Diastereoselective Synthesis of Hetero-[2]-Ladderanes

Conformationally rigid heterobicyclic motifs with well-defined exit vectors have emerged as valuable isosteric replacements for pyridine. While these rigid 3D structures successfully mimic 3,5-disubstituted pyridine derivatives, no isosteric analogues of 2,3-disubstituted pyridines have been reported, despite their widespread occurrence in bioactive compounds. Herein, we report the first diastereoselective synthesis of hetero-[2]-ladderanes, representing a new class of potential 2,3-disubstituted pyridine isosteres, via carbonyl photoexcitation. This protocol is amenable to a variety of 2-azetines and isatins, with remarkable functional-group tolerance, enabling rapid construction of complex spiro-oxa-aza-[2]-ladderanes as single diastereomers. Notably, benzaldehyde derivatives could also participate, affording oxa-aza-[2]-ladderanes with high stereoselectivity. Exit-vector analysis of an oxa-aza-[2]ladderane and a 2,3-disubstituted pyridine-based drug demonstrated the potential of this scaffold as a possible isosteric mimic of 2,3-disubstituted pyridine. Experimental-based mechanistic studies combined with density functional theory have rationalized the observed reactivity and selectivity. Finally, we explored an unprecedented strainenabled, aromaticity-driven Grob-type fragmentation of a hetero-[2]-ladderane, yielding synthetically valuable αhydroxy-β-amino ketone and aminotriol derivatives.