Evolution of the Total Synthesis of (−)-Okilactomycin Exploiting a Tandem Oxy-Cope Rearrangement/Oxidation, a Petasis−Ferrier Union/Rearrangement, and Ring-Closing Metathesis

• Published in: Journal of the American Chemical Society Vol. 131; no. 6; pp. 2348 - 2358
• Main Authors: Smith, Amos B, Bosanac, Todd, Basu, Kallol
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 18.02.2009; Amer Chemical Soc
• Subjects: Acetals - chemistry; Aldehydes - chemical synthesis; Aldehydes - chemistry; Chemistry; Chemistry, Multidisciplinary; Cyclization; Lactones - chemical synthesis; Macrocyclic Compounds - chemical synthesis; Oxidation-Reduction; Physical Sciences; Pyrans - chemical synthesis; Pyrans - chemistry; Science & Technology; Stereoisomerism; Streptomyces - chemistry; OXIDATION; DIELS-ALDER; NATURAL-PRODUCTS; CARBONYL-COMPOUNDS; ORGANIC HALIDES; ALDEHYDES; CLAISEN REARRANGEMENT; SELENIUM DIOXIDE; DERIVATIVES; OKILACTOMYCIN
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja8084669

An effective, asymmetric total synthesis of the antitumor antibiotic (−)-okilactomycin (1), as well as assignment of the absolute configuration, has been achieved exploiting a convergent strategy. Highlights of the synthesis include a diastereoselective oxy-Cope rearrangement/oxidation sequence to install the C(1) and C(13) stereogenic centers, a Petasis−Ferrier union/rearrangement to construct the highly functionalized tetrahydropyranone inscribed within the 13-membered macrocycle ring, employing for the first time a sterically demanding acetal, an intramolecular chemoselective acylation to access an embedded bicyclic lactone, and an efficient ring-closing metathesis (RCM) reaction to generate the macrocyclic ring.