178113-59-2

Upstream product

• 178113-60-5 (2S,5S,6R,10R,11S)-5-Benzyl-6-(tert-butyl-dimethyl-silanyloxy)-10-heptyl-2-isopropyl-11-methyl-1,9-dioxa-4-aza-cyclododecane-3,8,12-trione 
• 178113-57-0 (4S,5R)-5-{(R)-1-[(S)-1-((S)-1-Allyloxycarbonyl-2-methyl-propoxycarbonyl)-ethyl]-octyloxycarbonylmethyl}-4-benzyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester 
• 178113-55-8 (4S,5R)-4-Benzyl-5-[(R)-1-((S)-1-benzyloxycarbonyl-ethyl)-octyloxycarbonylmethyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester 
• 178113-58-1 (4S,5R)-4-Benzyl-5-{(R)-1-[(S)-1-((S)-1-carboxy-2-methyl-propoxycarbonyl)-ethyl]-octyloxycarbonylmethyl}-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester 
• 178113-53-6 (4S,5R)-3-((2S,3R)-3-hydroxy-2-methyl-1-oxodecanyl)-4-methyl-5-phenyl-2-oxazolidinone 
• 178113-54-7 benzyl (2S,3R)-3-hydroxy-2-methyldecanoate 
• 178113-56-9 L-2-hydroxy-3-methylbutanoic acid allyl ester 
• 158895-85-3 4(S)-Benzyl-3-(tert-butoxycarbonyl)-2,2-dimethyl-5(R)-oxazolidineacetic acid 
• 181715-13-9 (2S,3R)-3-[(3R,4S)-4-Benzyloxycarbonylamino-3-(tert-butyl-dimethyl-silanyloxy)-5-phenyl-pentanoyloxy]-2-methyl-decanoic acid 
• 181715-09-3 (1R,2R)-1-n-heptyl-2-methyl-3-butenyl acetate 
• 173326-39-1 (3R,4R)-3-methylundec-1-en-4-ol 
• 65138-05-8 (S)-2-hydroxy-3-methylbutyric acid benzyl ester 
• 124-13-0 Octanal 
• 17407-55-5 (S)-2-Hydroxy-3-methylbutanoic acid 

Downstream Products

• 178113-60-5 (2S,5S,6R,10R,11S)-5-Benzyl-6-(tert-butyl-dimethyl-silanyloxy)-10-heptyl-2-isopropyl-11-methyl-1,9-dioxa-4-aza-cyclododecane-3,8,12-trione 

Relevant academic research and scientific papers

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-phenyl-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 γ-hydroxy-β-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. Copyright (C) 1999 Elsevier Science Ltd.

Synthesis and conformational analysis of the multidrug resistance-reversing agent hapalosin and its non-N-methyl analog

Hapalosin was initially synthesized by macrolactonization, and a second synthesis was achieved by cycloamidation. In both syntheses, three of the five stereocenters in hapalosin were established by two Brown allylboration reactions. The synthesis of the non-N-Me analog of hapalosin involved chelation-controlled reduction of a γ-amino-β-keto ester and cycloamidation. In CDCl3 at 25°C, synthetic hapalosin exists as a 2.3:1 mixture of conformers, while its non-N-Me analog exists only as a single conformer. 1H,1H-NOESY and computation reveal that the configuration of the amide bond is responsible for the conformations of the two compounds. The major conformer of hapalosin is found to be an s-cis amide, the minor conformer an s-trans amide, and the non-N-Me analog an s-trans amide. Applying distance constraints to protons that exhibit NOESY correlations, computation shows that the major conformer of hapalosin and the non-N-Me analog have very different conformations. By contrast, the minor conformer of hapalosin and the non-N-Me analog have very similar conformations.

Chemical study on hapalosin, a cyclic depsipeptide possessing multidrug resistance reversing activities: Synthesis, structure and biological activity

Hapalosin 1 possessing a multidrug resistance reversing activity, has been synthesized from the corresponding hydroxy acids A, C and γ-amino acid B. The stereochemistry of the natural product 1 and N-demethylhapalosin 11 is discussed by means of spectroscopic manner as well as molecular modeling studies. Biological evaluation of 1 and 11 indicated that a cis-amide function is a crucial factor for the MDR reversing activity.

Synthetic study on hapalosin, a cyclic depsipeptide possessing multidrug resistance reversing activities

Hapalosin possessing a multidrug resistance reversing activity, has been synthesized from the corresponding hydroxy acids and γ-amino acids. The stereochemistry of the natural product and related derivatives is discussed.