Co-reporter:Vincent Diemer;Julien Maury;Bryden A. F. Le Bailly;Simon J. Webb
Chemical Communications 2017 vol. 53(Issue 78) pp:10768-10771
Publication Date(Web):2017/09/28
DOI:10.1039/C7CC06427F
Conformationally mobile oligomers with helical structures, or ‘dynamic foldamers’, may populate a mixture of screw-sense conformers whose relative proportion has been used as a means of communicating information on a molecular scale. The dibenzazepinyl urea provides a means of quantifying both the sense and degree of this screw-sense preference through a combination of circular dichroism (CD) and NMR spectroscopy. The dibenzazepinyl urea probe is synthetically versatile, readily accessible, and easy to introduce to the terminus of an amide or a urea foldamer.
Co-reporter:Romain Costil;Dr. Quentin Lefebvre; Jonathan Clayden
Angewandte Chemie International Edition 2017 Volume 56(Issue 46) pp:14602-14606
Publication Date(Web):2017/11/13
DOI:10.1002/anie.201708991
AbstractAnalogues of dibenzodiazepines, in which the seven-membered nitrogen heterocycle is replaced by a 9–12-membered ring, were made by an unactivated Smiles rearrangement of five- to eight-membered heterocyclic anthranilamides. The conformational preference of the tertiary amide in the starting material leads to intramolecular migration of a range of aryl rings, even those lacking electron-withdrawing activating groups, and provides a method for nn+4 ring expansion. The medium-ring products adopt a chiral ground state with an intramolecular, transannular hydrogen bond. The rate of interconversion of their enantiomeric conformers depends on solvent polarity. Ring size and adjacent steric hindrance modulate this hidden hydrophilicity, thus making this scaffold a good candidate for drug development.
Co-reporter:Julien Maury, Wojciech Zawodny, and Jonathan Clayden
Organic Letters 2017 Volume 19(Issue 3) pp:
Publication Date(Web):January 18, 2017
DOI:10.1021/acs.orglett.6b03603
Treatment of N′-aryl urea derivatives of enantiomerically enriched α-(2-pyridyl) and α-(3-pyridyl)alkylamines with a base leads to the migration of the N′-aryl substituent from N to C in a ‘nonclassical’ intramolecular nucleophilic aromatic substitution reaction. Both electron-rich and -poor rings migrate successfully. A new quaternary stereogenic center is formed adjacent to the pyridine ring with high stereospecificity, even when the intermediate anion is a presumably planar 2-picolyllithium. Base hydrolysis of the urea gives enantiomerically enriched α-pyridylalkylamines.
Co-reporter:Josep Mas-Roselló;Shuji Hachisu; Jonathan Clayden
Angewandte Chemie International Edition 2017 Volume 56(Issue 36) pp:10750-10754
Publication Date(Web):2017/08/28
DOI:10.1002/anie.201704908
Abstractα-Amino nitriles tethered to alkenes through a urea linkage undergo intramolecular C-alkenylation on treatment with base by attack of the lithionitrile derivatives on the N′-alkenyl group. A geometry-retentive alkene shift affords stereospecifically the E or Z isomer of the 5-alkenyl-4-iminohydantoin products from the corresponding starting E- or Z-N′-alkenyl urea, each of which may be formed from the same N-allyl precursor by stereodivergent alkene isomerization. The reaction, formally a nucleophilic substitution at an sp2 carbon atom, allows the direct regioselective incorporation of mono-, di-, tri-, and tetrasubstituted olefins at the α-carbon of amino acid derivatives. The initially formed 5-alkenyl iminohydantoins may be hydrolyzed and oxidatively deprotected to yield hydantoins and unsaturated α-quaternary amino acids.
