Evolution of a Protecting-Group-Free Total Synthesis: Studies en Route to the Neuroactive Marine Macrolide (−)-Palmyrolide A

• Published in: Journal of organic chemistry Vol. 77; no. 14; pp. 6271 - 6289
• Main Authors: Tello-Aburto, Rodolfo, Newar, Tara D, Maio, William A
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 20.07.2012; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Organic; Exact sciences and technology; Heterocyclic compounds; 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; MEDIATED COUPLING REACTIONS; PRACTICAL CHIRAL AUXILIARY; CYTOTOXIC MACROLIDES; OLEFIN CROSS-METATHESIS; ONE-POT; LYNGBYA-BOUILLONII; CYCLODEPSIPEPTIDE APRATOXIN-A; STEREOCHEMICAL DETERMINATION; BETA-HYDROXY KETONES; CYCLOPEPTIDE ALKALOIDS; Marine environment; Protecting group; Absolute configuration; Stereochemistry; Aldehyde; Oxygen heterocycle; Chemical synthesis; Macrolide; Degradation product; Diastereomer; Total synthesis
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo301121f

A full account of our synthetic work toward the first total synthesis of the neuroactive marine macrolide (−)-palmyrolide A is described. Our first-generation approach aimed to unlock the unknown C(5)–C(7) stereochemical relationship via the synthesis of four diastereomers of palmyrolide A aldehyde, a known degradation product. When these efforts provided inconclusive results, recourse to synthesizing all possible stereocombinations of the 15-membered macrolide was undertaken. These studies were critical in confirming the absolute stereochemistry, yielding the first total synthesis of (+)-ent-palmyrolide A. Subsequent to this work, the first protecting-group-free total synthesis of natural (−)-palmyrolide A is also reported.