Puckering the Planar Landscape of Fragments: Design and Synthesis of a 3D Cyclobutane Fragment Library

Abstract

Fragment-based drug discovery (FBDD) has a growing need for unique screening libraries. The cyclobutane moiety was identified as an underrepresented yet attractive three-dimensional (3D) scaffold. Synthetic strategies were developed via a key 3azido-cyclobutanone intermediate, giving potential access to a range of functional groups with accessible growth vectors. A focused set of 33 novel 3D cyclobutane fragments was synthesised, comprising three functionalities: secondary amines, amides, and sulfonamides. This library was designed using Principal Component Analysis (PCA) and an expanded version of the rule of three (RO3), followed by Principal Moment of Inertia (PMI) analysis to achieve both chemical diversity and high 3D character. Cis and trans ring isomers of library members were generated to maximise the shape diversity obtained, while limiting molecular complexity through avoiding enantiomers. Property analyses of the cyclobutane library indicated that it fares favourably against existing synthetic 3D fragment libraries in terms of shape and physicochemical properties.

Fragment-to-Lead Medicinal Chemistry Publications in 2022

“…The distribution of target classes from each year of the F2L Perspective (and the total distribution for all eight years) is shown in Figure 1. The entries to date total 198, with other enzymes (70), kinases (49), and other protein−protein interactions (PPIs) (30) respectively comprising the most prevalent target classes. In 2022, PPIs and nonkinase or protease enzyme classes comprise the largest categories (∼80% combined), with bromodomains (6%), kinases (5%), and other (5%) making up only a small proportion compared with previous years.…”

Three-Component Cyclobutylation via Silver(I)-Catalyzed Carbene Transfer Reactions with [1.1.1]Propellane

“…These derivatives offer conformational restriction and C­(sp 3 )-rich complexity, making them valuable alternatives to hydrocarbon linkers or as replacements for aryl ring structures . The incorporation of the cyclobutyl group leads to enhanced physicochemical properties and improved metabolic stability in drug molecules . In particular, alkylidenecyclobutanes have emerged as intriguing motifs of substantial value in natural product synthesis, serving as pivotal intermediates in synthesis and conjugation processes .…”

2 + 2 Trapping of Acyloxy-1,2-cyclohexadienes with Styrenes and Electron-Deficient Olefins

“…The cyclobutane subunit is found in a variety of natural products, and its 4-membered ring offers a rigid scaffold for the construction of unique screening libraries. 16,17 However, although far less strained than cyclic allenes, cyclobutanes nonetheless possess sufficient strain to present challenges in their preparation via standard cyclization methods. In addition, alternative [2 + 2] methods are often limited by the requirement for ultraviolet light or expensive transition metal catalysts.…”

“…This enhanced reactivity has been exploited to generate complex molecules in a single step, usually through the production of [2 + 2], [4 + 2], and more recently [3 + 2] cycloadducts. ,− The generation of [2 + 2] cycloadducts from cyclic allenes, a reaction that is proposed to occur through a stepwise radical mechanism, , is of particular interest as it provides access to cyclobutane-containing products. The cyclobutane subunit is found in a variety of natural products, and its 4-membered ring offers a rigid scaffold for the construction of unique screening libraries. , However, although far less strained than cyclic allenes, cyclobutanes nonetheless possess sufficient strain to present challenges in their preparation via standard cyclization methods. In addition, alternative [2 + 2] methods are often limited by the requirement for ultraviolet light or expensive transition metal catalysts.…”