Epoxide Syntheses and Ring-Opening Reactions in Drug Development

Abstract

This review concentrates on success stories from the synthesis of approved medicines and drug candidates using epoxide chemistry in the development of robust and efficient syntheses at large scale. The focus is on those parts of each synthesis related to the substrate-controlled/diastereoselective and catalytic asymmetric synthesis of epoxide intermediates and their subsequent ring-opening reactions with various nucleophiles. These are described in the form of case studies of high profile pharmaceuticals spanning a diverse range of indications and molecular scaffolds such as heterocycles, terpenes, steroids, peptidomimetics, alkaloids and main stream small molecules. Representative examples include, but are not limited to the antihypertensive diltiazem, the antidepressant reboxetine, the HIV protease inhibitors atazanavir and indinavir, efinaconazole and related triazole antifungals, tasimelteon for sleep disorders, the anticancer agent carfilzomib, the anticoagulant rivaroxaban the antibiotic linezolid and the antiviral oseltamivir. Emphasis is given on aspects of catalytic asymmetric epoxidation employing metals with chiral ligands particularly with the Sharpless and Jacobsen–Katsuki methods as well as organocatalysts such as the chiral ketones of Shi and Yang, Pages’s chiral iminium salts and typical chiral phase transfer agents.

Antiviral evaluation of hydroxyethylamine analogs: Inhibitors of SARS-CoV-2 main protease (3CLpro), a virtual screening and simulation approach

“…The parent compound, V was previously explored as an antiplasmodial agent by our group 38 and was resynthesized following slightly modified methods 40 . Microwave-assisted enantioselective 40 , 41 ring-opening of (2R,3S)-N-Boc-3-amino-1,2-epoxy-4-phenylbutane ( I ) with piperazine ( II ) was carried out in ethanol at 300 W by heating to 80 °C with a 2 min ramp and holding for 30 min to afford di-tert-butyl ((2S,2'S,3S,3'S)-piperazine-1,4-diylbis(3-hydroxy-1-phenylbutane-4,2-diyl))dicarbamate ( III ) ( Scheme 1 ). Deprotection was accomplished with excess of trifluoroacetic acid (TFA) in dichloromethane, and the obtained products were used for coupling reaction with (R)-2-(5-methyl-1,3-dioxoisoindolin-2-yl)-3-phenylpropanoic acid ( IV ) that afforded (2R,2'R)-N,N'-((2S,2'S,3S,3'S)-piperazine-1,4-diylbis(3-hydroxy-1-phenylbutane-4,2-diyl))bis(2-(5-methyl-1,3-dioxoisoindolin-2-yl)-3-phenylpropanamide) ( V ) in 59% yield.…”

A new and efficient methodology for olefin epoxidation catalyzed by supported cobalt nanoparticles

“…Among them, allylic oxidation and olefin epoxidation constitute fundamental tools for the synthesis of homoallylic alcohols or α,β-unsaturated carbonyl compounds, and epoxides, respectively. In particular, epoxides are pivotal building blocks for the synthetic chemists because they are present in many important (bio)organic compounds and also allow access to more functionalized or complex structures through different chemical transformations on the reactive oxirane ring [2][3][4][5][6][7][8][9][10][11][12]. Despite many methodologies for the synthesis of epoxides have been reported, efficient and selective epoxidation of olefins remains a challenge.…”

Rhodamine B oxidation promoted by P450-bioinspired Jacobsen catalysts/cellulose systems

“…9 Among numerous proposals to mimic monooxygenase active sites, metal-Schiff base complexes stand out, especially Jacobsen chiral catalysts. 12,[33][34][35][36][37][38] These salen complexes are efficient catalysts in homogeneous and heterogeneous environment reactions such as olen ring opening and polymerization, 39,40 allyl alkylation, 41 alkene epoxidation, 12,42,43 alkane oxidation, 38 and drug oxidation 37,[44][45][46][47] and act as P450 cytochromes model systems. 10,12,25,38,45,[48][49][50][51][52] An advantage of the Jacobsen complex is its simple preparation, for example, it can be synthesized on a large scale (in the order of kilograms) at a low cost (US$41.40 per gram).…”