General access to cubanes as benzene bioisosteres

Strain-Release Photocatalysis

“…Combining strain release with HAT to access the functionalization of bridge positions 48 (cf. MacMillan et al on cubanes 66 and BCPs 46 ) represents an uncharted territory to expand the toolbox defined by Baran (1,2-difunctionalized-BCPs) 29 with 1,2,3-trifunctional-BCPs. Similarly, we can envisage that the further elaboration of mbenzene isostere BCHep from [3.1.1]propellane would create new opportunities for drug discovery.…”

Synthesis of polysubstituted bicyclo[2.1.1]hexanes enabling access to new chemical space

“…Selective functionalisation of the bridge positions via C–H functionalisation or cross-coupling approaches is challenging, with only a handful of examples for bicyclo[1.1.1]pentanes 13,14 and the related cubanes reported. 15 For example, MacMillan and co-workers reported a two-step bridge functionalisation of bicyclo[1.1.1]pentanes via bromination and subsequent metallaphotoredox amination or arylation. 13 a Examples of the functionalisation of BCHs are particularly rare.…”

A practical synthesis of 1,3-disubstituted cubane derivatives

“…2 More recently, attention has turned to developing applications of cubanes, particularly within medicinal chemistry, where it has been suggested that cubanes may act as bioisosteres for the benzene ring. [3][4][5] However, the vast majority of work on the applications of cubanes has been focused on 1,4-disubstituted cubanes (Fig. 1), as only these derivatives are available on multigram-scale.…”

“…6 This is a particularly elegant and extremely concise route, but is not scalable, as it relies on the cyclobutadieneiron(tricarbonyl) complex (6), which is not commercial, is highly toxic and must be synthesised from expensive precursors. 7 The Pettit approach was very recently revisited by MacMillan and co-workers, 4 exploiting bicyclic diazetidine 7 8 as a new cyclobutadiene precursor. However, cyclobutadiene is very reactive and cycloadduct 3 is air-and moisture-sensitive, thus the route is feasible only on small scales (the sequence was demonstrated on 1 mmol scale), limiting its practicality.…”

“…Finally, 1,3-cubane diester 11 underwent selective monosaponification to give carboxylic acid 17 (Scheme 3), which is a versatile intermediate en route to diverse 1,3-disubstituted cubanes. Thus, in addition to the cross-coupling methodology recently reported by the MacMillan group, 4 17 also undergoes standard functional group interconversions, and five novel functionalised 1,3-disubstituted cubanes were prepared in short order, through iodination of the carboxylic acid moiety to give 18, formation of the corresponding Weinreb amide 19, Curtius rearrangement to give 20, and selective boranemediated reduction to give alcohol 21. In addition, aminolysis of the ester moiety in 17 through heating in allylamine gave amide 22 in excellent yield (Scheme 3).…”