One-Pot Selective Homodimerization/Hydrogenation Strategy for Sequential Dicarba Bridge Formation

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 Approach to the Tricyclic Marine Alkaloids (−)-Fasicularin and (−)-Lepadiformine A

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 <b>2</b> and a pro-forma synthesis of (−)-lepadiformine A <b>1</b>

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

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

A Formal Synthesis of (−)-Perhydrohistrionicotoxin Using a Cross Metathesis–Hydrogenation Approach

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

Dicarba α‑Conotoxin Vc1.1 Analogues with Differential Selectivity for Nicotinic Acetylcholine and GABA_B Receptors

Conotoxins have emerged as useful leads for the development of novel therapeutic analgesics. These peptides, isolated from marine molluscs of the genus <i>Conus</i>, 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 <i>Xenopus</i> 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 (GABA_B) 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

Dicarba Analogues of α‑Conotoxin RgIA. Structure, Stability, and Activity at Potential Pain Targets

α-Conotoxin RgIA is both an antagonist of the α9α10 nicotinic acetylcholine receptor (nAChR) subtype and an inhibitor of high-voltage-activated N-type calcium channel currents. 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 nonreducible dicarba bridges. Solution structures were determined by NMR, activity assessed against biological targets, and stability evaluated in human serum. [3,12]-Dicarba analogues retained inhibition of ACh-evoked currents at α9α10 nAChRs but not N-type calcium channel currents, whereas [2,8]-dicarba analogues displayed the opposite pattern of selectivity. The [2,8]-dicarba RgIA analogues were effective in HEK293 cells stably expressing human Ca_v2.2 channels and transfected with human GABA_B receptors. The analogues also exhibited improved serum stability over the native peptide. These selectively acting dicarba analogues may represent mechanistic probes to explore analgesia-related biological receptors