Total synthesis and conformational studies of hapalosin, N-desmethylhapalosin and 8-deoxyhapalosin

Hapalosin (2), a 12-membered cyclic depsipeptide possessing MDR-reversing a ctivity, and analogues (3) and (4) have been synthesized using macrolactami zation as an important ring-forming step. Three building blocks: (2S, 3R)-3 -(tert-butyldimethylsilyloxy)-2-methyl-decanoic acid (13), benzyl (S)-2-hyd roxy-3-methylbutanate (14), and (4S,3R)-4-(benzyloxycarbonylmethylamino)-3- methoxymethoxy-5-phenyl-pentanoic acid (28) were prepared from Evans's chir al imide (9), L-valine, and L-N-Boc phenylalanine (17), respectively, and w ere assembled together by applying twice Yamaguchi's coupling methodology. A new and efficient selective N-methylation of gamma-hydroxy-beta-amino est er taking advantage of the vicinal amino alcohol function was uncovered in the course of this study. Thus, treatment of compound 19 with HCHO in the p resence of catalytic amount of pTsOH followed by reduction (NaBH3CN, TFA, C H2Cl2) of the so-formed oxazolidine 2;4 gave the N-methylated product 25. F urthermore, a dual role of oxazolidine as protecting group of vicinal amino alcohol and latent N-methyl function was established which allowed synthes izing both hapalosin (2) and N-desmethylhapalosin (3) from the same linear precursor 32 in a step-efficient and atom economic way. In contrast to hapa losin (2) and N-desmethyl analogue (3), the amide bond of 8-deoxy hapalosin (4) exists at room temperature (CDCl3) exclusively in s-cis conformation a s evidenced by NOE studies. This observation has been explained on the basi s of computational studies. No significant MDR reversing activity of 8-deox y hapalosin (4) was observed in K562 R and S/Adriblastine against human ery throleucemic cell lines indicating thus the important contribution of hydro xy group to the bioactivity of hapalosin. (C) 1999 Elsevier Science Ltd. Al l rights reserved.