diols (1R,3S)-anti-4, (2S,4R)-anti-12, (2S,4S)-
anti-15, (2S,4R)-syn-15, (1R,2S,3S)-syn,anti-16, (1R,2R,3S)-
anti,syn-16, (2S,3R,4S)-anti,syn-17 and (2S,3S,4R)-anti,-
anti-17 were assigned by comparison with the specific op-
tical rotatory data reported in the literature (See Experi-
Scheme 5. i) Pd/C, MeOH, room temp., H2, 80 psi.
mental Section).
The absolute configurations of (1R,3S)-anti-13, (1R,3S)-
For diol 14, lipase-PS-mediated acetylation also had to
anti-l4 and (1S,2R,R)-anti,syn-18 were determined by chem- be investigated (Scheme 6), in order to establish the abso-
ical correlation. Compounds (1R,3S)-(+)-anti-13 and lute configurations of the baker’s-yeast-mediated reduction
(1S,2R,R)-(+)-anti,syn-18 were subjected to hydrogenolysis products. A search in the literature showed that the absolute
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Baker’s Yeast Reduction of β-Hydroxy Ketones
Table 2. Baker’s yeast reductions of the α-substituted-β-hydroxy ketones 1 and 9–10 to afford the diols 2 and 16–18.
[a] Percentages of total diols in the crude reaction mixtures calculated from 1H NMR spectra. [b] Ratios between anti and syn diols
1
calculated from the H NMR spectra of the crude reaction mixtures (anti diols: syn,anti + anti,syn; syn diols: syn,syn + anti,anti). The
molar ratios of the single diastereoisomers with respect to the less abundant ones are reported under each structure.
configuration of the derivative (+)-syn-21 was known,[15] When a 1:2 mixture of syn/anti diols 14, obtained upon
and we envisaged the possibility of functionalising the two NaBH4 reduction of the corresponding hydroxy ketone, was
hydroxy groups of diol 14 with high regioselectivity and treated with lipase PS in tert-butyl methyl ether solution in
enantioselectivity by enzyme-catalysed tranesterification. the presence of vinyl acetate, the monoacetate (+)-anti-22
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D. Acetti, E. Brenna, C. Fuganti, F. G. Gatti, S. Serra
FULL PAPER
Scheme 6. i) NaBH4, MeOH/CH2Cl2; ii) Lipase PS, tert-butyl methyl ether, vinyl acetate; column chromatography; iii) diethylmethoxy-
borane, THF/CH3OH, –78 °C; NaBH4; iv) MOMCl, iPr2NEt, CH2Cl2; v) KOH, MeOH.
could be recovered as a single pure compound, showing de cent to the aromatic ring, and also in aliphatic compounds
= 99% and ee = 99% (GC of the corresponding acetonide such as rac-8. The reactions are enantiospecific and are gen-
on a chiral column).
erally characterised by good diastereoselectivity. When the
When rac-syn-14, obtained by treatment of the corre- substituent at the α-carbon atom is part of to a ring (i.e.,
sponding hydroxy ketone with diethylmethoxyborane fol- rac-1 vs. rac-10, and rac-11 vs. rac-9) higher selectivity is
lowed by NaBH4, was treated with lipase PS under the observed: rac-syn-1 was not affected by baker’s yeast fer-
same conditions, the following derivatives could be isolated mentation and rac-anti-11 gave only (1S,2R,R)-anti,syn-18.
from the reaction mixture by column chromatography: the
The synthetic advantage of the transformation that we
diacetate (+)-syn-23 (ee = 99%, GC of the corresponding describe is that the enantioselective reduction of the car-
acetonide on a chiral column), the monoacetate (+)-syn-22 bonyl group occurs with diastereoselective discrimination
(ee = 99%, GC of the corresponding acetonide on a chiral through the configurations of the stereocentres already
column) and the unreacted diol (–)-syn-14 (ee = 99%, GC present in the starting racemic hydroxy ketones. These de-
of the corresponding acetonide on a chiral column).
rivatives can be readily prepared through aldol condensa-
The GC analysis of the corresponding acetonides on chi- tions, and by this one-pot procedure they can be converted
ral columns allowed us to establish that compound (+)-syn- into optically active 1,3-diols with simultaneous control
23 was the diacetate derivative of the enantiomer of the diol over the stereochemistry of two or three stereogenic carbon
syn-14, of configuration opposite to that of the syn diol atoms. The method represents an alternative to the two-
obtained by baker’s yeast reduction of the hydroxy ketone step sequence based on the diastereoselective reduction of
7. The configuration of the monoacetate (+)-syn-22 could optically active hydroxy ketones, which is well documented
be established by chemical correlation by the synthetic se- in the literature.[17]
quence shown in Scheme 6. Compound (+)-syn-22 was con-
This work might also serve to inspire others to look more
verted into the methoxymethyl ether derivative (+)-syn-24, closely at bioreductions of hydroxy ketones in the presence
which was then hydrolysed to afford compound (+)-syn-21, of more specific bioreagents, such as isolated and/or overex-
the absolute configuration of which was known to be pressed enzymes or engineered strains with higher reductase
(2R,4R).[15]
activity towards carbonyl groups. Nonetheless, the cheap
The relative syn and anti configurations of the diols 13 and easily handled baker’s yeast can still be the reagent of
were verified by conversion of racemic syn-13 into the cor- choice when it so happens that the complex multi-enzyme
responding acetonide. Its 1H NMR spectrum was consistent system operating during fermentation can perform bio-
with a diequatorial arrangement of the aryl and methyl transformations with high stereoselectivities.
groups [H–C(1): δ = 4.76 ppm, J = 11.1, 1.9 Hz, dd; H–
C(3): δ = 4.04 ppm, J = 11.7, 5.7, 2.2 Hz, dqd] and the
13C NMR resonances for the acetonide methyl groups were
Experimental Section
observed at δ = 30.3 and 19.8 ppm, which are characteristic
General Methods: Baker’s yeast from Lesaffre Italia (code number
values of syn acetonides.[16]
30509) was employed. TLC analyses were performed on Merck
Kieselgel 60 F254 plates. All the chromatographic separations were
carried out with silica gel columns. H and 13C NMR spectra were
1
Conclusions
recorded with a 400 MHz spectrometer. The chemical shift scale
Baker’s yeast reduction of β-hydroxy ketones has been
was based on internal tetramethylsilane. GC–MS analyses were
shown to be possible when the carbonyl moiety is not adja- performed with a HP-5MS column (30 mϫ0.25 mmϫ0.25 µm).
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Baker’s Yeast Reduction of β-Hydroxy Ketones
The following temperature program was employed: 60 °C (1 min)/
6 °Cmin–1/150 °C (1 min)/12 °Cmin–1/280 °C (5 min). The enantio-
meric excess values were determined by GC or HPLC analysis. GC
analysis was performed with a Chirasil DEX CB column (Chrom-
pack, 25 mϫ0.25 mm), installed on a DANI HT 86.10 gas chro-
matograph, under the following conditions:
(E)-4-Hydroxy-6-phenylhex-5-en-2-one (rac-5):[18] This compound
was obtained from cinnamaldehyde (16.5 g, 0.125 mol) and acetone
1
(7.25 g, 0.125 mol): 13.5 g (57%). H NMR (400 MHz, CDCl3): δ
= 7.45–7.20 (m, 5 H, aromatic H), 6.64 (dd, J = 15.9, 1.1 Hz, 1 H,
PhCH=), 6.20 (dd, J = 15.9, 6.1 Hz, 1 H, =CHCH), 4.76 (dq, J =
6.4, 1.1 Hz, 1 H, CHOH), 2.76 (d, J = 6.4 Hz, 1 H, CH2), 2.22 (s,
3 H, COCH3) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 208.1,
136.1, 130.4, 129.5, 125.9, 127.1, 128.1, 67.8, 49.7, 30.2 ppm.
a) Diacetate derivatives of syn- and anti-4: 60 °C (3 min)/
1.5 °Cmin–1/180 °C; diacetate of (1R,3S)-anti-4 tR = 39.25 min; di-
acetate of (1S,3R)-anti-4 tR = 39.49 min; diacetate of (1S,3S)-syn-
4 tR = 40.28 min; diacetate of (1R,3R)-syn-4 tR = 40.39 min.
