DOI: 10.1002/chem.201200655 Diastereodivergent Synthesis of ACHTUNGTRENNUNG3-Spirocyclopropyl-2-oxindoles through Direct Enantioselective Cyclopropanation of Oxindoles Xiaowei Dou and Yixin Lu* [a] Oxindoles are structural motifs that are widely present in natural products and medicinally important agents. [1] In par- ticular, spirocyclic oxindoles bearing a quaternary stereogen- ic center at the 3-position possess significant biological pro- files. In this context, syntheses of 3-spirocyclic oxindoles bearing a five- [2] or six-membered [3] ring system have been intensively investigated due to the biological importance of these molecules. Spirocyclopropyl oxindoles have shown re- markable biological activities (Scheme 1), [4] and as such are molecules of high synthetic value. [2c, 5] Surprisingly, methods for the preparation of 3-spirocyclopropane-2-oxindoles are very limited. [6] To the best of our knowledge, only one ex- ample of the enantioselective construction of cyclopropyl spirooxindoles has been reported recently; Bartoli, Benci- venni et al. utilized a Michael–alkylation cascade to realize the enantioselective nitrocyclopropanation of 3-alkylidene oxindoles. [7] As part of our ongoing efforts towards the effi- cient creation of quaternary stereogenic centers and chiral spirooxindole derivatives, [8] we became interested in devel- oping an enantioselective synthetic method for the direct cy- clopropanation of oxindole substrates. Asymmetric cyclopropanation reactions have fascinated organic chemists for decades because the cyclopropane motif is both synthetically useful and biologically impor- tant. [9] Well-established synthetic strategies for asymmetric cyclopropanation include the Simmons–Smith reaction, [10] transition-metal-catalyzed decomposition of diazoalkanes, [11] Michael-initiated ring-closure reactions, [12] and many others. [13] In the past few years, organocatalytic cyclopropa- nation has emerged as a powerful approach for the construc- tion of chiral cyclopropanes. [14] However, a direct cyclopro- panation method to access spirocyclopropyl oxindoles has yet to be developed. In the reported organocatalytic cyclo- propanation methods, [14] a-halogenated carbonyl compounds are commonly utilized as a C 1 synthon, which contains a nu- cleophilic/electrophilic center for the construction of cyclo- propanes. From a practical point of view, it would be ideal if simple oxindoles could be used directly as a C 1 synthon for the syn- thesis of cyclopropyl spirooxindoles. We envisioned that the employment of oxindoles containing a dinucleophilic center as a C 1 synthon, in combination with a suitable dielectro- philic C 2 synthon (e.g., halogenated nitroolefins), might pro- vide a straightforward cyclopropanation strategy. In the presence of a suitable catalyst, oxindole can readily add to a nitroolefin. After intramolecular proton transfer, an S N 2 substitution is expected to generate the cyclopropane core. Ostensibly, the O-alkylation product [15] may be formed in addition to the desired C-alkylation product (Scheme 2). It is noteworthy that utilization of a dinucleophilic C 1 synthon in asymmetric organocatalytic cyclopropanation is unknown, and the use of halogenated nitroolefins in asymmetric cyclo- propanation has also not been disclosed. Notably, Connon and co-workers have described a stereoselective synthesis of functionalized nitrocyclopropanes by employing nitroolefins as a reaction component. However, their attempt to utilize a halogenated nitroolefin in the asymmetric cyclopropana- tion led to disappointing results. [14f] Herein, we describe the first direct highly diastereoselective and enantioselective cy- clopropanation of oxindoles by employing oxindoles as a readily available C 1 synthon and (E)-b-bromo-b-nitroole- fins as a convenient C 2 synthon. We initiated our study by examining the reaction between N-Boc-protected oxindole 1a and (E)-b-bromo-b-nitrostyr- ene 2a (Table 1). Tertiary amine–thiourea catalysts [16] were [a] X. Dou, Prof. Dr. Y. Lu Department of Chemistry & Medicinal Chemistry Program Life Sciences Institute, National University of Singapore 3 Science Drive 3, 117543 (Singapore) Fax: (+ 65) 6779-1691 E-mail: chmlyx@nus.edu.sg Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201200655. Scheme 1. Bioactive molecules containing a spirocyclopropyl oxindole/in- doline motif. Chem. Eur. J. 2012, 18, 8315 – 8319  2012 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim 8315 COMMUNICATION