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The potential of “customizable units” to generate structural diversity for biological screenings is highlighted in this proof‐of‐concept synthesis of new peptides related to the potent antitumoral Sansalvamide A. Using L‐4‐hydroxyproline (Hyp) as a customizable unit in a linear parent peptide, an improved procedure for selective peptide modification was developed. A divergent Hyp scission‐reductive amination process was carried out, affording five linear peptides with cationic residues, and notably, an N‐alkyl moiety that affected the conformation of the peptide. After two steps (saponification and macrocyclization), sixteen differently N1‐substituted linear and cyclic peptides were obtained. For the first time, the activity of the linear and cyclic compounds was compared. Not only some linear analogs but also cyclic compounds with scarcely studied cationic residues were active against MCF7 breast cancer line. Thus, the structural diversity generated from customizable units can be valuable in drug discovery., This work was partly financed by the Consejo Nacional de Ciencia y Tecnología (CONACYT, Mexico) through project 2015‐01‐807, and by MINECO‐MCIU (Spain) with European Social Funds (ESF), through Programme Plan Estatal I+D‐RETOS (project SAF‐2013‐48399‐R). C. J. S. received a postdoctoral contract from the Torres Quevedo Programme (PTQ15‐07923) by MINECO/Min. Science and Innovation, cofinanced by BIOSIGMA SL. Finally, I.R−E. and F.C. thank CONACYT for Catedra contract 942 and predoctoral grant 305283 respectively.

The site-selective modification of peptide backbones allows an outstanding fine-tuning of peptide conformation, folding ability, and physico-chemical and biological properties. However, to achieve selectivity in the core of these biopolymers is challenging. In the last few years, many advances towards this goal have been developed. This review addresses the selective modification of Cα- and N-positions, from the use of “customizable units” to the residue-directed introduction of substituents. The site-selective modification of the peptide bond, i.e. the formation of thioamides or heterocycles, which alters backbone rigidity and ability to form hydrogen bonds or recognition by enzymes, is also described. Moreover, not only the modifications in internal backbone positions, but also in the N- and C-termini are discussed. In addition to chemical methodologies, the review addresses some reactions, catalyzed by natural or engineered enzymes, that afford unprecedent regio- and stereoselectivity in backbone modifications., This work was mainly financed by project ProID2020010134 (Subvenciones a la Realización I + D Mª Carmen Betancourt y Molina, ACIISI-Gobierno de Canarias, with European Funds for Regional Development-FEDER) with contributions from project APOGEO (MAC/1.1.b./226, Cooperation Program INTERREG-MAC 2014–20 with FEDER funds, as well as Consejo Nacional de Ciencia y Tecnología (CONACYT, Mexico) through project 2015-01-807. D. H. also acknowledges her current contract (TRANSALUDAGRO) financed by Cabildo de Tenerife, Program TF INNOVA 2016-21 (with MEDI & FDCAN Funds). C. J. S. is currently recipient of a “Agustín de Betancourt”-Tenerife 2030 postdoctoral grant (Universidad de La Laguna-Cabildo de Tenerife, cofinanced by MEDI & FDCAN Funds). I. R-E. thanks CONACYT for Catedra contract 942.

The selective manipulation of Hyp customizable units in DKP substrates allows the generation of a rigid scaffold with four tailor‐made chains which are spatially‐orientated. The key step is a domino radical scission‐oxidation process which allows the generation of N‐substituted DKPs. The versatility of this methodology to produce scaffolds in high optical purity for material and drug discovery is described herein., This work was partly financed by project APOGEO (Cooperation Program INTERREG‐MAC 2014–2020, with European Funds for Regional Development‐FEDER) and by projects SAF‐2013‐48399‐R, Plan Estatal I+D‐RETOS (MINECO‐MCIU)‐European Social Funds (ESF) and CONACYT 2015–01‐807 (CONACYT‐Mexico)

In this study, a series of novel 3

An expedient synthetic entry to cis-4-hydroxyphosphonic and cis-4-hydroxyphosphinic analogs of cis-4-hydroxypipecolic acid is presented in this paper. The main feature of this methodology is the highly regioselective addition of silyl phosphites or phosphonites to cyclic 1-benzyloxycarbonyl enaminones. Interestingly, the hydride reduction of the resulting 2-phospho-4-oxopiperidine proceeds with high diastereofacial preference using NaBH

