Baker's yeast mediated biohydrogenation of sulphur-functionalised methacrolein derivatives. Stereochemical aspects of the reaction and preparation of the two enantiomers of useful C4 bifunctional chiral synthons

Article abstract of DOI:10.1016/S0957-4166(01)00383-4

The baker's yeast mediated reduction of sulphur-functionalised methacroleins 11, 15 and 18 leads to the preparation of the bifunctional methyl branched C4 chiral synthons 6 and 7. The stereochemical aspects of the biohydrogenation have been investigated. Both the oxidation state of sulphur and the isomeric position of the double bond affected the enantioselectivity of the reduction strongly, thus, offering access to the two enantiomeric forms of 6 and 7.

Full text of DOI:10.1016/S0957-4166(01)00383-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 2191–2196
Baker’s yeast mediated biohydrogenation of
sulphur-functionalised methacrolein derivatives. Stereochemical
aspects of the reaction and preparation of the two enantiomers
of useful C4 bifunctional chiral synthons
Stefano Serra* and Claudio Fuganti
Dipartimento di Chimica del Politecnico, Centro CNR per lo Studio delle Sostanze Organiche Naturali, Via Mancinelli, 7
I-20131 Milan, Italy
Received 2 August 2001; accepted 30 August 2001
Abstract—The baker’s yeast mediated reduction of sulphur-functionalised methacroleins 11, 15 and 18 leads to the preparation of
the bifunctional methyl branched C4 chiral synthons 6 and 7. The stereochemical aspects of the biohydrogenation have been
investigated. Both the oxidation state of sulphur and the isomeric position of the double bond affected the enantioselectivity of
the reduction strongly, thus, offering access to the two enantiomeric forms of 6 and 7. © 2001 Elsevier Science Ltd. All rights
reserved.
1. Introduction
Herein, we wish to report the enantioselective prepara-
tion of useful bifunctional C4 building block of type 1
by baker’s yeast-mediated reduction of substituted
methacrolein of type 4 and 5. We selected the
phenylthio and the phenylsulfonyl groups as b-sub-
stituents of these aldehydes (RX=PhS or PhSO2) since
compounds of the type 6 and 7 have been already
The use of small (C3, C4, C5) and readily available
chiral building blocks in the preparation of complex
enantiomerically pure compounds is one of the most
employed synthetic strategies. In this context, 2-methyl
branched chiral C4 compounds of the type 1 are partic-
ularly suited for the synthesis of many biologically
active substances possessing at least one tertiary carbon
centre, typical of terpenoids and natural products of
propionate biosynthetic derivation.
X, Y = heteroatoms
X
Y
RO
O
OR'
HO
Several enantioselective syntheses of the above men-
tioned synthon have been developed with the use of
biocatalysts. The asymmetrised 2-methyl-1,3-propanedi-
ols 2 are the most used compounds1 of this class since
they are efficiently prepared either from the commer-
cially available (S) and (R)-3-hydroxy-2-methyl-
propanoic acid 3 and through different biocatalytic
approaches.1,2 Due to this fact, the activated forms of
synthon 1 in which X or Y are functional groups able
to give chain elongation, are prepared mainly from 2
and 3 by means of functional group manipulation (Fig.
1).
COOH
1
2
3
O
RX
RX
4
6
5
PhS
OH
PhSO2
OH
7
and their enantiomers
* Corresponding author.
Figure 1.
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00383-4

2192
S. Serra, C. Fuganti / Tetrahedron: Asymmetry 12 (2001) 2191–2196
employed in several synthetic applications3–5 and are
well suited to chain elongation reactions, for instance
by the Julia olefination protocol4 or alkylation–desul-
phurisation sequences.5 Until recently, these com-
pounds were prepared from synthons of the type 21,2a
In order to devise a large scale method for the prepara-
tion of homochiral 6 we performed the baker’s yeast
incubation of the above mentioned aldehyde supported
on a non-polar resin.10 This method shows several
advantages since it allowed us to conduct the reduction
on a hundred grams scale with a concentration of 10–15
g/L with a simple work-up procedure (see Section 4).
We found that after 4 days of fermentation, 11 was
reduced to a mixture of allylic alcohol 12 (64%), satu-
rated alcohol 6 (25%) and starting aldehyde 11 (6%).
