A convenient approach to chiral sulfoxides by enantioselective oxidation with a steroidal furylhydroperoxide

Article abstract of DOI:10.1016/S0957-4166(98)00163-3

The introduction of a steroidal residue into a position distant from the reaction center shows a beneficial effect on the reactivity of secondary furylhydroperoxides: chiral sulfoxides are obtained by asymmetric oxidation of sulfides and/or kinetic resolution of racemic sulfoxides with reduced reaction times and high enantiomeric excesses.

Full text of DOI:10.1016/S0957-4166(98)00163-3

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TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 1817–1822
A convenient approach to chiral sulfoxides by enantioselective
oxidation with a steroidal furylhydroperoxide
Laura Palombi,a Francesco Bonadies,a Alessandro Pazienza a and Arrigo Scettri b,∗
aCentro CNR per lo Studio della Chimica delle Sostanze Organiche Naturali,† Dipartimento di Chimica, Università ‘La
Sapienza’, P. le Aldo Moro 5, 00185 Roma, Italy
bDipartimento di Chimica, Università di Salerno, 84081 Baronissi (Salerno), Italy
Received 6 April 1998; accepted 21 April 1998
Abstract
The introduction of a steroidal residue into a position distant from the reaction center shows a beneficial effect on
the reactivity of secondary furylhydroperoxides: chiral sulfoxides are obtained by asymmetric oxidation of sulfides
and/or kinetic resolution of racemic sulfoxides with reduced reaction times and high enantiomeric excesses. © 1998
Elsevier Science Ltd. All rights reserved.
1. Introduction
Chiral sulfoxides are useful synthons in preparative organic chemistry and one of the typical syn-
thetic procedures is based on transition metal catalyzed asymmetric oxidation of sulfides. Recently,
several modifications of the methodologies proposed by Kagan1 and Modena2 have been reported: in
particular, different hydroperoxides and chiral auxiliaries3–6 have been employed in the asymmetric
sulfoxidation. Recently, we have achieved a convenient one-pot procedure for the synthesis of chiral
sulfoxides (70–>95% e.e.), involving two enantioconvergent processes of asymmetric oxidation and
kinetic resolution by the employment of furylhydroperoxides as oxidants (Fig. 1).7
2. Results and discussion
Our present interest concerning the preparation of chiral hydroperoxides, potentially stereoselective
oxidants,8 suggested an approach based on the synthesis of furylhydroperoxide 1a and the subsequent
†
∗
Associated to the National Institute of Biological Systems — CNR.
Corresponding author. E-mail: scettri@ponza.dia.unisa.it
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00163-3

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L. Palombi et al. / Tetrahedron: Asymmetry 9 (1998) 1817–1822
Fig. 1.
resolution of the resulting epimeric mixture. Unfortunately, this approach proved to be unsuccessful: in
fact, although 1a was easily accessible in 2–3 g scale by a known, efficient sequence starting from 3-
cholestanyl acetoacetate, the separation of the 1:1 diastereoisomeric mixture into enantiomerically pure
furylhydroperoxides by conventional crystallization or chromatographic techniques afforded unsatisfac-
tory results. Anyway, 1a proved to be of noteworthy synthetic value: chiral sulfoxides 3 were obtained
with good yields and high enantiomeric excesses through a modified procedure for the asymmetric
oxidation of sulfides 2 by the direct employment of 1a as a diastereoisomeric mixture in the presence
of L-diethyl tartrate (L-DET), as the chiral auxiliary (Scheme 1; Table 1).
Scheme 1.
This methodology proved to be characterized by high chemoselectivity: in fact, starting materials 2
were usually recovered in 20–35% yield, while only in entry a were negligible amounts of the corres-
ponding sulfone isolated (<3%). All the products 3 were obtained as the (R)-enantiomer preferentially,
confirming previous results indicating that the stereochemical outcome of the sulfoxidation does not
depend on the configuration of the stereogenic center bearing the hydroperoxy function.9 It has to be
noted that the presence of a steroidal residue significantly enhanced the reactivity of the oxidant under
the conditions reported in Table 1, so that oxidation required reaction times much shorter than the ones
reported for similar procedures.7
The problem related to the low enantioselectivity observed in the case of dialkyl sulfoxides (entry f)
Table 1
Asymmetric oxidation of sulfides 2 with 1a

