Mag: a Cα-Methylated, Side-chain Unsaturated α-Amino Acid. Introduction into Model Peptides and Conformational Preference

Peggion, Cristina; Flammengo, Roberto; Mossel, Eric; Broxterman, Quirinus B.; Kaptein, Bernard; Kamphuis, J.; Formaggio, Fernando; Crisma, Marco; Toniolo, Claudio

doi:10.1016/s0040-4020(00)00274-x

Cited by 18 publications

(31 citation statements)

References 36 publications

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“…Peptide-based catalysts [13][14][15][16][17] and peptide-based nanotechnology 18 -20 are benefiting from the adoption of unnatural and uncommon amino acids that exhibit specific conformational imperatives. Helical peptide foldamers have been obtained from amino acid analogues such as N-substituted glycines, 21,22 and ␣, ␤, dehydro, 23 D-, 24 -26 and chiral 17,27,28 and achiral 29,30 ␣,␣-dialkyl amino acids. The helical structures obtained from these residues necessarily undergo conformational fluctuations induced by ambient thermal energy.…”

Section: Introductionmentioning

confidence: 99%

Helix–helix interconversion rates of short ¹³C‐labeled helical peptides as measured by dynamic NMR spectroscopy

et al. 2005

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The rates at which a peptide hexamer and a peptide octamer interconvert between left- and right-handed helical forms in CD2Cl2 solution have been characterized by 13C dynamic NMR (DNMR) spectroscopy. The peptide esters studied are Fmoc-(Aib)n-OtBu (n = 6 and 8), where Fmoc is 9-fluorenylmethyoxycarbonyl and Aib is the strongly helix-forming residue alpha-aminoisobutyric acid. Because the Aib residue is itself achiral, homooligomers of this residue form a 50/50 mixture of enantiomeric 3(10)-helices in solution. It has been demonstrated (R.-P. Hummel, C. Toniolo, and G. Jung, Angewandte Chemie International Edition, 1987, Vol. 26, pp. 1150-1152) that oligomers of Aib interconvert on the millisecond timescale. We have performed lineshape analysis of 13C-NMR spectra collected for our peptides enriched with 13C at a single residue. Rate constants for the octamer range from 6 s(-1) at 196 K to about 56,500 s(-1) at 320 K. At all temperatures, the hexamer interconverts about three times faster than the octamer. Eyring plots of the data reveal experimentally indistinguishable DeltaH++ values for the hexamer and octamer of 37.8 +/- 0.6 and 37.6 +/- 0.4 kJ mol(-1) respectively. The difference in the rates of interconversion is dictated by entropic factors. The hexamer and octamer exhibit negative DeltaS++ values of -29.0(-1) +/- 2.5 and -37.3 +/- 1.7 J K(-1) mol(-1), respectively. A mechanism for the helix-helix interconversion is proposed. and calculated DeltaG++ values are compared to the estimate for a decamer undergoing a helix-helix interconversion.

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Section: Introductionmentioning

confidence: 99%

Helix–helix interconversion rates of short ¹³C‐labeled helical peptides as measured by dynamic NMR spectroscopy

et al. 2005

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“…The work reported here features (αMe)Nva with a n ‐propyl side‐chain, intermediate in length between the shorter side‐chains of Aib (methyl) (4–7,9) and Iva (ethyl) (12,13,16), and the much longer, highly lipophilic side‐chains of (αMe)Aoc ( n ‐hexyl) (14) and (αMe)Aun ( n ‐nonyl) (15). More specifically, we prepared a set of selected, model l (or S)‐(αMe)Nva peptides to the pentamer level either using the optically pure l ‐enantiomer obtained from a stereoselective chemical or a chemoenzymatic synthesis, or by side‐chain hydrogenation of the corresponding l ‐Mag peptides (17). In addition, a detailed conformational investigation of the (αMe)Nva peptides in solution, using FT‐IR absorption and 1 H NMR, and in the crystal state, using X‐ray diffraction, has been performed in comparison with related peptides based on l ‐Nva, the C α ‐unmethylated amino acid counterpart.…”

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confidence: 99%

(αMe)Nva: stereoselective syntheses and preferred conformations of selected model peptides

Moretto¹,

Peggion²,

Formaggio³

et al. 2000

The Journal of Peptide Research

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Using different stereoselective chemical and chemoenzymatic approaches we synthesized the chiral, Calpha-methylated alpha-amino acid L-(alphaMe)Nva with a short, linear side-chain. A set of terminally protected model peptides to the pentamer level containing either (alphaMe)Nva or Nva in combination with Ala and/or Aib was prepared using solution methods and characterized fully. Two (alphaMe)Nva peptides were also synthesized using side-chain hydrogenation of the corresponding Calpha-methyl, Calpha-allylglycine (Mag) peptides. A detailed solution and crystal-state conformational analysis based on FT-IR absorption, 1H NMR and X-ray diffraction techniques allowed us to define that: (i) (alphaMe)Nva is an effective beta-turn and 3(10)-helix former; and (ii) the relationship between (alphaMe)Nva chirality and the screw sense of the turn/helix formed is that typical of protein amino acids, i.e. L-(alphaMe)Nva induces the preferential formation of right-handed folded structures. In more general terms, this study reinforced previous conclusions that peptides based on alpha-amino acids with a Calpha-methyl substituent and a Calpha-linear alkyl substituent are characterized by a strong tendency to fold into turn and helical structures.