Prolonging the incubation time, a slow (about 3% for
each day) saturation of alcohol 12 increased the ratio of
6. In order to obtain pure saturated alcohol we con-
verted selectively the allylic alcohol to the starting
aldehyde by MnO2 oxidation of the crude mixture. The
aldehyde 11 was recovered in 69% yield and can be
recycled whilst alcohol 6 was separated in 22% of yield
and was converted into synthon 7 by oxidation with
MCPBA. The obtained 6 showed negative sign of opti-
cal rotation ([h]D20=−18.5 (c 1, CH2Cl2), Ref. 3c [h]D20=
−18.9 (c 3.5, CH2Cl2)) and thus was assigned
(R)-configuration in accord with the general trend of
reduction of prochiral double bonds.6a The enan-
tiomeric excess of (R)-(−)-6 was evaluated as 90% by
NMR analysis of its (S)-(−)-a-methoxy-a-trifluoro-
methylphenylacetate (MTPA ester).11
and
3,3a,b,d,4,5
using
enzyme-catalysed
kinetic
resolution2a or by auxiliary-based diastereoselective
alkylation of chiral amide enolates.3c The enantioselec-
tive synthesis of 6 and 7 from sulphur-functionalized
prochiral methacroleins compares favourably with these
known methods since the aldehydes 4 and 5 are inex-
pensive and the problems related to functional group
interconversion are overcome.
2. Results and discussion
The baker’s yeast-mediated asymmetric reduction of a
variety of sulphur funtionalised a,b-unsaturated alde-
hydes and ketones has been widely studied in the past.6
Moreover, in order to obtain a C5 chiral building block
for the synthesis of isoprenoids, many a,b-unsaturated
aldehydes or alcohols substituted with phenylsulfonyl,
dithianyl or phenylthio groups were reduced7 using
yeast. In spite of this, to our knowledge, the microbial
reduction of sulphur substituted methacroleins of the
type 4 and 5 were not investigated previously.
The study on the mode of yeast reduction of these
sulphur-functionalised methacroleins was subsequently
extended to aldehydes of the type 5. Accordingly, we
synthesised aldehyde 15 from acrolein 13 (Scheme 2)
through known procedures which involved base-
catalysed 1,4-addition12a of thiophenol to 13, protection
of the obtained aldehyde as its diethylacetal 14 and
methylenation of the latter by Mannich type reac-
tion.12b Thus, 15 was incubated with baker’s yeast
under the same experimental conditions described
above for 11. We observed completely different
behaviour both in terms of yield and enantioselectivity.
The double bond of the methacrolein 15 was saturated
readily and after four days of fermentation the expected
(S)-(+)-6 (40%) was the main product together with
allylic alcohol 16 (35%) and a small amount of residual
With the aim of preparing the C4 chiral building block
6 on a multigram scale, we envisaged that phenylthio
substituted methacroleins could be easily prepared from
inexpensive and commercially available compounds.
Accordingly, aldehyde 11 was prepared as depicted in
Scheme 1. Methacrolein 8 was converted stepwise to
the 3-bromoacrolein diethylacetal 9 by a known
method.8 Addition of bromine to 8, protection of the
carbonyl group and basic elimination of hydrogen bro-
mide afforded 9 as a mixture of regioisomers. Subse-
quent hydrolysis of the acetal functionality gave the
3-bromo-acrolein 10 which was converted without iso-
lation into aldehyde 11 by treatment with sodium thio-
phenate in THF solution.9 Interestingly enough, 11 was
obtained as a single (E) isomer.
i, ii, iii
iv
v
O
O
Br
OEt
OEt
Br
O
PhS
71%
55%
90%
11
8
9
10
vii
PhS
PhS
OH
12
vi
11
+
viii
OH
PhSO2
OH
91%
(R)-(-)-6 90% e.e.
(R)-(-)-7 90% e.e.
Scheme 1. (i) Br2, CH2Cl2; (ii) CH(OEt)3, EtOH, PTSA cat.; (iii) KOH, EtOH; (iv) H2O, PTSA cat.; (v) PhSNa, THF; (vi) baker’s
yeast, 4 days; (vii) MnO2, CHCl3, reflux; (viii) MCPBA, CH2Cl2.

S. Serra, C. Fuganti / Tetrahedron: Asymmetry 12 (2001) 2191–2196
2193
PhS
PhS
OH
OH
16
i, ii
iii
iv
O
PhS
OEt
OEt
O
PhS
+
92%
67%
13
14
15
v
(S)-(+)-6 65-80 % e.e.
92%
PhSO2
OH
(S)-(+)-7 65-80 % e.e.
Scheme 2. (i) PhSH, Et3N cat.; (ii) CH(OEt)3, PTSA cat.; (iii) Et2NH.HCl, CH2O aq. reflux; (iv) baker’s yeast, 4 days; (v)
MCPBA, CHCl3.
unsaturated aldehyde 15 (10%). Thus, the alcohol (S)-
(+)-6 and the related sulfone (S)-(+)-7 were prepared
from 15 in 36 and 33% overall yield, respectively.