4-Hydroxy-4-(4-methoxyphenyl)butan-2-one (rac-6):[18,19] This com-
pound was obtained from 4-methoxybenzaldehyde (17.0 g,
0.125 mol) and acetone (7.25 g, 0.125 mol): 13.4 g (55%). 1H NMR
(400 MHz, CDCl3): δ = 7.27 (m, 2 H, aromatic H), 6.87 (m, 2 H,
aromatic H), 5.09 (dd, J = 9.2, 3.3 Hz, 1 H, ArCHOH), 3.79 (s, 3
H, OCH3), 2.88 (dd, J = 17.3, 9.2 Hz, 1 H, CHH), 2.77 (dd, J =
17.3, 3.3 Hz, 1 H, CHH), 2.17 (s, 3 H, COCH3) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 208.0, 158.3, 135.1, 126.4, 113.1, 68.8,
54.4, 51.5, 29.9 ppm.
b) Acetonide derivatives of diols anti- and syn-14: 60 °C (3 min)/
1.5 °Cmin–1/180 °C; acetonide of (1R,3S)-anti-14 tR = 14.02 min;
acetonide of (1S,3R)-anti-14 tR = 14.32 min; acetonide of (1R,3R)-
syn-14 tR = 15.32 min; acetonide of (1S,3S)-syn-14 tR = 15.52 min.
HPLC analyses were performed with a Chiralcel OD column, in-
stalled on a Merck–Hitachi L-7100 instrument with a Merck–Hita-
chi -4250 UV/Vis detector, under the following conditions:
4-(Furan-2-yl)-4-hydroxybutan-2-one (rac-7):[20] This compound
was obtained from 2-furylaldehyde (7.50 g, 0.049 mol) and acetone
(7.25 g, 0.125 mol): 8.28 g (43%). H NMR (400 MHz, CDCl3): δ
a) Diacetate derivatives of diols syn- and anti-13: hexane/propan-
2-ol 98:2, flow 0.6 mLmin–1, 210 nm; diacetate of (1S,3S)-syn-13
tR = 9.60 min; diacetate of (1R,3R)-syn-13 tR = 10.25 min; diace-
tate of (1R,3S)-anti-13 tR = 11.27 min; diacetate of (1S,3R)-anti-13
tR = 12.47 min.
1
= 7.36 (m, 1 H, α furan H), 6.32 (m, 1 H, β furan H), 6.26 (m, 1
H, β furan H), 5.16 (dd, J = 8.6, 3.7 Hz, 1 H, CHOH), 3.05 (dd, J
= 17.9, 8.6 Hz, 1 H, CHH), 2.91 (dd, J = 17.9, 3.7 Hz, 1 H, CHH),
2.23 (s, 3 H, COCH3) ppm. 13C NMR (100.6 MHz, CDCl3): δ =
209.5, 156.6, 142.9, 110.9, 107.1, 63.8, 52.7, 31.4 ppm.
b) Diol derivatives anti,syn-17 and anti,anti-17: hexane/propan-2-ol
90:10, flow 0.6 mLmin–1, 254 nm; (+)-anti,syn-17 tR = 9.12 min,
(–)-anti,syn-17 tR = 12.59 min, (–)-anti,anti-17 tR = 10.80 min, (+)-
anti,anti-17 tR = 14.22 min.
4-Hydroxyoctan-2-one (rac-8): Compound rac-8 was obtained by
treatment of 2-methyloct-1-en-4-ol (17.0 g, 0.120 mol, prepared as
in ref.[21]) with O3 at –78 °C in CH2Cl2/MeOH (2:1, 500 mL) with
quenching of the reaction mixture with PPh3. The usual reaction
workup afforded, after purification by column chromatography
with elution with hexane and increasing amounts of AcOEt, rac-8
(10.9 g, 63%): 1H NMR (400 MHz, CDCl3): δ = 4.02 (m, 1 H, CH–
OH), 2.60 [dd, J = 17.0, 3.2 Hz, 1 H, H–C(3)], 2.53 [dd, J = 17.0,
8.7 Hz, 1 H, H–C(3)], 2.17 (s, 3 H, COCH3), 1.56–1.22 (m, 6 H,
CH2CH2CH2), 0.90 (t, J = 7.1 Hz, 3 H, CH3–CH2) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 208.6, 66.9, 49.7, 35.9, 29.9, 26.9, 21.8,
13.1 ppm.
c) Diols 18: hexane/propan-2-ol 95:5, flow 0.4 mLmin–1, 210 nm;
(1R,2R,S)-syn,anti-18 tR = 38.49 min; (1S,2S,R)-syn,anti-18 tR
=
52.30 min; (1R,2S,R)-syn,syn-18 tR = 42.32 min; (1S,2R,S)-syn,syn-
18 tR = 75.26 min; (1R,2S,S)-anti,syn-18 tR = 32.87 min, (1S,2R,R)-
anti,syn-18 tR = 48.08 min.
d) Hydroxy ketone anti-11: hexane/propan-2-ol 98:2, flow
0.6 mLmin–1, 210 nm; (2S,R)-anti-11 tR = 33.7 min; (2R,S)-anti-11
tR = 54.5 min;
Optical rotations were measured with a Dr. Kernchen Propol digi-
tal automatic polarimeter at 589 nm and are given in 10–1 deg
cm2 g–1.
syn- and anti-4-Hydroxy-3-methyl-4-phenylbutan-2-one (rac-9):[22]
This compound was obtained from benzaldehyde (13.2 g,
0.125 mol) and butan-2-one (9.0 g, 0.125 mol); a 0.7:1 mixture of
1
Synthesis of Hydroxy Ketones 3, 5–7 and 9–11: The hydroxy ketones
3, 5–7 and 9–11 were prepared through aldol condensations of suit-
able commercially available starting materials by the following pro-
cedure, demonstrated for the hydroxy ketone 11.
syn- and anti-9 was obtained (12.9 g, 58%): H NMR (400 MHz,
CDCl3): δ = 7.38–7.26 (m, aromatic H), 5.09 (d, J = 3.8 Hz, 1 H,
CHOH syn), 4.74 (d, J = 8.4 Hz, 1 H, CHOH anti), 2.93 (m, 1 H,
CHCH3 anti), 2.83 (m, 1 H, CHH syn ), 2.21 (s, 3 H, COCH3,
anti), 2.14 (s, 3 H, COCH3, syn), 1.09 (d, J = 7.4 Hz, CHCH3 syn),
0.94 (d, J = 7.4 Hz, CHCH3 anti) ppm.
A stirred solution of cyclohexanone (12.2 g, 0.125 mol) and benzal-
dehyde (13.2 g, 0.125 mol) in methanol (100 mL) was treated at
–10 °C with aqueous sodium hydroxide (40%, 1 mL). After 15 min
the slightly yellow solution was poured into excess ice/water con-
taining acetic acid (2 mL). The reaction mixture was extracted with
an ethyl acetate/hexane mixture (2:1). The organic phase was
washed with sat. NaHCO3 solution and dried with sodium sulfate.
