Abstract
Manzamine A and B were isolated from a marine sponge Haliclona sp. by Higa and co-workers in 1986 and 1987, respectively. It is well known that manzamine A has many interesting biological activities including strong antimalarial activity and has been synthesized by several groups including us. On the other hand, the biological activity of manzamine B has not been studied well due to its poor availability from natural sources. We have been studying total synthesis of manzamine B in order to provide enough amount of material for investigation of biological activity. We initially developed the asymmetric Diels-Alder reaction of aminodiene 2d and dienophile 1 using Cr-salen-F complex 3e as a promoter, which was originally reported by Rawal. After the reaction, the adduct 4d was triturated in hexane/AcOEt and enantiomerically pure 4d was obtained in 20 g scale. The adduct 4d was converted into oxabicyclo[2.2.2]octane 6 to control stereoselectivity of next alkylation. As expected, the Grignard reagent attacked from 13 face to avoid acetoamide moiety and gave desired compound 8 selectively. Aldol reaction of ketone 9 enabled introduction of Cl unit. However, the product was dehydrated enone 10 which was converted to thiophenyl ether 11. Pummerer reaction of 11 gave aldehyde 12. In this reaction, aminoalcohol group was converted into 2-CF3-oxazoline group, which is easily hydrolyzed under mild conditions. From compound 13, butenyl chain was successfully introduced for construction of C-ring by RCM. Hydrolysis of TFA amide and introduction of hexenoyl side chain are in progress.
