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Impact of Cross-Coupling Reactions in Drug Discovery and Development

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Impact of Cross-Coupling Reactions in Drug Discovery and Development molecules Review Impact of Cross-Coupling Reactions in Drug Discovery and Development Melissa J. Buskes and Maria-Jesus Blanco * Medicinal Chemistry. Sage Therapeutics, Inc. 215 First Street, Cambridge, MA 02142, USA; [email protected] * Correspondence: [email protected] Academic Editors: José Pérez Sestelo and Luis A. Sarandeses Received: 30 June 2020; Accepted: 29 July 2020; Published: 31 July 2020 Abstract: Cross-coupling reactions have played a critical role enabling the rapid expansion of structure–activity relationships (SAR) during the drug discovery phase to identify a clinical candidate and facilitate subsequent drug development processes. The reliability and flexibility of this methodology have attracted great interest in the pharmaceutical industry, becoming one of the most used approaches from Lead Generation to Lead Optimization. In this mini-review, we present an overview of cross-coupling reaction applications to medicinal chemistry efforts, in particular the Suzuki–Miyaura and Buchwald–Hartwig cross-coupling reactions as a remarkable resource for the generation of carbon–carbon and carbon–heteroatom bonds. To further appreciate the impact of this methodology, the authors discuss some recent examples of clinical candidates that utilize key cross-coupling reactions in their large-scale synthetic process. Looking into future opportunities, the authors highlight the versatility of the cross-coupling reactions towards new chemical modalities like DNA-encoded libraries (DELs), new generation of peptides and cyclopeptides, allosteric modulators, and proteolysis targeting chimera (PROTAC) approaches. Keywords: cross-coupling reactions; C-C bond forming reactions; C-Heteroatom bond forming reactions; palladium; clinical candidate; DNA-encoded libraries; cyclopeptides; allosteric modulators; PROTAC 1. Introduction Cross-coupling reactions have made an impressive impact in medicinal chemistry, and drug discovery and development for more than two decades. The success and popularity of this type of methodology comes from the fact that during the drug discovery phase, chemists are attracted to reactions that are reliable and reproducible. In drug discovery, medicinal chemists are designing and synthesizing novel compounds that could meet the criteria envisioned for the specific target product profile (TPP) to advance the eventual selected compound (referred to as Development Candidate) into clinical trials. During this period, medicinal chemists look for approaches to modify the structure in multiple ways to impart the corresponding pharmacological activity, pharmacokinetic and physicochemical attributes, in addition to a suitable safety profile, in general known as structure–activity relationships (SAR) and structure–property relationships (SPR). The cross-coupling methodology is a reliable and versatile approach that allows for the bond-formation of a sp2-hybridized aromatic halide (acting as an electrophile or 1) with an organometallic (nucleophile or 2) using a metal catalyst (Figure1). In particular, palladium-catalyzed cross-coupling reactions have been demonstrated as an extraordinary resource and robust class of reactions [1] for the creation of carbon–carbon and carbon–heteroatom bonds in the pharmaceutical industry. In this review, we want to highlight the impactful applications of cross-coupling reactions in medicinal chemistry with a few recent examples from the field, with an emphasis on the Suzuki–Miyaura and Buchwald–Hartwig methodologies due to their versatility to generate carbon–carbon and carbon–heteroatom bonds and their prevalence as Molecules 2020, 25, 3493; doi:10.3390/molecules25153493 www.mdpi.com/journal/molecules Molecules 2020, 25, x FOR PEER REVIEW 2 of 22 Molecules 2020, 25, 3493 2 of 22 a few recent examples from the field, with an emphasis on the Suzuki–Miyaura and Buchwald– Hartwig methodologies due to their versatility to generate carbon–carbon and carbon–heteroatom the twobonds most commonand their couplingprevalence reactions as the two that most contribute common to medicinalcoupling reactions chemistry that [2 ]contribute (For a broader to medicinal scope ofchemistry other cross-coupling [2] (For a broader reactions scope beyond of other the goals cross-co of thisupling review, reactions like Negishi beyond [3 the,4], goals Kumada of this [5], review, Stille [6]like and Negishi Chan-Lam [3,4], [7 ],Kumada the reader [5], is Stille referred [6] and to additional Chan-Lam reading.) [7], the Furthermore,reader is referred we present to additional specific recentreading.) cases Furthermore, for the identification we present of clinical specific candidates recent ca thatses for