The residue obtained upon evaporation of the solvent was chro-
matographed with increasing amounts of ethyl acetate in hexane,
affording syn-11 (6.12 g, 24%) and anti-11 (5.36 g, 21%).
syn- and anti-(E)-4-Hydroxy-3-methyl-6-phenylhex-5-en-2-one (rac-
10):[23] This compound was obtained from cinnamaldehyde (16.5 g,
0.125 mol) and butan-2-one (9.0 g, 0.125 mol); a 0.5:1 mixture of
1
syn- and anti-10 was obtained (13.5 g, 53%): H NMR (400 MHz,
CDCl3): δ = 7.45–7.15 (m, aromatic H), 6.70–6.55 (m, PhCH=),
6.20–6.10 (m, =CH–CH), 4.65 (ddd, J = 5.6, 3.8, 1.5 Hz, CHOH
syn ), 4.38 (t, J = 7.4 Hz, CHOH anti.), 2.90–2.65 (m, CHCH3),
2.23 (s, CH3CO anti), 2.22 (s, CH3CO syn), 1.20 (d, J = 7.3 Hz,
CH3CH syn), 1.14 (d, J = 7.1 Hz, CH3CH anti) ppm.
4-Hydroxy-4-phenylbutan-2-one (rac-3):[12] This compound was ob-
tained from benzaldehyde (13.2 g, 0.125 mol) and acetone (7.25 g,
syn- and anti-2-[Hydroxy(phenyl)methyl]cyclohexanone (rac-11):[24]
1
0.125 mol): 11.1 g (54%). H NMR (400 MHz, CDCl3): δ = 7.38– This compound was obtained from benzaldehyde (13.2 g,
7.22 (m, 5 H, aromatic H), 5.12 (dd, J = 9.1, 3.4 Hz, 1 H, CHOH),
2.87 (dd, J = 17.3, 9.1 Hz, 1 H, CHH), 2.77 (dd, J = 17.3, 3.4 Hz,
3 H, CHH), 2.16 (s, 3 H, COCH3) ppm. 13C NMR (100.6 MHz,
CDCl3): δ = 207.8, 142.8, 127.6, 126.6, 124.9, 68.9, 51.3, 29.6 ppm.
0.125 mol) and cyclohexanone (12.2 g, 0.125 mol); a 1:1 mixture of
syn- and anti-11 was obtained. The two diastereoisomers could be
separated by column chromatography, with elution with hexane
and increasing amounts of ethyl acetate.
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Compound syn-11:[24] 6.12 g (24%). H NMR (400 MHz, CDCl3):
δ = 7.36–7.28 (m, 5 H, aromatic H), 5.38 (d, J = 2.6 Hz, 1 H,
CHOH), 2.60 (m, 1 H, H cyclohexanone ring), 2.45 (m, 1 H, H
cyclohexanone ring), 2.36 (m, 1 H, H cyclohexanone ring), 2.07 (m,
1 H, H cyclohexanone ring), 1.88–1.46 (m, 5 H, H cyclohexanone
ring) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 213.3, 141.7, 127.5,
126.2, 125.3, 69.9, 56.6, 41.8, 27.0, 25.5, 24.1 ppm.
H, CH2), 1.26 (d, J = 6.4 Hz, 3 H, CH3) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 136.8, 132.0, 130.0, 128.6, 127.6, 126.5,
70.4, 65.4, 44.4, 23.7 ppm.
1
Baker’s Yeast Reduction of rac-6: Compound rac-6 (10.0 g,
0.052 mol) was subjected to baker’s yeast fermentation. After 72 h,
the reaction was worked up and the corresponding crude mixture
showed the following composition (NMR): the starting hydroxy
ketone 6 (77.6%), (–)-(1S,3S)-syn-13 (6.4%) and (+)-(1R,3S)-anti-
13 (16%). Column chromatography allowed the recovery of (+)-
anti-13 and (–)-syn-13 as single pure compounds.
Compound anti-11:[24] 5.36 g (21%). H NMR (400 MHz, CDCl3):
1
δ = 7.36–7.28 (m, 5 H, aromatic H), 4.79 (d, J = 8.7 Hz, 1 H,
CHOH), 2.61 (m, 1 H, H cyclohexanone ring), 2.46 (m, 1 H, H
cyclohexanone ring), 2.36 (m, 1 H, H cyclohexanone ring), 2.07 (m,
1 H, H cyclohexanone ring), 1.88–1.22 (m, 5 H, H cyclohexanone
ring) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 214.6, 140.7, 127.7,
126.5, 125.3, 73.8, 56.8, 41.8, 30.1, 27.2, 23.9 ppm.
(1S,3S)-1-(4-Methoxyphenyl)butane-1,3-diol [(–)-syn-13]:[25] 0.359 g
(3%); ee = 99% (HPLC of the corresponding diacetate). [α]D
=
–18.3 (c = 1.05, CHCl3) of a sample of 82% purity (NMR). 1H
NMR (400 MHz, CDCl3): δ = 7.27 (m, 2 H, aromatic H), 6.88 (m,
2 H, aromatic H), 4.90 (dd, J = 9.9, 2.9 Hz, 1 H, ArCHOH), 4.12
(m, 1 H, CHCH3), 3.80 (s, 3 H, OCH3), 1.88 (dt, J = 14.6, 9.9 Hz,
1 H,CHH), 1.74 (dt, J = 14.6, 2.9 Hz, 1 H, CHH), 1.23 (d, J =
6.4 Hz, 3 H, CH3) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 158.9,
136.7, 126.8, 113.7, 74.5, 68.4, 55.1, 46.9, 23.8 ppm.
Baker’s Yeast Reduction of Hydroxy Ketones 3 and 5–11: The hy-
droxy ketones 3 and 5–11 were subjected to baker’s yeast fermenta-
tion conditions in the following procedure, demonstrated for syn-
11. A solution of the ketone syn-11 (5.0 g, 0.024 mol) in ethanol
(10 mL) was added dropwise at 30 °C to a stirred mixture of baker’s
yeast (100 g) and -glucose (40 g) in tap water (1 L). After the sys-
tem had been kept for 48 h under these conditions, acetone
(500 mL) was added, followed by ethyl acetate/hexane (4:1,
500 mL). The mixture was filtered in a large Buchner funnel
through a thick Celite pad previously washed with acetone. The
two phases were then separated and the aqueous phase was ex-
tracted twice with an ethyl acetate/hexane mixture. The oily residue
obtained upon concentration of the washed and dried organic
phase was chromatographed with increasing amounts of ethyl ace-
tate in hexane, to provide the starting hydroxy ketone syn-11
(2.39 g, 49%), (1S,2R,S)-syn,syn-18 (0.618 g, 12.5%) and
(1S,2S,R)-syn,anti-18 (0.939 g, 19%). The 1,3-diols prepared by
baker’s yeast reduction were isolated from the corresponding mix-
tures by column chromatography.
A racemic sample of syn-13 was converted into the corresponding
acetonide by treatment with 2,2-dimethoxypropane in the presence
of pyridinium p-toluenesulfonate to verify the relative syn configu-
1
ration: H NMR (400 MHz, CDCl3): δ = 7.21 (m, 2 H, aromatic
H), 6.80 (m, 2 H, aromatic H), 4.76 (dd, J = 11.1, 2.0 Hz, 1 H,
ArCHO), 4.04 (dqd, J = 11.7, 5.7, 2.0 Hz, 1 H, CHCH3), 3.71 (s,
3 H, OCH3), 1.61 (dt, J = 13.0, 2.0 Hz, 1 H, CHH), 1.37 (m, 1 H,
CHH), 1.48 (s, 3 H, CCH3), 1.41 (s, 3 H, CCH3), 1.13 (d, J =
6.0 Hz, 3 H, CH3) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 159.1,
134.7, 127.2, 113.8, 98.9, 71.4, 65.3, 55.2, 40.9, 30.3, 22.1,
19.8 ppm.
