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

Enantiomerically pure N²-Z-N²-MeAsnOH (S)-14], 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, (S)-15], and this in turn was protected to give N²-Z-N³-Boc-N²-Me-L-A₂pr (S)-17]. Condensation of (S)-17 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 (S)-1] with an e.e. of 87 in 36% yield from (S)-14]. Coupling of (S)-1 with (S)-tris-Z-β-homoarginine (20a) 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 (S)-1 and 20a). Similarly, starting from (S)-1, a single diastereomer of the potent, less toxic TAN-1057A analogue 22b with a β-lysine side chain has been prepared. All described synthetic steps do not require column chromatography for purification of the products.