Michael Shevlin

Cobalt Precursors for High-Throughput Discovery of Base Metal Asymmetric Alkene Hydrogenation Catalysts

Lighter Hydrogenation Catalysts Enzymes have evolved to use abundant metals such as iron, cobalt, and nickel for redox catalysis. However, synthetic catalysis has generally relied on the rarer, heavier relatives of these elements: ruthenium, rhodium, iridium, palladium, and platinum (see the Perspective by Bullock). Friedfeld et al. (p. 1076) used high-throughput screening to show that the right cobalt precursor can be activated for asymmetric hydrogenation catalysis by using the traditional ligands developed for the precious metals. Zuo et al. (p. 1080) focused on iron, demonstrating a highly effective asymmetric transfer hydrogenation catalyst that uses a ligand rationally designed after careful mechanistic study. Jagadeesh et al. (p. 1073) prepared supported iron catalysts that selectively reduce nitro substituents on aromatic rings to amines, thereby facilitating the preparation of a wide range of aniline derivatives. High-throughput screening furnishes surprisingly effective cobalt catalysts from versatile precursors. [Also see Perspective by Bullock] Asymmetric hydrogenation of alkenes is one of the most widely used methods for the preparation of single enantiomer compounds, especially in the pharmaceutical and agrochemical industries. For more than four decades, precious metal complexes containing rhodium, iridium, and ruthenium have been predominantly used as catalysts. Here, we report rapid evaluation of libraries of chiral phosphine ligands with a set of simple cobalt precursors. From these studies, base metal precatalysts have been discovered for the hydrogenation of functionalized and unfunctionalized olefins with high enantiomeric excesses, demonstrating the potential utility of more earth-abundant metals in asymmetric hydrogenation.

Nanomole-scale high-throughput chemistry for the synthesis of complex molecules

Breaking through the milligram floor When chemists synthesize compounds, the threshold for success is at least a milligram of product. This has been true for decades—even though biochemical assays have long since descended into microgram territory—and results in part from the constraints of characterization methods. Buitrago Santanilla et al. present an automated dosing and characterization protocol for optimizing chemical reaction conditions on the microgram scale. This allowed them to screen numerous base and ligand combinations for catalytic C-N bond-forming reactions between complex pairs of compounds, in short supply, that resisted standard coupling conditions. Science, this issue p. 49 Automated technology enables chemical reaction optimization using micrograms of material. At the forefront of new synthetic endeavors, such as drug discovery or natural product synthesis, large quantities of material are rarely available and timelines are tight. A miniaturized automation platform enabling high-throughput experimentation for synthetic route scouting to identify conditions for preparative reaction scale-up would be a transformative advance. Because automated, miniaturized chemistry is difficult to carry out in the presence of solids or volatile organic solvents, most of the synthetic “toolkit” cannot be readily miniaturized. Using palladium-catalyzed cross-coupling reactions as a test case, we developed automation-friendly reactions to run in dimethyl sulfoxide at room temperature. This advance enabled us to couple the robotics used in biotechnology with emerging mass spectrometry–based high-throughput analysis techniques. More than 1500 chemistry experiments were carried out in less than a day, using as little as 0.02 milligrams of material per reaction.

Palladium‐Catalyzed Tandem Heck Reaction/CH Functionalization—Preparation of Spiro‐Indane‐Oxindoles

