Chaozhong Cai

Stereochemically defined C-substituted glutamic acids and their derivatives. 1. An efficient asymmetric synthesis of (2S,3S)-3-methyl- and -3-trifluoromethylpyroglutamic acids

Abstract An efficient asymmetric synthesis of biologically important (2 S ,3 S )-3-methyl- and (2 S ,3 S )-3-trifluoromethylpyroglutamic acid has been developed. The method consists of diastereoselective Michael addition reaction between ethyl crotonate or ethyl 4,4,4-trifluorocrotonate and a Ni(II) complex of the chiral non-racemic Schiff base of glycine with ( S )- o -[ N -( N -benzylprolyl)amino]benzophenone (BPB) followed by decomposition of the addition products by aq. HCl and treatment of the resultant glutamic acid derivatives with NH 4 OH to afford the target pyroglutamic acids along with recovery of the chiral auxiliary BPB. The stereochemical outcome of the addition reactions was found to be subjected to kinetic control. A mechanistic rationale for the observed stereochemical preferences is discussed.

Convenient, large-scale asymmetric synthesis of enantiomerically pure trans-cinnamylglycine and -α-alanine

Asymmetric syntheses of (S)-trans-cinnamylglycine and (S)-α-trans-cinnamyl-α-alanine via reactions of cinnamyl halides (Cl, Br) with Ni(II)-complexes of the chiral Schiff base of glycine or alanine with (S)-o-[N-(N-benzylprolyl)amino]benzophenone were developed. Inexpensive and readily available reagents and solvents were used, including an easily recyclable chiral auxiliary. The simplicity of the experimental procedures and the high stereochemical outcome make this method synthetically attractive for preparing the target amino acids on multi-gram scales.

Asymmetric synthesis of novel highly sterically constrained (2S,3S)-3-methyl-3-trifluoromethyl- and (2S,3S,4R)-3-trifluoromethyl-4-methylpyroglutamic acids

Abstract Asymmetric synthesis of the novel highly sterically constrained (2S,3S)-3-methyl-3-trifluoromethyl- and (2S,3S,4R)-3-trifluoromethyl-4-methylpyroglutamic acids has been developed via diastereoselective Michael addition reactions between a Ni(II) complex of the chiral non-racemic Schiff base of glycine with (S)-o-[N-(N-benzylprolyl)amino]benzophenone (BPB) and the corresponding trifluoromethyl-containing crotonates. Of particular synthetic interest is the reaction of the glycine Ni-complex with ethyl 3-trifluoromethyl crotonate featuring excellent diastereoselectivity (>98% de) as a result of complete stereochemical discrimination between the methyl and trifluoromethyl groups. A mechanistic rationale for the observed kinetically controlled stereochemical outcome is discussed.

Asymmetric Michael addition reactions of chiral Ni(II)-complex of glycine with (N-trans-enoyl)oxazolidines: improved reactivity and stereochemical outcome

Abstract Application of the ( N - trans -enoyl)oxazolidines as Michael acceptors in the kinetically controlled additions with a Ni(II)-complex of the chiral Schiff base of glycine with ( S )- o -[ N -( N -benzylprolyl)amino]benzophenone 1 was shown to be synthetically advantageous over the alkyl enoylates, allowing for remarkable improvement in reactivity and, in most cases, diastereoselectivity of the reactions. While the stereochemical outcome of the Michael additions of the aliphatic ( N - trans -enoyl)oxazolidines with complex 1 depended on the steric bulk of the alkyl group on the starting oxazolidines, the diastereoselectivity of the aromatic ( N - trans -enoyl)oxazolidines reactions was found to be controlled by the electronic properties of the aryl ring. In particular, the additions of complex 1 with ( N -cinnamoyl)oxazolidines, bearing electron-withdrawing substituents on the phenyl ring, afforded the (2 S ,3 R )-configured products with synthetically useful selectivity and in quantitative chemical yield, thus allowing an efficient access to sterically constrained β-substituted pyroglutamic acids and related compounds.

