Chiral cynthesis of D- and L-3,3-diphenylalanine (DIP), unusual α-amino acids for peptides of biological interest

Chen, Huai G.; Beylin, Vladimir G.; Marlatt, M.; Leja, Boguslawa; Goel, O. P.

doi:10.1016/s0040-4039(00)92070-7

Cited by 36 publications

(8 citation statements)

References 8 publications

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“…been described. 35 The key step for our synthesis of amino acids 7-12 involved an asymmetric alkylation of a Schiff base from a sultam-derived glycinate, 42, by the corresponding electrophiles, i.e., bromodiphenylmethane for Dip (7), 9-bromofluorene for Fig ( 8), 1-bromoindan (43) for (2S,3fi)-Ing ( 9) and (2S,3S)-Ing ( 10), and 1-bromobenz-[/lindan (44) for (2S,3fi)-Bfi (11) and (2S,3S)-Bfi (12), respectively. The yields of the alkylation step varied from 68% to 88%, the diastereoisomeric excess at the CQ chiral center was over 95 % as estimated from the NMR analysis, and only a slight induction on the ß center for the 1-indanyl and l-benz[/]indanyl probe was observed.…”

Section: Resultsmentioning

confidence: 99%

Design and Synthesis of Side-Chain Conformationally Restricted Phenylalanines and Their Use for Structure-Activity Studies on Tachykinin NK-1 Receptor

Josien¹,

Lavielle²,

Brunissen³

et al. 1994

J. Med. Chem.

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Constrained analogues of phenylalanine have been conceptually designed for analyzing the binding pockets of Phe7 (S7) and Phe8 (S8), two aromatic residues important for the pharmacological properties of SP, i.e., L-tetrahydroisoquinoleic acid, L-diphenylalanine, L-9-fluorenylglycine (Flg), 2-indanylglycine, the diastereomers of L-1-indanylglycine (Ing) and L-1-benz[f]indanylglycine (Bfi), and the Z and E isomers of dehydrophenylalanine (delta ZPhe, delta EPhe). Binding studies were performed with appropriate ligands and tissue preparations allowing the discrimination of the three tachykinin binding sites, NK-1, NK-2, and NK-3. The potencies of these agonists were evaluated in the guinea pig ileum bioassay. According to the binding data, we can conclude that the S7 subsite is small, only the gauche (-) probe [(2S,3S)-Ing7]SP presents a high affinity for specific NK-1 binding sites. Surprisingly, the [delta EPhe7]SP analogue, which projects the aromatic ring toward the trans orientation, is over 40-fold more potent than the Z isomer, [delta ZPhe7]SP. A plausible explanation of these conflictual results is that either the binding protein quenches the minor trans rotamer of [(2S,3S)-Ing7]SP in solution or this constrained amino acid side chain rotates when inserted in the protein. In position 8, the high binding affinities of [Flg8]SP and [(2S,3S)-Bfi8]SP suggest that the S8 subsite is large enough to accept two aromatic rings in the gauche (-) and one aromatic ring in the trans direction. Peptides bearing two conformational probes in positions 7, 8, or 9 led to postulate that S7, S8, and S9 subsites are independent from each other. The volumes available for side chains 7 and 8 can be estimated to be close to 110 and 240 A3, respectively. The large volume of the S8 subsite raises question on the localization of the SP-binding site in the NK-1 receptor. If SP were to bind in the transmembrane domains, the cleft defined by the seven transmembrane segments must rearrange during the binding process in order to bind a peptide in an alpha-helical structure and at least one large binding subsite in position 8. Thus, indirect topographical analysis with constrained amino acids might contribute to the analysis of the receptor/ligand dynamics. Finally, this study demonstrates that a good knowledge of the peptidic backbone structure and a combination of constrained amino acids are prerequisites to confidently attribute the preferred orientation(s) of an amino acid side chain.

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Section: Resultsmentioning

confidence: 99%

Design and Synthesis of Side-Chain Conformationally Restricted Phenylalanines and Their Use for Structure-Activity Studies on Tachykinin NK-1 Receptor

Josien¹,

Lavielle²,

Brunissen³

et al. 1994

J. Med. Chem.

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“…The chiral synthesis of d ‐ and l ‐3,3‐diphenylalanine with high enantiomeric purity (>99 %) was proposed by Chen et al [45a] . The substrate for the synthesis is 3,3‐diphenylpropanoic acid 47 (Scheme 8), carboxylic moiety of which is activated on the way of formation of pivaloyl mixed anhydride 48 .…”

Section: Human Immunodeficiency Virus and Hiv Protease Inhibitorsmentioning

confidence: 99%

“…The d ‐ or l ‐3,3‐diphenylalanine is obtained with satisfactory overall yield and high enantiomeric purity (Scheme 8). [45a] …”

Section: Human Immunodeficiency Virus and Hiv Protease Inhibitorsmentioning

confidence: 99%

Amino Acid and Peptide‐Based Antiviral Agents

2021

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A significant number of antiviral agents used in clinical practice are amino acids, short peptides, or peptidomimetics. Among them, several HIV protease inhibitors (e. g. lopinavir, atazanavir), HCV protease inhibitors (e. g. grazoprevir, glecaprevir), and HCV NS5A protein inhibitors have contributed to a significant decrease in mortality from AIDS and hepatitis. However, there is an ongoing need for the discovery of new antiviral agents and the development of existing drugs; amino acids, both proteinogenic and non‐proteinogenic in nature, serve as convenient building blocks for this purpose. The synthesis of non‐proteinogenic amino acid components of antiviral agents could be challenging due to the need for enantiomerically or diastereomerically pure products. Herein, we present a concise review of antiviral agents whose structures are based on amino acids of both natural and unnatural origin. Special attention is paid to the synthetic aspects of non‐proteinogenic amino acid components of those agents.

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“…After removal of the chiral auxiliary with LiOH/H202, the azido acid was hydrogenated over Pd/C (Fig. 19) (Evans et al, 1989(Evans et al, , 1990aChen et al, 1992;Beylin et al, 1993;Lundquist and Dix, 1998).…”

Section: Electrophilic Arninationmentioning

confidence: 99%