Tubulin modulating antifungal and antiproliferative pyrazinone derivatives.

A novel class of synthetic tubulin polymerization disruptors, based on a substituted pyrazin-2-one core, has been discovered. These molecules have proven to be potent broad spectrum fungicides, with activity on agriculturally important ascomycete and basidiomycete pathogens. They have also been found to be particularly potent against human rhabdomyosarcoma cells.

NMR-spectroscopic screening of spider venom reveals sulfated nucleosides as major components for the brown recluse and related species.

Extensive chemical analyses of spider venoms from many species have revealed complex mixtures of biologically active compounds, of which several have provided important leads for drug development. We have recently shown that NMR spectroscopy can be used advantageously for a direct structural characterization of the small-molecule content of such complex mixtures. Here, we report the application of this strategy to a larger-scale analysis of a collection of spider venoms representing >70 species, which, in combination with mass spectrometric analyses, allowed the identification of a wide range of known, and several previously undescribed, small molecules.

Scalable methodology for the catalytic, asymmetric alpha-bromination of acid chlorides.

The optimization of a practical, catalytic, asymmetric process for the alpha-bromination of acid chlorides to produce synthetically versatile, optically active alpha-bromoesters is reported. A range of products is produced in high enantioselectivity and moderate to good chemical yields with retention of both upon scale-up. The reactions herein are catalyzed by cinchona alkaloid derivatives, with the best performance achieved by the use of a proline cinchona alkaloid conjugate designed in a de novo fashion.

Study of the interaction of chlorisondamine and chlorisondamine analogues with an epitope of the alpha-2 neuronal acetylcholine nicotinic receptor subunit.

Chlorisondamine (CHL), a neuronal nicotinic ganglionic blocker, when injected in the cerebral ventricle of rats chronically blocks the increase in locomotion and rearing by subcutaneous nicotine injection. The blocking of the ion channel(s) prevents nicotine from exerting its rewarding effects on the CNS. When administered intraperitoneally, a dose 400-500 times the intracerebroventricular one is needed to cross the blood-brain barrier and to generate the same level of nicotine antagonism, resulting in severe side-effects, thus making it unlikely to be used as a therapeutical compound.

A new approach to natural products discovery exemplified by the identification of sulfated nucleosides in spider venom.

Using a new approach based on the NMR spectroscopic analysis of the entire, unpurified spider venom, we identified a family of unusual sulfated nucleoside derivatives from the venom of the hobo spider, Tegenaria agrestis. These compounds are ribonucleoside mono- and disulfates derived from guanosine and xanthosine, some of which are glycosylated, bearing one or two D-fucose units. The use of NMR spectroscopy to characterize the unfractionated venom was central to the discovery of this heretofore overlooked class of venom components.

Advances in the catalytic, asymmetric synthesis of beta-lactams.

In this Account, we illustrate our contribution to the catalytic, asymmetric synthesis of beta-lactams through a flexible [2 + 2] cycloaddition strategy. We also explore the scope of our methodology and comment on future directions.

Catalytic, asymmetric alpha-chlorination of acid halides.

We present a full account of a tandem catalytic, asymmetric chlorination/esterification process that produces highly optically enriched alpha-chloroesters from inexpensive, commercially available acid halides using cinchona alkaloid derivatives as catalysts and polychlorinated quinones as halogenating agents. We have performed kinetics and control experiments to investigate the reaction mechanism and establish conditions under which the reactions can be best performed. We have developed NaH and NaHCO3 shuttle base systems as the easiest and most cost-effective ways of conducting the reactions, rendering the methodology economically competitive with known chiral halogenation procedures.

A multistage, one-pot procedure mediated by a single catalyst: a new approach to the catalytic asymmetric synthesis of beta-amino acids.

A catalytic asymmetric procedure for the preparation of beta-amino acids (specifically beta-substituted aspartic acid derivatives) is reported. The cinchona alkaloid catalyst benzoylquinine (BQ) mediates up to five distinct steps of a reaction pathway, all in one reaction vessel. The products of this reaction, highly optically enriched beta-substituted aspartic acid derivatives, were prepared from N-acyl-alpha-chloroglycine esters and acid chlorides in the presence of the catalyst.

