CLUSTER ▌ 1197 cluster NHC-Catalyzed Ester Activation: Access to Sterically Congested Spirocyclic Oxindoles via Reaction of α-Aryl Esters and Unsaturated Imines NHC-Catalyzed Ester Activation Lin Hao, Chan Wei Chuen, Rakesh Ganguly, Yonggui Robin Chi* Division of Chemistry & Biological Chemistry, School of Physical & Mathematical Sciences, Nanyang Technological University, Singapore 637371, Singapore Fax +65 67911961; E-mail: robinchi@ntu.edu.sg Received: 01.04.2013; Accepted after revision: 19.04.2013 Abstract: Carboxylic esters can be readily obtained at low cost. Therefore, asymmetric catalytic activation of esters should provide useful strategies for organic synthesis. Here we report a N-hetero- cyclic carbene (NHC)-mediated reaction of α-aryl acetic esters with oxindole-derived α,ȕ-unsaturated imines. The reaction involves the formation of NHC-bound ester enolate intermediate from an ester as a key step, and furnishes spirocyclic oxindole products. The steri- cally congested spirocyclic oxindole bears a newly formed six- membered δ-lactams and cannot be easily prepared using other methods. Key words: N-heterocyclic carbene, ester activation, enolate, spirocyclic, oxindole Spirocyclic oxindole is a unique scaffold found in bioac- tive natural and synthetic products (Figure 1). 1 Organocat- alytic synthesis of this class of molecules has received considerable attentions in recent years. Representative or- ganocatalysts for spirocyclic oxindole synthesis include amines, 2 cinchona alkaloids, 3 thioureas, 4 phosphines, 5 and phosphoric acids, 6 as reported by Barbas, Melchiorre, Chen, Wang, Gong, Williams, Scheidt, and others. In the area of NHC catalysis, 7 the activation of enals or ketenes to react with isatin and its derivatives has furnished spiro- cyclic oxindole ȕ- and Ȗ-lactones or lactams, as disclosed by Nair, 8 Ye, 9 and our own laboratory. 10 Figure 1 Natural products and synthetic inhibitors with spirocyclic oxindole moiety containing six-membered rings We are interested in the activation of readily available and stable carboxylic esters via NHC to generate enolate and other intermediates for asymmetric synthesis. 11 Here we report the synthesis of spirocyclic oxindole derivatives containing a newly formed six-membered δ-lactam ring via NHC-catalyzed activation of α-aryl ester as a key step (Scheme 1). The six-membered lactam product bears a sterically bulky aryl substituent right adjacent to the spi- rocyclic carbon center and cannot be easily accessed using other approaches such as those based on enal 8,9b,9c,10 or ke- tene substrates. 9a Notably, the majority of previous meth- ods for spirocyclic oxindole synthesis via NHC and other organocatalysis led to spirooxindoles with a newly formed five-membered ring (Ȗ-lactam). 9c,10b In contrast, fewer studies 9d were directed toward six-membered ring- fused spirooxindoles structures (e.g., δ-lactams). This may limit the exploration of these molecules for biologi- cal activities. For instance, the spiroindolone NITD609 (Figure 1) has recently been found to kill blood stages of Plasmodium falciparum and Plasmodium vivax at a low nanomolar concentration. 1b This indicates that six-mem- bered-ring-containing spirooxindole compounds have po- tentials for the treatment of malaria. Scheme 1 NHC-catalyzed activation of α-aryl ester to synthesize spirocyclic oxindole δ-lactams We started by using phenyl acetic ester 1a and isatin-de- rived azadiene 2a as model substrates (Table 1). Evalua- tions on the NHC catalysts showed that triazolium-based precatalyst A and B could mediate the reaction to afford 3a with DIPEA as a suitable base (Table 1, entries 2 and NITD609 N H O NH O gelsemine N H Et O O Cl Cl MDM2-p53 interaction inhibitor N H O HN N H F Cl Ph O O R R = 4-O 2 NC 6 H 4 1a N N N Ph Ph O N + N N Ph H Ph O – N + N N Ph enolate N N Ph Ts O Me N N Ph O Ts Ph O Me 2a 3a base •• SYNLETT 2013, 24, 1197–1200 Advanced online publication: 17.05.20130936-52141437-2096 DOI: 10.1055/s-0033-1338945; Art ID: ST-2013-R0289-C © Georg Thieme Verlag Stuttgart · New York Downloaded by: Nanyang Technological University. Copyrighted material.