Baker's yeast-induced asymmetric reduction of α-ketosulfides: Synthesis of optically active 1-(benzothiazol-2-ylsulfanyl)-2- alkanols, 2-alkanols, and thiiranes

Article abstract of DOI:10.1016/S0957-4166(99)00199-8

1-(Benzothiazol-2-ylsulfanyl)-2-alkanols 3 were prepared in very high enantiomeric excess by baker's yeast-induced asymmetric reduction of 1- (benzothiazol-2-ylsulfanyl)-2-alkanones 1. Conversion of 3 into optically active simple 2-alkanols 4 and thiiranes 2 by reductive desulfurization and base treatment, respectively, is also described. The absolute configuration of the new compounds synthesized has been established by chemical correlation and specific rotation comparison.

Full text of DOI:10.1016/S0957-4166(99)00199-8

Pergamon
Tetrahedron: Asymmetry 10 (1999) 1913–1926
Baker’s yeast-induced asymmetric reduction of α-ketosulfides:
synthesis of optically active 1-(benzothiazol-2-ylsulfanyl)-2-
alkanols, 2-alkanols, and thiiranes
Leonardo Di Nunno,a,b Carlo Franchini,b Angelo Nacci,c Antonio Scilimati b,∗ and
Maria Stefania Sinicropi d
aCentro CNR di Studio sulle Metodologie Innovative di Sintesi Organiche, Dipartimento di Chimica, Università di Bari,
Via Amendola n.173-70126 Bari, Italy
bDipartimento Farmaco-Chimico, Università di Bari, Via Orabona n.4-70125 Bari, Italy
cDipartimento di Chimica, Università di Bari, Via Orabona n.4-70125 Bari, Italy
dDipartimento di Scienze Farmaceutiche, Università della Calabria, 87030 Arcavacata di Rende (CS)-Italy
Received 31 March 1999; accepted 17 May 1999
Abstract
1-(Benzothiazol-2-ylsulfanyl)-2-alkanols 3 were prepared in very high enantiomeric excess by baker’s yeast-
induced asymmetric reduction of 1-(benzothiazol-2-ylsulfanyl)-2-alkanones1. Conversion of 3 into optically active
simple 2-alkanols 4 and thiiranes 2 by reductive desulfurization and base treatment, respectively, is also described.
The absolute configuration of the new compounds synthesized has been established by chemical correlation and
specific rotation comparison. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
Thiiranes are suitable precursors for numerous products such as biologically active substances and
polymers. New technical applications of thiiranes have been developed for the preparation of liquid
crystals, photoresistors, components of paint and varnish coatings, antioxidant thermostable insula-
ting materials, heat-resistant polymers, semiconductors, elastomers, etc.1 The availability of a general
methodology to prepare enantiomerically pure thiiranes could open the way to the synthesis of the
above mentioned products with very high enantiomeric purity, which in the case of biologically active
substances represents a very crucial target.
Of similar importance are chiral 2-alkanols, widely used as building blocks in the asymmetric synthesis
of speciality chemicals.2
∗
Corresponding author. E-mail: ascilimati@farmchim.uniba.it
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00199-8

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Thiiranes are usually prepared from the corresponding oxiranes or vicinally substituted ethane
derivatives.3–7 The synthesis of thiiranes generally involves the previous transformation of a diol into the
corresponding epoxide and opening with thiocyanate ions or with thiourea, which are the most common
reagents used for this transformation.8–19 A recently described method for the synthesis of thiiranes
involves a previous transformation of allylic alcohols into cyclic xanthates.20–22 A new efficient and expe-
ditious synthesis of thiiranes from cyclic sulfates of vic-diols is also described; opening of cyclic sulfates
with potassium thioacetate or potassium thiocyanate followed by treatment with sodium methoxide lead
to thiiranes.23 Addition of organometallics to thioketones is an interesting route but low availability and
inherent instability of thiocarbonyls have deterred this method from further development.1 On the other
hand, the synthesis of optically active alkyl substituted thiiranes with an enantiomeric excess ranging
from 19% to 36% has already been published.3–6
Our previous studies on benzothiazole derivatives as versatile synthetic intermediates24 led us to a
simple synthesis of racemic thiiranes in high yield (Scheme 1)25–28 by reduction to the corresponding
alcohols (and subsequent transformation) of 1-(benzothiazol-2-ylsulfanyl)-2-alkanones 1, which in turn
were synthesized in 60–90% yield by reacting sodium (or potassium) benzothiazol-2-thiolate with the
corresponding bromoketones (Table 1). Among these, 1-bromo-2-hexanone, 1-bromo-2-octanone, and
1-bromo-2-dodecanone, not commercially available, were prepared by bromination of the epoxide pre-
cursors (1,2-epoxyhexane, 1,2-epoxyoctane or 1,2-epoxydodecane, respectively), in CCl4 under radical
conditions,29 affording the bromoketone (40–60% yield) and the bromohydrins, the latter possibly
formed by interaction of the epoxide with hydrobromic acid produced during the reaction.
Scheme 1.
As for the reduction of the carbonyl function of 1, baker’s yeast-induced enantioselective reduction
has now been investigated. It is known that baker’s yeast can mediate the reduction of a wide variety of
carbonyl compounds ranging from simple aldehydes and ketones to very complicated molecules such
as steroids.30,31 Though in some cases baker’s yeast-induced asymmetric reduction of ketones gives
alcohols with low enantiomeric excess (e.g. ee=23% starting from ethyl n-propyl ketone) in others, it
proceeds with fair to high stereoselectivity. For instance, yeast-mediated stereoselective reduction of
methyl and phenyl ketones (methyl ethyl ketone, methyl n-propyl ketone, methyl n-butyl ketone, methyl
t-butyl ketone, acetophenone, valerophenone, etc.) has been accomplished by fermenting yeast affording
alcohols with ees ranging between 61% and 90%.32 Baker’s yeast-induced asymmetric reduction of some
α-ketosulfides (1-phenylthio- and 1-benzylthio-2-alkanones) has also been reported,33,34 but in this case,
only the methyl derivatives showed any stereoselectivity. Thus, as is generally known, stereoselectivity is
not predictable in advance in all cases, depending on various factors. Among these, an important role is
exerted by the bulk (and nature) of the groups linked to the carbonyl. So, in this context, it seemed worth
investigating the behaviour towards the same carbonyl function biotransformation of α-ketosulfides 1, in
which a new group (benzothiazol-2-ylsulfanylmethyl) having quite different features from the previously
tested alkyl and aryl groups is present.
Thus, here we report our results on the preparation and baker’s yeast-mediated stereoselective reduc-
tion of ketones 1 into the corresponding optically active β-hydroxysulfides 3. In addition, the conversion
of the latter into both optically active thiiranes and 2-alkanols is also described (Scheme 2).

