Recent developments in the stereoselective synthesis of α-aminoacids

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 α-helix, β-sheet, β-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 χ1, χ2, 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 minic 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. © 1997 John Wiley & Sons, Inc. Biopoly 43: 219–266, 1997

Design of peptides, proteins, and peptidomimetics in chi space

2.03 – Pyrroles and their Benzo Derivatives: Synthesis

Chronic obstructive pulmonary disease, characterised by a slowly progressive, irreversible airways limitation, is a major worldwide cause of chronic morbidity and mortality. The imbalance between human neutrophil elastase and endogenous antiproteases may cause excess human neutrophil elastase in pulmonary tissues, which may be considered a major pathogenic factor in chronic obstructive pulmonary disease. Great effort has been devoted to finding a method to restore the balance, resulting in the discovery of potent two-typed small-molecular-weight human neutrophil elastase inhibitors. In the application of chronic obstructive pulmonary disease therapy, the human neutrophil elastase inhibitors mainly focused upon include ONO-5046, MR-889, L-694,458, CE-1037, GW-311616 and TEI-8362 as the acyl-enzyme inhibitors; and ONO-6818, AE-3763, FK-706, ICI-200,880, ZD-0892 and ZD-8321 as the transition-state inhibitors. In this review, various problems that remain to be solved in the clinical use of human neutrophil elastase inhibitors are discussed.

Neutrophil elastase inhibitors as treatment for COPD

Nucleophilic ring-opening reactions of 3-alkylaziridine-2-carboxylic esters are described. Without ring activation at nitrogen, ring opening could only be accomplished with ethereal hydrogen chloride. Introduction of electron-withdrawing activating groups at the nitrogen atom was necessary. Three types of activating groups were used, viz. acyl, alkoxycarbonyl and sulfonyl groups. In the presence of a Lewis-acid catalyst, ring opening with two nucleophiles, namely indole and benzenethiol, could be accomplished. SN2-type attack at C3 was observed exclusively. With Bronsted acids (hydrogen chloride, formic acid, acetic acid), ring opening could also be effected. 3-Formyloxy derivatives could also be prepared by reaction of the activated aziridines with N,N-dimethyl-formamide in the presence of boron trifluoride etherate. Reaction with sodium azide caused some difficulties; complex product mixtures were usually obtained. N-Sulfonylaziridine-2-carboxylic esters gave a mixture of the two possible regioisomers, resulting from attack at C2 and C3. Treatment of N-sulfonylaziridine-2-carboxylic esters with trimethylsilyl azide, however, gave products exclusively ring-opened at C2. On reaction of the activated aziridines with acetonitrile in the presence of boron trifluoride etherate, a ring-expansion reaction was observed, leading to imidazolines. On standing, these heterocyclic compounds slowly hydrolyzed to α,β-diamino carboxylic acid derivatives.

Synthesis of functionalized amino acids by ring‐opening reactions of aliphatically substituted aziridine‐2‐carboxylic esters

A compound of the formula :
 wherein R 1 is lower alkyl optionally substituted with a substituent selected from the group consisting of acyl,hydroxy, lower alkoxy, aryl, lower alkylthio and a group of the formula :
 in which R 5 is hydrogen or acyl and
 R 6 is hydrogen or lower alkyl; aryl; or amino optionally substituted with substituent(s) selected from the group consisting of lower alkyl and acyl; and R 2 is hydrogen or lower alkyl; or R 1 and R 2 are taken together with the attached nitrogen atom to form a heterocyclic group optionally substituted with substituent(s) selected from the group consisting of lower alkyl, hydroxy(lower)alkyl, lower alkoxy(lower)alkyl, acyl(lower)alkyl, oxo and acyl; R 3 is hydrogen or lower alkyl; and R 4 is lower alkyl; and its pharmaceutically acceptable salt, processes for the preparation thereof and pharmaceutical composition comprising the same.

New amino acid derivatives, processes for the preparation thereof and pharmaceutical composition comprising the same

Some (αR, βR) -1, β-dimethyltryptophans (5__∼) were prepared by the reaction of aziridine-2-carboxylates (4__∼), derived from D-threonine, and N-alkylindoles in the presence of BF3·OEt2.

Keisuke Imai

Papers

New amino acid derivatives, processes for the preparation thereof and pharmaceutical composition comprising the same

SYNTHESIS OF OPTICALLY ACTIVE β-METHYLTRYPTOPHANS FROM AZIRIDINE-2-CARBOXYLATES

Biochemical and pharmacological characterization of FK706, a novel elastase inhibitor

Amino Acid Derivatives