Racemization in Suzuki Couplings: A Quantitative Study Using 4-Hydroxyphenylglycine and Tyrosine Derivatives as Probe Molecules

Abstract

Reaction conditions considered to be typical in Suzuki couplings can cause significant (up to 34% of the unwanted enantiomer) loss of optical purity in sensitive substrates such as hydroxyphenylglycine 1. This may be remedied using sodium succinate instead of sodium carbonate as base, but chemical yields are somewhat lower. Optically pure biaryl amino acids related to those found in the chloropeptins and vancomycin were synthesized by Suzuki coupling of 1 with indolylboronic acids 6-8 and with cyclic boronic acid 9.

Benzoxaboroles – Old compounds with new applications

“…The most important synthetic application of benzoxaboroles is their use in Suzuki-Miyaura coupling (Scheme 6) [22,24,32,[38][39][40][42][43][44][45][46][47][48][49]. In this reaction benzoxaboroles or their esters react with aryl halides to give ortho-arylsubstituted benzyl alcohols in high yield.…”

Intramolecular Suzuki–Miyaura Reaction for the Total Synthesis of Signal Peptidase Inhibitors, Arylomycins A2 and B2

“…[22,23,37] The inherent need for a base in such cross-coupling reactions poses an epimerization problem. [38] It was assumed that the presence of the unprotected phenol could minimize the epimerization of 21. Treatment of a solution of 21 in DMSO (c = 0.02 m, 908C) in the presence of [PdCl 2 A C H T U N G T R E N N U N G (dppf)] [34] (0.05 equiv) and K 2 CO 3 (7 equiv) afforded macrocycle 23 in an encouraging 29 % yield (Table 1, entry 1).…”

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

“…Under these optimized conditions, a series of novel 5-substituted histidines 22 were prepared, but only in moderate yields and facilitated under microwave (MW) conditions. In an attempt to suppress the racemization of protected 3-bromo-4-methoxyphenylglycine (not shown), a substrate sensitive for racemization, Prieto and colleagues studied the Suzuki-Miyaura cross-coupling of protected phenylglycine with various aryl boronic acids [94]. It was found that, by means of mild bases, such as sodium succinate and potassium acetate, racemization could be avoided.…”

“…Similarly, Kotha synthesized dimers of protected phenylalanine 71 with racemic 4-boronophenylalanine and 4-iodophenylalanine ( Figure 11), along with several unnatural bis-armed amino acids containing a variable number (one to five) of benzene rings [131]. In addition to their investigations on the racemization of phenylglycine under Suzuki-Miyaura conditions [94], Prieto further elaborated on the cross-coupling between 4-hydroxyphenylglycine and tyrosine or tryptophan derived building blocks [132]. Using standard reaction conditions, up to 32% of undesired diastereoisomer was found.…”