Asymmetric synthesis of 5,5-disubstituted thiotetronic acids using allyl xanthate to dithiocarbonate rearrangement: Total synthesis of (5S)-thiolactomycin with revision of the absolute configuration of the natural product

An asymmetric synthesis of thiotetronic acids related to the antibiotics thiolactomycin 1 and thiotetromycin 2 has been developed in which the key step is a stereoselective [3.3]-rearrangement of an allyl xanthate to the corresponding dithiocarbonate. Thus, the xanthates (S)- and(R)-19 are rearranged efficiently to the dithiocarbonates (S)- and (R)-20. Hydrolysis of the dithiocarbonates with-in situ S-alkylation gives the thioethers (S)- and (R)-22 which are converted into the acyl imidazolides (S)and (R)-27. These are used to acylate methyl propanoate, methyl phenylacetate and ethyl acetate to give the keto esters 28-30 which are converted into the thiotetronic acids 31-33 by deprotection using trifluoroacetic acid-anisole. The 3-phenylthiotetronic acid 32 is completely enolic in both [H-2]chloroform and [H-2(6)]dimethyl sulfoxide, but 15% of the keto tautomer 40 of the 3-methyl compound 31 is present in [H-2]chloroform. The 3-unsubstituted thiotetronic acid 33 is 100% enolic in [H-2(6)]dimethyl sulfoxide and exists completely as the keto tautomer 41 in [H-2]chloroform. Ozonolysis of the thioether (S)-22 gives the aldehyde 45 which is converted into the diene 42. Hydroboration-oxidation of this diene gives the alcohol 79 which is converted into the selenide 80. This is taken through to the thiotetronic acid 85, which via selective Se-methylation and base-induced elimination gives (5S)-thiolactomycin (S)-1. This is laevorotatory and-hence is the enantiomer of the natural product which must therefore be the (5R)-enantiomer (R)-1.