Total Synthesis of the Antibiotic Sparsomycin, a Modified Uracil Amino Acid Monoxodithioacetal

Article abstract of DOI:10.1021/jo00329a027

The total syntheses of sparsomycin (1), a naturally occurring antibiotic and antitumor substance, and its three stereomers 65-67 are described for the first time.In a convergent approach, the carboxylic acid 2 and the amine 3 were synthesized followed by amide formation (Scheme I).The acid 2 was prepared (23percent yield) from 6-methyluracil (12) by coupling the aldehyde 19 with the phosphorane 20 (Scheme III).The synthesis of the amine 3, especially challenging because of the monoxodithioacetal moiety, was accomplished by the reaction of a cysteine α-halo sulfoxide derivative 8 with sodium methylmercaptide (Scheme II, route B).Alternatively, oxidation of the dithioacetals 23-26 was unsatisfactory, yielding predominantly the undesired regioisomers 27B-30B (Table I).Procedures are given for the preparation and separation of the α-halo sulfoxide diastereomers 33,35, 36-41, and 52-54.By use of these procedures, the amino alcohol monoxodithioacetals 3 and 60 were prepared in five steps (40percent yield) from the D-cystine derivative 59 having the S_C chirality of sparsomycin (Scheme VII).Finally, sparsomycin (1) and the S_C diastereomer 67 were prepared (40percent yield) by mixed anhydride coupling of 2 with 3 and 60, respectively (Schemes I and X).In addition, syntheses of the R_C enantiomer 65 and corresponding diastereomer 66 are described (Scheme IX).The CD spectra of 1 and its three stereomers are also discussed.