TY - JOUR
T1 - Nitrogen-Bridged, Natural Product Like Octahydrobenzofurans and Octahydroindoles
T2 - Scope and Mechanism of Bridge-Forming Reductive Amination via Caged Heteroadamantanes
AU - Wales, Steven M.
AU - Adcock, Holly V.
AU - Lewis, William
AU - Hamza, Daniel
AU - Moody, Christopher J.
PY - 2018/9/16
Y1 - 2018/9/16
N2 - The biological significance of sp3-rich synthetic scaffolds with natural product like features yet distinct global frameworks is being increasingly recognized in medicinal chemistry and biochemistry. Taking inspiration from the vast array of bioactive, bridged alkaloids, we report the synthesis of unique, densely functionalized tricyclic scaffolds based on nitrogen-bridged octahydrobenzofurans and octahydroindoles. These heterocycle-rich frameworks were assembled by a one-pot, two-step bridge-forming reductive amination process, which was shown to proceed via caged, heteroadamantane intermediates that thermodynamically drive an exo–endo epimerization, enabling intramolecular aza-Michael addition over the concave face of the fused bicyclic precursors. In addition to evaluating the scope of this aza-bridge-forming reaction, further stereochemical complexity was introduced by subsequent diastereoselective ketone reductions and other manipulations. Finally, strategic diversity points (amino, carboxy) were decorated with common medicinal chemistry fragments, providing a set of exemplar derivatives with Lipinski-compliant physicochemical properties.
AB - The biological significance of sp3-rich synthetic scaffolds with natural product like features yet distinct global frameworks is being increasingly recognized in medicinal chemistry and biochemistry. Taking inspiration from the vast array of bioactive, bridged alkaloids, we report the synthesis of unique, densely functionalized tricyclic scaffolds based on nitrogen-bridged octahydrobenzofurans and octahydroindoles. These heterocycle-rich frameworks were assembled by a one-pot, two-step bridge-forming reductive amination process, which was shown to proceed via caged, heteroadamantane intermediates that thermodynamically drive an exo–endo epimerization, enabling intramolecular aza-Michael addition over the concave face of the fused bicyclic precursors. In addition to evaluating the scope of this aza-bridge-forming reaction, further stereochemical complexity was introduced by subsequent diastereoselective ketone reductions and other manipulations. Finally, strategic diversity points (amino, carboxy) were decorated with common medicinal chemistry fragments, providing a set of exemplar derivatives with Lipinski-compliant physicochemical properties.
KW - Aza-Michael addition
KW - Bridged compounds
KW - Drug discovery
KW - Heterocycles
KW - Reductive amination
UR - http://www.scopus.com/inward/record.url?scp=85053048215&partnerID=8YFLogxK
U2 - 10.1002/ejoc.201800962
DO - 10.1002/ejoc.201800962
M3 - Article (Academic Journal)
AN - SCOPUS:85053048215
SN - 1434-193X
VL - 2018
SP - 4696
EP - 4704
JO - European Journal of Organic Chemistry
JF - European Journal of Organic Chemistry
IS - 34
ER -