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1915
Table 1
Yields of 1-(benzothiazol-2-ylsulfanyl)-2-alkanones isolated from the reaction of benzothiazol-2-
thiolate and 1-bromo-2-ketones
Scheme 2.
2. Results and discussion
Baker’s yeast-catalyzed reduction of 1-(benzothiazol-2-ylsulfanyl)-2-alkanones 1a–f was conducted
in a variety of conditions to optimize the medium and the temperature, parameters that affect both the
chemical yield and enantiomeric excess. So, the reduction was carried out by using several different
procedures (A–G: see Experimental and footnote of Table 2).
From a careful analysis of the data obtained under the experimental conditions used it emerges that, for
each substrate, the results [both different reaction times and different enantiomeric excesses (Table 2)] are

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Table 2
Reduction of α-ketosulfides 1 by baker’s yeast
dependent upon the medium used to perform the reduction, and addition of a small amount of co-solvent
(ca. 10%) such as ethanol or THF does not determine a remarkable change of the results. No effect on
the enantioselectivity was observed by changing the temperature in the range 20–37°C.
The yeast-catalyzed reduction proceeded cleanly, usually giving either the alcohols (R)-3 or a mixture
of the desired alcohols 3 and unreduced starting material 1. The crude products were routinely purified
by column chromatography and then fully characterized. The enantiomeric excess of such chiral alcohols
was determined via HPLC by using a chiral column (Chiralcel OD from Daicel).
The observed enantioselectivity was generally high, ranging between 64% and >99% (see Table 2).
In particular, the reduction of 1-(benzothiazol-2-ylsulfanyl)-propan-2-one 1a and 1-(benzothiazol-2-
ylsulfanyl)-hexan-2-one 1c provided the corresponding chiral alcohols with ee >99%. 1-(Benzothiazol-2-
ylsulfanyl)-butan-2-one 1b and 1-(benzothiazol-2-ylsulfanyl)-octan-2-one 1d gave alcohols with ee=74%
and 91%, respectively. No reaction at all was observed instead for the less water-soluble substrates 1e
(R=C10H21) and 1f (Ar=C6H5), even if they were incubated longer than 1a–d, possibly because of both
poor solubility and cell permeation, as well as for steric and (substrate 1f) electronic effects.
Extension to a gram scale for 1c–d, did not change the extent of conversion nor the enantiomeric
excess compared to the reactions carried out on a smaller scale.
As for the assignment of the absolute configurations of 3, it has been demonstrated to be R in the

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1917
cases of alkanols 3c and 3d. This was established by comparison of the specific rotations of the simple 2-
alkanols obtained by them (2-hexanol 4c and 2-octanol 4d, respectively), with those of authentic samples
commercially available [(S)-(+)-2-hexanol and (S)-(+)-2-octanol].35–38 Thus, at least with reference to
ketosulfides 1c and 1d, the stereochemical course during the baker’s yeast-induced asymmetric reduction
corresponds to a preferential hydrogen transfer on the Si-face of the prochiral ketone.
In the case of other previously examined α-ketosulfides (1-phenylthio- and 1-benzylthio-2-
alkanones),33,34 S-stereoselectivity (e.g. hydrogen attack on the Re-face) was instead observed for the
methyl ketone, and no stereoselectivity at all was obtained in the case of a ketone with a larger alkyl
group (C5H11), e.g. similar to those present in 1c and 1d.
On the other hand, the behaviour of 1-phenylthio- and 1-benzylthio-2-alkanones is in good agreement
with the commonly accepted rationale33,34 concerning the conditions for the stereoselectivity in the
reductions of prochiral ketones by baker’s yeast and based on the difference in steric requirements of the
two groups attached to the carbonyl function as the important factor. Accordingly, when such a difference
decreases, selectivity should in fact be reduced (or suppressed) correspondingly, as actually observed for
1-phenylthio- and 1-benzylthio-2-heptanone. In light of the same explanation, the behaviour observed
by us for ketones 1c and 1d seems anomalous. In fact, in spite of a steric situation presumably not
much different from 1-phenylthio- and 1-benzylthio-2-heptanone, selectivity not only is not suppressed,
but, on the contrary, is high. Our results could therefore suggest that different factors can perhaps also
be involved (e.g. some specific interaction between the benzothiazolyl moiety and the active site of an
enzyme).
However, apart from the considerations concerning the more general question of the mechanism of
enzyme action, our results seem appreciably interesting particularly from a synthetic point of view. In
fact, the presence of the benzothiazol-2-yl moiety in the place of the previously tested phenyl or benzyl
group in the α-ketosulfides allows the stereoselective reduction with high ees not only of methyl ketones,
but also of several more complex homologues.
This result is still more interesting when considering that the obtained optically active β-
hydroxysulfides 3 are in turn, as mentioned above, further convertible into other important chiral
products, some of which (e.g thiiranes) are obtainable just because of the presence, once again, of the
benzothiazol-2-yl moiety.1
So, for instance, compounds (R)-3c and (R)-3d, previously converted into the corresponding acetates
(quantitative yields), are easily transformed into (S)-4c and (S)-4d by reaction with tri-n-butyltin hydride
in toluene under reflux and then with K2CO3 in MeOH–H2O. Besides, (R)-3c and (R)-3d are allowed to
react with NaH in THF at room temperature affording thiiranes (S)-2c and (S)-2d (Scheme 2 and Table 3).
In all cases, the enantiomeric excesses for (S)-4c–d35,38 and (S)-2c–d37,38 did not change, compared to
the starting alkanols (R)-3c–d (Scheme 2 and Table 3).
On the other hand, the absolute S-configuration of alcohols 4c and 4d was established, as described
above, by direct comparison of optical rotations with those of the commercially available (S)-(+)-hexanol
and (S)-(+)-octanol. From this, not only R-configuration of alkanols precursor 3c and 3d, but also, by
considering that conversion of 3 into 2 occurs purely by inversion of configuration at the stereocentre,1
S-configuration of both thiiranes 2c and 2d was finally deduced (Scheme 3).
3. Conclusion
The baker’s yeast-induced asymmetric reduction of 1-(benzothiazol-2-ylsulfanyl)-2-alkanones was
found to be a useful method for the preparation of the corresponding optically active β-hydroxysulfides.

