David W. C. MacMillan

Visible Light Photoredox Catalysis with Transition Metal Complexes: Applications in Organic Synthesis

A fundamental aim in the field of catalysis is the development of new modes of small molecule activation. One approach toward the catalytic activation of organic molecules that has received much attention recently is visible light photoredox catalysis. In a general sense, this approach relies on the ability of metal complexes and organic dyes to engage in single-electron-transfer (SET) processes with organic substrates upon photoexcitation with visible light. Many of the most commonly employed visible light photocatalysts are polypyridyl complexes of ruthenium and iridium, and are typified by the complex tris(2,2′-bipyridine) ruthenium(II), or Ru(bpy)32+ (Figure 1). These complexes absorb light in the visible region of the electromagnetic spectrum to give stable, long-lived photoexcited states.1,2 The lifetime of the excited species is sufficiently long (1100 ns for Ru(bpy)32+) that it may engage in bimolecular electron-transfer reactions in competition with deactivation pathways.3 Although these species are poor single-electron oxidants and reductants in the ground state, excitation of an electron affords excited states that are very potent single-electron-transfer reagents. Importantly, the conversion of these bench stable, benign catalysts to redox-active species upon irradiation with simple household lightbulbs represents a remarkably chemoselective trigger to induce unique and valuable catalytic processes. Figure 1 Ruthenium polypyridyl complexes: versatile visible light photocatalysts. The ability of Ru(bpy)32+ and related complexes to function as visible light photocatalysts has been recognized and extensively investigated for applications in inorganic and materials chemistry. In particular, photoredox catalysts have been utilized to accomplish the splitting of water into hydrogen and oxygen4 and the reduction of carbon dioxide to methane.5 Ru(bpy)32+ and its analogues have been used (i) as components of dye-sensitized solar cells6 and organic light-emitting diodes,7 (ii) to initiate polymerization reactions,8 and (iii) in photo-dynamic therapy.9 Until recently, however, these complexes had been only sporadically employed as photocatalysts in the area of organic synthesis. The limited exploration of this area is perhaps surprising, as single-electron, radical processes have long been employed in C–C bond construction and often provide access to reactivity that is complementary to that of closed-shell, two-electron pathways.10 In 2008, concurrent reports from the Yoon group and our own lab detailed the use of Ru(bpy)32+ as a visible light photoredox catalyst to perform a [2 + 2] cycloaddition11 and an α-alkylation of aldehydes,12 respectively. Shortly thereafter, Stephenson and co-workers disclosed a photoredox reductive dehalogenation of activated alkyl halides mediated by the same catalyst.13 The combined efforts of these three research groups have helped to initiate a renewed interest in this field, prompting a diversity of studies into the utility of photoredox catalysis as a conceptually novel approach to synthetic organic reaction development. Much of the promise of visible light photoredox catalysis hinges on its ability to achieve unique, if not exotic bond constructions that are not possible using established protocols. For instance, photoredox catalysis may be employed to perform overall redox neutral reactions. As both oxidants and reductants may be transiently generated in the same reaction vessel, photoredox approaches may be used to develop reactions requiring both the donation and the reception of electrons at disparate points in the reaction mechanism. This approach stands in contrast to methods requiring stoichiometric chemical oxidants and reductants, which are often incompatible with each other, as well as to electrochemical approaches, which are not amenable to redox neutral transformations. Furthermore, single-electron-transfer events often provide access to radical ion intermediates having reactivity patterns fundamentally different from those of their ground electronic or excited states.14 Access to these intermediates using other means of activation is often challenging or requires conditions under which their unique reactivity cannot be productively harnessed. At the same time, photoredox catalysts such as Ru(bpy)32+ may also be employed to generate radicals for use in a diverse range of established radical chemistries. Photoredox reactions occur under extremely mild conditions, with most reactions proceeding at room temperature without the need for highly reactive radical initiators. The irradiation source is typically a commercial household light bulb, a significant advantage over the specialized equipment required for processes employing high-energy ultraviolet (UV) light. Additionally, because organic molecules generally do not absorb visible light, there is little potential for deleterious side reactions that might arise from photoexcitation of the substrate itself. Finally, photoredox catalysts may be employed at very low loadings, with 1 mole % or less being typical. This Review will highlight the early work on the use of transition metal complexes as photoredox catalysts to promote reactions of organic compounds (prior to 2008), as well as cover the surge of work that has appeared since 2008. We have for the most part grouped reactions according to whether the organic substrate undergoes reduction, oxidation, or a redox neutral reaction and throughout have sought to highlight the variety of reactive intermediates that may be accessed via this general reaction manifold.15 Studies on the use of transition metal complexes as visible light photocatalysts for organic synthesis have benefited tremendously from advances in the related fields of organic and semiconductor photocatalysis. Many organic molecules may function as visible light photocatalysts; analogous to metal complexes such as Ru(bpy)32+, organic dyes such as eosin Y, 9,10-dicyanoanthracene, and triphenylpyrylium salts absorb light in the visible region to give excited states capable of single-electron transfer. These catalysts have been employed to achieve a vast range of bond-forming reactions of broad utility in organic synthesis.16 Visible light photocatalysis has also been carried out with heterogeneous semiconductors such as mesoporous carbon nitride17 and various metal oxides and sulfides.18 These approaches are often complementary to photoredox catalysis with transition metal-polypyridyl complexes, and we have referred to work in these areas when it is similar to the chemistry under discussion. However, an in-depth discussion of the extensive literature in these fields is outside the scope of this Review, and readers are directed to existing reviews on these topics.16–18