In spite of this efficiency of the reduction step, the
enantiomeric purity of the above (S)-(+)-6 (also mea-
sured by NMR analysis of its MTPA ester) was only
65% e.e., whereas when fermentation was interrupted
after only 48 h the isolated 6 had greater e.e. of
80%.
3. Conclusions
A study on the baker’s yeast-mediated reduction of
sulphur-functionalised methacroleins is reported. We
found that the stereochemical behaviour of the double
bond biohydrogenation depends on the position of the
double bond and also on the oxidation state of sul-
phur. Taking advantage of this versatility we selected
the aldehydes 11, 15 and 18 as suitable precursors for
the preparation of the bifunctional methyl branched
C4 chiral synthons 6 and 7. Using our synthetic path-
way and combining enzymatic manipulations with
chemical ones, both enantiomeric forms of 6 and 7
were prepared in good yields.
These ambiguous results can be explained by consider-
ing that the heteroatom may assist the double bond
isomerisation by conjugation. The following reduction
of isomerised aldehyde affords the opposite enan-
tiomer (R)-(−)-6 lowering the enantiomeric purity of
the product. In order to demonstrate our explanation
and also in the aim of preparing (S)-(+)-7 in good
enantiomeric purity, we decided to study the reduction
of aldehyde 18 (Scheme 3) in which double bond iso-
merisation is disfavoured by the presence of the
phenylsulfonyl group. The latter compound was pre-
pared from aldehyde 15 by conversion into ketal 17,
oxidation of the thiophenyl group to phenylsulfonyl
and deprotection of the acetal functionality.
Seen together, these results show that the use of bak-
er’s yeast in organic synthesis, although widely
applied, still affords some new applications providing
that the relevant synthetic targets are investigated.
4. Experimental
4.1. General methods
The yeast reduction of methacrolein 18 provided the
allylic alcohol 19 (40%), (S)-(+)-7 (40%), and unre-
acted 18 (15%). The obtained (S)-(+)-7 was isolated
in 20% overall yield and showed very high enan-
tiomeric excess since, in NMR analysis of its MTPA
ester, only the (S) isomer was detected (1% sensitivity
so e.e. >98%).
1H NMR spectra were recorded in CDCl3 solution at
room temperature unless otherwise stated, on a Bruker
AC-250 spectrometer (250 MHz 1H). The chemical-
shift scale is based on internal tetramethylsilane. IR
spectra were recorded on a Perkin–Elmer 2000 FTIR
spectrometer. Mass spectra were measured on a Finni-
gan-MAT TSQ 70 spectrometer. Melting points were
PhSO2
OH
(S)-(+)-7 e.e. >98 %
ii, iii
85%
i
iv
O
PhS
O
PhSO2
PhS
OEt
OEt
+
88%
15
17
18
v
PhSO2
OH
19
Scheme 3. (i) CH(OEt)3, PTSA cat.; (ii) MCPBA, CHCl3; (iii) H2O/THF, PTSA cat.; (iv) baker’s yeast, 4 days; (v) MnO2, CHCl3,
reflux.

2194
S. Serra, C. Fuganti / Tetrahedron: Asymmetry 12 (2001) 2191–2196
measured on
a
Reichert melting-point apparatus,
again in CH2Cl2 (200 mL). The solution was treated with
PTSA (1 g, 5 mmol) and triethyl orthoformate (200 mL,
1.2 mol) at room temperature for 4 h. The reaction was
then diluted with further CH2Cl2 (300 mL), quenched
with saturated NaHCO3 (100 mL) and washed with
brine. The organic phase was separated, was dried
(Na2SO4) and was concentrated in vacuo. Distillation
of the residue gave pure (98% GC) 3-(thio-
phenyl)propionaldehyde diethyl acetal 1412a as a colour-
less oil (243 g, 1.01 mol, 92%): bp 145°C (0.4 mmHg);
1H NMR (l ppm): 7.38–7.11 (5H, m, ArH), 4.63 (1H,
t, J=5.6 Hz, CH(OEt)2), 3.72–3.57 (2H, m, OCH2CH3),
3.55–3.40 (2H, m, OCH2CH3), 2.98 (2H, t, J=7.4 Hz,
PhSCH2CH2), 2.00–1.89 (2H, m, PhSCH2CH2), 1.20
(6H, t, J=6.9 Hz, OCH2CH3); m/z (EI): 240 (M+, 34),
194 (M+−EtOH, 29), 149 (23), 137 (9), 123 (100), 110
(32), 103 (52), 85 (77), 75 (39), 57 (35); FT-IR (film)
2976, 1585, 1482, 1439, 1373, 1127, 1063, 739, 691 cm−1.
