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Synthesis of Novel Azaspirocycles as Multifunctional Modules in Drug Discovery Johannes A. Burkhard,?cCarine Gue′ rot,?rHenner Knust,?nCarine Gu erot,?aDong Bo Li,?oBoris H. Tchitchanov,?oMark Rogers-Evans,?and Erick M. Carreira*,? Abstract: Introduction: Methods: Results: Spirocyclic systems of heterocyclic spiro[3.3]heptanes may be considered as alternatives to 1,3-heteroatom-substituted cyclohexanes, which are otherwise insuf?ciently stable to allow their use in drug discovery. Figure1. straightforward access toward previously unreported substituted, heterocyclic spiro[3.3]heptanes is disclosed. 1,4-heteroatom substitution pattern in six-membered cycles is chemically stable, the alternative 1,3 relationship, for example in 1,3-oxazinane can lead to chemically unstable systems of rather limited use for drug design. Figure 2. 1,6-Heteroatom-substituted spiro[3.3]heptanes as alternatives to 1,3-heteroatom-substituted cyclohexanes. 1,6-heteroatom-substituted spiro[3.3]heptane ring systems have little precedence. The only example in the literature is a N-piperonyl substituted 6-oxa-1-azaspiro[3.3]heptane from previous work. With the exception of spirocycle 20, 1,6-heteroatom-substituted spiro[3.3]- heptanes 4 and 16-19 can be prepared from their corresponding four-membered cyclic ketones 6 following the same general strategy (Scheme 1). Oxetane 20 was obtained in one step from protected azetidin-3-one 1 using a “double Corey Chaykovsky” methylene insertion reaction.Subsequent to their preparation, stability tests have revealed that16-18, 24, and 25 remained essentially unaffected under stirring with 0.5 M HCl in THF/H2O for several hours, as assayed by 1H NMR spectroscopy and reisolation of the starting material. Scheme 1. Synthesis of Spirocyclic Building Blocks Previous syntheses of ketone 6 were rather low yielding and dif?cult to reproduce with larger amounts of material; therefore, we developed a new synthesis from commercially available dibromide 21