A facile stereospecific synthesis of chiral β-keto sulfoxides

Article abstract of DOI:10.1016/S0957-4166(99)00350-X

A synthetic strategy has been devised for the preparation of chiral β- keto sulfoxides (actually, α-vinylsulfinyl ketones) starting from the readily available C-6 substituted 2,3-dihydro-1,4-oxathiines. The procedure, which is characterized by high yields

Full text of DOI:10.1016/S0957-4166(99)00350-X

Pergamon
Tetrahedron: Asymmetry 10 (1999) 3463–3466
A facile stereospecific synthesis of chiral β-keto sulfoxides
Romualdo Caputo,a Federico Giordano,b Annalisa Guaragna,a Giovanni Palumbo a,∗ and
Silvana Pedatella a
aDipartimento di Chimica Organica e Biologica, Università di Napoli Federico II, Via Mezzocannone 16, 80134 Napoli, Italy
bDipartimento di Chimica, Università di Napoli Federico II, Via Mezzocannone 4, 80134 Napoli, Italy
Received 22 July 1999; accepted 11 August 1999
Abstract
A synthetic strategy has been devised for the preparation of chiral β-keto sulfoxides (actually, α-vinylsulfinyl
ketones) starting from the readily available C-6 substituted 2,3-dihydro-1,4-oxathiines. The procedure, which
is characterized by high yields and excellent enantiomeric excesses, represents an improvement in preparation
methods for chiral β-keto sulfoxides. © 1999 Published by Elsevier Science Ltd. All rights reserved.
Chiral β-keto sulfoxides have been extensively investigated and are commonly used in the synthesis of
natural products and biologically active compounds.1 Acyclic β-keto sulfoxides are generally prepared
according to a procedure based on the reaction of α-sulfinyl anions with esters, as described by Corey.2
Usually (+)-(R)-methyl p-tolyl sulfoxide, prepared by reaction of magnesium methyl iodide on a suitable
chiral sulfinate ester, is converted by lithium diethylamide into its corresponding sulfinyl anion and the
latter is then coupled with an ester.3 Other methods include Claisen-type condensation of the optically
active sulfinate ester with ketone enolate anions,4 as well as the reaction of α-sulfinyl anions with
cyclohexanones for the synthesis of chiral β-sulfinyl cyclohexanones.5
We wish to report in this paper a new procedure for the synthesis of chiral acyclic β-keto sulfoxides
starting from chiral cyclic sulfoxides that in turn are prepared, with both R and S configurations, from C-
6 substituted 2,3-dihydro-1,4-oxathiines. These starting compounds can be easily obtained from methyl
ketones via their 1,3-oxathiolanes (overall yield range 85–92%), according to a procedure we have
previously reported.6
The oxidation at the sulfur atom in the oxathiine ring is then performed under modified Sharpless
conditions,7,8 using cumene hydroperoxide (CHP) and TiIV isopropoxide in the presence of either L-(+)
or D-(−) diethyl tartrate, in dry methylene chloride at −18°C, as shown in Scheme 1. The molar ratio of
substrate and reagents is reported in Table 1. Other oxidation systems and substrate:reagent ratios were
also tested, as shown in Table 1, although the results were definitely less satisfactory, in terms of both
chemical yield and e.e.
∗
Corresponding author. E-mail: gipalumb@unina.it
0957-4166/99/$ - see front matter © 1999 Published by Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00350-X

3464
R. Caputo et al. / Tetrahedron: Asymmetry 10 (1999) 3463–3466
Scheme 1. Synthesis of the chiral cyclic sulfoxides
Table 1
Oxidation of 6-phenyl-2,3-dihydro-1,4-oxathiine under different conditions
The C-6 substituted 2,3-dihydro-4-oxo-1,4-oxathiines prepared under our experimental conditions are
reported in Table 2 with yields and e.e.s. Some preliminary results showed that the enantioselectivity of
the sulfur oxidation decreases sharply when a second substituent is present at the C-5 position of the
oxathiine ring.
Table 2
C-6 Substituted 2,3-dihydro-4-oxo-1,4-oxathiine
The target compounds, chiral β-keto sulfoxides, were obtained by treatment of the parent 2,3-
dihydro-4-oxo-1,4-oxathiines with lithium diisopropylamide in dry tetrahydrofuran at −78°C. Under
these conditions they undergo a very clean and nearly quantitative (98% yield) ring cleavage affording
the corresponding chiral α-vinylsulfinyl ketones (β-keto sulfoxides), as shown in Scheme 2. No evidence
of the occurrence of isomerization at the stereogenic sulfur atom could be found.

