Azetidines, spirocyclic

A review of the Pummerer reaction describes much of the breadth of this work [18], but a more recent paper expanded this chemistry to form spirocycles which contain adjacent quaternary carbons [20]. While the test cases (22 to form the spirocycle 23) proceeded smoothly, the application to a more complicated structure (24), which would be closer to the ring system seen in the natural product, crassanine, demonstrated that a nearby amine would interfere with the addition of the silyl enol ether as a nucleophile. While this precludes the utility of this reaction for the crassanine alkaloids, the unusual ring formed in 25, a C-3-azetidine spirocyclic indolenine, is found in the chartelline alkaoids. 

The nucleophilic reaction of Grignard reagents with azetidin-2,3-dione 270 yielded mainly fA-3-hydroxyazetidin-2-ones 271 (Equation 76) <2006S115>. A regio- and stereoselective reaction of azetidine-2,3-dione 272 with an organoindium compound led to the formation of azetidin-2-one-tethered homoallylic alcohol 273 (Equation 77), which has been used as precursor of spirocyclic azetidin-2-ones <2004TL6429>. 

It is also common to design libraries for addition to a corporate collection. A recent example from Astra Zeneca is illustrative of the approach. A set of spirocyclic diamines were identified as privileged templates, and a bis-azetidine core (Scheme 14.1), which is under represented in the AZ collection and patent literature, was selected. 

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