46 抗真菌抗生物質ベナノマイシンAの合成研究(口頭発表の部)

抄録

Benanomicin A, isolated from the culture broth of Actinomadura spadix MH193-16F4, exhibits excellent therapeutic effects against systemic fungal infection in mice and inhibits the infection of T-cell with HIV and the syncytium formation by the virus. This antibiotic consists of a benzo[a]naphthacenedione, D-alanine and 3-O-(D-xylopyranosyl)-D-fucopyranose. The unique structure and activities of benanomicin A prompted us to start a program directed toward the construction of the substituted benzo[a]naphthacenedione skeleton, i.e. benanomi-cinone and analogs. The retrosynthetic analysis of the 5,6-dihydrobenzo[a]naphthacenedione derivative is shown in Scheme 1 which involves Diels-Alder reaction of a tetralone, A-B ring with a naphthoquinone, D-E ring. The synthesis of non-substituted 5,6-dihydrobenzo[a]naphthacenedione (6) was accomplished as shown in Scheme 2. α-Tetralone (1) was converted to methoxy-diene (5) which was easily cyclized with naphthoquinone to give 6 in a good yield. The ester (8) derived from 5 was treated with LDA and TMSCl and chloronaphthoquinone (10) to give 9,14-dihydroxy-11-methoxy-5,6-dihydrobenzo[a]naphthacenedione (11) via ketene acetal (9) .The tri-substitued α-tetralone derivative (18), a key intermediate to benanomicinone, was synthesized from 14 in a low yield. The yield of 18 was improved by the decarboxylation of 21 via 24. Compound 18 was coupled with 10 to give penta-substituted 5,6-dihydrobenzotainaphthaceneciione (26) by a similar method to 6. The synthesis of 14-hydroxy derivative (28 ) is now in progress. The introduction of hydroxy groups at C-5 and -6 positions of 5,6-dihydrobenzo[a]-naphthacenedione will be also discussed.