An analysis of chemical reactions used in current medicinal chemistry (2014), three decades ago (1984), and in natural product total synthesis has been conducted. The analysis revealed that of the current most frequently used synthetic reactions, none were discovered within the past 20 years and only two in the 1980s and 1990s (Suzuki–Miyaura and Buchwald–Hartwig). This suggests an inherent high bar of impact for new synthetic reactions in drug discovery. The most frequently used reactions were amide bond formation, Suzuki–Miyaura coupling, and SNAr reactions, most likely due to commercial availability of reagents, high chemoselectivity, and a pressure on delivery. We show that these practices result in overpopulation of certain types of molecular shapes to the exclusion of others using simple PMI plots. We hope that these results will help catalyze improvements in integration of new synthetic methodologies as well as new library design.

Analysis of Past and Present Synthetic Methodologies on Medicinal Chemistry: Where Have All the New Reactions Gone?

Conventional methods for carrying out carbon–hydrogen functionalization and carbon–nitrogen bond formation are typically conducted at elevated temperatures, and rely on expensive catalysts as well as the use of stoichiometric, and perhaps toxic, oxidants. In this regard, electrochemical synthesis has recently been recognized as a sustainable and scalable strategy for the construction of challenging carbon–carbon and carbon–heteroatom bonds. Here, electrosynthesis has proven to be an environmentally benign, highly effective and versatile platform for achieving a wide range of nonclassical bond disconnections via generation of radical intermediates under mild reaction conditions. This review provides an overview on the use of anodic electrochemical methods for expediting the development of carbon–hydrogen functionalization and carbon–nitrogen bond formation strategies. Emphasis is placed on methodology development and mechanistic insight and aims to provide inspiration for future synthetic applications in the field of electrosynthesis.

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Electrochemical strategies for C-H functionalization and C-N bond formation.

The current status of homogeneous iron catalysis in organic chemistry is contemplated, as are the reasons why this particular research area only recently starts challenging the enduring dominance of the late and mostly noble metals over the field Centered in the middle of the d-block and able to support formal oxidation states ranging from −II to +VI, iron catalysts hold the promise of being able to encompass organic synthesis at large They are expected to serve reductive as well as oxidative regimes, can emulate “noble tasks”, but are also able to adopt “early” transition metal character Since a comprehensive coverage of this multidimensional agenda is beyond the scope of an Outlook anyway, emphasis is laid in this article on the analysis of the factors that perhaps allow one to control the multifarious chemical nature of this earth-abundant metal The challenges are significant, not least at the analytical frontier; their mastery mandates a mindset that differs from the routines that most organic che

http://pubs.acs.org/doi/pdf/10.1021/acscentsci.6b00272

Iron Catalysis in Organic Synthesis: A Critical Assessment of What It Takes To Make This Base Metal a Multitasking Champion

Cobalt has become increasingly attractive in homogeneous catalysis because of its unique characteristics and outstanding catalytic performance in addition to being cheap and earth-abundant. Hydride transfer processes are involved in a broad range of organic transformations that allow the facile preparation of various useful chemicals and synthetic building blocks. These reactions have continuously received great attention both from academia and industry. In this perspective, we review homogeneous cobalt-catalyzed hydride transfer reactions according to the classified reaction types and provide a comprehensive overview of the design, synthesis, and reactivity of cobalt catalysts, their catalytic applications, and reaction mechanisms.

Hydride Transfer Reactions Catalyzed by Cobalt Complexes.

Computational chemistry provides a versatile toolbox for studying mechanistic details of catalytic reactions and holds promise to deliver practical strategies to enable the rational in silico catalyst design. The versatile reactivity and nontrivial electronic structure effects, common for systems based on 3d transition metals, introduce additional complexity that may represent a particular challenge to the standard computational strategies. In this review, we discuss the challenges and capabilities of modern electronic structure methods for studying the reaction mechanisms promoted by 3d transition metal molecular catalysts. Particular focus will be placed on the ways of addressing the multiconfigurational problem in electronic structure calculations and the role of expert bias in the practical utilization of the available methods. The development of density functionals designed to address transition metals is also discussed. Special emphasis is placed on the methods that account for solvation effects and the multicomponent nature of practical catalytic systems. This is followed by an overview of recent computational studies addressing the mechanistic complexity of catalytic processes by molecular catalysts based on 3d metals. Cases that involve noninnocent ligands, multicomponent reaction systems, metal-ligand and metal-metal cooperativity, as well as modeling complex catalytic systems such as metal-organic frameworks are presented. Conventionally, computational studies on catalytic mechanisms are heavily dependent on the chemical intuition and expert input of the researcher. Recent developments in advanced automated methods for reaction path analysis hold promise for eliminating such human-bias from computational catalysis studies. A brief overview of these approaches is presented in the final section of the review. The paper is closed with general concluding remarks.