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“…As a result, we herewith report that by combining enzymatic resolution of the racemic a,adisubstituted side-chain w-unsaturated amino acid amides 3 [4,7] with subsequent cross-metathesis on the terminal olefin functions, the functionalized a-amino acids 1 are readily accessible (Scheme 1). Although we will not discuss any follow-up chemistry of the functionality introduced in the final products, it will be clear that the resulting functional group provides ample opportunity for further synthetic derivatization.…”

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confidence: 99%

“…[4,7] The synthesis of the homologous a-amino acids 11 and 12 proceeded in a different manner as shown in Scheme 2, but also involved an enzymatic resolution to obtain the (S)-a-amino acids in enantiopure form. The strategy commenced with methyl acetoacetate (4), which via standard alkylation with the required olefin, hydroxide-mediated saponification and subsequent acidic decarboxylation was converted into ketones 5 and 6 in good overall yields.…”

mentioning

confidence: 99%

“…[4,7] Next, we screened a series of differently protected racemic a-methyl a-amino acid derivatives (14-17) in combination with olefinic precursors in cross-metathesis reactions (Table 1). Based on various examples of cross-metathesis on a-H-amino acids, [9] the reactions were conducted in the presence of 5 mol % of the second generation Grubbs catalyst (13) and four equivalents of the cross-metathesis partner in toluene at room temperature.…”

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A Cross‐Metathesis Route to Functionalized α‐Methyl α‐Substituted Amino Acids

et al. 2007

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A chemoenzymatic approach to the synthesis of functionalized a-methyl a-substituted amino acids is detailed. This involves amidasemediated enzymatic resolution of a-methyl a-substituted side-chain w-unsaturated amino acids followed by functionalization via cross-metathesis.Keywords: amino amidase; cross-metathesis; enzyme catalysis; a-methyl a-substituted amino acids; side-chain w-unsaturated a-amino acids Enantiomerically pure a,a-disubstituted a-amino acids, especially a-methyl a-substituted amino acids, are of increasing interest for the agrochemical and pharmaceutical industry.[1] Compared to their a-H counterparts, peptides containing one or more such amino acids are less prone to epimerization, display enhanced metabolic stability and possess different folding behavior.[2] In line with our research on metathesis applications of side-chain w-unsaturated a-Hamino acids, [3] and inspired by successful ring-closing metathesis examples of a-methyl a-substituted amino acids from our own [4] and other groups, [5] we set out to explore the viability of a cross-metathesis [6] route to prepare functionalized a-methyl a-substituted amino acids. As a result, we herewith report that by combining enzymatic resolution of the racemic a,adisubstituted side-chain w-unsaturated amino acid amides 3 [4,7] with subsequent cross-metathesis on the terminal olefin functions, the functionalized a-amino acids 1 are readily accessible (Scheme 1). Although we will not discuss any follow-up chemistry of the functionality introduced in the final products, it will be clear that the resulting functional group provides ample opportunity for further synthetic derivatization.[8]Enantiopure a-methyl a-allylglycine amide (R)-7 and the corresponding acid (S)-10 were synthesized previously in our lab via a chemoenzymatic strategy. [4,7] The synthesis of the homologous a-amino acids 11 and 12 proceeded in a different manner as shown in Scheme 2, but also involved an enzymatic resolution to obtain the (S)-a-amino acids in enantiopure form. The strategy commenced with methyl acetoacetate (4), which via standard alkylation with the required olefin, hydroxide-mediated saponification and subsequent acidic decarboxylation was converted into ketones 5 and 6 in good overall yields. Subjection to Strecker conditions, followed by partial nitrile hydrolysis (NaOH, PhCHO, MeOH) and subsequent Schiff base hydrolysis (4 N HCl) provided the aamino acid amides 8 and 9 in good overall yields. They were made salt-free via extraction from a basic water layer (pH 10) with CH 2 Cl 2 and after concentration subjected to whole cells from Mycobacterium neoaurum ATCC 25795 in an aqueous solution starting at pH 8.3. After 18 h, the reaction mixtures were worked up, the products were separated and purified via ion exchange chromatography. Chiral HPLC analysis showed excellent ees for a-amino acids (S)-11 and (S)-12 of 99 and 98.5 %, respectively. These numScheme 1. Retrosynthesis of enantiopure side-chain w-unsaturated a-methyl a-amino acids.

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Mag: a Cα-Methylated, Side-chain Unsaturated α-Amino Acid. Introduction into Model Peptides and Conformational Preference

Cited by 18 publications

References 36 publications

Helix–helix interconversion rates of short ¹³C‐labeled helical peptides as measured by dynamic NMR spectroscopy

Helix–helix interconversion rates of short ¹³C‐labeled helical peptides as measured by dynamic NMR spectroscopy

(αMe)Nva: stereoselective syntheses and preferred conformations of selected model peptides

A Cross‐Metathesis Route to Functionalized α‐Methyl α‐Substituted Amino Acids

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Mag: a Cα-Methylated, Side-chain Unsaturated α-Amino Acid. Introduction into Model Peptides and Conformational Preference

Cited by 18 publications

References 36 publications

Helix–helix interconversion rates of short 13C‐labeled helical peptides as measured by dynamic NMR spectroscopy

Helix–helix interconversion rates of short 13C‐labeled helical peptides as measured by dynamic NMR spectroscopy

(αMe)Nva: stereoselective syntheses and preferred conformations of selected model peptides

A Cross‐Metathesis Route to Functionalized α‐Methyl α‐Substituted Amino Acids

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Helix–helix interconversion rates of short ¹³C‐labeled helical peptides as measured by dynamic NMR spectroscopy

Helix–helix interconversion rates of short ¹³C‐labeled helical peptides as measured by dynamic NMR spectroscopy