Efficient synthesis of cyclopropane-fused heterocycles with bromoethylsulfonium salt.

The 3-azabicycloACHTUNGTRENNUNG[3.1.0]hexane is a common motif in natural products. Furthermore this rigid framework represents a privileged class of pharmacologically active compounds, often showing enhanced binding affinities with their targets (Figure 1). These bicycles also represent conformationally restricted analogues of piperidines (e.g. trovafloxacin). When substituted with a carboxylic acid moiety, they resemble conformationally restricted analogues of glutamate, gamma-amino butyric acid (GABA) or a/b-proline analogues (Figure 2). Numerous methods have been developed for the construction of azabicyclo ACHTUNGTRENNUNG[3.1.0]hexanes. These include the Kulinkovich/de Meijere reaction, cyclisation of tethered amines with metals (Pd, Ru, Rh, Ag), cyclisation of tethered cyclopropanes and the Simmons–Smith/ Corey–Chaykovsky/sulfur ylide–Au cyclopropanations. These methods are usually only effective in the synthesis of one specific type of scaffold. We were keen to develop a general strategy that could deliver 3-azabicycloACHTUNGTRENNUNG[3.1.0]hexanes with a range of functional groups in a range of positions. Our design plan for the synthesis of the scaffold was to effect a tandem process initiated by conjugate addition of an unsaturated amine 1 to vinyl sulfonium salt 2, generated in situ from the stable and crystalline salt 3 (Scheme 1). The intermediate sulfur ylide 4 would undergo intramolecular addition to the Michael acceptor to give a sulfonium enolate 5, which would ring-close to the cyclopropane 6. This tandem process is related to the previously described reactions that bear aldehydes or imines in place of Michael