Toward design of a practical methodology for stereocontrolled synthesis of χ-constrained pyroglutamic acids and related compounds. Virtually complete control of simple diastereoselectivity in the Michael addition reactions of glycine Ni(II) complexes with N-(enoyl)oxazolidinones

A Ni(II) complex of the Schiff base of glycine with o-[N-α-picolylamino]benzophenone or -acetophenone as a nucleophilic glycine equivalent, and N-trans-enoyloxazolidinones, as a derivative of an α,β-unsaturated carboxylic acid, were found to be the substrates of choice in the corresponding Michael addition reactions. The reactions proceed at room temperature in the presence of catalytic amounts of DBU to afford quantitatively a virtually diastereocomplete formation of the corresponding addition products with (2R*,3R*) or (2R*,3S*) relative configuration, depending on the nature of the starting N-enoyloxazolidinones. Acidic decomposition of the products followed by treatment of the reaction mixture with NH4OH gives rise to the corresponding diastereomerically pure 3-substituted pyroglutamic acids.

A unique case of face diastereoselectivity in the Michael addition reactions between Ni(II)-complexes of glycine and chiral 3-(E-enoyl)-1,3-oxazolidin-2-ones

Abstract The origin of virtually complete face diastereoselectivity in the organic base-catalyzed, room temperature Michael addition reactions between Ni(II)-complexes of Schiff bases of glycine and chiral 3-( E -enoyl)-4-substituted-1,3-oxazolidin-2-ones was shown to stem from the unusual mode of steric interactions in determining the corresponding transition state.

Total asymmetric synthesis of highly constrained amino acids β-isopropyl-2′,6′-dimethyl-tyrosines

Abstract All four stereoisomers of the highly constrained aromatic α-amino acid β-isopropyl-2′,6′-dimethyltyrosine have been asymmetrically synthesized on a large scale. A catalytic asymmetric Michael addition of an organocuprate to a chiral α,β-unsaturated acyloxazolidinone and subsequent direct or indirect stereoselective electrophilic azidation of the α-position of the resulting product was followed by hydrolysis, hydrogenation and finally deprotection of the phenol group to afford the desired amino acids. The reactions generally proceeded in good stereoselectivitities (75–95% ee/de) and yields (70–90%), making these optically pure amino acids available in large scale practical for the synthesis of peptides and other studies.

A Convenient, Room-Temperature-Organic Base Protocol for Preparing Chiral 3-(Enoyl)-1,3-oxazolidin-2-ones

In this study, we developed a new protocol for the preparation of the chiral 3-[(E)-enoyl]-1,3-oxazolidin-2-ones under the ultimately simple reaction conditions starting with the corresponding enoyl chlorides and 1,3-oxazolidin-2-ones with Et3N/LiCl at room temperature. The method generally allows efficient preparation of various derivatives regardless of the steric and electronic nature of the substituents on both the enoyl or the oxazolidinone sites. Excellent yields, combined with the simplicity of the experimental procedures, render the present method immediately useful for preparing the target compounds.

Design of peptide agonists

Publisher Summary This chapter describes a systematic approach for designing potent and selective agonists for GPCRs. Sufficient and detailed experiments are provided in the chapter as a model to synthesize the peptide agonists successfully. The design of peptides resulting in potent and selective agonist activities is difficult because of several factors, but success can be normally obtained with a systematic approach. This approach requires highly interdisciplinary considerations that combine knowledge gathered from structure–biological activity relationships, conformational analysis, computer-assisted calculations and molecular design, biophysical analysis of structures (spectroscopy, crystallography, etc.), and in vivo and in vitro assays. In addition, new asymmetric syntheses and other synthetic methodologies are often important in preparing the designed compounds. Once a lead compound (whether from nature or from a peptide library prepared by combinatorial chemistry) has been defined based on the desired agonist activity, it is often desirable to determine the minimal structural requirements for bioactivity.

Synthesis of β and γ-Substituted Prolines for Conformation-Activity Relationship Studies of the α-MSH Analogue MT-II

Substituted prolines have limited rotational freedom about χ1 and χ2, and therefore can be used as unique probes for conformation-activity studies by incorporating them into biologically important peptides [1]. For example, substitution of Pro for His6 in the α-MSH analogue MT-II led to analogues with high agonist potency and selectivity for agonist activity at the human MC5R [2]. To explore this function, we have synthesized a series of novel, topographically constrained β and γ-substituted prolines and incorporated these optically pure substituted prolines into MT-II at positions 6 and 7.