First enantioselective synthesis of the novel antiinfective TAN-1057A via its aminomethyl-substituted dihydropyrimidinone heterocycle

Enantiomerically pure N2-Z-N2-MeAsnOH [], prepared in 8 steps (23% overall yield) from asparaginic acid, was first subjected to a Hofmann degradation with PhI(OCOCF3)2 yielding (S)-N2-Z-N2-methyl-2,3-diaminopropanoic acid [N2-Z-N2-Me-L-A2pr, ], and this in turn was protected to give N2-Z-N3-Boc-N2-Me-L-A2pr []. Condensation of with HNC(SMe)NHCONH2 followed by removal of the tert-butoxycarbonyl protecting group, cyclization and hydrogenolytic removal of the Z-group gave the heterocycle of TAN-1057A [] with an e.e. of 87 in 36% yield [from ]. Coupling of with (S)-tris-Z-β-homoarginine () in the presence of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) and iPr2NEt in N,N-dimethylacetamide followed by hydrogenolysis afforded the most active A-diastereomer of the natural antibiotic TAN-1057 in 52% yield (from and ). Similarly, starting from , a single diastereomer of the potent, less toxic TAN-1057A analogue with a β-lysine side chain has been prepared. All described synthetic steps do not require column chromatography for purification of the products.