Issue Date: May 1, 2017 | Web Date: April 30, 2017
Whipping phosphorus into chiral shape
Carbon isn’t the only type of chiral center found in organic compounds. Phosphorus can be chiral too. Many catalytic synthetic techniques do a great job at making carbon chiral centers. Comparable catalytic methods that synthesize chiral phosphates and phosphoramidates (phosphates with an NR2 instead of OH group) and do so with high stereoselectivity have been largely missing. But Daniel A. DiRocco and coworkers at Merck & Co. have now developed one (Science 2017, DOI: 10.1126/science.aam7936).
The method could ease access to nucleoside phosphoramidates, also called pronucleotides—prodrugs with chiral phosphorus centers. Nucleoside analogs such as the anti-HIV drug AZT constitute nearly half of approved antiviral and anticancer drugs, and pronucleotides have even better drug properties, making them a growing focus of drug discovery efforts.
For nucleoside analogs to do their jobs—blocking nucleic acid synthesis or inducing cell death—cells must shepherd them inside through membrane transporter proteins. Then the nucleoside analogs must be activated by three stages of enzymatic phosphorylation, an initial slow one and two fast ones. In contrast, pronucleotides enter cells on their own, without transporters; are activated quickly in cells by only the two fast phosphorylations; and are less prone to getting broken down enzymatically or being expelled from cells before they work. The first approved pronucleotide was Gilead Sciences’ hepatitis C drug, Sovaldi.
Direct asymmetric syntheses of chiral phosphates and phosphoramidates have been scarce, and the conversion and separation procedures more typically used to produce the compounds tend to be slow and inefficient.
To devise a direct, efficient catalytic synthesis, the Merck group started with dihydropyrroloimidazole frameworks that Wanbin Zhang of Shanghai Jiao Tong University and coworkers had developed earlier as chiral catalysts. Zhang’s best catalysts created phosphorus chiral centers with 74:26 stereoselectivity and 62% yield—good but not great for pharmaceutical production.
The Merck researchers used computational modeling, informatics, and kinetic analysis to develop modified catalysts with improved abilities. They designed these catalysts to form chiral phosphorus centers more efficiently by optimizing their ability to use three enzymelike mechanisms: leaving-group activation, nucleophilic activation, and electrostatic transition-state stabilization. The team’s best catalyst combined a chlorophosphoramidate and a nucleoside to make a pronucleotide drug candidate (shown) with 99:1 stereoselectivity at the phosphorus center and 92% yield—well suited to drug manufacturing. The pronucleotide, MK-3682, is currently in Phase III clinical trials for treating hepatitis C.
The modified catalyst “shows excellent stereocontrol in asymmetric phosphorylation,” Zhang says. “I am very happy to see this breakthrough discovery.”
Fabrizio Pertusati of Cardiff University, who helped develop early pronucleotides, notes that the new catalyst is stereoselective for R stereochemistry at phosphorus centers but that Sovaldi and another Gilead pronucleotide, Vemlidy, have S phosphorus chirality. Merck’s catalyst discovery method is already “extremely good,” Pertusati says, “and it would be extremely excellent if it can eventually make catalysts that synthesize S phosphorus centers as well.”
Indeed, DiRocco and coworkers believe their detailed understanding of the new catalyst’s enzymelike mechanism of action should enable them to design similar catalysts that could synthesize a wide range of chiral phosphorus compounds.
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