Enantioselective Total Syntheses of Manzamine A and Related Alkaloids

• Published in: Journal of the American Chemical Society 2002-07, Vol.124 (29), p.8584-8592
• Main Authors: Humphrey, John M, Liao, Yusheng, Ali, Amjad, Rein, Tobias, Wong, Yue-Ling, Chen, Hui-Ju, Courtney, Anne K, Martin, Stephen F
• Format: Article
• Language: English
• Subjects: Alkaloids - chemical synthesis; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; Carbazoles; Chemistry; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; Indoles - chemical synthesis; Medical sciences; Miscellaneous. Antibiotics with multiple activities; Organic chemistry; Pharmacology. Drug treatments; Preparations and properties; Pyrroles - chemical synthesis; Stereoisomerism
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja0202964

As a prelude to undertaking the total syntheses of the complex manzamine alkaloids, a series of model studies were conducted to establish the scope and limitations of intramolecular [4 + 2] cycloadditions of N-acylated vinylogous ureas with the trienic substrates 17a,b, 28a,b, and 34. These experiments clearly demonstrated that the geometry of the internal double bond and the presence of an electron-withdrawing group on the diene moiety were essential for the facile and stereoselective formation of the desired cycloadducts. The enantioselective syntheses of the manzamine alkaloids ircinol A (75), ircinal A (5), and manzamine A (1) were then completed by employing a convergent strategy that featured a novel domino Stille/Diels−Alder reaction to construct the tricyclic ABC ring core embodied in these alkaloids. Thus, the readily accessible chiral dihydropyrrole 58 was first converted in a single chemical operation into the key tricyclic intermediate 60. Two ring-closing metathesis reactions were then used to form the 13- and 8-membered rings leading to Z- 72 and 74, the latter of which was quickly elaborated into ircinal A (5) via ircinol A (75). The synthetic 5 thus obtained was converted into manzamine A (1) following literature precedent. This concise synthesis of ircinal A required a total of 24 operations from commercially available starting materials with the longest linear sequence being 21 steps.