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. The method requires only a low catalyst loading (2 mol %) and proceeds under mild reaction conditions. Both enantiomers are accessible in good yields and excellent stereoselectivities by using either Takemoto's catalyst or a cinchona alkaloid derivative. The synthetic methodology allowed establishment of a straightforward route to derivatives of the gastrin/cholecystokinin-B receptor antagonist AG-041R.

Stereoselective Synthesis of 3,3’‐Bisindolines by Organocatalytic Michael Additions of Fluorooxindole Enolates to Isatylidene Malononitriles in Aqueous Solution

“…[3] To this end, the simultaneous incorporation of contiguous stereocenters has attracted increasing attention. [4] The discovery of the potassium ion channel modulator Maxipost [5] and other biologically active fluorooxindoles has stimulated the development of various fluorination protocols that utilize readily available 3-alkyl and 3-aryloxindoles as starting material. [6] The alternative approach based on C-C bond formation with 3-fluorooxindoles bears relatively unexplored synthetic potential.…”

Catalytic Enantioselective and Diastereoselective Allylic Alkylation with Fluoroenolates: Efficient Access to C3‐Fluorinated and All‐Carbon Quaternary Oxindoles

“…[6] The synthesis of C3-substituted oxindoles carrying two or more contiguous stereogenic centers is equally demanding albeit a few impressive examples are known. [7] A catalytic method that affords 3-fluorooxindoles exhibiting vicinal chirality centers with one being fluorinated would achieve both tasks at once and significantly widen the scope and availability of this important class of compounds. [8] In this regard, Trost's asymmetric allylic alkylation (AAA) would be a preferable reaction due to its outstanding value in natural product synthesis.…”

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

“…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. [48 -57] The addition products, among which cnitrothioesters, [48 -50] b-amino thioesters, [51 -53] indoles, [54] dihydrocoumarins and dihydroquinolinones, [55] and oxindoles, [56] [57] contain aside from the thioester orthogonally addressable functional groups and are therefore valuable synthetic building blocks. The reactivity of the MTMs depends on the thio-and oxoester moieties, which also influence the stereoselectivity of the addition reactions.…”