(1R,3S)-1-(4-Methoxyphenyl)butane-1,3-diol [(+)-anti-13]:[25] 1.43 g
(12%); ee = 99% (HPLC of the corresponding diacetate). [α]D
=
+58.6 (c = 0.95, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.29
(m, 2 H, aromatic H), 6.89 (m, 2 H, aromatic H), 5.00 (dd, J = 7.6,
3.7 Hz, 1 H, ArCHOH), 4.07 (m, 1 H, CHCH3), 3.80 (s, 3 H,
OCH3), 1.87 (m, 2 H,CH2), 1.24 (d, J = 6.4 Hz, 3 H, CH3) ppm.
13C NMR (100.6 MHz, CDCl3): δ = 158.9, 136.6, 126.8, 113.8,
71.3, 65.3, 55.2, 46.2, 23.4 ppm.
Baker’s Yeast Reduction of rac-3: Compound rac-3 (10.0 g,
0.061 mol) was subjected to baker’s yeast fermentation. After 48 h,
the reaction was worked up and the corresponding crude mixture
showed the following composition (NMR): the starting hydroxy
ketone 3 (60%), (1R,3S)-anti-4 (34%) and (1S,3S)-syn-4 (6%). Col-
umn chromatography allowed the recovery of (+)-anti-4 as a single
pure compound.
Hydrogenolysis of (+)-anti-13: A solution of (+)-anti-13 (0.500 g,
2.55ϫ10–3 mol) in ethanol (20 mL) was treated with H2 (80 psi) at
room temperature for 48 h in the presence of Pd/C (50 mg). The
reaction mixture was filtered and concentrated under reduced pres-
sure, to give a residue that was purified by column chromatography
to afford (+)-19 (0.372 g, 81%): [α]D = +13.9 (c = 0.98, CHCl3)
{ref.[26] [α]D = +12.8 (c = 2.41, CHCl3) for (S)-19 with ee = 91%}.
1H NMR (400 MHz, CDCl3): δ = 7.11 (m, 2 H, aromatic H), 6.82
(m, 2 H, aromatic H), 3.81 (m, 1 H, CHOH), 3.78 (s, 3 H, OCH3),
2.65 (m, 2 H, CH2), 1.74 (m, 2 H, CH2), 1.22 (d, J = 6.0 Hz, 3 H,
CH3) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 157.8, 134.1, 129.2,
113.8, 67.4, 55.2, 41.0, 31.1, 23.6 ppm.
(1R,3S)-1-Phenylbutane-1,3-diol [(+)-anti-4]:[12] 2.93 g (29%); ee =
98% (GC of the corresponding diacetate on a chiral column). [α]D
= +58.6 (c = 1.12, CHCl3) {ref.[12] [α]D = +60.1 (c = 0.9, CHCl3)
1
for (1R,3S)-anti-4 with ee = 99%}. H NMR (400 MHz, CDCl3):
δ = 7.40–7.20 (m, 5 H, aromatic H), 5.00 (dd, J = 7.7, 3.7 Hz, 1 H,
PhCHOH), 4.04 (m, 1 H, CH3CHOH), 1.84 (m, 2 H, CH2), 1.21
(d, J = 6.3 Hz, 3 H, CHCH3) ppm. 13C NMR (100.6 MHz, CDCl3):
δ = 144.4, 128.4, 127.3, 125.5, 71.6, 65.3, 46.1, 23.4 ppm.
Baker’s Yeast Reduction of rac-5: Compound rac-5 (10.0 g,
0.053 mol) was subjected to baker’s yeast fermentation. After 48 h,
the reaction was worked up and the corresponding crude mixture
showed the following composition (NMR): the starting hydroxy
Baker’s Yeast Reduction of rac-7: Compound rac-7 (7.50 g,
0.049 mol) was subjected to baker’s yeast fermentation. After 48 h,
the reaction was worked up and the corresponding crude mixture
showed the following composition (NMR): the starting hydroxy
ketone 7 (76.0%), (1R,3S)-anti-14 (20.8%) and (1S,3S)-syn-14
(3.2%). Column chromatography allowed the recovery of (+)-anti-
14 as a single pure compound.
ketone
5
(77%) and (+)-(2S,4R)-anti-12 (23%). Column
chromatography allowed the recovery of (+)-anti-4 as a single pure
compound.
(2S,4R,E)-6-Phenylhex-5-ene-2,4-diol [(+)-anti-12]:[23] 1.83 g (18%).
[α]D = +39.7 (c = 1.15, CHCl3) {ref.[23] [α]D = +40.5 (c = 1.13,
CHCl3) for (2S,4R)-anti-12}. 1H NMR (400 MHz, CDCl3): δ =
7.40–7.20 (m, 5 H, aromatic H), 6.64 (dd, J = 15.9, 1.0 Hz, 1 H,
PhCH), 6.28 (dd, J = 15.9, 6.1 Hz, 1 H, =CHCH), 4.64 (qd, J =
(1R,3S)-1-(Furan-2-yl)butane-1,3-diol [(+)-anti-14]: 1.21 g (16%); ee
= 95% (GC of the corresponding acetonide). [α]D = +56.7 (c =
1.05, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.36 (m, 1 H, α
6.1, 1.0 Hz, 1 H, =CHCHOH), 4.20 (m, 1 H, CHCH3), 1.81 (m, 2 furan H), 6.33 (m, 1 H, β furan H), 6.26 (m, 1 H, β furan H), 5.04
148
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 142–151

Baker’s Yeast Reduction of β-Hydroxy Ketones
(dd, J = 7.6, 3.2 Hz, 1 H, Fu–CH–OH), 4.13 (m, 1 H, CH3CH– (d, J = 6.4 Hz, CH3CH) ppm. 13C NMR (100.6 MHz, CDCl3): δ =
OH), 2.04–1.87 (m, 2 H, CH2), 1.27 (d, J = 6.4 Hz, CH3CH) ppm. 170.0, 169.7, 151.6, 142.4, 110.1, 108.7, 67.6, 65.7, 38.4, 20.9,20.8,
13C NMR (100.6 MHz, CDCl3): δ = 156.8, 141.6, 110.0, 105.5, 19.9 ppm.
65.0, 64.9, 42.8, 23.2 ppm.
(2R,4R)-4-(Furan-2-yl)-4-hydroxybutan-2-yl Acetate [(+)-syn-22]: ee
The assignment of the relative configuration of diol anti-14 was
based on the 1H and 13C NMR spectra of the corresponding aceto-
nide, prepared by treatment with 2,2-dimethoxypropane in acetone
in the presence of pyridinium p-toluenesulfonate. A comparison
= 99% (GC of the corresponding acetonide). [α]D = +13.5 (c =
1.58, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.34 (m, 1 H, α
furan H), 6.30 (m, 1 H, β furan H), 6.20 (m, 1 H, β furan H), 4.95
(sextuplet, J = 6.0 Hz, 1 H, CH3CHOAc), 4.75 (t, J = 6.7 Hz, 1 H,
Fu–CH–OH), 2.18 (m, 1 H, CHH), 2.00 (m, 1 H, CHH), 1.96 (s,
3 H, CH3COO), 1.24 (d, J = 6.4 Hz, CH3CH) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 170.6, 155.9, 141.8, 110.0, 105.8, 68.4,
64.8, 41.3, 21.0, 19.8 ppm.