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Table 3
Enantiomeric excesses and yields of thiiranes 2 and alcohols 4, obtained by treating alcohols 3 with
NaH or tri-n-butyltin hydride and then with K2CO3
Scheme 3.
This transformation showed high selectivities with ketones bearing a small or medium-size alkyl group
(C1 to C6), giving in these cases satisfactory enantiomeric excesses (64% to >99%; depending on the
substrate features and the reaction medium). In contrast, ketones with a longer alkyl chain (C10) or
a phenyl group did not react at all, possibly due, however, to both lower water-solubility and cell
permeation, besides electronic and/or steric effects. No change in enantiomeric excess was observed
by converting the reduced products 3 into thiiranes 2 and 2-alkanols 4.
Thus, in a large number of cases the present method not only constitutes a convenient way for the
asymmetric reduction of the investigated ketosulfides into the corresponding alcohols but also provides
a direct route to chiral thiiranes, as well as another efficient way to simple optically active 2-alkanols,
which in turn are both valuable synthetic intermediates. In this context, new optically active compounds
were also obtained and their absolute configuration established.
Further studies aimed at verifying the extension of this methodology to the asymmetric reduction of
other not previously studied ketosulfides are in progress, in order to better define the behaviour of such
systems towards the baker’s yeast-induced asymmetric reduction of the carbonyl function, as well as to

L. Di Nunno et al. / Tetrahedron: Asymmetry 10 (1999) 1913–1926
1919
synthesize new C3 synthons containing other different groups. Such C3 synthons will then be further
elaborated to already existing biological active compounds or to new ones.
4. Experimental
4.1. General methods
Melting points taken on an Electrothermal apparatus were uncorrected. 1H NMR spectra were recorded
in CDCl3 on a Varian EM 390 or XL 200 spectrometer and chemical shifts were reported in parts per
million (δ) from internal Me4Si. Absolute values of the coupling constant were reported. IR spectra were
recorded on a Perkin–Elmer 681 spectrometer. GC analyses were performed by using an HP1 column
(methyl silicone gum; 5 m×0.53 mm×2.65 µm film thickness) on an HP 5890 model, series II. HPLC
analyses for the determination of enantiomeric excesses were carried out using a Daicel Chiralcel OD
column (tris-3,5-dimethylphenylcarbamate, derivatized cellulose film) on an HP series 1050 instrument.
Optical rotations were measured on a Perkin–Elmer digital polarimeter, model 241 MC. Thin-layer
chromatography (TLC) was performed on silica gel sheets with a fluorescent indicator (Statocrom SIF,
Carlo Erba), the spots on the TLC were observed under ultraviolet light or were visualized with I2 vapour.
Flash chromatography was conducted using silica gel with an average particle size of 60 µm, a particle
size distribution of 40–63 µm and 230–400 ASTM; GC–MS analyses were performed on an HP 5995C
model and microanalyses on an elemental analyzer 1106 — Carlo Erba instrument.
4.2. Materials
Solvents used were commercial grade. All other chemicals were further purified by distillation or
crystallization prior to use.
2-Bromoacetophenone, chloro-2-propanone, 1-bromo-2-butanone, 1,2-epoxyhexane, 1,2-epoxyoctane
and 1,2-epoxydodecane were purchased from Aldrich Chemical Co. 1-Bromo-2-hexanone, 1-bromo-
2-octanone and 1-bromo-2-dodecanone were not commercially available. They were prepared by the
action of bromine on the epoxide precursors (1,2-epoxyhexane, 1,2-epoxyoctane or 1,2-epoxydodecane,
respectively).29
4.3. Procedure for the synthesis of 1-bromo-2-hexanone (1-bromo-2-octanone or 1-bromo-2-
dodecanone, respectively)
To a solution of 1,2-epoxyhexane (1,2-epoxyoctane or 1,2-epoxydodecane) (10 g, 0.10 mol in 50
ml of CCl4), a solution of Br2 (7.9 g, 0.05 mol) in 10 ml of CCl4 was added at room temperature
as follows: a few drops of the bromine were added, obtaining a red-brownish reaction mixture that
was stirred at room temperature until it decolorized. Then, the bromine solution was slowly added.
The reaction mixture was stirred until all the bromine disappeared (the red coloured mixture became
colourless) and the epoxide was completely converted (6 h) into the two regioisomeric bromohydrins
and bromoketone in the ratio 30:30:40 (both GC and GC–MS analysis). During the whole reaction time
the mixture was irradiated. After 6 h the solution was washed with 10% sodium hydrogen carbonate,
dried over anhydrous sodium sulfate and the solvent evaporated to give a residue (a mixture of products
containing also the bromoketone) that was used in the reaction with the benzothiazol-2-thiolate, without
any further purification. The products were identified by their mass spectra.

