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Rigid bicycles are becoming more popular in the pharmaceutical industry because they allow for expansion to new and unique chemical spaces. This work describes a new strategy to construct 2‐azanorbornanes, which can act as rigid piperidine/pyrrolidine scaffolds with well‐defined exit vectors. To achieve the synthesis of 2‐azanorbornanes, new strain‐release reagent, azahousane, is introduced along with its photosensitized strain‐release formal cycloaddition with alkenes. Furthermore, new reactivity between a housane and an imine is disclosed. Both strategies lead to various substituted 2‐azanorbornanes with good selectivities.

 

A strategy for the photosensitized cycloaddition of alkenylboronates and allylic alcohols by a temporary coordination is presented. The process allows for the synthesis of a diverse range of cyclobutylboronates. Key to development of these reactions is the temporary coordination of the allylic alcohol to the Bpin unit. This not only allows for the reaction to proceed in an intramolecular manner but also allows for high levels of stereo and regiocontrol. A key aspect of these studies is the utility of the cycloadducts in the synthesis of complex natural products artochamin J and piperarborenine B. 

The crystal structures of three β-halolactic acids have been determined, namely, β-chlorolactic acid (systematic name: 3-chloro-2-hydroxypropanoic acid, C 3 H 5 ClO 3 ) (I), β-bromolactic acid (systematic name: 3-bromo-2-hydroxypropanoic acid, C 3 H 5 BrO 3 ) (II), and β-iodolactic acid (systematic name: 2-hydroxy-3-iodopropanoic acid, C 3 H 5 IO 3 ) (III). The number of molecules in the asymmetric unit of each crystal structure ( Z ′) was found to be two for I and II, and one for III, making I and II isostructural and III unique. The difference between the molecules in the asymmetric units of I and II is due to the direction of the hydrogen bond of the alcohol group to a neighboring molecule. Molecular packing shows that each structure has alternating layers of intermolecular hydrogen bonding and halogen–halogen interactions. Hirshfeld surfaces and two-dimensional fingerprint plots were analyzed to further explore the intermolecular interactions of these structures. In I and II, energy minimization is achieved by lowering of the symmetry to adopt two independent molecular conformations in the asymmetric unit. 

Aromatic ring isosteres and rigidified saturated hydrocarbons are important motifs to enable drug discovery. Herein we disclose [2]-ladderanes as a class ofmeta-substituted aromatic ring isosteres and rigidified cyclohexanes. A straightforward synthesis of the building blocks is presented along with representative derivatization. Preliminary studies reveal that the [2]-ladderanes offer similar metabolic and physicochemical properties thus establishing this class of molecules as interesting motifs.