Divergent Approach to a Family of Tyrosine-Derived Ru−Alkylidene Olefin Metathesis Catalysts

Authors

Ellen C. Gleeson, Zhen J. Wang, W. Roy Jackson, and Andrea J. Robinson

Published Journal of Organic Chemistry
Graphical abstract  

divergent

Abstract

A simple and generic approach to access a new family of Ru−alkylidene olefin metathesis catalysts with specialized properties is reported. This strategy utilizes a late stage, utilitarian Hoveyda-type ligand derived from tyrosine, which can be accessed via a multigram-scale synthesis. Further functionalization allows the catalyst properties to be tuned, giving access to modified second-generation Hoveyda−Grubbs-type catalysts. This divergent synthetic approach can be used to access solid-supported catalysts and catalysts that function under solvent-free and aqueous conditions.

Citation

Ellen C. Gleeson, Zhen J. Wang, W. Roy Jackson, and Andrea J. Robinson, J. Org. Chem., 201580(14), 7205–7211

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Doi 10.1021/acs.joc.5b01091
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Stereoselective Synthesis and Structural Elucidation of Dicarba Peptides

Authors Ellen C. Gleeson, Zhen J. Wang, Samuel D. Robinson, Sandeep Chhabra, Christopher A. MacRaild, W. Roy Jackson, Raymond S. Norton and Andrea J. Robinson
Published Chemical Communications
Graphical abstract  
Robinson-cover final
Abstract Preformed, orthogonally-protected Z– and E-diaminosuberic acid residues can be used to synthesise target dicarba peptides. Stereochemical assignment of dicarba peptides generated via RCM of linear sequences can be achieved using 13C NMR spectroscopy.
Citation Ellen C. Gleeson, Zhen J. Wang, Samuel D. Robinson, Sandeep Chhabra, Christopher A. MacRaild, W. Roy Jackson, Raymond S. Norton and Andrea J. Robinson, Chem. Commun., 2016in press
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Doi  10.1039/c5cc10540d
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Cross-metathesis of Brønsted acid-masked alkenyl amines with acrylates for the synthesis of polyamide monomers

Authors Szabolcs Solyom, Nicolas Daniel Spiccia, Clint Peter Woodward, William Roy Jackson, Andrea Jane Robinson
Published Journal of Organic Chemistry
Graphical abstract  

Nylon 2

Abstract Ruthenium-alkylidene catalyzed cross metathesis of a range of homologous alkenylamine salts provides expedient and high yielding routes to commercially valuable polyamide monomers using a single catalyst, telescopic workup and mild experimental conditions.
Citation Szabolcs Solyom, Nicolas Daniel Spiccia, Clint Peter Woodward, William Roy Jackson, Andrea Jane Robinson, J. Org. Chem., 2016in press
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Doi  10.1021/acs.joc.5b02484
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A one-pot selective homodimerisation/hydrogenation strategy for sequential dicarba bridge formation

Authors James Burnley, W. Roy Jackson and Andrea J. Robinson
Published Journal of Organic Chemistry
Graphical abstract  peptides2
Abstract

The installation of interlocked dicarba bridges into peptide sequences requires the development of regioselective and chemoselective methodology. This manuscript describes a one-pot, chemoselective synthesis of three 2,7-diaminosuberic acid derivatives from an alkyne, a cobalt-carbonyl protected alkyne and an alkene using metathesis and homogeneous hydrogenation catalysis.

Citation James Burnley, W. Roy Jackson and Andrea J. Robinson, J. Org. Chem., 2015, 80(18), 9057-9063
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Doi 10.1021/acs.joc.5b01312
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A Simple and Practical Preparation of an Efficient Water Soluble Olefin Metathesis Catalyst

Authors Zhen J. Wang and W. Roy Jackson and Andrea J. Robinson
Published Green Chemistry
Graphical abstract  

salt 

Abstract This study details homogeneous olefin metathesis in water catalysed by a di-ammonium functionalised Ru-alkylidene complex. A facile gram scale synthesis of an air stable catalyst precursor which can be readily converted to its water soluble derivative is described. The di-ammonium functionalised Ru-alkylidene complex facilitates a range of ring-closing metathesis (RCM) and cross-metathesis (CM) reactions in water.
Citation Z.J. Wang, W. R. Jackson and A. J. Robinson, Green Chem., 2015, 17(6), 3407-3414
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Doi DOI: 10.1039/c5gc00252d
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Dicarba Analogues of α-Conotoxin RgIA. Structure, Stability and Activity at Potential Pain Targets

Authors Sandeep Chhabra, Alessia Belgi, Peter Bartels, Bianca van Lierop, Samuel D. Robinson, Shiva N. Kompella, Andrew Hung, Brid P. Callaghan, David J. Adams, Andrea J. Robinson and Raymond S. Norton
Published Journal of Medicinal Chemistry
Graphical abstract  Rg1A
Abstract α-Conotoxin RgIA is an antagonist of the α9α10 nicotinic acetylcholine receptor (nAChR) subtype and inhibits high voltage-activated N-type calcium channels. RgIA has therapeutic potential for the treatment of pain but reduction of the disulfide bond framework under physiological conditions represents a potential liability for clinical applications. We synthesized four RgIA analogues that replaced native disulfide pairs with non-reducible dicarba bridges. The analogues also exhibited superior stability over native peptide.
Citation S. Chhabra, A. Belgi, P. Bartels, B. van Lierop, S. D. Robinson, S. N. Kompella, A. Hung, B. P. Callaghan, D. J. Adams, A. J. Robinson and R. S. Norton, J. Med. Chem, 2014, 57(23), 9933-9944
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Doi 10.1021/jm501126u.
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A Concise Cross-Metathesis Route to Enantiopure 1-Azaspirocycles

