Total synthesis and revised structure of biyouyanagin A.

Japan as a folk medicine for the treatment of female disorders. This compound exhibited significant and selective inhibitory activity against HIV replication in H9 lymphocytes (EC50= 0.798 mgmL ) compared with noninfected H9 lymphocytes (EC50> 25 mgmL ), which amounts to a therapeutic index (TI) of greater than 31.3. Furthermore, biyouyanagin A strongly inhibited lipopolysaccharide (LPS)-induced cytokine production (at 10 mgmL , IL-10= 0.03; IL-12= 0.02; tumor necrosis factor a (TNF a)= 0.48). In view of the potential of biyouyanagin A as a biological tool and a drug-discovery lead, and to clarify the remaining structural ambiguity (the stereochemistry at the C24 position), we set out to synthesize the two epimers 1a and 1b (Figure 1). Herein we report the total synthesis of both the (24S) and (24R) epimers of biyouyanagin A in their enantiomerically pure form, and the full structural elucidation of the natural product, which required not only assignment of the R configuration at the C24 position, but also revision of the stereochemistry at the C17 and C18 positions (2a and 2b, Figure 1). In our quest to synthesize biyouyanagin A, we decided to employ the rather apparent, but unprecedented [2+2] photocycloaddition reaction that involved the two required components, diene 3a (ent-7-epizingiberene) or 3b (ent-zingiberene) and enone 4, as shown retrosynthetically in Scheme 1a. Proposed as a biosynthetic pathway, this route had the advantage of optimum convergency, but left the stereochemical outcome of the [2+2] cycloaddition open.