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.
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.
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.
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.
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.
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.
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.
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