Synthesis of diazoketones derived from α-amino acids; problem of side reactions

Plucińska, K.; Liberek, Beata

doi:10.1016/s0040-4020(01)81643-4

Cited by 71 publications

(38 citation statements)

References 18 publications

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“…Independent of our own work on solid-phase peptide synthesis of p-peptides, there have been a couple of reports on the preparation of N-Fmoc-protected p3-amino acids [I61 and on a solid-phase /3-peptide synthesis ') ~7 1 . problems in obtaining diazo ketones la-g in good-to-excellent yields after FC and/or crystallization (Scheme 1). As reported in previous investigations [20] [22], the methyl ester formed by partial hydrolysis of the mixed anhydride (moisture in the ethereal CH,N, solution!) was found to be the major side product of this reaction (up to 15 % ) 6 ) .…”

Section: Synthesis Of N-fmoc-protected P3-amino Acids Somentioning

confidence: 60%

Preparation of N‐Fmoc‐Protected β²‐ and β3‐Amino Acids and their use as building blocks for the solid‐phase synthesis of β‐peptides

Guichard

Abele

Seebàch³

1998

Helvetica Chimica Acta

165

123

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Dedicated to Professor A. I. Meyers, University of Colorado, For! Collins, on the occasion of his 65th birthday N-Fmoc-Protected (Fmoc = (9H-fluoren-9-y1methoxy)carbonyl) /+amino acids are required for an efficient synthesis of fl-oligopeptides on solid support. Enantiomerically pure F~n o c -~~-a m i n o acids (f13: side chain and NH, at C(3)(= C(p))) were prepared from Fmoc-protected (S)-and (R)-a-amino acids with aliphatic, aromatic, and functionalized side chains, using the standard or an optimized Arndt-Eistert reaction sequence. Fmoc-P2-Amino acids (p' side chain a! C(2), NH, at C(3)( = C(fi))) configuration bearing the side chain o f Ala, Val, Leu, and Phe were synthesized viu the Evans' chiral auxiliary methodology. The target p3-heptapeptides 5-8, a f13-pentadecapeptide 9 and a f12-heptapeptide 10 were synthesized on a manual solid-phase synthesis apparatus using conventional solid-phase peptide synthesis procedures (Scheme 3). In the case of f13-peptides, two methods were used to anchor the first [j-amino acid: esterification of the ortho-chlorotrityl chloride resin with the first Fmoc-/l-amino acid 2 (Method I, Scheme 2) or acylation of the 4-(benzy1oxy)henzyl alcohol resin (Wung resin) with the ketene intermediates from the Worff rearrangement of amino-acid-derived diazo ketone 1 (Method II, Scheme 2). The former technique provided better results, as exemplified by the synthesis of the heptapeptides 5 and 6 (Table 2). The intermediate from the Wolffrearrangement of diazo ketones 1 was also used for sequential peptide-bond formation on solid support (synthesis of the tetrapeptides 11 and 12). The CD spectra of the p2-and P3-peptides 5, 9, and 10 show the typical pattern previously assigned to an (M) 3 , helical secondary structure (Fig.). The most intense CD absorption was observed with the pentadecapeptide 9 (strong broad negative Cotton effect at ca. 213 nm); compared to the analogous heptapeptide 5, this corresponds to a 2.5 fold increase in the molar ellipticity per residue!

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Section: Synthesis Of N-fmoc-protected P3-amino Acids Somentioning

confidence: 60%

Preparation of N‐Fmoc‐Protected β²‐ and β3‐Amino Acids and their use as building blocks for the solid‐phase synthesis of β‐peptides

Guichard

Abele

Seebàch³

1998

Helvetica Chimica Acta

165

123

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“…Boc-(S)-Phe-OH, Boc-(S)-Leu-OH, and Boc-(R)-Val-OH were synthesized by Arndt-Eistert homologation of Boc-(S)-Phe-OH, Boc-(S)-Leu-OH, and Boc-(S)-Val-OH (note the formal change of configuration assignment upon homologation), respectively. 19,20 Peptide couplings were mediated by N,N 0 -dicyclohexylcarbodiimide and 1-hydroxy benzotriazole. 18 Crude peptide 1 was purified by medium-pressure liquid chromatography on a reversephase C 18 (40-63 ) column and crude peptide 2 was purified by high pressure liquid chromatography (HPLC) on a C 18 (5-10 ) column using methanol-water gradients.…”