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4.4. 1-(Benzothiazol-2-ylsulfanyl)-2-alkanones: general procedure
A suspension of benzothiazole-2-thiol (0.056 mol) and potassium carbonate (0.028 mol) in 100 ml of
methanol was stirred at room temperature for 30 min. Then, the crude bromoketone (0.056 mol in 70
ml of methanol) was added. The reaction mixture was stirred at room temperature for a further 24 h,
then cooled at 0°C and treated with cold water. [For compounds 1a and 1f the reaction was conducted
by mixing an equimolar amount of benzothiazole-2-thiol (0.056 mol) and EtONa (0.056 mol, prepared
in situ) in ethanol, then kept under reflux for one hour.] A yellow solid precipitated. The crude α-
ketosulfides of benzothiazole-2-thiol were obtained by filtration. The product was separated from other
impurities by flash chromatography [eluent, petroleum ether:ethyl ether (5:1)] and then recrystallized
from methanol or as otherwise indicated. Yields of the ketosulfides ranged from between 60 and 90%
(see Table 1). Melting points and other analytical data are reported below.
4.4.1. 1-(Benzothiazol-2-ylsulfanyl)-propan-2-one 1a
Mp 64–65°C (ethanol) (lit.39 69°C, ethyl ether–pentane); IR (KBr): 3060, 2980, 2942, 1725, 1461,
1
1430, 1415, 1380, 1312, 1285, 1238, 1110, 1003, 760 cm−1; H NMR (CDCl3, δ): 7.86–7.71 (m, 2H,
aromatic protons), 7.44–7.25 (m, 2H, aromatic protons), 4.24 (s, 2H, CH2), 2.39 (s, 3H, CH3); GC–MS
(70 eV) m/z (rel. inten.) 223 (M+, 37), 182 (16), 181 (100), 180 (69), 166 (11), 148 (60), 136 (37), 122
(13), 109 (12), 108 (30), 90 (10), 82 (11), 77 (10), 69 (23), 63(18), 45 (32), 43 (85), 42 (11). Anal. calcd
for C10H9NOS2: C, 53.81; H, 4.04; N, 6.28. Found: C, 53.89; H, 4.10; N, 6.24.
4.4.2. 1-(Benzothiazol-2-ylsulfanyl)-butan-2-one 1b
Mp 88–90°C; IR (KBr): 3064, 2980, 2942, 1727, 1463, 1430, 1412, 1380, 1357, 1312, 1286, 1238,
1
1110, 1003, 761 cm−1; H NMR (CDCl3, δ): 7.84–7.71 (m, 2H, aromatic protons), 7.44–7.24 (m, 2H,
aromatic protons), 4.23 (s, 2H, -CH2-S-), 2.72 (q, J=7.3 Hz, 2H, -CO-CH2-), 1.13 (t, J=7.3 Hz, 3H, CH3);
GC–MS (70 eV) m/z (rel. inten.) 237 (M+, 32), 208 (29), 182 (13), 181 (100), 180 (38), 148 (35), 136
(21), 108 (18), 69 (11), 57 (49), 45 (16). Anal. calcd for C11H11NOS2: C, 55.70; H, 4.64; N, 5.91. Found:
C, 55.69; H, 4.65; N, 5.86.
4.4.3. 1-(Benzothiazol-2-ylsulfanyl)-hexan-2-one 1c
Mp 74–75°C; IR (KBr): 3035, 2978, 2960, 2942, 2880, 1730, 1472, 1448, 1363, 1320, 1300, 1245,
1
1140, 1130, 1056, 1039, 1012, 762 cm−1; H NMR (CDCl3, δ): 7.85–7.71 (m, 2H, aromatic protons),
7.44–7.25 (m, 2H, aromatic protons), 4.26 (s, 2H, -CH2-S-), 2.68 (t, J=7.3 Hz, -CO-CH2-), 1.67–1.56
(m, 2H, CH2), 1.43–1.24 (m, 2H, CH2), 0.90 (t, J=7.2 Hz, 2H, CH3); GC–MS (70 eV) m/z (rel. inten.)
265 (M+, 9), 208 (14), 182 (14), 181 (100), 180 (20), 149 (19), 148 (30), 136 (20), 108 (21), 85 (33), 77
(10), 69 (15), 57 (94), 45 (22), 41 (51), 39 (17). Anal. calcd for C13H15NOS2: C, 58.87; H, 5.66; N, 5.28.
Found: C, 58.82; H, 5.70; N, 5.25.
4.4.4. 1-(Benzothiazol-2-ylsulfanyl)-octan-2-one 1d
Mp 65–68°C; IR (KBr): 3078, 2970, 2940, 2965, 1728, 1470, 1440, 1365, 1320, 1240, 1138, 1085,
1010, 762 cm−1; 1H NMR (CDCl3, δ): 7.83–7.72 (m, 2H, aromatic protons), 7.42–7.26 (m, 2H, aromatic
protons), 4.24 (s, 2H, -CH2-S-), 2.67 (t, J=7.3 Hz, 2H, -CO-CH2-), 1.68–1.58 (m, 2H, CH2), 1.40–1.15
(m, 6H, -(CH2)3-), 0.85 (m, 3H, CH3); GC–MS (70 eV) m/z (rel. inten.) 293 (M+, 18), 208 (17), 182
(12), 181 (100), 180 (14), 148 (15), 136 (11), 108 (10), 43 (52), 41 (17). Anal. calcd for C15H19NOS2:
C, 61.43; H, 6.48; N, 4.78. Found: C, 61.49; H, 6.44; N, 4.75.

