catalysts Review Epoxide Syntheses and Ring-Opening Reactions in Drug Development Fotini Moschona, Ioanna Savvopoulou, Maria Tsitopoulou, Despoina Tataraki and Gerasimos Rassias * Department of Chemistry, University of Patras, 26504 Patra, Greece; [email protected] (F.M.); [email protected] (I.S.); [email protected] (M.T.); [email protected] (D.T.) * Correspondence: [email protected]; Tel.: +30-2610997912 Received: 23 August 2020; Accepted: 23 September 2020; Published: 27 September 2020 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. Keywords: epoxides; drug development; catalytic asymmetric epoxidation; organocatalysis; process development and manufacturing routes; Sharpless and Jacobsen–Katsuki asymmetric epoxidation; chiral ketones/dioxiranes; iminium/oxaziridinium salts; epoxide ring opening 1. Introduction Epoxides are versatile electrophiles that support the stereospecific formation of ring-opened products with a wide array of nucleophiles. The implications of this reactivity in the context of drug design and desired biologic action as well as manifestation of adverse effects has been reviewed previously [1–4] although these are best exemplified by the plethora of natural products and the 14 approved drugs containing the epoxide functionality [5,6]. In the context of organic synthesis, the ring strain-induced electrophilicity of epoxides renders them excellent reactive intermediates for constructing in stereoselective/specific manner key bonds in larger and more complex molecules. From an academic perspective, general aspects of epoxide synthesis and ring-opening reactions spanning various levels of organic chemistry research have been reviewed extensively [7–9]. What is lesser known is how pivotal has been the successful management of epoxide chemistry on scale leading to robust, cost-effective and safe manufacturing processes. Emphasis is also given in the way certain intermediates are handled due to safety, reactivity, inappropriate state (oils, low melting point solids) or physical properties (hygroscopicity, poor filtration characteristics) or even time constraints. For example, in several cases a “telescoped” process is implemented which is a process term to describe a reaction that despite work up, washes, filtration of unwanted materials (inorganics, charcoal), Catalysts 2020, 10, 1117; doi:10.3390/catal10101117 www.mdpi.com/journal/catalysts Catalysts 2020, 10, x FOR PEER REVIEW 2 of 69 Catalysts 2020, 10, x FOR PEER REVIEW 2 of 69 term to describe a reaction that despite work up, washes, filtration of unwanted materials (inorganics,term to describe charcoal), a reaction etc., avoids that any despite isolation work and up,a solution washes, of thefiltration intermediate of unwanted is carried materials forward Catalysts 2020, 10, 1117 2 of 65 in(inorganics, the next step, charcoal), not necessarily etc., avoids in any the isolationsame reactor. and a Thesolution more of common the intermediate term “one-pot” is carried implies forward no processing/workin the next step, notup andnecessarily the reagents in the for same the nextreactor. step The are addedmore common sequentially term in “one-pot” the same vessel.implies The no etc.,focusprocessing/work avoids of this any review isolationup and is thethe and reagentsimplementation a solution for the of next theof st intermediateepoxideep are addedchemistry is sequentially carried from forward a inprocess the insame thedevelopment vessel. next step, The notperspectivefocus necessarily of this and review in is the presented sameis the reactor. implementation through The morededicated common of epoxidediscussions term chemistry “one-pot” to high impliesfrom profile a no processapproved processing development drugs/work and up andclinicalperspective the candidates. reagents and foris presented the next step through are added dedicated sequentially discussions in thesame to high vessel. profile The focusapproved of this drugs review and is theclinical implementation candidates. of epoxide chemistry from a process development perspective and is presented through1.1. LY459477—Development dedicated