Diruthenium Tetracarboxylate-Catalyzed Enantioselective Cyclopropanation with Aryldiazoacetates.

A series of chiral bowl-shaped diruthenium(II,III) tetracarboxylate catalysts were prepared and evaluated in asymmetric cyclopropanations with donor/acceptor carbenes derived from aryldiazoacetates. The diruthenium catalysts self-assembled to generate C4-symmetric bowl-shaped structures in an analogous manner to their dirhodium counterparts. The optimum catalyst was found to be Ru2(S-TPPTTL)4·BArF [S-TPPTTL = (S)-2-(1,3-dioxo-4,5,6,7-tetraphenylisoindolin-2-yl)-3,3-dimethylbutanoate, BArF = tetrakis(3,5-bis(trifluoromethyl)phenyl)borate], which resulted in the cyclopropanation of a range of substrates in up to 94% ee. Synthesis and evaluation of first-row transition-metal congeners [Cu(II/II) and Co(II/II)] invariably resulted in catalysts that afforded little to no asymmetric induction. Computational studies indicate that the carbene complexes of these dicopper and dicobalt complexes, unlike the dirhodium and diruthenium systems, are prone to the loss of carboxylate ligands, which would destroy the bowl-shaped structure critical for asymmetric induction.

One-Pot Synthesis of Difluorobicyclo[1.1.1]pentanes from α-Allyldiazoacetates.

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.

In-situ Kinetic Studies of Rh(II)-Catalyzed C-H Functionalization to Achieve High Catalyst Turnover Numbers.

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 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) was achieved of cycloalkanes with a range of aryldiazoacetates as long as the aryldiazoacetate was not to 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.

Design, Synthesis, and Evaluation of Extended C4-Symmetric Dirhodium Tetracarboxylate Catalysts.

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.

Asymmetric synthesis of pharmaceutically relevant 1-aryl-2-heteroaryl- and 1,2-diheteroarylcyclopropane-1-carboxylates.

This study describes general methods for the enantioselective syntheses of pharmaceutically relevant 1-aryl-2-heteroaryl- and 1,2-diheteroarylcyclopropane-1-carboxylates through dirhodium tetracarboxylate-catalysed asymmetric cyclopropanation of vinyl heterocycles with aryl- or heteroaryldiazoacetates. The reactions are highly diastereoselective and high asymmetric induction could be achieved using either (R)-pantolactone as a chiral auxiliary or chiral dirhodium tetracarboxylate catalysts. For meta- or para-substituted aryl- or heteroaryldiazoacetates the optimum catalyst was Rh2(R-p-Ph-TPCP)4. In the case of ortho-substituted aryl- or heteroaryldiazoacetates, the optimum catalyst was Rh2(R-TPPTTL)4. For a highly enantioselective reaction with the ortho-substituted substrates, 2-chloropyridine was required as an additive in the presence of either 4 Å molecular sieves or 1,1,1,3,3,3-hexafluoroisopropanol (HFIP). Under the optimized conditions, the cyclopropanation could be conducted in the presence of a variety of heterocycles, such as pyridines, pyrazines, quinolines, indoles, oxadiazoles, thiophenes and pyrazoles.