Catalytic asymmetric acetalization of carboxylic acids for access to chiral phthalidyl ester prodrugs

Abstract

Carboxylic acids are common moieties in medicines. They can be converted to phthalidyl esters as prodrugs. Unfortunately, phthalidyl esters are now mostly prepared in racemic forms. This is not desirable because the two enantiomers of phthalidyl esters likely have different pharmacological effects. Here we address the synthetic challenges in enantioselective modification of carboxylic acids via asymmetric acetalizations. The key reaction step involves asymmetric addition of a carboxylic acid to the catalyst-bound intermediate. This addition step enantioselectively constructs a chiral acetal unit that lead to optically enriched phthalidyl esters. A broad range of carboxylic acids react effectively under mild and transition metal-free conditions. Preliminary bioactivity studies show that the two enantiomers of chlorambucil phthalidyl esters exhibit different anti-cancer activities to inhibit the growth of Hela cells. Our catalytic strategy of asymmetric acetalizations of carboxylic acids shall benefit future development of chiral phthalidyl ester prodrugs and related molecules.

Chiral Bicyclic Imidazole‐Catalyzed Acylative Dynamic Kinetic Resolution for the Synthesis of Chiral Phthalidyl Esters

“…[2] It was only recently that Chi and co‐workers developed a reaction to access chiral phthalidyl ester prodrugs via an intermolecular acetalization and NHC‐catalyzed intramolecular asymmetric acylation sequence (Scheme 1). [3] However, poor regioselectivity using unsymmetrical dialdehydes greatly limits structural diversity and thus further drug development. In addition, the utilization of hard‐to‐get catalysts and stoichiometric amounts of oxidants further diminishes the practical applicability of this methodology.…”

Carbene‐Catalyzed Dynamic Kinetic Resolution and Asymmetric Acylation of Hydroxyphthalides and Related Natural Products

“…Tang and co‐workers reported the dynamic kinetic diastereoselective acylation of lactols through chiral isothiourea catalytic reactions . We recently disclosed a carbene‐catalyzed enantioselective modification of carboxylic acids for asymmetric access to optically enriched acetal products (Figure b) …”

N‐Heterocyclic Carbene‐Catalyzed Asymmetric C−O Bond Construction Between Benzoic Acid and o‐Phthalaldehyde: Mechanism and Origin of Stereoselectivity

“…However, asymmetric construction of C−O bond catalyzed by NHC has rarely been investigated in both experiment and theory. Until recently, Chi and co‐workers have made a breakthrough contribution on NHC‐catalyzed asymmetric acetalization between benzoic acid and o ‐phthalaldehyde for preparation of optically enriched phthalidyl esters with high enantioselectivity (>95 : 5 er), [12] which opens a new door to deliver phthalidyl esters through stereoselective C−O bond formation. Therefore, understanding the origin of stereoselectivity for these kinds of C−O bond construction reactions should be highly desirable.…”