Decarboxylative-Allylation of Pyroglutamic Acid Derivatives: Stereocontrolled Access to Acyclic and Conformationally Restricted α,γ-Disubstituted γ-Amino Acids

Casas-Morales, Hugo; Hernández, Dácil; Ordoñez, Mario; Boto, Alicia; Romero-Estudillo, Ivan

doi:10.3390/molecules31122087

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Decarboxylative-Allylation of Pyroglutamic Acid Derivatives: Stereocontrolled Access to Acyclic and Conformationally Restricted α,γ-Disubstituted γ-Amino Acids

by

Hugo Casas-Morales

¹,

Dácil Hernández

²,

Mario Ordoñez

¹

,

Alicia Boto

^2,*

and

Ivan Romero-Estudillo

^1,*

¹

Centro de Investigaciones Químicas-IICBA, Universidad Autónoma del Estado de Morelos, Av. Universidad 1001, Cuernavaca 62209, Mexico

²

Instituto de Productos Naturales y Agrobiología del CSIC, Avda. Astrofísico Fco. Sánchez, 3, 38206 La Laguna, Spain

^*

Authors to whom correspondence should be addressed.

Molecules 2026, 31(12), 2087; https://doi.org/10.3390/molecules31122087 (registering DOI)

Submission received: 25 May 2026 / Revised: 10 June 2026 / Accepted: 11 June 2026 / Published: 14 June 2026

(This article belongs to the Special Issue A Themed Issue in Honor of the 20th Anniversary of the Mexican Academy of Organic Chemistry (AMQO))

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Abstract

The synthetic strategy relies on the highly diastereoselective alkylation at the C4 position of L-pyroglutamic acid derivatives, followed by a decarboxylation-allylation process that enables the incorporation of diverse substituents, including aromatic substituents, affording trans-3,5-disubstituted γ-lactams with excellent diastereiosmeric ratio (dr > 98:2). The resulting γ-lactams were efficiently transformed into a series of α,γ-disubstituted γ-amino acids through hydrogenation and acidic hydrolysis. Furthermore, cross-metathesis reactions with styrene and 1-decene enabled the introduction of structurally diverse lipophilic side chains, furnishing the corresponding γ-amino acids in good overall yields (71–77%) and high diastereoisomeric ratio from >98:2 to 92:8. In addition, N-allylation followed by ring-closing metathesis and hydrogenation provided access to a previously unexplored conformationally constrained γ-amino acid. Overall, seven α,γ-disubstituted γ-amino acids, including fluorinated and conformationally restricted derivatives, were synthesized from common intermediates with high stereocontrol. The developed methodology offers a versatile platform for the preparation of structurally diverse and underexplored γ-amino acid building blocks of potential interest in peptide synthesis, medicinal chemistry, and antimicrobial agent development.

Keywords: γ-amino acids; diastereoselective alkylation; decarboxylation-allylation; conformationally constrained; stereoselective synthesis

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MDPI and ACS Style

Casas-Morales, H.; Hernández, D.; Ordoñez, M.; Boto, A.; Romero-Estudillo, I. Decarboxylative-Allylation of Pyroglutamic Acid Derivatives: Stereocontrolled Access to Acyclic and Conformationally Restricted α,γ-Disubstituted γ-Amino Acids. Molecules 2026, 31, 2087. https://doi.org/10.3390/molecules31122087

AMA Style

Casas-Morales H, Hernández D, Ordoñez M, Boto A, Romero-Estudillo I. Decarboxylative-Allylation of Pyroglutamic Acid Derivatives: Stereocontrolled Access to Acyclic and Conformationally Restricted α,γ-Disubstituted γ-Amino Acids. Molecules. 2026; 31(12):2087. https://doi.org/10.3390/molecules31122087

Chicago/Turabian Style

Casas-Morales, Hugo, Dácil Hernández, Mario Ordoñez, Alicia Boto, and Ivan Romero-Estudillo. 2026. "Decarboxylative-Allylation of Pyroglutamic Acid Derivatives: Stereocontrolled Access to Acyclic and Conformationally Restricted α,γ-Disubstituted γ-Amino Acids" Molecules 31, no. 12: 2087. https://doi.org/10.3390/molecules31122087

APA Style

Casas-Morales, H., Hernández, D., Ordoñez, M., Boto, A., & Romero-Estudillo, I. (2026). Decarboxylative-Allylation of Pyroglutamic Acid Derivatives: Stereocontrolled Access to Acyclic and Conformationally Restricted α,γ-Disubstituted γ-Amino Acids. Molecules, 31(12), 2087. https://doi.org/10.3390/molecules31122087

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Decarboxylative-Allylation of Pyroglutamic Acid Derivatives: Stereocontrolled Access to Acyclic and Conformationally Restricted α,γ-Disubstituted γ-Amino Acids

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