Rebecca T. Ruck

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.

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.

Rapid catalyst identification for the synthesis of the pyrimidinone core of HIV integrase inhibitors.

A microscale chemistry improvement engine: a pre-dosed microscale high-throughput experimentation additives platform enables rapid, serendipitous reaction improvement. This platform allowed one chemist to set up 475 experiments and analyze the results using MISER chromatography in a single day, thus resulting in two high-quality catalytic systems for the construction of the title compound 1. Support for a single-electron transfer mechanism was obtained.

A multifunctional catalyst that stereoselectively assembles prodrugs

Getting phosphorus into healthy shape ProTide therapeutics play a trick on the body, getting nucleoside analogs where they need to be by decorating them with unnatural phosphoramidates in place of ordinary phosphates. These compounds pose an unusual synthetic challenge because their configuration must be controlled at phosphorus; most methods have been refined to manipulate the geometry of carbon. DiRocco et al. report a metal-free, small-molecule catalyst that attains high selectivity for nucleoside phosphoramidation by activating both reaction partners. Kinetic studies with an early prototype revealed a double role for the catalyst that inspired the rational design of a more active and selective dimeric structure. Science, this issue p. 426 A doubly activating catalyst efficiently forms key phosphorus-based chiral centers inherent to ProTide therapeutics. The catalytic stereoselective synthesis of compounds with chiral phosphorus centers remains an unsolved problem. State-of-the-art methods rely on resolution or stoichiometric chiral auxiliaries. Phosphoramidate prodrugs are a critical component of pronucleotide (ProTide) therapies used in the treatment of viral disease and cancer. Here we describe the development of a catalytic stereoselective method for the installation of phosphorus-stereogenic phosphoramidates to nucleosides through a dynamic stereoselective process. Detailed mechanistic studies and computational modeling led to the rational design of a multifunctional catalyst that enables stereoselectivity as high as 99:1.

Discovery of MK-8831, A Novel Spiro-Proline Macrocycle as a Pan-Genotypic HCV-NS3/4a Protease Inhibitor.

We have been focused on identifying a structurally different next generation inhibitor to MK-5172 (our Ns3/4a protease inhibitor currently under regulatory review), which would achieve superior pangenotypic activity with acceptable safety and pharmacokinetic profile. These efforts have led to the discovery of a novel class of HCV NS3/4a protease inhibitors containing a unique spirocyclic-proline structural motif. The design strategy involved a molecular-modeling based approach, and the optimization efforts on the series to obtain pan-genotypic coverage with good exposures on oral dosing. One of the key elements in this effort was the spirocyclization of the P2 quinoline group, which rigidified and constrained the binding conformation to provide a novel core. A second focus of the team was also to improve the activity against genotype 3a and the key mutant variants of genotype 1b. The rational application of structural chemistry with molecular modeling guided the design and optimization of the structure-activity relationships have resulted in the identification of the clinical candidate MK-8831 with excellent pan-genotypic activity and safety profile.

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.

The Discovery of MK-4256, a Potent SSTR3 Antagonist as a Potential Treatment of Type 2 Diabetes

A structure-activity relationship study of the imidazolyl-β-tetrahydrocarboline series identified MK-4256 as a potent, selective SSTR3 antagonist, which demonstrated superior efficacy in a mouse oGTT model. MK-4256 reduced glucose excursion in a dose-dependent fashion with maximal efficacy achieved at doses as low as 0.03 mg/kg po. As compared with glipizide, MK-4256 showed a minimal hypoglycemia risk in mice.

Structure–activity relationships of proline modifications around the tetracyclic-indole class of NS5A inhibitors

We describe the impact of proline modifications, in our tetracyclic-indole based series of nonstructural protein 5A (NS5A) inhibitors, to their replicon profiles. This work identified NS5A inhibitors with an improved and flattened resistance profiles.

Cobalt-catalyzed asymmetric hydrogenation of enamides enabled by single-electron reduction

Reduction can make cobalt act precious Enzymes rely on abundant metals such as iron and nickel to manipulate hydrogen. Chemists, on the other hand, have largely had to rely on precious metals such as platinum and rhodium for the task. Friedfeld et al. now report a simple trick to make cobalt act more like rhodium. Reduction of Co(II) to Co(I) by zinc reinforced binding of phosphine ligands to the metal to facilitate its use in asymmetric hydrogenation of alkenes. The cobalt catalysts tolerated alcohol solvents, unlike their rhodium congeners, and could be applied to a 200-gram-scale reduction at 0.08% loading. Science, this issue p. 888 Zinc reduction of cobalt bolsters its binding of chiral phosphine ligands in applications to asymmetric hydrogenation. Identifying catalyst activation modes that exploit one-electron chemistry and overcome associated deactivation pathways will be transformative for developing first-row transition metal catalysts with performance equal or, ideally, superior to precious metals. Here we describe a zinc-activation method compatible with high-throughput reaction discovery that identified scores of cobalt-phosphine combinations for the asymmetric hydrogenation of functionalized alkenes. An optimized catalyst prepared from (R,R)-Ph-BPE {Ph-BPE, 1,2-bis[(2R,5R)-2,5-diphenylphospholano]ethane} and cobalt chloride [CoCl2·6H2O] exhibited high activity and enantioselectivity in protic media and enabled the asymmetric synthesis of the epilepsy medication levetiracetam at 200-gram scale with 0.08 mole % catalyst loading. Stoichiometric studies established that the cobalt (II) catalyst precursor (R,R)-Ph-BPECoCl2 underwent ligand displacement by methanol, and zinc promoted facile one-electron reduction to cobalt (I), which more stably bound the phosphine.

Solution to the C3–Arylation of Indazoles: Development of a Scalable Method

3-(Hetero)arylindazoles are important motifs in several biologically active compounds. Mild and flexible palladium-mediated Negishi reaction conditions are reported for the introduction of (hetero)aryl moieties at the 3-position of N(2)-SEM-protected indazoles in high yields. The requisite Zn-species are readily obtained via regioselective deprotonation and subsequent transmetalation. The methodology tolerates a variety of functional groups on both coupling partners and has been extended to bis-haloarene and heteroarene coupling partners where the most reactive halogen reacts first, leaving the second halogen for subsequent functionalization.