Highly Enantioselective Intermolecular Cu(I)-Catalyzed Cyclopropanation of Cyclic Enol Ethers. Asymmetric Total Synthesis of (+)-Quebrachamine

Abstract

A set of cyclic enol ethers derived from 2,3-dihydrofuran 35 and 3,4-dihydropyran 8 with a varying substitution pattern at the olefinic system were synthesized. Evans's ligand 5 with Cu(I)OTf was found to be an effective catalyst in the cyclopropanation reaction between cyclic enol ethers 14, 19, 28-31, and 33 and ethyl diazoacetate 6 to give diastereoselectivities up to exo/endo = 95:5 and enantioselectivities higher than 95% in nearly all cases. Because of the selective building of a quarternary carbon center and good yields in the formation of bicyclic structures 34c-h, the reaction was used as a key step in the asymmetric synthesis of (+)-quebrachamine 7, an indole alkaloid of the Aspidosperma family. After acid-induced ring opening of bicyclic compound 34f to lactone 40 followed by LiAlH(4) reduction to the masked aldehyde 41, a reaction with tryptamine gave intermediate 42. This alcohol was efficiently converted into the indole alkaloid (+)-quebrachamine 7 in an overall yield of 37% starting from the chiral synthon 34f. Moreover it revealed the absolute configuration of the quarternary center of the cyclopropanation product 34f to be S.

Toward General Access to the <i>Aspidosperma</i>-Type Terpenoid Indole Alkaloids: Synthesis of the Key 3,3-Disubstituted Piperidones through Enantioselective Intramolecular Heck-Type Reaction of Chloroformamides

“…Among these studies, strategies based on chiral auxiliary are dominant, and catalytic enantioselective method remains as a challenging task. [10][11][12][13] Enantioselective Heck reaction has been well recognized as a powerful method to construct quaternary carbon centers (Fig. 2a).…”

Formal total syntheses of classic natural product target molecules via palladium-catalyzed enantioselective alkylation

“…Due to its structural complexity and biological activities, quebrachamine has received considerable attention from the chemistry community. A number of total syntheses have been reported [86–88], with several examples of asymmetric syntheses [89–91]. …”

Catalytic Conversion of Furans and Pyrroles to Natural Products and Analogues Utilizing Donor‐Acceptor Substituted Cyclopropanes as Key Intermediates

“…From the early work of Wenkert and Fowler, it was already known that cyclopropanations to adducts of type 4 and 5 are highly diastereoselective, orienting the ester moiety onto the convex face of the bicycles as well. Although only few enantioselective cyclopropanations of furans with simple diazoesters had been attempted with limited success when we started our program, we were confident that these reactions could be rendered asymmetric, based on the highly efficient copper(I)‐semicorrin and ‐bis(oxazoline) catalysts pioneered independently by the groups of Pfaltz, Masamune, and Evans, which had been already proven to give excellent results for cyclopropanations of dihydrofurans and silylenolethers . Moreover, related aza(bis)oxazolines of these ligands are available that can be readily immobilized on various supports and thus pave the road for scale‐up of such cyclopropanations by facilitating the removal and recycling of the chiral catalysts…”