Highly Diastereoselective Esterification of Ketenes Generated In Situ from Acyl Chlorides with (R)‐Pantolactone Derivatives

Abstract

Our mechanistic investigations have revealed that Et3N is a key requirement for the highly diastereoselective formation of esters from the corresponding acyl chlorides with (R)‐pantolactone via ketene‐derived complexes. Furthermore, we have discovered that (R)‐N‐benzyl‐pantolactam is a more effective chiral alcohol than (R)‐pantolactone for the esterification of in situ generated ketenes.

Metal‐Free Deoxygenation of α‐Hydroxy Carbonyl Compounds and Beyond

“…Secondary and tertiary alcohols in positions α to amide or ester groups are efficiently reduced as shown in Scheme . Remarkably, Yamagami et al demonstrated that this process could be easily scale‐up to a kilogram‐scale to generate an advanced intermediate in the synthesis of a potent glucokinase activator (GKA) .…”

“…Cyanohydrines are also converted into the deoxygenated products although the reaction substrates may decompose partially in the reaction mixture to give the corresponding ketones. [30b]…”

“…As seen above (Section 2.1), this side reaction was observed with TMSCl‐NaI reagent. [30b] Dehydroxylation of alcohols in the position α to carbonyls groups can be performed by HI in the presence of red phosphorus (Scheme a) , , . In 2012, the group of König reported the deoxygenation of α‐hydroxy ketone, amide and ester derivatives using a biphasic reaction medium consisting of aqueous hydriodic acid and toluene (Scheme ) .…”

Scalable Synthesis of a Nonracemic α-Arylpropionic Acid via Ketene Desymmetrization for a Glucokinase Activator

“…Among them, small-molecule glucokinase activators (GKAs) represent a new strategy . ( R )-2-[4-(Cyclopropylsulfonyl)phenyl]- N -pyrazin-2-yl-3-(tetrahydro-2 H -pyran-4-yl) propanamide ( R )-1 has been regarded as a potent GKA . For use in nonclinical studies and clinical trials, Prosidion developed a scalable methodology using the enantioselective hydrogenation of acrylic acid ( E )-3 as a key reaction for the construction of stereochemistry at the α-carbon center to give the key intermediate ( R )-2 , followed by amidation with 2-aminopyrazine, giving ( R )-1 (Scheme , route a). , According to their reaction conditions, a high pressure (>700 psig) of hydrogen was required to promote the reaction.…”