1
was made with the H and 13C NMR spectra of the acetonide of
diol syn-14 reported in the literature.[15]
1
Acetonide of Diol anti-14: H NMR (400 MHz, CDCl3): δ = 7.38
(m, 1 H, α furan H), 6.32 (m, 1 H, β furan H), 6.25 (m, 1 H, β
furan H), 4.92 (dd, J = 8.3, 6.4 Hz, 1 H, Fu–CH–O), 4.15 (m, 1 H,
CHOCH3), 2.22 (m, 1 H, CHH), 1.78 (m, 1 H, CHH), 1.45 (s, 3
H, CH3), 1.34 (s, 3 H, CH3), 1.25 (d, J = 6.1 Hz, CH3CH) ppm.
13C NMR (100.6 MHz, CDCl3): δ = 154.3, 142.3, 110.1, 107.1,
(1S,3S)-1-(Furan-2-yl)butane-1,3-diol [(–)-syn-14]: ee = 99% (GC of
1
the corresponding acetonide). [α]D = –31.8 (c = 0.66, CHCl3). H
NMR (400 MHz, CDCl3): δ = 7.36 (m, 1 H, α furan H), 6.32 (m,
1 H, β furan H), 6.24 (m, 1 H, β furan H), 4.94 (dd, J = 9.4, 3.8 Hz,
1 H, Fu–CH–OH), 4.09 (m, 1 H, CH3CH–OH), 2.04–1.87 (m, 2 H,
CH2), 1.23 (d, J = 6.4 Hz, CH3CH) ppm. 13C NMR (100.6 MHz,
CDCl3): δ = 156.3, 141.7, 110.0, 105.5, 67.9, 67.7, 43.1, 23.7 ppm.
100.3, 62.9, 62.6, 36.7, 26.1, 24.2, 21.7 ppm. GC/MS: = tR
=
11.96 min, m/z 196 (12) [M]+, 181 (15), 121 (100).
Acetonide of Diol syn-14: 1H NMR (400 MHz, CDCl3): δ = 7.37
(m, 1 H, α furan H), 6.33 (m, 1 H, β furan H), 6.28 (m, 1 H, β
furan H), 4.96 (m, 1 H, Fu–CH–O), 4.10 (m, 1 H, CHOCH3), 1.73
(m, 2 H, CH2), 1.56 (s, 3 H, CH3), 1.46 (s, 3 H, CH3), 1.24 (d, J =
6.0 Hz, CH3CH) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 154.5,
142.1, 110.0, 106.5, 99.0, 65.2, 64.9, 36.6, 30.1, 22.0, 19.6 ppm. GC/
MS: tR = 12.47 min, m/z 196 (12) [M]+, 181 (12), 121 (100).
Determination of the Absolute Configuration of the Monoacetate
(+)-syn-22. Preparation of (2R,4R)-4-(Furan-2-yl)-4-(methoxymeth-
oxy)butan-2-yl Acetate [(+)-syn-24]: The monoacetate (+)-syn-22
(0.900 g, 4.55ϫ10–3 mol) was treated with MOMCl (0.805 g,
0.010 mol) and iPr2Net (1.81 g, 0.014 mol) in CH2Cl2 (50 mL). The
reaction mixture was stirred at room temperature for 12 h and was
then diluted with AcOEt and saturated NaHCO3. The mixture was
extracted with AcOEt, dried and concentrated under reduced pres-
sure. The residue was purified by column chromatograph with elu-
tion with hexane/ethyl acetate to afford the MOM derivative (+)-
syn-24 (0.793 g, 72%): [α]D = +101 (c = 1.21, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 7.38 (m, 1 H, α furan H), 6.32 (m, 1 H, β
furan H), 6.26 (m, 1 H, β furan H), 4.84 (m, 1 H, CH3CH–OAc),
4.69 (t, J = 6.9 Hz, 1 H, Fu–CH–OMOM), 4.58 (d, J = 6.9 Hz, 1
H, OCHHO), 4.50 (d, J = 6.9 Hz, 1 H, OCHHO), 3.35 (s, 3 H,
OCH3), 2.26 (m, 1 H, CHH), 2.06 (m, 1 H, CHH), 1.99 (s, 3 H,
Lipase-Mediated Acetylation of Diols syn- and anti-14: In a typical
experiment, a solution of diol 14 (3.12 g, 0.020 mol) in vinyl ace-
tate/tert-butyl methyl ether (1:1, 40 mL) was stirred at room tem-
perature for 2 d with lipase Amano PS (Burkholderia cepacia,
3.0 g). The filtered solution was concentrated and the residue was
chromatographed with increasing amounts of ethyl acetate in hex-
ane.
Under these conditions, the 1:2 mixture of syn/anti-14 (3.12 g,
0.020 mol) obtained by NaBH4 reduction of hydroxy ketone 7 in
CH2Cl2/MeOH solution at 0 °C afforded the monoacetate deriva-
tive (+)-anti-22 (0.396 g, 10%), followed by an inseparable mixture
of other isomeric monoacetates and, finally, by the unconverted
starting diols (1.28 g, 41%).
COCH3), 1.23 (d,
J =
6.4 Hz, CH3CH) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 170.0, 152.9, 142.4, 109.9, 108.5, 93.8,
67.95, 67.90, 55.4, 39.9, 20.9, 19.8 ppm.
(2R,4R)-4-(Furan-2-yl)-4-(methoxymethoxy)butan-2-ol
[(+)-syn-
21]:[15] The MOM derivative (+)-syn-24 (0.650 g, 2.68ϫ10–3 mol)
was treated with KOH (0.226 g, 4.03ϫ10–3 mol) in MeOH
(2R,4S)-4-(Furan-2-yl)-4-hydroxybutan-2-yl Acetate [(+)-anti-22]: ee
= 95% (HPLC of the corresponding acetonide). [α]D = +8.6 (c =
0.56, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.34 (m, 1 H, α
furan H), 6.29 (m, 1 H, β furan H), 6.22 (m, 1 H, β furan H), 5.14
(dqd, J = 8.8, 6.2, 3.5 Hz, 1 H, CH3CHOAc), 4.40 (dd, J = 9.1,
4.4 Hz, 1 H, Fu–CH–OH), 2.02 (m, 2 H, CH2), 1.99 (s, 3 H,
(50 mL), to afford compound (+)-syn-21 (0.444 g, 83%): [α]D
=
+180 (c = 1.45, CHCl3) {ref.[15] [α]D = +177 (c = 1.21, CHCl3) for
1
(2R,4R)-syn-21}. H NMR (400 MHz, CDCl3): δ = 7.29 (m, 1 H,
α furan H), 6.22 (m, 2 H, 2 β furan H), 4.76 (dd, J = 8.2, 6.0 Hz,
1 H, Fu–CH–OMOM), 4.51 (d, J = 6.7 Hz, 1 H, OCHHO), 4.41
(d, J = 6.7 Hz, 1 H, OCHHO), 3.77 (m, 1 H, CH3CH–OH), 3.26
(s, 3 H, OCH3), 2.15 (dt, J = 13.9, 8.2 Hz, 1 H, CHH), 1.80 (ddd,
CH3COO), 1.26 (d,
J =
6.2 Hz, CH3CH) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 171.2, 156.1, 141.7, 109.9, 105.5, 67.9,
63.8, 41.8, 20.9, 20.3 ppm.
J
= 13.9, 6.0, 3.2 Hz, 1 H, CHH), 1.21 (d, J = 6.0 Hz,
Under the same conditions, the diol syn-14 (5.10 g, 0.033 mol, ob-
tained upon stereoselective reduction of the corresponding hydroxy
ketone 7 by treatment with diethylmethoxyborane[27] followed by
NaBH4) afforded the diacetate (+)-syn-23 (1.82 g, 23%), the
monoacetate (+)-syn-22 (1.04 g, 16%) and the diol (–)-syn-14
(2.01 g, 39%).
CH3CH) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 153.0, 142.2,
109.8, 108.2, 93.5, 69.7, 65.7, 55.2, 42.6, 23.2 ppm.