Section: Peptide Synthesis and Crystallizationmentioning

confidence: 99%

Peptide hairpins with strand segments containing α‐ and β‐amino acid residues: Cross‐strand aromatic interactions of facing Phe residues

et al. 2005

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The incporation of beta-amino acid residues into the strand segments of designed beta-hairpin leads to the formation of polar sheets, since in the case of beta-peptide strands, all adjacent carbonyl groups point in one direction and the amide groups orient in the opposite direction. The conformational analysis of two designed peptide hairpins composed of alpha/beta-hybrid segments are described: Boc-Leu-betaPhe-Val-(D)-Pro-Gly-Leu-betaPhe-Val-OMe (1) and Boc-betaLeu-Phe-betaVal-D-Pro-Gly-betaLeu-Phe-betaVal-OMe (2). A 500-MHz 1H-NMR (nuclear magnetic resonance) analysis in methanol supports a significant population of hairpin conformations in both peptides. Diagnostic nuclear Overhauser effects (NOEs) are observed in both cases. X-ray diffraction studies on single crystals of peptide 1 reveal a beta-hairpin conformation in both the molecules, which constitute the crystallographic asymmetric unit. Three cross-strand hydrogen bonds and a nucleating type II' beta-turn at the D-Pro-Gly segment are observed in the two independent molecules. In peptide 1, the betaPhe residues at positions 2 and 7 occur at the nonhydrogen-bonding position, with the benzyl side chains pointing on opposite faces of the beta-sheet. The observed aromatic centroid-to-centroid distances are 8.92 A (molecule A) and 8.94 A (molecule B). In peptide 2, the aromatic rings must occupy facing positions in antiparallel strands, in the NMR-derived structure. Peptide 1 yields a normal "hairpin-like" CD spectrum in methanol with a minimum at 224 nm. The CD spectrum of peptide 2 reveals a negative band at 234 nm and a positive band at 221 nm, suggestive of an exciton split doublet. Modeling of the facing Phe side chains at the hydrogen-bonding position of a canonical beta-hairpin suggests that interring separation is approximately 4.78 A for the gauche+ gauche- (g+ g-) rotamer. A previously reported peptide beta-hairpin composed of only alpha-amino acids, Boc-Leu-Phe-Val-D-Pro-Gly-Leu-Phe-Val-OMe also exhibited an anomalous far-UV (ultraviolet) CD (circular dichroism) spectrum, which was interpreted in terms of interactions between facing aromatic chromophores, Phe 2 and Phe 7 (C. Zhao, P. L. Polavarapu, C. Das, and P. Balaram, Journal of the American Chemical Society, 2000, Vol 122, pp. 8228-8231).

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“…Nevertheless, with this method traces of water are present in the ethereal solution which lead to a partial hydrolysis of the activated amino acid. 10 Consequently varying amounts of the amino acid methyl ester are isolated as side products. Unfortunately, the corresponding trimethylsilylsubstituted diazomethane (TMS-CHN 2 ), which can be purchased as a water-free solution and is occasionally used as a stubstitute for diazomethane, is not sufficiently reactive for formation of the amino acid-derived diazoketone.…”

Section: Formation Of Diazoketonesmentioning

confidence: 99%

Preparation of Enantiopure β-Amino Acids by Homologation of α-Amino Acids

Podlech

2005

Enantioselective Synthesis of Β-Amino Acids

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Synthesis of diazoketones derived from α-amino acids; problem of side reactions

Cited by 71 publications

References 18 publications

Preparation of N‐Fmoc‐Protected β²‐ and β3‐Amino Acids and their use as building blocks for the solid‐phase synthesis of β‐peptides

Preparation of N‐Fmoc‐Protected β²‐ and β3‐Amino Acids and their use as building blocks for the solid‐phase synthesis of β‐peptides

Peptide hairpins with strand segments containing α‐ and β‐amino acid residues: Cross‐strand aromatic interactions of facing Phe residues

Preparation of Enantiopure β-Amino Acids by Homologation of α-Amino Acids

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Synthesis of diazoketones derived from α-amino acids; problem of side reactions

Cited by 71 publications

References 18 publications

Preparation of N‐Fmoc‐Protected β2‐ and β3‐Amino Acids and their use as building blocks for the solid‐phase synthesis of β‐peptides

Preparation of N‐Fmoc‐Protected β2‐ and β3‐Amino Acids and their use as building blocks for the solid‐phase synthesis of β‐peptides

Peptide hairpins with strand segments containing α‐ and β‐amino acid residues: Cross‐strand aromatic interactions of facing Phe residues

Preparation of Enantiopure β-Amino Acids by Homologation of α-Amino Acids

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Preparation of N‐Fmoc‐Protected β²‐ and β3‐Amino Acids and their use as building blocks for the solid‐phase synthesis of β‐peptides

Preparation of N‐Fmoc‐Protected β²‐ and β3‐Amino Acids and their use as building blocks for the solid‐phase synthesis of β‐peptides