Formation of single diastereomers of β-hydroxy-sulfoxides by biotransformation of β-ketosulfides using Helminthosporium species NRRL 4671

Article abstract of DOI:10.1139/v02-091

Single biotransformations of 1-(phenylthio)-2-propanone and 1-(p-methoxyphenylthio)-2-propanone by the fungus Helminthosporium species NRRL 4671 resulted in both sulfur oxidation to the sulfoxide and carbonyl reduction to the alcohol. The corresponding (S_S,S_C)-1-sulfinyl-2-propanols were obtained as single diastereomers following simple crystallization.

Full text of DOI:10.1139/v02-091

640
Formation of single diastereomers of -hydroxy-
sulfoxides by biotransformation of -ketosulfides
using Helminthosporium species NRRL 4671
Herbert L. Holland, Nancy Ihasz, and Brendan J. Lounsbery
Abstract: Single biotransformations of 1-(phenylthio)-2-propanone and 1-(p-methoxyphenylthio)-2-propanone by the
fungus Helminthosporium species NRRL 4671 resulted in both sulfur oxidation to the sulfoxide and carbonyl reduction
to the alcohol. The corresponding (SS,SC)-1-sulfinyl-2-propanols were obtained as single diastereomers following simple
crystallization.
Key words: biocatalysis, biotransformation, carbonyl reduction, Helminthosporium sp. NRRL 4671, sulfoxidation.
Résumé : Des biotransformations uniques de la 1-(phénylthio)propan-2-one et de la 1-(4-méthoxyphénylthio)propan-2-
one sous l’influence de champignons de l’espèce Helminthosporium NRRL 4761 provoquent à la fois une oxydation du
soufre en sulfoxyde et une réduction du groupement carbonyle en alcool. Après une simple cristallisation, on a obtenu
les (SSSC)-1-sulfinylpropano-2-ols sous la forme d’un seul diastéréomère.
Mots clés : biocatalyse, biotransformation, réduction d’un groupe carbonyle, Helminthosporium NRRL 4671, sulfoxy-
dation.
[Traduit par la Rédaction] Holland et al. 642
Introduction
sulfoxides from aryl sulfides, products possessing three
chiral centres (two of which are alcohols) that are formed by
the activity of a single enzyme (7). The combined applica-
tion of two or more different enzymes to generate two dif-
ferent chiral centres from a non-chiral substrate is also
unusual, but has been reported in the whole-cell biocatalysis
of conjugated unsaturated carbonyl substrates to give satu-
rated alcohol products, which involves a combination of
enoate reductase and alcohol dehydrogenase activities (8).
The present communication presents a new combined bio-
catalysis reaction, involving both the oxidation of sulfides
and reduction of carbonyls in a single biotransformation pro-
cess, resulting in the formation of chiral sulfoxide alcohols
in high diastereomeric excess (de). Potential values of such
1,3-sulfoxide alcohols lie in their use as chiral synthons and
reagents, the latter in the presence of metal catalysts with
which they can execute hydrogen-bonding interactions.
One of the key features of biocatalytic reactions is their
ability to produce chiral products from non-chiral starting
materials. This is particularly common for carbonyl groups,
which can be reduced to secondary alcohols (1) or converted
to cyanohydrins (2), and the oxidation of sulfides to generate
sulfoxides (3). In contrast, however, the generation of two or
more independent chiral centres from a non-chiral starting
material in a single biotransformation is unusual. The forma-
tion of two chiral centres is primarily achieved by either the
reduction of diketones to chiral diols (4), the use of an aro-
matic dioxygenase enzyme to produce an arene dihydrodiol
(5), or the conversion of ketones into chiral diols by a com-
bination of carbonyl reduction and hydroxylation reactions
(6). The latter process, requiring the combined activity of
two different enzymes, is carried out only by whole-cell
biocatalysts.
Even more unusual is the formation of a product with two
different chiral centres from a single non-chiral substrate. It
has recently been reported that the dioxygenase activity of
Pseudomonas putida results in the formation of dihydrodiol
Results and discussion
Biotransformation of 1-(phenylthio)-2-propanone (1a) and
1-(p-methoxyphenylthio)-2-propanone (1b) by Helmintho-
sporium species NRRL 4671 resulted in the formation of the
corresponding sulfoxide alcohols 2a and 2b as illustrated in
Scheme 1 and summarized in Table 1. The configurations at
the carbon and sulfur of 2a and 2b were determined inde-
pendently by conversion to the sulfone alcohols (S)-3a and
(S)-3b and the sulfoxide ketones 4a and 4b as shown in
Scheme 2. Optical rotations of sulfones 3 were identical
with those reported for stereochemically pure versions pro-
duced by biotransformation of the corresponding sulfone
ketones (9). Enantiomeric purity was confirmed as ≥95% ee
Received 19 February 2002. Published on the NRC Research
Press Web site at http://canjchem.nrc.ca on 23 May 2002.
This communication is dedicated to Professor J. Bryan Jones
as both a pioneer and a current expert in fundamental areas
of biocatalysis.
H.L. Holland,1 N. Ihasz, and B.J. Lounsbery. Department
of Chemistry, Brock University, St. Catharines, ON L2S 3A1,
Canada.
1Corresponding author (e-mail: holland@chemiris.labs.brocku.ca).
Can. J. Chem. 80: 640–642 (2002)
DOI: 10.1139/V02-091
© 2002 NRC Canada

