We report the first desymmetrization of bisallylic amides by enantioselective bromocyclization with BINAP monoxide as a catalyst. Depending upon the substitution pattern of the alkene moieties, densely functionalized, optically active oxazoline or dihydrooxazine compounds were obtained in a highly stereoselective manner. The remaining alkene moiety was subjected to various functional group manipulations to afford a diverse array of chiral molecules with multiple stereogenic centers.

The mechanism of our previously reported catalytic asymmetric bromocyclization reactions using 2,2′-bis­(diphenylphosphino)-1,1′-binaphthyl (BINAP) monoxide was examined in detail by the means of control experiments, NMR studies, X-ray structure analysis, and CryoSpray electrospray ionization mass spectrometry (ESI-MS) analysis. The chiral BINAP monoxide was transformed to a key catalyst precursor, proton-bridged bisphosphine oxide complex (POHOP·Br), in the presence of N-bromosuccinimide (NBS) and contaminating water. The thus-formed POHOP further reacts with NBS to afford BINAP dioxide and molecular bromine (Br2) simultaneously in equimolar amounts. While the resulting Br2 is activated by NBS to form a more reactive brominating reagent (Br2NBS), BINAP dioxide serves as a bifunctional catalyst, acting as both a Lewis base that reacts with Br2NBS to form a chiral brominating agent (PO+Br) and also as a Brønsted base for the activation of the substrate. By taking advantage of this novel concerted Lewis/Brønsted base catalysis by BINAP dioxide, we achieved the first regio- and chemodivergent parallel kinetic resolutions (PKRs) of racemic unsymmetrical bisallylic amides via bromocyclization.

We describe a concise enantioselective synthesis of the HIV-protease inhibitor nelfinavir (1) via a new route in which the key step is construction of the central optically active 1,2-amino alcohol framework via asymmetric bromocyclization of bisallylic amide with N-bromosuccinimide in the presence of a catalytic amount of ( S)-BINAP or ( S)-BINAP monoxide. The remaining alkene and bromo functionalities were used to install the requisite thioether and chiral perhydroisoquinoline units, respectively.