Baker’s Yeast Reduction of rac-8: Compound rac-8 (10.0 g,
0.069 mol) was subjected to baker’s yeast fermentation. After 72 h,
the reaction was worked up and the corresponding crude mixture
showed the following composition (NMR): the hydroxy ketone 8
(56%), (+)-(2S,4S)-anti-15 (20%) and (+)-(2S,4R)-syn-15 (24%).
Column chromatography allowed the recovery of (+)-anti-15 and
(+)-syn-15 as single pure compounds.
(1R,3R)-1-(Furan-2-yl)butane-1,3-diyl Diacetate [(+)-syn-23]: ee =
99% (GC of the corresponding acetonide). [α]D = +106.1 (c = 1.04,
1
CHCl3). H NMR (400 MHz, CDCl3): δ = 7.37 (m, 1 H, α furan
H), 6.31 (m, 2 H, 2 β furan H), 5.92 (t, J = 7.6 Hz, 1 H, Fu–CH–
OAc), 4.81 (sextuplet, J = 6.4 Hz, 1 H, CH3CHOAc), 2.27 (ddd, J
= 13.9, 7.6, 6.4 Hz, 1 H, CHH), 2.16 (ddd, J = 13.9, 7.6, 6.1 Hz, 1
(2S,4R)-Octane-2,4-diol [(+)-syn-15]:[28] 1.41 g (14%). [α]D = +6.5
(c = 1.17, EtOH) {ref.[28] [α]D = –1.3 (c = 1.40, EtOH) for (2R,4S)-
H, CHH), 2.04 (s, 3 H, CH3COO), 1.99 (s, 3 H, CH3COO), 1.24 syn-15 with ee = 24%}. 1H NMR (400 MHz, CDCl3): δ = 3.91 (m,
Eur. J. Org. Chem. 2010, 142–151
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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149

D. Acetti, E. Brenna, C. Fuganti, F. G. Gatti, S. Serra
1 H, CH–OH), 3.70 (m, 1 H, CH–OH), 1.49–1.14 (m, 8 H, CHCl3) {ref.[23] [α]D = +16.5 (c = = 1.31, CHCl3) for (2S,3S,4R,E)-
FULL PAPER
4ϫCH2), 1.08 (d, J = 6.4 Hz, 3 H, CH3–CH), 0.80 (t, J = 6.9 Hz,
CH2CH3) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 72.4, 68.5,
44.3, 37.5, 27.3, 23.7, 22.4, 13.7 ppm.
anti,anti-17 with ee Ͼ 99%}. 1H NMR (400 MHz, CDCl3): δ =
7.40–7.20 (m, 5 H, aromatic H), 6.58 (d, J = 15.7 Hz, 1 H,
PhCH=), 6.21 (dd, J = 15.7, 8.0 Hz, 1 H, PhCH=CHCH), 4.23 (t,
J = 8.0 Hz, 1 H, =CHCHOH), 3.85 (dq, J = 8.0, 6.2 Hz, 1 H,
CH3CHOH), 1.68 (m, 1 H, CHCH3), 1.25 (d, J = 6.1 Hz, 3 H,
CH3CHOH), 0.82 (d, J = 6.7 Hz, 3 H, CHCH3) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 136.6, 131.9, 131.0, 128.5, 127.6, 126.5,
78.6, 72.6, 45.5, 21.6, 13.2 ppm.
(2S,4S)-Octane-2,4-diol [(+)-anti-15]:[28] 1.81 g (18%). [α]D = +21.8
(c = 0.66, EtOH) {ref.[28] [α]D = –5.4 (c = 1.40, EtOH) for (2R,4R)-
syn-15 with ee = 25%}. 1H NMR (400 MHz, CDCl3): δ = 4.10
(sextuplet, J = 6.0 Hz, 1 H, CH–OH), 3.87 (m, 1 H, CH–OH), 1.54
(t, J = 6.0 Hz, CH2), 1.51–1.22 (m, 6 H, 3ϫCH2), 1.18 (d, J =
6.4 Hz, 3 H, CH3–CH), 0.87 (t, J = 6.9 Hz, CH2CH3) ppm. 13C
NMR (100.6 MHz, CDCl3): δ = 69.1, 65.1, 44.1, 37.0, 27.9, 23.3,
22.6, 13.9 ppm.
Baker’s Yeast Reduction of syn-11: Compound rac-syn-11 (5.0 g,
0.024 mol) was subjected to baker’s yeast fermentation. After 48 h,
the reaction was worked up and the corresponding crude mixture
showed the following composition (NMR): the starting hydroxy
ketone syn-11 (57.5%), (1S,2R,S)-syn,syn-18 (17.5%) and
(1S,2S,R)-syn,anti-18 (25%). Column chromatography allowed the
recovery of (–)-syn,syn-18 and (+)-syn,anti-18 as single pure com-
pounds.
Baker’s Yeast Reduction of the 0.7:1 Mixture of Racemic syn- and
anti-9: Compound rac-9 (10.0 g, 0.056 mol) was subjected to
baker’s yeast fermentation. After 48 h, the reaction was worked up
and the corresponding crude mixture showed the following compo-
sition (NMR): the hydroxy ketone 9 (syn-9 28.5%, anti-9, 48.2%),
(1S,2R,3S)-syn,syn-16 (2.6%), (1R,2S,3S)-syn,anti-16 (12.4%),
(1R,2R,3S)-anti,syn-16 (5.7%) and (1S,2S,3S)-anti,anti-16 (2.6%).
Column chromatography allowed the recovery of (+)-syn,anti-16
and (–)-anti,syn-16 as single pure compounds.
(1R,2S,3S)-2-Methyl-1-phenylbutane-1,3-diol [(+)-syn,anti-16]:[29]
0.907 g (9%). [α]D = +50.9 (c = 1.02, CH2Cl2) {ref.[29] [α]D = +52.3
(c = 1.12, CH2Cl2) for (1R,2S,3S)-syn,anti-16 with ee = 99%}; op-
tical purity = 96%. 1H NMR (400 MHz, CDCl3): δ = 7.40–7.20
(m, 5 H, aromatic H), 5.06 (d, J = 3.0 Hz, 1 H, PhCHOH), 3.78
(quintet, J = 6.4 Hz, 1 H, CH3CHOH), 1.80 [m, 1 H, CHC(2)],
1.25 (d, J = 6.4 Hz, 3 H, CH3CHOH), 0.77 [d, J = 6.9 Hz, 3 H,
CH3C(2)] ppm. 13C NMR (100.6 MHz, CDCl3): δ = 142.7, 128.0,
127.0, 126.1, 74.7, 70.9, 45.7, 21.9, 11.3 ppm.
(1S,2R)-2-[(S)-Hydroxy(phenyl)methyl]cyclohexanol
[(–)-syn,syn-
18]:[30] M.p. 95 °C. 0.618 g (12.5%); ee = 99% (HPLC). [α]D = –13
(c = 0.99, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.36–7.28 (m,
5 H, aromatic H), 4.97 (d, J = 3.3 Hz, PhCHOH), 4.16 (m, 1 H,
CHOH of the ring), 1.83–1.03 (m, 9 H, 9H of the ring) ppm. 13C
NMR (100.6 MHz, CDCl3): δ = 143.2, 127.9, 126.9, 125.8, 122.2,
77.8, 71.2, 47.7, 33.7, 25.6, 19.6, 18.4 ppm.