Alpha-imino esters: versatile substrates for the catalytic, asymmetric synthesis of alpha- and beta-amino acids and beta-lactams.

The catalytic asymmetric addition of organic nucleophiles to alpha-imino esters has emerged as one of the most promising and intensely investigated routes to optically enriched alpha- and beta-amino acid derivatives and beta-lactams. The importance of alpha-imino esters stems not only from the vast appeal of the potential product classes,(1) but also from their remarkable reactivity as highly electrophilic imines. With each passing year, the number of publications concerning the asymmetric alkylation of imino esters grows significantly.

Sequential column asymmetric catalysis.

Since the introduction of catalysts and reagents on solid-support, researchers have developed new reaction systems to take advantage of their insoluble nature by designing multistep reaction sequences, high-throughput purification techniques, and combinatorial synthesis methods. The continuous flow system is one of these advancements and represents the foundation of a new technique termed sequential column asymmetric catalysis (CAC). In this strategy, reagents and catalysts are attached to a solid-phase support and loaded onto sequentially-linked columns.

The development of the first catalyzed reaction of ketenes and imines: catalytic, asymmetric synthesis of beta-lactams.

We report practical methodology for the catalytic, asymmetric synthesis of beta-lactams resulting from the development of a catalyzed reaction of ketenes (or their derived zwitterionic enolates) and imines. The products of these asymmetric reactions can serve as precursors to a number of enzyme inhibitors and drug candidates as well as valuable synthetic intermediates. We present a detailed study of the mechanism of the beta-lactam forming reaction with proton sponge as the stoichiometric base, including kinetics and isotopic labeling studies.

Bifunctional asymmetric catalysis: a tandem nucleophile/Lewis acid promoted synthesis of beta-lactams.

[reaction: see text]. We describe a superior procedure for the catalytic, asymmetric synthesis of beta-lactams using a bifunctional catalyst system consisting of a chiral nucleophile and an achiral Lewis acid.

Generation of ketenes from acid chlorides using NaH/crown ether shuttle-deprotonation for use in asymmetric catalysis.

[reaction: see text] We describe methodology for the in situ generation of reactive monosubstituted ketenes from acid chlorides through a shuttle deprotonation process using NaH as an inexpensive stoichiometric base and a crown ether cocatalyst. We have successfully applied this new procedure to the catalytic, asymmetric synthesis of beta-lactams and alpha-haloesters.

A catalyst that plays multiple roles: asymmetric synthesis of beta-substituted aspartic acid derivatives through a four-stage, one-pot procedure.

We report a new method for the catalytic, asymmetric synthesis of beta-substituted aspartic acid derivatives in which the nucleophilic catalyst serves up to four discrete roles in a one-pot procedure: catalytic dehydrohalogenation of acid chlorides to form ketenes; catalytic dehydrohalogenation of alpha-chloroamines to form the corresponding imines; catalyzed [2 + 2]-cycloaddition to produce intermediate acyl beta-lactams; and finally, nucleophilic ring opening to afford optically enriched beta-substituted aspartic acids in high enantioselectivity and diastereoselectivity.

Catalytic, enantioselective alkylation of alpha-imino esters: the synthesis of nonnatural alpha-amino acid derivatives.

Methodology for the practical synthesis of nonnatural amino acids has been developed through the catalytic, asymmetric alkylation of alpha-imino esters and N,O-acetals by enol silanes, ketene acetals, alkenes, and allylsilanes using chiral transition metal-phosphine complexes as catalysts (1-5 mol %). The alkylation products, which are prepared with high enantioselectivity (up to 99% ee) and diastereoselectivity (up to 25:1/anti:syn), are protected nonnatural amino acids that represent potential precursors to natural products and pharmaceuticals. A kinetic analysis of the catalyzed reaction of alkenes with alpha-imino esters is presented to shed light on the mechanism of this reaction.