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Recent years have seen novel modalities emerge for the treatment of human diseases resulting in an increase in beyond rule of 5 (bRo5) chemical matter. As a result, synthetic innovations aiming to enable rapid access to complex bRo5 molecular entities have become increasingly valuable for medicinal chemists’ toolkits. Herein, we report the general synthesis of a new class of noncanonical amino acids (ncAA) with a cyclopropyl backbone to achieve conformational constraint and bearing C(sp3)-rich benzene bioisosteres. We also demonstrate preliminary studies toward utilities of these ncAA as building blocks for medicinal chemistry research.

Described herein is our effort toward achieving the decarboxylative functionalization of 2,2-difluorobicyclo[1.1.1]pentane (BCP-F2) building blocks. When compared with the nonfluorinated bicyclo[1.1.1]pentane (BCP) analogues, we discovered divergent reactivities. This is the first successful decarboxylative coupling of BCP-F2building blocks reported via the photoredox mechanism.

The replacement of benzene rings with sp3-hybridized bioisosteres in drug candidates generally improves pharmacokinetic properties while retaining biological activity1–5. Rigid, strained frameworks such as bicyclo[1.1.1]pentane and cubane are particularly well suited as the ring strain imparts high bond strength and thus metabolic stability on their C–H bonds. Cubane is the ideal bioisostere as it provides the closest geometric match to benzene6,7. At present, however, all cubanes in drug design, like almost all benzene bioisosteres, act solely as substitutes for mono- or para-substituted benzene rings1–7. This is owing to the difficulty of accessing 1,3- and 1,2-disubstituted cubane precursors. The adoption of cubane in drug design has been further hindered by the poor compatibility of cross-coupling reactions with the cubane scaffold, owing to a competing metal-catalysed valence isomerization8–11. Here we report expedient routes to 1,3- and 1,2-disubstituted cubane building blocks using a convenient cyclobutadiene precursor and a photolytic C–H carboxylation reaction, respectively. Moreover, we leverage the slow oxidative addition and rapid reductive elimination of copper to develop C–N, C–C(sp3), C–C(sp2) and C–CF3cross-coupling protocols12,13. Our research enables facile elaboration of all cubane isomers into drug candidates, thus enabling ideal bioisosteric replacement of ortho-, meta- and para-substituted benzenes.

The replacement of aryl rings with saturated carbocyclic structures has garnered significant interest in drug discovery due to the potential for improved pharmacokinetic properties upon substitution. In particular, 1,3-difunctionalized bicyclo[1.1.1]pentanes (BCPs) have been widely adopted as bioisosteres for parasubstituted arene rings, appearing in a number of lead pharmaceutical candidates. However, despite the pharmaceutical value of 2-substituted BCPs as replacements for ortho- or meta-substituted arene rings, general and rapid syntheses of these scaffolds remain elusive. Current approaches to 2-substituted BCPs rely on installation of the bridge substituent prior to BCP core construction, leading to lengthy step counts and often nonmodular sequences. While challenging, direct functionalization of the strong bridge BCP C–H bonds would offer a more streamlined pathway to diverse 2-substituted BCPs. Here, we report a generalizable synthetic linchpin strategy for bridge functionalization via radical C–H abstraction of the BCP core. Through mild generation of a strong hydrogen atom abstractor, we rapidly synthesize novel 2-substituted BCP synthetic linchpins in one pot. These synthetic linchpins then serve as common precursors to complex 2-substituted BCPs, allowing one-step access to a number of previously inaccessible electrophile and nucleophile fragments at the 2-position via two new metallaphotoredox protocols. Altogether, this platform enables the expedient synthesis of four pharmaceutical analogues, all of which show similar or improved properties compared to their aryl-containing equivalents, demonstrating the potential of these 2-substituted BCPs in drug development.

We describe the first general transition-metal-free synthesis of gem-diboromethyl-substituted bicyclo[1.1.1]pentane (BCP) and other related C(sp3)-rich carbocyclic benzene bioisosteres from their corresponding p-tosylhydrazones. These novel functionalized benzene bioisosteres demonstrated unique reactivities toward palladium-catalyzed C(sp2)–C(sp3) cross couplings. The overall transformation can be applied to relatively complex substrates with potential utility in drug discovery.

Herein we report the synthesis of bicyclo[1.1.1]pentane (BCP)‐containing sulfonamides via a transition metal‐free process of a three‐component reaction among BCP‐containing N‐tosyl hydrazones, 1,4‐diazabicyclo[2.2.2]octane bis(sulfur dioxide) adduct (DABSO), and amines. Different from existing methods to synthesize BCP‐containing sulfonamides, our method avoids the usage of sulfonyl halides, which could be challenging due to chemical instabilities. We have also demonstrated that this methodology is suitable for library synthesis of such sulfonamides. As a result, we can expect future application in drug discovery. We report a facile synthesis of BCP‐containing sulfonamides from the corresponding N‐tosyl hydrazones and amines. The reaction can be achieved via a transition metal‐free condition, which is highly amenable to library synthesis in parallel medicinal chemistry. The preliminary substrates demonstrated a broad scope in BCP‐substitutions, functional groups on amines, and various cyclic amine structure classes. We also demonstrated the synthesis of the corresponding primary sulfonamide via a slightly modified condition.