(1S,2S)-2-[(R)-Hydroxy(phenyl)methyl]cyclohexanol [(+)-syn,anti-
18]:[30] M.p. 101 °C. 0.939 g (19%); ee = 99% (HPLC). [α]D = +32
(c = 0.95, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.36–7.28 (m,
5 H, aromatic H), 4.96 (d, J = 3.3 Hz, PhCHOH), 3.52 (td, J =
10.3, 4.4 Hz, 1 H, CHOH of the ring), 1.99–0.80 (m, 9 H, 9H of
the ring) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 141.9, 127.8,
126.9, 126.6, 126.1, 76.2, 71.2, 50.1, 35.4, 25.7, 25.2, 24.3 ppm.
(1R,2R,3S)-2-Methyl-1-phenylbutane-1,3-diol [(–)-anti,syn-16]:[29]
0.302 g (3%). [α]D = –24.7 (c = 1.04, CH2Cl2) {ref.[29] [α]D = +25.2
(c = 1.1, CH2Cl2) for (1S,2S,3R)-anti,syn-16 with ee = 99%}; op-
Baker’s Yeast Reduction of anti-11: Compound rac-anti-11 (5.0 g,
0.024 mol) was subjected to baker’s yeast fermentation. After 48 h,
the reaction was worked up and the corresponding crude mixture
showed the following composition (NMR): the starting hydroxy
ketone anti-11 (55.6%, showing ee = 73% by HPLC analysis) and
(1S,2R,R)-anti,syn-18 (44.4%). Column chromatography allowed
the recovery of (+)-anti,syn-18 as a single pure compound.
1
tical purity 97%. H NMR (400 MHz, CDCl3): δ = 7.40–7.20 (m,
5 H, aromatic H), 4.70 (d, J = 7.1 Hz, 1 H, PhCHOH), 4.05 (qd,
J = 6.4, 2.1 Hz, 1 H, CH3CHOH), 1.95 [m, 1 H, CHC-(2)], 1.22
(d, J = 6.5 Hz, 3 H, CH3CHOH), 0.82 [d, J = 6.9 Hz, 3 H,
CH3C(2)] ppm. 13C NMR (100.6 MHz, CDCl3): δ = 143.7, 128.2,
127.6, 126.4, 77.7, 68.9, 44.4, 18.9, 12.0 ppm.
(1S,2R)-2-[(R)-Hydroxy(phenyl)methyl]cyclohexanol [(+)-anti,syn-
18]: 1.92 g (39%); ee = 99% (HPLC). [α]D = +40.4 (c = 1.25,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.40–7.26 (m, 5 H, aro-
matic H), 4.73 (d, J = 5.1 Hz, PhCHOH), 4.10 (m, 1 H, CHOH
of the ring), 1.80–1.16 (m, 9 H, 9H of the ring) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 143.6, 128.0, 127.0, 126.1, 76.8, 66.9,
46.9, 32.7, 25.1, 24.5, 20.2 ppm.
Baker’s Yeast Reduction of the 0.5:1 Mixture of Racemic syn- and
anti-10: Compound rac-10 (10.0 g, 0.049 mol) was subjected to
baker’s yeast fermentation. After 48 h, the reaction was worked up
and the corresponding crude mixture showed the following compo-
sition (NMR): the starting hydroxy ketone 10 (syn-10 28.3%, anti-
10 49.0%), (2S,3R,4R)-syn,syn-17 (2.4%), (2S,3S,4S)-syn,anti-17
(4.8%), (2S,3R,4S)-anti,syn-17 (10.7%) and (2S,3S,4R)-anti,anti-17
(4.8%). Column chromatography allowed the recovery of (+)-anti,
syn-17 and (+)-anti,anti-17 single pure compounds.
Hydrogenolysis of (+)-anti,syn-18: A solution of (+)-anti,syn-18
(0.500 g, 2.43ϫ10–3 mol) in ethanol (20 mL) was treated with H2
(80 psi) at room temperature for 48 h in the presence of Pd/C
(50 mg). The reaction mixture was filtered and concentrated under
reduced pressure to give a residue that was purified by column
chromatography to afford (+)-20 (0.392 g, 85%): [α]D = +27.5 (c =
1.05, CHCl3) {ref.[31] [α]D = +28 (c = 1.0, CHCl3) for (1S,2S)-(+)-
20}. 1H NMR (400 MHz, CDCl3): δ = 7.40–7.26 (m, 5 H, aromatic
H), 3.78 (m, 1 H, CHOH), 2.72 (dd, J = 13.3, 7.3 Hz, PhCHH),
2.54 (dd, J = 13.3, 7.6 Hz, PhCHH), 1.81–1.14 (m, 9 H, 9H of the
ring) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 141.0, 129.0, 128.1,
125.7, 68.5, 43.5, 38.6, 33.3, 26.4, 25.2, 20.3 ppm.
(2S,3R,4S,E)-3-Methyl-6-phenylhex-5-ene-2,4-diol
[(+)-anti,syn-
17]:[23] 0.807 g (8%). ee = 99% (HPLC). [α]D = +8.01 (c = 1.05,
CHCl3) {ref.[23] [α]D = +7.36 (c = 0.92, CHCl3) for (2S,3R,4S)-
anti,syn-17 with ee = 97%}. 1H NMR (400 MHz, CDCl3): δ =
7.60–7.20 (m, 5 H, aromatic H), 6.63 (d, J = 15.7 Hz, 1 H,
PhCH=), 6.25 (dd, J = 15.7, 6.7 Hz, 1 H, PhCH=CHCH), 4.32 (t,
J = 6.7 Hz, 1 H, =CHCHOH), 4.18 (qd, J = 6.4, 2.2 Hz, 1 H,
CH3CHOH), 1.78 (dquintuplet, J = 2.8, 7.1 Hz, 1 H, CHCH3),
1.23 (d, J = 6.4 Hz, 3 H, CH3CHOH), 0.96 (d, J = 7.1 Hz, 3 H,
CHCH3) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 136.7, 131.5,
131.1, 128.6, 127.6, 126.5, 76.5, 69.2, 43.4, 19.6, 11.5 ppm.
[1] a) V. Malathong, S. D. Rychnovsky, Org. Lett. 2009, 11, 4220–
4223; b) S. Raghavan, K. Rathore, Synlett 2009, 1285–1288; c)
G. Sabitha, P. Gopal, J. S. Yadav, Tetrahedron: Asymmetry
(2S,3S,4R,E)-3-Methyl-6-phenylhex-5-ene-2,4-diol
[(+)-anti,anti-
17]:[23] 0.302 g (3%); ee = 99% (HPLC). [α]D = +15.9 (c = 1.15,
150
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Eur. J. Org. Chem. 2010, 142–151

Baker’s Yeast Reduction of β-Hydroxy Ketones
2009, 20, 1493–1499; d) J. E. D. Martins, M. Wills, Tetrahedron
2009, 65, 5782–5786; e) N. Hayashi, T. Suzuki, K. Usui, M.
Nakada, Tetrahedron 2009, 65, 888–895.
[11]
[12]
R. Chênevert, S. Thiboutot, Can. J. Chem. 1986, 64, 1599–
1601.
K. Ahmad, S. Koul, S. C. Taneja, A. P. Singh, M. Kapoor, R.-
ul-Hassan, V. Verma, G. N. Qazi, Tetrahedron: Asymmetry
2004, 15, 1685–1692.
G. F. Sabitha, P. Padmaja, K. B. Reddy, J. S. Yadav, Tetrahe-
dron Lett. 2008, 49, 919–922.
T. K. Chakraborty, S. Das, Chem. Lett. 2000, 80–81.
Y. Kobayashi, M. Matsuumi, J. Org. Chem. 2000, 65, 7221–
7224.
[2] a) R. H. Morris, Chem. Soc. Rev. 2009, 38, 2282–2291; b) C. A.
Sandoval, Y. Li, K. Ding, R. Noyori, Chem. Asian J. 2008, 3,
1801–1810; c) Y. L. Ren, X. Z. Tian, K. P. Sun, J. Xu, X. L.
