Radical-relay SmI2 catalysis: Expedient access to new bioisosteres for medicinal chemistry

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During the last decade, attempts to 'escape from flatland have led medicinal chemists to pursue small, compact sp3-rich structures that retain conformational control whilst improving solubility and selectivity. The replacement of benzene rings with saturated bioisosteres has become an important strategy to obtain new, patent-free molecules with improved biological activity and physicochemical profiles. Bicyclohexanes (BCHs) are an emerging class of bioisostere for use in drug discovery, however, synthetic access to these bicyclic architectures remains limited when compared to better-known bicyclopentane (BCP) bioisosteres. BCHs are amongst the first emerging bioisosteres for ortho-disubstituted benzenes, a common motif in drugs. While BCH bioisosteres with substituents attached in mode a have been reported, BCH bioisosteres with substituents attached in mode b have received little attention - our preliminary studies suggest the structure represents a better bioisostere for ortho-disubstituted benzenes.Amidst the current renaissance in radical chemistry, single electron transfer (SET) is used to generate radicals and the well-known reagent, samarium(II) diiodide (SmI2), remains one of the most important SET reagents, as evidenced by its commercial availability and widespread use. Despite 1000s of publications describing its use, a well-known disadvantage shadows SmI2; the reagent must almost always be used in stoichiometric excess. The handful of previous studies on catalysis with SmI2 invariably require super stoichiometric amounts of co-reductant and are impractical, however the Procter group have recently described the first C-C couplings catalyzed by SmI2; which represents a key step towards overcoming the major limitation associated with the reagent's use.We now propose to extend the synthetic reach of this radical relay catalysis by exploring the catalytic couplings of readily-accessible bicyclobutane (BCB) ketones with alkene partners to deliver bicyclo[2.2.1]hexane (BCH) ketones; a formal insertion of an alkene (or alkyne) into a C-C bond. In unpublished preliminary results, using as little as 7.5 mol% of SmI2, BCB ketones underwent chemoselective, catalytic coupling with acrylonitrile, divinyl sulfone, and acrylates to give BCHs in high isolated yield.Of note, branching in the alkyl (R1) substituent of the ketone appears to be well-tolerated. Furthermore, preliminary experiments have shown how the product BCH scaffold can be readily maniplulated; can be converted to ester and amide in near quantitative yield. We will also evaluate BCB carboxylic acid derivatives as partners, including esters and amides. A range of new alkene and alkyne partners will also be assessed in the catalytic couplings, including alkenes bearing a and b-substitution, alkynoates, and alkenes that deliver interesting quaternary a-aminoacids. Following an initial investigation of reaction scope, we will utilise these catalytic radical couplings, and further validate BCHs as sp3-rich bioisosteres for ortho-disubstituted benzenes and fused-bicyclic systems, by preparing saturated versions of thalidomide analogues.While IMiDs are blockbuster therapies in their own right, for example lenalidomide, they are currently of especially high interest due to their utility as CRBN ligase binders in clinically-evaluated chemical degraders (PROTACs). Enantioselective catalytic coupling of BCB ketone, capable of two-point binding to Sm, with methyl acrylate will give; subsequent Baeyer-Villiger oxidation, selective reduction of the more accessible ester, and bromination will deliver enantioenriched bromide. Alkylation of known amine with BCH bromo ester will provide Lenalidomide analogue. Additional substitution on the starting BCB ketones will deliver saturated analogues bearing an additional exit vector for possible use in the construction of drug conjugates.