title: Stereo- and regioselective synthesis of polysubstituted chiral 1,4-oxazepanes.
abstract: The number of cyclic molecular scaffolds available to medicinal chemists remains limited, and simple structures such as oxazepanes are still made using multistep procedures, including a number of protection/deprotection steps and purifications. We report herein an expedient and efficient synthesis of chiral polysubstituted oxazepanes. The developed method relies on a regio- and stereoselective 7-endo cyclization through haloetherification. Mechanistic studies using a combination of computations and experiments confirmed the expected role of the asymmetry of the chiral bromonium intermediate on the haloetherification regioselectivity. Computations also suggested that the bromonium intermediate is formed with no transition state; hence, the stereoselectivity is controlled primarily by the conformation of the substrate. Applied to a set of 16 substrates, tetra- and pentasubstituted oxazepanes were prepared with good yields and moderate to excellent regio- and stereoselectivities.
authors.affiliation: Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, Québec, Canada H3A 2K6.
authors.forename: Michelle
authors.initials: M
authors.lastname: Bezanson
authors.forename: Joshua
authors.initials: J
authors.lastname: Pottel
authors.forename: Rana
authors.initials: R
authors.lastname: Bilbeisi
authors.forename: Sylvestre
authors.initials: S
authors.lastname: Toumieux
authors.forename: Mickaël
authors.initials: M
authors.lastname: Cueto
authors.forename: Nicolas
authors.initials: N
authors.lastname: Moitessier
mesh_terms: D003500:Cyclization; D004987:Ethers / Q000737:chemistry*; D054879:Halogenation; D015394:Molecular Structure; D010077:Oxazepines / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism
chemical_list: D004987:Ethers; D010077:Oxazepines