Intramolecular Amide Stacking and Its Competition with Hydrogen Bonding in a Small Foldamer

James, William H.; Müller, Christian; Buchanan, Evan G.; Nix, Michael G. D.; Li, Guo; Roskop, Luke; Gordon, Mark S.; Slipchenko, Lyudmila V.; Gellman, Samuel H.; Zwier, Timothy S.

doi:10.1021/ja9054965

Cited by 60 publications

(123 citation statements)

References 21 publications

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“…The appropriate reaction conditions of peptide bond formation with H-AFU-OH are depending both on structure and substituents of the β-SAAs. Both N-acylation and N(Me)-amid formation reactions were tested on our AFUs (1 and 2) giving either Ac-RibAFU(ip)-NHMe (26) or the xylo epimer AcXylAFU(ip)-NHMe (27) the simplest and smallest models of homo-and hetero-oligomers of peptides (Perczel 1991;James 2009;Knapp 2014). Both 3-azido-3-deoxy-furanuronic acids (6 and 7) are adequate intermediates for the synthesis of 26 and 27 respectively, standing for a β-amino acids with amide bonds at both ends (Scheme 7).…”

Section: Methodsmentioning

confidence: 99%

C-3 epimers of sugar amino acids as foldameric building blocks: improved synthesis, useful derivatives, coupling strategies

et al. 2016

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To obtain key sugar derivatives of making homooligomeric foldamers or α/β-chimera peptides, economic and multigram scale synthetic methods were to be developed. Though described in the literature, the cost-effective making of both 3-amino-3-deoxy-ribofuranuronic acid (H-tX-OH) and its C-3 epimeric stereoisomer, the 3-amino-3-deoxy-xylofuranuronic acid (H-cX-OH) from D-glucose is described here. The present synthetic route elaborated is i) appropriate for large-scale synthesis, ii) reagent costs reduced (e.g. by a factor of 400), iii) yields optimized are ~80% or higher for all six consecutive steps concluding -tX-or -cX-and iv) reaction times shortened. Thus, a new synthetic route step-by-step optimized for yield, cost, time and purification is given both for D-xylo and D-riboamino-furanuronic acids using sustainable chemistry (e.g. less chromatography with organic solvents; using continuous flow reactor). Multigram scale syntheses of these β-sugar amino acids, β-SAAs, now available on a larger scale made possible to test and optimize coupling reactions and conditions of making α/β-chimera peptides. Our study encompasses necessary building blocks (e.g. -X-OMe, -X-O i Pr, -X-NHMe, Fmoc-X-OH) and key coupling reactions making -Aaa-tX-Aaa-or -Aaa-tX-tXAaa-type "inserts". Completed for both stereoisomers of X, including the newly synthetized FmoccX-OH, producing longer oligomers for drug design and discovery is more of a reality than a wish. 2Graphical abstract: From D-glucose in 6 (7) steps both C-3 epimers of an azido-furanuronic acid (cAFU and tAFU) are obtained. Yield optimized, scalable and robust reactions made possible to get β-sugar amino acids in a more environment-friendly way. Useful derivatives were synthesized and probed as key intermediates of foldameric "Lego element" now ready to be built in into α/β-chimera peptides supporting drug design and discovery.3

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Section: Methodsmentioning

confidence: 99%

C-3 epimers of sugar amino acids as foldameric building blocks: improved synthesis, useful derivatives, coupling strategies

et al. 2016

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“…Yet, experimental techniques exist to measure conformational distribution [47], and even conformational energetics [149]. Even though conformational distributions have indeed been measured for a few peptides [47,71,72,125,126], conformational energetics have been measured only for slightly simpler systems [149,180,181]. Conclusions about conformational energetics from the majority of experiments have thus been limited so far to identifying major and minor conformations of the distribution.…”

Section: Lessons From the Confrontation mentioning

confidence: 99%

Isolated Neutral Peptides

Gloaguen

Mons

2014

Topics in Current Chemistry

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This chapter examines the structural characterisation of isolated neutral amino-acids and peptides. After a presentation of the experimental and theoretical state-of-the-art in the field, a review of the major structures and shaping interactions is presented. Special focus is made on conformationally-resolved studies which enable one to go beyond simple structural characterisation; probing flexibility and excited-state photophysics are given as examples of promising future directions.

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“…Another scenario considers n→π* charge transfer from the O lone pairs to the carbonyl antibonding orbital of the other subunit 4,6,10,11,17 . With specific regard to amide units, recent studies of diand tripeptides in the gas phase have found occasions where a pair of peptide units are stacked above one another [13][14][15] , as opposed to forming the normally expected NH···O H-bonds.…”

Section: Influence Of C=o Dipole-dipole Attractionsmentioning

confidence: 99%

“…A second, and more recent, concept that underlies interpeptide attraction arises from studies of small oligopeptides in the gas phase [13][14][15][16] . In some of the conformations observed, pairs of peptide units arrange themselves parallel to one another, in a stacked geometry.…”

Section: Introductionmentioning

confidence: 99%

Preferred Configurations of Peptide–Peptide Interactions

Adhikari

Scheiner

2013

J. Phys. Chem. A

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The natural and fundamental proclivities of interaction between a pair of peptide units is examined using high-level ab initio calculations. The NH···O H-bonded structure is found to be the most stable configuration of the N-methylacetamide (NMA) model dimer, but only slightly more so than a stacked arrangement. The H-bonded geometry is destabilized by only a small amount if the NH group is lifted out of the plane of the proton-accepting amide. This out-of-plane motion is facilitated by a stabilizing charge transfer from the CO π bond to the NH σ* antibonding orbital. The parallel and anti-parallel stacked dimers are nearly equal in energy, both only slightly less stable than the NH···O H-bonded structure. Both are stabilized by a combination of CH···O H-bonding and a π→π* transfer between the two CO bonds.There are no minima on the surface that are associated with O lp →π*(CO) transfers, due in large part to strong electrostatic repulsion between the two O atoms which resists an approach of a carbonyl O from above the C=O bond of the other amide.

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Intramolecular Amide Stacking and Its Competition with Hydrogen Bonding in a Small Foldamer

Cited by 60 publications

References 21 publications

C-3 epimers of sugar amino acids as foldameric building blocks: improved synthesis, useful derivatives, coupling strategies

C-3 epimers of sugar amino acids as foldameric building blocks: improved synthesis, useful derivatives, coupling strategies

Isolated Neutral Peptides

Preferred Configurations of Peptide–Peptide Interactions

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