incorporate the identification cross-coupling of clinical reactions candidates during theirthat large-scaleincorporate manufacturing cross-coupling process. reactions As aduring forward their outlook large-scale of these applications,manufacturing we reviewprocess. As a several examplesforward outlook of broader of utilizationthese applications, of cross-coupling we review reactions several to examples new chemical of broader modalities, utilization such as of cross- DNA-encodedcoupling libraries reactions (DELs), to new synthesis chemical of novel modalities, cyclopeptides, such as allostericDNA-encoded modulators, libraries and (DELs), proteolysis synthesis of targetingnovel chimera cyclopeptides, (PROTAC) allosteric approaches. modulators, and proteolysis targeting chimera (PROTAC) approaches. (a) (b) Figure 1.Figure(a) Fundamentals1. (a) Fundamentals of cross-coupling of cross-coupling methodology; methodology; (b) ( exampleb) example of of Suzuki–Miyaura Suzuki–Miyaura Csp2- 2 2 Csp -CspCspcoupling.2 coupling. The nomenclatureThe nomenclature for cross-coupling for cross-coupling reactions reactions is based is based on the on type the type of nucleophile of nucleophile utilized. utilized. For For example,example, using using organoboranes organoboranes as nucleophiles as nucleophiles is referred is referred to as Suzuki–Miyaura to as Suzuki–Miyaura reactions reactions (Figure 1(Figure), 1), while usingwhile organozinc using organozinc nucleophiles nucleophiles is known is asknown the Negishi as the Negishi reaction. reaction. French chemistFrench chemist Andre Job Andre was Job the was first the person first toperson combine to combine organometallic organometallic reagents reagents with catalysis with catalysis in an effective fashion [8]. He reported mixing the Grignard PhMgBr with NiCl2 to incorporate CO, NO, in an effective fashion [8]. He reported mixing the Grignard PhMgBr with NiCl2 to incorporate CO, C2H4,C2H2, or H2. Building on this initial discovery, in 1941, Kharasch published on metal-catalyzed NO, C2H4, C2H2, or H2. Building on this initial discovery, in 1941, Kharasch published on metal- homo-couplingscatalyzed of homo-couplings organomagnesium of orga reagentsnomagnesium [9]. Kharasch reagents used catalytic[9]. Kharasch amounts used of FeClcatalytic3, CoCl amounts2, of MnCl2, or NiCl2 with Grignard reagents and alkyl or aryl halides for the homo-coupling reaction. FeCl3, CoCl2, MnCl2, or NiCl2 with Grignard reagents and alkyl or aryl halides for the homo-coupling After key contributions from Heck and others, Kochi [10] disclosed an FeCl3-catalyzed reaction reaction. After key contributions from Heck and others, Kochi [10] disclosed an FeCl3-catalyzed 2 betweenreaction Csp –Br between electrophiles Csp2–Br and electrophiles Grignard reagents. and Grignard In 1976, reagents. Negishi [In11 ]1976, demonstrated Negishi [11] that demonstrated other organometallicthat other reagents organometallic could be usedreagents instead could of Grignardbe used instead reagents. of DueGrignard to its benchreagents. stability Due to and its bench high reactivity,stability palladium and high was reactivity, considered palladium the preferred was metalconsidered for cross-coupling the preferred reactions, metal for and cross-coupling is now utilizedreactions, in a routine and basis is now across utilized medicinal in a routine chemistry basi therapeutics across medicinal areas. chemistry therapeutic areas. 2. C-C Reaction: Suzuki–Miyaura Reaction 2. C-C Reaction: Suzuki–Miyaura Reaction In a recent study analyzing the most common reactions in medicinal chemistry [2], it was revealed In a recent study analyzing the most common reactions in medicinal chemistry [2], it was that, in 2014, the Suzuki–Miyaura coupling was the second most utilized transformation after the revealed that, in 2014, the Suzuki–Miyaura coupling was the second most utilized transformation amide bond formation. As a testimony to the impact of this reaction, it is possible to see a biphenyl moiety or aryl-heterocycle groups in a variety of approved drugs (Figure2). Molecules 2020, 25, x FOR PEER REVIEW 3 of 22 after the amide bond formation. As a testimony to the impact of this reaction, it is possible to see a biphenyl moiety or aryl-heterocycle groups in a variety of approved drugs (Figure 2). As an example, the synthesis of Losartan (4) [12] is shown in Scheme 1 [13]. Losartan (4), one of the most prescribed medicines in the world, is the first angiotensin II receptor antagonist discovered by scientists at Dupont to treat high blood pressure. A key cross-coupling step in the synthetic route required further optimization in order to obtain a high yield. It was found that heating Pd(OAc)2 and triphenylphosphine in tetrahydrofuran (THF) led to the preparation of an active catalyst, instead of using tetrakis (triphenylphosphine) palladium,
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