Authors Zhen James Wang, Nicolas Daniel Spiccia, Christopher James Gartshore, Jayamini Illesinghe, William Roy Jackson and Andrea Jane Robinson
Published Synthesis
Graphical abstract  

Spiro

Abstract

The 1-azaspirocyclic ring system can be found in a number of bioactive natural product families. Lepadiformine, cephalotaxine and cylindricine A all share a common spirocyclic pyrrolidine core, and fasicularin, halichlorine, histrionicotoxin and cylindricine B possess a homologous spirocyclic piperidine centre. This paper describes a concise synthesis of spiropyrrolidines and spiropiperidines which employs a ruthenium–alkylidene-catalysed cross-metathesis reaction of enantiopure N-protected allylglycine with methylenecycloalkanes. The resultant alkene intermediates can then undergo a tandem acid-catalysed cyclisation to form spiropyrrolidines. Ring expansion of the spiropyrrolidine system, via an aziridinium intermediate, grants access to the homologous spiropiperidine ring system with excellent stereo-retention.

Citation Z. J. Wang, N. D. Spiccia, C. J. Gartshore, J. Illesinghe, W. R. Jackson, A. J. Robinson, Synthesis, 2013, 45(22), 3118-3124.
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Doi DOI: 10.1055/s-0033-1338527
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Combinatorial Approach for the Rapid Determination of Thermochromic Behavior of Binary and Ternary Cholesteric Liquid Crystalline Mixtures

Authors Louise C. van der Werff, Andrea J. Robinson and Ilias L. Kyratzis
Published ACS Combinatorial Science
Graphical abstract  

TLC

Abstract

A combinatorial approach was developed for the rapid 
determination of thermochromic behavior of a large number of binary 
and ternary sterol based thermochromic liquid crystalline formulations. This approach 
allowed expedient examination of the thermochromic behavior for a large range of liquid crystal formulations. The accuracy of the rapid combinatorial technique was validated on selected thermochromic liquid crystal mixture compositions by comparing well thermochromic output with that observed using UV−vis spectroscopy on gram quantities of material.

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Citation L. C. van der Werff, A. J. Robinson, I. L. Kyratzis, ACS Combinatorial Science, 2012, 14(11), 605-12.
Doi DOI: 10.1021/co3000874
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A one pot, metathesis–hydrogenation sequence for the selective formation of carbon–carbon bonds

Authors Andrea J. Robinson, Jomana Elaridi, Jim Patel and W. Roy Jackson
Published Chemical Communications
Graphical abstract  

DAS - 3 bonds

Abstract

The selective formation of C–C bonds in complex molecules is one of the major challenges in organic chemistry. Olefin metathesis provides an efficient methodology for C–C bond synthesis and in this paper we demonstrate the application of this technology for the formation of three identical dicarba bridges by selective and successive formation of three diaminosuberic acid derivatives. A combination of homogeneous hydrogenation and metathesis reactions allows highly efficient, stepwise chemo- and stereo- selective formation of three separate 2,7-diaminosuberic acid derivatives in a single pot without isolation of intermediates.

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Citation A. J. Robinson, J. Elaridi, J. Patel and W. R. Jackson, Chem. Commun., 2005, 5544–5545.
Doi DOI: 10.1039/b510420c
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Solid phase synthesis and structural analysis of novel A-chain dicarba analogs of human relaxin-3 (INSL7) that exhibit full biological activity

Authors Mohammed Akhter Hossain, K. Johan Rosengren, Suode Zhang, Ross A. D. Bathgate, Geoffrey W. Tregear, Bianca J. van Lierop, Andrea J. Robinson and John D. Wade
Published Organic & Biomolecular Chemistry
Graphical abstract  Relaxin
Abstract

Replacement of disulfide bonds with non-reducible isosteres can be a useful means of increasing the 
in vivo stability of a protein. We describe the replacement of the A-chain intramolecular disulfide bond of human relaxin-3 (H3 relaxin, INSL7), an insulin-like peptide that has potential applications in the treatment of stress and obesity, with the physiologically stable dicarba bond. Solid phase peptide synthesis was used to prepare an A-chain analogue in which the two cysteine residues that form the intramolecular bond were replaced with allylglycine. On-resin microwave-mediated ring closing metathesis was then employed to generate the dicarba bridge. Subsequent cleavage of the peptide from the solid support, purification of two isomers and their combination with the B-chain via two intermolecular disulfide bonds, then furnished two isomers of dicarba-H3 relaxin. These were characterized by CD spectroscopy, which suggested a structural similarity to the native peptide. Additional analysis by solution NMR spectroscopy also identified the likely cis/trans form of the analogs. Both peptides demonstrated binding affinities that were equivalent to native H3 relaxin on RXFP1 and RXFP3 expressing cells. However, although the cAMP activity of the analogs on RXFP3 expressing cells was similar to the native peptide, the potency on RXFP1 expressing cells was slightly lower. The data confirmed the use of a dicarba bond as a useful isosteric replacement of the disulfide bond.

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Citation M. A. Hossain, K. J. Rosengren, S. Zhang, R. A. D. Bathgate, G. W. Tregear, B. J. van Lierop, A. J. Robinson and J. D. Wade, Org. Biomol. Chem., 2009, 7, 1547–1553.
Doi DOI: 10.1039/B821882J
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