Dirhodium tetracarboxylates are versatile catalysts for the reactions of donor/acceptor carbenes. They catalyze a variety of transformations, including enantioselective intermolecular cyclopropanations. This study is focused on understanding the kinetics of the rhodium-catalyzed cyclopropanation, and this information was used to develop conditions for conducting the reactions with very low catalyst loadings. The enantioselective cyclopropanation of styrenes can be conducted with a catalyst loading of 0.001 mol % and still maintain high levels of enantioselectivity (86−99% ee). A triarylcyclopropanecarboxylate (TPCP) catalyst, Rh 2 (p-Ph-TPCP) 4 , was the optimum catalyst for maintaining high enantioselectivity with very low catalyst loading. The reaction also benefited from using dimethyl carbonate as the solvent, an environmentally benign and nontoxic material.

The dirhodium tetracarboxylate-catalysed asymmetric cyclopropanation has been applied to the enantioselective syntheses of pharmaceutically relevant 1-aryl-2-heteroaryl- and 1,2-diheteroarylcyclopropane-1-carboxylates.

We report the development and demonstration of a continuous-flow process for the safe formation, extraction, and drying of aryldiazoacetate 2, which enables direct use in a fed-batch dirhodium-catalyzed enantioselective cyclopropanation reaction to provide cyclopropane 4. Designing this process with safety as a primary objective, we identified the appropriate arylsulfonyl hydrazone starting material and organic soluble base to facilitate a Bamford–Stevens diazo-generating flow process at 30 °C, well below the thermal onset temperature (T onset = 57 °C), while also minimizing accumulation of the highly energetic diazo intermediate (ΔH D = −729 J/g). The Bamford–Stevens reaction byproducts are efficiently removed via a continuous aqueous extraction utilizing a liquid–liquid hydrophobic membrane separator. Continuous molecular sieve drying of the organic layer was demonstrated to maintain water levels <100 ppm in the final aryldiazoacetate solution, thereby ensuring acceptable reactivity, selectivity, and purity in the water sensitive cyclopropanation reaction. The full process was successfully executed on a 100 g scale, setting the foundation for the wider application of this and related chemistries on a kilogram scale.

The synthesis and evaluation of six C4-symmetric bowl-shaped dirhodium tetracarboxylate catalysts are described. These elaborate high-symmetry catalysts are readily generated by means of the self-assembly of four C1-symmetric ligands around the dirhodium core. These catalysts are capable of highly site-selective, diastereoselective, and enantioselective C–H functionalization reactions by means of donor/acceptor carbene-induced C–H insertions.

Detailed kinetic studies on the functionalization of unactivated hydrocarbon sp3 C–H bonds by dirhodium-catalyzed reaction of aryldiazoacetates revealed that the C–H functionalization step is rate determining. The efficiency of this step was increased by using the hydrocarbon as a solvent and using donor/acceptor carbenes with an electron-withdrawing substituent on the aryl donor group. The optimum catalyst for these reactions is the tetraphenylphthalimido derivative Rh2(R-TPPTTL)4, and a further beneficial refinement was obtained by using N,N′-dicyclohexylcarbodiimide as an additive. Under the optimum conditions with a catalyst loading of 0.001 mol %, effective enantioselective C–H functionalization (66–97% yield, 83–97% ee) of cycloalkanes was achieved with a range of aryldiazoacetates as long as the aryldiazoacetate was not sterically demanding. The reaction with cyclohexane using a catalyst loading of 0.0005 mol % could be recharged twice with additional aryldiazoacetate, resulting in an overall dirhodium catalyst turnover number of 580,000.

This study describes general methods for the enantioselective syntheses of disubstituted cyclopropane carboxylates including substitution patterns or heterocycle functionality previously observed as significant limitations. The key step is the dirhodium tetracarboxylate-catalyzed asymmetric cyclopropanation of vinyl arenes with aryl- or heteroaryldiazoacetates. The reactions are highly diastereoselective and high asymmetric induction could be achieved using either (<i>R</i>)-pantolactone as a chiral auxiliary or chiral dirhodium tetracarboxylate catalysts.

In the presence of 1,1,1,3,3,3-hexafluoroisopropanol (HFIP), nucleophilic and reactive reagents are prevented from interacting with a rhodium carbene, allowing asymmetric cyclopropanation to occur with high yield and stereoselectivity on a variety of compounds. A high-throughput screen was conducted on cyclopropanation with a complementary catalytic system in the presence of 90 different poisonous nucleophiles and varying amounts of HFIP (10 equiv, used as reaction solvent). The scope of both the aryl/heteroaryl diazoacetate and the olefin was expanded, and the study culminated in the enantioselective functionalization of complex molecules including API and natural products.

Rapid access to 2,2-difluorobicylco[1.1.1]­pentanes is enabled from an α-allyldiazoacetate precursor in a one-pot process through cyclopropanation to afford a 3-aryl bicyclo[1.1.0]­butane, followed by reaction with difluorocarbene in the same reaction flask. The modular synthesis of these diazo compounds affords novel 2,2-difluorobicyclo[1.1.1]­pentanes that were inaccessible through previously reported methods. The reactions of chiral 2-arylbicyclo[1.1.0]­butanes in the same manner generate altogether different products with high asymmetric induction, methylene-difluorocyclobutanes. Larger ring systems including bicyclo[3.1.0]­hexanes are also rapidly furnished due to the modular nature of the diazo starting material.