Stereoselective chemo-enzymatic approaches to the synthesis of C 2 1,3-dithiane-1,3-dioxide

Article abstract of DOI:10.1080/10426500902856446

Two enzyme-mediated methods are presented for the preparation of enantiomerically enriched C² 1,3-dithiane-1,3-dioxide. The first takes advantage of a trans stereoselective oxidation by NaIO4 of enantiomerically pure (R) 1,3-dithiane-1-oxide ob

Full text of DOI:10.1080/10426500902856446

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Phosphorus, Sulfur, and Silicon
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Stereoselective Chemo-
Enzymatic Approaches to
the Synthesis of C 2 1,3-
Dithiane-1,3-dioxide
N. Gaggero a , S. Colonna a , D. Albanese b , G.
Ottolina c & F. Del Monte a
a Istituto di Chimica Organica “A. Marchesini” ,
Milano, Italy
b Dipartimento di Chimica Organica e Industriale ,
Milano, Italy
c Istituto di Chimica del Riconoscimento
Molecolare–CNR , Milano, Italy
Published online: 28 Apr 2009.
To cite this article: N. Gaggero , S. Colonna , D. Albanese , G. Ottolina & F. Del Monte
(2009) Stereoselective Chemo-Enzymatic Approaches to the Synthesis of C 2 1,3-
Dithiane-1,3-dioxide, Phosphorus, Sulfur, and Silicon and the Related Elements, 184:5,
1332-1339, DOI: 10.1080/10426500902856446
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Phosphorus, Sulfur, and Silicon, 184:1332–1339, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500902856446
Stereoselective Chemo-Enzymatic Approaches to the
Synthesis of C2 1,3-Dithiane-1,3-dioxide
N. Gaggero,1 S. Colonna,1 D. Albanese,2 G. Ottolina,3
and F. Del Monte1
1Istituto di Chimica Organica “A. Marchesini,” Milano, Italy
2Dipartimento di Chimica Organica e Industriale, Milano, Italy
3Istituto di Chimica del Riconoscimento Molecolare–CNR, Milano, Italy
Two enzyme-mediated methods are presented for the preparation of enantiomeri-
cally enriched C2 1,3-dithiane-1,3-dioxide. The first takes advantage of a trans stere-
oselective oxidation by NaIO4 of enantiomerically pure (R) 1,3-dithiane-1-oxide
obtained by cyclohexanone monooxygenase. In the second method, a kinetic resolu-
tion consisting of a domino hydrolysis-decarboxylation process of ( ) 2-carbethoxy-
1,3-dithiane-trans-1,3-dioxide is described. The target molecule is obtained with
enantiomeric excesses up to 90%.
Keywords C2-symmetric bis(sulfoxides); cyclohexanone monooxygenase; 1,3-dithiane-
trans-1,3-dioxide; kinetic resolution; pig liver esterase; subtilisin Carlsberg
INTRODUCTION
C2-Symmetric bis(sulfoxides) have attracted great interest in the last
ten years for their intrinsic advantages in asymmetric synthesis. In
particular, enantiopure 1,3-dithiane-trans-1,3-dioxide (3) is easily met-
allated at the C-2 carbon atom giving rise to a chiral carbonyl an-
ion, which shows a high level of stereocontrol in addition reactions
with aromatic aldehydes.1–3 The resulting alcohol intermediate can
be transformed into a series of α-hydroxycarbonyl derivatives, such as
esters, amides, ketones, and aldehydes.4,5 Moreover, 2-methylene 1,3-
dithiane-trans-1,3-dioxide is synthetically equivalent to chiral ketenes
in cycloadditions such as Diels–Alder reactions.6
The direct stereoselective titanium-catalyzed oxidation of the parent
1,3-dithioacetal (1) appears as the most appealing method to achieve
Received 31 January 2008; accepted 14 February 2008.
Dedicated to Professor Marian Mikołajczyk, CBMiM PAN in Ło´dz´, Poland, on the
occasion of his 70th birthday.
Address correspondence to N. Gaggero, Istituto di Chimica Organica “A. Marchesini,”
Via Venezian 21, 20133 Milano, Italy. E-mail: nicoletta.gaggero@unimi.it
1332

