The Tungsten-Promoted Synthesis of Piperidyl-Modified <i>erythro</i>-Methylphenidate Derivatives

Due to its efficacy
as a dopamine receptor agonist, methylphenidate
(MPH) is of interest as a potential therapeutic for cocaine addiction.
While numerous derivatives of MPH have been investigated for their
potential medicinal value, functionalization of the piperidine ring
has not been explored. The pyridine borane ligand in WTp­(NO)­(PMe3)­(η2-pyBH3) is dearomatized by
the metal and can be elaborated to the analogous η2-mesylpyridinium complex. Installing a methyl phenylacetate moiety
at the C2′ position via a Reformatsky reaction followed by
a tandem protonation/nucleophilic addition sequence results in a library
of erythro MPH analogues functionalized at the piperidyl
C5′ position. The functional group is added chemoselectively
to C5′, cis to the methyl phenylacetate. Repeating
this procedure with an enantioenriched source of the tungsten reagent
results in enantioenriched MPH derivatives. All identities of the
newly reported compounds are supported by comprehensive 2D NMR and
HRMS data or crystallographic data.