Access to Complex Scaffolds Through [2 + 2] Cycloadditions of Strained Cyclic Allenes.

We report the strain-induced [2 + 2] cycloadditions of cyclic allenes for the assembly of highly substituted cyclobutanes. By judicious choice of trapping agent, complex scaffolds bearing heteroatoms, fused rings, contiguous stereocenters, spirocycles, and quaternary centers are ultimately accessible. Moreover, we show that the resulting cycloadducts can undergo thermal isomerization. This study provides an alternative strategy to photochemical [2 + 2] cycloadditions for accessing highly functionalized cyclobutanes, while validating the use of underexplored strained intermediates for the assembly of complex architectures.

Fragment-Guided Genome Mining of Octacyclic Cyclophane Alkaloids from Fungi.

Nature uses compact but functionalized biosynthetic fragments as building blocks to generate complex natural products. To leverage this strategy for the discovery of natural products with new scaffolds, we performed genome mining to identify biosynthetic gene clusters (BGCs) in fungi that embed genes that can synthesize targeted fragments. The three-enzyme pathway that biosynthesizes the strained dityrosine cyclophane in the herquline A pathway was used to identify a large number of potential BGCs that may use the cyclophane as a fragment. Characterization of a conserved BGC from fungal strains led to the isolation of octacyclin A, an octacyclic natural product with an unprecedented structure, including two hetero-[3.3.1]bicycles and a combination of fused, bridged, and macrocyclic rings. Biosynthetic steps leading to octacyclin A were fully elucidated using pathway reconstitution and enzymatic assays, unveiling intriguing chemical logic and new enzymatic reactions in building the octacyclic core. Our work demonstrates the potential utility of fragment-guided genome mining in expanding natural product chemical space.

Small molecule inhibition of RNA binding proteins in haematologic cancer.

In recent years, advances in biomedicine have revealed an important role for post-transcriptional mechanisms of gene expression regulation in pathologic conditions. In cancer in general and leukaemia specifically, RNA binding proteins have emerged as important regulator of RNA homoeostasis that are often dysregulated in the disease state. Having established the importance of these pathogenetic mechanisms, there have been a number of efforts to target RNA binding proteins using oligonucleotide-based strategies, as well as with small organic molecules. The field is at an exciting inflection point with the convergence of biomedical knowledge, small molecule screening strategies and improved chemical methods for synthesis and construction of sophisticated small molecules. Here, we review the mechanisms of post-transcriptional gene regulation, specifically in leukaemia, current small-molecule based efforts to target RNA binding proteins, and future prospects.

Total Synthesis of Lissodendoric Acid A.

We describe a full account of our synthetic strategy leading to the first total synthesis of the manzamine alkaloid lissodendoric acid A . These efforts demonstrate that strained cyclic allenes are valuable synthetic building blocks and can be employed efficiently in total synthesis.

Generation and reactivity of unsymmetrical strained heterocyclic allenes.

Strained cyclic allenes are short-lived intermediates that confine a functional group with a preferred linear geometry, an allene, into a small ring, inducing strain-driven reactivity. Nitrogen-containing variants, or azacyclic allenes, have proved valuable for the assembly of complex nitrogen-containing compounds. Whereas 3,4-azacyclic allenes, which bear a symmetrical core, have been the focus of multiple studies, their unsymmetrical 2,3-azacyclic counterparts have remained underexplored. In the present study, we report density functional theory studies investigating the structure of such unsymmetrical azacyclic allenes and experimental efforts to access and engage them in strain-promoted cycloadditions under mild conditions. Control experiments support either concerted or stepwise diradical mechanisms for these reactions, depending on the type of cycloaddition examined. Moreover, we generate the corresponding 2,3-oxacyclic allene and demonstrate its reactivity in cycloadditions and a metal-catalysed process. Given the scaffolds accessed, coupled with the observed selectivity trends, these results are expected to encourage the application of unsymmetrical heterocyclic allenes for the synthesis of heterocycles that bear a high fraction of sp3-hybridized atoms.

Enantioselective nickel-catalyzed Mizoroki-Heck cyclizations of amide electrophiles.

Amide cross-couplings that rely on C-N bond activation by transition metal catalysts have emerged as valuable synthetic tools. Despite numerous discoveries in this field, no catalytic asymmetric variants have been disclosed to date. Herein, we demonstrate the first such transformation, which is the Mizoroki-Heck cyclization of amide substrates using asymmetric nickel catalysis. This proof-of-concept study provides an entryway to complex enantioenriched polycyclic scaffolds and advances the field of amide C-N bond activation chemistry.

Evaluation of Retro-Aldol vs Retro-Carbonyl-Ene Mechanistic Pathways in a Complexity-Generating C-C Bond Fragmentation.

We report an experimental and computational investigation of the likely mechanism of a cascade reaction. The reaction involves an intramolecular Diels-Alder reaction, followed by a C-C bond cleavage, to afford a complex bridged bicyclic product. As multiple reaction pathways could be envisioned for the latter step, the mechanism of the C-C bond cleavage step was investigated. Two reasonable reaction pathways were evaluated. Both computations and experiments indicate that the C-C bond cleavage step proceeds by a retro-carbonyl-ene pathway rather than a retro-aldol pathway. This report underscores the synergy between computational and experimental studies and establishes the mechanism of an interesting complexity-generating transformation.

Diels-Alder Cycloadditions of Oxacyclic Allenes and α-Pyrones.

Reactions of α-pyrones with oxacyclic allenes in Diels-Alder trappings are described. We investigate regioselectivity trends and perform competition experiments to assess the influence of structural and electronic features on relative reaction rates. We also demonstrate the stereospecific trapping of an oxacyclic allene, which proceeds in high optical yield. This study provides insight into strained cyclic allene reactivity, as well as new synthetic tools for the rapid construction of complex, heterocyclic scaffolds.