We report here an alternative and practical method for the preparation of 1,2,3,4-tetrahydroisoquinoline-1-phosphonic acid and the first synthesis of 1,2,3,4-tetrahydroisoquinoline-1-H-phosphinic and 1,2,3,4-tetrahydroisoquinoline-1-phenylphosphinic acids through Kabachnik–Fields and aza-Pudovik reaction. This methodology does not require any metallic catalyst and proceeds under mild reaction conditions., The authors thank the Consejo Nacional de Ciencia y Tecnología (CONACyT) for financial support through projects 286614, 807, and Cátedra contract 942, and Gobierno de Aragón-FEDER (Grupo Aminoácidos y Péptidos E19_17R; FEDER 2014-2020 ‘Construyendo Europa desde Aragón’). J.T.H.-M. also wishes to thank CONACyT for Graduate Scholarship 335029.

This review outlines the most recent papers describing the stereoselective synthesis of γ-amino acids. In this update, the γ-amino acids have been classified according to the type of compounds, position and number of substituents, and depending on the type of substrate, acyclic, carbocyclic or azacyclic derivatives, following in the first case an order related to the strategy used, whereas in the second and third cases the classification is based on the ring size., The authors thank CONACYT-Mexico for financial support via projects 181816 and 248868. Ministerio de Ciencia e Innovación–FEDER-Spain (grant CTQ2010-17436) and Gobierno de Aragón–FSE (research group E40).

In this paper, we report the synthesis of a new series of α-aminophosphonates derivatives based in an efficient three-component reaction. All compounds prepared showed significant anti-inflammatory activity, being the compounds 1a, 1c, 1d, 1f, 2b and 2c the most promising ones, in terms of maximal efficacy (over 95%), potency (ED50 range between 0.7 and 10.1 mg/ear) and relative potency (range from 0.04 to 0.67). Compounds 1a, 1c, 1d and 1f significantly decrease the number of neutrophils (range from 46.7 to 63.0%) and monocytes (18.9–34.1%) in blood samples from the orbital sinus. Additionally, QSAR model revealed that the spherical molecular shape and the location of the HOMO on the phenyl ring improves the anti-inflammatory activity of the compounds. The values of R2, Q2, s and F statistical parameters and the QUIK, asymptotic Q2 and Overfitting rules validate the descriptive and predictive ability of the QSAR model. Altogether these results suggest that these new α-aminophosphonates are potential agents for the treatment of inflammation.

The alkylation reaction of diethyl N-(diphenylmethylene)aminomethylphosphonate (6) with alkyl dihalides under phase-transfer catalysis followed by hydrolysis of the benzophenone imine moiety and subsequent cyclization provides a simple and convenient method for the synthesis of known and new cyclic α-aminophosphonates 1–5 in moderate to good yields.

Contract grant sponsor: Research Programs SAF-2013–48399-R and CTQ2009-07109. Contract grant sponsor: Plan Estatal de I1D, Ministerio de Economia y Competitividad, Spain. Contract grant sponsor: European Social Funds (FSE) .Contract grant sponsor: CSIC (Spanish Research Council) for a JAE predoctoral contract.

2,5‐Disubstituted oxazoles with a variety of alkyl and aryl groups are efficiently formed from N‐acylamino acids, by a one‐pot radical decarboxylation–oxidation–enolization and iodine‐promoted cyclization process. Remarkably, the reaction takes place under mild conditions, and no metal catalysis is needed. The process can be useful for the direct modification of small peptides., This work was supported by Plan Nacional de I+D (CTQ2009‐07109 and SAF‐2013‐48399‐R), MICINN/MINECO, Spain, and European Regional Development (FEDER) Funds. I.R.E. thanks CSIC for a JAE predoctoral contract.

