Enantioselective Total Synthesis of the Antitumor Macrolide Rhizoxin D

• Published in: Journal of organic chemistry Vol. 68; no. 11; pp. 4215 - 4234
• Main Authors: Lafontaine, Jennifer A, Provencal, David P, Gardelli, Cristina, Leahy, James W
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 30.05.2003; Amer Chemical Soc
• Subjects: Alkenes - chemistry; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Catalysis; Chemistry; Chemistry, Organic; Cyclization; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with n hetero atom and also o and/or s, se, te hetero atoms; Indicators and Reagents; Lactones - chemical synthesis; Lactones - pharmacology; Macrolides; Molecular Structure; Organic chemistry; Physical Sciences; Preparations and properties; Science & Technology; Stereoisomerism; CARBON BOND FORMATION; 1ST TOTAL SYNTHESIS; TRANSITION-METAL CATALYSIS; DESS-MARTIN PERIODINANE; ASYMMETRIC ALDOL REACTION; WADSWORTH-EMMONS REACTION; FUNGUS RHIZOPUS-CHINENSIS; MACROCYCLIC LACTONE ANTIBIOTICS; STEREOSELECTIVE SYNTHESES; CONTROLLED CARBOMETALATION; Enantioselectivity; Olefination; Alcohol; Lactone; Horner Emmons reaction; Oxygen heterocycle; Macrolide; Total synthesis; Cyclization; Polyenic compound; Lactonization; Chemical synthesis; Oxazole derivatives; Oxygen nitrogen heterocycle
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo034011x

The convergent, highly enantioselective synthesis of rhizoxin D, a natural product possessing potent antitumor and antifungal bioactivity, is described. The C(1)−C(9) fragment of the molecule was synthesized utilizing a threefold pseudosymmetric intermediate ultimately derived from γ-butyrolactone. The central core of rhizoxin D was prepared via a chiral resolution/asymmetric aldol protocol. Several methods for the generation of the polyene fragment were explored, and the side-chain was ultimately prepared from serine in six steps. The unification of the left and right wings of the molecule was achieved using a one-step olefination protocol, and the macrocyclization was carried out using a Horner−Emmons olefination at the C(2)−C(3) olefin.