Cyclobutanes in Small‐Molecule Drug Candidates

Abstract

Cyclobutanes are increasingly used in medicinal chemistry in the search for relevant biological properties. Important characteristics of the cyclobutane ring include its unique puckered structure, longer CÀ C bond lengths, increased CÀ C π-character and relative chemical inertness for a highly strained carbocycle. This review will focus on contributions of cyclobutane rings in drug candidates to arrive at favorable properties. Cyclobutanes have been employed for improving multiple factors such as preventing cis/trans-isomerization by replacing alkenes, replacing larger cyclic systems, increasing metabolic stability, directing key pharmacophore groups, inducing conformational restriction, reducing planarity, as aryl isostere and filling hydrophobic pockets.[a] M. R. van der Kolk, M.

Expanding the Chemical Space of 1,2-Difunctionalized Cyclobutanes

“…The increasingly important role of the cyclobutane framework for pharmaceutical and medicinal chemistry , is closely related to its structural features. The nonplanarity and sp 3 -enrichment, − relatively rigid structure, and stereochemical aspects associated with introduction of a cyclobutane core into the parent molecules endow them with unique biological characteristics while largely retaining the chemical properties.…”

Coordination Polymer-Mediated Molecular Surgery for Precise Interconversion of Dicyclobutane Compounds

“…The rigid cyclobutane backbone is an important structural scaffold for biologically active compounds and a popular synthetic target for drug development. − The photoinduced [2 + 2] cycloaddition reaction is the most atom-economical and straightforward approach for constructing this motif. , However, this method suffers from poor selectivity and therefore, a potentially tedious separation, especially for the synthesis of multi-cyclic isomers . CPs can supply stereo-directive templating through olefin pre-arrangement; − however, the preorganization of multiple CC pairs is challenging to manage at the molecular level because of the dynamic nature of CC bonds .…”

Synthesis of novel α-trifluoromethyl cyclobutane-containing building blocks

“…1,3-Substituted cyclobutanes are achiral 3D-shaped motifs, which makes them valuable in drug discovery. In medicinal chemistry, they are often considered as restricted mimics of alkyl chains and have been applied for the design of several drugs or drug candidates, as well as valuable tools for chemical biology [1].…”