Abstract Glutarimide-containing Cereblon (CRBN) ligands are critical motifs for PROTACs, molecular glue degraders and next-generation Cereblon E3 ligase modulatory drugs (CELMoDs), which represent promising therapeutic modalities in targeted protein degradation. However, the multistep synthetic routes required to access glutarimide scaffolds continue to present formidable challenges for medicinal chemists, limiting rapid structure–activity relationship (SAR) exploration and late-stage diversification. To streamline access to these privileged motifs, modular and efficient methodologies are still highly desirable. Here, we report a unified organocatalytic synthesis platform for the rapid assembly of diverse glutarimide derivatives from readily available nitrogen heterocycles. Employing a sequence of phosphine-catalysed C–N bond formation, metal-free Giese addition and acid-mediated cyclisation, this approach provides high selectivity, broad functional group tolerance and operational simplicity under conditions amenable to both multigram synthesis and high-throughput parallel synthesis. Using this platform, we rapidly prepare CRBN binder libraries, access control analogues (for example, N ‑alkylated glutarimides) and perform late‑stage functionalisation of bioactive molecules. This strategy could offer a transformative solution for the efficient and cost-effective synthesis of CRBN-targeted therapeutics and chemical biology probes, overcoming longstanding synthetic bottlenecks in the field.

The 2-azabicyclo[2.1.1]hexane (2-aza-BCH) and 2-oxabicyclo[2.1.1]hexane (2-oxa-BCH) motifs are bridged, saturated heterocycles with vast utility in medicinal chemistry, including isosteric replacement of phenyl rings and rigid replacements of pyrrolidines and tetrahydrofurans. Over the past decades, chemists have explored numerous routes for their preparation, allowing access to a variety of substitution patterns and a number of applications in the pharmaceutical sciences. This review acts as a roadmap of the synthetic routes to access these heterocycles, allowing for comparisions of these two exciting classes of saturated heterocycles whilst hopefully inspiring new directions in the field.

The synthesis and characterization of the first examples of cubane containing interlocked molecules are reported. Catenanes and rotaxanes have been prepared by hydrogen bond templation with cubane-1,3-dicarboxamides replacing isophthalamide motifs.

A review of recent advances in 4-π-photocyclization reactions is presented, including an overview of the current substrate scope, innovations in scale-up, and applications of the strained cyclobutene products as versatile building blocks in drug discovery and total synthesis, as strained monomers for novel polymers suitable for post-polymerization derivatization, and as precursors to reactive intermediates such as cyclobutadienes.

The previously unreported combination of nucleophilic phosphine catalysis and energy transfer catalysis allows for the rapid construction of structurally distinct 2-oxabicyclo[2.1.1]hexanes (2-oxa-BCH) from readily available building blocks with high atom economy. Previous multistep routes to these important phenyl ring bioisosteres have largely depended on the use of bespoke strain-release agents or on multiple post-functionalisation reactions to access structural diversity of the scaffold. In contrast, this cascade reaction allows the medicinal chemist to exploit the breadth of commercial allyl alcohols to synthesise systematically diverse 2-oxa-BCH architectures. Using a combination of polar and radical disconnections in the same reaction flask, every position of the scaffold can be substituted with useful functional handles such as protected amines, esters and alcohols, as well as arenes and alkyl groups. Cyclic allyl alcohols can even be employed to yield single diastereomers of sp3-rich bridged spirocyclic structures. Aromatic groups at the 1-position can be varied to incorporate a plethora of arenes including medicinally relevant heterocycles such as indole, pyrazole and pyridine.

A telescoped three-step sequence to functionalised spirocyclic oxetanes is reported, involving Paternò-Büchi reactions between maleic acid derivatives and cyclic ketones. p-Xylene suppresses the competing alkene dimerization that has plagued previous work, allowing access to 35 novel spirocyclic oxetanes that cannot be prepared using existing methodologies, and which represent versatile intermediates for further elaboration.

A robust multigram-scale synthesis of 1,3-disubstituted cubanes (previously only available on milligram-scale) is reported. The approach exploits a readily available enone intermediate previously used for the synthesis of 1,4-disubstituted cubanes, by introducing a novel Wharton transposition to access useful quantities of 1,3-disubstituted cubanes for diverse applications.

An optimized multigram-scale route to phototropone (bicyclo[3.2.0]hepta-2,6-dien-7-one) is reported via the 4-π-photocyclization of tropone complexed to Lewis acid. Phototropone is a highly versatile molecular building block, and its conversion into 18 novel derivatives using standard transformations is demonstrated, allowing access to a variety of rigid bicyclic scaffolds.

