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

Abstract

The ability to rapidly navigate a wide diversity of chemical space from simple building blocks is a cornerstone of medicinal chemistry campaigns. Aza-bicyclo[2.1.1]hexane (aza-BCH) and bicyclo[1.1.1]pentane (BCP) scaffolds have recently emerged as attractive classes of sp3-rich cores for replacing flat, aromatic scaffolds with metabolically resistant, three-dimensional frameworks. Over the last decade, these pharmaceutically desirable properties and increased synthetic accessibility have led to a marked increase in the adoption of aza-BCHs and BCPs into drug scaffolds. While multiple, independent methods have been developed for the preparation of these structural motifs, 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 bearing substituents that can be further derivatized.

Halogen-Free Ciamician-Dennstedt Single-Atom Skeletal Editing

“…2a, a range of N-TBS-indoles bearing electrondonating or electron-withdrawing substituents at the 4-, 5-, 6-, or 7-positions afforded the corresponding 3-tri uoromethyl quinoline products in good to excellent yields (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). Many functional groups, such as methyl (5-8), ester (9), acetyl (10), halogens (11, 18, 19, 21, and 22), ethers (12, 16, and 20), amine (13), phenyl (14), pyridine (15), and phenylethynyl (17) were well tolerated, although electron-donating substituents afforded slightly reduced yields of the 3-tri uoromethylated quinolines (e.g., 5-8, 12, 13, and 20). In contrast to this moderate electronic in uence, steric factors can play a crucial role in the reaction; for example, 3-methyl-TBS-indole produced ring expansion product 4 in ~ 20% yield.…”

“…As such, synthetic and medicinal chemists are particularly attracted to direct heterocycle-to-heterocycle transmutation by the insertion or deletion of single-atoms from the heterocyclic core of a given active pharmaceutical ingredient [5][6][7][8] . Within this eld, signi cant advances have been made in single-atom skeletal editing of aliphatic heterocycles, presumably due to the relative ease of activation and manipulation of these frameworks [9][10][11][12][13][14][15][16][17] . However, the execution of this concept in the setting of heteroaromatic scaffolds is far more challenging [19][20][21][22][23][24][25][26] , owing to the high energy barriers encountered during the initial dearomatization processes required for single-atom insertion, which in turn can impose limitations on the range of insertion reagents, or reaction conditions 26,27 .…”

Enantiodivergent dearomative skeletal ring expansion of indoles through carbon atom insertion

“…In particular, the notionally idealized "single-atom skeletal editing methodology" has the prospect of transforming chemistry by offering chemists a simple route to tweak a drug candidate's core scaffold without changing existing substitution patterns. [3][4][5] Seminal contributions from Sarpong, [8][9][10][11] , Levin, [12][13][14][15][16] Morandi, [17][18][19] Dong, [20][21][22] Glorius, 23 and others [24][25][26][27][28] have demonstrated a range of reliable skeletal editing methodologies, allowing chemists to surgically insert, delete, or swap one or two atoms in the core skeleton of heterocycles (Fig. 1A).…”

Direct Oxygen Insertion into C-C Bond of Styrenes with Air

“…However, it is still a challenging issue because the selective modi cation of inert C-C bonds is required in complicated reaction system. Despite these challenges, some signi cant achievements have been reported in the context of formal-single-atom skeletal editing including boron 10,11 , carbon [12][13][14][15][16][17] , or nitrogen [18][19][20][21] atom insertion and deletion reaction [22][23][24][25][26][27][28] (Fig. 1a).…”