The development of an efficient, high yielding six-step convergent synthesis of the semisynthetic alkaloid (−)-perhydrohistrionicotoxin is described. The key transformations include the cross metathesis of a Brønsted-acid masked primary homoallylic amine with a vinyl cyclohexenone and a regioselective palladium catalyzed hydrogenation. This sequence generated the advanced Winterfeldt spirocyclic precursor in 47% overall yield, with a longest linear sequence of five steps.

A cross-metathesis protocol has been developed to provide facile access to highly hindered trisubstituted α-branched olefins, which when coupled with a cationic azaspirocyclization reaction, generates the marine alkaloids (−)-fasicularin 2 and a pro-forma synthesis of (−)-lepadiformine A 1.

An efficient and expedient route to the synthesis of dicarba peptides from protecting group-free sequences is reported using Ru-alkylidene catalysed olefin metathesis. A range of cyclic peptides was prepared from linear peptides containing two Z-crotyl glycine residues. Free amine groups were masked as salts with Brønsted acids preventing in situ catalyst decomposition. Excellent RCM conversion was obtained in both DMF and methanol.

A facile stereoselective synthesis of cis and trans unsaturated dicarba peptides has been established using preformed diaminosuberic acid derivatives as bridging units. In addition, characteristic spectral differences in the 13C-NMR spectra of the cis- and trans-isomers show that the chemical shift of carbons in the Δ4,5-diaminosuberic acid residue can be used to assign stereochemistry in unsaturated dicarba peptides formed from ring closing metathesis of linear peptide sequences.

•Metathesis can be employed to stabilize peptide structure.•Native disulfide bridges can be replaced with metabolically stable carbon-based bridges.•Dicarba analogues can be used to elucidate mechanism of action of bioactive peptides.This review highlights developments in the field of ring-closing metathesis applied to the synthesis of cyclic peptides. Special attention is focussed on the synthesis of dicarba peptides that mimic native cystine containing peptides. Recent advances in the field are discussed, including the stereoselective synthesis of carbon-bridged peptides and RCM in aqueous media.Figure optionsDownload full-size imageDownload as PowerPoint slide

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.

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.

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.

The installation of interlocked dicarba bridges into peptide sequences requires the development of a 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.

Cross-metathesis of a wide range of previously unreactive, sterically demanding alkenes can be achieved in fair to excellent yield using a commercially available catalyst by a facile strategy involving reversal of steric preference.

Conotoxins have emerged as useful leads for the development of novel therapeutic analgesics. These peptides, isolated from marine molluscs of the genus Conus, have evolved exquisite selectivity for receptors and ion channels of excitable tissue. One such peptide, α-conotoxin Vc1.1, is a 16-mer possessing an interlocked disulfide framework. Despite its emergence as a potent analgesic lead, the molecular target and mechanism of action of Vc1.1 have not been elucidated to date. In this paper we describe the regioselective synthesis of dicarba analogues of Vc1.1 using olefin metathesis. The ability of these peptides to inhibit acetylcholine-evoked current at rat α9α10 and α3β4 nicotinic acetylcholine receptors (nAChR) expressed in Xenopus oocytes has been assessed in addition to their ability to inhibit high voltage-activated (HVA) calcium channel current in isolated rat DRG neurons. Their solution structures were determined by NMR spectroscopy. Significantly, we have found that regioselective replacement of the native cystine framework with a dicarba bridge can be used to selectively tune the cyclic peptide’s innate biological activity for one receptor over another. The 2,8-dicarba Vc1.1 isomer retains activity at γ-aminobutyric acid (GABAB) G protein-coupled receptors, whereas the isomeric 3,16-dicarba Vc1.1 peptide retains activity at the α9α10 nAChR subtype. These singularly acting analogues will enable the elucidation of the biological target responsible for the peptide’s potent analgesic activity.

A quaternary ammonium Hoveyda-Grubbs olefin metathesis pre-catalyst has been reversibly immobilized on sulphonic acid-functionalised silica-coated iron oxide magnetic particles to affect ring closing metathesis with easy removal, reuse and regeneration.

Acyclic diamines are valuable feedstocks for polyamide synthesis. Ruthenium-alkylidene catalysed cross metathesis of amino alkenes is problematic and acyl derivatisation can result in less efficient syntheses, poor catalyst turnover and isomerisation. Temporary amine masking via stable and soluble ammonium salts delivers cyclic and acyclic aminoalkenes in high yield and purity.

Acyclic diamines are valuable feedstocks for polyamide synthesis. Ruthenium-alkylidene catalysed cross metathesis of amino alkenes is problematic and acyl derivatisation can result in less efficient syntheses, poor catalyst turnover and isomerisation. Temporary amine masking via stable and soluble ammonium salts delivers cyclic and acyclic aminoalkenes in high yield and purity.

A facile stereoselective synthesis of cis and trans unsaturated dicarba peptides has been established using preformed diaminosuberic acid derivatives as bridging units. In addition, characteristic spectral differences in the 13C-NMR spectra of the cis- and trans-isomers show that the chemical shift of carbons in the Δ4,5-diaminosuberic acid residue can be used to assign stereochemistry in unsaturated dicarba peptides formed from ring closing metathesis of linear peptide sequences.