Synthesis of bicyclo[3.1.1]heptanes, meta-substituted arene isosteres, from [3.1.1]propellane

Journal article : Review

The use of saturated small-ring bridged hydrocarbons as bioisosteres for aromatic rings has become a popular tactic in drug discovery. Perhaps the best known of such hydrocarbons is bicyclo[1.1.1]pentane, for which the angle between the exit vectors of the bridgehead substituents is identical to that of a para-substituted arene (180°). The development of meta-arene (bio)isosteres is much less explored due to the challenge of identifying an accurate geometric mimic (substituent exit vector angle ~120°, dihedral angle ~0°). To address this, we recently reported straightforward access to bicyclo[3.1.1]heptanes (BCHeps), which exactly meet these geometric properties, via radical ring-opening reactions of [3.1.1]propellane. This required the development of a scalable synthesis of [3.1.1]propellane, as well as the implementation of various ring-opening reactions and derivatizations. Here we describe methodology for a multigram scale synthesis of [3.1.1]propellane in five steps from commercially available ethyl 4-chlorobutanoate, which proceeds in an overall yield of 26–37%. We also describe the functionalization of [3.1.1]propellane to three key classes of BCHep iodides by photocatalyzed-atom transfer radical addition reactions using 456 nm blue light. We further report protocols for the elaboration of these products to other useful derivatives, via iron-catalyzed Kumada coupling with aryl Grignard reagents and conversion of a pivalate ester to a carboxylic acid through hydrolysis/oxidation. The total times required to synthesize [3.1.1]propellane, the BCHep iodides and the BCHep carboxylic acid are ~53, 6–8 and 40 h, respectively, requiring an average level of synthetic chemistry expertise (for example, masters and/or graduate students).

Authors: Paul, B; Dasgupta, A; Frank, N; Nugent, J; Anderson, EA

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Springer Nature
• Journal: Nature Protocols
• Volume: 20
• Issue: 7
• Pages: 2056-2082
• Publication date: 2025-02-17
• Acceptance date: 2024-11-07
• DOI: 10.1038/s41596-024-01109-5
• EISSN: 1750-2799
• ISSN: 1754-2189
• Pmid: 39962198
• Language: English
• Keywords: drug discovery and development; synthetic chemistry methodology
• Subtype: Review