Mechanochemical Nucleophilic Substitution of Alcohols via Isouronium Intermediates.

An expansion of the solvent-free synthetic toolbox is essential for advances in the sustainable chemical industry. Mechanochemical reactions offer a superior safety profile and reduced amount of waste compared to conventional solvent-based synthesis. Herein a new mechanochemical method was developed for nucleophilic substitution of alcohols using fluoro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TFFH) and K2 HPO4 as an alcohol-activating reagent and a base, respectively. Alcohol activation and reaction with a nucleophile were performed in one milling jar via reactive isouronium intermediates. Nucleophilic substitution with amines afforded alkylated amines in 31-91 % yields. The complete stereoinversion occurred for the SN 2 reaction of (R)- and (S)-ethyl lactates. Substitution with halide anions (F- , Br- , I- ) and oxygen-centered (CH3 OH, PhO- ) nucleophiles was also tested. Application of the method to the synthesis of active pharmaceutical ingredients has been demonstrated.

New azole derivatives of [17(20)E]-21-norpregnene: Synthesis and inhibition of prostate carcinoma cell growth.

A number of isoxazole, 1,2,3-triazole, tetrazole, and 1,2,4-oxadiazole derivatives of [17(20)E]-21-norpregnene comprising 3ß-hydroxy-5-ene and 3-oxo-4-ene fragments were prepared. Among the key steps for the synthesis of isoxazoles, 1,2,3-triazoles, and tetrazoles were (i) 1,3-dipolar cycloaddition of nitrile oxides or azides to acetylenes or nitriles and ii) dehydration of 17ß-hydroxy-17α-methylene-azoles to [17(20)E]-21-norpregnene derivatives. 1,2,4-Oxadiazoles were prepared through the formation of acetimidamides. Potency of the synthesized compounds to inhibit CYP17A1 and to suppress growth of prostate carcinoma cells was investigated. Among the new azole derivatives, four compounds were found possessing high anti-proliferative activity.

Synthesis of ergostane-type brassinosteroids with modifications in ring A.

Herein, we present a new strategy for the preparation of a broad range of brassinosteroid biosynthetic precursors/metabolites differing by the ring A fragment. The protocol is based on the use of readily available phytohormones of this class bearing a 2α,3α-diol moiety (epibrassinolide or epicastasterone) as starting materials. The required functionalities (Δ2-, 2α,3α- and 2ß,3ß-epoxy-, 2α,3ß-, 2ß,3α-, and 2ß,3ß-dihydroxy-, 3-keto-, 3α- and 3ß-hydroxy-, 2α-hydroxy-3-keto-) were synthesized from 2α,3α-diols in a few simple steps (Corey-Winter reaction, epoxidation, oxidation, hydride reduction, etc.).

C-H Acetoxylation-Based Chemical Synthesis of 17 ß-Hydroxymethyl-17 α-methyl-18-norandrost-13-ene Steroids.

Palladium-catalyzed C-H acetoxylation has been proposed as a key transformation in the first chemical synthesis of steroids bearing a unique 17ß-hydroxymethyl-17α-methyl-18-nor-13-ene D-fragment. This C-H functionalization step was crucial for inverting the configuration at the quaternary stereocenter of a readily available synthetic intermediate. The developed approach was applied to prepare the metandienone metabolite needed as a reference substance in anti-doping analysis to control the abuse of this androgenic anabolic steroid.