Asymmetric synthesis of stereochemically-defined and conformationally-constrained novel amino acids via direct alkylation of chiral nickel(II)-coordinated Schiff bases of glycine and alanine, and design and synthesis of selective peptide and non-peptide ligands for the delta-opioid receptor

Abstract

A systematic practical method to prepare highly chi (χ)-constrained amino acids has been developed. It was found that increasing the size of R¹ (see figure) from H to Me to Et to n-Pr led to decreased reactivity of the starting complexes. In the case of R¹ as i-Pr, no alkylation was observed. With an increase of the size of R² from H to Me to Et to i-Bu, the reactivities of the alkyl bromides decreased. The starting Schiff bases had more effective stereocontrol at the α-carbon center than at the β-carbon center. The starting Schiff bases showed differential reactivity toward the racemic electrophile (kinetic resolution). Satisfactory differentiations were obtained at room temperature which makes this method synthetically useful. In the case of R¹ as H (NiGlyBPB), the thermodynamically-controlled stereoselectivity of alkylation was as high as 30:1. [DIAGRAM OMITTED]* A series of dipeptide analogues (TMT-Tic and DMT-Tic) were designed and synthesized to mimic the potent and highly selective delta-opioid receptor pentapeptide ligand-[(2S,3R)TMT¹]-DPDPE and thus to explore the topographical requirements for recognition of ligands at the opioid receptor through bioassays and NMR studies to facilitate the design of non-peptide compounds to be used as therapeutic agents for pain. (2S,3R)-TMT-L-Tic was found to have best binding affinities at the δ-opioid receptor in TMT-Tic series. In preliminary NMR studies, it was found that these designed peptide ligands have their own distinct conformations in the aqueous media. Meanwhile some modified non-peptide analogues of SL-3111 were prepared to continue our efforts to find effective non-peptide ligands for the δ-opioid receptor. More systematic studies are still ongoing using NMR and computational methods. *Please refer to dissertation for diagram.