Synthesis of Unnatural α-Amino Acid Derivatives via a Three-Component Coupling Method Utilizing an Allylpalladium Umpolung

Abstract

Highly substituted unnatural α-amino esters, for example, ethyl 3-alkyl-4-(aryl or vinyl)-2-(N-4-methoxyphenyl­amine)pent-4-enoates were prepared in a regiocontrolled and diastereoselective manner via Pd(II)-catalyzed three-component coupling of boronic acids and allenes with ethyl iminoacetate relying on the umpolung of the traditional electrophilicity of mono-π-allylpalladium complexes. The 2-aminopent-4-enoates were subjected to N-allylation and intramolecular ring-closing metathesis to afford tetrahydropyridines featuring an α-amino ester group.

Key words

amino acids - allyl complexes - multicomponent reactions - umpolung - palladium

References

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15

For a brief discussion of the effects of the nature of the N-protecting group in the imines on the three-component coupling reaction, see reference 6.

16

An X-ray crystallographic analysis of the single crystal of a homoallylic amine arising from the coupling of an N-PMP-protected imine derived from 3-pyridinecarboxaldehyde, nona-1,2-diene, and 4-methoxycarbonylphenylboronic acid indicated that anti-diastereomer was generated with 50:1 diastereoselectivity (see reference 6). However, the preference for the formation of anti-products could not be unequivocally established for reactions with ethyl imino­-acetates.

18

This uncertainty regarding the relative stereochemistry in the major diastereomer of amino esters 1a-g precludes a detailed discussion of the structures of the transition states for the allyl transfer (e.g., open or closed transition states).

23

Computational analyses performed on tetrahydropyridine 3a revealed that the correlations observed by NOE analyses on 3a would be present in both cis- and trans-isomers (see reference 6).