Modular Total Synthesis of Archazolid A and B

• Published in: Journal of organic chemistry Vol. 74; no. 19; pp. 7220 - 7229
• Main Authors: Menche, Dirk, Hassfeld, Jorma, Li, Jun, Mayer, Kerstin, Rudolph, Sven
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 02.10.2009; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Organic; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with n hetero atom and also o and/or s, se, te hetero atoms; Heterocyclic compounds with o, s, se, te hetero atom and condensed derivatives; Macrolides - chemical synthesis; Macrolides - chemistry; Molecular Conformation; Organic chemistry; Physical Sciences; Preparations and properties; Science & Technology; Stereoisomerism; Thiazoles - chemical synthesis; Thiazoles - chemistry; Vacuolar Proton-Translocating ATPases - antagonists & inhibitors; STRUCTURAL ELUCIDATION; THIOL AUXILIARY; AMINO-ACIDS; MYXOBACTERIUM CYSTOBACTER-VIOLACEUS; ALDOL REACTIONS; STEREOCHEMICAL DETERMINATION; PALLADIUM-CATALYZED VINYLATION; V-ATPASE INHIBITOR; ANTI; ARCHANGIUM-GEPHYRA; Antineoplastic agent; Hydroboration; Heck reaction; Molecular interaction; Horner Emmons reaction; Selectivity; Oxygen heterocycle; Aldol condensation; Macrocycle; Alkene; Structure activity relation; Asymmetric synthesis; Macrocyclization; Chemical synthesis; Sulfur nitrogen heterocycle; Molecular flexibility; Trienic compound; Enzyme; Olefination; Adenosinetriphosphatase; Enzyme inhibitor; Organic boron compounds; Steric hindrance; Lactone; Dienic compound; Macrolide; Diastereoselectivity; Total synthesis; Polyketide; Antibiotic; Hydrolases; Ethylenic compound; Nucleophile; Successive reaction
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo901565n

A modular total synthesis of the potent V-ATPase inhibitors archazolid A and B is reported. The convergent preparation was accomplished by late-stage diversification of joint intermediates. Key synthetic steps involve asymmetric boron-mediated aldol reactions, two consecutive Still−Gennari olefinations to set the characteristic (Z,Z)-diene system, a Brown crotyboration, and a diastereoselective aldol condensation of highly elaborate intermediates. For macrocyclization, both an HWE reaction and a Heck coupling were successfully employed to close the 24-membered macrolactone. During the synthetic campaign, a generally useful protocol for an E-selective Heck reaction of nonactivated alkenes and a method for the direct nucleophilic displacement of the Abiko−Masamune auxiliary with sterically hindered nucleophiles were developed. The expedient and flexible strategy will enable further SAR studies of the archazolids and more detailed evaluations of target-inhibitor interactions.