Bridge Functionalisation of Bicyclo[1.1.1]pentane Derivatives

Abstract

Escaping from flatland", by increasing the saturation level and three-dimensionality of drug-like compounds, can enhance their potency, selectivity and pharmacokinetic profile. One approach that has attracted considerable recent attention is the bioisosteric replacement of aromatic rings, internal alkynes and tert-butyl groups with bicyclo[1.1.1]pentane (BCP) units. While functionalisation of the tertiary bridgehead positions of BCP derivatives is well-documented, functionalisation of the three concyclic secondary bridge positions remains an emerging field. The unique properties of the BCP core present considerable synthetic challenges to the development of such transformations. However, the bridge positions provide novel vectors for drug discovery and applications in materials science, providing entry to novel chemical and intellectual property space. This review aims to consolidate the major advances in the field, serving as a useful reference to guide further work that is expected in the coming years. Joseph Anderson completed his MChem in 2020 (University of Oxford, Prof. Timothy Donohoe) working on cobalt-catalysed transformations of boronic acids. He subsequently joined the GSK/University of Strathclyde Collaborative Industrial PhD Programme, where he is currently working under the supervision of Dr Darren Poole, Dr Nicholas Measom and Prof. John Murphy on bicyclo[1.1.1]pentane methodology. Nicholas Measom completed his PhD in 2017 (GSK/University of Strathclyde Collaborative Industrial PhD programme, Dr David Hirst and Dr Craig Jamieson) working on the synthesis and application of bicyclo[1.1.1]pentanes within Lp-PLA2 inhibitors. He joined GSK as a synthetic medicinal chemist in 2017 and became an Investigator in 2020. Darren Poole completed his DPhil in 2014 (University of Oxford, Prof. Timothy Donohoe) where he worked on nucleophilic dearomatisation reactions, and hydrogen borrowing reactions of methanol. He joined GSK's Flexible Discovery Unit as a synthetic chemist in 2014, and is now a Scientific Leader and GSK Fellow in the Medicinal Chemistry department. His research interests are particularly focussed on the application of new synthetic methodologies and technologies in drug discovery. John Murphy was born in Dublin and educated at the University of Dublin (TCD) and the University of Cambridge. After Fellowships at Alberta and Oxford, he was appointed as Lecturer, then Reader, at the University of Nottingham. Since 1995, he has held the Merck-Pauson Professorship at the University of Strathclyde. His interests are in mechanism and synthesis.

Photochemical Formal (4 + 2)-Cycloaddition of Imine-Substituted Bicyclo[1.1.1]pentanes and Alkenes

“…All-carbon ring systems such as the bicyclo[1.1.1]­pentane system are of particular interest due to their inert nature and potential phenyl bioisosterism . However, despite recent innovations in the synthesis of 2-substituted bicyclo[1.1.1]­pentanes (Qin, Pfizer, Merck, and academic collaborators) and (oxa)­bicyclo[2.1.1]­hexanes (Enamine, Ltd.), most commercial compounds in this class are mono- or “ para ”-disubstituted. − Furthermore, commercial C sp 3 -rich polycyclic building blocks are often achiral, despite stereochemical complexity’s negative correlation with promiscuity and positive correlation with drug candidate success . The invention of new synthetic methods to access polysubstituted bicyclic cores with uniquely disposed exit vectors will allow for a more complete biological evaluation of low molecular weight, sp 3 -rich chemical space …”

Bioisosteres of the Phenyl Ring: Recent Strategic Applications in Lead Optimization and Drug Design

“…Although this design principle met with some success in the specific context of mGluR1α antagonists, replacement of the fluorophenyl ring of the γ-secretase inhibitor avegacestat ( 52a ) with a BCP moiety ( 52b ) provided a more compelling example of its potential in drug design that set the stage for a much broader application (Table ). Indeed, it was this study that catalyzed the extensive effort that has occurred over the past decade to develop synthetic methodologies to access variants of this compact and interesting ring system. ,,− The single crystal X-ray structures of 52a and 52b , depicted in Figure , confirmed their isosteric similarity that fully extended to a bioisosteric relationship, with 52b being marginally more potent than the progenitor 52a . However, the significant advantage of the BCP moiety over the phenyl ring in this context was manifested in the physicochemical properties of 52b , which were markedly different.…”

“…However, cubanes have only been explored as replacements for terminal and para -substituted phenyl rings, presumably a function of poorly developed synthetic accessibility to cubanes with unsymmetrical substitution patterns that might offer mimicry of ortho - and meta -substituted phenyl rings . This is analogous to the still evolving circumstance surrounding bicyclo[1.1.1]­pentane (BCP) as a phenyl ring mimetic ( vide infra ), where the development of new synthetic methodologies is facilitating broader exploration and application. , …”

“…Thus, successful applications of phenyl isosteres typically require further iterative molecular refinements that rely upon the simultaneous optimization of multiple parameters. The advances in the synthesis of molecules containing the BCP ring system that have occurred over the past decade provide an illustrative example of the benefits of the development of synthetic methodologies to a medicinal chemistry community that is actively seeking improved designs and architectures. , Convenient synthetic access to functionalized building blocks is a fundamental underpinning of the creative and effective application of phenyl bioisosteres in the design of the drugs of the future. The length of time (∼25 years) between the publication of Eaton’s hypothesis that the cubane polycycle could be an effective mimic of a para -substituted benzene ring and its practical validation reflects, in part, the absence of convenient synthetic access. , Similarly, applications of a cyclohexane ring as a benzene isostere may have been blunted, in part, by the perceived complications associated with the introduction and control of multiple chiral centers.…”

Synthesis of meta-substituted arene bioisosteres from [3.1.1]propellane

“…However, in stark contrast to the numerous sp 3 -rich bioisosteres for ortho-and para-substituted arenes (7)(8)(9)11), a geometrically-accurate bioisostere for meta-arenes is yet to be discovered. Recent reports on the use of (hetero)bicyclo[2.1.1]hexanes (12)(13)(14)(15)(16) and bridge-substituted BCPs (17)(18)(19) have contributed to this arena (Fig. 1B).…”