L. Di Nunno et al. / Tetrahedron: Asymmetry 10 (1999) 1913–1926
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4.4.5. 1-(Benzothiazol-2-ylsulfanyl)-dodecan-2-one 1e
Mp 58–61°C; IR (KBr): 3045, 2940, 2910, 2840, 1718, 1472, 1465, 1449, 1421, 1353, 1308, 1235,
998, 750 cm−1; 1H NMR (CDCl3, δ): 7.83–7.72 (m, 2H, aromatic protons), 7.42–7.24 (m, 2H, aromatic
protons), 4.24 (s, 2H, -CH2-S-), 2.66 (t, J=7.3 Hz, 2H, -CO-CH2-), 1.90–1.70 (m, 2H, CH2), 1.70–1.57
(m, 2H, CH2), 1.38–1.13 (m, 12H, -(CH2)6-), 0.93–0.78 (m, 3H, CH3); GC–MS (70 eV) m/z (rel. inten.)
349 (M+, 18), 208 (17), 183 (10), 182 (13), 181 (100), 149 (30), 148 (12), 57 (12), 43 (22), 41 (16). Anal.
calcd for C19H27NOS2: C, 65.33; H, 7.74; N, 4.01. Found: C, 65.40; H, 7.75; N, 3.99.
4.4.6. 2-(Benzothiazol-2-ylsulfanyl)-1-phenyl-ethanone 1f
Mp 110–112°C; IR (CCl4): 3035, 2958, 2900, 2840, 1680, 1590, 1450, 1438, 1419, 1260, 1182, 1001,
675 cm−1; 1H NMR (CDCl3, δ): 8.11–7.30 (m, 9H, aromatic protons), 4.98 (s, 2H, CH2); GC–MS (70
eV) m/z (rel. inten.) 285 (M+, 50), 253 (17), 252 (17), 225 (11), 180 (36), 105 (100), 77 (49), 51 (14), 45
(11). Anal. calcd for C15H11NOS2: C, 63.16; H, 3.86; N, 4.91. Found: C, 63.20; H, 4.00; N, 4.86.
4.5. Reduction of 1-(benzothiazol-2-ylsulfanyl)-2-alkanones by NaBH4/MeOH: general procedure
To a mixture of ketosulfides (4.2 mmol) in methyl alcohol (50 ml) kept in an ice-bath was added NaBH4
(5 mmol). The reaction mixture was stirred at 0°C for 2 h. Then, the methyl alcohol was evaporated in
vacuo. The residue was treated with 30 ml of H2O and extracted three times with EtOAc (30 ml). The
extracts were dried over Na2SO4 and the solvent evaporated. The products were obtained in quantitative
yields.
These racemic alcohols were prepared for two main reasons, firstly to compare the analytical data of
the corresponding products derived from the reduction of the ketosulfides performed in the presence of
the baker’s yeast, and secondly to set the conditions for the HPLC analysis to determine the enantiomeric
excesses of the optically active alcohols 3.
The HPLC retention time (tR) and the separation factor (α) found for the (ꢀ)-alcohols 3 is shown
below:
The HPLC analyses were executed in an isocratic manner, flow rate=1 ml/min, sparge=25 ml/min,
mobile phase, hexane:i-PrOH (98:2).
4.6. Baker’s yeast-mediated reduction of 1-(benzothiazole-2-ylsulphanyl)-2-alkanones
A typical procedure for the reduction of 1 is described below (Procedure A).
Fresh Golievit baker’s yeast (140 g) was dispersed to give a smooth paste in tap water (1.4 l). Glucose
(140 g) was added to the heterogeneous mixture which was stirred at 37°C and 250 rpm for 30 min. Then,
ketosulfides 1 (1 g) were slowly added. The reaction was followed by TLC and stopped at the indicated
time (see Table 2). The mixture was saturated with sodium chloride and centrifuged; the liquid phase was
extracted with EtOAc several times. The combined organic extracts were dried over anhydrous sodium
sulfate. The solvent was removed under reduced pressure and the alcohol 3 was purified or separated from
the remaining substrate 1 by flash chromatography on SiO2 [eluent, petroleum ether:EtOAc (14:1)].
The salt:substrate molar ratio was 1:1 when the reaction was carried out in the presence of a mineral
supplement: procedures B, C, D, E, F and G.

