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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

Stereochemical Stability of Phenylglycine in Peptide Synthesis: Stereoretentive Coupling and Deprotection Strategies

by
Zeping Wang
1,
Shoko Ishikawa
1,
Yuki Fukuda
1,
Sayaka Yamada
1,
Meika Inomoto
1,
Desita Triana Aziz
1,
Xueyu Yang
1,
Zetry Puteri Tachrim
1,2,
Takeyuki Suzuki
3,
Yuta Murai
1 and
Makoto Hashimoto
1,*
1
Division of Applied Science, Graduate School of Agriculture, Hokkaido University, Sapporo 060-8589, Japan
2
Research Center for Pharmaceutical Ingredient and Traditional Medicine, National Research and Innovation Agency, Kawasan Sains Teknologi (KST) BJ Habibie, Serpong, South Tangerang 15314, Indonesia
3
The Institute of Scientific and Industrial Research, Osaka University, Mihogaoka, Ibaraki-shi, Osaka 567-0047, Japan
*
Author to whom correspondence should be addressed.
Organics 2026, 7(3), 27; https://doi.org/10.3390/org7030027
Submission received: 12 May 2026 / Revised: 3 June 2026 / Accepted: 29 June 2026 / Published: 3 July 2026
Versions Notes

Abstract

Phenylglycine (Phg) is a nonproteinogenic α-amino acid found in various bioactive molecules. The C-terminal activation of N-acyl Phg is often accompanied by oxazolone-mediated racemization, arising from the direct attachment of the phenyl ring to the α-carbon. After peptide bond formation with another chiral amino acid, this stereochemical erosion is observed as Phg-site epimerization and diastereomer formation. N-acyl activated esters, particularly N-hydroxysuccinimide (OSu) esters, are widely used for peptide bond formation with proteinogenic α-amino acids. Our previous study on N-trifluoroacetyl phenylglycine (TFA-Phg-OH) revealed that Phg-site epimer formation could still occur when TFA-Phg-OSu was employed as an acyl donor for coupling with amino acid ester hydrochlorides (AA–OMe·HCl) in the presence of a soluble organic base. To address these issues, in this study, we report a base-limited one-pot coupling of TFA-Phg-OH with α-amino acid ester hydrochlorides (AA–OR·HCl; R = Me or tert-Bu) using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD·HCl), which effectively suppresses Phg epimerization. The resulting TFA-Phg–AA–OR dipeptides (AA = Ala, Val, Leu, Met, Phg) were all obtained at a >60% yield with a diastereomeric excess (de) ≥ 98.5%. Notably, reducing the amount of triethylamine further minimized epimer formation, while Ba(OH)2·8H2O and trifluoroacetic acid enabled stereoretentive deprotection of the N-TFA group and tert-butyl ester, respectively. This workflow provides practical access to both protected and deprotected Phg–AA motifs, thereby facilitating the preparation of unprotected Phg-containing peptide building blocks.
Keywords: phenylglycine (Phg); Phg epimerization; diastereomeric excess; carbodiimide coupling; trifluoroacetyl (TFA) protection; Ba(OH)2 deprotection; liquid-phase peptide synthesis phenylglycine (Phg); Phg epimerization; diastereomeric excess; carbodiimide coupling; trifluoroacetyl (TFA) protection; Ba(OH)2 deprotection; liquid-phase peptide synthesis

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MDPI and ACS Style

Wang, Z.; Ishikawa, S.; Fukuda, Y.; Yamada, S.; Inomoto, M.; Aziz, D.T.; Yang, X.; Tachrim, Z.P.; Suzuki, T.; Murai, Y.; et al. Stereochemical Stability of Phenylglycine in Peptide Synthesis: Stereoretentive Coupling and Deprotection Strategies. Organics 2026, 7, 27. https://doi.org/10.3390/org7030027

AMA Style

Wang Z, Ishikawa S, Fukuda Y, Yamada S, Inomoto M, Aziz DT, Yang X, Tachrim ZP, Suzuki T, Murai Y, et al. Stereochemical Stability of Phenylglycine in Peptide Synthesis: Stereoretentive Coupling and Deprotection Strategies. Organics. 2026; 7(3):27. https://doi.org/10.3390/org7030027

Chicago/Turabian Style

Wang, Zeping, Shoko Ishikawa, Yuki Fukuda, Sayaka Yamada, Meika Inomoto, Desita Triana Aziz, Xueyu Yang, Zetry Puteri Tachrim, Takeyuki Suzuki, Yuta Murai, and et al. 2026. "Stereochemical Stability of Phenylglycine in Peptide Synthesis: Stereoretentive Coupling and Deprotection Strategies" Organics 7, no. 3: 27. https://doi.org/10.3390/org7030027

APA Style

Wang, Z., Ishikawa, S., Fukuda, Y., Yamada, S., Inomoto, M., Aziz, D. T., Yang, X., Tachrim, Z. P., Suzuki, T., Murai, Y., & Hashimoto, M. (2026). Stereochemical Stability of Phenylglycine in Peptide Synthesis: Stereoretentive Coupling and Deprotection Strategies. Organics, 7(3), 27. https://doi.org/10.3390/org7030027

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