Thèse Vers la Synthèse d'Aza-Hétérocycles Saturés Chiraux par Auto-Transfert d'Hydrogène Ath H/F - 69

Établissement : INSA Lyon
École doctorale : Chimie de Lyon
Laboratoire de recherche : ICBMS - Institut de Chimie et Biochimie Moléculaires et Supramoléculaires
Direction de la thèse : Florence POPOWYCZ ORCID 000000020297295X
Début de la thèse : 2026-10-01
Date limite de candidature : 2026-04-30T23:59:59

Over the last decades, the borrowing hydrogen (BH) methodology has emerged as an attractive strategy for the construction of novel CN bonds from an alcohol and an amine. This one-pot process involves a catalytic reduction of an unreactive alcohol into a carbonyl, followed by in situ imine formation and subsequent reduction. Metals such as Ir, Ru, Fe and Mn enable this transformation with water as the sole by-product.
In recent years, our group has applied this strategy for the valorization of bio-based alcohols, such as isohexides and 1,4-D-sorbitan, to access chiral amines and amino alcohols.
Despite significant advances reported in the literature, access to chiral saturated N-heterocycles via the BH methodology remains a major synthetic challenge. The first objective of this PhD project will focus on the synthesis of chiral substituted piperidines and pyrrolidines directly from racemic triols
The second objective of the project will exploit the BH process for the preparation of polyhydroxypyrrolidines and piperidines from biomass-derived polyols

More recently, we reported the use of this methodology for the construction of N-heterocycles, such piperidines and pyrrolidines. These valuable compounds occur in many natural alkaloids and rank as the most prevalent saturated heterocycles in drugs approved by the U.S. Food and Drug Administration. The advantage of our approach lies in the use of triols, which provide access to pyrrolidinols and piperidinols that
can be further post-functionalized through novel C-N or C-C bond formation.
We have recently shown that the use of chiral 1,2,4-butanetriol results in a loss of chirality, most likely due to racemization via an enaminol intermediate. Therefore, the reduction step appears to be enantiodetermining. To address this issue, two strategies will be investigated for the synthesis of chiral piperidinol and pyrrolidinol: (i)
the use of chiral amines as chiral auxiliaries, or (ii) cooperative catalysis combining a chiral phosphoric acid with a metal catalyst. Taking advantage of our expertise on preparation and functionalization of saturated Nheterocycles, we also envision to tackle the preparation of chiral 3-substituted pyrrolidines and 4-substituted piperidines via asymmetric N or C-alkylation using racemic 3-pyrrolidinol and 4-piperidinol.