Strain-promoted reactions of 1,2,3-cyclohexatriene and its derivatives.

Since 18251, compounds with the molecular formula C6H6-most notably benzene-have been the subject of rigorous scientific investigation2-7. Of these compounds, 1,2,3-cyclohexatriene has been largely overlooked. This strained isomer is substantially (approximately 100 kcal mol-1) higher in energy compared with benzene and, similar to its relatives benzyne and 1,2-cyclohexadiene, should undergo strain-promoted reactions. However, few experimental studies of 1,2,3-cyclohexatriene are known8-12. Here we demonstrate that 1,2,3-cyclohexatriene and its derivatives participate in a host of reaction modes, including diverse cycloadditions, nucleophilic additions and σ-bond insertions. Experimental and computational studies of an unsymmetrical derivative of 1,2,3-cyclohexatriene demonstrate the potential for highly selective reactions of strained trienes despite their high reactivity and short lifetimes. Finally, the integration of 1,2,3-cyclohexatrienes into multistep syntheses demonstrates their use in rapidly assembling topologically and stereochemically complex molecules. Collectively, these efforts should enable further investigation of the strained C6H6 isomer 1,2,3-cyclohexatriene and its derivatives, as well as their application in the synthesis of important compounds.

Intercepting fleeting cyclic allenes with asymmetric nickel catalysis.

Strained cyclic organic molecules, such as arynes, cyclic alkynes and cyclic allenes, have intrigued chemists for more than a century with their unusual structures and high chemical reactivity1. The considerable ring strain (30-50 kilocalories per mole)2,3 that characterizes these transient intermediates imparts high reactivity in many reactions, including cycloadditions and nucleophilic trappings, often generating structurally complex products4. Although strategies to control absolute stereochemistry in these reactions have been reported using stoichiometric chiral reagents5,6, catalytic asymmetric variants to generate enantioenriched products have remained difficult to achieve. Here we report the interception of racemic cyclic allene intermediates in a catalytic asymmetric reaction and provide evidence for two distinct mechanisms that control absolute stereochemistry in such transformations: kinetic differentiation of allene enantiomers and desymmetrization of intermediate π-allylnickel complexes. Computational studies implicate a catalytic mechanism involving initial kinetic differentiation of the cyclic allene enantiomers through stereoselective olefin insertion, loss of the resultant stereochemical information, and subsequent introduction of absolute stereochemistry through desymmetrization of an intermediate π-allylnickel complex. These results reveal reactivity that is available to cyclic allenes beyond the traditional cycloadditions and nucleophilic trappings previously reported, thus expanding the types of product accessible from this class of intermediates. Additionally, our computational studies suggest two potential strategies for stereocontrol in reactions of cyclic allenes. Combined, these results lay the foundation for the development of catalytic asymmetric reactions involving these classically avoided strained intermediates.

An enzymatic Alder-ene reaction.

An ongoing challenge in chemical research is to design catalysts that select the outcomes of the reactions of complex molecules. Chemists rely on organocatalysts or transition metal catalysts to control stereoselectivity, regioselectivity and periselectivity (selectivity among possible pericyclic reactions). Nature achieves these types of selectivity with a variety of enzymes such as the recently discovered pericyclases-a family of enzymes that catalyse pericyclic reactions1. Most characterized enzymatic pericyclic reactions have been cycloadditions, and it has been difficult to rationalize how the observed selectivities are achieved2-13. Here we report the discovery of two homologous groups of pericyclases that catalyse distinct reactions: one group catalyses an Alder-ene reaction that was, to our knowledge, previously unknown in biology; the second catalyses a stereoselective hetero-Diels-Alder reaction. Guided by computational studies, we have rationalized the observed differences in reactivities and designed mutant enzymes that reverse periselectivities from Alder-ene to hetero-Diels-Alder and vice versa. A combination of in vitro biochemical characterizations, computational studies, enzyme co-crystal structures, and mutational studies illustrate how high regioselectivity and periselectivity are achieved in nearly identical active sites.

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.

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.

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.

Catalyst-Controlled Annulations of Strained Cyclic Allenes with π-Allylpalladium Complexes.

Strained cyclic allenes are a class of in situ-generated fleeting intermediates that, despite being discovered more than 50 years ago, has received significantly less attention from the synthetic community compared to related strained intermediates. Examples of trapping strained cyclic allenes that involve transition metal catalysis are especially rare. We report the first annulations of highly reactive cyclic allenes with in situ-generated π-allylpalladium species. By varying the ligand employed, either of two isomeric polycyclic scaffolds can be obtained with high selectivity. The products are heterocyclic and sp3-rich and bear two or three new stereocenters. This study should encourage the further development of fragment couplings that rely on transition metal catalysis and strained cyclic allenes for the rapid assembly of complex scaffolds.

Electrochemical Oxidation of Δ9-Tetrahydrocannabinol at Nanomolar Concentrations.