Holland et al.
641
Table 1. Biotransformations of 1-(phenylthio)-2-propanone (1a) and 1-(p-methoxyphenylthio)-2-propanone (1b) by Helminthosporium sp.
Yield
(%)
Original
de (%)a
Final
de (%)
Substrate
Product
Configuration
1a
1b
2a
2b
90
70
89
85
≥ 95
≥ 95
(SS,SC)
(SS,SC)
aDiastereomeric excess obtained directly from biotransformation and prior to crystallization.
Scheme 1. Biotransformations by Helminthosporium sp.
Scheme 2. Conversions to determine configurations at C and S.
1
by H NMR analysis using Eu(thfc)3 as a chiral-shift re-
agent.
Stereochemical analyses of sulfoxides (S)-4 were carried
1
out by H NMR analyses using the Kagan chiral-shift re-
agent (R)-(–)-N-(3,5-dinitrobenzoyl)-α-methylbenzylamine (10,
11), confirming that the materials were 85-89% ee, which
corresponds with the estimated original de values of prod-
1
ucts 2a and 2b that were determined by their H NMR anal-
yses (see Experimental). The (S)-configurations of 4 were
determined by their optical rotations (negative) (3, 12, 13)
and by the H NMR shifts in the presence of Kagan reagent
(SS,SC)-1-(Phenylsulfinyl)-2-propanol (2a)
mp 55–57oC. [α]D –260 (c 1.0, CHCl3). H NMR (CDCl3)
1
1
(10, 11).
δ: 1.32 (d, 3H), 2.74 and 3.0 (m of ABX, 2H), 3.63 (br s,
1H, OH), 4.45 (m, 1H), 7.52 (m, 3H), 7.70 (d, 2H). 13C
NMR (CDCl3) δ: 23.7, 64.1, 65.5, 124.2, 129.9, 131.9,
Crystallization of products 2a and 2b gave samples with
≥95% de; it is apparent from the stereochemical analysis
presented above that these arose from materials with a single
configuration (S) at the carbon and a mixed configuration
(ca. S:R = 93:7) at the sulfur. Both (S)-configurations are
consistent with those produced by biotransformations of ke-
tones (12) and sulfides (3) by Helminthosporium.
1
144.0. The (RS,SC) isomer produced two different sets of H
NMR peaks, located at δ 1.25 (d) (cf. 1.32 (d)) and 4.30 (m)
(cf. 4.45 (m)), integration of which peaks together with the
major ones at δ 1.32 and 4.45 was used to determine the ini-
tial de of 89%.
The biotransformation of β-ketosulfides to produce chiral
β-hydroxysulfoxides represents a new version of single
biocatalysis for the formation of molecules with two differ-
ent chiral centres from non-chiral starting materials. This
process is now under investigation using a variety of such
substrates for microbial biocatalysts known for their ability
to carry out both sulfide oxidation and carbonyl reduction
reactions when applied to different independent substrates.
(SS,SC)-1-(p-Methoxyphenylsulfinyl)-2-propanol (2b)
1
mp 84–86oC. [α]D –267 (c 1.0, CHCl3). H NMR (CDCl3)
