One-Pot Syntheses of Substituted Oxazoles and Imidazoles from the Isocyanide Asmic.

Substituted oxazoles and imidazoles are synthesized in one pot from the isocyanide building block Asmic (anisylsulfanylmethyl isocyanide), an alkyl halide, and an acid chloride or nitrile, respectively. The modular assembly employs sequential deprotonation-alkylation and deprotonation-acylation or imination of Asmic, followed by an unusual carbon-sulfur bond cleavage to construct the azole. The strategy is robust, highly efficient, and affords C4-C5 disubstituted oxazoles or imidazoles in a single operation.

One-step synthesis of imidazoles from Asmic (anisylsulfanylmethyl isocyanide).

Substituted imidazoles are readily prepared by condensing the versatile isocyanide Asmic, anisylsulfanylmethylisocyanide, with nitrogenous π-electrophiles. Deprotonating Asmic with lithium hexamethyldisilazide effectively generates a potent nucleophile that efficiently intercepts nitrile and imine electrophiles to afford imidazoles. In situ cyclization to the imidazole is promoted by the conjugate acid, hexamethyldisilazane, which facilitates the requisite series of proton transfers. The rapid formation of imidazoles and the interchange of the anisylsulfanyl for hydrogen with Raney nickel make the method a valuable route to mono- and disubstituted imidazoles.

Empirical Analysis of Drug Targets for Nervous System Disorders.

The discovery and development of drugs to treat diseases of the nervous system remains challenging. There is a higher attrition rate in the clinical stage for nervous system experimental drugs compared to other disease areas. In the preclinical stage, additional challenges arise from the considerable effort required to find molecules that penetrate the blood-brain barrier (BBB) coupled with the poor predictive value of many preclinical models of nervous system diseases. In the era of target-based drug discovery, the critical first step of drug discovery projects is the selection of a therapeutic target which is largely driven by its presumed pathogenic involvement. For nervous system diseases, however, the feasibility of identifying potent molecules within the stringent range of molecular properties necessary for BBB penetration should represent another important factor in target selection. To address the latter, the present review analyzes the distribution of human protein targets of FDA-approved drugs for nervous system disorders and compares it with drugs for other disease areas. We observed a substantial difference in the distribution of therapeutic targets across the two clusters. We expanded on this finding by analyzing the physicochemical properties of nervous and non-nervous system drugs in each target class by using the central nervous system multiparameter optimization (CNS MPO) algorithm. These data may serve as useful guidance in making more informed decisions when selecting therapeutic targets for nervous system disorders.

Neutral sphingomyelinase 2 inhibitors based on the pyrazolo[1,5-a]pyrimidin-3-amine scaffold.

Neutral sphingomyelinase 2 (nSMase2) has gained increasing attention as a therapeutic target to regulate ceramide production in various disease conditions. Phenyl (R)-(1-(3-(3,4-dimethoxyphenyl)-2,6-dimethylimidazo[1,2-b]pyridazin-8-yl)-pyrrolidin-3-yl)carbamate (PDDC) is a submicromolar nSMase2 inhibitor and has been widely used to study the pharmacological effects of nSMase2 inhibition. Through screening of compounds containing a bicyclic 5-6 fused ring, larotrectinib containing a pyrazolo[1,5-a]pyrimidine ring was identified as a low micromolar inhibitor of nSMase2. This prompted us to investigate the pyrazolo[1,5-a]pyrimidin-3-amine ring as a novel scaffold to replace the imidazo[1,2-b]pyridazine-8-amine ring of PDDC. A series of molecules containing a pyrazolo[1,5-a]pyrimidin-3-amine ring were synthesized and tested for their ability to inhibit human nSMase2. Several compounds exhibited nSMase2 inhibitory potency superior to that of PDDC. Among these, N,N-dimethyl-5-morpholinopyrazolo[1,5-a]pyrimidin-3-amine (11j) was found to be metabolically stable in liver microsomes and orally available with a favorable brain-to-plasma ratio, demonstrating the potential of pyrazolo[1,5-a]pyrimidine ring as an effective scaffold for nSMase2 inhibition.

Oxazole Synthesis by Sequential Asmic-Ester Condensations and Sulfanyl-Lithium Exchange-Trapping.

Oxazoles are rapidly assembled through a sequential deprotonation-condensation of Asmic, anisylsulfanylmethylisocyanide, with esters followed by sulfanyl-lithium exchange-trapping. Deprotonating Asmic affords a metalated isocyanide that efficiently traps esters to afford oxazoles bearing a versatile C-4 anisylsulfanyl substituent. Interchange of the anisylsulfanyl substituent is readily achieved through a first-in-class sulfur-lithium exchange-electrophilic trapping sequence whose versatility is illustrated in the three-step synthesis of the bioactive natural product streptochlorin.

Access to Highly Functionalized Cyclopentenones via Diastereoselective Pauson-Khand Reaction of Siloxy-Tethered 1,7-Enynes.

A diastereoselective Co2(CO)8-mediated Pauson-Khand reaction (PKR) of siloxy-tethered 1,7-enynes for the synthesis of cyclopentaoxasilinones has been developed. This transformation can be performed on a multigram scale and is characterized by a broad substrate scope, functional group compatibility, and high chemo- and diastereoselectivity. Oxidation of the resulting cyclopentaoxasilinones delivers stereoenriched ß-alkylated cyclopentenones, which are inaccessible by intermolecular PKRs. This research provides a practical solution to the challenges associated with the classical intermolecular PKR.