Synthesis of Multi-Substituted Bicycloalkyl Boronates: An Intramolecular Coupling Approach to Alkyl Bioisosteres

Abstract

<p>Bicyclic hydrocarbons, bicyclo[1.1.1]pentanes (BCPs) in particular, play an emerging role as saturated bioisosteres in pharmaceutical, agrochemical, and material chemistry. Taking advantage of strain release strategies, prior synthetic studies have featured the synthesis of bridgehead-substituted (C1, C3) BCPs from [1.1.1]propellane. This work describes a novel approach to accessing multi-substituted BCPs via a new type of intramolecular cyclization. In addition to the C1, C3-disubstituted BCPs, this method also enables the construction of yet underexplored tri-substituted (C1, C2 and C3) BCPs from readily accessible cyclobutanones. The broad generality of this cyclization is examined through synthesis of a variety of caged bicyclic molecules, ranging from [1.1.1] to [3.2.1] scaffolds. The modularity afforded by the pendant bridgehead Bpin resulted from the cyclization is demonstrated via several downstream functionalizations, highlighting the ability of this approach for programmed and divergent synthesis of multi-substituted bicyclic hydrocarbons.<br></p>

Bridge Functionalisation of Bicyclo[1.1.1]pentane Derivatives

“…In early 2021, Qin presented an elegant contemporary adaptation (Scheme 18 B ) [73] of the original intramolecular displacement methodology employed in the first synthesis of bicyclo[1.1.1]pentane (Scheme 18 A ). [ 44 , 74 ] Cyclobutanones 118 were accessed through the group's boron‐preserving cross‐coupling of aldehydes 117 followed by ketal hydrolysis.…”

“…The methodology of Qin [73] also provided BCP derivative 133 containing a bridge BPin substituent (Scheme 21 ). Likewise, no transformations of the bridge functionality were then explored.…”

The Powerful Symbiosis Between Synthetic and Medicinal Chemistry

“…The Baran group, in collaboration with scientists at Pfizer, developed the synthesis of 1,2-disubstituted BCP building blocks bearing two synthetic handles for further derivatization [12], whereas scientists at Merck Sharp & Dohme (Merck & Co., Inc.) reported on the synthesis of 1-amino-2-alkyl BCPs [13]. Even more highly substituted BCPs are becoming synthetically accessible (e.g., 1,3-disubstituted 2,2difluoro-BCP building blocks [14,15] and 1,2,3-trisubstituted BCPs [16]). However, more straightforward methods for accessing different substitution patterns for cubanes still need to be developed.…”

1,2-Difunctionalized bicyclo[1.1.1]pentanes: Long–sought-after mimetics for ortho / meta -substituted arenes

“…1A). Only recently have reports emerged delineating creative approaches to fill this gap [an initial disclosure of this study was deposited on ChemRxiv (21); subsequently, two additional reports (22,23) have appeared describing different and orthogonal strategies]. This is certainly due to the absence of synthetic methods to achieve 1,2-difunctionalization of BCPs rather than the lack of desire to replace orthoand metadisubstituted benzenes in bioactive molecules, which has been regularly mentioned over the years (3)(4)(5)(6)(7)(8).…”