Abstract
A new reductive strategy for the stereo- and regioselective synthesis of functionalized isoquinuclidines has been developed. Pivoting on the chemoselective iridium(I)-catalyzed reductive activation of β,γ-unsaturated δ-lactams, the efficiently produced reactive dienamine intermediates readily undergo [4 + 2] cycloaddition reactions with a wide range of dienophiles, resulting in the formation of bridged bicyclic amine products. This new synthetic approach was extended to aliphatic starting materials, resulting in the efficient formation of cyclohexenamine products, and readily applied as the key step in the shortest (five-step) total synthesis of vinca alkaloid catharanthine to date, proceeding via its elusive biosynthetic precursor, dehydrosecodine.
Highlights
A new reductive strategy for the stereo- and regioselective synthesis of functionalized isoquinuclidines has been developed
Because of the important role of these compounds, and the challenges associated with their generation, we recognized that a mild and general reductive functionalization approach to access 1,2-dihydropyridines using readily available lactam starting materials could be of high synthetic value
Mechanistic studies from our group on the iridium-catalyzed reductive nitro-Mannich reaction revealed that tertiary lactams have a strong propensity to form enamines from the silylated hemiaminal intermediates via their corresponding iminium species.11a−f Aware of this, and the tolerance of alkene moieties to the reductive activation conditions,11g−v we reasoned that in the presence of suitably placed β,γ-unsaturation in the lactam ring of 15 (Scheme 1e), the 1,2-dihydropyridine species would likely arise from iminium ion 17 via silylated hemiaminal 16
Summary
P.G. is grateful to the EPSRC Centre for Doctoral Training in Synthesis for Biology and Medicine (EP/L015838/1) for a studentship, generously supported by AstraZeneca, Diamond. Z.R.W. is grateful to the CN Yang Scholars Programme of Nanyang.
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