Synthesis of Water-Soluble Carbosilane Dendrimers

Nucleophilic reactions between mercapto-substituted amphiphiles and carbosilane dendrimers bearing (chloromethyl)silyl groups on their terminal branches gave, in high yields, amphiphilic dendrimers with hydrophobic carbosilane cores and alcohol, dimethylamino, or sodium sulfonate amphiphilic groups at the periphery. The negatively charged, sulfonate-terminated dendrimers were soluble in water, as were positively charged poly(ammonium) salts prepared from the dimethylamino-terminated derivatives. These new amphiphilic dendrimers were characterized by spectroscopic and mass spectrometric techniques. Preliminary studies of the aqueous solution behavior of the second generation, sulfonate-terminated dendrimer demonstrated its ability to enhance the solubility of lipophilic alkyl-substituted benzene derivatives, a characteristic property of micelles

Synthesis of Water-Soluble Carbosilane Dendrimers

Nucleophilic reactions between mercapto-substituted amphiphiles and carbosilane dendrimers bearing (chloromethyl)silyl groups on their terminal branches gave, in high yields, amphiphilic dendrimers with hydrophobic carbosilane cores and alcohol, dimethylamino, or sodium sulfonate amphiphilic groups at the periphery. The negatively charged, sulfonate-terminated dendrimers were soluble in water, as were positively charged poly(ammonium) salts prepared from the dimethylamino-terminated derivatives. These new amphiphilic dendrimers were characterized by spectroscopic and mass spectrometric techniques. Preliminary studies of the aqueous solution behavior of the second generation, sulfonate-terminated dendrimer demonstrated its ability to enhance the solubility of lipophilic alkyl-substituted benzene derivatives, a characteristic property of micelles

Reversed-Polarity Synthesis of Diaryl Ketones via Palladium-Catalyzed Cross-Coupling of Acylsilanes

Acylsilanes serve as acyl anion equivalents in a palladium-catalyzed cross-coupling reaction with aryl bromides to give unsymmetrical diaryl ketones. Water plays a unique and crucial activating role in these reactions. High-throughput experimentation techniques provided successful reaction conditions initially involving phosphites as ligands. Ultimately, 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane was identified as giving a longer-lived catalyst with higher turnover numbers. Its use, in conjunction with a palladacycle precatalyst, led to optimal reaction rates and yields. Scope and limitations of this novel method are presented along with initial mechanistic insight

Enantioselective Hydrogenation of α-Aryloxy α,β-Unsaturated Acids. Asymmetric Synthesis of α-Aryloxycarboxylic Acids

A facile preparation of chiral α-aryloxy carboxylic acids via asymmetric hydrogenation of the corresponding unsaturated acids has been discovered. A number of catalysts have been identified that give high product enantioselectivity, and the scope of the reaction has been examined with respect to substitution on the aromatic ring and olefin

Use of Steric Hindrance and a Metallacyclobutene Resting State to Develop Robust and Kinetically Characterizable Zirconium-Based Imine Metathesis Catalysts

Use of Steric Hindrance and a Metallacyclobutene Resting State to Develop Robust and Kinetically Characterizable Zirconium-Based Imine Metathesis Catalyst

A Soluble Copper(I) Source and Stable Salts of Volatile Ligands for Copper-Catalyzed C–X Couplings

A stable adduct of CuI with Bu4NI, soluble in organic solvents, has been identified as an effective catalyst for copper-catalyzed C–N and C–O couplings. In addition, stable nonhygroscopic salts of some high performance ligands (diamine MsOH salts/CuX and copper­(II) diketonates) were shown to be of similar and sometimes greater reactivity compared to the literature reagents for these couplings. Furthermore, these more robust conditions result in more reproducible results

A Neophyl Palladacycle as an Air- and Thermally Stable Precursor to Oxidative Addition Complexes

The utilization of isolated Palladium Oxidative Addition Complexes (OACs) has had a significant impact on Pd-catalyzed and Pd-mediated cross-coupling reactions. Despite their importance, widespread utility of OACs has been limited by the instability of their precursor complexes. Herein, we report the use of Cámpora’s palladacycle as a new, more stable precursor to Pd OACs. Using this palladacycle, a series of biarylphosphine ligated OACs, including those with pharmaceutical-derived aryl halides and relevance to bioconjugation, were prepared

