Enantioselective Synthesis of Pyrroloindolines by a Formal [3 + 2] Cycloaddition Reaction

Abstract

(R)-BINOL•SnCl4 was found to catalyze a formal [3+2] cycloaddition reaction between C(3)-substituted indoles and 2-amidoacrylates to provide pyrroloindolines. A variety of pyrroloindolines were prepared with high enantioselectivity in one step from simple precursors. This methodology is expected to facilitate the total synthesis of pyrroloindoline alkaloids, an important class of biologically active natural products.

Enantioselective Synthesis of Tryptophan Derivatives by a Tandem Friedel–Crafts Conjugate Addition/Asymmetric Protonation Reaction

“…In 2010, we reported a new reaction for the preparation of enantioenriched pyrroloindolines ( 3 ) in which ( R )-BINOL•SnCl 4 catalyzes a formal (3 + 2) cycloaddition reaction between 1,3-disubstituted indoles ( 1 ) and benzyl 2-trifluoroacetamidoacrylate ( 2a ) (Scheme 1, a ). 8 Good yields, moderate exo:endo diastereoselectivities, and high enantioselectivities were obtained for a variety of indole substrates (Table 1). The enantio- and diastereoselectivity of pyrroloindoline formation were found to be dependent on the identity of the acrylate; the highest ee values were observed using acrylate 2a .…”

Synthesis of Enantioenriched Indolines by a Conjugate Addition/Asymmetric Protonation/Aza‐Prins Cascade Reaction

“…4,5 Mechanistic investigations suggest that this reaction proceeds by a reversible conjugate addition of 1 to 2, followed by a highly selective, catalyst-controlled protonation of enolate 3, in which a SnCl 4 ·L1 complex serves as a chiral Lewis acid-assisted Brønsted acid (LBA). 6 Subsequent studies in our group determined that persistent indolinium ion 4 can be trapped with hydride to provide direct access to the corresponding indoline 6.…”

“…Exposure of a mixture of indole 7a and amidoacrylate 2a to SnCl 4 (1.2 equiv) and (R)-BINOL (L1, 20 mol %) -the standard conditions developed for the previously reported pyrroloindoline formation 4 -provided hexahydrocarbazole 8 in low yield but with promising levels of diastereo-and enantioselection ( Table 1, entry 1). Presumably 8 arises from a conjugate addition/asymmetric protonation/aza-Prins cyclization cascade, with chloride trapping of the resulting carbocation.…”

“…A screen of additional Lewis acids revealed that ZrCl 4 provides slightly higher yield of 8, although the major diastereomer (8a) was produced with lower ee. Notably, Zr(O t Bu) 4 and related metal alkoxides failed to catalyze the reaction. 10 A further survey of alternate chiral diols in combination with ZrCl 4 determined that (R)-3,3'-dibromo-BINOL (L3) delivers hexahydrocarbazole 8 in 40% yield and 7:1 dr; 8a was formed with 76% ee (entry 7).…”

“…16 In conclusion, a conjugate addition/asymmetric protonation/aza-Prins cyclization reaction to prepare enantioenriched indolines has been developed. This reaction provides direct access to functionalized heterocyclic products in a single step from simple indole derivatives, and is the first example of a transformation in which a ZrCl 4 •BINOL complex serves as a chiral LBA. This transformation demonstrates the utility of asymmetric cascade catalysis for rapidly generating molecules of complexity.…”