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(OCOCF 3 ) 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)NHCONH 2 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 i Pr 2 NEt 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.