Core-structure-oriented asymmetric organocatalytic substitution of 3-hydroxyoxindoles: application in the enantioselective total synthesis of (+)-folicanthine.

rial and cytostatic activity, but is also a potent inhibitor of a lysine-specific histone methyltransferase. The compound WIN 64821, first isolated from Aspergillus sp., is a potent competitive substance P antagonist with respect to human neurokinin-1 and the cholecystokinin B receptor. Moreover, other members of the cyclotryptamine alkaloid family have also been found to exhibit important biological and pharmaceutical activities. In addition to their wide range of bioactivities, the cyclotryptamine alkaloids contain an octahydro-3a,3’abispyrrolo[2,3-b]indole subunit (core structure A, Figure 1), which is characterized by vicinal all-carbon quaternary stereogenic centers. These compounds have been a longstanding challenge in organic synthesis. The unique structural arrays and interesting biological activities displayed by these alkaloids have led to a demand for efficient asymmetric synthetic methods. Much effort has been directed toward the development of new synthetic methods for the construction of hexahydropyrroloindole skeletons from research groups around the world. Overman and co-workers reported the enantioselective total synthesis of optically pure chimonanthines, wherein intramolecular double Heck and dialkylation reactions were exploited to construct the cyclotryptamine core, and the stereochemical control came from a tartrate derivative. Movassaghi and co-workers have established a reductive homodimerization of 3-bromo-hexahydropyrroloindole, readily derived from l-tryptophan, which provided facile construction of the vicinal quaternary stereogenic centers that led to the enantioselective total synthesis of several optically pure cyclotryptamine alkaloids. Very recently, Sodeoka and co-workers applied a related strategy to the total synthesis of (+)-chaetocin. In addition, Overman and co-workers have described the catalyst-controlled enantioselective total syntheses of cyclotryptamine alkaloids from meso derivates of the core structure A. 11] In spite of these elegant achievements, the development of an enantioselective catalytic method to access cyclotryptamine structures of type A still holds great importance in the total synthesis of the hexahydropyrroloindole alkaloid family. Over the past several years, numerous endeavors have been directed toward the enantioselective synthesis of allcarbon quaternary 3,3’-disubstituted oxindoles, but these protocols have not provided a chiral intermediate for the synthesis of the 3a,3a’-bispyrrolidino[2,3-b]indoline skeleton. The unmet challenge of this catalytic enantioselective synthesis prompted us to consider a new approach. Our strategy to synthesize the core structure A, as indicated by the retrosynthetic analysis in Scheme 1, involves accessing structures of type A from diamide 1 by the Rodrigo protocol. The diamide 1 would be prepared from 2 through oxidation/ alkylation reactions. A Beckmann rearrangement reaction would give 2 from 3, which is considered to be the key intermediate for the synthesis of the core structure A, and could be obtained from an enantioselective substitution Figure 1. Representative cyclotryptamine alkaloids. Bn =benzyl.