We report our efforts toward achieving C(sp2)–C(sp3) coupling reactions with 2,2-difluorobicyclo[1.1.1]pentane (BCP-F2) building blocks. By comparing the reactivities of matching pairs of bicyclo[1.1.1]pentane (BCP) and BCP-F2analogues, we discovered that the Barluenga coupling reaction was the only cross-coupling protocol that translated well between the two structural motifs in contrast to other reported protocols. In this chemistry, a BCP-F2bearing a tosylhydrazone functional group is cross-coupled with an arylboronic acid. These results further expanded the scope of BCP-F2building blocks for potential applications in organic chemistry as well as medicinal chemistry.

Compared to the abundance of methodologies accessing 1-substituted and 1,3-disubstuted bicyclo[1.1.1] pentanes (BCPs), the synthetic accessibility of BCPs with substitutions at the methylene position has been limited. Herein, we report a selective synthesis of 1-dialkylamino-2-alkylbicyclo[1.1.1]pentanes from prefunctionalized starting materials. We also achieved further functionalizations of these 1,2-disubstituted BCPs and developed a synthesis of these compounds with minimum necessity of chromatographic purifications starting from 1,3-dichloroacetone. Finally, we also detailed the synthesis of a 1,2,3-trisubstituted BCP analogue.

Within a medicinal chemist's toolbox, one of the most effective strategies to improve the overall properties of a biologically active compound is bioisosteric replacement. Ever since the first example of replacing benzene with a bicyclo[1.1.1]pentane (BCP) group was published in the late 1990s,[1]the medicinal chemistry community has continually been expanding the scope of such phenyl bioisosteric replacements. Recent interest from academia has focused on novel synthetic strategies to access C(sp3)‐rich bicyclic hydrocarbons with expanded ring sizes. Herein, we summarize some of these transformations and reveal that most rely on strain releasing cycloadditions with bicyclo[1.1.0]butane (BCB) and bicyclo[2.1.0]pentane (housane). We have organized this review based on the mechanism of such strain release strategies, namely, carbene cycloadditions, energy transfer photocatalyzed cycloadditions, electron transfer catalyzed cycloadditions, and polar cycloadditions. In this minireview, we discuss different cycloaddition methods to access strained C(sp3)‐rich bicyclic hydrocarbons, which are promising bioisosteres of aromatic rings. Each cycloaddition example is organized by four reaction paradigms, carbene cycloadditions, energy transfer promoted cycloadditions, electron transfer promoted cycloadditions, and cycloadditions occurring through polar pathways. A common theme we observed is strain energy and, where possible, we discuss its involvement.

This Minireview focuses on selected topics in the syntheses of bicyclo[1.1.1]pentane (BCP) analogues. A brief historical introduction was included. The content covers various synthetic routes of 1‐substituted and 1,3‐disubstituted BCPs. Selective examples of synthetically useful building blocks are summarized for each category for synthetic organic chemists’ and medicinal chemists’ reference. A compare‐and‐contrast analysis is also applied to evaluate these routes and to demonstrate the progress of strategic functional group transformations using modern organic methodologies. By systematically analyzing the synthetic strategies to access these strained molecules, we also hope that this Minireview will provide inspirations for future developments in this area. Like riding a bicyclopentane: In this Minireview, different synthetic strategies and novel organic methodologies to access bicyclo[1.1.1]pentane (BCP) analogues with diverse substitution patterns are discussed. In each section, these strategies are compared and contrasted, and selective examples of synthetically useful building blocks are provided.

The bicyclo[1.1.1]pentane (BCP) motif has been utilized as bioisosteres in drug candidates to replace phenyl, tert-butyl, and alkynyl fragments in order to improve physicochemical properties. However, bceause of the difficulty of synthesis, most BCP analogues prepared only bear 1,3-“para”-substituents. We report the first selective synthesis of 2,2-difluorobicyclo[1.1.1]pentanes via difluorocarbene insertion into bicyclo[1.1.0]butanes. Moreover, this methodology should inspire future studies on synthesis of other “ortho/meta-substituted” BCPs via similar mechanisms.

Oncogenic mutations in the RASgene account for 30% of all human tumors; more than 60% of which present as KRAS mutations at the hotspot codon 12. After decades of intense pursuit, a covalent inhibition strategy has enabled selective targeting of this previously “undruggable” target. Herein, we disclose our journey toward the discovery of MK-1084, an orally bioavailable and low-dose KRASG12Ccovalent inhibitor currently in phase I clinical trials (NCT05067283). We leveraged structure-based drug design to identify a macrocyclic core structure, and hypothesis-driven optimization of biopharmaceutical properties to further improve metabolic stability and tolerability.