Guigen Li

Design of peptides, proteins, and peptidomimetics in chi space

Peptide and protein biological activities depend on their three dimensionals structures in the free state and when interacting with their receptors/acceptors. The backbone conformations such as alpha-helix, beta-sheet, beta-turn, and so forth provide critical templates for the three-dimensional structure, but the overall shape and intrinsic stereoelectronic properties of the peptide or protein important for molecular recognition, signal transduction, enzymatic specificity, immunomodulation, and other biological effects depend on arrangement of the side chain groups in three-dimensional chi space (their chi 1, chi 2, etc. torsional angles). In this paper we explore approaches to the de novo design of polypeptides and peptidomimetics with biased or specific conformational/topographical properties in chi space. We consider computational and experimental methods that can be used to examine the effects of specific structural modifications in constraining side chain groups of amino acid residues and their similarities in chi space to the natural amino acids to evaluate what sort of mimetics are likely to mimic normal amino acids. We then examine some of the asymmetric synthetic methods that are being developed to obtain the amino acid mimetics. Finally, we consider selected examples in the literature where these specialized amino acids have been incorporated in biologically active peptides and the specific insights they have provided regarding the topographical requirements for bioactive peptide potency, selectivity, and other biochemical and pharmacological properties. Constraints in chi space show great promise as useful tools in peptide, protein, and peptidomimetic de novo design of structures and pharmacophores with specific stereostructural, biochemical and biological properties.

Diastereospecific tandem Michael-like addition / electrophilic bromination: A one-pot tandem asymmetric synthesis of precursors of unusual amino acids

Abstract A systematic series of key intermediates of unusual β-methyl-amino acids have been synthesized by using a modified Evans auxiliary in an asymmetric Michael-like reaction followed by direct bromination in a one-pot reaction.

Asymmetric synthesis of unusual amino acids: An enantioselective synthesis of the four isomers of D- and L-O-Methyl-2′, β-Dimethyltyrosine

Abstract The four individual isomers of D- and L-O-methyl-2′, β-dimethyltyrosines have been synthesized in high optical purity. The evidence for asymmetric induction was cofirmed by the X-ray analysis of one of the key intermediates.

1,2-Asymmetric cis induction and its application to the asymmetric synthesis of precursors of β-branched unusual amino acids

Abstract A new method for the asymmetric synthesis of key intermediates of unusual amino acids has been established by utilizing β-carbon chirality for asymmetric induction in allylic-strained boron enolates.

Asymmetric synthesis of (2R, 3S) and (2S, 3R) precursors of β-methyl-histidine, -phenylalanine and -tyrosine

Abstract A systematic series of (2S, 3R) and (2R, 3S) precursors to β-methyl-histidine, -phenylalanine and -tyrosine, which are of significant importance in the design of peptide and protein ligands, have been synthesized in high optically purity and yield.

A new strategy for the synthesis of four individual isomers of β-methylphenylalanine

Abstract The application of an allylic strain effect in boron enolates and asymmetric Michael-like addition/electrophilic bromination reactions is reported for the asymmetric synthesis of the individual isomers of unusual constrained amino acids. For β-substituted α-amino acids, all of the final optically pure products were identical to authentic samples, which provided further and unequivocal evidence to confirm the assignments of stereochemical control of the new methods in this report.

Exploration for large-scale stereoselective synthesis of unusual amino acids by using 4-phenyloxazolidin-2-one as a new chiral resolution reagent

Individual isomers of β-branched α-amino acids have been stereoselectively and asymmetrically synthesized in high yield by a new method which uses 4-phenyloxazolidin-2-one as a novel chiral resolution reagent acting simultaneously as the auxiliary.