1,3-Dithiane-1,3-dioxide
1333
1,3-dithiane-trans-1,3-dioxide (3), but unfortunately it leads to an al-
most racemic product. In order to obtain a high enantiomeric excess,
Aggarwal et al. used a two-step procedure involving the Modena-
modified oxidation of 2-carbethoxy-1,3-dithiane, followed by hydrolysis
and decarboxylation.7 Moreover, in spite of good enantioselectivity, this
method is time-consuming and suffers from modest overall chemical
yield.
It is universally recognized that remarkable features of enzymatic
methods are mild reaction conditions, high chemo-, regio- and stereo-
selectivity. They often lead to enantiomerically pure products; and be-
ing devoided of salts and metal waste, and at the same time realiz-
ing energy savings. In this article, we describe our studies to prepare
enantiomerically enriched 1,3-dithiane-trans-1,3-dioxide (3) by chemo-
enzymatic methods.
RESULTS AND DISCUSSION
To the best of our knowledge, no useful biocatalytic direct bis-oxidation
of 1,3-dithioacetals to the corresponding bis(sulfoxides) is reported in
the literature.
Cyclohexanone monooxygenase (CHMO) (EC 1.14.13.22) from Acine-
tobacter calcoaceticus NCIB 9871 is a NADPH-dependent flavo enzyme
that is able to oxidize a wide range of alkyl aryl sulfides8 and dialkyl
sulfides9 to the corresponding sulfoxides.
We have already shown that the monooxidation of 1,3-dithiane (1) to
the (R)-monosulfoxide (2) with CHMO occurs with almost total enan-
tioselectivity in high chemical yield.10 The oxidation of 1 was performed
in Tris-HCl buffer pH 8.6, containing CHMO, NADPH, and the system
glucose-6-phosphate/glucose-6-phosphate dehydrogenase to regenerate
the cofactor,8 for 16 h.
Unfortunately, the use of this NADPH-dependent enzyme was lim-
ited by the necessity of recycling the expensive cofactor, which pre-
vented its application to a multigram scale even with a membrane
reactor type system. This has been overcome by some of us by using
a whole-cell approach that led to the 1,3-dithiane monosulfoxide (2) in
one gram scale.11
We have now envisaged a chemo-enzymatic route to enantiomerically
enriched 1,3-dithiane-trans-1,3-dioxide (3).
Indeed, the straightforward addition of sodium metaperiodate to
a methanol/water mixture containing the crude monosulfoxide (R)-
2, obtained via enzymatic oxidation, gave C2 (R, R)-bis(sulfoxide) 3
in 90% yield and 90% enantiomeric excess (Scheme 1). The absolute

1334
N. Gaggero et al.
SCHEME 1
configuration of 3 was determined by chiral HPLC comparison with a
sample prepared according to the method of Aggarwal et al.7
Our second approach was a kinetic resolution of the starting racemic
2-carbethoxy-1,3-dithiane-trans-1,3-dioxide (4) to the corresponding
acid (5), catalyzed by serine-hydrolases, followed by a chemical de-
carboxylation step via the typical domino reaction pathway (Scheme 2).
Several enzyme-mediated kinetic resolutions of a variety of sulfinylcar-
boxylates have already been achieved by using commercially available
hydrolytic enzymes.12
SCHEME 2
The serine hydrolases used in this work were commercially avail-
able subtilisin Carlsberg (EC 3.4.21.14) and a crude preparation of pig
liver esterase (PLE) (EC 3.1.1.1). Racemic 2-carbethoxy-1,3-dithiane-
trans-1,3-dioxide (4) was obtained by oxidation of the commercial 2-
carbethoxy-1,3-dithiane with meta-chloroperbenzoic acid, as described
in the literature.7 The enzymatic hydrolysis and decarboxylation of
4 were performed at room temperature, in sodium borate buffer pH
8, with an enzyme:substrate weight ratio of 1:1, for variable reaction
times (Table I).