Zirconium-Mediated Metathesis of Imines: A Study of the Scope, Longevity, and Mechanism of a Complicated Catalytic System

By kinetically stabilizing imidozirconocene complexes through the use of a sterically demanding ligand, or by generating a more thermodynamically stable resting state with addition of diphenylacetylene, we have developed transition metal-catalyzed imine metathesis reactions that are mechanistically analogous to olefin metathesis reactions catalyzed by metal carbene complexes. When 5 mol % of Cp*Cp(THF)ZrNtBu is used as the catalyst precursor in the metathesis reaction between PhCHNPh and p-TolCHN-p-Tol, a 1:1:1:1 equilibrium mixture with the two mixed imines p-TolCHNPh and PhCHN-p-Tol is generated in C6D6 at 105 °C. The catalyst was still active after 20 days with an estimated 847 turnovers (t1/2 170 m; TON = 1.77 h-1). When the azametallacyclobutene Cp2Zr(N(Tol)C(Ph)C(Ph)) is used as the catalyst precursor under similar reaction conditions, a total of 410 turnovers are obtained after 4 days (t1/2 170 m; TON = 4.3 h-1). An extensive kinetic and equilibrium analysis of the metallacyclobutene-catalyzed metathesis of PhCHN-p-Tol and p-F-C6H4CHN-p-F-C6H4 was carried out by monitoring the concentrations of imines and observable metal-containing intermediates over time. Numerical integration methods were used to fit these data to a detailed mechanism involving coordinatively unsaturated (16-electron) imido complexes as critical intermediates. Examination of the scope of reaction between different organic imines revealed characteristic selectivity that appears to be unique to the zirconium-mediated system. Several zirconocene complexes that could generate the catalytically active “CpCp‘ZrNAr” (Cp‘ = Cp or Cp*) species in situ were found to be effective agents in the metathetical exchange between different N-aryl imines. N-Alkyl aldimines were found to be completely unreactive toward metathesis with N-aryl aldimines, and metathesis reactions involving the two N-alkyl imines TolCHNPr and PhCHNMe gave slow or erratic results, depending on the catalyst used. Metathesis was observed between N-aryl ketimines and N-aryl aldimines, but for N-aryl ketimine substrates, the catalyst resting state consists of zirconocene enamido complexes, generated by the formal C−H activation of the α position of the ketimine substrates

Copper-Catalyzed Cross-Coupling of Benzylic C–H Bonds and Azoles with Controlled <i>N</i>‑Site Selectivity

Azoles are important motifs in medicinal chemistry, and elaboration of their structures via direct N–H/C–H coupling could have broad utility in drug discovery. The ambident reactivity of many azoles, however, presents significant selectivity challenges. Here, we report a copper-catalyzed method that achieves site-selective cross-coupling of pyrazoles and other N–H heterocycles with substrates bearing (hetero)­benzylic C–H bonds. Excellent N-site selectivity is achieved, with the preferred site controlled by the identity of co-catalytic additives. This cross-coupling strategy features broad scope for both the N–H heterocycle and benzylic C–H coupling partners, enabling application of this method to complex molecule synthesis and medicinal chemistry

Merging Late-Stage Diversification with Solid-Phase Peptide Synthesis Enabled by High-Throughput On-Resin Reaction Screening

An integrated workflow is described that combines micromole-scale high-throughput experimentation (HTE) reaction screening and solid-phase peptide synthesis (SPPS) to enable rapid synthetic method development for on-resin peptide diversification. Using this new approach, we have identified several sets of robust Suzuki–Miyaura coupling conditions with complementary scope that collectively display broad coverage with respect to both resin-bound peptide substrates containing aryl halide side chains and (hetero)­arylboronic acid coupling partners. We have also demonstrated the utility of this integrated SPPS/chemical diversification method by synthesizing a multidimensional library of diverse peptides in high yields