A novel, concise, stereospecific synthesis of the vitamin biotin (1) an essential nutrient and growth promotant of limited availability from natural sources is proposed. Of crucial importance in this synthesis is the introduction of all three substituents on the tetrahydrothiophene ring in the cis geometry. The proposed starting material for this synthesis is the abundantly available 2,5-dihydrothiophene 1,1-dioxide (33). We envision four key steps for introduction of the vicinal diamines and the pentanoate side chain. First the double bond in 2,5-dihydrothiophene 1,1-dioxide (33) will be cis vicinally diaminated to afford diamine derivative 34. One appealing method to accomplish this involves intramolecular delivery of nitrogen to assure formation of the cis diamine. Other methods to be investigated for performing cis vicinal diamination include nitrene addition, [2+2]- cycloaddition of 1,2,4-triazole-3,5-diones, and transition metal promoted direct diamination. The diaminosulfone (34) will be reduced to a sulfide (35) which will be halogenated to an alpha-halo thioether (36). The final key synthetic step involves attachment of the pentanoate side chain by displacement of the halogen with a carbon nucleophile, most conveniently an organometallic. In order to gain familiarity with this reaction, particularly its stereochemical outcome, we have performed preliminary investigations with model organocuprates and we have observed that only the desired cis isomer (37) is formed. Optically active alpha-halo thioether 36 will be prepared by resolution or by a novel chiral Pummerer rearrangement. Utilization of optically active 36 in the proposed synthesis will enable the preparation of optically active d-(+)-biotin.
