Debenzylative cyclisation : Development of a new strategy for the synthesis of complex tetrahydrofuran and highly valuable fluorinated analogues Renewal

Project: Research

Project Details

Description

Tetrahydrofuran is a major structural feature found in many synthetic and natural products
displaying a variety of biological properties. Nucleosides analogues constitute nowadays a
very important class of natural and artificial molecules that have been successfully applied
either for therapeutic applications or for fundamental purposes in chemical biology. One of
the main synthetic strategy relies on the construction of the protected γ-lactone followed by
the addition of the aglycon moiety. Indeed, Gemcitabine (anticancer agent) and Sofosbuvir
(antiviral agent) are both synthetized from their fluorinated γ-lactones. The objective of this
project, is to explore a debenzylative cyclisation as key reaction to access highly valuable
tetrahydrofuran derivatives. When a benzyl ether and an electrophilic center are in a 1,4-
relationship, a concomitant debenzylative cyclisation can occurs under mildly acidic or even
neutral conditions, yielding a tetrahydrofuran moiety. Our recently published review in the
field, demonstrate the regio- and stereo-selectivity of this reaction that gives access to the
five-membered ring rather than the tetrahydropyran form thanks to a favorable conformation
properly positioning the nucleophilic O-ether for a SN reaction. This highlight the potential of
this methodology to access γ-lactones, without develop a multi-steps strategy to
regioselectively protect the alcohols of the initial polyol.
First, the strategy has to be validated and the best activating agent of the electrophilic
center has to be determined. Next, the scope of this methodology will be extend from
several commercial sugars and the synthesis of the 2,2’-difluoro-γ-lactone and 2,2’-deoxy-γ-
lactone will be investigated. Simultaneously, the total synthesis of 2,2’-difluoro-UDPgalactofuranose
will be developed to create new potential inhibitor of UGM enzyme, a
validated therapeutic target against tuberculosis.
Short titleNew access to complex tetrahydrofuran
StatusFinished
Effective start/end date1/01/1514/09/18