Asymmetric Synthesis of α-Allyl-α-Aryl α-Amino Acids by Tandem Alkylation/π-Allylation of α-Iminoesters

Abstract

The first asymmetric synthesis of α-allyl-α-aryl α-amino acids by means of a three-component coupling of α-iminoesters, Grignard reagents, and cinnamyl acetate is reported. Notably, the enolate from the tandem process provides a much higher level of reactivity and selectivity than the same enolate generated via direct deprotonation, presumably due to differences in the solvation/aggregation state. A novel method for removal of a homoallylic amine protecting group delivers the free amine congeners. The α-allyl group offers a means to generate further valuable α-amino acid structures as exemplified by ring closing metathesis to generate a higher ring homologue of α-aryl-proline.

α-Allyl-α-aryl α-Amino Esters in the Asymmetric Synthesis of Acyclic and Cyclic Amino Acid Derivatives by Alkene Metathesis

“… 8 α-Aryl α-amino acids pose a challenge to AAA because of the large steric bulk of the aryl ring near the nucleophilic carbon of the α-amino acids. Recently, we developed an asymmetric method for synthesizing α-allyl-α-aryl α-amino acids, 9 which relies on the formation of a chelated magnesium enolate 10 that is generated in situ. This work was the first example of an asymmetric tandem N -alkylation/π-allylation of α-iminoesters (Scheme 1 ).…”

“…Scheme 2 displays representative examples of the three-component coupling by N -alkylation/π-allylation of α-iminoesters. 9 The phenyl substituent on 1 could be substituted with electron-donating or -withdrawing groups, representing the first asymmetric synthesis of α-allyl-α-aryl α-amino acids where the aryl is other than phenyl. 7 Further variation of the phenyl group on 2 to the 2-naphthalene or 2-thiophene also proceeded well.…”

The chemistry of the carbon-transition metal double and triple bond: Annual survey covering the year 2014

“…256) [665], homoisofagomines and analogs [666], cycloheptenes derived from two proline units [667], tuberostemospiroline and stemona lactone R [668], a cyclic α-amino acid derivative (e.g. 257) [669], tetrapetolone (through a diastereoselective RCM employing a substrate with diastereotopic vinyl groups using a chiral molybdenum complex catalyst) [670], and tricyclic IAP inhibitors (e.g. 258) [671]; (14) seven-and eight-membered ring allylic amines (and related acyclic allylamines through cross metathesis) [672]; (15) seven-and eight-membered ring cyclic hydrazines (e.g.…”

Recent Advances in Asymmetric Catalytic Methods for the Formation of Acyclic α,α-Disubstituted α-Amino Acids

“…Specifically, N-alkylation provides enolate 15, which undergoes palladium-catalyzed π-allylation with ligand 16 to provide amino ester precursors 17 (72-89% yield, 74-92% ee, Scheme 4). 18 With a homoallylic Grignard, the N-alkyl group was readily removed using Grotjahn's catalyst 19 (Figure 1) to generate the primary amines. The PMP group is removed using CAN.…”