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L. Di Nunno et al. / Tetrahedron: Asymmetry 10 (1999) 1913–1926
Procedure B; the same as procedure A with MgSO4. Procedure C; the same as procedure A with
ZnSO4. Procedure D; ketosulfides 1 (1 g), distilled water (250 ml), yeast (16 g), sucrose (4 g). Procedure
E; the same as procedure D with KH2PO4, MgSO4 and CaCO3. Procedure F; the same as procedure D
with MgSO4. Procedure G; the same as procedure D with ZnSO4. The workup and product isolation in
the reaction performed following procedures B, C, D, E, F and G were carried out as described above for
procedure A.
The same amount of baker’s yeast and medium were added every two days for reactions with an
incubation time longer than two days.
4.6.1. (+)-1-(Benzothiazol-2-ylsulfanyl)-propan-2-ol 3a
([α]D20=+15.1, c=1 in CHCl3, ee=99%); oil; IR (neat): 3650–3120, 3083, 2992, 2978, 2900, 1683,
1
1475, 1435, 1320, 1250, 1139, 1130, 1089, 1060, 1030, 1010, 765, 735 cm−1; H NMR (CDCl3, δ):
7.85–7.68 (m, 2H, aromatic protons), 7.46–7.25 (m, 2H, aromatic protons), 4.33–4.17 (m, 1H, -CH-),
3.80–3.58 (bs, 1H, OH: exchange with D2O), 3.51 (dd, J=3.3 Hz and 14.3 Hz, 1H, -CH2-S-), 3.35 (dd,
J=6.9 Hz and 14.3 Hz, 1H, -CH2-S-), 1.35 (d, J=6.3 Hz, 3H, CH3); GC–MS (70 eV) m/z (rel. inten.) 225
(M+, 11), 181 (44), 180 (21), 168 (19), 167 (100), 148 (54), 136 (18), 135 (11), 109 (11), 108 (23), 69
(18), 63 (11), 45 (41), 43 (13). Anal. calcd for C10H11NOS2: C, 53.33; H, 4.89; N, 6.22. Found: C, 53.30;
H, 4.65; N, 6.23.
4.6.2. (−)-1-(Benzothiazol-2-ylsulfanyl)-butan-2-ol 3b
([α]D20=−15.5, c=1 in CHCl3, ee=64%); oil; IR (neat): 3650–3120, 3085, 2990, 2980, 2900, 1685,
1
1470, 1438, 1320, 1250, 1138, 1129, 1089, 1060, 1030, 1010, 765, 735 cm−1; H NMR (CDCl3, δ):
7.84–7.67 (m, 2H, aromatic protons), 7.42–7.24 (m, 2H, aromatic protons), 4.30–3.98 (bs, 1H, OH:
exchange with D2O), 3.97–3.88 (m, 1H, -CH-), 3.51 (dd, J=2.8 Hz and 14.3 Hz, 1H, -CH2-S-), 3.32 (dd,
J=7.2 Hz and 14.3 Hz, 1H, -CH2-S-), 1.74–1.58 (m, 2H, CH2), 1.00 (t, J=7.4 Hz, 3H, CH3); GC–MS (70
eV) m/z (rel. inten.) 239 (M+, 7), 210 (30), 181 (46), 180 (20), 169 (10), 168 (27), 167 (100), 148 (53),
136 (17), 135 (11), 109 (11), 108 (24), 59 (12), 45 (21), 43 (11). Anal. calcd for C11H13NOS2: C, 55.23;
H, 5.44; N, 5.86. Found: C, 55.15; H, 5.38; N, 5.88.
4.6.3. (R)-(−)-1-(Benzothiazol-2-ylsulfanyl)-hexan-2-ol 3c
([α]D20=−28.1, c=1 in CHCl3, ee=99%); mp 28–30°C; IR (neat): 3700–3110, 3081, 2982, 2951, 2880,
1
1672, 1470, 1445, 1381, 1324, 1250, 1138, 1090, 1058, 1030, 1010, 765 cm−1; H NMR (CDCl3, δ):
7.84–7.69 (m, 2H, aromatic protons), 7.42–7.25 (m, 2H, aromatic protons), 4.40–4.10 (bs, 1H, OH:
exchange with D2O), 4.05–3.98 (m, 1H, -CH-), 3.53 (dd, J=3.1 Hz and 14.3 Hz, 1H, -CH2-S-), 3.31 (dd,
J=7.2 Hz and 14.3 Hz, 1H, -CH2-S-), 1.70–1.55 (m, 2H, CH-CH2-), 1.42–1.26 (m, 4H, -(CH2)2-), 0.90
(t, J=7.1 Hz, 3H, CH3); GC–MS (70 eV) m/z (rel. inten.) 267 (M+, 7), 210 (33), 181 (60), 180 (16),
169 (11), 168 (34), 167 (100), 148 (46), 136 (12), 108 (14), 69 (12), 45 (11), 41 (19). Anal. calcd for
C13H17NOS2: C, 58.43; H, 6.37; N, 5.24. Found: C, 58.40; H, 6.65; N, 5.23.
4.6.4. (R)-(−)-1-(Benzothiazol-2-ylsulfanyl)-octan-2-ol 3d
([α]D20=−8.3, c=1 in CHCl3, ee=91%); oil; IR (neat): 3700–3110, 3080, 2980, 2950, 2878, 1670,
1470, 1447, 1380, 1320, 1250, 1138, 1090, 1058, 1030, 1010, 765 cm−1; 1H NMR (CDCl3, δ): 7.86–7.67
(m, 2H, aromatic protons), 7.43–7.24 (m, 2H, aromatic protons), 4.50–4.20 (bs, 1H, OH: exchange with
D2O), 4.08–3.97 (m, 1H, CH), 3.52 (dd, J=2.8 Hz and 14.3 Hz, 1H, -CH2-S-), 3.31 (dd, J=7.2 Hz and
14.3 Hz, 1H, -CH2-S-), 1.70–1.15 (m, 10H, -(CH2)5-), 0.85 (m, 3H, CH3); GC–MS (70 eV) m/z (rel.
inten.) 295 (M+, 4), 210 (33), 181 (65), 180 (16), 169 (12), 168 (41), 167 (100), 148 (38), 136 (12), 108