1,3-Dithiane-1,3-dioxide
1335
TABLE I Resolution of 4 Catalyzed by Serine
Hydrolases
Enzyme
Time (h)
Conva (%)
ee (3)b (%)
Subtilisin Carlsberg
PLEc
72
2
20
50
20 (S, S)
25 (S, S)
aDetermined by 1H NMR spectroscopy.
bDetermined by HPLC.
cPig liver esterase.
It is worth noting that the starting ester 4 remained unreacted in
the absence of the enzyme.
Subtilisin Carlsberg gave (S,S)-3 with an enantiomeric excess of 20%
at the conversion of 20% (Table I). Therefore this enzyme afforded the
opposite enantiomer to that obtained by CHMO-NaIO4 oxidation.
Variations of the solvent system by the addition of organic cosol-
vents are quite frequently used methods to improve the selectivity of
hydrolytic enzymes.13 We have screened different organic solvents14 in
the resolutions of 2-carbethoxy-1,3-dithiane-trans-1,3-dioxide (4) cat-
alyzed by subtilisin Carlsberg. However, we could not observe any im-
provement in the enantioselectivity of the reaction.
The influence of the substrate structure was also investi-
gated. Racemic phenyl 2-carboxylate-1,3-dithiane-trans-1,3-dioxide
(6), 2-carboxamide-1,3-dithiane-trans-1,3-dioxide (7), and 2-(N-iso-
propyl)carboxamide-1,3-dithiane-trans-1,3-dioxide (8) were prepared.
Unfortunately, none of these compounds was suitable for the protease,
and only the starting material was recovered after long reaction time.
When the enzymatic hydrolysis of 4 was carried out in the presence
of pig liver esterase (PLE), a fast reaction was observed, although with
25% ee (Table I).
In analogy to our results, the study of the kinetic resolution of a
series of trans 2-alkoxycarbonyl-3,6-dihydro-2H-thiopyran S-oxides to
the corresponding acids by PLE has shown that the presence of an
electron-withdrawing substituent in the α position to the carboxylic
functionality produced the spontaneous decarboxylation of the acid un-
der the reaction conditions used,12 the enantiomeric excesses not being
determined.
In conclusion, resolution of ( )-2-carbethoxy-1,3-dithiane-trans-1,3-
dioxide expands the synthetic application of hydrolytic enzymes in the
field of organo sulfur compounds and opens a new route for the prepa-
ration of 3, in spite of the modest enantiomeric excesses obtained in
this work.

1336
N. Gaggero et al.
The CHMO-NaIO4 oxidation of 1,3-dithiane (1) represents an easy
access to the enantiomerically pure target bis(sulfoxide) 3 and competes
favorably with titanium-mediated oxidation in terms of chemical yield,
and mild and environmentally acceptable conditions.
EXPERIMENTAL
¨
Melting points were determined on a BUCHI 535 and are corrected.
NMR spectra were recorded with a Bruker AC 300 or AC 200 spec-
trometer, operating at 300.13 or 200.13 MHz for 1H and 75.3 or 50
MHz for 13C. Coupling constants J are given in Hz. Chemical shifts are
reported using CHCl3 as external standard (7.24 ppm for 1H NMR and
77.0 for 13C NMR).
Chiral HPLC separations were performed on an Agilent HP 1100
apparatus, equipped with a diode array detector, and the volume of
injection was 20 µL.
2-Carbethoxy-1,3-dithiane was purchased from Aldrich and used
without purification. Crude lyophylized pig liver esterase (PLE) and
subtilisin Carlsberg were purchased from Sigma.
Preparation of (R)-1,3-Dithiane-1-oxide (2) by Oxidation of
1,3-Dithiane (1) with CHMO
The dithioacetal (1) (0.04 mmol, 5 mg) was reacted at 25◦C under mag-
netic stirring in 2.5 mL of 0,05 M Tris-HCl buffer, containing NADP
–3
(3.5 × 10 mmol, 2.7 mg), glucose-6-phosphate (0.2 mmol, 67.8 mg),
3.36 units of partially purified from E. Coli TOP10 strain CHMO, and
10 units of glucose-6-phosphate dehydrogenase. After 20 h, the reaction
mixture was extracted with CH2Cl2 (4 × 5 mL). The combined organic
extracts were dried over sodium sulfate. Removal of solvent under re-
duced pressure gave 4.5 mg of the title compound, yield 79%. 1H NMR
(CDCl3): δ = 2.17–2.27 (m, 1H), 2.50–2.71 (m, 4H), 3.32 (m, 1H), 3.64
(d, J = 12.8 Hz, 1H), 4.01 (d, J = 12.8 Hz, 1H). 13C NMR (CDCl3): δ =
27.2 (CH2), 28.2 (CH2), 50.4 (CH2), 52.8 (CH2). HPLC (Chiralcel OJ-H,
iPrOH-hexane 30–70, 0.6 mL/min, λ 220 nm), tR (S, S) 12.7 min, tR (R, R)
15.1 min, ee 90%. Anal. Calcd. for C4H8OS2: C, 35.26; H, 5.92; S, 47.07.
Found: C, 35.19; H, 5.91; S, 47.02%.
Preparation of (R,R)-1,3-Dithiane-1,3-dioxide (3) by Oxidation
of (R)-1,3-Dithiane-1-oxide (2) with NaIO4
(R)-1,3-dithiane-1-oxide (2) (4.5 mg) was dissolved in 2 mL of a 1:4
MeOH:H2O solvent mixture. Solid NaIO4 (0.05 mmol, 11 mg) was added

