Applications of vinylogous Mannich reactions. Concise enantiospecific total syntheses of (+)-croomine

Because the vinylogous Mannich reaction of substituted furans with iminium ions is a useful construction in alkaloid synthesis,it is important to know what effects substituents on the two reacting partners have upon the stere oselectivity of the reaction. Toward this end, the additions of the methyla ted furans 9a-h to the iminium ion generated in situ from the ethoxy carbam ate 10 were examined. Generally, mixtures (3-24:1) of the three and erythro adducts 11a-h and 12a-h were obtained in 50-96% combined yields, with the three isomers being the major products. Two extraordinarily concise asymmet ric syntheses of (+)-croomine (1) have been completed using a novel strateg y, highlighted by two vinylogous Mannich reactions as key constructions. Th e first such reaction involved the addition of 5-(4-bromobut-1-yl)-3-methyl -2-(triisopropyl-silyloxy)furan to the N-acyliminium salt derived from the L-pyroglutamic acid derivative 17 to give the adduct [5(S),2'(S),5'(S)]-5-( 4 "-bromobut-1 " yl)-5-[N-(tert-butoxycarbonyl)-2'-(methoxycarbonyl)-pyrrol idin-5'-yl]-3-methyl-2(5H)-furanone (18) as the major product. Refunctional ization of 18 led to the tricyclic intermediate [3'S-[3'alpha,9'alpha(S*),9 'a alpha]]-decahydro-4-methyl-5-oxospiro[furan-2(3H),9'-[9H]pyrrolo[1,2-a]a zepin]-3'-carboxylic acid, hydrobromide salt, which was, in turn, converted to an iminium salt that underwent a second vinylogous Mannich reaction to give [3'S-[3'alpha(R*),9'alpha(S*),9'a alpha]]-3'-(2,5-dihydro-4-methyl-5-o xo-2-furanyl)decahydro-4-methylspiro[furan-2(5H),9'-[9H]pyrrolo[1,2-a]azepi n-5-one (24) as the major adduct. Stereoselective reduction of the unsatura ted lactone 24 gave 1, completing a synthesis that required a total of only 11 chemical steps from commercially available starting materials. In a sec ond approach, the initial Mannich adduct [5(S),2'(S),5'(S)]-5-(4 "-bromobut -1 "-yl)-5-[2'-(methoxycarbonyl)pyrrolidin-5'-yl]-3-methyl-2(5H)-furanone w as transformed into the unsaturated tricyclic intermediate [3'S-[3'alpha(R* ),9'alpha(S*),9'alpha a]-3'-(2,5-dihydro-4-methyl-5-oxo-2-furanyl)-1',2',3' ,5',6',7',8'-octahydro-4-methylspiro[furan-2(5H),9'-[9H]-pyrrolo[1,2-a]azep in]-5-one, which underwent hydrogenation to give 1 as the only isolable pro duct, thereby completing a synthesis that required only 10 steps.