Selective lipase-catalyzed acylation of epimeric α-sulfinyl alcohols: An efficient method of separation

Article abstract of DOI:10.1016/S0957-4166(99)00026-9

A facile and efficient separation of mixtures of epimeric α-sulfinyl alcohols 2:3 can be accomplished by selective lipase-catalyzed acylation with neat vinyl acetate. Pseudomonas cepacia and Candida rugosa lipase showed opposite epimer differentiation in

Full text of DOI:10.1016/S0957-4166(99)00026-9

Pergamon
Tetrahedron: Asymmetry 10 (1999) 561–566
Selective lipase-catalyzed acylation of epimeric α-sulfinyl
alcohols: an efficient method of separation
Mercedes Medio-Simón,∗ Jesús Gil, Pedro Aleman, Teresa Varea and Gregorio Asensio
Departamento de Quimica Organica, Campus de Burjassot, Avda. V. Andres Estelles s/n, 46100 Burjassot, Spain
Received 23 December 1998; accepted 19 January 1999
Abstract
A facile and efficient separation of mixtures of epimeric α-sulfinyl alcohols 2:3 can be accomplished by selective
lipase-catalyzed acylation with neat vinyl acetate. Pseudomonas cepacia and Candida rugosa lipase showed
opposite epimer differentiation in the esterification. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
Enantiomerically pure sulfoxides are now widely used to bring about numerous asymmetric
transformations.1,2 In particular, the diastereocontrolled reduction of α-sulfinyl ketones, which leads
to enantiomerically pure alcohols after elimination of the sulfinyl group, has been frequently reported.
By applying this strategy, Solladié was able to synthesize several natural compounds.1 In addition
to their application as building blocks, α-sulfinyl alcohols are also effective chiral proton sources
for the enantioselective protonation of prochiral enolates.3,4 The most suitable method for preparing
enantiopure α-sulfinyl alcohols is the stereoselective reduction of α-sulfinyl ketones 1 with DIBALH or
DIBALH/ZnCl25 to yield the diastereomers 2 or 3, respectively (Scheme 1).
Scheme 1. Preparation of α-sulfinyl alcohols.
The utility of this method depends on a highly diastereoselective reduction (d.e. >95%), since mixtures
of α-sulfinyl alcohols 2 and 3 are very difficult to separate. The degree of diastereoselection achieved in
∗
Corresponding author. Fax: 34-963864939; e-mail: mercedes.medio@uv.es
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00026-9

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the reduction with DIBALH is highly dependent on the nature of the R group bonded to the carbonyl
carbon. When R is a non-branched or a small group, reduction with DIBALH gives d.e. values of
about 80%, whereas with DIBALH/ZnCl2, diastereoselection fails with α-sulfinyl ketones bearing co-
ordinating groups.6 Consequently, this methodology could be greatly improved if a straightforward and
efficient procedure for separating the sulfinyl alcohol diastereoisomers 2 and 3 was found.
The lipase-catalyzed transesterification of hydroxylated substrates in organic solvents is now a well-
established method that has been extensively used to prepare enantiomerically pure chiral compounds.7
This prompted us to apply this enzyme method to obtain enantiopure α-sulfinyl alcohols by kinetic
separation of the mixture of diastereoisomers obtained in the reduction of α-sulfinyl ketones.
2. Results and discussion
In the course of our studies on the enantioselective protonation reaction of enolates with α-sulfinyl
alcohols, we needed to prepare α-sulfinyl alcohols 2a–d.3 Reduction of the corresponding α-sulfinyl
ketones 1a–d with DIBALH was performed according to previous literature,8,9 with only partial stereo-
selection, leading to the major diastereomer 2 along with the inseparable minor epimer 3. Attempts to
purify alcohols 2a–d by crystallization gave unsatisfactory yields (∼60%), and preparation of the cor-
responding acetates did not allow chromatographic purification. On the other hand, we achieved efficient
epimer separation by using lipase-catalyzed acylation reactions that enabled the selective conversion
of 2 and 3 to their corresponding acetates 4 and 5 (Scheme 2). Acetylation was assayed with three
commercially available lipases: porcine pancreatic lipase (PPL), Pseudomonas cepacia lipase (PCL) and
Candida rugosa lipase (CRL).
Scheme 2. Selective enzyme mediated acylation of α-sulfinyl alcohols
The preparation of α-sulfinyl alcohol (S,Rs)-2a in a enantiomerically pure form has been reported
previously, and involves the diastereoselective oxidation of the corresponding chiral p-tolylthio alcohol to
give a (2:1) diastereomeric mixture of (S,Rs)-2a:(S,Ss)-3a.10 Using a complex protocol of crystallization,
the isolation of (S,Rs)-2a from this mixture in 51% yield has been described. By contrast, our procedure,
which is based on enzyme-catalyzed acylation using lipases and vinyl acetate (VA) allows us to obtain
readily (S,Rs)-2a with a better yield and also a high enantiomeric excess. α-Sulfinyl ketone 1a was
reduced with DIBALH to give a 90:10 mixture of 2a:3a. This mixture was allowed to react with neat
VA in the presence of PPL (2 mg/mg of alcohol) at room temperature for 3 days, and the lipase was
renewed every 24 h (entry 1). Under these conditions, complete conversion of (R,Rs)-3a into the acetate
derivative (R,Rs)-5a took place with high selectivity, while nearly optically pure (S,Rs)-2a was recovered
in 93% yield (72% yield from α-sulfinyl ketone). The reaction time could be shortened by increasing the
temperature to 40°C without any loss of selectivity (entry 2). A faster and also highly selective conversion
of (R,Rs)-3a to (R,Rs)-5a was achieved by using VA and PCL (1 mg/mg of alcohol) instead of PPL
(entry 3). When acylation was catalyzed by CRL (2 mg/mg alcohol), (S,Rs)-2a reacted rapidly, and the
corresponding derivative (S,Rs)-4a was obtained in 70% yield and >90% d.e. (entry 4). No improvement
in the yield of (S,Rs)-4a was achieved with longer reaction times (entry 5). The reverse selectivity showed
by CRL and PCL towards 2a and 3a, respectively, reflected the general trend followed by all the α-
sulfinyl alcohols in the series; CRL preferentially acylated alcohol 2 while PCL preferably acylated its