1,3-Dithiane-1,3-dioxide
1337
to the reaction mixture. After 24 h of stirring at room temperature, the
mixture was extracted with dichloromethane (4 × 10 mL), and the com-
bined organic extracts were dried over sodium sulfate. Removal of the
solvent under reduced pressure gave 4.5 mg of the title compound, yield
1
90%. H NMR (CDCl3): δ = 2.70 (m, 2H), 3.05 (m, 2H), 3.18 (m, 2H),
4.05 (s, 2H). HPLC (Chiralcel OJ-H, EtOH:hexane 40:60, 0.6 mL/min,
λ 220 nm) tR (R, R) 15.9 min, tR (S, S) 19.5 min, ee 90%. Anal. Calcd.
for C4H8O2S2: C, 31.56; H, 5.30; S, 42.13. Found: C, 31.46; H, 5.29; S,
42.05%.
Preparation of (S,S)-1,3-Dithiane-trans-1,3-dioxide (3) by
Resolution of Racemic 2-Carbethoxy-1,3-dithiane-
trans-1,3-dioxide (4)
Racemic 2-carbethoxy-1,3-dithiane-trans-1,3-dioxide (4) (2 mg)7 was re-
acted at 25◦C under stirring in 5 mL of borate buffer pH 8 in the pres-
ence of 2 mg of PLE or subtilisin Carlsberg. The reaction course was
followed by TLC using AcOEt:EtOH 7:3 as eluent. When the desired
degree of conversion was reached, the reaction was quenched by adding
3 mL of ethanol, and the solvent was evaporated at reduced pressure
and at room temperature to avoid the spontaneous decarboxylation
of the unreacted starting material. The crude reaction mixture was
used without purification for 1H NMR and HPLC analysis. The conver-
sion has been determined by 1H NMR spectroscopy by the ratio of two
different singlets for C-2 protons of 4 and 3. HPLC (Chiralcel OJ-H,
EtOH-hexane 40–60, 0.6 mL/min, λ 220 nm) tR (R, R) 15.9 min, tR (S, S)
19.5 min, ee 25%. Anal. Calcd. for C4H8O2S2: C, 31.56; H, 5.30; S, 42.13.
Found: C, 31.51; H, 5.30; S, 42.09%.
Preparation of 2-Carboxamide-1,3-dithiane
To a stirred solution of dithiane carboxylic acid15 (1 g, 6 mmol) in
anhydrous dichloromethane (50 mL) under a dry nitrogen atmosphere,
one drop of dimethylformamide and dropwise thionyl chloride (0.798
g, 6.7 mmol) was added. The solution was stirred for 15 min at room
temperature, and then the solvent was evaporated, affording the crude
acyl chloride as a red-orange solid. This was dissolved in anhydrous
dichloromethane (50 mL), and NH3 was bubbled in for 10 min. The
solution became muddy, and after chilling to 0◦C, a precipitate formed.
The solid material was recovered and purified by crystallization (EtOH)
to give 0.82 g (yield 82%) of the title compound, mp 170–172◦C.16 1
NMR (CDCl3): δ = 2.01–2.19 (m, 2H), 2.69–2.81 (m, 2H), 3.05–3.19
H