Computational Approach to Molecular Catalysis by 3d Transition Metals: Challenges and Opportunities

The olefin metathesis reaction of two unsaturated substrates is one of the most powerful carbon-carbon-bond-forming reactions in organic chemistry. Specifically, the catalytic olefin metathesis reaction has led to profound developments in the synthesis of molecules relevant to the petroleum, materials, agricultural and pharmaceutical industries. These reactions are characterized by their use of discrete metal alkylidene catalysts that operate via a well-established mechanism. While the corresponding carbonyl-olefin metathesis reaction can also be used to construct carbon-carbon bonds, currently available methods are scarce and severely hampered by either harsh reaction conditions or the required use of stoichiometric transition metals as reagents. To date, no general protocol for catalytic carbonyl-olefin metathesis has been reported. Here we demonstrate a catalytic carbonyl-olefin ring-closing metathesis reaction that uses iron, an Earth-abundant and environmentally benign transition metal, as a catalyst. This transformation accommodates a variety of substrates and is distinguished by its operational simplicity, mild reaction conditions, high functional-group tolerance, and amenability to gram-scale synthesis. We anticipate that these characteristics, coupled with the efficiency of this reaction, will allow for further advances in areas that have historically been enhanced by olefin metathesis.

Iron( III )-catalysed carbonyl–olefin metathesis

Catalyst: Sustainable Catalysis

Polycyclic aromatic hydrocarbons are important structural motifs in organic chemistry, pharmaceutical chemistry, and materials science. The development of a new synthetic strategy toward these compounds is described based on the design principle of iron(III)-catalyzed carbonyl–olefin metathesis reactions. This approach is characterized by its operational simplicity, high functional group compatibility, and regioselectivity while relying on FeCl3 as an environmentally benign, earth-abundant metal catalyst. Experimental evidence for oxetanes as reactive intermediates in the catalytic carbonyl–olefin ring-closing metathesis has been obtained.

Polycyclic Aromatic Hydrocarbons via Iron(III)-Catalyzed Carbonyl-Olefin Metathesis.

Intermolecular [2+2] photocycloadditions represent a powerful method for the synthesis of highly strained, four-membered rings. Although this approach is commonly employed for the synthesis of oxetanes and cyclobutanes, the synthesis of azetidines via intermolecular aza Paterno–Buchi reactions remains highly underdeveloped. Here we report a visible-light-mediated intermolecular aza Paterno–Buchi reaction that utilizes the unique triplet state reactivity of oximes, specifically 2-isoxazoline-3-carboxylates. The reactivity of this class of oximes can be harnessed via the triplet energy transfer from a commercially available iridium photocatalyst and allows for [2+2] cycloaddition with a wide range of alkenes. This approach is characterized by its operational simplicity, mild conditions and broad scope, and allows for the synthesis of highly functionalized azetidines from readily available precursors. Importantly, the accessible azetidine products can be readily converted into free, unprotected azetidines, which represents a new approach to access these highly desirable synthetic targets. Although azetidines represent highly desirable building blocks in drug discovery, methods for their efficient and straightforward synthesis remain underdeveloped. Now, it has been shown that highly functionalized azetidines can be prepared via an intermolecular [2+2] photocycloaddition reaction between cyclic oximes and alkenes, in a process enabled by a visible-light-mediated triplet energy transfer.

Synthesis of azetidines via visible-light-mediated intermolecular [2+2] photocycloadditions.

Azetidines are four-membered nitrogen-containing heterocycles that hold great promise in current medicinal chemistry due to their desirable pharmacokinetic effects. However, a lack of efficient synthetic methods to access functionalized azetidines has hampered their incorporation into pharmaceutical lead structures. As a [2+2] cycloaddition reaction between imines and alkenes, the aza Paterno-Buchi reaction arguably represents the most direct approach to functionalized azetidines. Hampered by competing reaction paths accessible upon photochemical excitation of the substrates, the current synthetic utility of these transformations is greatly restricted. We herein report the development of a visible light-enabled aza Paterno-Buchi reaction that surmounts existing limitations and represents a mild solution for the direct formation of functionalized azetidines from imine and alkene containing precursors.

/pdf/functionalized-azetidines-via-visible-light-enabled-aza-4sgfz7p7sb.pdf

Corinna S. Schindler

Papers

Iron( III )-catalysed carbonyl–olefin metathesis

Catalyst: Sustainable Catalysis

Polycyclic Aromatic Hydrocarbons via Iron(III)-Catalyzed Carbonyl-Olefin Metathesis.

Synthesis of azetidines via visible-light-mediated intermolecular [2+2] photocycloadditions.

Functionalized azetidines via visible light-enabled aza Paternò-Büchi reactions.