The scarcity of precious metals has led to the development of sustainable strategies for metal-catalyzed cross-coupling reactions. The establishment of new catalytic methods using iron is attractive owing to the low cost, abundance, ready availability, and very low toxicity of iron. In the last few years, sustainable methods for iron-catalyzed cross-couplings have entered the critical area of pharmaceutical research. Most notably, iron is one of the very few metals that have been successfully field-tested as highly effective base-metal catalysts in practical, kilogram-scale industrial cross-couplings. In this Minireview, we critically discuss the strategic benefits of using iron catalysts as green and sustainable alternatives to precious metals in cross-coupling applications for the synthesis of pharmaceuticals. The Minireview provides an essential introduction to the fundamental aspects of practical iron catalysis, highlights areas for improvement, and identifies new fields to be explored.

Iron-Catalyzed Cross-Couplings in the Synthesis of Pharmaceuticals: In Pursuit of Sustainability.

This is the thirteenth installment of the comprehensive survey series in high throughput chemistry.1 Biologically active libraries reported in 2009 are captured in Tables 1–5 under the headings of proteases, nonproteolytic enzymes, GPCRs, nonGPCRs, and oncolytics/antiinfectives. Table 6 lists molecular probes. Compound collections without disclosed biological activity are delineated in Tables 7–10 under the headings of scaffold derivatization/acyclic synthesis, monocyclic-, bicyclic/spirocyclic-, and polycyclic/macrocyclic synthesis. Polymer-supported reagents/scavengers/linkers are presented in Tables 11 (nonfluorous) and Table 12 (fluorous). There are 370 libraries and 24 molecular probes extracted from 355 literature citations.2–491 Approximately 90% of the citations originated from academic laboratories, with the majority of these from European and Asian laboratories. Solution-phase methodology accounted for ca. 85% of chemical library synthesis.

/pdf/comprehensive-survey-of-chemical-libraries-for-drug-1nhxuuozxq.pdf

Comprehensive Survey of Chemical Libraries for Drug Discovery and Chemical Biology: 2009

Benzothiazepines are one such class of heterocyclic scaffolds with celebrated biological activities. The flooding of the pharmaceutical market with cardiovascular drugs like diltiazem, clentiazem and siratiazem bearing the benzothiazepine core confirms the biological importance of the core. This review presents a comprehensive vision of the various synthetic tactics adopted till now to afford benzothiazepine cores.

Benzothiazepines: chemistry of a privileged scaffold

Prospective therapeutic agents for obesity: molecular modification approaches of centrally and peripherally acting selective cannabinoid 1 receptor antagonists.

A convenient method for the synthesis of monodisperse, superparamagnetic copper ferrite (CuFe 2 O 4 ) nanoparticles with high surface area has been described. The synthesized material was characterized by various techniques. XRD showed the nanocrystalline nature of CuFe 2 O 4 with a crystallite size of 6 nm. TEM analysis showed that uniform spherical CuFe 2 O 4 particles are formed with a size of 55 ± 5 nm. N 2 adsorption/desorption measurements confirmed the mesoporous nature of the sample with surface area >216 m 2  g −1 . The field dependent magnetization, illustrated by VSM and saturation magnetization was found to be 44 emu g −1 . The catalytic applications of the synthesized CuFe 2 O 4 nanoparticles were explored for the cross-coupling of thiols with diverse range of aryl halides. Aryl iodides and bromides result in biarylsulfides in good to excellent yields (62–98%) whereas aryl chlorides gave significant amount of diaryldisulfide. Scope of this catalytic protocol further extended to one-pot synthesis of biologically important tricyclic dibenzothiazepines. The superparamagnetic nature of CuFe 2 O 4 nanoparticles was found to be advantageous for their easy, quick and quantitative separation from the reaction mixture. Negligible leaching of Cu and Fe in consecutive cycles makes the catalyst economical and environmentally benign.

https://www.tpbin.com/Uploads/Subjects/d9c988c2-c9f8-41ae-b477-d8371eec3778.pdf

Heterogeneous magnetic catalyst for S-arylation reactions

A novel class of CB1 inverse agonists was discovered. To efficiently establish structure-activity relationships (SARs), new synthetic methodologies amenable for parallel synthesis were developed. The compounds were evaluated in a mammalian cell-based functional assay and in radioligand binding assays expressing recombinant human cannabinoid receptors (CB1 and CB2). In general, all of the compounds exhibited high binding selectivity at CB1 vs CB2 and the general SAR revealed a lead compound 11-(4-chlorophenyl)dibenzo[b,f][1,4]thiazepine-8-carboxylic acid butylamide (12e) which showed excellent in vivo activity in pharmacodynamic models related to CB1 receptor activity. The low solubility that hampered the development of 12e was solved leading to a potential preclinical candidate 11-(3-chloro-4-fluorophenyl)dibenzo[b,f][1,4]thiazepine-8-carboxylic acid butylamide (12h).

Darren Craig

Papers

Synthesis and evaluation of dibenzothiazepines: a novel class of selective cannabinoid-1 receptor inverse agonists.