Concise Total Synthesis and Stereochemical Revision of all (−)-Trigonoliimines

Abstract

The concise and enantioselective total syntheses of (−)-trigonoliimines A, B, and C are described. Our unified strategy to all three natural products is based on asymmetric oxidation and reorganization of a single bistryptamine, a sequence of transformations with possible biogenetic relevance. We revise the absolute stereochemistry of (−)-trigonoliimines A, B, and C.

Total Synthesis, Stereochemical Assignment, and Biological Activity of All Known (−)-Trigonoliimines

“…Gratifyingly, we discovered that (+)-((8,8-dichlorocamphoryl)sulfonyl) oxaziridine 41 , originally reported by the Davis research group, 40 afforded hydroxyindolenines (+)- 36 and (+)- 38 ( 36 : 38 = 2.2:1) in 95% yield and with an outstanding level of enantioselection for both regioisomers (96% ee, Table 3, entry 12). 8 We envisioned that hydroxyindolenine (+)- 36 would serve as a synthetic precursor for trigonoliimines A ( 1 ) and C ( 3 ) and hydroxyindolenine (+)- 38 as a precursor for trigonoliimine B ( 2 ) and isotrigonoliimine C ( 4 ).…”

“…X-ray crystal structure analysis of the enantiomerically enriched (96% ee) C18-bromide derivative of (−)- 60 enabled us to unequivocally assign the S -configuration at C14. 8 …”

“…All 1 H and 13 C NMR data of our synthetic (−)-trigonoliimines C ( 3 ) matched those provided in the isolation report. 1 While regioisomeric intermediates mentioned above could be separated earlier in the synthetic sequence for independent examination, 8 the ease of separation of (−)-trigonoliimine C ( 3 ) and (−)-isotrigonoliimine C ( 4 ) by silica gel column chromatography allowed a practical processing of the earlier intermediates as mixtures until the final stage of the synthesis. 48 …”

“…Our observations regarding the propensity of bistryptamine 32 to undergo air oxidation (Table 3, entry 2) lends further credence to this hypothesis. 8,49 …”

“…In 2011, we completed the first total synthesis of all known (−)-trigonoliimines A ( 1 ), B ( 2 ) and C ( 3 ) using a synthetic strategy based on asymmetric oxidation and reorganization of a single heterodimeric bistryptamine and revised the absolute stereochemistry of all (−)-trigonoliimines. 8 In a contemporaneous study, Tambar and coworkers reported the total synthesis of (±)-trigonoliimine C, 9 and shortly after, Hao and coworkers published the synthesis of the pentacyclic skeleton of (±)-trigonoliimine C using a similar oxidation and 1,2-alkyl shift strategy. 10 Interest toward these fascinating natural products has continued and Shi and coworkers reported the synthesis of the desmethoxy hexacyclic skeleton of (±)-trigonoliimines A and B using carbanion mediated seven-membered ring formation as a key step.…”