The design and synthesis of novel michellamine B analogues targeting HIV

The dimeric naphthylisoquinoline alkaloid michellamine B, with its moderate anti-HIV activity, has gained significant interest as a potential lead compound. Herein, both monomeric and dimeric analogues with novel isoquinoline units were synthesized to evaluate the importance of this isoquinoline unit for HIV RT inhibitory activity. The synthesis started from the preparation of key precursors of naphthylboronic acid/ester and halogenated dihydroisoquinolines. The naphthylboronic acid 37 was synthesized by a Diels-Alder method over 8 steps proceeding in 37% overall yield from commercially available 3,3-dimethylacrylic acid 59. The naphthylboronic ester 38, with an ethyl ester substituent in the naphthyl ring, was prepared by a Wittig method over 7 steps with an overall yield of 43%. Halogenated 3,4-dihydroisoquinolines (39-41) featuring methoxy groups and double bonds between C1 and N were obtained from a four-step synthesis proceeding in 39-48% overall yields from commercially available benzaldehydes. Brominated 3,4-dihydroisoquinolin-1(2H)-ones 42 with a carbonyl group were successfully prepared over 4 steps with an overall yield of 18%.