Sulfoximine-Based Modular Enantioselective Synthesis of Azaspirocycles Featuring Sulfoximine Displacement, Dianion Cycloalkylation, RCM and N-Acyliminium Ion Formation

We describe a modular, enantioselective synthesis of functionalised azaspirocycles with a range of ring sizes. The synthesis exploits the special features of sulfoximines, including chirality, carbanion‐stabilisation, nucleophilicity, and nucleofugacity. Diastereoselective intramolecular amination of hydroxyalkyl‐substituted cycloalkenylsulfoximines by the carbamate method gave bicyclic oxazinanones containing an amino‐substituted tertiary C atom. Cycloalkylation of the corresponding C,N‐dianions with biselectrophiles afforded sulfoximine‐substituted spirocycles. Monoalkylation of the C,N‐dianions with functionalised electrophiles, having a double bond and acetal group, furnished the corresponding C‐alkylated bicyclic sulfoximines. Displacement of the sulfoximine group of bicyclic and spirocyclic sulfoximines by haloformate reactions gave the corresponding halides (Cl, I). Alkylation of the bicyclic halides with functionalised cuprates and reduction of the sulfoximine‐substituted bicycles, carrying an alkyl group at the Cα atom, gave starting materials for a step‐wise construction of the heterocyclic ring. Ring‐closing metathesis of a bicyclic C,N‐dienyl derivative furnished the corresponding spirocycle with an unsaturated piperidine ring. Cyclisation of an acetal group containing bicyclic oxazinanone gave spirocycles containing O,N‐acetal and enamide groups. The diastereoselective reaction of a spirocyclic O,N‐acetal with an allylsilane furnished the corresponding spirocycle, carrying an allyl group at the C atom adjacent to the N atom. Attempts to lithiate a bicyclic carbamate at the CH2 group adjacent to the N atom were not successful. A modular, enantioselective synthesis of azaspirocycles was devised based on the special features of sulfoximines, including chirality, carbanion stabilization, nucleofugacity, and nucleophilicity. Key steps are intramolecular amination, C,N‐dianion cycloalkylation, sulfoximine displacement, N‐acyliminium ion formation, and ring‐closing metathesis.