Total synthesis and conformational studies of hapalosin, N-desmethylhapalosin and 8-deoxyhapalosin.
Hapalosin (2), a 12-membered cyclic depsipeptide possessing MDR-reversing activity, and analogues (3) and (4) have been synthesized using macrolactamization as an important ring-forming step. Three building blocks: (2S,3R)-3-(tert-butyldimethylsilyloxy)-2-methyl-decanoic acid (13), benzyl (S)-2-hydroxy-3-methylbutanate (14), and (4S,3R)-4-(benzyloxycarbonyl-methylamino)-3-methoxymethoxy-5-pheny l-pentanoic acid (28) were prepared from Evans's chiral imide (9), L-valine, and L-N-Boc phenylalanine (17), respectively, and were assembled together by applying twice Yamaguchi's coupling methodology. A new and efficient selective N-methylation of gamma-hydroxy-beta-amino ester 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 presence of catalytic amount of pTsOH followed by reduction (NaBH3CN, TFA, CH2Cl2) of the so-formed oxazolidine 24 gave the N-methylated product 25. Furthermore, a dual role of oxazolidine as protecting group of vicinal amino alcohol and latent N-methyl function was established which allowed synthesizing both hapalosin (2) and N-desmethylhapalosin (3) from the same linear precursor 32 in a step-efficient and atom economic way. In contrast to hapalosin (2) and N-desmethyl analogue (3), the amide bond of 8-deoxy hapalosin (4) exists at room temperature (CDCl3) exclusively in s-cis conformation as evidenced by NOE studies. This observation has been explained on the basis of computational studies. No significant MDR reversing activity of 8-deoxy hapalosin (4) was observed in K562 R and S/Adriblastine against human erythroleucemic cell lines indicating thus the important contribution of hydroxy group to the bioactivity of hapalosin.
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette, France.
B
B
Wagner
G I
GI
Gonzalez
M E
ME
Tran Hun Dau
J
J
Zhu
D047630:Depsipeptides; D018432:Drug Resistance, Multiple; D006801:Humans; D020128:Inhibitory Concentration 50; D020014:K562 Cells; D007700:Kinetics; D007769:Lactams / Q000138:chemical synthesis* / Q000737:chemistry*; D007783:Lactones / Q000138:chemical synthesis* / Q000737:chemistry*; D018942:Macrolides / Q000138:chemical synthesis* / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D008958:Models, Molecular; D011487:Protein Conformation; D014407:Tumor Cells, Cultured
C121488:8-deoxyhapalosin; D047630:Depsipeptides; D007769:Lactams; D007783:Lactones; D018942:Macrolides; C121489:desmethylhapalosin; C111358:hapalosin