R. Caputo et al. / Tetrahedron: Asymmetry 10 (1999) 3463–3466
3465
Scheme 2. Conversion of the chiral cyclic sulfoxides into β-keto sulfoxides
To the best of our knowledge, α-vinylsulfinyl ketones have not been reported so far and, therefore, we
tested their stereoselective reduction according to the procedures11 previously reported for the reduction
of α-alkyl (or phenyl) sulfinyl ketones: (R)-1-phenyl-2-(vinylsulfinyl)-1-ethanone [low-melting solid,
25
[α]D −194 (c=1.2 in CHCl3)], from (S)-6-phenyl-2,3-dihydro-4-oxo-1,4-oxathiine, was in fact treated
with DIBAL and led to a diastereomeric mixture of β-hydroxy sulfoxides [yield 95%, m.p. 126–128°C
25
from hexane–ethanol, (1S,SR) d.e.=92%, [α]D −89 (c=1.2 in CH3OH)] which was separated by
chromatography. The more abundant diastereomer was then desulfurized with Ra-Ni to give (1R)-
phenylethanol (e.e.=98%).
When treated with DIBAL/ZnCl2, (R)-1-phenyl-2-(vinylsulfinyl)-1-ethanone led again to a diastereo-
25
meric mixture [yield 87%, m.p. 76–78°C from hexane–ethanol, (1R,SR) d.e.=94%, [α]D −125 (c=1.1
in CH3OH)] and the desulfurization of the more abundant diasteromer by Ra-Ni gave (1S)-phenylethanol
(e.e.=97%). Satisfactory C,H microanalyses were obtained for all the new compounds. 1H NMR spectra12
were consistent with the proposed structures.
These results match very well with that reported11 for the stereoselective reduction of (R)-1-phenyl-
2-(p-tolylsulfinyl)-1-ethanone. It is noteworthy that, in those instances where the sulfur moiety has to be
removed after the reduction, the availability of the two chiral cyclic sulfoxides (and the β-keto sulfoxides
therefrom) with opposite configuration, which can both be obtained under our conditions, affords a better
chance to work with an enantiomerically pure starting β-keto sulfoxide.
Considering the final production of chiral 1-substituted ethanol, our procedure may be regarded
as a formal stereoselective reduction of ethanones and differs from the already mentioned previous
procedures11 where the parent ethanone is produced by coupling of an α-sulfinyl anion with esters.
Acknowledgements
This work represents a partial fulfilment of the degree thesis by Stefania Colarusso. Financial support
by Regione Campania (Ricerca Scientifica) to G.P. is gratefully acknowledged.
References
1. Solladié, G.; Carreño, M. C. In Organosulfur Chemistry. Synthetic Aspects: Optically Active β-Keto Sulfoxides and
Analogues in Asymmetric Synthesis; Page, P., Ed.; Academic Press: London, 1995; pp. 1–47.
2. Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1345–1353.
3. Carreño, M. C. Chem. Rev. 1995, 95, 1717–1760.
4. Schneider, F.; Simon, R. Synthesis 1986, 582–584.
5. Carreño, M. C.; García Ruano, J. L.; Pedregal, C.; Rubio, A. J. Chem. Soc., Perkin Trans. 1 1989, 1335–1337.
6. Caputo, R.; Longobardo, L.; Palumbo, G.; Pedatella, S. Synlett 1995, 1274.
7. Aggarwal, V. K.; Evans, G.; Moya, E.; Dowden, J. J. Org. Chem. 1992, 57, 6390–6391.
8. Di Furia, F.; Licini, G.; Modena, G. Gazz. Chim. Ital. 1990, 120, 165–170.
9. X-Ray: (C10H10O2S·H2O; Mw=212.3); monoclinic system, space group P21, a=8.439(2) Å, b=5.326(1) Å, c=11.513(3)
Å, β=98.87(1)° and Z=2. A total of 1175 independent reflections were collected at room temperature on an Enraf–Nonius
CAD4-F diffractometer using Cu Kα radiation.

