Diastereo- and enantioselective [3 + 3] cycloaddition of spirocyclopropyl oxindoles using both aldonitrones and ketonitrones

Abstract

Optically active spirocyclic compounds play an important role in drug discovery, and new synthetic strategies for the efficient generation of spiro stereocenters are in much demand. Here we report a catalytic enantioselective cycloaddition using spirocyclic donor–acceptor cyclopropanes as a promising approach for the generation of spiro stereocenters. A diastereo- and enantioselective [3 + 3] cycloaddition of spirocyclopropyl oxindoles with both aldonitrones and ketonitrones is developed. The key to reaction development is the activation of spirocyclopropyl oxindoles by a suitable electron-withdrawing N-protecting group. This activation approach offers the promise of a general solution to enable spirocyclopropyl oxindoles as synthons for catalytic enantioselective synthesis of spirocyclic oxindoles featuring a C3 spiro stereocenter, a prominent structural motif in drugs and pharmaceutically active compounds. This protocol also constitutes the catalytic enantioselective reaction using unactivated achiral ketonitrones to construct tetrasubstituted carbon stereocenters.

Recent Advances in Stereoselective Ring Expansion of Spirocyclopropanes: Access to the Spirocyclic Compounds

“…Recently, Zhou and co-workers employed these fascinating molecular entities in Ni(II)-catalyzed asymmetric (3 + 3)-cycloaddition of spirocyclopropyl oxindoles 7 for the synthesis of enantioenriched spiro-annulated oxindole-tetrahydro-1,2-oxazines 9 with excellent diastereoselectivity using chiral bisoxazoline L1 ( Scheme 3 ). 10 The introduction of the N -diethoxyphosphoryl group can have a dual effect in the activation of spirocyclopropyl oxindole. First, the electron-withdrawing property of this protecting group can efficiently stabilize the in situ generated negative charge on the oxindole unit when exposed to Lewis acid catalysis; second, it may assist the coordination of the oxindole moiety to the chiral metal complex in order to display a high level of stereoinduction.…”

Asymmetric Catalytic Reactions of Donor–Acceptor Cyclopropanes

“…greatly improved the diastereoselectivity by switching from bisoxazoline/Ni II to trisoxazoline L11 /Ni II catalyst, which was also used in the kinetic resolution of cyclopropanes 23 , leading to the recovery of optically active cyclopropanes (Scheme 12 b). [23a] Enantioselective [3+3] cycloaddition of spirocyclopropyl oxindoles with aldonitrones/ketonitrones was also employed to synthesize spirocyclic tetrahydro‐1,2‐oxazines via a kinetic resolution process [23b] …”

One-Pot Sequential [3 + 3] Dipolar Cycloaddition of Aldehyde or Ketone and Hydroxylamine with Spirocyclopropyl Oxindole

“…This strategy was further successfully applied to the total synthesis of nakadomarin A and (+)-phyllantidine as well as the construction of other privileged scaffolds. − Their meaningful results encouraged us to develop a one-pot method for the facile construction of a library of spirocylic oxindole-1,2-oxazines for biological evaluation, although ketones have not been incorporated to such a one-pot protocol and the corresponding catalytic enantioselective one-pot version remains undeveloped. As part of our research program for the efficient construction of spirocyclic oxindoles for biological evaluation, , we attempted to develop a highly diastereoselective one-pot [3 + 3] cycloaddition of aldehydes or ketones and hydroxylamines with spirocyclopropyl oxindoles, along with a catalytic enantioselective version (Scheme C). Here, we report our research work and the initial results of biological evaluation.…”

“…The merger of this heterocycle into spirocycles is interesting to develop novel molecules for medicinal studies. Recently, inspired by the pioneering work of Young and Kerr in [3 + 3] cycloaddition of nitrones and donor–acceptor (D–A) cyclopropanes for the flexible construction of tetrahydro-1,2-oxazines, as well as the efforts of the Sibi and Tang groups in developing catalytic asymmetric versions, we developed a highly diastereo- and enantioselective [3 + 3] cycloaddition of spirocyclopropyl oxindoles with both aldonitrones and ketonitrones (Scheme A) . This enables the facile synthesis of oxindole-based spirocyclic tetrahydro-1,2-oxazines.…”