29 THE TOTAL SYNTHESIS OF STREPTONIGRIN

Abstract

Streptonigrin (1), an antitumor antibiotic natural product isolated from a few species of Streptmyces, was shown by chemical studies, CMR and X-ray analysis to have sturucture (1). We report here the first total synthesis of streptonigrin. Epoxydation of aldehyde (4), followed by Grignard reaction with vinylmagnesium bromide gave alcohol (6). Oxidation of (6) yielded the α,β-unsaturated aldehyde (7), which was converted to diene (8). Diels-Alder reaction of (8) with methoxyhydantoin (9) gave the desired adduct (10) along with regioisomer (11). Hydrolysis of adducts (10) and (11), followed by esterification afforded (13), and then aromatization of (13) gave the desired pyridine (14). Rearrangement of N-oxide (15) with acetic anhydride afforded acetate (16), followed by hydrolysis and chlorination gave chloride (18), which was alkylated with N-cyanomethylpyrrolidine to form quaternary salt (19). Treatment of (19) with t-BuOK and then oxalic acid yielded aldehyde (20). Oxidation of (20) with PTFA gave N-oxide (21) which was further oxidized to carboxylic acid (22). Curtius rearrangement of (22) afforded amine (23) which was converted to aldehyde (26) with three steps. This aldehyde (26) was led to hydroxyphosphonate (27) and oxidation of (27) provided ketophosphonate (28). Condensation of (28) with nitroaldehyde (29) gave nitrochalchone (30). Reductive cyclization of (30) gave the tetracyclic compound (31) and removal of sulfonate of (31) yielded the A-ring phenol (32). Fremy's salt oxidation of (32) produced quinone (33), which was converted to the aminoquinone (34). Debenzylation of (34), followed by hydrolysis of the ester group of (35) afforded synthetic streptonigrin (1) indistinguishable from the natural product.