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563
epimer 3. This result is opposite many examples found in the literature, where these lipases are reported
to show the same selectivity.11
The enzymatic acylation reaction was also applied to the mixture of α-sulfinyl alcohols epimers 2b:3b.
When PPL was used, longer reaction times were required (five days) than in the separation of the mixture
2a:3a. On the other hand, the acylation reaction was even more selective, since no formation of the (S,Rs)-
4b derivative could be detected (entries 6 and 7). The results in the acylation of the mixture 2b:3b with
PCL and CRL were comparable to those obtained in the separation of the mixture 2a:3a (entries 8 and
9).
PPL was not effective for promoting the acylation of alcohol (R,Rs)-3c, probably because of the greater
size of the R group, and the mixture 2c:3c was recovered unchanged after prolonged heating at 40°C
(entries 10 and 11). However, when the mixture 2c:3c was treated with VA and PCL (1 mg/mg alcohol)
for 64 h, (R,Rs)-3c could be converted into the acetate (R,Rs)-5c with high yield and d.e., while the
alcohol (S,Rs)-2c was recovered unchanged (entry 12). No appreciable reduction in the reaction time (24
h) was observed by using 2 mg of lipase/mg alcohol (entry 13). On the other hand, CRL promoted the
acylation of (S,Rs)-2c with VA to give (S,Rs)-4c with high diastereoselectivity (entry 14).
Lipase-catalyzed acylation was also successfully applied to the mixture of α-sulfinyl alcohols 2d:3d,
which are precursors of allylic alcohols. When VA/PPL or PCL were used, acylation of alcohol (R,Rs)-
3d took place, but the reaction proceeded very slowly (entries 15–17). CRL required long reaction times
also to transform the alcohol (S,Rs)-2d into the ester (S,Rs)-4d. Despite the relatively long reaction time
required, purification of this mixture by diastereoselective acetylation appears to be the procedure of
choice for these alcohols due to the difficulty of obtaining optically pure crystalline products by fractional
crystallization.
3. Conclusions
Since α-sulfinyl ketones are readily obtained by reacting α-sulfinyl carbanions with esters, the
diastereoselective reduction of α-sulfinyl ketones with DIBALH is a suitable method for obtaining α-
sulfinyl alcohols 2. However, in some instances where the diastereoselectivity of the reduction is only
moderate, the simultaneous formation of the diastereomer 3 limits the scope of this method. The lipase-
catalyzed acylation of the mixture of alcohols 2 and 3 allows us to overcome this drawback. In addition,
provided that PCL and CRL show the opposite selectivity for each diastereomer, this method can be
applied in all cases in which the diastereoselectivity in the reduction of the corresponding ketone is not
complete, and allows us to obtain alcohols 2 or 3 of high optical purity as desired. This method has
considerable advantages regarding yields and optical purity and allows us to isolate the products while
avoiding cumbersome time-consuming derivatization or crystallization procedures.
4. Experimental
1H NMR and 13C NMR spectra were recorded on a Bruker AC-250 with tetramethylsilane as an
internal reference and CDCl3 as a solvent. Melting points were determined with a Cambridge Instruments
apparatus and are uncorrected. Optical rotation measurements were determined on a Perkin–Elmer 241
polarimeter at room temperature. High resolution mass spectra (HRMS) were recorded on a Fisons VG
Autospec instrument. Lipases were purchased from Sigma (PPL and CRL) and Amano (PCL). Ketones
1a–d were prepared as described in previous literature.8,9,12

