Remote proton elimination: C-H activation enabled by distal acidification.

Generally, the acidity of carbon-hydrogen bonds is most sensitive to functionality just one or two bonds away. Here, we present an approach to the formation of carbon-carbon σ bonds by remote proton elimination, a distinct mode of carbon-hydrogen activation enabled by distal acidification through five carbon-carbon bonds. Application of remote proton elimination to cyclodecyl cations unveiled an appealing method for the synthesis of decalins. The transformation is regioconvergent, proceeds without the need for a directing group or precious metal, and demonstrates exquisite site selectivity. An in-depth computational study illuminated the reaction mechanism. Additionally, we describe the complete stereoisomeric enrichment of the decalin products through epimerization mediated by hydrogen atom transfer.

Azide-Enolate Cycloaddition-Rearrangement Enables Direct α-Amination of Amides and Enelactam Synthesis from Esters.

Invited for the cover of this issue are Dan Furkert, Joe Bell-Tyrer and co-workers at the University of Auckland and Victoria University of Wellington. The image depicts a tandem cycloaddition-rearrangement process delivering a diverse range of molecular frameworks from simple precursors. Read the full text of the article at 10.1002/chem.202300261.

Total Synthesis of Spiroketal Alkaloids Lycibarbarines A-C.

Lycibarbarines A-C are spirocyclic alkaloids with a unique tetracyclic framework, consisting of tetrahydroquinoline and spiro-fused oxazine-sugar spiroketal subunits. The first total syntheses of lycibarbarines A-C were achieved over 10 steps (longest linear sequence) each. Through this work, it was discovered that the spiroketal unit of lycibarbarines A-C exhibits unusually high resistance to acid-mediated isomerization and epimerization, likely due to the basic nitrogen atom. As such, the lycibarbarines present an interesting case study in preventing the interconversion of spiroketal isomers, which may prove to be instructive in efforts to obtain nonthermodynamic spiroketal frameworks.

Biomimetic Cationic Cyclopropanation Enables an Efficient Chemoenzymatic Synthesis of 6,8-Cycloeudesmanes.

Cationic cyclopropanation involves the γ-elimination at carbocations to form a new σ-C-C bond through proton loss. While exceedingly rare in bulk solution, it is recognized as one of the main biosynthetic cyclopropanation pathways. Despite the rich history of bioinspired synthetic chemistry, cationic cyclopropanation has not been appropriated for the synthetic toolbox, likely due to the preference of carbocations to undergo competing E1 ß-elimination pathways. Here, we present an in-depth synthetic and computational study of cationic cyclopropanation, focusing on the 6,8-cycloeudesmanes as a platform for this investigation. We were able to apply biomimetic cationic cyclopropanation to the synthesis of several 6,8-cycloeudesmanes and non-natural analogues─in doing so, we showcase the power of this transformation in the preparation of complex cyclopropanes.

Azide-Enolate Cycloaddition-Rearrangement Enables Direct α-Amination of Amides and Enelactam Synthesis from Esters.

Azide-enolate cycloaddition-rearrangements offer potential for rapid access to diverse molecular frameworks from simple precursors. We report here that investigations into the cycloadditions of ester or amide enolates with vinyl azides led to the identification of two reaction processes - direct α-amination of amides and lactams, and the synthesis of ene-γ-lactams from esters. The outcomes of these reactions depended on the fate of key vinyl triazoline intermediates generated in the initial cycloaddition step. Isolation of reaction intermediates in the ene-γ-lactam synthesis revealed the unexpected addition of two enolate equivalents, one of which is later eliminated. Computational studies further suggested an unusual reaction pathway involving direct addition of an enolate to the terminal carbon of the N-vinyl triazoline. In contrast, the α-amination of amides and lactams proceeded by rearrangement of the intermediate triazoline to give an imine, hydrolysis or reduction of which gave access to primary or secondary α-amino amides or lactams.

Direct Stereodivergent Olefination of Carbonyl Compounds with Sulfur Ylides.

The reactivity of phosphorus and sulfur ylides toward carbonyl compounds constitutes a well-known dichotomy that is a common educational device in organic chemistry─the former gives olefins, while the latter gives epoxides. Herein, we report a stereodivergent carbonyl olefination that challenges this dichotomy, showcasing thiouronium ylides as valuable olefination reagents. With this method, aldehydes are converted to Z-alkenes with high stereoselectivity and broad substrate scope, while N-tosylimines provide a similarly proficient entry to E-alkenes. In-depth computational and experimental studies clarified the mechanistic details of this unusual reactivity.

ent-Atisane diterpenoids: isolation, structure and bioactivity.

Covering: up to 2020 ent-Atisane diterpenoids are a class of over 150 members with diverse structures and valuable bioactivities. These compounds share a curious history in which the synthesis of the archetypal member preceded its isolation from natural sources. In this review, we provide a comprehensive summary of the isolation, structure, and bioactivity of ent-atisane diterpenoids from their discovery in 1965 to the present day.

seco-Labdanes: A Study of Terpenoid Structural Diversity Resulting from Biosynthetic C-C Bond Cleavage.

