ABSTRACT
Charged intermediates and reagents are ubiquitous in organic transformations. The interaction of these ionic species with chiral neutral, anionic, or cationic small molecules has emerged as a powerful strategy for catalytic, enantioselective synthesis. This review describes developments in the burgeoning field of asymmetric ion-pairing catalysis with an emphasis on the insights that have been gleaned into the structural and mechanistic features that contribute to high asymmetric induction.
Subject(s)
Catalysis , Chemistry, Organic/methods , Ions/chemistry , Organic Chemicals/chemistry , Models, Molecular , Molecular Structure , Organic Chemistry Phenomena , StereoisomerismABSTRACT
The Rh(I)-catalyzed addition of alkenyl and aryl MIDA boronates to N-tert-butanesulfinyl aromatic and aliphatic imines proceeds in good yields (up to 99%) and with very high selectivity (98:2 to >99:1). In comparison to trifluoroborates, higher yields and selectivities are observed for the addition to N-tert-butanesulfinyl aromatic imines. This new method expands upon the versatility of the Rh(I)-catalyzed addition of boron reagents to imines, thereby further enabling the synthesis of chiral alpha-branched amines.
Subject(s)
Amines/chemical synthesis , Boronic Acids/chemistry , Butanes/chemistry , Imines/chemistry , Imino Acids/chemistry , Rhodium/chemistry , Sulfonium Compounds/chemistry , Borates/chemistryABSTRACT
The concise total synthesis of (-)-aurantioclavine has been achieved by taking advantage of strategies for the asymmetric alkenylation of N-tert-butanesulfinyl imines. The enantiomerically pure natural product was prepared in 6 steps and 27% overall yield by using Rh-catalyzed addition of a N-methyliminodiacetic acid (MIDA) boronate and in 5 steps and 29% yield by employing a Grignard reagent addition sequence.
Subject(s)
Ergot Alkaloids/chemical synthesis , StereoisomerismABSTRACT
A century after discovering that the Trypanosoma cruzi parasite is the etiological agent of Chagas disease, treatment is still plagued by limited efficacy, toxicity, and the emergence of drug resistance. The development of inhibitors of the major T. cruzi cysteine protease, cruzain, has been demonstrated to be a promising drug discovery avenue for this neglected disease. Here we establish that a nonpeptidic tetrafluorophenoxymethyl ketone cruzain inhibitor substantially ameliorates symptoms of acute Chagas disease in a mouse model with no apparent toxicity. A high-resolution crystal structure confirmed the mode of inhibition and revealed key binding interactions of this novel inhibitor class. Subsequent structure-guided optimization then resulted in inhibitor analogues with improvements in potency despite minimal or no additions in molecular weight. Evaluation of the analogues in cell culture showed enhanced activity. These results suggest that nonpeptidic tetrafluorophenoxymethyl ketone cruzain inhibitors have the potential to fulfill the urgent need for improved Chagas disease chemotherapy.
Subject(s)
Chagas Disease/drug therapy , Ketones/chemical synthesis , Protozoan Proteins/antagonists & inhibitors , Trypanocidal Agents/chemical synthesis , Animals , Cattle , Cells, Cultured , Cysteine Endopeptidases , Female , Ketones/chemistry , Ketones/pharmacology , Macrophages/drug effects , Macrophages/parasitology , Mice , Mice, Inbred C3H , Models, Molecular , Parasitic Sensitivity Tests , Quinolines/chemical synthesis , Quinolines/chemistry , Quinolines/pharmacology , Stereoisomerism , Structure-Activity Relationship , Triazoles/chemical synthesis , Triazoles/chemistry , Triazoles/pharmacology , Trypanocidal Agents/chemistry , Trypanocidal Agents/pharmacology , Trypanosoma cruzi/drug effectsABSTRACT
The one-pot preparation of N-sulfinylamine diastereomers proceeds in excellent yields (84-98%) for a diverse set of N-sulfinyl imine addition products. The method is operationally simple and extractive isolation provides analytically pure mixtures of diastereomers as standards for the rapid and accurate determination of N-sulfinylamine diastereomeric purity.
