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. 2023 May 24;145(20):10960-10966.
doi: 10.1021/jacs.3c02616. Epub 2023 May 5.

Skeletal Editing Approach to Bridge-Functionalized Bicyclo[1.1.1]pentanes from Azabicyclo[2.1.1]hexanes

Brandon A Wright  1 , Anastassia Matviitsuk  2 , Michael J Black  1 , Pablo García-Reynaga  2 , Luke E Hanna  2 , Aaron T Herrmann  2 , Michael K Ameriks  2 , Richmond Sarpong  1 , Terry P Lebold  2
Affiliations

Skeletal Editing Approach to Bridge-Functionalized Bicyclo[1.1.1]pentanes from Azabicyclo[2.1.1]hexanes

Brandon A Wright et al. J Am Chem Soc. .

Abstract

Azabicyclo[2.1.1]hexanes (aza-BCHs) and bicyclo[1.1.1]pentanes (BCPs) have emerged as attractive classes of sp3-rich cores for replacing flat, aromatic groups with metabolically resistant, three-dimensional frameworks in drug scaffolds. Strategies to directly convert, or "scaffold hop", between these bioisosteric subclasses through single-atom skeletal editing would enable efficient interpolation within this valuable chemical space. Herein, we describe a strategy to "scaffold hop" between aza-BCH and BCP cores through a nitrogen-deleting skeletal edit. Photochemical [2+2] cycloadditions, used to prepare multifunctionalized aza-BCH frameworks, are coupled with a subsequent deamination step to afford bridge-functionalized BCPs, for which few synthetic solutions currently exist. The modular sequence provides access to various privileged bridged bicycles of pharmaceutical relevance.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1.
Figure 1.
A) Chemical space according to substituent display. B) Preclinical candidates including aza-BCH or BCP motifs. C) Skeletal editing as a strategy for late-stage core modification. D) N-atom deletion as a strategy for scaffold hopping between aza-BCH and BCP cores.
Figure 2.
Figure 2.
A) Previous approaches for aza-BCH synthesis. B) Known strategies for 1,2-BCP preparation. C) Nitrogen deletion to form BCPs through progressive formation of ring strain.
Scheme 1.
Scheme 1.
A) Synthetic Sequence to Access Aza-BCH Cores and B) Synthesis of Monosubstituted BCPs through Nitrogen Deletiona,b aYields are based on NMR comparison to internal standard. bPMP = p-methoxyphenyl.
Scheme 2.
Scheme 2.
A) Diastereoconvergent [2+2] Photocycloaddition to Access 1,2-Substituted Aza-BCH Scaffolds and B) Synthesis of 1,2-Substituted BCPs through Nitrogen Deletion
Scheme 3.
Scheme 3.. Aryl Scope of 1,2-Substituted BCPs through Nitrogen Deletion
aMixture of diastereomers. bNitrogen deletion carried out on mixture of diastereomers. cDiastereomeric ratio not determined due to the instability of the intermediate. NMR yields indicated in parentheses.
Scheme 4.
Scheme 4.. A) Scope of Substituted Allyl Amines in Nitrogen Deletion, B) Synthesis of 1,2,4-Substituted BCPs, and C) Gram-Scale Preparation of Aza-BCH and BCP Cores
aMixture of diastereomers. bNitrogen deletion carried out on mixture of diastereomers. NMR yields indicated in parentheses.
See this image and copyright information in PMC

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