Substituted morpholine derivatives appear frequently in biologically active compounds and thus novel routes towards such structures are of great synthetic interest. Herein, we report the total syntheses of chelonin A, a morpholine-derived marine natural product with reported antibacterial and anti-inflammatory activity. The key step in this process was a rhodium carbenoid 1,3-insertion into a bromohydrin O−H bond, followed by annulation, leading to a 2,6-disubstituted-3,4-dihydro-2H-1,4-oxazine core. This work was then extended to deliver the first asymmetric total synthesis of (−)-chelonin A using an enantioenriched bromohydrin prepared in-turn via asymmetric transfer hydrogenation of an -bromoketone.
The 2-iodoxybenzoic acid (IBX)-controlled oxidative dearomatization
of pyrroles occurs very slowly (or not all) in many organic solvents,
including DMSO in which IBX is soluble. Interestingly, although IBX
is only partially soluble in acetic acid, this solvent mediates the
pyrrole oxidative dearomatization. With the aid of density functional
theory (DFT) calculations, we have discovered a new mode of reactivity,
termed the periodinane oxy-assisted (POA) oxidation mechanism, which
explains this observation.
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