71239-66-2Relevant academic research and scientific papers
Applications of vinylogous mannich reactions. Concise enantiospecific total syntheses of (+)-croomine
Martin, Stephen F.,Barr, Kenneth J.,Smith, Dudley W.,Bur, Scott K.
, p. 6990 - 6997 (2007/10/03)
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 stereoselectivity of the reaction. Toward this end, the additions of the methylated furans 9a-h to the iminium ion generated in situ from the ethoxy carbamate 10 were examined. Generally, mixtures (3-24:1) of the threo and erythro adducts 11a-h and 12a-h were obtained in 50-96% combined yields, with the threo isomers being the major products. Two extraordinarily concise asymmetric syntheses of (+)-croomine (1) have been completed using a novel strategy, highlighted by two vinylogous Mannich reactions as key constructions. The first such reaction involved the addition of 5-(4-bromobut-1-yl)-3-methyl-2-(triisopropylsilyloxy)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)-pyrrolidin-5′-yl]-3-methyl- 2(5H)-furanone (18) as the major product. Refunctionalization of 18 led to the tricyclic intermediate [3′S-[3′α,9′α(5*),9′aα]]- decahydro-4-methyl-5-oxospiro[furan-2(3H),9′-[9H]pyrrolo[1,2-a]azepin]- 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′α(R*),9′α(S*), 9′aα]]-3′-(2,5-dihydro-4-methyl-5-oxo-2-furanyl)decahydro-4- methylspiro[furan-2(5H),9′-[9H]pyrrolo[1,2-a]azepin-5-one (24) as the major adduct. Stereoselective reduction of the unsaturated lactone 24 gave 1, completing a synthesis that required a total of only 11 chemical steps from commercially available starting materials. In a second 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 was transformed into the unsaturated tricyclic intermediate [3′S-[3′α(R*),9′α(S*), 9′aα]]-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]azepin]-5-one, which underwent hydrogenation to give 1 as the only isolable product, thereby completing a synthesis that required only 10 steps.
Vinylogous Mannich reactions. The asymmetric total synthesis of (+)-croomine
Martin,Barr
, p. 3299 - 3300 (2007/10/03)
We have recently investigated the vinylogous Mannich reaction as a key construction for the synthesis of alkaloid natural products. The general plan is illustrated by the nucleophilic addition of 2-trialkylsilyloxy furan to the cyclic iminium ion to provide a mixture of the isomeric adducts threo-5 and erythro-5 in which the threo-5 product typically dominates. Since the stereochemistry at the newly created stereogenic centers in the threo-5 adduct corresponds to the pairwise relationships at C(9)-C(9a) and C(3)-C(14) of croomine (1), it occurred to us that vinylogous Mannich reactions might be applied to the design of a highly convergent strategy for the synthesis of 1 and related alkaloids. We report the successful implementation of this strategy in an extraordinarily concise, asymmetric synthesis of (+)-croomine (1).