Xu, S. J. Lu, Tetrahedron Lett. 2006, 47, 463–465; W. H. Zhang,
Y. Cai, X. Liu, Y. Fang, J. H. Xu, Prog. Chem. 2007, 19, 1537–
1552.
[3] a) T. Matsuda, R. Yamanaka, K. Nakamura, Tetrahedron:
Asymmetry 2009, 20, 513–557; b) B. T. Grau, P. N. Devine, L.
N Di Michele, B. Kosjek, Org. Lett. 2007, 9, 4951–4954; c) J. C.
Moore, D. J. Pollard, B. Kosjek, P. N. Devine, Acc. Chem. Res.
2007, 40, 1412–1419; d) I. A. Kaluzna, J. D. Rozzell, S. Kam-
bourakis, Tetrahedron: Asymmetry 2005, 16, 3682–3689.
[4] M. T. Reetz, J. Org. Chem. 2009, 74, 5767–5778.
[5] a) K. Nakamura, R. Yamanaka, T. Matsuda, T. Harada, Tetra-
hedron: Asymmetry 2003, 14, 2659–2681; b) H. L. Ni, Y. X.
Guan, S. J. Yao, J. Chem. Technol. Biotechnol. 2009, 84, 186–
191; c) F. R. Bisogno, I. Lavandera, W. Kroutil, V. Gotor, J.
Org. Chem. 2009, 74, 1730–1732; d) S. Ludeke, M. Richter, M.
Muller, Adv. Synth. Catal. 2009, 351, 253–259; e) S. Broussy,
R. W. Cheloha, D. B. Berkowitz, Org. Lett. 2009, 11, 305–308;
f) B. Kosjek, J. Nti-Gyabaah, K. Telari, L. Dunne, J. C. Moore,
Org. Proc. Res. Devel. 2008, 12, 584–588; g) J. C. Moore, D. J.
Pollard, B. Kosjek, P. N. Devine, Acc. Chem. Res. 2007, 40,
1412–1419.
[13]
[14]
[15]
[16]
[17]
S. D. Rychnovsky, D. J. Skalitzky, Tetrahedron Lett. 1990, 31,
945–948; D. A. Evans, D. L. Rieger, J. R. Gage, Tetrahedron
Lett. 1990, 31, 7099–7100.
G. E. Keck, C. A. Wager, Org. Lett. 2000, 2, 2307; P. R. Cho-
pade, T. A. Davis, E. Prasad, R. A. Flowers, Org. Lett. 2004,
6, 2685; O. Labeeuw, C. Roche, P. Phansavath, J.-P. Genet, Org.
Lett. 2007, 9, 105; J. L. Vicario, D. Badia, L. Carrillo, E. Dom-
inguez, M. Rodriguez, J. Org. Chem. 2000, 65, 3754.
H. Shulman, C. Makarov, A. K. Ogawa, F. Romesberg, E. Kei-
nan, J. Am. Chem. Soc. 2000, 122, 10743–10753.
A. Crdova, K. D. Janda, J. Am. Chem. Soc. 2001, 123, 8248–
8259.
[18]
[19]
[20]
[21]
R. Fernandez-Lopez, J. Kofoed, M. Machuqueiro, T. Darbre,
Eur. J. Org. Chem. 2005, 5268–5276.
B. Janza, A. Studer, J. Org. Chem. 2005, 70, 6991–6994.
[22] syn-9: T. Yakura, Y. Yoshimoto, C. Ishida, S. Mabuchi, Tetra-
hedron 2007, 63, 4429–4438; anti-9: M. Sato, S. Sunami, Y. Sug-
ita, C. Kaneko, Heterocycles 1995, 41, 1435–1444.
[6] D. A. Evans, L. Kvaerno, T. B. Dunn, A. Beauchemin, B.
Raymer, J. A. Mulder, E. J. Olhava, M. Juhl, K. Kagechika,
D. A. Favor, J. Am. Chem. Soc. 2008, 130, 16295–16315; B. M. [23] A. Abate, E. Brenna, A. Costantini, C. Fuganti, F. G. Gatti,
Trost, J. Waser, A. Meyer, J. Am. Chem. Soc. 2008, 130, 16424–
16434; K. C. Nicolaou, J. Org. Chem. 2009, 74, 951–972.
[7] L. C. Dias, C. D. S. Goncalves, Adv. Synth. Catal. 2008, 350,
1017–1021; G. E. Keck, R. L. Giles, V. J. Cee, C. A. Wager, T.
Yu, M. B. Kraft, J. Org. Chem. 2008, 73, 9675–9691; M. Hel-
liwell, S. Karim, E. R. Parmee, E. J. Thomas, Org. Biomol.
Chem. 2005, 3, 3636–3653; A. A. Salaskar, N. V. Mayekar, A.
Sharma, S. K. Nayak, A. Chattopadhyaya, S. Chattopadhyay,
Synthesis-Stuttgart 2005, 2777–2781.
[8] R. N. Patel, A. Banerjee, C. G. McNamee, D. Brzozowski,
R. L. Hanson, L. J. Szarka, Enzyme Microb. Technol. 1993, 15,
1014–1021; R. N. Patel, C. G. McNamee, A. Banerjee, L. J.
Szarka, EP-A569998, 1993; D. J. Stewart, Curr. Opin. Biotech-
nol. 2000, 11, 363–368; M. J. Sorgedrager, F. van Rantwijk,
L. Malpezzi, S. Serra, J. Org. Chem. 2006, 71, 5228–5240.
[24] J.-R. Chen, H.-H. Lu, X.-Y. Li, L. Cheng, J. Wan, W.-J. Xiao,
Org. Lett. 2005, 7, 4543–4545.
[25] T. Cohen, I. H. Jeong, B. Mudryk, M. Bhupathy, M. M. A.
Awad, J. Org. Chem. 1990, 55, 1528–1536.
[26] M. M. Musa, K. I. Ziegelmann-Fjield, C. Vieille, J. G. Zeikus,
R. S. Phillips, J. Org. Chem. 2007, 72, 30–34.
[27] K.-M. Chen, G. E. Hardtmann, K. Prasad, O. Repicˇ, M. J.
Shapiro, Tetrahedron Lett. 1987, 28, 155–158.
[28] K. Edegger, W. Stampfer, B. Seisser, K. Faber, S. F. Mayer, R.
Oehrlein, A. Hafner, W. Kroutil, Eur. J. Org. Chem. 2006,
1904–1909.
[29] A. Abate, E. Brenna, C. Fuganti, F. G. Gatti, T. Giovenzana,
L. Malpezzi, S. Serra, J. Org. Chem. 2005, 70, 1281–1290.
G. W. Huisman, R. A. Sheldon, Adv. Synth. Catal. 2008, 350, [30] S. H. J. Thompson, M. F. Mahon, K. C. Molloy, M. S. Hadley,
2322–2328; D. Kalaitzakis, J. D. Rozzell, I. Smonou, S. Kam-
bourakis, Adv. Synth. Catal. 2006, 348, 1958–1969.
[9] D. Acetti, E. Brenna, C. Fuganti, F. G. Gatti, L. Malpezzi, S.
Serra, Eur. J. Org. Chem. 2008, 5125–5134.
T. Gallagher, J. Chem. Soc. Perkin Trans. 1 1995, 379–383.
[31] G. Fronza, G. Fogliato, C. Fuganti, S. Lanati, R. Rallo, S.
Servi, Tetrahedron Lett. 1995, 36, 123–124.
Received: September 3, 2009
[10] S. Servi, Synthesis 1990, 1–25.
Published Online: November 17, 2009
Eur. J. Org. Chem. 2010, 142–151
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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