Synthesis of tetra-substituted cyclobutyl alkynes: Potential access to multi-size bicyclic compounds
Date
2025
Authors
Krueckl, Liam
Dhake, Kushal
Leitch, David C.
Journal Title
Journal ISSN
Volume Title
Publisher
University Of Victoria
Abstract
Bioisosteres – defined as chemical substituents that impart broadly similar properties when substituted with their counterparts on drug molecules – are tools used in the pharmaceutical industry to “fine tune” the biological activity of drug molecules. One group of bioisosteres that is receiving significant attention from medicinal chemists is the replacement of aromatic groups with rigid, saturated bicyclic alkanes. These bioisosteres are known to improve drug-like properties like solubility, selectivity and absorption but have not seen widespread adoption due to the challenges posed when synthesizing them. As such, there has been a “rallying call” amongst organic chemists to develop new methodologies that enable simple and efficient access to this class of bioisosteres. In accordance with this, the Leitch group has been engaged in research that utilizes bicyclo[1.1.0]butanes (BCBs) to access larger bicyclic alkanes through strain-release cycloadditions. Although to date BCBs have been successfully utilized to access a number of larger bicyclic compounds, success has been limited as certain products have only been accessed under hazardous conditions, using expensive rare earth metals, or not at all. Two examples that demonstrate this are alkyne substituted BCBs and bicyclo[1.1.1]pentanes (BCPs); the former only previously accessed with a rare earth catalyst, and the latter under hazardous conditions. To address this issue I have turned my attention to investigating alkyne substituted cyclobutanes as key intermediates towards the synthesis of hard-to-access bicyclic alkanes. A divergent synthetic route has enabled the synthesis of alkyne substituted BCBs without the use of a metal catalyst, and shown promise towards a simple synthesis of BCPs under benign conditions.
Description
Keywords
bioisostere, icyclobutane, synthesis, cyclobutane, alkyne