Easy-To-Synthesize Spirocyclic Compounds Possess Remarkable in Vivo Activity against Mycobacterium tuberculosis.

Society urgently needs new, effective medicines for the treatment of tuberculosis. To kick-start the required hit-to-lead campaigns, the libraries of pharmaceutical companies have recently been evaluated for starting points. The GlaxoSmithKline (GSK) library yielded many high-quality hits, and the associated data were placed in the public domain to stimulate engagement by the wider community. One such series, the spiro compounds, are described here. The compounds were explored by a combination of traditional in-house research and open source methods. The series benefits from a particularly simple structure and a short associated synthetic chemistry route. Many members of the series displayed striking potency and low toxicity, and highly promising in vivo activity in a mouse model was confirmed with one of the analogues. Ultimately the series was discontinued due to concerns over safety, but the associated data remain public domain, empowering others to resume the series if the perceived deficiencies can be overcome.

Stereocontrolled approach to phenyl cyclitols from (SR)-[(p-tolylsulfinyl)methyl]-p-quinol.

Reactions of enantiopure (SR)-[(p-tolylsulfinyl)methyl]-p-quinol with ArAlMe(2) reagents allowed a highly diastereoselective 1,4-addition of the aryl group with an efficient desymmetrization of the prochiral cyclohexadienone moiety. The asymmetric synthesis of phenyl-substituted polyoxygenated cyclohexane derivatives was achieved by combining this reaction with a stereoselective reduction and elimination of the beta-hydroxysulfoxide, after oxidation to sulfone, to recover a carbonyl group, and a stereoselective epoxidation.

Facile synthesis of highly functionalized ethyltrifluoroborates.

Organotrifluoroborates are generating increased interest because of their ease of preparation and purification and indefinite shelf life. Herein we report the preparation of organotrifluoroborates bearing functional groups that can be manipulated at different stages of the synthetic route, exploiting the inertness of their carbon-boron bonds. The alkylation of 2,2-dicyanoethyltrifluoroborate with a variety of electrophiles and of (EWG)2CH2 with potassium iodomethyltrifluoroborate resulted in di- and trisubstituted ethyltrifluoroborates in good to excellent yields.

Synthesis of 4-aminotropones from [(sulfinyl or sulfonyl)methyl]-substituted p-quinamines.

An efficient synthesis of 4-aminotropones has been achieved in excellent yields by simple treatment of 4-amino-4-[(p-tolylsulfinyl)methyl]-2,5-cyclohexadienones (p-quinamines) with NaH. The method allowed regiocontrolled access to 3-methyl, 5-methyl- and 3,5-dimethyl-substituted derivatives starting from p-quinamines with adequate substituents at the cyclohexadienone moiety and/or at the carbon linked to the sulfur function. The p-quinamines in turn were easily accessible from N-Boc p-anisidines (Boc=tert-butoxycarbonyl) by electrochemical oxidation in MeOH to quinone imine monoketals, followed by addition of a alpha-lithium sulfinyl carbanion to the imino group, and ketal hydrolysis. Oxidation of the sulfoxide gave the sulfonyl-substituted p-quinamines that, upon basic treatment, behave similarly. The p-quinamine 55 and bis-p-quinamine 56, resulting in the addition of the anion derived from dimethyl sulfone to the p-quinonimine ketal 14, also gave the 4-aminotropone. The mechanism involves the initial formation of a alpha-sulfonyl carbanion, which intramolecularly attacks the cyclohexadienone giving a norcaradiene-like enolate intermediate, the evolution of which through a ring-expansion process, pushes off a methyl sulfinate anion or SO2. This efficient process fulfils the criteria of atom economy. The introduction of a proline substituent in the nitrogen of the starting p-quinamine allowed the synthesis of an enantiopure 4-aminotropone, the asymmetric Diels-Alder reactions of which with maleimide occurred in a highly endo and pi-facial diastereoselective manner.