discussions of a to Selective high profile Route approved via a Desymmetrization drugs and clinical Process candidates. of a Meso-Epoxide 1.1. LY459477—DevelopmentLY459477 (1) is a potent of a(EC Selective50 1 nm) Route orthosteric via a Desymmetrization agonist for rodent Process and of a humanMeso-Epoxide mGlu2 and 1.1. LY459477—Development of a Selective Route via a Desymmetrization Process of a Meso-Epoxide mGlu3LY459477 receptors. (1 )Development is a potent (EC of an50 1appropriate nm) orthosteric large-scale agonist synthesis for rodent of LY459477 and human was mGlu2required and to supportmGlu3LY459477 receptors. clinical (1 )trials isDevelopment a potent for schizophrenia, (EC 50of 1an nm) appropriate orthosteric generalized la agonistrge-scale anxiety for synthesis rodentdisorder and of and LY459477 human bipolar mGlu2 was disorders required and mGlu3 [10]. to receptors.Moreover,support clinical Developmentthe supply trials forroute of schizophrenia, an for appropriate LY459477 generalized large-scaleserved as synthesisan anxiety excellent disorder of LY459477platform and wasfor bipolar the required development disorders to support [10]. of clinicalsubsequentMoreover, trials the structurally for supply schizophrenia, route related for mGlu2/3 generalizedLY459477 agonists served anxiety as as drug disorderan excellent candidates and bipolarplatform for neuropsychiatric disorders for the development [10]. Moreover,disorders of the[11].subsequent supply routestructurally for LY459477 related servedmGlu2/3 as agonists an excellent as drug platform candidates for the for development neuropsychiatric of subsequent disorders structurally[11]. The chemotype related mGlu2 of LY459477/3 agonists was asbased drug on candidates a cyclopentene for neuropsychiatric scaffold first introduced disorders [by11 ].Hodgson and Thescientists chemotypechemotype at GlaxoSmithKline ofof LY459477 LY459477 was was (then based based Glaxo on on a cyclopentene aWe cyclopllcome)entene [12] sca scaffoldff whereold first firstthe introduced keyintroduced intermediate, by Hodgson by Hodgson chiral and scientistsalcoholand scientists 2,at was GlaxoSmithKline obtainedat GlaxoSmithKline from (thendesymmetrization Glaxo(then Wellcome)Glaxo ofWe thellcome) [12 meso] where [12]epoxide the where key 3 (Scheme intermediate,the key 1).intermediate, chiral alcohol chiral2, wasalcohol obtained 2, was from obtained desymmetrization from desymmetrization of the meso of epoxide the meso3 (Schemeepoxide 13). (Scheme 1). Scheme 1. Retrosynthesis of LY459477 into the key alcohol and epoxide intermediates. Scheme 1. Retrosynthesis of LY459477 into the key alcohol and epoxide intermediates. Scheme 1. Retrosynthesis of LY459477 into the key alcohol and epoxide intermediates. A team of process chemists from Eli Lilly developed the original synthesis further in order to A team of process chemists from Eli Lilly developed the original synthesis further in order to deliver deliverA teamcyclopentene of process precursor chemists 5 onfrom a multikilogram Eli Lilly developed scale (Scheme the original 2). The synthesis synthesis further comprises in order of six to cyclopentene precursor 5 on a multikilogram scale (Scheme2). The synthesis comprises of six discreet discreetdeliver cyclopentene steps but proceeds precursor through 5 on aseveral multikilogram telescoped scale stages (Scheme with 2).only The two synthesis isolable comprises intermediates; of six steps but proceeds through several telescoped stages with only two isolable intermediates; monoacid 4 monoaciddiscreet steps 4 and but proceedscyclopentene through 5. Peracid-mediated several telescoped epoxidation stages with ofonly 5 twodelivers isolable the intermediates;oxygen atom and cyclopentene 5. Peracid-mediated epoxidation of 5 delivers the oxygen atom preferentially on the preferentiallymonoacid 4 and on the cyclopentene same face of 5 the. Peracid-mediated cyclopentene as theepoxidation NHBoc subs of tituent5 delivers as result the ofoxygen a hydrogen atom same face of the cyclopentene as the NHBoc substituent as result of a hydrogen bonding interaction