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 Minireview 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.

Recent Progress in Accessing Multi-functionalized Caged Hydrocarbons: En Route to Highly Functionalized Saturated (Bio)isosteres of Benzene Rings

“…52 However, obtaining a bridge-functionalized BCP is still challenging. 53 In this section, recent examples of such attempts are explained with categorization of the reaction pattern.…”

Photoinduced Alkylation of Diazines with N-(Acyloxy)phthalimides in the Presence of Triethylamine

“…The decarboxylative coupling of glycyrrhetinic acid derivative with 2-chloropyrimidine ( 2 ) proceeded in a diastereoselective manner (for 15 ). The method also proved useful for linking 2-chloropyrimidine ( 2 ) with bicylo[2.2.2]octane and bicyclo[1.1.1]pentane 34 at their bridgehead positions (for 16 and 17 ), although the installation of a cubane moiety displayed lower reactivity (for 18 ). It should be noted that the alkylation process with a primary alkyl radical was inefficient, resulting in a moderate yield of 19 after a longer reaction time.…”

Rapid Access to 2-Substituted Bicyclo[1.1.1]pentanes

“…Following optimization, we turned to evaluate the scope of the arylation reaction for a range of BCP bromides and aryl bromide coupling partners (Figure 3). Pleasingly, both disubstituted and monosubstituted BCP bromides could be successfully coupled (10)(11)(12)(13)(14)(15). A wide range of aryl bromides were also found to serve as productive coupling partners: para-substituted electron-deficient and electron-rich substituents could be coupled in excellent yield (16)(17)(18)(19)(20)(21).…”

“…While there is substantial interest in synthesizing these bridge-substituted BCPs (i.e. BCPs substituted at the 2-position) as a means to access novel chemical space and replace ortho-or meta-substituted arene rings in bioactive molecules, [12][13][14] no methods exist that allow the direct preparation of complex 2-substituted BCP scaffolds. Although current approaches have enabled the introduction of some drug-like substituents at the bridge position, they suffer from long step counts and often lack modularity as they require pre-installation of the desired 2-substitutent prior to BCP core construction.…”

“…Overall, we speculated these milder conditions would favor bridge monofunctionalization over multifunctionalization and/or ring opened products which are traditionally favored in BCP C-H bridge functionalization protocols. 13 We first examined this bromination protocol with the commercially available 1,3-dicarboxylic acid BCP 1. Pleasingly, exposure of 1,3-dicarboxylic acid BCP and NCS to visible light (450 nm) conditions, in the presence of brominating agent bromotrichloromethane, led to the formation of 2-brominated-1,3dicarboxylic acid BCP 3 in moderate yield (Table S1-4).…”