Anal. calcd for C13H20O2S: C, 64.96; H, 8.39. Found: C,
64.90; H, 8.40%.
equipped with a Reichert microscope, and are uncor-
rected. Optical rotations were determined on a Propol
automatic digital polarimeter. Microanalyses were
determined on an Analyser 1106 Carlo Erba. TLC
analyses were performed on Merck Kieselgel 60 F254
plates. All chromatographic separations were carried
out on silica gel columns. All baker’s yeast biotransfor-
mations were performed using fresh baker’s yeast
(Marca Distillerie Italiane) commercially available from
LIEVITALIA S.p.a.
4.2. Synthesis of the substrates
4.2.1.
(E)-3-Thiophenyl-2-methylpropen-1-al
1113.
Bromine (91 mL, 1.77 mol) was added dropwise to a
stirred solution of methacrolein 8 (145 mL, 1.76 mol) in
CH2Cl2 (250 mL) maintaining the temperature below
10°C by external cooling (ice bath). The resulting mix-
ture was diluted with ethanol (100 mL), was treated with
PTSA (1 g, 5 mmol). Triethyl orthoformate (320 mL,
1.92 mol) was then added in a few portions. The cooling
bath was then removed and the reaction mixture was
stirred at room temperature overnight. The resulting
solution was washed with saturated NaHCO3 (100 mL)
and concentrated under reduced pressure. The obtained
oil was dissolved in ethanol (300 mL) and treated with
ethanolic KOH (110 g, 1.96 mol KOH in 250 mL) under
reflux for 3 h. After cooling, the reaction was quenched
with ice and extracted with diethyl ether (3×200 mL).
The combined organic phases were concentrated in
vacuo and the residue was distilled to give 98 (216 g, 969
mmol, 55%) as an E/Z mixture (3:1 by GC analysis).
Water (400 mL) and PTSA (1 g, 5 mmol) were added to
9 and the resulting heterogeneous mixture was heated at
80°C stirring for 20 min. The reaction was then cooled
and extracted with diethyl ether (2×200 mL). The
organic phase was washed with brine and concentrated
under reduced pressure. The obtained crude 108 (3:1
E/Z mixture, 102 g, 685 mmol, 71%), was added to a
stirred suspension of sodium thiophenate (0.7 mol),
prepared from thiophenol (77.2 g, 0.7 mol) and NaH
(28.1 g of a 60% suspension in oil, 702 mmol), in dry
THF. The mixture was stirred for 2 h at room temper-
ature and then poured in ice and extracted with diethyl
ether (2×200 mL). The organic phase was washed with
brine, dried (Na2SO4) and concentrated in vacuo. The
residue was purified by distillation to give pure (98%
GC) 1113 as a colourless oil (110 g, 618 mmol, 90%): bp
The acetal 14 was combined with 36% aq. formalin (170
g, 2.04 mol), Et2NH.HCl (224 g, 2.04 mol),
hydroquinone (1 g, 9 mmol) and was stirred at 100°C for
3 h. The reaction mixture was poured into ice water
followed by extraction with diethyl ether (3×200 mL).
The organic layer was washed with saturated NaHCO3
solution (2×100 mL), was dried (Na2SO4) and was
concentrated in vacuo. The residue was purified by
distillation to give pure (96% GC) aldehyde 1512b (121 g,
0.68 mol, 67%) as a colourless oil: bp 115°C (0.6
1
mmHg); H NMR (l ppm): 9.56 (1H, s, CHO), 7.34–
7.14 (5H, m, ArH), 6.27 (1H, t, J=1.1 Hz, CꢀCHH),
6.04 (1H, s, CꢀCHH), 3.71 (2H, d, J=1.1 Hz,
PhSCH2C); m/z (EI): 179 (M++1, 10), 178 (M+, 84), 177
(M+−1, 14), 160 (8), 145 (12), 134 (9), 116 (19), 110 (57),
91 (5), 84 (6), 77 (13), 68 (100); FT-IR (film) 1684, 1583,
1481, 1439, 1320, 955, 741, 692 cm−1. Anal. calcd for
C10H10OS: C, 67.38; H, 5.65. Found: C, 67.30; H, 5.67%.
4.2.3. 3-(Phenylsulfonyl)-2-methylenepropan-1-al 1814a
.
The aldehyde 15 (63 g, 354 mmol) was dissolved in
triethyl orthoformate (200 mL, 1.2 mol) and the solution
treated with PTSA (1 g, 5 mmol) and hydroquinone (0.5
g, 4.5 mmol) stirring at 50°C for 3 days. After this time
the mixture was concentrated under reduced pressure,
the residue was diluted with diethyl ether (400 mL) and
washed with a solution of saturated NaHCO3 (100 mL).