The advent and development of organocatalysis

The use of small organic molecules as catalysts has been known for more than a century. But only in the past decade has organocatalysis become a thriving area of general concepts and widely applicable asymmetric reactions. Here I present my opinion on why the field of organocatalysis has blossomed so dramatically over the past decade.

Merging Photoredox Catalysis with Organocatalysis: The Direct Asymmetric Alkylation of Aldehydes

Photoredox catalysis and organocatalysis represent two powerful fields of molecule activation that have found widespread application in the areas of inorganic and organic chemistry, respectively. We merged these two catalysis fields to solve problems in asymmetric chemical synthesis. Specifically, the enantioselective intermolecular α-alkylation of aldehydes has been accomplished using an interwoven activation pathway that combines both the photoredox catalyst Ru(bpy)3Cl2 (where bpy is 2,2′-bipyridine) and an imidazolidinone organocatalyst. This broadly applicable, yet previously elusive, alkylation reaction is now highly enantioselective and operationally trivial.

Trifluoromethylation of arenes and heteroarenes by means of photoredox catalysis

Modern drug discovery relies on the continual development of synthetic methodology to address the many challenges associated with the design of new pharmaceutical agents. One such challenge arises from the enzymatic metabolism of drugs in vivo by cytochrome P450 oxidases, which use single-electron oxidative mechanisms to rapidly modify small molecules to facilitate their excretion. A commonly used synthetic strategy to protect against in vivo metabolism involves the incorporation of electron-withdrawing functionality, such as the trifluoromethyl (CF3) group, into drug candidates. The CF3 group enjoys a privileged role in the realm of medicinal chemistry because its incorporation into small molecules often enhances efficacy by promoting electrostatic interactions with targets, improving cellular membrane permeability, and increasing robustness towards oxidative metabolism of the drug. Although common pharmacophores often bear CF3 motifs in an aromatic system, access to such analogues typically requires the incorporation of the CF3 group, or a surrogate moiety, at the start of a multi-step synthetic sequence. Here we report a mild, operationally simple strategy for the direct trifluoromethylation of unactivated arenes and heteroarenes through a radical-mediated mechanism using commercial photocatalysts and a household light bulb. We demonstrate the broad utility of this transformation through addition of CF3 to a number of heteroaromatic and aromatic systems. The benefit to medicinal chemistry and applicability to late-stage drug development is also shown through examples of the direct trifluoromethylation of widely prescribed pharmaceutical agents.

Enantioselective α-Trifluoromethylation of Aldehydes via Photoredox Organocatalysis

The first enantioselective, organocatalytic alpha-trifluoromethylation and alpha-perfluoroalkylation of aldehydes have been accomplished using a readily available iridium photocatalyst and a chiral imidazolidinone catalyst. A range of alpha-trifluoromethyl and alpha-perfluoroalkyl aldehydes were obtained from commercially available perfluoroalkyl halides with high efficiency and enantioselectivity. The resulting alpha-trifluoromethyl aldehydes were subsequently shown to be versatile precursors for the construction of a variety of enantioenriched trifluoromethylated building blocks.

Merging photoredox with nickel catalysis: Coupling of α-carboxyl sp3-carbons with aryl halides

A bright outlook for carbon coupling In contemporary organic chemistry, it is straightforward to forge bonds between unsaturated carbons (i.e., carbons already engaged in double bonds) using cross-coupling catalysis. The protocol runs into some trouble, however, if one or both starting carbon centers are saturated (purely single-bonded). Tellis et al. and Zuo et al. independently found that combining a second, light-activated catalyst with a nickel cross-coupling catalyst could achieve selective coupling of saturated and unsaturated reagents (see the Perspective by Lloyd-Jones and Ball). Their methods rely on single-electron transfer from the light-activated catalyst to the saturated carbon, thereby enhancing its reactivity more effectively than the twoelectron mechanisms prevailing in traditional protocols. Science, this issue p. 433, p. 437; see also p. 381 Combining two catalysts, one light-activated, facilitates bond formation between saturated and unsaturated carbons. [Also see Perspective by Lloyd-Jones and Ball] Over the past 40 years, transition metal catalysis has enabled bond formation between aryl and olefinic (sp2) carbons in a selective and predictable manner with high functional group tolerance. Couplings involving alkyl (sp3) carbons have proven more challenging. Here, we demonstrate that the synergistic combination of photoredox catalysis and nickel catalysis provides an alternative cross-coupling paradigm, in which simple and readily available organic molecules can be systematically used as coupling partners. By using this photoredox-metal catalysis approach, we have achieved a direct decarboxylative sp3–sp2 cross-coupling of amino acids, as well as α-O– or phenyl-substituted carboxylic acids, with aryl halides. Moreover, this mode of catalysis can be applied to direct cross-coupling of Csp3–H in dimethylaniline with aryl halides via C–H functionalization.

