Total synthesis and biological evaluation of pederin, psymberin, and highly potent analogs.

The potent cytotoxins pederin and psymberin have been prepared through concise synthetic routes (10 and 14 steps in the longest linear sequences, respectively) that proceed via a late-stage multicomponent approach to construct the N-acyl aminal linkages. This route allowed for the facile preparation of a number of analogs that were designed to explore the importance of the alkoxy group in the N-acyl aminal and functional groups in the two major subunits on biological activity. These analogs, including a pederin/psymberin chimera, were analyzed for their growth inhibitory effects, revealing several new potent cytotoxins and leading to postulates regarding the molecular conformational and hydrogen bonding patterns that are required for biological activity. Second generation analogs have been prepared based on the results of the initial assays and a structure-based model for the binding of these compounds to the ribosome. The growth inhibitory properties of these compounds are reported. These studies show the profound role that organic chemistry in general and specifically late-stage multicomponent reactions can play in the development of unique and potent effectors for biological responses.

Multicomponent approach to the synthesis of oxidized amides through nitrile hydrozirconation.

"Oxidized" amides, as represented by acyl aminals and acyl hemiaminals, are integral subunits of several natural products that exhibit useful biological activity. In this paper a multicomponent approach to these groups from acylimine intermediates is demonstrated. The acylimines are accessed through a sequence of nitrile hydrozirconation and acylation, making this highly versatile amide synthesis useful for a range of applications in target- and diversity-oriented synthesis.

Azetidine and Piperidine Carbamates as Efficient, Covalent Inhibitors of Monoacylglycerol Lipase.

Monoacylglycerol lipase (MAGL) is the main enzyme responsible for degradation of the endocannabinoid 2-arachidonoylglycerol (2-AG) in the CNS. MAGL catalyzes the conversion of 2-AG to arachidonic acid (AA), a precursor to the proinflammatory eicosannoids such as prostaglandins. Herein we describe highly efficient MAGL inhibitors, identified through a parallel medicinal chemistry approach that highlighted the improved efficiency of azetidine and piperidine-derived carbamates. The discovery and optimization of 3-substituted azetidine carbamate irreversible inhibitors of MAGL were aided by the generation of inhibitor-bound MAGL crystal structures. Compound 6, a highly efficient and selective MAGL inhibitor against recombinant enzyme and in a cellular context, was tested in vivo and shown to elevate central 2-AG levels at a 10 mg/kg dose.

Multicomponent synthesis of alpha-branched amides.

Alpha-branched amides are prepared by multicomponent reactions in which nitriles undergo hydrozirconation to form metalloimines that react with acyl chlorides. The resulting acylimines react with a variety of pi-nucleophiles in the presence of Lewis acids to form the desired amides.

An experimental and computational approach to defining structure/reactivity relationships for intramolecular addition reactions to bicyclic epoxonium ions.

In this manuscript we report that oxidative cleavage reactions can be used to form oxocarbenium ions that react with pendent epoxides to form bicyclic epoxonium ions as an entry to the formation of cyclic oligoether compounds. Bicyclic epoxonium ion structure was shown to have a dramatic impact on the ratio of exo- to endo-cyclization reactions, with bicyclo[4.1.0] intermediates showing a strong preference for endo-closures and bicyclo[3.1.0] intermediates showing a preference for exo-closures. Computational studies on the structures and energetics of the transition states using the B3LYP/6-31G(d) method provide substantial insight into the origins of this selectivity.

Oxidative cyclorelease from soluble polymeric supports.

[reaction: see text] Single electron oxidation is shown to be a viable method for effecting concomitant cyclization and cleavage (cyclorelease) of a series of polymer bound homobenzylic ethers. Soluble oligonorbornene polymers are stable toward redox chemistry and are isolable through precipitation with methanol, making them excellent supports for this process. These oxidative conditions are also shown to cleave secondary and tertiary alcohols and ethers in a new traceless approach to polymer-supported aldehyde and ketone synthesis.