The oxindole framework is a motif common to natural products and pharmaceutically active compounds. In particular, 3,3-disubstituted oxindoles have shown promising biological activity. Considerable efforts have been dedicated to developing new methods for the preparation of these pharmacaphores, especially spiro-oxindoles: functionalization of heterocycles, variations of the Stolle reaction, epoxide rearrangement, Lewis acid promoted cyclization, Pummerer rearrangement, and various palladium-catalyzed methodologies. Within that last category, the intramolecular Heck reaction is of particular relevance here. Although tremendous efforts have been invested in the discovery of new palladium-catalyzed processes, there remains limited overlap between two key transformations, namely the Heck reaction and the direct arylation reaction, which appear to be orthogonal methodologies. Most relevant examples of reaction commonality entail carbopalladation to form a vinylpalladium intermediate and subsequent C H functionalization. The two examples that proceed by olefin insertion to form an alkylpalladium intermediate undergo C H insertion to form a cyclobutane product after reductive elimination. Of particular relevance to this work is the report from Grigg et al. on a Heck reaction that forms an alkylpalladium complex and then undergoes a heteroatom-directed arylation reaction to make a fivemembered ring. Herein we report an efficient preparation of spiro-fused indane-oxindoles by carbopalladation to form an alkylpalladium intermediate and subsequent functionalization of an unactivated aryl C H bond. (Scheme 1). To investigate the viability of a tandem Heck/arylation reaction sequence, we prepared N-(2-bromophenyl)acrylamides (5a–h) in a five-step sequence from 2-bromoaniline (1) (Scheme 2). Reductive amination between p-anisaldehyde and 2-bromoaniline afforded PMB-protected aniline 2 (PMB= p-methoxybenzyl). Amide bond formation between compound 2 and potassium mono-methyl malonate provided malonamic acid methyl ester 3, which was alkylated with the requisite substituted benzyl bromide to afford alkylation products 4a–h. Hydrolysis of the methyl ester, and treatment of the liberated carboxylic acid with diethylamine and paraformaldehyde, furnished acrylamides 5a–h in good yields. Initial efforts to effect the desired transformation from compound 5a to 6a employed the catalytic system reported by Fagnou and co-workers: Pd(OAc)2 (10 mol%), PtBu3HBF4 (20 mol%), and K2CO3 in DMA at 130 8C. [15,17] Gratifyingly, spiro-fused indane-oxindole 6a was observed under these conditions. A second product (7; see Scheme 4), assigned as the product formed by a reductive Heck reaction, was also observed in the complex reaction mixture. A series of palladium sources and ligands was screened in an effort to develop a cleaner reaction. Decreasing the catalyst loading in Scheme 1. Heck/C H functionalization tandem reaction. PMB=pmethoxybenzyl.

Cobalt-Catalyzed Enantioselective Hydrogenation of Minimally Functionalized Alkenes: Isotopic Labeling Provides Insight into the Origin of Stereoselectivity and Alkene Insertion Preferences

The asymmetric hydrogenation of cyclic alkenes lacking coordinating functionality with a C1-symmetric bis(imino)pyridine cobalt catalyst is described and has been applied to the synthesis of important substructures found in natural products and biologically active compounds. High activities and enantioselectivities were observed with substituted benzo-fused five-, six-, and seven-membered alkenes. The stereochemical outcome was dependent on both the ring size and exo/endo disposition. Deuterium labeling experiments support rapid and reversible 2,1-insertion that is unproductive for generating alkane product but accounts for the unusual isotopic distribution in deuterated alkanes. Analysis of the stereochemical outcome of the hydrogenated products coupled with isotopic labeling, stoichiometric, and kinetic studies established 1,2-alkene insertion as both turnover limiting and enantiodetermining with no evidence for erosion of cobalt alkyl stereochemistry by competing β-hydrogen elimination processes. A stereochemical model accounting for the preferred antipodes of the alkanes is proposed and relies on the subtle influence of the achiral aryl imine substituent on the cobalt catalyst.

Iridium-catalyzed X-H insertions of sulfoxonium ylides.

The unique reactivity of sulfoxonium ylides as a carbene source is described for a variety of X-H bond insertions, taking advantage of a simple, commercially available iridium catalyst. This method has applications in both intra- and intermolecular reactivity, including a practical ring-expansion strategy for lactams. The safety and stability of sulfoxonium ylides recommend them as preferable surrogates to traditional diazo ketones and esters.

