Stereo- and Regioselective Synthesis of Polysubstituted Chiral 1,4-Oxazepanes

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.