The replacement of benzene rings with sp3-hybridized bioisosteres in drug candidates generally improves pharmacokinetic properties while retaining biological activity. Rigid, strained frameworks such as bicyclo[1.1.1]pentane and cubane are particularly well-suited since the ring strain imparts high bond strength and thus metabolic stability on its C–H bonds. Cubane is the ideal bioisostere since it provides the closest geometric match to benzene. At present, however, all cubanes in drug design, like almost all benzene bioisosteres, act solely as substitutes for mono- or para-substituted benzene rings. This is due 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 incompatibility of cross-coupling reactions with the cubane scaffold, owing to a competing metal-catalyzed valence isomerization. Herein, we disclose 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–CF3 cross-coupling protocols. 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 benzene rings with sp(3)-hybridized bioisosteres in drug candidates generally improves pharmacokinetic properties while retaining biological activity(1-5). 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 benzene(6,7). At present, however, all cubanes in drug design, like almost all benzene bioisosteres, act solely as substitutes for mono- or para-substituted benzene rings(1-7). 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 isomerization(8-11). 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(sp(3)), C-C(sp(2)) and C-CF3 cross-coupling protocols(12,13). 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 [2+2] photocycloaddition of two double-bond moieties is arguably the most efficient way to form a four-membered ring, but this route is rarely used to construct azetidine rings. Now, the development of an isoxazoline carboxylate cycloaddition partner offers a general approach to synthesize diverse azetidine products.

This minireview highlights the scope of 4‐π‐photocyclizations (photoinduced electrocyclizations that involve 4 pi electrons and generate bicyclic cyclobutenes from 1,3‐dienes), including an overview of the historical progressions as well as recent developments. A range of 1,3‐diene substrates is covered, including cycloheptatrienes, tropones, tropolones, cyclic 1,3‐dienes, 2‐pyrones, 2‐pyridones, pyrimidines, 1,2‐dihydropyridines, and 1,2‐dihydro‐pyridazines. The bicyclic cyclobutene products formed through the photocyclizations are highly versatile synthetic intermediates, and examples of the application of these building blocks in the context of synthetic methodology development, natural product synthesis, medicinal chemistry and materials chemistry are featured throughout.

The reactivity of 1,2-dihydropyridazines under various conditions is described, leading to the formation of a variety of products, including 2-aminopyrroles, phenylenediamines, and several novel heterocyclic motifs.

The 4-π-photocyclization of a range of 1,2-dihydropyridazines is described, generating bicyclic 1,2-diazetidines in high yields on multigram scale. The key bicyclic 1,2-diazetidines are versatile synthetic intermediates and were easily converted into a range of novel derivatives, including functionalized 1,2-diazetidines, cyclobutenes, cyclobutanes, and 1,3-dienes.

Abstract: This minireview highlights the scope of 4-πphotocyclizations (photoinduced electrocyclizations that involve 4 pi electrons and generate bicyclic cyclobutenes from 1,3-dienes), including an overview of the historical progressions as well as recent developments. A range of 1,3-diene substrates is covered, including cycloheptatrienes, tropones, tropolones, cyclic 1,3-dienes, 2-pyrones, 2-pyridones, pyrimidines, 1,2-dihydropyridines and 1,2-dihydropyridazines. The bicyclic cyclobutene products formed through the photocyclizations are highly versatile synthetic intermediates, and examples of the application of these building blocks in the context of synthetic methodology development, natural product synthesis, medicinal chemistry and materials chemistry are featured throughout.

A convenient, scalable synthesis of 1,2-dihydropyridazines is presented, based on the Diels-Alder cycloaddition of 1-acetoxy-1,3-butadiene with a variety of azo compounds, followed by a palladium-catalysed elimination. The products are produced on multigram scale and the new method is particularly efficient and atom-economical when compared with previous preparations of 1,2-dihydropyridazines. (C) 2019 Elsevier Ltd. All rights reserved.

A strategy for the enantioselective [2+2] photocycloaddition of isoquinolones with alkenes is presented, in which the formation of a supramolecular complex between a chiral template and the substrate ensures high enantioface differentiation by shielding one face of the substrate. Fifteen different electron-deficient alkenes and ten different substituted isoquinolones undergo efficient photocycloaddition, yielding the cyclobutane products in excellent yields and with outstanding regio-, diastereo- and enantioselectivities (up to 99% ee). The mechanism of the reaction is investigated by means of triplet sensitization/quenching and radical clock experiments, the results of which are consistent with the involvement of a triplet excited state and a 1,4-biradical intermediate. The variety of functionalized cyclobutanes obtained using this approach can be further increased by straightforward synthetic transformations of the photoadducts, allowing rapid access to libraries of compounds for various applications.