A Concise Synthesis of a β-Lactamase Inhibitor

MK-7655 (1) is a β-lactamase inhibitor in clinical trials as a combination therapy for the treatment of bacterial infection resistant to β-lactam antibiotics. Its unusual structural challenges have inspired a rapid synthesis featuring an iridium-catalyzed N-H insertion and a series of late stage transformations designed around the reactivity of the labile bicyclo[3.2.1]urea at the core of the target.

Catalytic, Asymmetric, and Stereodivergent Synthesis of Non-Symmetric β,β-Diaryl-α-Amino Acids

We report a concise, enantio- and diastereoselective route to novel nonsymmetrically substituted N-protected β,β-diaryl-α-amino acids and esters, through the asymmetric hydrogenation of tetrasubstituted olefins, some of the most challenging examples in the field. Stereoselective generation of an E- or Z-enol tosylate, when combined with stereoretentive Suzuki-Miyaura cross-coupling and enantioselective hydrogenation catalyzed by (NBD)2RhBF4 and a Josiphos ligand, allows for full control over the two vicinal stereogenic centers. High yields and excellent enantioselectivities (up to 99% ee) were obtained for a variety of N-acetyl, N-methoxycarbonyl, and N-Boc β,β-diaryldehydroamino acids, containing a diverse and previously unreported series of heterocyclic and aryl substituted groups (24 examples) and allowing access to all four stereoisomers of these valuable building blocks.

Nickel-Catalyzed Asymmetric Alkene Hydrogenation of α,β-Unsaturated Esters: High-Throughput Experimentation-Enabled Reaction Discovery, Optimization, and Mechanistic Elucidation

A highly active and enantioselective phosphine-nickel catalyst for the asymmetric hydrogenation of α,β-unsaturated esters has been discovered. The coordination chemistry and catalytic behavior of nickel halide, acetate, and mixed halide-acetate with chiral bidentate phosphines have been explored and deuterium labeling studies, the method of continuous variation, nonlinear studies, and kinetic measurements have provided mechanistic understanding. Activation of molecular hydrogen by a trimeric (Me-DuPhos)3Ni3(OAc)5I complex was established as turnover limiting followed by rapid conjugate addition of a nickel hydride and nonselective protonation to release the substrate. In addition to reaction discovery and optimization, the previously unreported utility high-throughput experimentation for mechanistic elucidation is also described.

Double-Asymmetric Hydrogenation Strategy for the Reduction of 1,1-Diaryl Olefins Applied to an Improved Synthesis of CuIPhEt, a C2-Symmetric N-Heterocyclic Carbenoid

A library of iridium and rhodium phosphine catalysts have been screened for the double-asymmetric hydrogenation of 2,6-di-(1-phenylethenyl)-4-methylaniline to produce the C2-symmetric aniline precursor of the N-heterocyclic carbenoid CuIPhEt. The best catalyst produced the desired enantiomer in 98.6% selectivity. This rare example of a highly selective hydrogenation of a 1,1-diaryl olefin enables a four-step asymmetric synthesis of the C2-symmetric phenylethyl imidazolium ion (IPhEt) from p-toluidine and phenylacetylene and its conversion to the hydrosilylation catalyst CuIPhEt.

Enantioselective Synthesis of α-Methyl-β-cyclopropyldihydrocinnamates

α- and β-substitution of dihydrocinnamates has been shown to increase the biological activity of various drug candidates. Recently, we identified enantio- and diastereopure α-methyl-β-cyclopropyldihydrocinnamates to be important pharmacophores in one of our drug discovery programs and endeavored to devise an asymmetric hydrogenation strategy to improve access to this valuable framework. We used high throughput experimentation to define stereoconvergent Suzuki-Miyaura cross-coupling conditions affording (Z)-α-methyl-β-cyclopropylcinnamates and subsequent ruthenium-catalyzed asymmetric hydrogenation conditions affording the desired products in excellent enantio- and diastereoselectivities. These conditions were executed on multigram to kilogram scale to provide three key enantiopure α-methyl-β-cyclopropyldihydrocinnamates with high selectivity.