C3ob41415a 6502..6509 ++

Natural products and their signature fragments are an enduring resource for identifying biological modulators. A number of biologically active alkaloids, such as strychnofoline and isorhynchophylline (Fig. 1), feature spiroindolizidine oxindoles. This fragment is considered ‘privileged’ for potential therapeutic investigation and there is much interest in developing expedient synthesis of such structures. Target spiroindolizidineoxindole structures may be efficiently accessed by 1,3-dipolar cycloaddition of 3-alkylideneindoline-2-ones. Serov et al. described reactions between N-phenylacylquinolinium ylides with 3-alkylidene oxindoles, while extended studies of this type of reaction have recently been reported. The latter cycloadducts have a relatively high molecular weight due to additional aromatic rings and it is not easy to envisage strategies for their transformation into natural products or drug-like scaffolds. There are no literature descriptions of corresponding 1,3dipolar cycloadditions of pyridinium ylides to 3-alkylidene oxindoles, yet such cycloadducts would be attractive for access to spirooxindole alkaloids and possible therapeutics. Cycloaddition reactions of pyridinium ylides have previously been reported but in situ oxidation is commonly used, leading to valuable unsaturated indolizines. Of course, such oxidations destroy the rich stereochemical information accumulated during the cycloaddition. Early investigation of general pyridinium ylide cycloadditions noted limited stability of the tetrahydroindolizine cycloadducts and this may have discouraged further investigation of these products. The 1,2-dihydropyridine motif embedded within tetrahydroindolizine cycloadducts is generally regarded as unstable with few exceptions, although there have been exciting developments in unlocking their synthetic potential. This report demonstrates that cycloaddition reactions between pyridinium ylides 2 (Table 1) and 3-alkylidene oxindoles