An Application of the Phosphine-Catalyzed [4 + 2] Annulation in Indole Alkaloid Synthesis:  Formal Syntheses of (±)-Alstonerine and (±)-Macroline

Abstract

[reaction: see text] An application of the phosphine-catalyzed [4 + 2] annulation in the formal synthesis of alstonerine and macroline is reported. A phosphine-catalyzed [4 + 2] reaction between imine 7a and allene 8 formed the D ring of the target indole alkaloids. A subsequent intramolecular Friedel-Crafts acylation provided the C ring of the bridged tetracycle. Deprotection, followed by methylation of the bridged nitrogen, deoxygenation of the C6 ketone, and reduction of the C16 carbethoxy group provided the previously known intermediate 3.

Enantioselective catalysis and complexity generation from allenoates

“…In a subsequent report, Tran and Kwon applied this method in the target-oriented syntheses of two naturally occurring alkaloids, (AE)-alstonerine and (AE)-macroline. 33 Mechanistically, this [4 + 2]-cycloaddition reaction is rationalized by consideration of zwitterionic intermediate 83 (Scheme 22). a-Substitution of allenoate 84 is thought to deter addition to the imine through the a-centered anion 83a and promote g-centered anion 83c addition to the imine.…”

Phosphine‐Catalyzed [3 + 2] Annulation: Synthesis of Ethyl 5‐(tert‐Butyl)‐2‐Phenyl‐1‐Tosyl‐3‐Pyrroline‐3‐Carboxylate

“…6,7 Our laboratory discovered that α-alkyl allenoates behave as 1,4-dipole–like species in novel [4 + 2] annulations with imines to form tetrahydropyridines. 8 This broadly applicable reaction has since been applied to natural product synthesis 9 and has been developed into an asymmetric process. 10 The utility of the phosphine-catalyzed [4 + 2] annulation was further enhanced upon the successful application of activated alkenes to form functionalized cyclohexenes 11 and of trifluoromethyl ketones to form dihydropyrans.…”

Phosphine‐Catalyzed [4+2] Annulation: Synthesis of Ethyl 6‐Phenyl‐1‐Tosyl‐1,2,5,6‐Tetrahydropyridine‐3‐Carboxylate

“…One of the most broadly useful reactions is the phosphine-catalyzed [4+2] annulation of α-alkyl allenoates and imines to form tetrahydropyridines 7. This reaction, like Lu’s [3+2] reaction, has been applied in natural product syntheses,8,9 and an enantioselective variant of the reaction employing Gladiali’s phosphepine has provided products with up to 99% ee 9. Recently, we disclosed an all-carbon variant of the [4+2] reaction, which we used to synthesize cyclohexenes from α-alkyl allenoates and activated olefins 10…”