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Methylphenidate, commonly known is Ritalin, is widely prescribed to treat symptoms of ADHD. It is also of great synthetic interest as a potential scaffold for a pharmacotherapy that treats cocaine addiction. We can access a mesyl- MPH precursor by dearomatizing pyridine. A wide range of unique mesyl-MPH tetrahydropyridines can be synthesized by doing a tandem protonation/second nucleophile addition to a methyl phenylacetate dihydropyridine complex. These MPH THPs can then be isolated off the metal by oxidative liberation. Studies are ongoing to broaden the scope of the electrophiles, nucleophiles, and functionalization of the final THP olefin (once off the metal).
Replacing hydrogen with deuterium on drugs can substantially alter the rates of metabolic pathways. Piperidine ring attrition can be reduced, leading to greater therapeutic effects observed by incorporating deuterium on piperidine scaffolds; yet techniques capable of selective deuterium incorporation are lacking. Regio- and stereoselective additions of hydride and deuteride to a proteo mesyl-pyridinium tungsten complex and d5-mesyl pyridinium complex allows for the synthesis of various isotopologues and Isotopomers of various tetrahydropyridines. Investigations of stereoselective deuteration using deuterotriflic acid are ongoing. Isolated THPs are also being investigated for hydrogenation to saturated piperidines.
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