Co-reporter:Romain Costil;Harvey J. A. Dale;Dr. Natalie Fey;George Whitcombe;Dr. Johnathan V. Matlock; Jonathan Clayden
Angewandte Chemie International Edition 2017 Volume 56(Issue 41) pp:12533-12537
Publication Date(Web):2017/10/02
DOI:10.1002/anie.201706341
AbstractDiarylamines find use as metal ligands and as structural components of drug molecules, and are commonly made by metal-catalyzed C−N coupling. However, the limited tolerance to steric hindrance of these couplings restricts the synthetic availability of more substituted diarylamines. Here we report a remarkable variant of the Smiles rearrangement that employs readily accessible N-aryl anthranilamides as precursors to diarylamines. Conformational predisposition of the anthranilamide starting material brings the aryl rings into proximity and allows the rearrangement to take place despite the absence of electron-withdrawing substituents, and even with sterically encumbered doubly ortho-substituted substrates. Some of the diarylamine products are resolvable into atropisomeric enantiomers, and are the first simple diarylamines to display atropisomerism.
Co-reporter:Brian P. Corbet, Johnathan V. Matlock, Josep Mas-Roselló, Jonathan Clayden
Comptes Rendus Chimie 2017 Volume 20, Issue 6(Volume 20, Issue 6) pp:
Publication Date(Web):1 June 2017
DOI:10.1016/j.crci.2017.01.006
Treatment of urea or carbamate derived benzomorpholines with lithium diisopropylamide generates N-vinyl ureas or N-vinyl carbamates by elimination of a phenoxide anion, cleaving the benzomorpholine ring. Simultaneous formation of a carbanion α to a stabilising aryl or nitrile group allows migration of the newly formed N-vinyl substituent to the carbanionic centre, in some cases with high enantiospecificity. Mild hydrolysis of the resulting urea or carbamate returns a C-vinylated amine, alcohol or hydantoin, in some cases with high enantiomeric purity. This ‘masked’ vinylation strategy avoids the need to use the reactive and volatile vinyl isocyanate as a starting material.
Co-reporter:Michael Tomsett;Irene Maffucci;Bryden A. F. Le Bailly;Liam Byrne;Stefan M. Bijvoets;M. Giovanna Lizio;James Raftery;Craig P. Butts;Simon J. Webb;Alessandro Contini
Chemical Science (2010-Present) 2017 vol. 8(Issue 4) pp:3007-3018
Publication Date(Web):2017/03/28
DOI:10.1039/C6SC05474A
Helical oligomers of achiral monomers adopt domains of uniform screw sense, which are occasionally interrupted by screw-sense reversals. These rare, elusive, and fast-moving features have eluded detailed characterization. We now describe the structure and habits of a screw-sense reversal trapped within a fragment of a helical oligoamide foldamer of the achiral quaternary amino acid 2-aminoisobutyric acid (Aib). The reversal was enforced by compelling the amide oligomer to adopt a right-handed screw sense at one end and a left-handed screw sense at the other. The trapped reversal was characterized by X-ray crystallography, and its dynamic properties were monitored by NMR and circular dichroism, and modelled computationally. Raman spectroscopy indicated that a predominantly helical architecture was maintained despite the reversal. NMR and computational results indicated a stepwise shift from one screw sense to another on moving along the helical chain, indicating that in solution the reversal is not localised at a specific location, but is free to migrate across a number of residues. Analogous unconstrained screw-sense reversals that are free to move within a helical structure are likely to provide the mechanism by which comparable helical polymers and foldamers undergo screw-sense inversion.
Co-reporter:Katharina Gratzer;Vincent Diemer
Organic & Biomolecular Chemistry 2017 vol. 15(Issue 17) pp:3585-3589
Publication Date(Web):2017/05/03
DOI:10.1039/C7OB00660H
The transduction of biological signals depends on the spatial communication of conformational change. We report a synthetic mimic of this signal transduction process in which non-covalent binding induces a change in the position of equilibrium between two rapidly interconverting screw-sense conformers of a synthetic helical polyamide. Selectivity was achieved by incorporating at the N-terminus of the polyamide a urea-based anion recognition site capable of binding chiral phosphate anions. As a result of solvent-dependent binding, an induced conformational change propagates from the binding site through the amide chain, leading to a screw-sense preference detectable in the form of a chemical shift separation between two NMR active 13C labels. The remote induction of screw sense preference indicates successful communication of a signal originating solely from non-covalent binding.
