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An overview of synthetic methods developed to build [c]fused bicyclic proline analogues is presented. The focus is on the preparation of azabicycles that bear a carbocyclic ring fused to the [c] face of the pyrrolidine unit. Attention is paid both to procedures that afford the desired compounds in racemic form and to asymmetric strategies. Procedures are or-ganized according to the size of the carbocycle that is fused to the pyrrolidine moiety. Strategies able to provide multigram quantities of enantiopure compounds that have application in the synthesis of marketed drugs are highlighted., This study was supported by the Russian Foundation for Basic Research (RFBR), Russia (Projects No. 14-03-31685, 14-03-31709, 14-03-01114).

Trabajo presentado a la Small Molecule NMR Conference celebrada en Santiago de Compostela (España) del 22 al 25 de septiembre de 2013., The high significance of proline in peptide conformation and biology stimulates the development of proline analogues with tailored properties. The attachment of substituents to the five-membered ring is particularly atractive in this regard. Such substituents may serve to incorporate additional functionality as well as to modulate the conformational properties of proline. In this context, we have explored the effect produced by a phenyl substituent attached to the β-carbon atom of proline on the puckering modes adopted by the pyrrolidine ring. Both the cis and trans configurations of the β-phenyl group relative to the carbonyl moiety have been considered. The puckering modes of such proline analogues, cis- and trans-β-phenylproline, have been examined by NMR when incorporated into model dipeptides. We observed that the pyrrolidine conformation is significantly affected by the presence of the β-phenyl group. Those conformations that alleviate most the steric hindrance introduced by the bulky phenyl substituent are preferred. The orientation adopted by the aromatic moiety is much more restricted in the cis isomer. Thus, cis-β-phenylproline shows a highly marked propensity to adopt a Cγ-endo arrangement. In contrast, the trans derivative exhibits a higher flexibility, with Cγ-endo and Cγ-exo pyrrolidine shapes being accessible, as for proline itself.

A versatile methodology for the preparation of racemic δ,δ- dimethylproline derivatives has been developed. Methyl N-Boc-δ,δ- dimethylprolinate was synthesized from a β-amino acid in six steps and 55 % overall yield. The route is amenable to the preparation of a broad range of δ,δ-disubstituted prolines by starting with the adequate β-amino acids. In addition, one of the intermediate compounds in the synthetic route has been used for the preparation of a δ,δ- dimethylproline derivative that is substituted at the β-position with a phenyl group. This has been achieved by coupling phenylboronic acid with a regioselectively generated vinyl triflate followed by a stereoselective hydrogenation. δ,δ-Dimethylproline derivatives have been efficiently synthesized by employing a β-amino acid as the starting material. The methodology is amenable to the preparation of other δ,δ- disubstituted prolines. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim., Financial support from the Ministerio de Ciencia e Innovación – FEDER (grant CTQ2010-17436; FPI fellowship to I. R.), and the Gobierno de Aragón – FSE (research group E40) is gratefully acknowledged.

El pdf del artículo es la versión pre-print., The preparation of all four stereoisomers of the proline analog that bears a phenyl group attached to the β carbon either cis or trans to the carboxylic acid (cis- and trans-β-phenylproline, respectively) has been addressed. The methodology developed allows access to multigram quantities of the target amino acids in enantiomerically pure form and suitably protected for use in peptide synthesis. Racemic precursors of cis-β-phenylproline and trans-β-phenylproline were prepared from easily available starting materials and subjected to high-performance liquid chromatography enantioseparation. Semipreparative columns (250 × 20 mm) containing chiral stationary phases based on amylose (Chiralpak IA) (Daicel-Chiral Technologies Europe, Illkirch, France) or cellulose (Chiralpak IC) were used respectively for the resolution of the cis- and trans-β-phenylproline precursors., P. F. is grateful to the Ministerio de Ciencia e Innovación for an FPU grant.

Recently, we reported a database (Noncoded Amino acids Database; http://recerca.upc.edu/imem/index.htm) that was built to compile information about the intrinsic conformational preferences of nonproteinogenic residues determined by quantum mechanical calculations, as well as bibliographic information about their synthesis, physical and spectroscopic characterization, the experimentally established conformational propensities, and applications (Revilla-López et al., J Phys Chem B 2010;114:7413-7422). The database initially contained the information available for α-tetrasubstituted α-amino acids. In this work, we extend NCAD to three families of compounds, which can be used to engineer peptides and proteins incorporating modifications at the--NHCO--peptide bond. Such families are: N-substituted α-amino acids, thio-α-amino acids, and diamines and diacids used to build retropeptides. The conformational preferences of these compounds have been analyzed and described based on the information captured in the database. In addition, we provide an example of the utility of the database and of the compounds it compiles in protein and peptide engineering. Specifically, the symmetry of a sequence engineered to stabilize the 3(10)-helix with respect to the α-helix has been broken without perturbing significantly the secondary structure through targeted replacements using the information contained in the database.

Recently, we reported a database (NCAD, Non-Coded Amino acids Database; http://recerca.upc.edu/imem/index.htm) that was built to compile information about the intrinsic conformational preferences of non-proteinogenic residues determined by quantum mechanical calculations, as well as bibliographic information about their synthesis, physical and spectroscopic characterization, the experimentally-established conformational propensities, and applications (J. Phys. Chem. B 2010, 114, 7413). The database initially contained the information available for α-tetrasubstituted α-amino acids. In this work, we extend NCAD to three families of compounds,which can be used to engineer peptides and proteins incorporating modifications at the -NHCO-peptide bond. Such families are: N-substituted α-amino acids, thio-α-amino acids, and diamines and diacids used to build retropeptides. The conformational preferences of these compounds have been analyzed and described based on the information captured in the database. In addition, we provide an example of the utility of the database and of the compounds it compiles in protein and peptide engineering. Specifically, the symmetry of a sequence engineered to stabilize the 310-helix with respect to the α-helix has been broken without perturbing significantly the secondary structure through targeted replacements using the information contained in the database.

El pdf del artículo es la versión de autor.-- et al., Recently, we reported a database (Noncoded Amino acids Database) that was built to compile information about the intrinsic conformational preferences of nonproteinogenic residues determined by quantum mechanical calculations, as well as bibliographic information about their synthesis, physical and spectroscopic characterization, the experimentally established conformational propensities, and applications (Revilla-López et al., J Phys Chem B 2010;114:7413-7422). The database initially contained the information available for α-tetrasubstituted α-amino acids. In this work, we extend NCAD to three families of compounds, which can be used to engineer peptides and proteins incorporating modifications at the -NHCO- peptide bond. Such families are: N-substituted α-amino acids, thio-α-amino acids, and diamines and diacids used to build retropeptides. The conformational preferences of these compounds have been analyzed and described based on the information captured in the database. In addition, we provide an example of the utility of the database and of the compounds it compiles in protein and peptide engineering. Specifically, the symmetry of a sequence engineered to stabilize the 310-helix with respect to the α-helix has been broken without perturbing significantly the secondary structure through targeted replacements using the information contained in the database. © 2011 Wiley-Liss, Inc.