The Tungsten-Promoted Synthesis of Piperidyl-Modified erythro-Methylphenidate Derivatives

Abstract

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)(PMe 3 )(η 2 -pyBH 3 ) is dearomatized by the metal and can be elaborated to the analogous η 2 -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.

Synthesis of 1-Azatriene Complexes of Tungsten: Metal-Promoted Ring-Opening of Dihydropyridine

“…10 This experiment suggests that the asymmetric unit {WTp(NO)(PMe 3 )} stabilizes the transition state (II in Figure 5) of distal DHP complexes significantly more than for the proximal diastereomers. Attempts to oxidatively decomplex the 1-azatriene complex 18D using CAN, DDQ, or O 2 /silica were unsuccessful; 11,27 CAN and DDQ both resulted in observable degradation of the complex with no identifiable free organics, while O 2 /silica rendered only starting material.…”

“…Attempts to oxidatively decomplex the 1-azatriene complex 18D using CAN, DDQ, or O 2 /silica were unsuccessful; , CAN and DDQ both resulted in observable degradation of the complex with no identifiable free organics, while O 2 /silica rendered only starting material.…”