3466
R. Caputo et al. / Tetrahedron: Asymmetry 10 (1999) 3463–3466
Least squares refinement of 1154 reflections with I>3σ(I) converged upon the structure with R=0.033, Rw=0.041 and a
goodness of fit=1.172. The inverted structure converged with the following values: R=0.037, Rw=0.046. Correspondence
regarding the X-ray data should be addressed to F.G.
10. Pirkle, W. H.; Beare, S. D.; Muntz, R. L. Tetrahedron Lett. 1974, 2295–2298.
11. Solladié, G.; Demailly, G.; Greck, C. Tetrahedron Lett. 1985, 26, 435–438.
12. (S)-6-Phenyl-2,3-dihydro-4-oxo-1,4-oxathiine (250 MHz, CDCl3): δ 2.75–2.84 (m, 1H, Ha-3); 2.90–3.10 (m, 1H, Hb-3);
4.60–4.82 (m, 2H, H-2); 6.28 (d, 1H, J=2.1 Hz, H-5); 7.35–7.50 (m, 3H, H aromatic); 7.65 (dd, 2H, Jortho =8.0 Hz, Jmeta=1.8
Hz, H aromatic). (R)-6-t-Butyl-2,3-dihydro-4-oxo-1,4-oxathiine (200 MHz, CDCl3): δ 1.15 (s, 9H, CMe3); 2.51–2.69 (m,
1H, Ha-3); 2.81–2.93 (m, 1H, Hb-3); 4.38–4.62 (m, 2H, H-2); 5.74 (d, 1H, J=1.5 Hz, H-5). (R)-1-Phenyl-2-(vinylsulfinyl)-
1-ethanone (400 MHz, CDCl3): δ 4.32 (d, 1H, J=14.3 Hz, Ha-2); 4.48 (d, 1H, J=14.3 Hz, Hb-2); 6.01 (d, 1H, Jcis=9.8
Hz, Ha β-vinylic); 6.18 (d, 1H, Jtrans=16.5 Hz, Hb β-vinylic); 6.89 (dd, 1H, Jcis=9.8 Hz, Jtrans=16.5 Hz, H α-vinylic);
7.47–7.55 (m, 2H, H aromatic); 7.60–7.64 (m, 1H, H aromatic); 7.96 (d, 2H, Jortho=8.5 Hz, H aromatic). (1S,SR)-1-
Phenyl-2-(vinylsulfinyl)-1-ethanol (400 MHz, CD3OD): δ 2.91 (dd, 1H, J2a,1=2.5 Hz, J2a,2b=14.0 Hz, Ha-2); 3.22 (dd,
1H, J2b,1=11.0 Hz, J2b,2a=14.0 Hz, Hb-2); 5.18 (dd, 1H, J1,2a=2.5 Hz, J1,2b=11.0 Hz, H-1); 6.05 (d, 1H, Jcis=9.8 Hz, Ha
β-vinylic); 6.08 (d, 1H, Jtrans=16.5 Hz, Hb β-vinylic); 6.93 (dd, 1H, Jcis=9.8 Hz, Jtrans=16.5 Hz, H α-vinylic); 7.31–7.41
(m, 5H, H aromatic). (1R,SR)-1-Phenyl-2-(vinylsulfinyl)-1-ethanol (400 MHz, CD3OD): δ 3.23 (d, 2H, J2,1=6.6 Hz, H-2);
5.15 (t, 1H, J1,2=6.6 Hz, H-1); 6.04 (d, 1H, Jcis=10.0 Hz, Ha β-vinylic); 6.07 (d, 1H, Jtrans=16.6 Hz, Hb β-vinylic); 6.98
(dd, 1H, Jcis=9.7 Hz, Jtrans=16.6 Hz, H α-vinylic); 7.31–7.46 (m, 5H, H aromatic).