Mark A. Huffman

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.

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.

Improved stereoselectivity in the heterogeneous catalytic synthesis of enalapril obtained through multidimensional screening

Abstract A multidimensional screening of catalysts and additives led to the discovery of improved conditions for the diastereoselective reductive amination which produces enalapril. Additives acetic acid and potassium fluoride, which in isolation are detrimental, work together to improve the SSS : RSS selectivity with Ra-Ni in ethanol to 17 : 1 from 11 : 1.

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.

A convenient synthesis of 3-aryl-δ-lactones

Abstract Various (±)-3-aryl-δ-lactones have been prepared from the corresponding arylacetic acids. The lithium dianion of the acid is alkylated with 1-bromo-3-chloropropane and the unpurified product is cyclized with DBU in typically ca. 80% yield over both steps. We have shown that lactones of this type can be converted to their corresponding 5,6-dihydropyan-2-ones and pyran-2-ones, which potentially provide useful sites for further functionalization of the lactone ring.

Quantitative analysis of dimethyl titanocene by iodometric titration, gas chromatography and NMR

In this study we report the use of an automated iodometric titration method and a novel gas chromatography (GC) method for the quantitative analysis of dimethyl titanocene (DMT), a key raw material in drug synthesis. Both approaches are based on the reaction of DMT in toluene or tetrahydrofuran solutions with iodine. In the case of iodometric titration, excess iodine is titrated with a standardized aqueous sodium thiosulfate solution to a potentiometric end-point for the determination of DMT concentration. Alternatively, GC is employed to measure the concentration of iodomethane, a product of the reaction between DMT and iodine, in order to determine the concentration of DMT in the solution. Excellent agreement between iodometric titration, GC and NMR results using several DMT samples confirms the accuracy of the two methods and strongly supports the use of either method as a replacement to the expensive NMR for quantitative DMT analysis. The relatively few sources of error associated with the two methods, their ubiquitous nature and ease of application in routine analysis make them the analytical methods of choice, among all. Both methods have been validated according to ICH requirements. The use of iodometric titration method for DMT analysis is demonstrated with a couple of applications.

Improved Stability of Proline-Derived Direct Thrombin Inhibitors through Hydroxyl to Heterocycle Replacement

Modification of the previously disclosed (S)-N-(2-(aminomethyl)-5-chlorobenzyl)-1-((R)-2-hydroxy-3,3-dimethylbutanoyl)pyrrolidine-2-carboxamide 2 by optimization of the P3 group afforded novel, low molecular weight thrombin inhibitors. Heterocycle replacement of the hydroxyl functional group helped maintain thrombin in vitro potency while improving the chemical stability and pharmacokinetic profile. These modifications led to the identification of compound 10, which showed excellent selectivity over related serine proteases as well as in vivo efficacy in the rat arteriovenous shunt. Compound 10 exhibited significantly improved chemical stability and pharmacokinetic properties over 2 and may be utilized as a structurally differentiated preclinical tool comparator to dabigatran etexilate (Pro-1) to interrogate the on- and off-target effects of oral direct thrombin inhibitors.