The metal-free, direct conversion of readily available proline derivatives into 2-aryl-3-iodopyrrolidines is carried out under mild conditions and in good yields, using a sequential radical decarboxylation–oxidation–iodination–arylation reaction. These iodinated pyrrolidines are valuable precursors of other compounds. For instance, they can be cyclized to tricyclic compounds or undergo dehalogenation to 2-aryl-2,5-dihydro-1H-pyrroles, which are iminosugar and 2-arylpyrrole precursors. This process provides a short pathway to a variety of alkaloid and drug analogues of potential pharmaceutical interest., This work was supported by the Research Programs CTQ2009-07109 and SAF2013-48399-R of the Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica, Ministerio de Economía y Competitividad, Spain. We also acknowledge financial support from FEDER and FSE funds (European Funds for Regional Development/European Social Funds). J. M. and V. R. B. thank CSIC for a JAE predoctoral fellowship and a postdoctoral contract, respectively.

This review outlines the most recent papers describing the stereoselective synthesis of γ-amino acids. In this update, the γ-amino acids have been classified according to the type of compounds, position and number of substituents, and depending on the type of substrate, acyclic, carbocyclic or azacyclic derivatives, following in the first case an order related to the strategy used, whereas in the second and third cases the classification is based on the ring size.

The alkylation reaction of diethyl N-(diphenylmethylene)aminomethylphosphonate (6) with alkyl dihalides under phase-transfer catalysis followed by hydrolysis of the benzophenone imine moiety and subsequent cyclization provides a simple and convenient method for the synthesis of known and new cyclic α-aminophosphonates 1–5 in moderate to good yields.

A straightforward and novel method for transformation of readily available 1,3-benzoxazines to secondary phosphonates and &alpha, aminophosphonates using boron trifluoride etherate as catalyst is developed. The formation of phosphonates proceeds through ortho-quinone methide (o-QM) generated in situ, followed by a phospha-Michael addition reaction. On the other hand, the &alpha, aminophosphonates were obtained by iminium ion formation and the subsequence nucleophilic substitution of alkylphosphites. This method can be also used for the preparation of o-hydroxybenzyl ethers through oxa-Michael addition.

The development of peptide libraries by site-selective modification of a few parent peptides would save valuable time and materials in discovery processes but still is a difficult synthetic challenge. Herein, we introduce natural hydroxyproline as a convertible unit for the production of a variety of optically pure amino acids, including expensive N-alkyl amino acids, homoserine lactones, and Agl lactams, and to achieve the mild, efficient, and site-selective modification of peptides. A domino process is used to cleave the customizable Hyp unit under mild, metal-free conditions. Both terminal and internal positions can be modified, and similar customizable units can be differentiated. The resulting products possess two reactive chains which can be manipulated independently. The versatility and scope of this process is highlighted by its application to the ligation of two peptide chains, and the generation of peptides with several chains and peptides with conformational restrictions., This work is dedicated to Prof. Troels Skrydstrup and Prof. William D. Lubell, and it was mainly supported by the Research Program SAF-2013-48399-R, but also by CTQ2009-07109, Plan Estatal de I+D, Ministerio de Economía y Competitividad, Spain, and European Social Funds (FSE). I.R.-E. thanks CSIC (Spanish Research Council) for a JAE predoctoral contract.

This work was supported by Plan Nacional de I+D (CTQ2009‐07109 and SAF‐2013‐48399‐R), MICINN/MINECO, Spain, and European Regional Development (FEDER) Funds. I.R.E. thanks CSIC for a JAE predoctoral contract.

The development of peptide libraries by site-selective modification of a few parent peptides would save valuable time and materials in discovery processes, but still is a difficult synthetic challenge. Herein natural hydroxyproline is introduced as a >convertible> unit for the production of a variety of optically pure amino acids, including expensive N-alkyl amino acids, and to achieve the mild, efficient, and site-selective modification of peptides.

Decarboxylation/alkylation allows the introduction of alkyl, allyl or aryl substituents at the position of the carboxyl group.

Common β-hydroxy amino acids (such as threonine) can be readily transformed into 1,2-amino alcohols with excellent stereoselectivity. This one-pot decarboxylation-alkylation process allows the replacement of the carboxyl group by alkyl, allyl, or aryl groups, generally in high yields. A variation of the process (decarboxylation-Diels-Alder) allows the formation of bi- and polycyclic systems, which are useful precursors of alkaloid cores or iminosugars., This work was supported by the Research Program CTQ2009-07109 of the Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica, Ministerio de Ciencia e Innovación, Spain. We also acknowledge financial support from FEDER funds. I.R.E. thanks CSIC for a predoctoral JAE fellowship.