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L. Palombi et al. / Tetrahedron: Asymmetry 9 (1998) 1817–1822
1819
was partially circumvented by using 1a in a process of kinetic resolution based on the enantioselective
oxidation of racemic sulfoxides to sulfones (Scheme 2).
Scheme 2.
In fact, after racemic methyl n-octyl sulfoxide was submitted to the experimental conditions reported in
Table 2 (entry a), the highly preferential oxidation of the S-enantiomer took place so that the R-sulfoxide
could be recovered in satisfactory yield and very high e.e.
Kinetic resolution of racemic aryl methyl sulfoxides was shown to proceed with similar efficiency and
selectivity (entries b–f). It has to be noted that when diisopropyl tartrate was used as the chiral auxiliary,
a significant lowering of e.e.s was generally observed (25–50%).
This methodology seems to be particularly attractive since the operationally simple introduction of
different chiral alcohol residues in structure 1 allows access to a set of hydroperoxides employable in
similar asymmetric oxidations. For example, easily available furylhydroperoxide 1b (R=bornyl) afforded
very satisfactory results both in asymmetric oxidation and in kinetic resolution, as reported in Scheme 3.
3. Experimental
3.1. General information
1H-NMR and 13C-NMR spectra were recorded on a Varian Gemini-200 spectrometer. Splitting
patterns are designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet). Chemical shifts
are reported in δ (ppm) relative to internal CHCl3 for 1H-NMR and CDCl3 (77.0) for 13C-NMR.
Silica gel (230–400 mesh, Merck) was used for flash chromatography. Analytical thin layer chrom-
atography was carried out on Merck Kieselgel F254 plates. Dichloromethane was stored over activated
4A molecular sieves (2 days at 160°C). Other chemicals (Aldrich or Fluka) were used as commercial
products.
Table 2
Kinetic resolution of racemic sulfoxides 3 with 1a

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Scheme 3.
3.2. General procedure for the synthesis of 1a and 1b
5α-Cholestan-3β-yl and (1S-endo)-(−)-bornyl 3-oxo-butanoate11 (18 mmol) were submitted to alkyl-
ation with trans-2-butenyl bromide (20 mmol) in the presence of lithium hydroxide monohydrate (20
mmol) in anhydrous THF solution12 (40 ml) at 45°C for 4 days. Then Et2O (250 ml) was added and
the organic phase was washed with brine till neutrality. Silica gel column chromatography afforded pure
alkylated 1,3-dicarbonyl compounds in >70% yields.
3.3. 2-(2-Butenyl)-5α-cholestan-3β-yl 3-oxo-butanoate (inseparable mixture of diastereoisomers)
White powder; 1H-NMR (CDCl3): 5.6–5.1 (m, 2H); 4.8–4.6 (m, 1H); 3.37 (t, 1H, J=7.2 Hz); 2.47 (t,
2H, J=7 Hz); 2.18 (s, 3H); 1.63 (d, 3H, J=6.8 Hz); 0.93 (s, 3H); 0.89 (s, 3H); 0.83 (s, 3H). 13C-NMR
(CDCl3): 202.6; 168.8; 128.0; 126.7; 74.7; 60.0; 56.4; 54.1; 44.6; 42.5; 40.0; 39.5; 36.6; 36.1; 35.8; 35.4;
33.9; 33.7; 31.9; 31.1; 28.8; 28.5; 28.2; 27.9; 27.3; 27.2; 24.1; 23.8; 22.8; 22.5; 21.1; 18.6; 17.9; 12.2;
12.0. Anal. calcd for C35H58O3: C, 79.79; H, 11.10%. Found: C, 79.82; H, 11.15%.
3.4. 2-(2-Butenyl)-[(1S-endo)]-(−)-bornyl 3-oxo-butanoate (inseparable mixture of diastereoisomers)
1
White powder; H-NMR (CDCl3): 5.6–5.2 (m, 2H); 4.9–4.6 (m, 1H); 3.5–3.4 (m, 1H); 2.5 (t, 2H,
J=6.6 Hz); 2.2 (s, 3H); 0.88 (s, 3H); 0.85 (s, 3H); 0.82 (s, 3H). 13C-NMR (selected data for keto-form)
(CDCl3, 76.95 ppm): 202.4; 169.5; 128.0; 126.5; 80.9; 50.8; 48.7; 47.7; 44.7; 36.5; 31.1; 28.9; 27.8;
26.9; 19.5; 18.6; 17.7; 13.3. Anal. calcd for C18H28O3: C, 73.93; H, 9.65%. Found: C, 73.90; H, 9.65%.
2-(2-Alkenyl)-1,3-dicarbonyl compounds (10 mmol) were converted into furylhydroperoxides 1a and
1b according to the three-step sequence reported in the literature.13,14 Because of the high yields of