Repression of the transcriptional activity of ERRα with sequence-specific DNA-binding polyamides.

The orphan nuclear receptors estrogen-related receptors (ERRs) bind to the estrogen-related receptor response element (ERRE) to regulate transcriptional programs in cellular metabolism and cancer cell growth. In this study, we evaluated the potential for a pyrrole-imidazole polyamide to block ERRα binding to ERREs to inhibit gene expression. We demonstrated that the ERRE-targeted polyamide 1 blocked the binding of ERRα to the consensus ERRE and reduced the transcriptional activity of ERRα in cell culture. We further showed that inhibiting ERRα transcriptional activity with polyamide 1 led to reduced mitochondrial oxygen consumption, a primary biological effect regulated by ERRα. Finally, our data demonstrated that polyamide 1 is an inhibitor for cancer cell growth.

Concise enantiospecific total synthesis of tubingensin A.

We report the enantiospecific total synthesis of (+)-tubingensin A. Our synthesis features an aryne cyclization to efficiently introduce the vicinal quaternary stereocenters of the natural product and proceeds in only nine steps (longest linear sequence) from known compounds.

Iron-catalyzed alkylations of aryl sulfamates and carbamates.

The alkylation of aryl sulfamates and carbamates using iron catalysis is reported. The method constructs sp(2)-sp(3) carbon-carbon bonds and provides synthetically useful yields across a range of substrates (>35 examples). The directing group ability of sulfamates and carbamates, accompanied by their low reactivity toward conventional cross-couplings, renders these substrates useful for the synthesis of polyfunctionalized arenes.

Suzuki-Miyaura cross-coupling of aryl carbamates and sulfamates: experimental and computational studies.

The first Suzuki-Miyaura cross-coupling reactions of the synthetically versatile aryl O-carbamate and O-sulfamate groups are described. The transformations utilize the inexpensive, bench-stable catalyst NiCl(2)(PCy(3))(2) to furnish biaryls in good to excellent yields. A broad scope for this methodology has been demonstrated. Substrates with electron-donating and electron-withdrawing groups are tolerated, in addition to those that possess ortho substituents. Furthermore, heteroaryl substrates may be employed as coupling partners. A computational study providing the full catalytic cycles for these cross-coupling reactions is described. The oxidative addition with carbamates or sulfamates occurs via a five-centered transition state, resulting in the exclusive cleavage of the aryl C-O bond. Water is found to stabilize the Ni-carbamate catalyst resting state, which thus provides rationalization of the relative decreased rate of coupling of carbamates. Several synthetic applications are presented to showcase the utility of the methodology in the synthesis of polysubstituted aromatic compounds of natural product and bioactive molecule interest.

Nickel-catalyzed amination of aryl carbamates and sequential site-selective cross-couplings.

We report the amination of aryl carbamates using nickel-catalysis. The methodology is broad in scope with respect to both coupling partners and delivers aminated products in synthetically useful yields. Computational studies provide the full catalytic cycle of this transformation, and suggest that reductive elimination is the rate-determining step. Given that carbamates are easy to prepare, robust, inert to Pd-catalysis, and useful for arene functionalization, these substrates are particularly attractive partners for use in synthesis. The sequential use of carbamate functionalization/site-selective cross-coupling processes highlights the utility of this methodology.