Stereoselective synthesis of a-Amino-C-phosphinic acids and derivatives

a-Amino-C-phosphinic acids and derivatives are an important group of compounds of synthetic and medicinal interest and particular attention has been dedicated to their stereoselective synthesis in recent years. Among these, phosphinic pseudopeptides have acquired pharmacological importance in influencing physiologic and pathologic processes, primarily acting as inhibitors for proteolytic enzymes where molecular stereochemistry has proven to be critical. This review summarizes the latest developments in the asymmetric synthesis of acyclic and phosphacyclic a-amino-C-phosphinic acids and derivatives, following in the first case an order according to the strategy used, whereas for cyclic compounds the nitrogen embedding in the heterocyclic core is considered. In addition selected examples of pharmacological implications of title compounds are also disclosed

Stereoselective synthesis of α-amino-C-phosphinic acids and derivatives

α-Amino-C-phosphinic acids and derivatives are an important group of compounds of synthetic and medicinal interest and particular attention has been dedicated to their stereoselective synthesis in recent years. Among these, phosphinic pseudopeptides have acquired pharmacological importance in influencing physiologic and pathologic processes, primarily acting as inhibitors for proteolytic enzymes where molecular stereochemistry has proven to be critical. This review summarizes the latest developments in the asymmetric synthesis of acyclic and phosphacyclic α-amino-C-phosphinic acids and derivatives, following in the first case an order according to the strategy used, whereas for cyclic compounds the nitrogen embedding in the heterocyclic core is considered. In addition selected examples of pharmacological implications of title compounds are also disclosed.The authors gratefully acknowledge the CONACYT (grant 181816, 248868) and PRODEP (project UAEMOR-PTC-379) of Mexico, Ministerio de Economía y Competitividad (grant CTQ2013-40855-R) and Gobierno de Aragón-FSE (research group E40) for their financial support.We acknowledge support by the CSIC Open Access Publication Initiative through its Unit of Information Resources for Research (URICI)

First practical and efficient synthesis of 3-phosphorylated β-carboline derivatives using the Pictet-Spengler reaction

We report here the first practical and efficient synthesis of the diethyl 1,2,3,4-tetrahydro-β-carboline-3-phosphonates 3 and 4 as well as diethyl 9H-β-carboline-3-phosphonates 5 and 6. The target compounds were prepared in good yields by application of the Pictet-Spengler reaction of easily ob-tainable phosphotryptophan diethyl ester 7. The procedure is based on simple preparation of racemic 7 followed by a Pictet-Spengler reaction with several aldehydes and subsequent oxidation chemistry.The authors are thankful for financial support by the Mexican Consejo Nacional de Ciencia y Tecnología (CONACYT) for financial support via project 181816, by the Spanish Ministerio de Ciencia e Innovación (MICINN), FEDER (grant number CTQ2010- 17436) and by the Gobierno de Aragón-FSE (research group E40). J. L. V.-C. also thank CONACYT for graduate scholarships.Peer Reviewe

Stereoselective synthesis of α-amino-H-phosphinic acids and derivatives

α-Amino-H-phosphinic acids and derivatives are an important group of compounds of synthetic and pharmacological interest, and particular attention has been dedicated toward their stereoselective synthesis in recent years. While some of these compounds show activity by themselves, they are also valuable starting materials in the synthesis of phosphinic bioisosteres of natural peptides, where the hydrolyzable bond is substituted by a phosphinic functionality that mimics the transition state of peptide hydrolysis, thus acting as efficient enzyme­ inhibitors in which the molecular stereochemistry is demonstrated to be critical. This review summarizes the latest developments on the asymmetric synthesis of acyclic and phosphacyclic α-amino-H-phosphinic acids and derivatives following an order according to the strategy used; in addition, some implications in medicinal chemistry are disclosed.The authors gratefully acknowledge CONACYT (grant 181816, 248868) and PRODEP (project UAEMOR-PTC-379) of Mexico, Ministerio de Economía y Competitividad (grant CTQ2013-40855-R) and Gobierno de Aragón – FSE (research group E40) for their financial support.Peer reviewe

An update on the stereoselective synthesis of α-aminophosphonic acids and derivatives

Optically active α-aminoalkylphosphonic acids 1 are structural analogues of α-amino acids 2, obtained by isosteric substitution of the planar and less bulky carboxylic acid (CO2H) by a tetrahedral phosphonic acid functionality (PO3H2). Several α-aminoalkylphosphonic acids and derivatives have been isolated from natural sources, either as free amino acids or as constituents of more complex molecules. These classes of compounds are currently attracting interest in organic and medicinal chemistry, as well as in agriculture, due to their important biological and pharmacological properties. Additionally, the α-aminophosphonates have been used as key synthetic intermediates for the preparation of more complex compounds1b, and as organocatalysts.We gratefully acknowledge CONACyT of Mexico (grant 181816), Ministerio de Economía y Competitividad (grant CTQ2013-40855-R), and Gobierno de Aragón -FSE (research group E40).Peer Reviewe

First synthesis of (R)- and (S)-1,2,3,4-tetrahydroisoquinoline-3-phosphonic acid (TicP) using a pictet-spengler reaction

We report here a practical and efficient synthesis of diethyl 1,2,3,4-tetrahydroisoquinoline-3-phosphonate derivatives. The target compounds were prepared in good yield using a Pictet-Spengler reaction involving α-amino phosphonates that were easily obtained. We have paid special attention to the synthesis of (R)- and (S)-1,2,3,4-tetrahydroisoquinoline-3-phosphonic acid (Tic) 2a, a conformationally constrained analogue of phosphophenylalanine Phe. The procedure is based on the preparation of racemic phosphophenylalanine (Phe) diethyl ester followed by chiral chromatographic separation and subsequent Pictet-Spengler chemistry.The authors thank Consejo Nacional de Ciencia y Tecnología (CONACYT) for financial support through projects 181816 and 248868, the Ministerio de Ciencia e Innovación – FEDER (grant CTQ2010-17436), and the Gobierno de Aragón-FSE (research group E40).Peer Reviewe

New approaches towards the synthesis of 1,2,3,4-tetrahydro isoquinoline-3-phosphonic acid (TicP)

Two new strategies for the efficient synthesis of racemic 1,2,3,4-tetrahydroisoquinoline-3-phosphonic acid (TicP) (±)-2 have been developed. The first strategy involves the electron-transfer reduction of the easily obtained α,β-dehydro phosphonophenylalanine followed by a Pictet–Spengler cyclization. The second strategy involves a radical decarboxylation–phosphorylation reaction on 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic). In both strategies, the highly electrophilic N-acyliminium ion is formed as a key intermediate, and the target compound is obtained in good yield using mild reaction conditions and readily available starting materials, complementing existing methodologies and contributing to the easy accessibility of (±)-2 for further research.This work was supported by Consejo Nacional de Ciencia y Tecnología (CONACYT) through projects 286614 and 256985, and Gobierno de Aragon-FEDER (Grupo Aminoacidos y Peptidos E19-17R; FEDER 2014-2020 “Construyendo Europa desde Aragon”).Peer reviewe