The organic phase was concentrated in vacuo and the
residue was purified by chromathography eluting with
hexane–ethyl acetate (95:5) to give pure (97% GC)
1
116°C (0.2 mmHg); H NMR (l ppm): 9.31 (1H, s,
CHO), 7.54–7.35 (6H, m, ArH+CHꢀC), 1.87 (3H, d,
J=0.8 Hz, MeC); m/z (EI): 179 (M++1, 10), 178 (M+,
75), 177 (M+−1, 31), 149 (5), 134 (12), 115 (9), 110 (100),
100 (10), 77 (9); FT-IR (film) 1667, 1582, 1482, 1441,
1327, 1177, 1019, 817, 744 cm−1. Anal. calcd for
C10H10OS: C, 67.38; H, 5.65. Found: C, 67.45; H, 5.65%.
3-(thiophenyl)-2-methylene-propionaldehyde
diethyl
acetal 1714b as a colourless oil (79 g, 313 mmol, 88%): 1H
NMR (400 MHz, l ppm: 7.36–7.30 (2H, m, ArH),
7.28–7.22 (2H, m, ArH), 7.18–7.12 (1H, m, ArH), 5.30
(1H, s), 5.21 (1H, s), 4.96 (1H, s), 3.66–3.57 (2H, m,
OCH2CH3), 3.64 (2H, s, PhSCH2C), 3.52–3.43 (2H, m,
OCH2CH3), 1.22 (6H, t, J=7 Hz, OCH2CH3); m/z (EI):
252 (M+, 21), 207 (16), 173 (32), 161 (100), 149 (23), 142
(73), 114 (70), 86 (36), 69 (46); FT-IR (film) 2976, 1584,
1482, 1439, 1115, 1062, 923, 739, 691 cm−1. Anal. calcd
for C14H20O2S: C, 66.63; H, 7.99. Found: C, 66.70; H,
8.02%.
4.2.2. 3-(Phenylthio)-2-methylenepropan-1-al 1512b. Thio-
phenol (121 g, 1.1 mol) was added dropwise to a CH2Cl2
(350 mL) solution of acrolein 13 (80 mL, 1.2 mol) and
triethylamine (1 mL, 7 mmol) stirring at 0°C for 1 h. In
order to remove the amine, the obtained mixture was
concentrated under reduced pressure and dissolved

S. Serra, C. Fuganti / Tetrahedron: Asymmetry 12 (2001) 2191–2196
2195
The acetal 17 was dissolved in CH2Cl2 (200 mL) cooled
4.3.2.
(R)-(−)-2-Methyl-3-(phenylthio)propan-1-ol
62a,b,3,a,c by BY reduction of 11. Obtained as described
above as a colorless oil (99% GC): bp 118–120°C/0.2
mmHg; [h]2D0=−18.5 (c 1, CH2Cl2); e.e.=90%; Ref. 2a
[h]D25=−19.9 (c 1.4, CH2Cl2); Ref. 2b [h]2D0=−13.8 (c 3,
at −78°C and treated under stirring with a solution of
MCPBA (160 g of a 70% commercial reagent, 649
mmol) in CH2Cl2 (250 mL) over 1 h. The reaction
mixture was allowed to warm to room temperature and
was stirred for further 2 h. The MCBA was eliminated
by filtration and the solution was washed in turn with
saturated NaHCO3 solution (2×100 mL), and 5% aq.
Na2SO3 (100 mL). The organic layer was concentrated
under reduced pressure and the residue was dissolved in
a THF/water (5:1) mixture (200 mL). The obtained
solution was treated with PTSA (1 g, 5 mmol) stirring
at rt for 2 h. After this time the reaction was quenched
by addition of water and extraction with ethyl acetate
(3×150 mL). The organic phase was washed with brine,
was dried (Na2SO4) and concentrated in vacuo. The
residue was purified by chromatography eluting with
hexane–ethyl acetate (9:1“7:3) to give pure (99% GC)
1814a as colourless crystals (56 g, 267 mmol, 85%): mp
1
CH2Cl2); Ref. 3c [h]2D0=−18.9 c 3.5, CH2Cl2); H NMR
(l ppm): 7.38−7.22 (4H, m, ArH), 7.20–7.12 (1H, m,
ArH), 3.66–3.53 (2H, m, CHCH2OH), 3.06 (1H, dd,
J=12.9, 6.9 Hz, SCHHCH), 2.82 (1H, dd, J=12.9, 6.9
Hz, SCHHCH), 2.04–1.84 (1H, m, CH3CH), 1.83 (1H,
s, OH), 1.04 (3H, d, J=6.8 Hz, CH3CH); m/z (EI): 183
(M++1, 8), 182 (M+, 68), 164 (1), 149 (4), 123 (38), 110
(100), 91 (5), 84 (3), 77 (8), 72 (9), 65 (9), 57 (10);
FT-IR (film) 3355, 1584, 1481, 1438, 1026, 738, 691
cm−1. Anal. calcd for C10H14OS: C, 65.89; H, 7.74.
