Bicyclo[1.1.1]pentane (BCP) derivatives are of high interest in medicinal chemistry as non-classical bioisosteres for phenyl, tert-butyl and acetylene groups. Overall, they improve the physicochemical properties (such as permeability, solubility and metabolic stability) of the molecule in which they are incorporated. Effective methods to produce carbon-disubstituted BCPs are scarce and usually require early installation in a synthesis, mediated by UV light irradiation, or super-stoichiometric amounts of organometallic reagents at high temperatures. We have developed a mild, efficent and highly functional group-tolerant BEt3-initiated atom transfer radical addition of organohalides to tricyclo[1.1.1.01,3]pentane (TCP, 1), producing halogenated BCPs containing α-carbonyl, α-sulfonyl, alkyl, benzyl and 1,3-dicarbonyl groups. The carbon-halide bond can be readily reduced using tris(trimethylsilyl)silane, with BEt3 again used as the radical initiator. The combination of these methods allows access to complex BCP-containing molecules, such as nucleoside 2, aspartame analogue 3 and fentanyl analogue 4. Further studies have shown that iodoBCPs are reactive under iron-catalyzed Kumada cross-coupling conditions, yielding 1,3-carbon-disubstituted BCP in only two steps from TCP. The development of these chemistries will be discussed in this presentation.

Synthesis and cross-coupling of 1-halo-3-substituted bicyclo[1.1.1]pentanes: En route to 1,4-disubstituted phenyl bioisosteres

256th National Meeting (2018)

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