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

Abstract

Enantiomerically pure N-2-Z-N-2-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)-N-2-Z-N-2-methyl-2,3-diaminopropanoic acid [N-2-Z-N-2-Me-L-A(2)pr, (S)-15], and this in turn was protected to give N-2-Z-N-3-Boc-N-2-Me-L-A(2)pr [(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-beta-homoarginine (20a) in the presence of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) and iPr(2)NEt in N,N-dimethyl-acetamide 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 beta-lysine side chain has been prepared. All described synthetic steps do not require column chromatography for purification of the products. (C) 2004 Elsevier Ltd. All rights reserved.