ABSTRACT
The field of medicinal chemistry is currently witnessing a deuterium rush owing to the remarkable properties of this element as bioisoster of hydrogen atom. Aromatic hydrogen isotope exchange (HIE) is one of the most studied strategies nowadays as it promises to access deuterium-modified drugs directly from their non-labeled parents. While most of the recent studies focus on metal-catalyzed C-H activation strategy, the use of superacidic conditions has been largely overlooked. This study shows that the use of TfOD as reaction medium allows the late-stage polydeuteration of a broad library of pharmaceuticals bearing a wide array of functional groups, complementing existing procedures.
Subject(s)
Hydrogen , Deuterium/chemistry , Hydrogen/chemistry , Pharmaceutical PreparationsABSTRACT
Site-selective functionalization of arenes that is complementary to classical aromatic substitution reactions remains a long-standing quest in organic synthesis. Exploiting the generation of halenium ion through oxidative process and the protonation of the nitrogen containing function in HF/SbF5 , the chlorination and iodination of classically inert Csp2 -H bonds of aromatic amines occurs. Furthermore, the superacid-promoted (poly)protonation of the molecules acts as a protection, favoring the late-stage selective halogenation of natural alkaloids and active pharmaceutical ingredients.
ABSTRACT
Upon activation under superacid conditions, functionalized tailor-made N-SCF3 sulfenamides served as reagents for the trifluoromethylthiolation of aromatic amines. This method has a broad substrate scope and can be used for the late-stage functionalization of complex molecules such as alkaloids or steroids. Mechanistic studies based on in situ low-temperature NMR spectroscopy revealed the involvement of dicationic superelectrophilic intermediates.
ABSTRACT
A series of substituted pyrrolidines and piperidines were synthesized using superacid HF/SbF5 chemistry. Investigated as inhibitors of several human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, i.e. the cytosolic hCA I and II as well as the tumor-associated transmembrane isoforms hCA IX and XII, these compounds showed a never yet reported selectivity toward the human carbonic anhydrase hCA II. In the tertiary benzenesulfonamide family, this class of inhibitors points out a new mechanism of action for human carbonic anhydrase II inhibition.
Subject(s)
Carbonic Anhydrase II/antagonists & inhibitors , Carbonic Anhydrase Inhibitors/pharmacology , Piperidines/pharmacology , Pyrrolidines/pharmacology , Sulfonamides/pharmacology , Carbonic Anhydrase II/metabolism , Carbonic Anhydrase Inhibitors/chemical synthesis , Carbonic Anhydrase Inhibitors/chemistry , Dose-Response Relationship, Drug , Humans , Molecular Structure , Piperidines/chemistry , Pyrrolidines/chemistry , Structure-Activity Relationship , Sulfonamides/chemistry , BenzenesulfonamidesABSTRACT
[reaction: see text]. (-)-PF1163B, a new macrocyclic antifungal antibiotic isolated from Streptomyces sp., has been prepared in eight steps from (S)-citronellene. The key step is a ring-closing metathesis reaction of an ester and amide derivative obtained from a substituted N-methyl-l-tyrosine.