Found: C, 65.96; H, 7.75%.
4.3.3. (S)-(+)-2-Methyl-3-(phenylthio)propan-1-ol 64b by
BY reduction of 15. The BY reduction of 15 (50 g, 280
mmol) afforded a mixture of alcohol 6 (40%), alcohol
16 (35%) starting aldehyde 15 (10%), and isomerised
alcohol 12 (4%). MnO2 oxidation, purification by chro-
matography and distillation gave pure (98% GC) (S)-
(+)-6 (18.2 g, 100 mmol, 36%) as a colourless oil:
[h]2D0=+13.3 (c 1.2, CH2Cl2); e.e.=65%; a similar reduc-
tion (30 g, 168 mmol) performed with an incubation of
48 h afforded (S)-(+)-6 (6.2 g, 34 mmol, 20%); [h]2D0=
+15.9 (c 1.2, CH2Cl2); e.e.=80% (the optical rotation
value for (S)-(+)-6 has not been previous reported);
both sample of (S)-(+)-6 show analytical data identical
to those above reported for (R)-(−)-6.
1
69°C (hexane/ethyl acetate); H NMR (l ppm): 9.36
(1H, s, CHO), 7.89–7.81 (2H, m, ArH), 7.70–7.61 (1H,
m, ArH), 7.59–7.50 (2H, m, ArH), 6.76 (1H, s,
CꢀCHH), 6.41 (1H, s, CꢀCHH), 4.11 (2H, s,
SO2CH2C); m/z (EI): 210 (M+, 1), 192 (3), 175 (2), 163
(2), 141 (51), 125 (28), 115 (5), 77 (100), 69 (30), 51 (23);
FT-IR (nujol) 1682, 1332, 1305, 1250, 1168, 1134, 1086,
979, 903, 856, 801, 761, 713, 690 cm−1. Anal. calcd for
C10H10O3S: C, 57.13; H, 4.79. Found: C, 57.10; H,
4.80%.
4.3. Baker’s yeast (BY) biotransformations
4.3.1. General procedure. Representative example on 100
g scale performed for the reduction of 11: A 10 litre open
cylindrical glass vessel equipped with a mechanical
stirrer was charged with tap water (6 L) and glucose
(350 g). Fresh BY (1 Kg) was added in small pieces to
the stirred mixture and fermentation allowed to proceed
for 1 h. The aldehyde 11 (100 g, 562 mmol), adsorbed
on XAD 1180 resin (400 g), was added in one portion.
The mixture was vigorously stirred for 4 days at room
temperature. During this time additional BY (250 g)
and glucose (100 g) were added 24 and 48 h after
fermentation started. The resin was separated by filtra-
tion on a sintered glass funnel (porosity 0, >160 mm)
and the water phase extracted again with further resin
(100 g). The combined resin crops were extracted with
ethyl acetate (5×200 mL) and the acetate solution was
washed with brine. The dried organic phase (Na2SO4)
was concentrated under reduced pressure to give an oil.
This latter was composed of saturated alcohol (25%)
together with unreacted aldehyde (6%) and the related
unsaturated allylic alcohol 12 (64%), also produced by
microbiological reduction. In order to obtain pure satu-
rated alcohol we converted selectively the allylic alcohol
into the starting aldehyde by MnO2 oxidation. The
crude mixture was dissolved in CHCl3 and treated with
MnO2 (200 g) stirring under reflux until no more allylic
alcohol was detected by GC analysis (12 h). The residue
obtained upon filtration and evaporation of the CHCl3
phase was purified by column chromatography using
hexane–ethyl acetate (95:5“8:2) as eluent to give recov-
ery aldehyde 11 (69 g after distillation, 388 mmol, 69%)
and alcohol 6 (22.4 g after distillation, 123 mmol, 22%)
4.3.4. (S)-(+)-2-Methyl-3-phenylsulfonylpropan-1-ol 7 by
BY reduction of 18. The BY reduction of 18 (40 g, 190
mmol) afforded a mixture of alcohol 19 (40%), alcohol
7 (40%) and starting aldehyde 18 (15%). MnO2 oxida-
tion and purification by chromatography gave aldehyde
18 (11.1 g, 53 mmol, 28%) and pure (98% GC) (S)-(+)-7
(8.15 g, 38 mmol, 20%) as a pale yellow oil: [h]2D0=+9.3
(c 1.1, CHCl3); e.e. >98% (the optical rotation value for
1
(S)-(+)-7 has not been previously reported); H NMR
(l ppm): 7.96–7.88 (2H, m, ArH), 7.71–7.52 (3H, m,
ArH), 3.69 (1H, dd, J=10.9, 4.9 Hz, SO2CHHCH),
3.51–3.32 (2H, m, CHCH2OH), 2.95 (1H, dd, J=14,
6.8 Hz, SO2CHHCH), 2.58 (1H, s, OH), 2.39–2.19 (1H,
m, CH3CH), 1.08 (3H, d, J=6.9 Hz, CH3CH); m/z
(EI): 196 (M+−H2O, 1), 184 (8), 172 (36), 156 (8), 143
(100), 142 (91), 132 (7), 125 (25), 107 (6), 94 (14), 78
(84), 77 (78), 55 (30); FT-IR (film) 3516, 1586, 1448,
1303, 1148, 1086, 1040, 742, 689 cm−1. Anal. calcd for
C10H14O3S: C, 56.05; H, 6.59. Found: C, 56.13; H,
6.56%.
