Nisha Mittal

A Dual-Catalysis Approach to the Asymmetric Steglich Rearrangement and Catalytic Enantioselective Addition of O-Acylated Azlactones to Isoquinolines

A dual-catalysis approach, namely the combination of an achiral nucleophilic catalyst and a chiral anion-binding catalyst, was applied to the Steglich rearrangement to provide α,α-disubstituted amino acid derivatives in a highly enantioselective fashion. Replacement of the nucleophilic co-catalyst for isoquinoline resulted in a divergent reaction pathway and an unprecedented transformation of O-acylated azlactones. This strategy provided highly substituted α,β-diamino acid derivatives with excellent levels of stereocontrol.

A Dual-Catalysis/Anion-Binding Approach to the Kinetic Resolution of Allylic Amines

A dual-catalysis approach enables the small-molecule catalyzed kinetic resolution of allylic amines by acylation. By employing 2 mol % of each 4-(pyrrolidino)pyridine (PPY) and a readily available chiral hydrogen-bonding cocatalyst, the first nonenzymatic kinetic resolution of allylic amines was accomplished with s factors of up to 20.

A Dual-Catalysis Anion-Binding Approach to the Kinetic Resolution of Amines: Insights into the Mechanism via a Combined Experimental and Computational Study.

Racemic benzylic amines undergo kinetic resolution via benzoylation with benzoic anhydride in the presence of a dual catalyst system consisting of a readily available amide-thiourea catalyst and 4-dimethylaminopyridine (DMAP). An evaluation of various experimental parameters was performed in order to derive a more detailed understanding of what renders this process selective. The catalysts aggregation behavior and anion-binding ability were evaluated in regard to their relevance for the catalytic process. Alternate scenarios, such as catalyst deprotonation or the in situ formation of a neutral chiral acylating reagent were ruled out. Detailed computational studies at the M06/6-31G(d,p) level of theory including solvent modeling utilizing a polarized continuum model provide additional insights into the nature of the ion pair and reveal a range of important secondary interactions that are responsible for efficient enantiodiscrimination.

Conjugate-base-stabilized Brønsted acids: catalytic enantioselective Pictet-Spengler reactions with unmodified tryptamine.

A conjugate-base-stabilized Brønsted acid facilitates catalytic enantioselective Pictet-Spengler reactions with unmodified tryptamine. The chiral carboxylic acid catalyst is readily assembled in just two steps and enables the formation of β-carbolines with up to 92% ee. Achiral acid additives or in situ Boc-protection facilitate catalyst turnover.

Conjugate‐Base‐Stabilized Brønsted Acids as Asymmetric Catalysts: Enantioselective Povarov Reactions with Secondary Aromatic Amines

Triggered largely by the seminal studies of Akiyama et al. and Uraguchi and Terada nearly a decade ago, the field of asymmetric Brønsted acid catalysis has experienced rapid growth. Chiral phosphoric acids in particular have enabled an ever increasing number of asymmetric transformations. In a continuing trend, catalysts that surpass the acidity of phosphoric acids are being prepared for the purpose of activating moderately basic substrates through asymmetric ion-pairing catalysis. Cooperative approaches in which a Brønsted acid acts in concert with either another Brønsted acid or with a (thio)urea catalyst have emerged and hold exceptional promise. Intriguing applications of asymmetric cooperative Brønsted acid catalysis have been reported by Jacobsen and co-workers who have demonstrated that a combination of achiral Brønsted acids and chiral (thio)urea catalysts can enable a range of enantioselective transformations. The main role of the (thio)urea catalyst is to act as a chiral anion receptor for the Brønsted acid s conjugate base. 10] Herein we introduce a complementary concept for asymmetric Brønsted acid catalysis which merges certain features of previous approaches while perhaps offering some unique advantages. As illustrated in Figure 1, we envisioned a new type of chiral Brønsted acid in which the acidic site of the catalyst is connected by an appropriate linker to an anion receptor moiety such as a thiourea. Upon substrate protonation, the conjugate base associates with the anion recognition site, thus resulting in the formation of a substrate/catalyst ion pair of type I. Alternatively, the catalyst could facilitate the condensation of two different substrates to result in an ion pair of type II. While the anion may still interact with the substrate through hydrogen bonding in the type I ion pair, hydrogen bonding between the ions should be reduced markedly in the type II ion pair, thus resulting in strict ion pairing. Importantly, both types of ion pairs feature a rigid anion which should facilitate an efficient transfer of chirality. While a range of acidic groups, XH, may be linked to an anion recognition site, we were particularly intrigued by the idea of using simple carboxylic acids. Although there are notable exceptions, in particular the prominent work of the Maruoka group, chiral carboxylic acids have not yet found widespread applications as asymmetric Brønsted acid catalysts. This is likely because carboxylic acids are ultimately limited by their relatively weak acidities, thus restricting the number of substrates which can be activated. The propensity of carboxylate to engage in hydrogen bonding with a protonated substrate also reduces the potential level of substrate activation, as this interaction lowers the electrophilicity of the protonated species. Internal stabilization of the conjugate base (e.g., carboxylate) should circumvent both of these problems. Firstly, anion binding to the conjugate base is expected to lower the pKa value of the acid, thus allowing an increase in acidity beyond what can typically be achieved for carboxylic acids. Secondly, internal anion binding reduces the ability of the carboxylate anion to participate in additional hydrogen-bonding interactions with the activated cationic substrate, thus increasing the electrophilicity of the latter. In addition, covalent attachment of the acidic site to the chiral acceptor as opposed to a dual catalysis approach addresses the potential issue of background reactivity caused by the achiral acid. A number of chiral catalysts containing a carboxylic acid connected to an anion recognition site were readily assembled in as little as two steps (Figure 2). We decided to test these catalysts in a challenging Povarov reaction with indoline as Figure 1. Internal anion-binding concept for asymmetric Brønsted acid/chiral anion catalysis.

