Asymmetric Synthesis of Spiro-3,3′-cyclopropyl Oxindoles via Vinylogous Michael Initiated Ring Closure Reaction

Abstract

A novel organocatalytic cascade approach for the synthesis of spiro-cyclopropyl oxindole derivatives has been developed. The methodology is based on asymmetric vinylogous Michael addition of 4-nitroisoxazole derivatives to N-Boc isatylidene malonates followed by intramolecular alkylation. Its remarkable stereocontrol, wide substrate scope, and scalability highlight this new developed strategy. Moreover, this work represents the first example of vinylogous Michael initiated ring closure (MIRC) reaction for the synthesis of chiral 3,3′-cyclopropyl oxindole.

Organocatalytic Asymmetric Direct Vinylogous Michael Initiated Ring Closure Reaction of 4-Nitroisoxazole Derivatives to 3-Isopropylidene Oxindoles

“…In continuation with our previous work, we initiated our investigation by reacting N -boc-isopropylidene oxindole ( 1a ) and 5-(chloromethyl)-3-methyl-4-nitroisoxazole ( 2a ) in the presence of 10 mol % of quinine C1 and 1.0 equiv of NaHCO 3 in dichloromethane at room temperature. The product 3aa was isolated in 27% yield with a 10:1 dr and 8% ee for the major diastereomer.…”

“…We also demonstrated the synthetic utility of the spirocyclopropyl oxindole products of our methodology. In this direction, spirocyclopropyl oxindole 3ga was transformed into 10 by cleaving the isoxazole ring using KMnO 4 in THF/ acetone 7 followed by esterification using ethyl iodide in the presence of DBU (Scheme 3c). 18 Furthermore, treatment of 12 with trifluoroacetic acid in DCM provided HIV-1 NNRT Inhibitor II with 98% yield, 99% ee, and >20:1 dr. 7 In conclusion, we have reported spirocyclopropanation of 3isopropylidene oxindole via vinylogous MIRC.…”

“…Considering their immense synthetic and biological importance, much attention has been paid to their synthesis in the last two decades. The Michael addition initiated cascade approach is one of the most used strategies to synthesize spirocyclopropyl oxindole derivatives …”

“…The Michael addition initiated cascade approach is one of the most used strategies to synthesize spirocyclopropyl oxindole derivatives. 7 In this direction, the transformation of electron-deficient 3alkylidene oxindole into spirocyclopropyl oxindole has been well explored. However, the electron-releasing group containing alkylidene oxindoles such as 3-isopropylidene oxindole has never been employed for the same (Scheme 1).…”

“…9 However, to the best of our knowledge, a vinylogous Michael initiated cyclopropanation using 3isopropylidene oxindole as an electrophile has never been explored and demands attention. In continuation with our ongoing research in the development of direct vinylogous Michael initiated cyclopropanation reaction, 7 we were interested in harnessing the challenging reactivities (electrophilicity vs nucleophilicity) of isopropylidene oxindoles. Along these research lines, a unified approach was envisioned where 3-methyl-4-nitroisoxazol derivatives can be exploited as nucleophiles with 3-isopropylidene oxindoles in the vinylogous MIRC concept.…”