δ: 1.32 (d, 3H), 2.73 and 3.0 (m of ABX, 2H), 3.73 (br s,
1H, OH), 3.82 (s, 3H), 4.45 (m, 1H), 7.02 and 7.58 (q of
AB, 4H). 13C NMR (CDCl3) δ: 23.7, 56.0, 64.1, 65.4, 115.4,
126.5, 134.8, 162.7. The (RS,SC) isomer produced two differ-
1
ent sets of H NMR peaks located at δ 1.25 (d) (cf. 1.32 (d))
and 4.30 (m) (cf. 4.45 (m)), integration of which peaks to-
gether with the major ones at δ 1.32 and 4.45 was used to
determine the initial de of 85%.
Experimental
Maintenance, growth, and biotransformations using
Helminthosporium species NRRL 4671 were carried out as
previously described (13). Isolated yields of products from
1 g of substrate were obtained as presented in Table 1. Prep-
arations of 3a and 3b in yields of 85 and 97%, respectively,
were performed by oxidations of 2a and 2b by the standard
procedure using 1.5 equivalents of m-chlorobenzoic acid in
CH2Cl2 at room temperature for 48 h. Preparations of 4a and
4b were performed by standard Jones oxidations at 0oC of
2a and 2b in yields of 71 and 60%, respectively.
(S)-1-(Phenylsulfonyl)-2-propanol (3a)
Oil. [α]D +19.8 (c 1.0, CHCl3) (Lit. (9) [α]D + 15.7 (c 1.0,
CHCl3, 95% ee) ≥95% ee. 1H NMR (CDCl3) δ: 1.19 (d, 3H),
3.14 and 3.24 (m ABX, 2H), 3.87 (br s, 1H, OH), 4.27 (m,
1H), 7.5–7.9 (m, 5H). 13C NMR (CDCl3) δ: 23.1, 62.8, 63.7,
128.3, 129.8, 134.1, 139.6.
(S)-1-(p-Methoxyphenylsulfonyl)-2-propanol (3b)
mp 53–55oC. [α]D +14.8 (c 1.0, CHCl3) (Lit. (9) [α]D + 15.7
1
Analytical data for biotransformation products 2 and their
derivatives 3 and 4 are listed below.
(c 1.0, CHCl3, 95% ee), ≥95% ee. H NMR (CDCl3) δ: 1.21
(d, 3H), 3.10 and 3.19 (m of ABX, 2H), 3.87 (s, 3H), 4.27
© 2002 NRC Canada

642
Can. J. Chem. Vol. 80, 2002
(m, 1H), 7.02 and 7.83 (q of AB, 4H). 13C NMR (CDCl3) δ:
22.9, 56.2, 62.8, 64.0, 115.1, 130.6, 130.9, 164.4.
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(CDCl3) δ: 2.20 (s, 3H), 3.7 and 3.9 (q of AB, 2H), 7.5–7.63
(5H, m). 13C NMR (CDCl3) δ: 32.4, 69.0, 124.4, 129.9,
132.1, 143.2, 199.8.
(S)-1-(p-Methoxyphenylsulfinyl)-2-propanone (4b)
mp 58–60oC. [α]D –169 (c 1.0, CHCl3), 85% ee. H NMR
1
(CDCl3) δ: 2.21 (s, 3H), 3.80 (m, 5H), 7.02 and 7.58 (q of
AB, 4H). 13C NMR (CDCl3) δ: 32.5, 56.0, 69.1, 115.4,
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Acknowledgments
This work was funded by the Natural Sciences and Engi-
neering Research Council of Canada (NSERC). We are
grateful to Mr. T. Jones of Brock University for help with
the acquisition of spectral data.
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© 2002 NRC Canada