合成路线1

An alternative route to (+)-lipoic acid used ethyl 4,6-di-O-acetyl-2,3-dideoxy-alpha-D-erythro-hexopyranoside (XX), prepared from triacetyl-D-glucal, as the chiral starting point. Deacetylation of (XX) with sodium methoxide under Zemplen conditions gave diol (XXI) which, after conventional benzylation, led to the 4,6-di-O-benzyl derivative (XXII). Ring opening of the cyclic acetal (XXII) with propanediol in the presence of boron trifluoride afforded the dithiane derivative (XXIII). The free hydroxyl group of (XXIII) was converted into xanthate (XXIV) by reaction with NaH and CS2, followed by methyl iodide. Reductive cleavage of the xanthate group by means of Bu3SnH and AIBN provided (XXV). Hydrolysis of the thioacetal function with HgO and BF3 provided aldehyde (XXVI). Chain homologation was performed by Wittig reaction of aldehyde (XXVI) with phosphorane (XXVII) to afford the unsaturated ester (XXVIII). Simultaneous double bond hydrogenation and benzyl ether cleavage in the presence of Raney nickel led to dihydroxy ester (XXIX). This was converted to the corresponding dimesylate (XXX), which was further cyclized to disulfide (XXXI) using the in situ generated sodium disulfide as in the precedent Schemes. Finally, basic hydrolysis of the ethyl ester (XXXI) yielded the title carboxylic acid.