Co-reporter:Daniela Mazzier; Marco Crisma; Matteo De Poli; Giulia Marafon; Cristina Peggion; Jonathan Clayden;Alessandro Moretto
Journal of the American Chemical Society 2016 Volume 138(Issue 25) pp:8007-8018
Publication Date(Web):June 3, 2016
DOI:10.1021/jacs.6b04435
An E unsaturated fumaramide linkage may be introduced into Aib peptide foldamer structures by standard coupling methods and photoisomerized to its Z (maleamide) isomer by irradiation with UV light. As a result of the photoisomerization, a new hydrogen-bonded contact becomes possible between the peptide domains located on either side of the unsaturated linkage. Using the fumaramide/maleamide linker to couple a chiral and an achiral fragment allows the change in hydrogen bond network to communicate a conformational preference, inducing a screw sense preference in the achiral domain of the maleamide-linked foldamers that is absent from the fumaramides. Evidence for the induced screw sense preference is provided by NMR and CD, and also by the turning on by light of the diastereoselectivity of a peptide chain extension reaction. The fumaramide/maleamide linker thus acts as a “conformational photodiode” that conducts stereochemical information as a result of irradiation by UV light.
Co-reporter:Bryden A. F. Le Bailly and Jonathan Clayden
Chemical Communications 2016 vol. 52(Issue 27) pp:4852-4863
Publication Date(Web):02 Mar 2016
DOI:10.1039/C6CC00788K
Foldamers can be made more than pieces of static, conformationally uniform molecular architecture by designing into their structure the conformational dynamism characteristic of functional molecular machines. We show that these dynamic foldamers display biomimetic properties reminiscent of allosteric proteins and receptor molecules. They can translate chemical signals into conformational changes, and hence into chemical outputs such as control of reactivity and selectivity. Future developments could see dynamic foldamers operating in the membrane phase providing artificial mechanisms for communication and control that integrate synthetic chemistry into synthetic biology.
Co-reporter:Josep Mas Roselló, Samantha Staniland, Nicholas J. Turner, Jonathan Clayden
Tetrahedron 2016 Volume 72(Issue 34) pp:5172-5177
Publication Date(Web):25 August 2016
DOI:10.1016/j.tet.2016.01.037
A series of 1-aryl-3,4-dihydroisoquinolines (DHIQs) were synthesized and their barriers to bond rotation were determined by means of VT-NMR, dynamic HPLC or racemization studies. Although they all presented lower rotational stability than the related 1-arylisoquinolines (such as QUINAP), certain 1-aryl-DHIQ structures had a sufficiently high barrier to bond rotation to show axial chirality. These compounds included 1-(2-triflyl-1-naphthyl)-4,5-dihydroisoquinoline 4h and 1-(2-diphenylphosphanyl-1-naphthyl)-4,5-dihydroisoquinoline 4i. This discovery opens the door to the development of a new group of axially chiral N,P ligands for asymmetric synthesis and also potentially to new strategies for the synthesis of axially chiral 1-arylisoquinolines.
Co-reporter:Wojciech Zawodny;Ophélie Quinonero;Matteo De Poli;Mark Lorch;Simon J. Webb
Science 2016 Volume 352(Issue 6285) pp:575-580
Publication Date(Web):29 Apr 2016
DOI:10.1126/science.aad8352
Synthetic twists among lipids
Proteins embedded in cell membranes perform a wide variety of signaling and transport functions through conformational shifts. De Poli et al. examined how a much smaller, simpler construct might begin to achieve similar aims (see the Perspective by Thiele and Ulrich). Specifically, they designed an artificial peptide with a photosensitive group at one end and embedded it in a phospholipid bilayer akin to a membrane. Nuclear magnetic resonance spectroscopy revealed how light-induced isomerization influenced conformational dynamics at the other end. The results point the way toward development of small-molecule–based switches in membrane environments.