1338
N. Gaggero et al.
(m, 2H), 4.41 (s, 1H), 5.71 (bs, 1H), 6.43 (bs, 1H). Anal. Calcd. for
C5H9NOS2: C, 36.78; H, 5.56; N, 8.58; S, 39.28. Found: C, 36.81; H,
5.54; N, 8.60; S, 39.31%.
Preparation of 2-(N-iso-Propyl)carboxamide-1,3-dithiane
The crude acyl chloride (6 mmol), obtained as described above, was dis-
solved in anhydrous dichloromethane (50 mL), and N-iso-propylamine
(1 mL, 12 mmol) was added at 10◦C. The mixture was stirred for 30 min
at 10◦C and then washed with 10 mL of saturated aqueous NaCl. The
organic phase was dried and evaporated at reduced pressure to give a
yellowish solid that was purified by silica gel flash chromatography us-
ing CH2Cl2:CH3OH 85:15 as eluent. 1H NMR (CDCl3): δ = 1.13 (d, J =
6.8 Hz, 6H), 2.05–2.15 (m, 2H), 2.70–2.75 (m, 2H), 3.10–3.17 (m, 2H),
4.01 (m, 1H), 4.34 (s, 1H), 6.20 (bs, 1H). Anal. Calcd. for C5H9NOS2: C,
36.78; H, 5.56; N, 8.58; S, 39.28. Found: C, 36.79; H, 5.57; N, 8.61; S,
39.28%.
Preparation of 2-Substituted-1,3-dithiane-trans-1,3-dioxides
6–8: General Procedure
To a stirred solution of 2-substituted-1,3-dithiane (2.5 mmol) in 7 mL
of diethyl ether at 0◦C, 70% m−CPBA (1.23 g, 5 mmol) dissolved in
12 mL of diethyl ether was added. After 1–3 h of stirring at the same
temperature, the reaction was deemed complete by TLC, and the mix-
ture was filtered through a sintered-glass funnel. The solid residue
was washed with several aliquots of cold ether. The solvent was evapo-
rated at reduced pressure, and the resulting crude was purified by flash
chromatography.
Phenyl 2-Carboxylate-1,3-dithiane-trans-1,3-dioxide (6)
1
41%, 279 mg. AcOEt:acetone 95 :5, mp 194–195◦C. H NMR (300
MHz, CDCl3): δ = 2.41–2.80 (m, 2H), 3.30 (m, 1H), 3.37 (m, 1H),
3.690–3.84 (m, 2H), 5.31 (s, 1H), 7.16–7.48 (m, 5H). Anal. Calcd. for
C11H12O4S2: C, 48.51; H, 4.44; S, 23.55. Found: C, 48.49; H, 4.43; S,
23.56%.
2-Carboxamide-1,3-dithiane-trans-1,3-dioxide (7)
The reaction has been carried out in MeOH. 34%, 166 mg. CH2Cl2/
MeOH 92:8 to 80:20, mp 175◦C. 1H NMR (DMSO-d6): δ = 1.88–1.97 (m,
2H), 2.68–2.76 (m, 2H), 3.16–3.30 (m, 2H), 4.49 (s, 1H), 7.09 (bs, 1H),
7.38 (bs, 1H). 13C NMR (DMSO-d6): δ = 25.1 (CH2), 27.1 (CH2), 43.9

1,3-Dithiane-1,3-dioxide
1339
(CH), 170.4 (C). Anal. Calcd. for C5H9NO3S2: C, 30.76; H, 4.65; N, 7.17;
S, 32.84. Found: C, 30.75; H, 4.65; N, 7.19; S, 32.85%.
2-(N-iso-Propyl)carboxamide-1,3-dithiane-trans-1,3-dioxide (8)
1
36%, 213 mg. CH2Cl2:MeOH 9:1. H NMR (300 MHz, CDCl3): δ =
1.11 (d, J = 6.7 Hz, 6H), 2.37–2.45 (m, 2H), 3.04–3.10 (m, 2H), 3.21–
3.28 (m, 1H), 3.51 (ddd, J = 2.9, 7.5, 12.8 Hz, 1H), 3.92 (m, 1H), 4.84
(s, 1H), 8.17 (d, J = 7.3 Hz).13C NMR (DMSO-d6): δ = 14.9 (CH2), 22.0
(CH3), 22.2 (CH3), 41.4 (CH), 45.9 (CH2), 48.4 (CH2), 74.3 (CH), 160.9
(C). Anal. Calcd. for C8H15NO3S2: C, 40,48; H, 6.37; N, 5.90; S, 27.02.
Found: C, 40.44; H, 6.36; N, 5.91; S, 27.04%.
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