RESUMEN
An enantioselective isothiourea-catalysed [2 + 2] cycloaddition of C(1)-ammonium enolates with pyrazol-4,5-diones is used to construct spirocyclic ß-lactones in good yields, excellent enantioselectivity (99 : 1 er) but with modest diastereocontrol (typically 70 : 30 dr). Upon ring-opening with morpholine or alternative nucleophilic amines and alcohols ß-hydroxyamide and ß-hydroxyester products are generated with enhanced diastereocontrol (up to >95 : 5 dr). Control experiments show that stereoconvergence is observed in the ring-opening of diastereoisomeric ß-lactones, leading to a single product (>95 : 5 dr, >99 : 1 er). Mechanistic studies and DFT analysis indicate a substrate controlled Dynamic Kinetic Asymmetric Transformation (DyKAT) involving epimerisation at C(3) of the ß-lactone under the reaction conditions, coupled with a hydrogen bond-assisted nucleophilic addition to the Si-face of the ß-lactone and stereodetermining ring-opening. The scope and limitations of a one-pot protocol consisting of isothiourea-catalysed enantio-determining [2 + 2] cycloaddition followed by diastereo-determining ring-opening are subsequently developed. Variation within the anhydride ammonium enolate precursor, as well as N(1) and C(3) within the pyrazol-4,5-dione scaffold is demonstrated, giving a range of functionalised ß-hydroxyamides with high diastereo- and enantiocontrol (>20 examples, up to >95 : 5 dr and >99 : 1 er) via this DyKAT.
RESUMEN
Enantioselective [2 + 2] cycloaddition of C(1)-ammonium enolates generated catalytically using the isothiourea HyperBTM with N-alkyl isatins gives spirocyclic ß-lactones. In situ ring opening with an amine nucleophile generates isolable highly enantioenriched products in up to 92:8 dr and in >99:1 er.
Asunto(s)
Compuestos de Amonio , Isatina , Ácidos Carboxílicos , Catálisis , Reacción de Cicloadición , Estructura Molecular , Estereoisomerismo , TioureaRESUMEN
The widespread adoption of earth-abundant metal catalysis lags behind that of the second- and third-row transition metals due to the often challenging practical requirements needed to generate the active low oxidation-state catalysts. Here we report the development of a single endogenous activation protocol across five reaction classes using both iron- and cobalt pre-catalysts. This simple catalytic manifold uses commercially available, bench-stable iron- or cobalt tetrafluoroborate salts to perform regiodivergent alkene and alkyne hydrosilylation, 1,3-diene hydrosilylation, hydrogenation, [2π + 2π]-cycloaddition and C-H borylation. The activation protocol proceeds by fluoride dissociation from the counterion, in situ formation of a hydridic activator and generation of a low oxidation-state catalyst.
RESUMEN
Trypanosomatid parasites are the infectious agents causing Chagas disease, visceral and cutaneous leishmaniasis and human African trypanosomiasis. Recent work of others has implicated an aldo-keto reductase (AKR) in the susceptibility and resistance of Trypanosoma cruzi to benznidazole, a drug used to treat Chagas disease. Here, we show that TcAKR and homologues in the related parasites Trypanosoma brucei and Leishmania donovani do not reductively activate monocyclic (benznidazole, nifurtimox and fexinidazole) or bicyclic nitro-drugs such as PA-824. Rather, these enzymes metabolise a variety of toxic ketoaldehydes, such as glyoxal and methylglyoxal, suggesting a role in cellular defence against chemical stress. UPLC-QToF/MS analysis of benznidazole bioactivation by T. cruzi cell lysates confirms previous reports identifying numerous drug metabolites, including a dihydro-dihydroxy intermediate that can dissociate to form N-benzyl-2-guanidinoacetamide and glyoxal, a toxic DNA-glycating and cross-linking agent. Thus, we propose that TcAKR contributes to benznidazole resistance by the removal of toxic glyoxal. In addition, three of the four enzymes studied here display activity as prostaglandin F2α synthases, despite the fact that there are no credible cyclooxygenases in these parasites to account for formation of the precursor PGH2 from arachidonic acid. Our studies suggest that arachidonic acid is first converted non-enzymatically in parasite lysates to (PGH2-like) regioisomers by free radical-mediated peroxidation and that AKRs convert these lipid peroxides into isoprostanes, including prostaglandin F2α and 8-iso-prostaglandin F2α.