Science, this issue p. 575; see also p. 520
Co-reporter:Dr. Bryden A. F. LeBailly;Dr. Liam Byrne; Jonathan Clayden
Angewandte Chemie International Edition 2016 Volume 55( Issue 6) pp:2132-2136
Publication Date(Web):
DOI:10.1002/anie.201510605
Abstract
Small changes in the structure of a foldamer may lead to gross changes in conformational preference. We show that the simple insertion or deletion of a single hydrogen bond by changes in pH or by photochemical deprotection is sufficient to refold a helical oligomer, interconverting M and P screw-sense preference. As a consequence of the switch, information may be transmitted to a remote catalytic site, selectively directing the formation of either of two enantiomeric products by a reaction involving 1,22-remote intermolecular asymmetric induction.
Co-reporter:Romina Wechsel;Dr. James Raftery;Dr. Dominique Cavagnat;Dr. Gilles Guichard; Jonathan Clayden
Angewandte Chemie International Edition 2016 Volume 55( Issue 33) pp:9657-9661
Publication Date(Web):
DOI:10.1002/anie.201604496
Abstract
Oligoureas (up to n=6) of meso cyclohexane-1,2-diamine were synthesized by chain extension with an enzymatically desymmetrized monomer 2. Despite being achiral, the meso oligomers adopt chiral canonical 2.5-helical conformations, the equally populated enantiomeric screw-sense conformers of which are in slow exchange on the NMR timescale, with a barrier to screw-sense inversion of about 70 kJ mol−1. Screw-sense inversion in these helical foldamers is coupled with cyclohexane ring-flipping, and results in a reversal of the directionality of the hydrogen bonding in the helix. The termini of the meso oligomers are enantiotopic, and desymmetrized analogues of the oligoureas with differentially and enantioselectively protected termini display moderate screw-sense preferences. A screw-sense preference may furthermore be induced in the achiral, meso oligoureas by formation of a 1:1 hydrogen-bonded complex with the carboxylate anion of Boc-d-proline. The meso oligoureas are the first examples of hydrogen-bonded foldamers with reversible hydrogen-bond directionality.
Co-reporter:Romina Wechsel;Dr. James Raftery;Dr. Dominique Cavagnat;Dr. Gilles Guichard; Jonathan Clayden
Angewandte Chemie 2016 Volume 128( Issue 33) pp:9809-9813
Publication Date(Web):
DOI:10.1002/ange.201604496
Abstract
Oligoureas (up to n=6) of meso cyclohexane-1,2-diamine were synthesized by chain extension with an enzymatically desymmetrized monomer 2. Despite being achiral, the meso oligomers adopt chiral canonical 2.5-helical conformations, the equally populated enantiomeric screw-sense conformers of which are in slow exchange on the NMR timescale, with a barrier to screw-sense inversion of about 70 kJ mol−1. Screw-sense inversion in these helical foldamers is coupled with cyclohexane ring-flipping, and results in a reversal of the directionality of the hydrogen bonding in the helix. The termini of the meso oligomers are enantiotopic, and desymmetrized analogues of the oligoureas with differentially and enantioselectively protected termini display moderate screw-sense preferences. A screw-sense preference may furthermore be induced in the achiral, meso oligoureas by formation of a 1:1 hydrogen-bonded complex with the carboxylate anion of Boc-d-proline. The meso oligoureas are the first examples of hydrogen-bonded foldamers with reversible hydrogen-bond directionality.
Co-reporter:Dr. Bryden A. F. LeBailly;Dr. Liam Byrne; Jonathan Clayden
Angewandte Chemie 2016 Volume 128( Issue 6) pp:2172-2176
Publication Date(Web):
DOI:10.1002/ange.201510605
Abstract
Small changes in the structure of a foldamer may lead to gross changes in conformational preference. We show that the simple insertion or deletion of a single hydrogen bond by changes in pH or by photochemical deprotection is sufficient to refold a helical oligomer, interconverting M and P screw-sense preference. As a consequence of the switch, information may be transmitted to a remote catalytic site, selectively directing the formation of either of two enantiomeric products by a reaction involving 1,22-remote intermolecular asymmetric induction.
