An enantioselective, modular, and general route to the cytochalasins: synthesis of L-696,474 and cytochalasin B.
The cytochalasins are structurally complex natural products with a broad range of apparently unrelated effects in different biological systems. Different members of the family have variously demonstrated inhibitory activity toward the formation of actin filaments, toward the functioning of HIV protease, and toward the process of angiogenesis. The structural series is defined by a largely conserved, rigid bicyclic isoindolone core that is fused to a macrocyclic appendage. The latter structural component varies widely within the cytochalasins and seems to play an important role in the determination of biological activity. In this work, we describe the development of a convergent and enantioselective synthetic route to the cytochalasins that allows for the late-stage introduction of macrocyclic appendages of different sizes and constitutions. We illustrate the route with the synthesis of the 14-membered macrolactone cytochalasin B (1, an inhibitor of the formation of actin filaments) and the 11-membered macrocarbocyclic cytochalasin L-696,474 (2, an inhibitor of HIV protease) by using common precursors.
Haidle
Andrew M
AM
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
Myers
Andrew G
AG
D002625:Chemistry, Organic / Q000379:methods; D003571:Cytochalasin B / Q000138:chemical synthesis* / Q000737:chemistry; D003572:Cytochalasins / Q000138:chemical synthesis* / Q000737:chemistry; D054833:Isoindoles; D015394:Molecular Structure; D013237:Stereoisomerism
D003572:Cytochalasins; D054833:Isoindoles; C075543:18-dehydroxycytochalasin H; D003571:Cytochalasin B