A General Methodology for the Enantioselective Synthesis of 1‐Substituted Tetrahydroisoquinoline Alkaloids

Abstract

Starting from tricyclic lactam 2, which is easily accessible by cyclocondensation of δ‐oxoester 1 with (R)‐phenylglycinol, a three‐step synthetic route to enantiopure 1‐substituted tetrahydroisoquinolines, including 1‐alkyl‐, 1‐aryl‐, and 1‐benzyltetrahydroisoquinoline alkaloids, as well as the tricyclic alkaloid (–)‐crispine A, has been developed. The key step is a stereoselective α‐amidoalkylation reaction using the appropriate Grignard reagent.

Single step syntheses of (1S)-aryl-tetrahydroisoquinolines by norcoclaurine synthases

“…Enantioselective syntheses of small molecules are meaningful because each enantiomer can possess different biological activities. Synthetic routes involve a chiral inductor 9 or most commonly, a stereoselective reduction of the imine using an inorganic catalyst (often iridium-based) [10][11][12] . These catalysts can, however have narrow substrate scopes.…”

Cyclocondensation Reactions between 2‐Acyl‐3‐indoleacetic Acid Derivatives and Phenylglycinol: Enantioselective Synthesis of 1‐Substituted Tetrahydro‐β‐carboline Alkaloids

“…In previous work we have demonstrated that lactam 1, easily accessible by a cyclocondensation reaction of methyl 2-formyl-3,4dimethoxyphenylacetate with (R)-phenylglycinol, provides general access to enantiopure 1-substituted tetrahydroisoquinoline alkaloids [11] (Scheme 1). The key step of the synthetic sequence is a stereoselective Grignard reagent-promoted α-amidoalkylation reaction for the introduction of the substituent at the hydroisoquinoline C-1 position.…”

Enantioselective Synthesis of Alkaloids from Phenylglycinol-Derived Lactams

“…A related approach involving the direct generation of C-10b substituted lactams starting from acylphenyl-acetic acid derivatives has been reported by Meyers [32]. The above protocol provides access to (-)-norcryptostyline II, (-)-norcryptostyline III, and the alkaloids (-)salsolidine and (-)-O,O-dimethylcoclaurine [33]. Taking into account previous correlations [34], the above syntheses also constitute a formal synthesis of the alkaloids (-)-carnegine, (+)-cryptostyline II, (+)cryptostyline III, (+)-O-methylarmepavine, and (+)demethylcoclaurine (Scheme 24).…”