L. Di Nunno et al. / Tetrahedron: Asymmetry 10 (1999) 1913–1926
1923
(13), 69 (10), 55 (18), 45 (11), 43 (28), 49 (31). Anal. calcd for C15H21NOS2: C, 61.02; H, 7.12; N, 4.75.
Found: C, 61.01; H, 7.09; N, 4.63.
4.6.5. 1-(Benzothiazol-2-ylsulfanyl)-dodecan-2-ol 3e
Oil; IR (neat): 3700–3110, 3080, 2980, 2950, 2878, 1670, 1470, 1447, 1380, 1320, 1250, 1138, 1090,
1058, 1030, 1010, 765 cm−1; 1H NMR (CDCl3, δ): 7.80–7.68 (m, 2H, aromatic protons), 7.60–7.19 (m,
2H, aromatic protons), 4.40–4.20 (bs, 1H, OH: exchange with D2O), 4.15–3.90 (m, 1H, CH), 3.51 (dd,
J=2.9 Hz and 14.3 Hz, 1H, -CH2-S-), 3.32 (dd, J=7.2 Hz and 14.3 Hz, 1H, -CH2-S-), 1.80–1.10 (m, 18H,
-(CH2)9-), 0.89 (m, 3H, CH3); GC–MS (70 eV) m/z (rel. inten.) 351 (M+, 4), 210 (33), 181 (67), 180
(11), 169 (13), 168 (49), 167 (100), 148 (25), 55 (13), 43 (29), 41 (27). Anal. calcd for C19H29NOS2: C,
64.96; H, 8.26; N, 3.99. Found: C, 64.89; H, 8.65; N, 4.01.
4.6.6. 2-(Benzothiazol-2-ylsulfanyl)-1-phenylethanol 3f
Oil; IR (CCl4): 3605, 3580–3120, 3060, 3020, 2950, 2920, 1670, 1460, 1451, 1425, 1306, 1257, 1136,
1078, 1050, 1016, 1022, 755 cm−1; 1H NMR (CDCl3, δ): 7.96–7.70 (m, 2H, aromatic protons), 7.48–7.25
(m, 7H, aromatic protons), 5.19 (dd, J=7.9 Hz and 3.0 Hz, 1H, -CHOH-), 3.72 (dd, J=14.5 Hz and 3.0
Hz, 1H, -CH2-S-), 3.45 (dd, J=14.5 Hz and 7.9 Hz, 1H, -CH2-S-), 3.40–2.50 (bs, 1H, OH: exchange with
D2O); GC–MS (70 eV) m/z (rel. inten.) 287 (M+, 3), 183 (10), 182 (12), 181 (100), 180 (17), 168 (17),
167 (38), 148 (40), 136 (12), 108 (12), 107 (12), 79 (25), 77 (29), 51 (11). Anal. calcd for C15H13NOS2:
C, 62.72; H, 4.53; N, 4.87. Found: C, 62.70; H, 4.65; N, 4.83.
4.7. 1-(Benzothiazol-2-ylsulfanyl)-2-acetoxy derivatives of 3: general procedure
A solution of alcohol 5 (3 mmol) in pyridine (8 ml) and Ac2O (6 ml) was stirred at room temperature
until TLC analysis showed complete conversion of 5 into the acetoxyalkane (2 h). The reaction was
quenched with H2O, diluted with EtOAc (10 ml) and then washed with 5% HCl (2×10 ml). The
organic layer was dried (Na2SO4) and concentrated under reduced pressure. The product was isolated
in quantitative yield as an orange yellowish oil.
4.7.1. (R)-(−)-1-(Benzothiazol-2-ylsulfanyl)-2-acetoxyhexane
([α]D20=−39.7, c=1 in CHCl3, ee=99%); 1H NMR (CDCl3, δ): 7.87–7.72 (m, 2H, aromatic protons),
7.45–7.25 (m, 2H, aromatic protons), 5.26–5.14 (m, 1H, -CHOAc), 3.78 (dd, J=4.3 Hz and 13.8 Hz, 1H,
-CH2-S-), 3.42 (dd, J=6.9 Hz and 13.8 Hz, 1H, -CH2-S-), 2.00 (s, 3H, -OCOCH3), 1.89–1.62 (m, 2H,
CH-CH2-), 1.42–1.27 (m, 4H, -(CH2)2-), 0.95–0.85 (m, 3H, CH3); GC–MS (70 eV) m/z (rel. inten.) 309
(M+, 18), 249 (13), 216 (21), 193 (13), 192 (90), 181 (17), 180 (11), 169 (11), 168 (28), 167 (100), 166
(10), 148 (14), 136 (11), 108 (13), 55 (11), 43 (67), 41 (9). Anal. calcd for C15H19NO2S2: C, 58.25; H,
6.15; N, 4.53. Found: C, 58.30; H, 6.25; N, 4.23.
4.7.2. (R)-(−)-1-(Benzothiazol-2-ylsulfanyl)-2-acetoxyoctane
([α]D20=−11.2, c=1 in CHCl3, ee=91%); 1H NMR (CDCl3, δ): 7.86–7.70 (m, 2H, aromatic protons),
7.43–7.22 (m, 2H, aromatic protons), 5.28–5.13 (m, 1H, -CHOAc), 3.76 (dd, J=4.3 Hz, 13.8 Hz, 1H,
-CH2-S-), 3.42 (dd, J=6.9 Hz, 13.8 Hz, 1H, -CH2-S-), 2.00 (s, 3H, -OCOCH3), 1.83–1.63 (m, 2H,
CH-CH2-), 1.50–1.25 (m, 6H, -(CH2)3-), 1.00–0.85 (m, 3H, CH3); GC–MS (70 eV) m/z (rel. inten.) 337
(M+, 3), 192 (35), 168 (13), 167 (38), 69 (14), 55 (10), 43 (100), 41 (25). Anal. calcd for C17H23NO2S2:
C, 60.53; H, 6.82; N, 4.15. Found: C, 60.25; H, 6.55; N, 4.13.

