Synthesis of Unnatural Amino Acids via Suzuki Cross-Coupling of Enantiopure Vinyloxazolidine Derivatives

Abstract

[formula: see text] (R and S)-alpha-Amino alcohols and alpha-amino acids, including 4-methoxyhomophenylalanine, with a variety of unnatural side chains have been synthesized via palladium-catalyzed cross-coupling Suzuki reactions. The key building blocks 1 and 2, synthesized from the common achiral precursor 2-butene-1,4-diol, were made enantiopure utilizing a Pseudomonas cepacia lipase-catalyzed kinetic resolution. The optimal conditions for the Suzuki cross-coupling and the subsequent oxidations of the resultant alpha-amino alcohols are described.

The Suzuki–Miyaura Cross-Coupling as a Versatile Tool for Peptide Diversification and Cyclization

“…These have been prepared via hydroboration of protected allylglycine [121][122][123][124][125], quenching of a lithiated serine analogue with triisopropylborate [126], a Cu-catalyzed cross-coupling of gem-diborylalkanes with primary alkyl halides [127], and very recently by Pd-catalyzed C(sp 3 )-H bond activation (selected examples are shown in Figure 10, left side) [128]. Campbell prepared bishomophenylalanine derivatives 58 by hydroboration of protected allylated oxazolidine 56 with 9-borabicyclo[3,3,1]nonane (9-BBN), followed by Suzuki-Miyaura reaction with aryl iodides and phenyl bromide in good yields ( Figure 10A) [121].…”

“…The homologated phenylalanine analogues were obtained in mediocre yields (30%-50%) after oxidation with Jones' reagent (CrO 3 /H 2 SO 4 ) (not shown). Comparable work was also published by Sabat, which expanded the scope of the reaction to aryl triflates and heteroaryl bromides as substrates, giving way to oxazolidines like 58 in decent yields [122]. The oxidation protocol was further optimized to obtain the α-amino acid analogues in yields up to 82% with excellent optical purity.…”

Synthesis of Unnatural/Nonproteinogenic α‐Amino Acids

“…The Suzuki reaction has proven useful for the latter, although the amino acid does need to be protected (Scheme 12.11) [41], and sometimes the protected amino alcohol, rather than acid, has been employed [42][43][44].…”

Selective Synthesis of Unnatural α‐, β‐ and γ‐Amino Esters

“…[5] Versatile methodologies are also available for the asymmetric synthesis of β-amino amination product of 1h is converted in two additional steps to a protected chiral 2-methylpyrrolidine 4h, which is an advanced amine intermediate for pharmaceutical drugs, e.g. ABT-239.…”