title: Enantioselective synthesis of (R)-tolterodine using lithiation/borylation-protodeboronation methodology.
abstract: The synthesis of the pharmaceutical (R)-tolterodine is reported using lithiation/borylation-protodeboronation of a homoallyl carbamate as the key step. This step was tested with two permutations: an electron-neutral aryl Li-carbamate reacting with an electron-rich boronic ester and an electron-rich aryl Li-carbamate reacting with an electron-neutral boronic ester. It was found that the latter arrangement was considerably better than the former. Further improvements were achieved using magnesium bromide in methanol leading to a process that gave high yield and high enantioselectivity in the lithiation/borylation reaction. The key step was used in an efficient synthesis of (R)-tolterodine in a total of eight steps in a 30% overall yield and 90% ee.
authors.affiliation: School of Chemistry, University of Bristol, Cantock's Close, Bristol, BS8 1TS, UK.
authors.forename: Stefan
authors.initials: S
authors.lastname: Roesner
authors.forename: Varinder K
authors.initials: VK
authors.lastname: Aggarwal
keywords: asymmetric synthesis; boronic esters; gem-diarylalkyl; lithiation/borylation reaction; tolterodine