With increasing marijuana legalization, there is a growing need for technology that can determine if an individual is impaired due to recent marijuana usage. The electrochemical oxidation of Δ9-THC to form its corresponding quinones can be used as a framework to develop an electrochemical sensor for Δ9-THC. This study describes an electrochemical oxidation of Δ9-THC that uses a copper anode, a platinum cathode, and an atmosphere of oxygen. The oxidation is feasible at nanomolar concentrations, which approaches the reactivity that is necessary for developing a real-world marijuana breathalyzer. Moreover, we show that vaporized Δ9-THC can be captured directly in an electrolyte medium and subjected to electrochemical oxidation, thus paving the way for use in future technology development.

A symmetry-driven approach toward the total synthesis of dodecahedrane.

Herein, we describe our progress toward the total synthesis of dodecahedrane, a complex and highly symmetrical hydrocarbon that bears twelve fused rings arranged in a cage-like architecture. Central to our approach is a late-stage [2+2+2+2+2] polyene cyclization cascade, which is expected to construct five new bonds and ten new rings in a single transformation. Toward this end, we describe efforts to synthesize key monomeric fragments, along with successful dimerization studies using a pinacol coupling approach. Subsequent studies include an attempted olefin metathesis rearrangement cascade in addition to a successful intramolecular photochemical [2+2] reaction. Although attempts to elaborate the photocycloaddition product were unsuccessful, our studies provide access to complex dimeric scaffolds and are expected to help guide our future total synthesis studies.

Palladium-Catalyzed Annulations of Strained Cyclic Allenes.

We report Pd-catalyzed annulations of in situ generated strained cyclic allenes. This methodology employs aryl halides and cyclic allene precursors as the reaction partners in order to generate fused heterocyclic products. The annulation proceeds via the formation of two new bonds and an sp3 center. Moreover, both diastereo- and enantioselective variants of this methodology are validated, with the latter ultimately enabling the rapid enantioselective synthesis of a complex hexacyclic product. Studies leveraging transition metal catalysis to intercept cyclic allenes represent a departure from the more common, historical modes of cyclic allene trapping that rely on nucleophiles or cycloaddition partners. As such, this study is expected to fuel the development of reactions that strategically merge transition metal catalysis and transient strained intermediate chemistry for the synthesis of complex scaffolds.

Total Synthesis of (-)-Strictosidine and Interception of Aryne Natural Product Derivatives "Strictosidyne" and "Strictosamidyne".

Monoterpene indole alkaloids are a large class of natural products derived from a single biosynthetic precursor, strictosidine. We describe a synthetic approach to strictosidine that relies on a key facially selective Diels-Alder reaction between a glucosyl-modified alkene and an enal to set the C15-C20-C21 stereotriad. DFT calculations were used to examine the origin of stereoselectivity in this key step, wherein two of 16 possible isomers are predominantly formed. These calculations suggest the presence of a glucosyl unit, also inherent in the strictosidine structure, guides diastereoselectivity, with the reactive conformation of the vinyl glycoside dienophile being controlled by an exo-anomeric effect. (-)-Strictosidine was subsequently accessed using late-stage synthetic manipulations and an enzymatic Pictet-Spengler reaction. Several new natural product analogs were also accessed, including precursors to two unusual aryne natural product derivatives termed "strictosidyne" and "strictosamidyne". These studies provide a strategy for accessing glycosylic natural products and a new platform to access monoterpene indole alkaloids and their derivatives.

Taming Radical Pairs in the Crystalline Solid State: Discovery and Total Synthesis of Psychotriadine.

Solid-state photodecarbonylation is an attractive but underutilized methodology to forge hindered C-C bonds in complex molecules. This study discloses the use of this reaction to assemble the vicinal quaternary stereocenter motif present in bis(cyclotryptamine) alkaloids. Our strategy was enabled by experimental and computational investigations of the role of substrate conformation on the success or failure of the solid-state photodecarbonylation reaction. This informed a crystal engineering strategy to optimize the key step of the total synthesis. Ultimately, this endeavor culminated in the successful synthesis of the bis(cyclotryptamine) alkaloid "psychotriadine," which features the elusive piperidinoindoline framework. Psychotriadine, a previously unknown compound, was identified in the extracts of the flower Psychotria colorata, suggesting it is a naturally occurring metabolite.

Conversion of amides to esters by the nickel-catalysed activation of amide C-N bonds.

Amides are common functional groups that have been studied for more than a century. They are the key building blocks of proteins and are present in a broad range of other natural and synthetic compounds. Amides are known to be poor electrophiles, which is typically attributed to the resonance stability of the amide bond. Although amides can readily be cleaved by enzymes such as proteases, it is difficult to selectively break the carbon-nitrogen bond of an amide using synthetic chemistry. Here we demonstrate that amide carbon-nitrogen bonds can be activated and cleaved using nickel catalysts. We use this methodology to convert amides to esters, which is a challenging and underdeveloped transformation. The reaction methodology proceeds under exceptionally mild reaction conditions, and avoids the use of a large excess of an alcohol nucleophile. Density functional theory calculations provide insight into the thermodynamics and catalytic cycle of the amide-to-ester transformation. Our results provide a way to harness amide functional groups as synthetic building blocks and are expected to lead to the further use of amides in the construction of carbon-heteroatom or carbon-carbon bonds using non-precious-metal catalysis.

