Highly Enantioselective Decarboxylative Mannich Reaction of Malonic Acid Half Oxyesters with Cyclic Trifluoromethyl Ketimines: Synthesis of β‐Amino Esters and Anti‐HIV Drug DPC 083

Abstract

An organocatalytic enantioselective decarboxylative Mannich reaction of malonic acid half oxyesters with cyclic ketimines was developed for the preparation of enantioenriched β‐amino esters with a quaternary stereogenic center and the anti‐HIV drug DPC 083 (see scheme).

Synthesis of Condensed Heterocycles, Containing Partially Saturated Pyrimidine Nuclei, from Aromatic Pyrimidine Derivatives

“…Similar regularities were also observed in the asymmetric organocatalytic Mannich reaction of cyclic 4‐trifluoromethylketimines with less reactive malonic acid half oxyesters .…”

“…In continuation of the study the possibility of organocatalyzed carbon–carbon‐forming reactions in 4‐trifluoromethylquinazolin‐2(1 H )‐one series, J.‐A. Ma and coworkers reported the enantioselective decarboxylative Mannich reaction of β‐ketoacids and malonic acid half oxyesters with these electrophilic acceptors.…”

“…It was shown that the hydrogen‐bond‐directed enantioselective decarboxylative Mannich reaction was promoted by saccharide‐derived amino thioureas bifunctional organocatalysts . For example, the condensation of ketimine 58 with of 3‐oxo‐3‐phenylpropanoic acid (2 eq) in THF at −20°C in the presence of 10 mol% 63 as catalyst afforded 64 in 99% yield and 99% ee enantioselectivity (Scheme ).…”

Core-structure-inspired asymmetric addition reactions: enantioselective synthesis of dihydrobenzoxazinone- and dihydroquinazolinone-based anti-HIV agents

“…43 The same bifunctional organocatalyst 43 once again proved to be efficient to promote the decarboxylic Mannich reaction between ketimine 26 and 3-oxo-3-phenoxypropanoic acid 46, delivering chiral dihydroquinazolinone 47 in 97% yield with 97% ee (Scheme 14). 43 The same bifunctional organocatalyst 43 once again proved to be efficient to promote the decarboxylic Mannich reaction between ketimine 26 and 3-oxo-3-phenoxypropanoic acid 46, delivering chiral dihydroquinazolinone 47 in 97% yield with 97% ee (Scheme 14).…”

Catalytic Asymmetric Synthesis of Enantioenriched Heterocycles Bearing a CCF3 Stereogenic Center

“…[73] Shortly thereafter, in the same year, Ma and co-workers expanded this asymmetric DMR methodology for less reactive malonic acid half oxyesters, and the ability of the DMR product to undergo a further five-step total synthesis of DPC 083 considerably enhanced the importance of this methodology. [74] From the point of view of drug-resistant virus strains, the exploration of new NNRTIs bearing a CF 3 -dihydroquinazolinone skeleton is quite necessary. In this context, besides serving as prochiral building blocks for fabricating DPC 963 and DPC 083, cyclic ketimines 62 have been asymmetrically transformed to other enantioenriched dihydroquinazolinone derivatives to improve drug potency.…”