A convenient method for the synthesis of norstatine derivatives from N-Fmoc or N-Boc amino acids

Kourtal, Saïd; Pâris, J.

doi:10.1007/bf00126736

Cited by 5 publications

(3 citation statements)

References 33 publications

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“…Norstatines can be derived directly or indirectly from a-amino aldehydes through the addition of various C1 nucleophiles. Cyanide anions, [17,18] isocyanide-based multicomponent reactions, [19][20][21][22] and formaldehyde hydrazones [23,24] have been reported as C nucleophiles in these umpolung reactions; additionally, vinyl Grignard and lithium organic compounds [25][26][27][28][29] have been used as masked C1 anion equivalents. In these reactions, the stereocontrol in positions 2 and 3 is problematic due to the facile racemization of the amino aldehyde building block and the limited stereospecificity of the nucleophilic attack.…”

Section: Resultsmentioning

confidence: 99%

The Potential of P1 Site Alterations in Peptidomimetic Protease Inhibitors as Suggested by Virtual Screening and Explored by the Use of CC‐Coupling Reagents

et al. 2006

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A synthetic concept is presented that allows the construction of peptide isostere libraries through polymer-supported C-acylation reactions. A phosphorane linker reagent is used as a carbanion equivalent; by employing MSNT as a coupling reagent, the C-acylation can be conducted without racemization. Diastereoselective reduction was effected with L-selectride. The reagent linker allows the preparation of a norstatine library with full variation of the isosteric positions including the P1 side chain that addresses the protease S1 pocket. Therefore, the concept was employed to investigate the P1 site specificity of peptide isostere inhibitors systematically. The S1 pocket of several aspartic proteases including plasmepsin II and cathepsin D was modeled and docked with approximately 500 amino acid side chains. Inspired by this virtual screen, a P1 site mutation library was designed, synthesized, and screened against three aspartic proteases (plasmepsin II, HIV protease, and cathepsin D). The potency of norstatine inhibitors was found to depend strongly on the P1 substituent. Large, hydrophobic residues such as biphenyl, 4-bromophenyl, and 4-nitrophenyl enhanced the inhibitory activity (IC50) by up to 70-fold against plasmepsin II. In addition, P1 variation introduced significant selectivity, as up to 9-fold greater activity was found against plasmepsin II relative to human cathepsin D. The active P1 site residues did not fit into the crystal structure; however, molecular dynamics simulation suggested a possible alternative binding mode.

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Section: Resultsmentioning

confidence: 99%

The Potential of P1 Site Alterations in Peptidomimetic Protease Inhibitors as Suggested by Virtual Screening and Explored by the Use of CC‐Coupling Reagents

et al. 2006

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“…Reduction of the carbonyl moiety by sodium borohydride in the presence of lanthanoid chlorides yielded the propargylic alcohol with syn diastereoselectivity and good yields. After protection of the hydroxyl group, the propargylic ethers were converted to the norstatine derivatives 61 as previously described (Kourtal and Paris, 1996).…”

Section: Synthesis Of Amino Arid Derivatives From N-protected Carboxymentioning

confidence: 99%

Some of the amino acid chemistry going on in the Laboratory of Amino Acids, Peptides and Proteins

et al. 1999

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Some of the chemistry of amino acids going on in our laboratory (Laboratoire des Amino acides Peptides et Protéines) is described as well as some mass spectrometry methodology for their characterization particularly on solid supports. Several aspects are presented including: (i) the stereoselective synthesis of natural and unnatural amino acids using 2-hydroxypinan-3-one as chiral auxiliary; (ii) the stereoselective synthesis of natural and unnatural amino acids by deracemization of alpha-amino acids via their ketene derivatives; (iii) the synthesis of alpha-aryl-alpha-amino acids via reaction of organometallics with a glycine cation; (iv) the diastereoselective synthesis of glycosyl-alpha-amino acids; (v) the synthesis of beta-amino acids using alpha-aminopyrrolidinopiperazinediones as chiral templates; (vi) the reactivity of urethane-N-protected N-carboxyanhydrides. To characterize natural and non natural amino acids through their immonium ions by mass spectrometry, some methodology is also described.

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“…7 We have previously described a general method for the preparation of norstatines from N-protected aminoaldehydes. 8 The key step was the reaction of ethynylmagnesium bromide with N-protected aminoaldehydes to a¡ord propargylic alcohols with syn diastereoselectivity. We propose here an alternative route to prepare norstatines from UNCAs 1 (Scheme 1).…”

mentioning

confidence: 99%

Diastereoselective Synthesis of N-Protected β-Amino-α-hydroxyacids (Norstatines) from Urethane N-Carboxyanhydrides (UNCAs)

Audin¹,

Pothion²,

Fehrentz³

et al. 1999

J. Chem. Res.

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A convenient method for the synthesis of norstatine derivatives from N-Fmoc or N-Boc amino acids

Cited by 5 publications

References 33 publications

The Potential of P1 Site Alterations in Peptidomimetic Protease Inhibitors as Suggested by Virtual Screening and Explored by the Use of CC‐Coupling Reagents

The Potential of P1 Site Alterations in Peptidomimetic Protease Inhibitors as Suggested by Virtual Screening and Explored by the Use of CC‐Coupling Reagents

Some of the amino acid chemistry going on in the Laboratory of Amino Acids, Peptides and Proteins

Diastereoselective Synthesis of N-Protected β-Amino-α-hydroxyacids (Norstatines) from Urethane N-Carboxyanhydrides (UNCAs)

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