Interception of 1,2-cyclohexadiene with TEMPO radical.

Transient strained cyclic intermediates, such as strained cyclic allenes, are useful building blocks for the synthesis of structurally and stereochemically complex scaffolds. Trappings of strained cyclic allenes are thought to occur primarily through either two or one electron processes. Regarding the latter, diradical intermediates have been invoked in (2 + 2) cycloadditions and (3 + 2) nitrone cycloadditions. The present study questions if a monoradical pathway could exist for strained cyclic allene reactivity, as examined in the reaction of 1,2-cyclohexadiene and TEMPO radical. Our findings suggest the viability of this monoradical pathway.

Origins of Endo Selectivity in Diels-Alder Reactions of Cyclic Allene Dienophiles.

Strained cyclic allenes, first discovered in 1966 by Wittig and co-workers, have recently emerged as valuable synthetic building blocks. Previous experimental investigations, and computations reported here, demonstrate that the Diels-Alder reactions of furans and pyrroles with 1,2-cyclohexadiene and oxa- and azaheterocyclic analogs proceed with endo selectivity. This endo selectivity gives the adduct with the allylic saturated carbon of the cyclic allene endo to the diene carbons. The selectivity is very general and useful in synthetic applications. Our computational study establishes the origins of this endo selectivity. We analyze the helical frontier molecular orbitals of strained cyclic allenes and show how secondary orbital and electrostatic effects influence stereoselectivity. The LUMO of carbon-3 of the allene (C-3 is not involved in primary orbital interactions) interacts in a stabilizing fashion with the HOMO of the diene in such a way that the carbon of the cyclic allene attached to C-1 favors the endo position in the transition state. The furan LUMO, allene HOMO interaction reinforces this preference. These mechanistic studies are expected to prompt the further use of long-avoided strained cyclic allenes in chemical synthesis.

Cycloaddition Cascades of Strained Alkynes and Oxadiazinones.

We report a computational and experimental study of the reaction of oxadiazinones and strained alkynes to give polycyclic aromatic hydrocarbons (PAHs). The reaction proceeds by way of a pericyclic reaction cascade and leads to the formation of four new carbon-carbon bonds. Using M06-2X DFT calculations, we interrogate several mechanistic aspects of the reaction, such as why the use of non-aromatic strained alkynes can be used to access unsymmetrical PAHs, whereas the use of arynes in the methodology leads to symmetrical PAHs. In addition, experimental studies enable the rapid synthesis of new PAHs, including tetracene and pentacene scaffolds. These studies not only provide fundamental insight regarding the aforementioned cycloaddition cascades and synthetic access to PAH scaffolds, but are also expected to enable the synthesis of new materials.

Reductive Arylation of Amides via a Nickel-Catalyzed Suzuki-Miyaura-Coupling and Transfer-Hydrogenation Cascade.

We report a means to achieve the addition of two disparate nucleophiles to the amide carbonyl carbon in a single operational step. Our method takes advantage of non-precious-metal catalysis and allows for the facile conversion of amides to chiral alcohols via a one-pot Suzuki-Miyaura cross-coupling/transfer-hydrogenation process. This study is anticipated to promote the development of new transformations that allow for the conversion of carboxylic acid derivatives to functional groups bearing stereogenic centers via cascade processes.

How organic chemistry became one of UCLA's most popular classes.

Organic chemistry has a bad reputation, despite having a tremendous impact on our everyday lives. It has remained a notorious "weed-out" class for decades-striking fear in the hearts of students-and has long been viewed as a gatekeeper course for those interested in pursuing a career in medicine or other health-related professions. This personal account examines the underlying teaching philosophies that transformed organic chemistry into one of the most popular classes on the UCLA campus. Special emphasis is placed on ways to increase engagement and help students feel connected. Educational initiatives, including organic chemistry music videos and various online resources created in partnerships with students, will be discussed. It is hoped that this account will stimulate ideas that transcend scientific disciplines all for the benefit of student education.

Discovery and Total Synthesis of a Bis(cyclotryptamine) Alkaloid Bearing the Elusive Piperidinoindoline Scaffold.

Bis(cyclotryptamine) alkaloids have been popular topics of study for many decades. Five possible scaffolds for bis(cyclotryptamine) alkaloids were originally postulated in the 1950s, but only four of these scaffolds have been observed in natural products to date. We describe synthetic access to the elusive fifth scaffold, the piperidinoindoline, through syntheses of compounds now termed "dihydropsychotriadine" and "psychotriadine". The latter of these compounds was subsequently identified in extracts of the flower Psychotria colorata. Our synthetic route features a stereospecific solid-state photodecarbonylation reaction to introduce the key vicinal quaternary stereocenters.