Synthesis of α-aminoboronic acids.

This review describes available methods for the preparation of α-aminoboronic acids in their racemic or in their enantiopure form. Both, highly stereoselective syntheses and asymmetric procedures leading to the stereocontrolled generation of α-aminoboronic acid derivatives are included. The preparation of acyclic, carbocyclic and azacyclic α-aminoboronic acid derivatives is covered. Within each section, the different synthetic approaches have been classified according to the key bond which is formed to complete the α-aminoboronic acid skeleton.

Access to enantiomerically pure cis- and trans-ß-phenylproline by high-performance liquid chromatography resolution.

The preparation of all four stereoisomers of the proline analog that bears a phenyl group attached to the ß carbon either cis or trans to the carboxylic acid (cis- and trans-ß-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-ß-phenylproline and trans-ß-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-ß-phenylproline precursors.

ß-Phenylproline: the high ß-turn forming propensity of proline combined with an aromatic side chain.

The conformational propensities of the proline analogue bearing a phenyl substituent attached to the ß carbon, in either a cis or a trans configuration relative to the carbonyl group, have been investigated. The behaviour of cis- and trans(ßPh)Pro has been compared with that of proline in homochiral and heterochiral dipeptide sequences. NMR and IR studies as well as X-ray diffraction analysis provide evidence that the ß-phenyl substituent does not disrupt the tendency of proline to occupy the i+1 position of a ß-turn. The puckering of the pyrrolidine ring is significantly affected by the presence of the aromatic substituent, which tends to occupy positions that minimize steric repulsions. As a consequence, this substituent adopts specific well-defined orientations, which are more restricted for the cis derivative. Interactions between this aromatic group and that in the adjacent phenylalanine residue may be responsible for some of the conformational differences observed among the different peptides studied.

Practical access to the proline analogs (S,S,S)- and (R,R,R)-2-methyloctahydroindole-2-carboxylic acids by HPLC enantioseparation.

An efficient methodology for the preparation of the α-tetrasubstituted proline analog (S,S,S)-2-methyloctahydroindole-2-carboxylic acid, (S,S,S)-(αMe)Oic, and its enantiomer, (R,R,R)-(αMe)Oic, has been developed. Starting from easily available substrates and through simple transformations, a racemic precursor has been synthesized in excellent yield and further subjected to HPLC resolution using a cellulose-derived chiral stationary phase. Specifically, a semipreparative (250 mm × 20 mm ID) Chiralpak® IC column has allowed the efficient resolution of more than 4 g of racemate using a mixture of n-hexane/tert-butyl methyl ether/2-propanol as the eluent. Multigram quantities of the target amino acids have been isolated in enantiomerically pure form and suitably protected for incorporation into peptides.

NCAD, a database integrating the intrinsic conformational preferences of non-coded amino acids.

Peptides and proteins find an ever-increasing number of applications in the biomedical and materials engineering fields. The use of non-proteinogenic amino acids endowed with diverse physicochemical and structural features opens the possibility to design proteins and peptides with novel properties and functions. Moreover, non-proteinogenic residues are particularly useful to control the three-dimensional arrangement of peptidic chains, which is a crucial issue for most applications. However, information regarding such amino acids--also called non-coded, non-canonical, or non-standard--is usually scattered among publications specialized in quite diverse fields as well as in patents. Making all these data useful to the scientific community requires new tools and a framework for their assembly and coherent organization. We have successfully compiled, organized, and built a database (NCAD, Non-Coded Amino acids Database) containing 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, conformational propensities established experimentally, and applications. The architecture of the database is presented in this work together with the first family of non-coded residues included, namely, alpha-tetrasubstituted alpha-amino acids. Furthermore, the NCAD usefulness is demonstrated through a test-case application example.

In silico molecular engineering for a targeted replacement in a tumor-homing peptide.

A new amino acid has been designed as a replacement for arginine (Arg, R) to protect the tumor-homing pentapeptide CREKA (Cys-Arg-Glu-Lys-Ala) from proteases. This amino acid, denoted (Pro)hArg, is characterized by a proline skeleton bearing a specifically oriented guanidinium side chain. This residue combines the ability of Pro to induce turn-like conformations with the Arg side-chain functionality. The conformational profile of the CREKA analogue incorporating this Arg substitute has been investigated by a combination of simulated annealing and molecular dynamics. Comparison of the results with those previously obtained for the natural CREKA shows that (Pro)hArg significantly reduces the conformational flexibility of the peptide. Although some changes are observed in the backbone...backbone and side-chain...side-chain interactions, the modified peptide exhibits a strong tendency to accommodate turn conformations centered at the (Pro)hArg residue and the overall shape of the molecule in the lowest energy conformations characterized for the natural and the modified peptides exhibit a high degree of similarity. In particular, the turn orients the backbone such that the Arg, Glu, and Lys side chains face the same side of the molecule, which is considered important for bioactivity. These results suggest that replacement of Arg by (Pro)hArg in CREKA may be useful in providing resistance against proteolytic enzymes while retaining conformational features which are essential for tumor-homing activity.