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4.8. Synthesis of thiiranes: general procedure
The alcohol was dissolved in dry THF containing a stoichiometric amount of sodium hydride. The
suspension was stirred at room temperature for 5 h. After evaporation of the solvent, the residue was
washed with 5% aq. NaOH to remove 2-hydroxybenzothiazole, then with water and finally dried. The
solvent was evaporated and the thiirane was obtained in almost pure form.
4.8.1. (S)-(+)-2-Butylthiirane 2c
([α]D20=+17.8, c=13 in hexane, ee=99%) (lit.4,40,41 [α]D25=−4.51, c=13.3 in hexane, ee=25%, R-
1
configuration); IR (neat): 2998, 1445, 1372, 1264, 1105, 1030, 905, 715 cm−1; H NMR (CDCl3, δ):
2.95–2.80 (m, 1H, -CH-S-), 2.47 (d, J=6.0 Hz, 1H, -CH2-S-), 2.13 (d, J=6.0 Hz, 1H, -CH2-S-), 1.90–0.60
(m, 9H); GC–MS (70 eV) m/z (rel. inten.) 116 (M+, 70), 115 (18), 87 (26), 83 (35), 82 (17), 75 (22), 74
(76), 73 (18), 69 (18), 67 (54), 60 (26), 59 (24), 55 (53), 47 (20), 45 (49), 42 (17), 41 (100), 39 (43). IR
and 1H NMR data were consistent with the reported values.4
4.8.2. (S)-(+)-2-Hexylthiirane 2d
([α]D20=+14.9, c=13 in hexane, ee=91%) (lit.4,42 [α]D25=−3.45, c=13.3 in hexane, ee=21%, R-
1
configuration); IR (neat): 2995, 1445, 1370, 1265, 1107, 1030, 905, 715 cm−1; H NMR (CDCl3, δ):
2.70–3.16 (m, 1H, -CH-S-), 2.50 (d, J=6.0 Hz, 1H, -CH2-S-), 2.17 (d, J=6.0 Hz, 1H, -CH2-S-), 2.00–0.60
(m, 13H); GC–MS (70 eV) m/z (rel. inten.) 144 (M+, 20), 115 (18), 110 (12), 101 (10), 97 (10), 87 (26),
81 (35), 74 (64), 73 (14), 69 (55), 68 (20), 67 (30), 60 (19), 59 (16), 55 (75), 54 (22), 47 (18), 45 (35), 43
(29), 42 (17), 41 (100), 39 (40). IR and 1H NMR data were consistent with the reported values.4
4.9. Conversion of 1-(benzothiazol-2-ylsulfanyl)-2-acetoxyhexane and 1-(benzothiazol-2-ylsulfanyl)-2-
acetoxyoctane into the corresponding acetoxyalkanes by tri-n-butyltin hydride
Bu3SnH (378 mg, 1.3 mol) was added under a nitrogen atmosphere to a mixture containing 1-
(benzothiazole-2-ylsulfanyl)-2-acetoxyhexane (200 mg, 0.65 mol), 2,20-azobis(2-methylpropionitrile)
(1%) in 3 ml anhydrous toluene, using a nitrogen-flushed three necked flask equipped with a magnetic
stirrer, nitrogen inlet and reflux condenser. The reaction was kept at 110°C overnight, then the toluene
was distilled and the residue chromatographed on silica gel [eluent, petroleum ether:ethyl acetate (14:1)].
The product was obtained in 72% yield (67 mg).
(S)-(+)-2-Acetoxyhexane and (S)-(+)-2-acetoxyoctane were prepared by reacting the commercially
available 2-hexanol and 2-octanol, respectively, and acetic anhydride in pyridine for direct comparison
of the sign and specific rotation of the products isolated from the reaction of the 1-(benzothiazol-
2-ylsulfanyl)-2-acetoxyalkanes and Bu3SnH. In addition, (S)-(+)-2-acetoxyhexane and (S)-(+)-
2-acetoxyoctane from the reaction of (R)-(−)-1-(benzothiazol-2-ylsulfanyl)-2-acetoxyhexane and
(R)-(−)-1-(benzothiazol-2-ylsulfanyl)-2-acetoxyoctane were saponified to (S)-(+)-2-hexanol 4c and
(S)-(+)-2-octanol 4d by treatment with 1.2 M K2CO3/MeOH–H2O, room temperature 1 h, 80% and 85%
yields, respectively.
4.9.1. (S)-(+)-Acetoxyhexane
([α]D20=+4.8, c=1 in CHCl3, ee=99%); 1H NMR (CDCl3, δ): 4.90–4.80 (m, 1H, -CHOAc-), 1.99 (s,
3H, CH3CO-), 1.63–1.20 (m, 6H, -(CH2)3-), 1.16 (d, J=6.14 Hz, 3H, CH3-CH-), 0.95 (m, 3H, CH3-);
GC–MS (70 eV) m/z (rel. inten.) 129 (M+−15, 5), 113 (10), 112 (6), 87 (20), 70 (9), 57 (6), 56 (75), 55

L. Di Nunno et al. / Tetrahedron: Asymmetry 10 (1999) 1913–1926
1925
(12), 43 (100), 41 (22). All the analytical data were consistent with the values obtained on the sample
prepared from commercial (S)-(+)-2-hexanol.
4.9.2. (S)-(+)-2-Acetoxyoctane
([α]D20=+5.1, c=1 in CHCl3, ee=91%); 1H NMR (CDCl3, δ): 4.91–4.83 (m, 1H, -CHOAc-), 2.00 (s,
3H, CH3CO-), 1.61–1.23 (m, 10H, -(CH2)5-), 1.19 (d, J=6.32 Hz, 3H, CH3-CH-), 0.85 (m, 3H, CH3-);
GC–MS (70 eV) m/z (rel. inten.) 172 (M+, 0.2), 112 (17), 87 (37), 70 (16), 58 (12), 57 (8), 56 (11), 55
(14), 43 (100), 41 (12). All the analytical data were consistent with the values obtained on the sample
prepared from commercial (S)-(+)-2-octanol.
Acknowledgements
This work was carried out under the framework of the National Project ‘Stereoselezione in Sintesi
Organica. Metodologie ed Applicazioni’ supported by the Ministero dell’Università e della Ricerca
Scientifica e Tecnologica (MURST, Rome), and by the University of Bari and CNR (Rome). Thanks
are also due to Professor V. Calò, University of Bari, for helpful comments and discussions.
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