Stereoselective Organocatalytic Synthesis of Oxindoles with Adjacent Tetrasubstituted Stereocenters

Abstract

Oxindoles with adjacent tetrasubstituted stereocenters were obtained in high yields and stereoselectivities by organocatalyzed conjugate addition reactions of monothiomalonates (MTMs) to isatin-derived N-Cbz ketimines.T he method requires only al ow catalyst loading (2 mol %) and proceeds under mild reaction conditions.Both enantiomers are accessible in good yields and excellent stereoselectivities by using either Takemotos catalyst or ac inchona alkaloid derivative.T he synthetic methodology allowed establishment of as traightforwardr oute to derivatives of the gastrin/ cholecystokinin-B receptor antagonist AG-041R.

Direct Access to N‐Unprotected α‐ and/or β‐Tetrasubstituted Amino Acid Esters via Direct Catalytic Mannich‐Type Reactions Using N‐Unprotected Trifluoromethyl Ketimines

“…[21] Application to stereoselective construction of vicinal tetrasubstituted chiral stereocenters Based on the above resultsu sing N-unprotected ketimines and active methylene compounds, we next explored the construction of vicinal tetrasubstituted chiral stereocenters using active methine compounds as the nucleophile. Although N-protected ketimines can be used for the stereoselective synthesis of vicinal tetrasubstituted carbon stereocenters, [22] deprotection of the N-protectiveg roups of the Mannicha dducts to give N-unprotected primary aminesi so ften problematic and is not achieved in some cases. Moreover,N -unprotected ketimines have not been used in such reactions.…”

Synthesis of Monothiomalonates – Versatile Thioester Enolate Equivalents for C–C Bond Formations

“…For example, even weak bases such as tertiary amines promote the decarboxylation of MAHTs as shown by Brunner . We chose the formation of a p ‐methoxybenzyl (PMB) ester to develop the reaction conditions for the esterification since it is a versatile protecting group for carboxylic acids that can be easily removed under acidic conditions …”

“…Among the most straightforward methods are C–C bond formations that utilize thioester enolates . [ ][ ] The formation of thioester enolates under mild conditions is not trivial due to the comparatively low acidity of the H‐atom at the α ‐carbon (C( α )) combined with the reactivity of thioesters towards nucleophilic bases . Organocatalytic methods that use surrogates of thioester enolates have therefore become popular for the stereoselective incorporation of thioester moieties into organic molecules.…”

“…Organocatalytic methods that use surrogates of thioester enolates have therefore become popular for the stereoselective incorporation of thioester moieties into organic molecules. [ ][ ][ ] …”

“…Moreover, MTMs bearing a removable protecting group on the oxoester moiety allow for a controlled addition reaction and subsequent decarboxylation upon removal of the protecting group. Organocatalytic addition reactions between MTMs and electrophiles proceed therefore in the presence of low catalyst loadings (1 – 5 mol‐%) and provide the corresponding addition products in enhanced yields and stereoselectivities compared to reactions with MAHTs . The addition products, among which γ ‐nitrothioesters, β ‐amino thioesters, indoles, dihydrocoumarins and dihydroquinolinones, and oxindoles, [ ][ ] contain aside from the thioester orthogonally addressable functional groups and are therefore valuable synthetic building blocks.…”