Kinetic Resolution of Amines via Dual Catalysis: Remarkable Dependence of Selectivity on the Achiral Cocatalyst

A dual-catalysis/anion-binding approach with a chiral hydrogen bonding (HB) catalyst and an achiral nucleophilic cocatalyst was applied to the kinetic resolution of amines. Out of a structurally diverse collection of 22 nucleophilic species, 4-di-n-propylaminopyridine emerged as the most efficient cocatalyst, allowing for the kinetic resolution of benzylic amines with s-factors of up to 67.

A Novel Small-Molecule Inhibitor of the Mycobacterium tuberculosis Demethylmenaquinone Methyltransferase MenG Is Bactericidal to Both Growing and Nutritionally Deprived Persister Cells

ABSTRACT Active tuberculosis (TB) and latent Mycobacterium tuberculosis infection both require lengthy treatments to achieve durable cures. This problem has partly been attributable to the existence of nonreplicating M. tuberculosis “persisters” that are difficult to kill using conventional anti-TB treatments. Compounds that target the respiratory pathway have the potential to kill both replicating and persistent M. tuberculosis and shorten TB treatment, as this pathway is essential in both metabolic states. We developed a novel respiratory pathway-specific whole-cell screen to identify new respiration inhibitors. This screen identified the biphenyl amide GSK1733953A (DG70) as a likely respiration inhibitor. DG70 inhibited both clinical drug-susceptible and drug-resistant M. tuberculosis strains. Whole-genome sequencing of DG70-resistant colonies identified mutations in menG (rv0558), which is responsible for the final step in menaquinone biosynthesis and required for respiration. Overexpression of menG from wild-type and DG70-resistant isolates increased the DG70 MIC by 4× and 8× to 30×, respectively. Radiolabeling and high-resolution mass spectrometry studies confirmed that DG70 inhibited the final step in menaquinone biosynthesis. DG70 also inhibited oxygen utilization and ATP biosynthesis, which was reversed by external menaquinone supplementation. DG70 was bactericidal in actively replicating cultures and in a nutritionally deprived persistence model. DG70 was synergistic with the first-line TB drugs isoniazid, rifampin, and the respiratory inhibitor bedaquiline. The combination of DG70 and isoniazid completely sterilized cultures in the persistence model by day 10. These results suggest that MenG is a good therapeutic target and that compounds targeting MenG along with standard TB therapy have the potential to shorten TB treatment duration. IMPORTANCE This study shows that MenG, which is responsible for the last enzymatic step in menaquinone biosynthesis, may be a good drug target for improving TB treatments. We describe the first small-molecule inhibitor (DG70) of Mycobacterium tuberculosis MenG and show that DG70 has characteristics that are highly desirable for a new antitubercular agent, including bactericidality against both actively growing and nonreplicating mycobacteria and synergy with several first-line drugs that are currently used to treat TB. IMPORTANCE This study shows that MenG, which is responsible for the last enzymatic step in menaquinone biosynthesis, may be a good drug target for improving TB treatments. We describe the first small-molecule inhibitor (DG70) of Mycobacterium tuberculosis MenG and show that DG70 has characteristics that are highly desirable for a new antitubercular agent, including bactericidality against both actively growing and nonreplicating mycobacteria and synergy with several first-line drugs that are currently used to treat TB.

Combining Metabolite-Based Pharmacophores with Bayesian Machine Learning Models for Mycobacterium tuberculosis Drug Discovery

Integrated computational approaches for Mycobacterium tuberculosis (Mtb) are useful to identify new molecules that could lead to future tuberculosis (TB) drugs. Our approach uses information derived from the TBCyc pathway and genome database, the Collaborative Drug Discovery TB database combined with 3D pharmacophores and dual event Bayesian models of whole-cell activity and lack of cytotoxicity. We have prioritized a large number of molecules that may act as mimics of substrates and metabolites in the TB metabolome. We computationally searched over 200,000 commercial molecules using 66 pharmacophores based on substrates and metabolites from Mtb and further filtering with Bayesian models. We ultimately tested 110 compounds in vitro that resulted in two compounds of interest, BAS 04912643 and BAS 00623753 (MIC of 2.5 and 5 μg/mL, respectively). These molecules were used as a starting point for hit-to-lead optimization. The most promising class proved to be the quinoxaline di-N-oxides, evidenced by transcriptional profiling to induce mRNA level perturbations most closely resembling known protonophores. One of these, SRI58 exhibited an MIC = 1.25 μg/mL versus Mtb and a CC50 in Vero cells of >40 μg/mL, while featuring fair Caco-2 A-B permeability (2.3 x 10−6 cm/s), kinetic solubility (125 μM at pH 7.4 in PBS) and mouse metabolic stability (63.6% remaining after 1 h incubation with mouse liver microsomes). Despite demonstration of how a combined bioinformatics/cheminformatics approach afforded a small molecule with promising in vitro profiles, we found that SRI58 did not exhibit quantifiable blood levels in mice.

Chiral bisoxazoline ligands designed to stabilize bimetallic complexes

Chiral bisoxazoline ligands containing naphthyridine, pyridazine, pyrazole, and phenol bridging units were prepared and shown to form bimetallic complexes with various metal salts. X-ray crystal structures of bis-nickel naphthyridine-bridged, bis-zinc pyridazine-bridged, and bis-nickel as well as bis-palladium pyrazole-bridged complexes were obtained.