Co-reporter:Jennifer E. Jones; Vincent Diemer; Catherine Adam; James Raftery; Rebecca E. Ruscoe; Jason T. Sengel; Mark I. Wallace; Antoine Bader; Scott L. Cockroft; Jonathan Clayden;Simon J. Webb
Journal of the American Chemical Society 2015 Volume 138(Issue 2) pp:688-695
Publication Date(Web):December 23, 2015
DOI:10.1021/jacs.5b12057
The synthetic biology toolbox lacks extendable and conformationally controllable yet easy-to-synthesize building blocks that are long enough to span membranes. To meet this need, an iterative synthesis of α-aminoisobutyric acid (Aib) oligomers was used to create a library of homologous rigid-rod 310-helical foldamers, which have incrementally increasing lengths and functionalizable N- and C-termini. This library was used to probe the inter-relationship of foldamer length, self-association strength, and ionophoric ability, which is poorly understood. Although foldamer self-association in nonpolar chloroform increased with length, with a ∼14-fold increase in dimerization constant from Aib6 to Aib11, ionophoric activity in bilayers showed a stronger length dependence, with the observed rate constant for Aib11 ∼70-fold greater than that of Aib6. The strongest ionophoric activity was observed for foldamers with >10 Aib residues, which have end-to-end distances greater than the hydrophobic width of the bilayers used (∼2.8 nm); X-ray crystallography showed that Aib11 is 2.93 nm long. These studies suggest that being long enough to span the membrane is more important for good ionophoric activity than strong self-association in the bilayer. Planar bilayer conductance measurements showed that Aib11 and Aib13, but not Aib7, could form pores. This pore-forming behavior is strong evidence that Aibm (m ≥ 10) building blocks can span bilayers.
Co-reporter:Sarah J. Pike, Jennifer E. Jones, James Raftery, Jonathan Clayden and Simon J. Webb
Organic & Biomolecular Chemistry 2015 vol. 13(Issue 37) pp:9580-9584
Publication Date(Web):21 Aug 2015
DOI:10.1039/C5OB01652E
Helical peptide foldamers rich in α-aminoisobutyric acid (Aib) act as peptaibol-mimicking ionophores in the phospholipid bilayers of artificial vesicles. Racemic samples of these foldamers are more active than their enantiopure counterparts, which was attributed to differing propensities to form aggregates with crystal-like features in the bilayer.
Co-reporter:Julien Maury and Jonathan Clayden
The Journal of Organic Chemistry 2015 Volume 80(Issue 21) pp:10757-10768
Publication Date(Web):September 30, 2015
DOI:10.1021/acs.joc.5b01912
Pyrrolidine-2-carboxylate esters substituted in the 3-, 4- or 5-positions were converted to their N′-aryl urea derivatives. Deprotonation at the 2-position to form a potassium enolate led to migration of the N′-aryl substituent to the 2 position of the pyrrolidine ring, followed by cyclization of the resulting urea to give bicyclic α-aryl hydantoin derivatives of substituted prolines. Depending on the substitution pattern of the starting material, high diastereoselectivity was observed in the aryl migration, allowing formation of the products in enantiomerically enriched form, despite the intermediacy of a planar enolate. The hydrolysis of the bicyclic hydantoins under basic conditions gave a range of enantiopure and enantioenriched quaternary α-aryl proline derivatives.
Co-reporter:Bryden A. F. Le Bailly and Jonathan Clayden
Chemical Communications 2016 - vol. 52(Issue 27) pp:NaN4863-4863
Publication Date(Web):2016/03/02
DOI:10.1039/C6CC00788K
Foldamers can be made more than pieces of static, conformationally uniform molecular architecture by designing into their structure the conformational dynamism characteristic of functional molecular machines. We show that these dynamic foldamers display biomimetic properties reminiscent of allosteric proteins and receptor molecules. They can translate chemical signals into conformational changes, and hence into chemical outputs such as control of reactivity and selectivity. Future developments could see dynamic foldamers operating in the membrane phase providing artificial mechanisms for communication and control that integrate synthetic chemistry into synthetic biology.
