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.
Humphrey
John M
JM
Department of Chemistry and Biochemistry, The University of Texas, Austin, Texas 78712, USA.
Liao
Yusheng
Y
Ali
Amjad
A
Rein
Tobias
T
Wong
Yue-Ling
YL
Chen
Hui-Ju
HJ
Courtney
Anne K
AK
Martin
Stephen F
SF
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