An Unconventional Redox Cross Claisen Condensation–Aromatization of 4‑Hydroxyprolines with Ketones

Reaction
of α-amino acids, particularly prolines and their
derivatives with carbonyl compounds via decarboxylative redox process,
is a viable strategy for synthesis of structurally diverse nitrogen
centered heterocyclics. In these processes, the decarboxylation is
the essential driving force for the processes. The realization of
the redox process without decarboxylation may offer an opportunity
to explore new reactions. Herein, we report the discovery of an unprecedented
redox Claisen-type condensation aromatization cascade reaction of
4-substituted 4-hydroxyproline and its esters with unreactive ketones.
We found that the use of propionic acid as a catalyst and a co-solvent
can change the reaction course. The commonly observed redox decarboxylation
and aldol condensation reactions are significantly minimized. Moreover,
unreactive ketones can effectively participate in the Claisen condensation
reaction. The new reactivity enables a redox cyclization via an unconventional
Claisen-type condensation reaction of in situ formed
enamine intermediates from ketone precursors with 4-substituted 4-hydroxyproline
and its esters as electrophilic acylation partners. Under the reaction
conditions, the cascade process proceeds highly regio- and stereoselectively
to afford highly synthetically and biologically valued cis-2,3-dihydro-1H-pyrrolizin-1-ones with a broad substrate
scope in efficient ‘one-pot’ operation, whereas such
structures generally require multiple steps.