Co-reporter:Sarah J. Pike, Jennifer E. Jones, James Raftery, Jonathan Clayden and Simon J. Webb
Organic & Biomolecular Chemistry 2015 - vol. 13(Issue 37) pp:NaN9584-9584
Publication Date(Web):2015/08/21
DOI:10.1039/C5OB01652E
Helical peptide foldamers rich in α-aminoisobutyric acid (Aib) act as peptaibol-mimicking ionophores in the phospholipid bilayers of artificial vesicles. Racemic samples of these foldamers are more active than their enantiopure counterparts, which was attributed to differing propensities to form aggregates with crystal-like features in the bilayer.
Co-reporter:Michael Tomsett, Irene Maffucci, Bryden A. F. Le Bailly, Liam Byrne, Stefan M. Bijvoets, M. Giovanna Lizio, James Raftery, Craig P. Butts, Simon J. Webb, Alessandro Contini and Jonathan Clayden
Chemical Science (2010-Present) 2017 - vol. 8(Issue 4) pp:NaN3018-3018
Publication Date(Web):2017/01/25
DOI:10.1039/C6SC05474A
Helical oligomers of achiral monomers adopt domains of uniform screw sense, which are occasionally interrupted by screw-sense reversals. These rare, elusive, and fast-moving features have eluded detailed characterization. We now describe the structure and habits of a screw-sense reversal trapped within a fragment of a helical oligoamide foldamer of the achiral quaternary amino acid 2-aminoisobutyric acid (Aib). The reversal was enforced by compelling the amide oligomer to adopt a right-handed screw sense at one end and a left-handed screw sense at the other. The trapped reversal was characterized by X-ray crystallography, and its dynamic properties were monitored by NMR and circular dichroism, and modelled computationally. Raman spectroscopy indicated that a predominantly helical architecture was maintained despite the reversal. NMR and computational results indicated a stepwise shift from one screw sense to another on moving along the helical chain, indicating that in solution the reversal is not localised at a specific location, but is free to migrate across a number of residues. Analogous unconstrained screw-sense reversals that are free to move within a helical structure are likely to provide the mechanism by which comparable helical polymers and foldamers undergo screw-sense inversion.
Co-reporter:Katharina Gratzer, Vincent Diemer and Jonathan Clayden
Organic & Biomolecular Chemistry 2017 - vol. 15(Issue 17) pp:NaN3589-3589
Publication Date(Web):2017/03/31
DOI:10.1039/C7OB00660H
The transduction of biological signals depends on the spatial communication of conformational change. We report a synthetic mimic of this signal transduction process in which non-covalent binding induces a change in the position of equilibrium between two rapidly interconverting screw-sense conformers of a synthetic helical polyamide. Selectivity was achieved by incorporating at the N-terminus of the polyamide a urea-based anion recognition site capable of binding chiral phosphate anions. As a result of solvent-dependent binding, an induced conformational change propagates from the binding site through the amide chain, leading to a screw-sense preference detectable in the form of a chemical shift separation between two NMR active 13C labels. The remote induction of screw sense preference indicates successful communication of a signal originating solely from non-covalent binding.
![Propanedioic acid, [(1S)-2-nitro-1-phenylethyl]-, dimethyl ester](http://img.cochemist.com/ccimg/252400/252338-26-4.png)
![Propanedioic acid, [(1S)-2-nitro-1-phenylethyl]-, dimethyl ester](http://img.cochemist.com/ccimg/252400/252338-26-4_b.png)
![Propanedioic acid, [(1R)-2-nitro-1-phenylethyl]-, diethyl ester](http://img.cochemist.com/ccimg/196400/196399-51-6.png)
![Propanedioic acid, [(1R)-2-nitro-1-phenylethyl]-, diethyl ester](http://img.cochemist.com/ccimg/196400/196399-51-6_b.png)
![Propanedioic acid, [(1R)-2-nitro-1-phenylethyl]-, dimethyl ester](http://img.cochemist.com/ccimg/773200/773148-47-3.png)
![Propanedioic acid, [(1R)-2-nitro-1-phenylethyl]-, dimethyl ester](http://img.cochemist.com/ccimg/773200/773148-47-3_b.png)
