Exploitation of new synthetic reagents and their application to the total synthesis of biologically active natural products

Abstract

Diphenyl phosphorazidate (DPPA), diethyl phosphorocyanidate (DEPC), and trimethylsilyldiazomethane (TMSCHN2) have been introduced as versatile reagents for organic synthesis. Total syntheses of several biologically active natural products containing various different carbon skeletons have been achieved by use of DPPA, DEPC, and reactions developed by our group. Cytotoxic and/or antineoplastic cyclic peptides 1-7 of marine origin have been prepared using DPPA and DEPC as peptide coupling reagents and their cytotoxic activities against L 1210 murine leukemia cells have been explored. Preferred conformation of ascidiacyclamide (4), a representative of cytotoxic cyclic peptides, has been determined by X-ray crystallography and it has been proven that ascidiacyclamide (4) has no ionophoric activity toward alkali metal ions. Synthesis of dolastatin 3 bearing the revised structure 2 has been described. Cytotoxic depsipeptides from a tunicate, didemnins A (11c), B (12c), and their relatives (11b and 12b), have been efficiently prepared by condensation of the key eastern (13) and western (14b and 14a) fragments. The absolute configuration of avellanin B (26b), a fungal cyclic peptide exhibiting a pressor effect, has been determined by its synthesis. Its analog, avellanin A (26a), has been also efficiently prepared. Synthesis of AI-77-B (27), which was isolated from Baccilus pumilus AI-77 and has an interesting antiulcer activity, has been stereoselectively achieved starting from the 6-methylsalicylic acid ester (30), the L-leucinal derivative (31), and D-pyroglutamic acid (36).