4.4. Oxidation of sulphide 6 to sulfone 7
4.4.1. Preparation of (R)-(−)-73a,4a from (R)-(−)-6. A
solution of alcohol (R)-(−)-6 (3 g, 16.5 mmol, 90% e.e.)
in CH2Cl2 (60 mL) was cooled to −78°C and treated
under stirring with MCPBA (8.5 g of a 70% commercial
reagent, 34 mmol). After 1 h the reaction was allowed
to warm to room temperature and stirred for further 2
h. The MCBA was removed by filtration and the filtrate
was washed in turn with saturated NaHCO3 solution

2196
S. Serra, C. Fuganti / Tetrahedron: Asymmetry 12 (2001) 2191–2196
(40 mL), and 5% aq. Na2SO3 (40 mL). The organic
layer was concentrated under reduced pressure and the
residue was purified by chromathography eluting with
hexane–ethyl acetate (9:1“6:4) to afford pure (98%
GC) (R)-(−)-7 (3.2 g, 15 mmol, 91%): [h]2D0=−8.5 (c 1,
CHCl3); Ref. 3a [h]2D0=−8.8 (c 1.17, CHCl3); analytical
data identical to those above reported for (S)-(+)-7.
References
1. Banfi, L.; Guanti, G. Synthesis 1993, 1029–1056 and
references cited therein.
2. (a) Nordin, O.; Nguyen, B. V.; Vo¨rde, C.; Hedenstro¨m,
E.; Ho¨gberg, H. E. J. Chem. Soc., Perkin Trans. 1 2000,
367–376; (b) Alexandre, F. R.; Huet, F. Tetrahedron:
Asymmetry 1998, 9, 2301–2310; (c) Ferraboschi, P.; Reza
Elahi, S.; Verza, E.; Meroni Rivolta, F.; Santaniello, E.
Synlett 1996, 1176–1178.
3. (a) Smith, P. M.; Thomas, E. J. J. Chem. Soc., Perkin
Trans. 1 1998, 3541–3556; (b) Schmittberger, T.; Uguen,
D. Tetrahedron Lett. 1997, 38, 2837–2840; (c) Baker, R.;
O’Mahony, M.; Swain, C. J. J. Chem. Soc., Perkin Trans.
1 1987, 1623–1633; (d) Mori, K.; Senda, S. Tetrahedron
1985, 41, 541–546.
4. (a) Oddon, G.; Uguen, D.; De Cian, A.; Fischer, J.
Tetrahedron Lett. 1998, 39, 1149–1152; (b) Guanti, G.;
Banfi, L.; Schmid, G. Tetrahedron Lett. 1994, 35, 4239–
4242; (c) Hird, N. W.; Lee, T. V.; Leigh, A. J.; Maxwell,
J. R.; Peakmann, T. M. Tetrahedron Lett. 1989, 30,
4867–4870; (d) Paterson, I.; Boddy, I.; Mason, I. Tetra-
hedron Lett. 1987, 28, 5205–5208.
5. (a) White, J. D.; Kawasaki, M. J. Org. Chem. 1992, 57,
5292–5300; (b) Mori, K.; Wu, J. Liebigs Ann. Chem.
1991, 783–788; (c) Mori, K.; Harada, H.; Zagatti, P.;
Cork, A.; Hall, D. R. Liebigs Ann. Chem. 1991, 259–267.
6. (a) Servi, S. Synthesis, 1990, 1–25; for more recent exam-
ple, see: (b) Anthonsen, T.; Hoff, B. H.; Hofsløkken, N.