Synergistic catalysis: A powerful synthetic strategy for new reaction development

Synergistic catalysis is a synthetic strategy wherein both the nucleophile and the electrophile are simultaneously activated by two separate and distinct catalysts to afford a single chemical transformation. This powerful catalysis strategy leads to several benefits, specifically synergistic catalysis can (i) introduce new, previously unattainable chemical transformations, (ii) improve the efficiency of existing transformations, and (iii) create or improve catalytic enantioselectivity where stereocontrol was previously absent or challenging. This perspective aims to highlight these benefits using many of the successful examples of synergistic catalysis found in the literature.

Discovery of an α-Amino C–H Arylation Reaction Using the Strategy of Accelerated Serendipity

An unanticipated photocatalytic carbon-carbon bond-forming reaction emerged from screening many unusual reagent combinations. Serendipity has long been a welcome yet elusive phenomenon in the advancement of chemistry. We sought to exploit serendipity as a means of rapidly identifying unanticipated chemical transformations. By using a high-throughput, automated workflow and evaluating a large number of random reactions, we have discovered a photoredox-catalyzed C–H arylation reaction for the construction of benzylic amines, an important structural motif within pharmaceutical compounds that is not readily accessed via simple substrates. The mechanism directly couples tertiary amines with cyanoaromatics by using mild and operationally trivial conditions.

Enantioselective Organocatalysis Using SOMO Activation

One proposed strategy for controlling the transmission of insect-borne pathogens uses a drive mechanism to ensure the rapid spread of transgenes conferring disease refractoriness throughout wild populations. Here, we report the creation of maternal-effect selfish genetic elements in Drosophila that drive population replacement and are resistant to recombination-mediated dissociation of drive and disease refractoriness functions. These selfish elements use microRNA-mediated silencing of a maternally expressed gene essential for embryogenesis, which is coupled with early zygotic expression of a rescuing transgene.The phosphoinositide phosphatase PTEN is mutated in many human cancers. Although the role of PTEN has been studied extensively, the relative contributions of its numerous potential downstream effectors to deregulated growth and tumorigenesis remain uncertain. We provide genetic evidence in Drosophila melanogaster for the paramount importance of the protein kinase Akt [also called protein kinase B (PKB)] in mediating the effects of increased phosphatidylinositol 3,4,5-trisphosphate (PIP3) concentrations that are caused by the loss of PTEN function. A mutation in the pleckstrin homology (PH) domain of Akt that reduces its affinity for PIP3 sufficed to rescue the lethality of flies devoid of PTEN activity. Thus, Akt appears to be the only critical target activated by increased PIP3 concentrations in Drosophila.Using genomic and mass spectrometry-based proteomic methods, we evaluated gene expression, identified key activities, and examined partitioning of metabolic functions in a natural acid mine drainage (AMD) microbial biofilm community. We detected 2033 proteins from the five most abundant species in the biofilm, including 48% of the predicted proteins from the dominant biofilm organism, Leptospirillum group II. Proteins involved in protein refolding and response to oxidative stress appeared to be highly expressed, which suggests that damage to biomolecules is a key challenge for survival. We validated and estimated the relative abundance and cellular localization of 357 unique and 215 conserved novel proteins and determined that one abundant novel protein is a cytochrome central to iron oxidation and AMD formation.

Collective synthesis of natural products by means of organocascade catalysis

Organic chemists are now able to synthesize small quantities of almost any known natural product, given sufficient time, resources and effort. However, translation of the academic successes in total synthesis to the large-scale construction of complex natural products and the development of large collections of biologically relevant molecules present significant challenges to synthetic chemists. Here we show that the application of two nature-inspired techniques, namely organocascade catalysis and collective natural product synthesis, can facilitate the preparation of useful quantities of a range of structurally diverse natural products from a common molecular scaffold. The power of this concept has been demonstrated through the expedient, asymmetric total syntheses of six well-known alkaloid natural products: strychnine, aspidospermidine, vincadifformine, akuammicine, kopsanone and kopsinine.