A straightforward route to enantiopure alpha-substituted derivatives of (2S,3aS,7aS)-octahydroindole-2-carboxylic acid.

High yielding and remarkably selective alkylations of a suitably protected derivative of (2S,3aS,7aS)-octahydroindole-2-carboxylic acid are described. The fused bicyclic structure of this proline analogue greatly influences the stereochemical outcome of direct alkylation reactions taking place at the alpha-carbon and provides access to alpha-substituted analogues with retention of the configuration. The overall procedure allows the preparation of enantiopure alpha-substituted derivatives of this Oic isomer, suitably protected for their incorporation into peptides, in a straightforward manner.

Towards the stereoselective synthesis of alpha-methylated (2S,3aS,7aS)-octahydroindole-2-carboxylic acid.

A high yielding and remarkably stereoselective alpha-methylation reaction of the (2S,3aS,7aS) stereoisomer of octahydroindole-2-carboxylic acid, (S,S,S)-Oic, suitably protected is described. The severe steric hindrance imposed by the fused cyclohexane ring, which prevents the application of Seebach's self-reproduction of chirality methodology, accounts for the formation of (S,S,S)-(alphaMe)Oic with high selectivity and retention of configuration.

Versatile methodology for the synthesis and α-functionalization of (2R,3aS,7aS)-octahydroindole-2-carboxylic acid.

An improved strategy for the effective synthesis of enantiomerically pure (2R,3aS,7aS)-octahydroindole-2-carboxylic acid (Oic), based on the formation of a trichloromethyloxazolidinone derivative, has been developed. Additionally, the completely diastereoselective α-alkylation of such oxazolidinone provides a very convenient and concise route to enantiopure α-tetrasubstituted derivatives of this Oic stereoisomer.

Stereoselective Synthesis of Quaternary Proline Analogues.

This review describes available methods for the diastereoselective and asymmetric synthesis of quaternary prolines. The focus is on the preparation of alpha-functionalized prolines with the pyrrolidine moiety not embedded in a polycyclic frame. The diverse synthetic approaches are classified according to the bond which is formed to complete the quaternary skeleton.

Stanna-Brook rearrangement of carboxylic acid derivatives. Synthetic utility and mechanistic studies.

[reaction: see text] The reaction of R(3)SnLi with carboxylic acid derivatives proceeds through a novel, very fast stanna-Brook rearrangement that generates alpha-alkoxyorganolithium compounds as intermediates. The outcome of these reactions depends on the nature of the carboxyl derivatives. Reaction of R(3)SnLi with ester derivatives gives rise to coupled products through a novel C-C bond formation reaction. Experimental evidence of the detailed reaction mechanism is provided.

Stereoselective S N 2-substitutions using polyfunctional lithium arylcuprates prepared by an iodine-copper exchange.

[reaction: see text] Polyfunctional mixed lithium arylcuprates of the type (FG-Ar)(PhMe(2)CCH(2))CuLi obtained via iodine- or bromine-copper exchange with (PhMe(2)CCH(2))(2)CuLi react with cyclic 2-iodoallylic acetates with high S(N)2 selectivity. The addition of ZnBr(2) changes this selectivity and allows the performance of highly regioselective and enantioselective anti S(N)2' substitutions using open-chain allylic pentafluorobenzoates.

Substrate-controlled highly diastereoselective synthesis of primary and secondary diorganozinc reagents by hydroboration/boron-zinc exchange sequence.

The scope of substrate-controlled diastereoselective hydroborations can be considerably enhanced by a boron-zinc exchange reaction, providing organozinc derivatives that react with a broad range of electrophiles. Even normally unreactive boronic esters, obtained by Rh-catalyzed hydroboration with catecholborane, react readily with iPr2Zn providing the corresponding zinc reagents in high diastereoselectivity.

Highly stereoselective anti SN2' substitutions of (Z)-allylic pentafluorobenzoates with polyfunctionalized zinc-copper reagents.

[reaction: see text] Allylic substitution reactions of zinc-copper organometallics on (Z)-allylic pentafluorobenzoates proceed with very high regioselectivity and excellent anti selectivity. The high fidelity in transfer of stereochemical information allowed a short synthesis of (+)-ibuprofen (97% ee).

Highly anti-selective SN2' substitutions of chiral cyclic 2-iodo-allylic alcohol derivatives with mixed zinc-copper reagents.

[reaction: see text] Functionalized allylic electrophilic reagents such as chiral 2-iodo-1-cyclohexenyl and -cyclopentenyl phosphates undergo highly stereoselective anti-S(N)2'-allylic substitution reactions with a wide range of organozinc reagents (R(2)Zn and RZnI) leading to chiral products with a transfer of the chiral information >95%. The use of functionalized organozinc iodides allows preparation of the bicyclic enones 8 and 9 in >or=93% ee.