U.; Skattebøl, L.; Sundby, E. Acta Chem. Scandinavica,
1999, 53, 360–365; (c) Koul, S.; Crout, D. H. G.; Erring-
ton, W.; Tax, J., J. Chem. Soc. Perkin Trans. 1 1995,
2969–2988; (d) Ho¨gberg, H. E.; Hedenstro¨m, E.; Fa¨ger-
hag, J.; Servi, S. J. Org. Chem. 1992, 57, 2052–2059; (e)
Fujisawa, T.; Yamanaka, K.; Mobele, B. I.; Shimizu, M.
Tetrahedron Lett. 1991, 32, 399–400.
7. Sato, T.; Hanayama, K.; Fujisawa, T. Tetrahedron Lett.
1988, 29, 2197–2200.
8. Pino, P.; Ercoli, R. Gazz. Chim. Ital. 1951, 81, 757–763.
9. For a similar addition of thiols to the aldehyde 11, see:
Mapp, A. K.; Heathcock, C. H. J. Org. Chem. 1999, 64,
23–27.
10. For a previous examples of baker’s yeast reduction of
unsaturated aldehydes supported on a resin, see: (a)
Fuganti, C.; Serra, S. J. Chem. Soc., Perkin Trans. 1
2000, 3758–3764; (b) Fuganti, C.; Serra, S. J. Chem. Soc.,
Perkin Trans. 1 2000, 97–101; (c) Fuganti, C.; Serra, S.;
Dulio, A. J. Chem. Soc., Perkin Trans. 1 1999, 279–282.
11. Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem.
1968, 34, 2543–2548.
12. (a) Mandai, T.; Osaka, K.; Wada, T.; Kawada, M.;
Otera, J. Tetrahedron Lett. 1983, 24, 1171–1174; (b)
Mandai, T.; Osaka, K.; Kawagishi, M.; Kawada, M.;
Otera, J. J. Org. Chem. 1984, 49, 3595–3600.
4.4.2. Preparation of (S)-(+)-7 from (S)-(+)-6. The alco-
hol (S)-(+)-6 (4 g, 22 mmol, 65% e.e.) was oxidised
using the same conditions described above to give pure
(97% GC) (S)-(+)-7 (4.32 g, 20.2 mmol, 92%): [h]2D0=
+6.2 (c 1, CHCl3); analytical data identical to those
above reported for (S)-(+)-7.
4.5. Determination of the optical purity of compounds
6 and 7
4.5.1. Preparation of ( )-6 and ( )-7. A sample of ( )-6
was prepared by base catalysed addition of thiophenol
on methacrolein 8 using the same conditions described
above in the preparation of acetal 14. The obtained
aldehyde was reduced with NaBH4 to give the ( )-6. A
sample of ( )-7 was prepared by MCPBA oxidation of
( )-6 using the same conditions for the preparation of
(R)-(−)-7 from (R)-(−)-6.
4.5.2. Preparation of the (S)-(−)-MTPA esters11 of the
samples of 6 and 7. (Representative example). A solution
of ( )-6 (20 mg, 0.11 mmol) in CCl4 (0.4 mL) was
treated with (S)-(−)-MTPACl11 (30 mg, 0.12 mmol) and
pyridine (0.2 mL) at room temperature for 24 h. The
mixture was diluted with diethyl ether (40 mL) and
washed in turn with 5% HCl aq. (50 mL) and saturated
NaHCO3 (10 mL). The organic phase was dried
(Na2SO4) and concentrated under reduced pressure.
The residual (S)-(−)-MTPA ester was analysed without
further purification.
The (S)-(−)-MTPA esters of ( )-7 and of the different
samples of enantioenriched 6 and 7 were prepared using
the above described procedure. The NMR analysis of
(S)-(−)-MTPA esters of ( )-6 and ( )-7 (250 MHz,
CDCl3) shows that the signal of methyl group became a
well resolved double doublet:
( )-6-(S)-(−)-MTPA esters: l ppm: 1.04 and 1.06, J=
6.8 Hz
( )-7-(S)-(−)-MTPA esters: l ppm: 1.10 and 1.14, J=
6.8 Hz
The enantiomeric purity of all samples was determined
by comparison of the area of the two peaks of these
different doublets.
13. For a previous preparation of compound 11 as a mixture
of E and Z isomers, see: Harada, K.; Choshi, T.; Sugino,
E.; Sato, K.; Hibino, S. Heterocycles 1996, 42, 213–218.
14. (a) For a previous preparation of compound 18 by a
different synthetic pathway, see: Ghera, E.; Ramesh, N.
G.; Laxer, A.; Hassner, A. Tetrahedron Lett. 1995, 36,
1333–1336; (b) Compound 17 was not described in the
literature before.
Acknowledgements
The financial support of COFIN-MURST is acknow-
ledged.