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Synthetic strategies were developed via a key 3\u2010azido\u2010cyclobutanone 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. <jats:italic>Cis<\/jats:italic> and <jats:italic>trans<\/jats:italic> 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.<\/jats:p>","DOI":"10.1002\/cmdc.202200113","type":"journal-article","created":{"date-parts":[[2022,3,11]],"date-time":"2022-03-11T22:18:18Z","timestamp":1647037098000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Puckering the Planar Landscape of Fragments: Design and Synthesis of a 3D Cyclobutane Fragment Library"],"prefix":"10.1002","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3030-9485","authenticated-orcid":false,"given":"David J.","family":"Hamilton","sequence":"first","affiliation":[{"name":"Amsterdam Institute of Molecular and Life Sciences (AIMMS) Vrije Universiteit Amsterdam  De Boelelaan 1108 1081 HZ Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marieke","family":"Beemsterboer","sequence":"additional","affiliation":[{"name":"Amsterdam Institute of Molecular and Life Sciences (AIMMS) Vrije Universiteit Amsterdam  De Boelelaan 1108 1081 HZ Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline M.","family":"Carter","sequence":"additional","affiliation":[{"name":"Amsterdam Institute of Molecular and Life Sciences (AIMMS) Vrije Universiteit Amsterdam  De Boelelaan 1108 1081 HZ Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasmina","family":"Elsayed","sequence":"additional","affiliation":[{"name":"Amsterdam Institute of Molecular and Life Sciences (AIMMS) Vrije Universiteit Amsterdam  De Boelelaan 1108 1081 HZ Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5885-084X","authenticated-orcid":false,"given":"Rilana E. 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