Subject(s)
Amines/chemical synthesis , Butanes/chemical synthesis , Sulfonium Compounds/chemical synthesis , Amines/chemistry , Butanes/chemistry , Stereoisomerism , Substrate Specificity , Sulfonium Compounds/chemistryABSTRACT
The first Rh(I)-catalyzed addition of alkenylboron reagents to imines is described. The Rh(I)-catalyzed addition of potassium alkenyltrifluoroborate salts to both aromatic and aliphatic N-tert-butanesulfinyl aldimines proceeds in good yields (up to 97%) and with very high diastereoselectivities (95:5 to >99:1). This new method enables the general and efficient asymmetric synthesis of the important class of alpha-branched allylic amines from readily available and stable starting materials.
Subject(s)
Amines/chemical synthesis , Borates , Catalysis , Imines , RhodiumABSTRACT
Cruzain is the major cysteine protease of Trypanosoma cruzi, which is the causative agent of Chagas disease and is a promising target for the development of new chemotherapy. With the goal of developing potent nonpeptidic inhibitors of cruzain, the substrate activity screening (SAS) method was used to screen a library of protease substrates initially designed to target the homologous human protease cathepsin S. Structure-based design was next used to further improve substrate cleavage efficiency by introducing additional binding interactions in the S3 pocket of cruzain. The optimized substrates were then converted to inhibitors by the introduction of cysteine protease mechanism-based pharmacophores. Inhibitor 38 was determined to be reversible even though it incorporated the vinyl sulfone pharmacophore that is well documented to give irreversible cruzain inhibition for peptidic inhibitors. The previously unexplored beta-chloro vinyl sulfone pharmacophore provided mechanistic insight that led to the development of potent irreversible acyl- and aryl-oxymethyl ketone cruzain inhibitors. For these inhibitors, potency did not solely depend on leaving group p K a, with 2,3,5,6-tetrafluorophenoxymethyl ketone 54 identified as one of the most potent inhibitors with a second-order inactivation constant of 147,000 s (-1) M (-1). This inhibitor completely eradicated the T. cruzi parasite from mammalian cell cultures and consequently has the potential to lead to new chemotherapeutics for Chagas disease.
Subject(s)
Cysteine Proteinase Inhibitors/chemistry , Cysteine Proteinase Inhibitors/pharmacology , Ketones/chemistry , Ketones/pharmacology , Protozoan Proteins/antagonists & inhibitors , Amino Acid Sequence , Animals , Cathepsins/chemistry , Cathepsins/metabolism , Cathepsins/pharmacology , Coumarins/chemistry , Coumarins/metabolism , Cysteine Endopeptidases/chemistry , Cysteine Endopeptidases/metabolism , Cysteine Proteinase Inhibitors/metabolism , Drug Design , Ketones/metabolism , Macrophages/parasitology , Mice , Molecular Sequence Data , Protozoan Proteins/chemistry , Protozoan Proteins/metabolism , Sequence Alignment , Structure-Activity Relationship , Sulfones/chemistry , Sulfones/metabolism , Sulfones/pharmacology , Triazoles , Trypanosoma cruzi/drug effects , Trypanosoma cruzi/enzymologyABSTRACT
In the schedule-induced polydipsia model, hungry rats receiving a food pellet every minute will display excessive drinking behaviour (compulsive behaviour). We aimed 1) to evaluate if electrical stimulation in the nucleus accumbens (N ACC), the mediodorsal thalamic nucleus (MD) or the bed nucleus of the stria terminalis (BST) can decrease water intake in the schedule-induced polydipsia model; 2) to compare water intake between these groups for different stimulation amplitudes; and 3) to compare the effect of low frequency (2 Hz) with high frequency (100 Hz) stimulation. Rats were randomly divided into four groups: electrode implanted in the 1) N ACC (n=7), 2) MD (n=8), 3) BST (n=8), or 4) a sham-operated control group (n=7). Postoperatively, each rat of group 1, 2 and 3 was randomly tested in the model using pulses with a frequency of 2 Hz and 100 Hz, each at an amplitude of 0.1, 0.2, 0.3, 0.4 and 0.5 mA, or without stimulation. Group 4 was tested 11 times without stimulation. Each day the rats were tested in random order. High-frequency electrical stimulation in all three brain areas decreased water intake significantly at an amplitude of 0.2 mA or higher, however, without differences between the brain areas. Based on these results, we expect a decrease in compulsions in patients suffering from treatment-resistant obsessive-compulsive disorder during electrical stimulation in the N ACC, the MD and the BST. However, we foresee no difference in energy consumption to decrease symptoms during electrical stimulation between these brain areas.
