Application of the tethered Biginelli reaction for enantioselective synthesis of batzelladine alkaloids. Absolute configuration of the tricyclic guanidine portion of batzelladine B

Tethered Biginelli condensation of enantioenriched hexahydropyrrolopyrimidi nes 8 with beta-ketoesters provides efficient asymmetric access to tricycli c guanidines 9 having a syn relationship of the angular C2a and C8a hydroge ns. This reaction was employed to realize the first practical enantioselect ive access to this fragment-of batzelladine alkaloids B (2) and E (5). The efficiency of this strategy is illustrated in the synthesis of the dextroro tatory enantiomer of batzelladine B methanolysis product 10 in 10 steps and 25% overall yield from 2-nonanone and methyl acetoacetate. The asymmetric synthesis of 10 establishes that the absolute configuration of the tricycli c portion of batzelladine B (2) is 25aR,28S,30R. The 4-methyl-7-alkyl-1,2,2 a,3,4,5,6,7,8,8a-decahydro-5,6,8b-triazaacenaphthalene-3-carboxylic acid su bunit, e.g., 29, of batzelladine alkaloids A (1), D (4), F (6), and G was a lso prepared for the first time by catalytic hydrogenation of tricyclic gua nidines 26 having the 2a,8a-anti stereochemistry.