Controlling the stereochemistry in 2-oxo-aldehyde-derived Ugi adducts through the cinchona alkaloid-promoted electrophilic fluorination

Abstract

In this report, we introduce a new strategy for controlling the stereochemistry in Ugi adducts. Instead of controlling stereochemistry directly during the Ugi reaction we have attempted to stereodefine the chiral center at the peptidyl position through the post-Ugi functionalization. In order to achieve this, we chose to study 2-oxo-aldehyde-derived Ugi adducts many of which partially or fully exist in the enol form that lacks the aforementioned chiral center. This in turn led to their increased nucleophilicity as compared to the standard Ugi adducts. As such, the stereocenter at the peptidyl position could be installed and stereodefined through the reaction with a suitable electrophile. Towards this end, we were able to deploy an asymmetric cinchona alkaloid-promoted electrophilic fluorination producing enantioenriched post-Ugi adducts fluorinated at the peptidyl position.

Oxidation: C–X Bond Formation (X = Halogen, S, Se)

“…The reactivity and the enantioselectivity strongly depend on the nature of the alkaloid used (13 alkaloids tested) as well as on the nature of the substrate substituents (Scheme 2 ). 2 Scheme 2 Enantioselective electrophilic fluorination of Ugi adducts, -amino keto amides In 2013, two new chiral fluorinating agents were developed. The Gouverneur group prepared a reagent by adding aryl groups to Selectfluor's framework (Figure 1) for use in asymmetric tandem electrophilic fluorination-cyclization reactions (see volume 5).…”

N‐Fluoro Ammonium Salts of Cinchona Alkaloids in Enantioselective Electrophilic Fluorination

“…Peshkov and co‐workers in 2020 (Scheme 20). [55] Notably, the use of a catalytic quantity of quinine led to much lower yield and ee value compared to the same reaction under stoichiometric conditions. Although an extensive investigation was carried out, the highest enantioselectivity observed did not exceed 74 % ee value.…”