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Table 1
Enzymatic selective acylation of α-sulfinyl alcohols with VA
4.1. General procedure for the lipase-catalyzed acylation of alcohols 2:3
To a solution of alcohols 2:3 in neat VA was added the appropriate lipase (1 or 2 mg/mg alcohol). The
reaction mixture was vigorously stirred for the time and temperature shown in Table 1. The reaction was
stopped by enzyme filtration and purified by column chromatography.
4.2. (S,Rs)-(+)-1-(4-Methylphenylsulfinyl)-2-propanol 2a
1
Yield 93%; m.p. 130–131°C (lit.10 128°C); [α]D=+258.0 (c=1, ethanol) (lit.10 +314.5); H NMR, δ
1.24 (d, 3H, J=7.5 Hz), 2.43 (s, 3H), 2.62 (dd, 1H, J=12.5 and 1.8 Hz), 3.08 (dd, 1H, J=12.5 and 10 Hz),
4.07 (bb, 1H), 4.35–4.45 (m, 1H), 7.36 (d, 2H, J=7.5 Hz), 7.53 (d, 2H, J=7.5 Hz); 13C NMR, δ 21.3 (q),
23.2 (q), 62.5 (t), 63.4 (d), 123.9 (d), 130.0 (d), 139.4 (s), 141.5 (s); HRMS analysis (EI, M+): 198.0708,
calcd (C10H14O2S) 198.0714.
4.3. (S,Rs)-(+)-1-(4-Methylphenylsulfinyl)-2-butanol 2b
Yield 97%; m.p.: 70–71°C. [α]D=+305.9 (c=2, CHCl3). 1H NMR, δ 0.90 (t, 3H, J=7.5 Hz), 1.44–1.65
(m, 2H), 2.43 (s, 3H), 2.65 (dd, 1H, J=12.5 and 2.5 Hz), 3.06 (dd, 1H, J=12.5 and 10 Hz), 3.75 (bb, 1H),
4.04–4.17 (m, 1H), 7.36 (d, 2H, J=7.5 Hz), 7.53 (d, 2H, J=7.5 Hz); 13C NMR, δ 9.5 (q), 21.2 (q), 29.9
(t), 63.1 (t), 66.9 (d), 123.8 (d), 129.8 (d), 139.8 (s), 141.2 (s); HRMS analysis (EI, M+): 212.0874, calcd
(C11H16O2S) 212.0871.