The cleavage of a C-C bond is a complexity generating process, which complements oxidation and cyclisation events in the biosynthesis of terpenoids. This process leads to increased structural diversity in a cluster of related secondary metabolites by modification of the parent carbocyclic core. In this review, we highlight the diversifying effect of C-C bond cleavage by examining the literature related to seco-labdanes-a class of diterpenoids arising from such C-C bond cleavage events.

Total Synthesis of (±)-Leonuketal.

Leonuketal is an 8,9-seco-labdane terpenoid with a unique tetracyclic structure, owing to a diversity-generating biosynthetic C-C bond cleavage event. The first total synthesis of leonuketal is reported, featuring a Ti(III)-mediated reductive cyclization of an epoxy nitrile ether, an unusual ring-opening alkyne formation as part of an auxiliary ring strategy, and the previously undescribed Au(I)-catalyzed cyclization of a ß-keto(enol)lactone to assemble the core spiroketal motif.

Divalent cannabinoid-1 receptor ligands: A linker attachment point survey of SR141716A for development of high-affinity CB1R molecular probes.

The cannabinoid-1 receptor (CB1R) inverse agonist SR141716A has proven useful for study of the endocannabinoid system, including development of divalent CB1R ligands possessing a second functional motif attached via a linker unit. These have predominantly employed the C3 position of the central pyrazole ring for linker attachment. Despite this precedent, a novel series of C3-linked CB1R-D2R divalent ligands exhibited extremely high affinity at the D2R, but only poor affinity for the CB1R. A systematic linker attachment point survey of the SR141716A pharmacophore was therefore undertaken, establishing the C5 position as the optimal site for linker conjugation. This linker attachment survey enabled the identification of a novel divalent ligand as a lead compound to inform ongoing development of high-affinity CB1R molecular probes.

Catalyst-Free Deaminative Functionalizations of Primary Amines by Photoinduced Single-Electron Transfer.

The use of pyridinium-activated primary amines as photoactive functional groups for deaminative generation of alkyl radicals under catalyst-free conditions is described. By taking advantage of the visible light absorptivity of electron donor-acceptor complexes between Katritzky pyridinium salts and either Hantzsch ester or Et3 N, photoinduced single-electron transfer could be initiated in the absence of a photocatalyst. This general reactivity platform has been applied to deaminative alkylation (Giese), allylation, vinylation, alkynylation, thioetherification, and hydrodeamination reactions. The mild conditions are amenable to a diverse range of primary and secondary alkyl pyridiniums and demonstrate broad functional group tolerance.

Synthesis of the Bicyclic Lactone Core of Leonuketal, Enabled by a Telescoped Diels-Alder Reaction Sequence.

The Diels-Alder cycloaddition reaction has become established as a fundamental approach for the preparation of complex natural products; however, successful application of the intermolecular Diels-Alder cycloaddition reaction to the synthesis of particularly congested scaffolds remains surprisingly problematic. Inspired by the terpenoid spiroketal natural product leonuketal, a challenging telescoped reaction sequence has been realized to access the core [2.2.2]-bicyclic lactone ring system and its [3.2.1] isomer. Our four-step, protecting-group-free process required detailed investigation to circumvent the problems of adduct fragmentation and intermediate instability. Successful solution of these practical issues, along with unambiguous structural determination of the target structures, provide useful insights that will facilitate future applications of the Diels-Alder cycloaddition reaction to challenging, highly congested molecular scaffolds and ongoing synthetic efforts towards this natural product.

Affinity and Efficacy Studies of Tetrahydrocannabinolic Acid A at Cannabinoid Receptor Types One and Two.

Introduction:Cannabis biosynthesizes Δ9-tetrahydrocannabinolic acid (THCA-A), which decarboxylates into Δ9-tetrahydrocannabinol (THC). There is growing interest in the therapeutic use of THCA-A, but its clinical application may be hampered by instability. THCA-A lacks cannabimimetic effects; we hypothesize that it has little binding affinity at cannabinoid receptor 1 (CB1). Materials and Methods: Purity of certified reference standards were tested with high performance liquid chromatography (HPLC). Binding affinity of THCA-A and THC at human (h) CB1 and hCB2 was measured in competition binding assays, using transfected HEK cells and [3H]CP55,940. Efficacy at hCB1 and hCB2 was measured in a cyclic adenosine monophosphase (cAMP) assay, using a Bioluminescence Resonance Energy Transfer (BRET) biosensor. Results: The THCA-A reagent contained 2% THC. THCA-A displayed small but measurable binding at both hCB1 and hCB2, equating to approximate Ki values of 3.1µM and 12.5µM, respectively. THC showed 62-fold greater affinity at hCB1 and 125-fold greater affinity at hCB2. In efficacy tests, THCA-A (10µM) slightly inhibited forskolin-stimulated cAMP at hCB1, suggestive of weak agonist activity, and no measurable efficacy at hCB2. Discussion: The presence of THC in our THCA-A certified standard agrees with decarboxylation kinetics (literature reviewed herein), which indicate contamination with THC is nearly unavoidable. THCA-A binding at 10µM approximated THC binding at 200nM. We therefore suspect some of our THCA-A binding curve was artifact-from its inevitable decarboxylation into THC-and the binding affinity of THCA-A is even weaker than our estimated values. We conclude that THCA-A has little affinity or efficacy at CB1 or CB2.