Synthesis of chiral disulfides: potential reagents for enantioselective sulfurization

Abstract

Synthesis of chiral phosphorothioates for use as antisense oligonucleotides might benefit from the use of chiral disulfides. This paper reports the synthesis of chiral analogs of phenylacetyl disulfide and of 5-methyl-3H-1,2,4-dithiazol-3-one from the same set of 2-arylalkanoic acids. The X-ray crystal structures of the disulfides derived from (R) and [S]-2-phenylpropanoic acid establish the stereochemistry and the helicity of these materials, and density functional theory calculations suggest that the high specific rotations can be due to preferred retention of this helicity in solution. Chiral HPLC showed that the final products were formed with enantiomeric purities from 86.1% to>99.9%.

Keywords:

• chiral disulfides
• X-ray
• chiral HPLC
• phosphorothioate oligonucleotides

Acknowledgements

J.A.M. and W.H.H. thank Queens College for the purchase of HPLC equipment and the City University of New York PSC-CUNY Research Award Program for the financial support.

Supplementary data

Experimental procedures for the synthesis of 1b, resolution of 1e, synthesis of 4a and d and data for 4a–e; tables of observed and literature specific rotations of 1, the salts used for resolutions, and 4; experimental data, spectra, and HPLC chromatograms for new compounds; coordinates from DFT calculations; details of the structure determination. Supplementary data associated with this article can be found in the online version.

Notes

The usual name quoted in the literature, 3-methyl-1,2,4-dithiazolin-5-one, appears to us to be in error; the parent ring system is fully unsaturated (hence the “ol” ring termination) and the position of the unsaturation is indicated by giving the H the lowest available number.

The highest de's for phosphite triester sulfurization with the disulfides reported here for R _PS and S _PS phosphorothioates were 14.7% and 7.9%, respectively.

Crystallographic data (excluding structure factors) for the structures in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication nos. CCDC 779771 and 779772. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (Fax: [phone] or Email: [email protected]).