Palladium-catalyzed reactions
. A research team, lead by Stephen Buchwald, professor of chemistry at the Massachusetts Institute of Technology (MIT), reported
on a new way to attach a trifluoromethyl group to certain compounds, which has important implications for pharmaceutical compounds.
A trifluoromethyl group may be attached to a pharmaceutical compound as a strategy to prevent the drug from breaking down
too rapidly in the body. The trifluoromethyl group is a component of several drugs, including the antidepressant Prozac (fluoxetine
hydrochloride) by Eli Lilly, the arthritis medication Celebrex (celecoxib) by Pfizer, and the antidiabetes drug Januvia (sitagliptin
phosphate) by Merck & Co., according to a June 24, 2010, MIT press release.
According to the MIT researchers, no general method existed for installing trifluoromethyl groups onto functionalized aromatic
substrates. Commonly used methods either required the use of harsh reaction conditions or had limited substrate scope. In
their work, the researchers reported on the palladium-catalyzed trifluoromethylation of aryl chlorides under mild conditions
to permit transformation of various substrates, including heterocycles. The process tolerated functional groups, such as esters,
amides, ethers, acetals, nitriles, and tertiary amines, thereby making them useful for late-stage modifications of advanced
intermediates (5). An important component to the palladium-based catalyst system was the BrettPhos ligand, a biarylmonophosphine
ligand. During the reaction, a trifluoromethyl group was transferred from a silicon carrier to the palladium, displacing a
chlorine atom. Subsequently, the aryl–trifluoromethyl unit was released, and the catalytic cycle began. The researchers tried
the synthesis with various aryl compounds and achieved yields ranging from 70 to 94% of the trifluoromethylated products,
according to the MIT release.
Buchwald previously reported on the BrettPhos ligand in a catalyst system for carbon–nitrogen cross-coupling reactions. The
system enabled the use of aryl mesylates as a coupling partner in carbon–nitrogen bond-forming reactions. He and his research
team reported on the use of the BrettPhos ligand in a catalyst system to achieve the selective monoarylation of various primary
aliphatic amines and anilines at low catalyst loadings with fast reaction times, including the monoarylation of methylamine
(6).
Biocatalytic route to simvastatin.
Researchers at the University of California Los Angeles (UCLA) recently reported on a biocatalytic route to simvastatin,
the active ingredient in Merck & Co.'s anticholesterol drug, Zocor and also now off patent as a generic drug (7, 8). Simvastatin
is a semisynthetic derivative of lovastatin. Adding a methyl group to convert lovastatin into simvastatin requires a multistep
chemical synthesis that includes protecting and deprotecting other functionalities in the lovastatin molecule. In one process
route, lovastatin is hydrolyzed to the triol, monacolin J, followed by protection by selective silylation, esterification
with dimethyl butyryl chloride, and deprotection (7). Another route involves protection of the carboxylic acid and alcohol
functionalities, followed by methylation with methyl iodide and deprotection. Both routes had less than 70% percent overall
yield. The UCLA researchers developed an improved biocatalytic route based on directed evolution of the biocatalyst (7).
The researchers first cloned and identified LovD, a natural acyltransferase in Aspergillus terreus, which is involved in the synthesis of lovastatin and can accept nonnatural acyl donors. LovD converts the inactive monacolin
J acid into lovastatin. LovD can also synthesize simvastatin using monacolin J acid and a synthetic a-dimethylbutyryl thioester
although with less-than optimal properties as a biocatalyst. The researchers used directed evolution to improve the properties
of LovD toward a semisynthetic route of simvastatin. Mutants with improved catalytic efficiency, solubility, and thermal stability
were obtained, with the best mutant displaying an approximate 11-fold increase in an Escherichia coli-based biocatalytic system (7, 8).
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