Skeletal Editing Approach to Bridge-Functionalized Bicyclo[1.1.1]pentanes from Azabicyclo[2.1.1]hexanes

Abstract

Azabicyclo[2.1.1]hexanes (aza-BCHs) and bicyclo[1.1.1]pentanes (BCPs) have emerged as attractive classes of sp 3-rich cores for replacing flat, aromatic groups with metabolically resistant, three-dimensional frameworks in drug scaffolds. Strategies to directly convert, or “scaffold hop”, between these bioisosteric subclasses through single-atom skeletal editing would enable efficient interpolation within this valuable chemical space. Herein, we describe a strategy to “scaffold hop” between aza-BCH and BCP cores through a nitrogen-deleting skeletal edit. Photochemical [2+2] cycloadditions, used to prepare multifunctionalized aza-BCH frameworks, are coupled with a subsequent deamination step to afford bridge-functionalized BCPs, for which few synthetic solutions currently exist. The modular sequence provides access to various privileged bridged bicycles of pharmaceutical relevance.

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

“…Acylation of the pendant alcohol of 2q was possible in 96% yield, as was saponification of the ethyl ester in 2u . 17 b …”

“…16 De novo approaches which install additional substituents directly and offer a complementary approach to this challenge are emerging, but remain uncommon. 17 The recent reports of fragment insertion into bicyclo[1.1.0]butanes are powerful examples of the concept. 18,19 Cleavage of the central C–C bond enables insertion of alkenes, 18 a – e , g , i , k ketones 18 h or even ring-opened cyclopropanes 18 j , f and leads to a range of bridge-substituted structures.…”

“…22 Recently, Mykhailiuk and co-workers reported a UV light/benzophenone-mediated protocol to bridge-substituted 1,5-disubstituted BCHs that could function as ortho -substituted benzene bioisosteres (Scheme 1C). 17 b ,23,24 However, this reactivity platform is extremely versatile and we believed it could be used to give targeted access to the 10 different exit vectors of BCHs (Scheme 1D). This in turn would enable preparation of a whole range of differently-substituted BCHs, containing various combinations of bridge and bridgehead substituents, consistent with the reaction design criteria outlined above.…”

Deaminative ring contraction for the synthesis of polycyclic heteroaromatics: a concise total synthesis of toddaquinoline

“…39 While unoptimized, this observation suggests that other benzo[ h ]quinoline substitution patterns could be accessible via S N Ar of an appropriately halogenated precursor. Due to the preliminary efficiency of this deaminative contraction method and its potential orthogonality to recent oxidative deaminative ring contraction methods, 40,41 we set out to develop a general build-cyclize-contract strategy to prepare polycyclic heteroaromatics (Fig. 4).…”

Toward the Generation of 2-Amino-3-Formyl Difunctionalized Chromones via Pd-Enabled Rearrangement Strategy

“…Some classic reactions, such as Favorskii, Wolff, Beckmann, Bayer–Villiger and semipinacol rearrangements, have been widely applied in the ring-contraction or ring-expansion reactions by deletion or insertion of a single atom (C, N or O) into parent skeletons, respectively . Recently, Levin, Sarpong, Morandi, Lu, Antonchick, Wei, et al, accomplished the elegant transfigurations of n-member ring to (n-1)- or (n+1)-member ring through skeletal editing technologies (Figure b). These strategies would enable the rapid mutation of skeletons without laborious multistep synthesis, thus providing powerful tools for synthetic science.…”