Enantioselective total syntheses of manzamine a and related alkaloids.
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.
Department of Chemistry and Biochemistry, The University of Texas, Austin, Texas 78712, USA.
John M
JM
Humphrey
Yusheng
Y
Liao
Amjad
A
Ali
Tobias
T
Rein
Yue-Ling
YL
Wong
Hui-Ju
HJ
Chen
Anne K
AK
Courtney
Stephen F
SF
Martin
D000470:Alkaloids / Q000138:chemical synthesis*; D002227:Carbazoles; D007211:Indoles / Q000138:chemical synthesis*; D011758:Pyrroles / Q000138:chemical synthesis*; D013237:Stereoisomerism
D000470:Alkaloids; D002227:Carbazoles; D007211:Indoles; D011758:Pyrroles; C078290:manzamine A