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

Hapalosin I (R1 = Me, R2 = OH), a 12-membered cyclic depsipeptide possessing MDR-reversing activity, and its analogs, N-desmethylhapalosin I (R1 = H, R2 = OH) and 8-deoxyhapalosin I (R1 = Me, R2 = H), have been synthesized using macrolactamization as an important ring-forming step. Three building blocks: (2S,3R)-3-(tert-butyldimethylsilyloxy)-2-methyldecanoic acid, benzyl (S)-2-hydroxy-3-methylbutanoate, and (4S,3R)-4-(benzyloxycarbonyl-methylamino)-3-methoxymethoxy-5-phenylpentanoic acid were prepd. from Evans's chiral imide II, H-Val-OH, and Boc-Phe-OH, resp., and were assembled together by applying twice Yamaguchi's coupling methodol. A new and efficient selective N-methylation of gamma -hydroxy-beta -amino ester taking advantage of the vicinal amino alc. function was uncovered in the course of this study. Thus, treatment of compd. III with HCHO in the presence of catalytic amt. of p-TsOH followed by redn. (NaBH3CN, TFA, CH2Cl2) of the so-formed oxazolidine IV gave the N-methylated product V. Furthermore, a dual role of oxazolidine as protecting group of vicinal amino alc. and latent N-Me function was established which allowed synthesizing both hapalosin and N-desmethylhapalosin from the same linear precursor VI in a step-efficient and atom economic way. In contrast to hapalosin and N-desmethylhapalosin, the amide bond of 8-deoxyhapalosin exists at room temp. (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-deoxyhapalosin was obsd. in K562 R and S/Adriblastine against human erythroleucemic cell lines indicating thus the important contribution of hydroxy group to the bioactivity of hapalosin. [on SciFinder (R)]


Published in:
Bioorganic & Medicinal Chemistry, 7, 5, 737-747
Year:
1999
Keywords:
Note:
CAN 131:157966
34-3
Amino Acids, Peptides, and Proteins
Institut de Chimie des Substances Naturelles, CNRS,Gif-sur-Yvette,Fr.
Journal
0968-0896
written in English.
182621-47-2P (8-Deoxyhapalosin) Role: BAC (Biological activity or effector, except adverse), BSU (Biological study, unclassified), PRP (Properties), SPN (Synthetic preparation), BIOL (Biological study), PREP (Preparation) (total synthesis and conformational studies of hapalosin, N-desmethylhapalosin and 8-deoxyhapalosin); 124-13-0 (Octanal); 13734-34-4; 65138-05-8 (Benzyl 2S-hydroxy-3-methylbutanoate) Role: RCT (Reactant), RACT (Reactant or reagent) (total synthesis and conformational studies of hapalosin, N-desmethylhapalosin and 8-deoxyhapalosin); 72155-47-6P; 101711-78-8P; 112271-08-6P; 174623-90-6P; 182621-36-9P; 182621-37-0P; 182621-38-1P; 182621-40-5P; 182621-41-6P; 182621-43-8P; 182621-44-9P; 182621-46-1P; 182822-93-1P; 223908-34-7P; 236747-32-3P; 236747-33-4P; 236747-34-5P; 236747-35-6P; 236749-56-7P Role: RCT (Reactant), SPN (Synthetic preparation), PREP (Preparation), RACT (Reactant or reagent) (total synthesis and conformational studies of hapalosin, N-desmethylhapalosin and 8-deoxyhapalosin); 72155-46-5P; 159542-04-8P (Hapalosin); 178113-59-2P (N-Desmethylhapalosin); 182621-42-7P; 236747-29-8P; 236747-30-1P Role: SPN (Synthetic preparation), PREP (Preparation) (total synthesis and conformational studies of hapalosin, N-desmethylhapalosin and 8-deoxyhapalosin)
Laboratories:




 Record created 2010-11-25, last modified 2018-03-17


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