Pyranonaphthoquinone antibiotics. Part 2. Syntheses of (±)-nanaomycin A and (±)-eleutherins

Abstract

Two routes for the synthesis of (±)-nanaomycin A (1) starting with 2-bromo-8-methoxy-1,4-naphthoquinone (2) are described. The benzindanone (3) prepared from (2) in three steps was treated with methylmagnesium iodide and then with hydrochloric acid to afford the benzindene (8). Lemieux–Johnson oxidation of (8) gave the ketoaldehyde (9), which was converted into the conjugated ester (10) by reaction with methoxycarbonylmethylenetriphenylphosphorane. Reductive cyclisation of (10) with sodium borohydride afforded a ca. 1 : 1.9 mixture of the cis-naphthopyran (11) and its trans-isomer (12). Oxidative demethylation of (11) and (12) with cerium (IV) followed by treatment with aluminium chloride yielded the corresponding quinones (15) and (16). Ester hydrolysis of (16) formed (±)-nanaomycin A (1). Reductive methylation of the 2-allyl derivative of (2) afforded the bromonaphthalene (18), which was treated with butyl-lithium followed by acetaldehyde to give the naphthylcarbinol (19). The lactol (20) obtained by Lemieux–Johnson oxidation of (19) was treated with trimethyl phosphonoacetate–sodium hydride to yield a ca. 2.1 : 1 mixture of the naphthopyrans (11) and (12). Cyclisation of (19) with mercury-(II) acetate–sodium borohydride yielded a ca. 1 : 0.9 mixture of the cis-naphthopyran (21) and its trans-isomer (22), which were oxidatively demethylated to give (±)-eleutherin (4) and (±)-isoeleutherin (5) respectively.