8(B-4) 抗HIVグアニジンアルカロイドBatzelladine類の全合成及び活性発現機構の解析(口頭発表の部)

抄録

Batzelladines A-E, members of a novel class of guanidine alkaloids containing a tricyclic guanidine subunit, were isolated from Caribbean sponge by scientists at SmithKline Beecham in 1995. Later in 1997, four other metabolites, termed batzelladines F-I, were also obtained from the similar source. Batzelladines A (1), B and D (2) were reported to inhibit the binding of the HIV glycoprotein gp120 to the human CD4 receptor on T cells, while batzelladines F-I induce the dissociation of the protein kinase p56^<lck> from CD4. The unique structures of these guanidine alkaloids and their important biological activities resulting from modulation of protein-protein interaction have inspired considerable synthetic attention. We describe the enantioselective total synthesis of batzelladine A (1) and D (2). Our synthesis features 1) stereoselective construction of the cyclic guanidine system via successive 1,3-dipolar cycloaddition reactions and subsequent cyclizations, 2) one-step formation of the α,β-unsaturated aldehyde 25 from the primary alcohol 19 with TPAP-NMO, providing an efficient route to the lefthand bicyclic guanidine alcohol 18 and 3) direct esterification of the bicyclic carboxylic acid 17 with the guanidine alcohol 18 to construct the whole carbon skeleton of batzelladine alkaloids. The synthetic route we have developed is very straightforward and should be flexible enough to prepare variety of batzelladines and their derivatives. To elucidate the binding inhibition mechanism of batzelladine alkaloids, affinity gel-assisted HPLC analyses were examined. As a result, batzelladines were realized to bind to CD4 selectively.