Sustainable Palladium-Catalyzed Tsuji-Trost Reactions Enabled by Aqueous Micellar Catalysis.

Palladium-catalyzed allylic substitution, or "Tsuji-Trost" reactions, can be run under micellar catalysis conditions featuring not only chemistry in water but also numerous combinations of reaction partners that require low levels of palladium, typically on the order of 1000 ppm (0.1 mol %). These couplings are further characterized by especially mild conditions, leading to a number of cases not previously reported in an aqueous micellar medium. Inclusion of diverse nucleophiles, such as N-H heterocycles, alcohols, dicarbonyl compounds, and sulfonamides is described. Intramolecular cyclizations further illustrate the broad utility of this process. In addition to recycling studies, a multigram scale example is reported, indicative of the prospects for scale up.

Coolade. A Low-Foaming Surfactant for Organic Synthesis in Water.

Several types of reduction reactions in organic synthesis are performed under aqueous micellar-catalysis conditions (in water at ambient temperature), which produce a significant volume of foam owing to the combination of the surfactant and the presence of gas evolution. The newly engineered surfactant "Coolade" minimizes this important technical issue owing to its low-foaming properties. Coolade is the latest in a series of designer surfactants specifically tailored to enable organic synthesis in water. This study reports the synthesis of this new surfactant along with its applications to gas-involving reactions.

Development of an Effective Scalable Enantioselective Synthesis of the HIV-1 Entry Inhibitor BNM-III-170 as the Bis-Trifluoroacetate Salt.

We report here the development and optimization of a process synthesis for the HIV-1 entry inhibitor BNM-III-170 bis-TFA salt (1). The synthesis features a dynamic-kinetic resolution (DKR) to establish the initial stereogenicity. By taking advantage of significant sequence modifications of our first generation synthesis, inconjunction with the low solubility of late-stage intermediates, the overall efficiency of the synthesis has been significantly improved, now to proceed in an overall yield of 9.64% for the 16-steps, requiring only a single chromatographic separation.

Copper-Catalyzed Oxidative Cleavage of Electron-Rich Olefins in Water at Room Temperature.

A copper-catalyzed oxidative cleavage of electron-rich olefins into their corresponding carbonyl derivatives is described as an alternative to ozonolysis. The scope includes various precursors to aryl ketone derivatives, as well as oxidations of enol ethers bearing atypical alkyl and dialkyl substitution, the first of their kind among such metal catalyzed alkene cleavage reactions. The use of an inexpensive copper salt, room temperature conditions, an aerobic atmosphere, and water as the global reaction medium highlight the green features of this new method. Associated mechanistic investigations are also presented.

Synthesis of Functionalized 1,3-Butadienes via Pd-Catalyzed Cross-Couplings of Substituted Allenic Esters in Water at Room Temperature.

An environmentally responsible, mild method for the synthesis of functionalized 1,3-butadienes is presented. It utilizes allenic esters of varying substitution patterns, as well as a wide range of boron-based nucleophiles under palladium catalysis, generating sp-sp2, sp2-sp2, and sp2-sp3 bonds. Functional group tolerance measured via robustness screening, along with room temperature and aqueous reaction conditions highlight the methodology's breadth and potential utility in synthesis.

Synthesis of Functionalized [3], [4], [5] and [6]Dendralenes through Palladium-Catalyzed Cross-Couplings of Substituted Allenoates.

A mild method for the synthesis of highly functionalized [3]-[6]dendralenes is reported, representing a general strategy to diversely substituted higher homologues of the dendralenes. The methodology utilizes allenoates bearing various substitution patterns, along with a wide range of boron and alkenyl nucleophiles that couple under palladium catalysis leading to sp-, sp2 -, and sp3 -substituted arrays. Regioselective transformations of the newly formed unsymmetrical dendralene derivatives are demonstrated. The use of micellar catalysis, where water is the global reaction medium, and room temperature reaction conditions, highlights the green nature of this technology.

Asymmetric gold-catalyzed lactonizations in water at room temperature.

Asymmetric gold-catalyzed hydrocarboxylations are reported that show broad substrate scope. The hydrophobic effect associated with in situ-formed aqueous nanomicelles gives good to excellent ee's of product lactones. In-flask product isolation, along with the recycling of the catalyst and the reaction medium, are combined to arrive at an especially environmentally friendly process.

Stereoselective silylcupration of conjugated alkynes in water at room temperature.

Micellar catalysis enables copper-catalyzed silylcupration of a variety of electron-deficient alkynes, thereby providing access to isomerically pure E- or Z-ß-silyl-substituted carbonyl derivatives. These reactions take place in minutes, afford high yields and stereoselectivity, and are especially tolerant of functional groups present in the substrates. The aqueous reaction medium has been successfully recycled several times, and a substrate/catalyst ratio of 10,000:1 has been documented for this methodology.

Leveraging the micellar effect: gold-catalyzed dehydrative cyclizations in water at room temperature.

The first examples of gold-catalyzed cyclizations of diols and triols to the corresponding hetero- or spirocycles in an aqueous medium are presented. These reactions take place within nanomicelles, where the hydrophobic effect is operating, thereby driving the dehydrations, notwithstanding the surrounding water. By the addition of simple salts such as sodium chloride, reaction times and catalyst loadings can be significantly decreased.

p53 Dimers associate with a head-to-tail response element to repress cyclin B transcription.

DNA damage induced by the topoisomerase I inhibitor SN38 activates cell cycle checkpoints which promote cell cycle arrest. This arrest can be abrogated in p53-defective cells by the Chk1 inhibitor 7-hydroxystaurosporine (UCN-01). Previously, we compared p53 wild-type MCF10A cells with derivatives whose p53 function was inhibited by over-expression of the tetramerization domain (MCF10A/OD) or expression of shRNA against p53 (MCF10A/Δp53). Treatment of SN38-arrested MCF10A/OD cells with UCN-01 abrogated S, but not G2 arrest, while the MCF10A/Δp53 cells abrogated both S and G2 arrest. The MCF10A/OD cells had reduced levels of cyclin B, suggesting that tetramerization of p53 is not required for repression of cyclin B gene expression. In the present study, we analyzed p53 oligomerization status using glutaraldehyde cross-linking. Following SN38 treatment, MCF10A cells contained oligomeric forms of p53 with molecular weights approximating monomers, dimers, trimers, and tetramers. However, MCF10A/OD cells possessed only monomers and dimers suggesting that these complexes may be involved in repression of cyclin B. While genes transcriptionally activated by p53 contain a consensus sequence with elements repeated in a head-to-head orientation, the cyclin B promoter contains similar elements oriented head-to-tail. Chromatin immunoprecipitation (ChIP) assays revealed that p53 associates with this head-to-tail element in both MCF10A and MCF10A/OD. Electrophoretic mobility shift assays (EMSA) using a biotin-labeled probe containing the head-to-tail element showed a shift in mobility consistent with the molecular weight of tetramers and dimers in MCF10A nuclear extract, but only the dimer in MCF10A/OD nuclear extract. Taken together, these results suggest a novel mechanism whereby p53 dimers associate with the head-to-tail element to repress cyclin B transcription.