Isothiocyanate Strategy for the Synthesis of Quaternary α‐Amino Acids Bearing a Spirocyclic Ring System

Abstract

This study demonstrates that isothiocyanates derived from α‐substituted α‐amino acids are useful building blocks in the heteroannulation reactions with electron‐deficient olefins. The developed strategy proceeds in a cascade manner and involves Michael addition followed by a cyclization via nucleophilic addition. Target, spirocyclic heterocycles bearing either a quaternary α‐amino acid moiety or α‐aminophosphonate group have been efficiently synthesized in very high yield (up to 99%) and with excellent stereocontrol. The usefulness of heterocycles obtained has been demonstrated in selected transformations.magnified image

A review of the synthetic strategies toward spirobarbiturate-fused 3- to 7-membered rings

“…A remarkable solvent effect on the diastereoselectivity was observed in toluene and THF solvent to synthesize a quaternary α-amino acid moiety or α-aminophosphonate core, attached to spirobarbiturate, respectively (Scheme 28). 70 In 2019, Du and co-workers described an example of trifluoromethylated dispirobarbituric acid derivatives created by consecutive Michael and Mannich [3 + 2] cycloaddition reactions aided by a chiral squaramide catalyst. Thus, a highly enantioselective and diastereoselective synthesis of dispirobarbiturate scaffolds containing three stereocenters was achieved using barbiturate-based olefins, and N-2,2,2-trifluoroethyl isatin ketimines 36 (trifluoroethyl-substituted isatin imines) in up to 99% yield, with dr: 99 : 1 and ee up to 99%.…”

Asymmetric Synthesis of Tetrasubstituted α-Aminophosphonic Acid Derivatives

“…More recently, Albrecht and colleagues described the synthesis of tetrasubstituted spirocyclic chiral α-aminoesters and α-aminophosphonates 173 through a conjugate addition of α-isocyanates 171 to conjugated barbiturates 172 in the presence of squaramide catalyst X ( Scheme 34 ) [ 70 ]. Although the scope is limited, spirocyclic α-aminophosphonates 173 are obtained in high yields and stereocontrol (60–99%, 88:12 to >95:5 dr, 92–98% ee).…”

Asymmetric Organocatalytic Synthesis of aza‐Spirocyclic Compounds from Isothiocyanates and Isocyanides

“…Spirocyclic heterocycles bearing a quaternary α-amino acid moiety were obtained by reaction with alkylidene barbiturates with high diastereo-and enantioselectivity (Scheme 31). [48] The reaction was proven to be compatible, after modulating the solvent, with isothiocyanates derived from phosphonate esters to give spirocyclic α-aminophosphonates. Additionally, variability of the dipolarophile was shown by a single example with an olefin derived from Meldrum's acid, providing high diastereoselectivity, although only moderate enantioselectivity.…”