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 hexahydropyrrolopyrimidines 8 with beta-ketoesters provides efficient asymmetric access to tricyclic guanidines 9 having a syn relationship of the angular C2a and C8a hydrogens. This reaction was employed to realize the first practical enantioselective access to this fragment of batzelladine alkaloids B (2) and E (5). The efficiency of this strategy is illustrated in the synthesis of the dextrorotatory 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 tricyclic portion of batzelladine B (2) is 25aR,28S,30R. The 4-methyl-7-alkyl-1,2,2a,3,4,5,6,7,8,8a-decahydro-5,6,8b-triazaacenaphthalene-3-carboxylic acid subunit, e.g., 29, of batzelladine alkaloids A (1), D (4), F (6), and G was also prepared for the first time by catalytic hydrogenation of tricyclic guanidines 26 having the 2a,8a-anti stereochemistry.
Franklin
Alison S.
AS
Department of Chemistry, 516 Rowland Hall, University of California, Irvine, California 92697-2025.
Ly
Sylvie K.
SK
Mackin
Gilbert H.
GH
Overman
Larry E.
LE
Shaka
A. J.
AJ