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565
4.4. (S,Rs)-(+)-1-(4-Methylphenylsulfinyl)-2-pentanol 2c
Yield 90%; m.p. 84–85°C; [α]D=+282.2 (c=2, CHCl3); 1H NMR, δ 0.88 (t, 3H, J=7.5 Hz), 1.29–1.62
(m, 4H), 2.42 (s, 3H), 2.75 (dd, 1H, J=13.2 and 2 Hz), 2.95 (dd, 1H, J=13.2 and 10 Hz), 4.15–4.31 (m,
1H), 4.61 (d, 1H, J=4 Hz), 7.33 (d, 2H, J=8 Hz), 7.53 (d, 2H, J=8 Hz); 13C NMR, δ 13.7 (q), 18.3 (q),
21.3 (t), 39.1 (t), 63.1 (t), 65.6 (d), 123.8 (d), 129.9 (d), 139.7 (s), 141.3 (t); HRMS analysis (EI, M+):
226.1032, calcd (C12H18O2S) 226.1027.
4.5. (S,Rs)-(+)-5-(4-Methylphenylsulfinyl)-2-penten-4-ol 2d
Yield 92%; m.p. 64–66°C; [α]D=+270 (c=2, CHCl3); 1H NMR, δ 1.67 (d, 3H, J=6.2 Hz), 2.42 (s, 3H),
2.74 (dd, 1H, J=13.2 and 2 Hz), 3.01 (dd, 1H, J=13.2 and 9.7 Hz), 4.01 (bb, 1H), 4.52–4.70 (m, 1H), 5.49
(ddd J=16.8, 6.3 and 1.5 Hz), 5.68–5.82 (m, 1H), 7.34 (d, 2H, J=8 Hz), 7.53 (d, 2H, J=8 Hz); 13C NMR,
δ 17.4 (q), 21.1 (q), 63.5 (t), 66.5 (d), 123.7 (d), 127.3 (d), 129.8 (d), 131.3 (d), 139.7 (s), 141.2 (s);
HRMS analysis (EI, M+): 224.0873, calcd (C12H16O2S) 224.0871.
4.6. (S,Rs)-(+)-1-(4-Methylphenyl)sulfinylmethylethyl acetate 4a
Yield 75%, [α]D=+178.6 (c=2, CHCl3); 1H NMR, δ 1.38 (d, 3H, J=6.5 Hz), 2.07 (s, 3H), 2.42 (s, 3H),
2.91–3.00 (m, 2H), 5.30–5.44 (m, 1H), 7.34 (d, 2H, J=8Hz), 7.55 (d, 2H, J=8 Hz); 13C NMR, δ 19.9 (q),
20.2 (q), 21.1 (q), 63.7 (t), 65.2 (d), 123.6 (d), 129.8 (d), 140.5 (s), 141.4 (s), 169.7 (s); HRMS analysis
(CI, MH+): 241.0888, calcd (C12H17O3S) 241.0898.
4.7. (S,Rs)-(+)-1-(4-Methylphenyl)sulfinylmethylpropyl acetate 4b
Yield 80%, [α]D=+156.2 (c=2, CHCl3); 1H NMR, δ 0.92 (t, 3H, J=7.5 Hz), 1.68–1.81 (m, 2H), 2.08
(s, 3H), 2.42 (s, 3H), 2.85–3.01 (m, 2H), 5.21–5.33 (m, 1H), 7.34 (d, 2H, J=8 Hz), 7.54 (d, 2H, J=8 Hz);
13C NMR, δ 8.8 (q), 20.6 (q), 21.0 (q), 26.8 (t), 61.9 (t), 69.2 (d), 123.5 (d), 129.7 (d), 140.5 (s), 141.3
(s), 169.7 (s); HRMS analysis (CI, MH+): 255.1053, calcd (C13H19O3S) 255.1054.
4.8. (S,Rs)-(+)-1-(4-Methylphenyl)sulfinylmethylbutyl acetate 4c
1
Yield 89%, [α]D=+150.2 (c=2, CHCl3); H NMR, δ 0.82 (t, 3H, J=7.2 Hz), 1.15–1.31 (m, 2H),
1.49–1.67 (m, 2H), 1.99 (s, 3H), 2.32 (s, 3H), 2.75–2.92 (m, 2H), 5.15–5.31 (m, 1H), 7.25 (d, 2H,
J=8 Hz), 7.46 (d, 2H, J=8 Hz); 13C NMR, δ 13.5 (q), 17.9 (q), 20.7 (q), 21.1 (t), 36.0 (t), 62.5 (t), 68.2
(d), 123.7 (d), 129.8 (d), 140.5 (s), 141.5 (s), 169.9 (s); HRMS analysis (CI, MH+): 269.1214, calcd
(C14H21O3S) 269.1211.
4.9. (S,Rs)-(+)-1-(4-Methylphenyl)sulfinylmethyl-2-butenyl acetate 4d
Yield 55%; m.p. 94–96°C; [α]D=+208.5 (c=2, CHCl3); NMR, 1H δ 1.62 (dd, 3H, J=6.5 and 1.2 Hz),
2.01 (s, 3H), 2.35 (s, 3H), 2.90–2.94 (m, 2H) 5.31–5.42 (m, 1H), 5.55 (dd, 1H, J=13.5 and 7 Hz),
5.70–5.84 (m, 1H), 7.26 (d, 2H, J=8 Hz), 7.47 (d, 2H, J=8 Hz); NMR, 13C δ 17.6 (q), 21.0 (q), 21.3
(q), 62.6 (t), 68.9 (d), 123.9 (d), 127.1 (d), 129.9 (d), 131.1 (d),140.6 (s), 141.6 (s), 169.5(s); HRMS
analysis (EI, M+) 266.0980, calcd (C14H18O3S) 266.0976.

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Acknowledgements
We thank Dirección General de Enseñanza Superior (PB96-0757) for financial support and Generalitat
Valenciana for a grant (P.A.).
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