Octane Skeleton Research Articles

A Bis (BICAAC) Palladium(II) Complex: Synthesis and Implementation as Catalyst in Heck-Mizoroki and Suzuki-Miyaura Cross Coupling Reactions.

Carbenes are one of the most appealing, well-explored, and exciting ligands in modern chemistry due to their tunable stereoelectronic properties and a wide area of applications. A palladium complex (BICAAC)2PdCl2 with a recently discovered cyclic (alkyl)(amino)carbene having bicyclo[2.2.2] octane skeleton (BICAAC) was synthesized and characterized. The enhanced σ-donating and π-accepting ability of this carbene lend a hand to form a robust Pd-carbene bond, which allowed us to probe its reactivity as a precatalyst in Heck-Mizoroki and Suzuki-Miyaura cross-coupling reactions with low catalyst loading in open-air conditions. The diverse range of substrates was explored for both the cross-coupling reactions. To get a better understanding of the catalytic reactions, several analytical techniques such as field-emission scanning electron microscopy, high-resolution transmission electron microscopy, and powder X-ray diffraction were employed in a conclusive manner.

Visible Light-Induced Pericyclic Cascade Reaction for the Synthesis of Quinolinone Derivatives with an Oxabicyclo[4.2.0]octene Skeleton.

A photoinduced pericyclic cascade reaction has been developed to afford oxabicyclo[4.2.0]octenes. Mechanistic studies show that this reaction undergoes [2 + 2]-photocycloaddition, base-promoted elimination, retro-4π-electrocyclization, [1,5]-H shift, and 4π-electrocyclization procedures. This reaction features wide substrate scope, good functional group tolerance, and excellent diastereoselectivity.

Tetracyclic Diterpenoid Synthesis Facilitated by ODI-Cascade Approaches to Bicyclo[3.2.1]octane Skeletons.

Tetracyclic diterpenoids (C20) mainly refer to the plant terpenoids bearing biogenetically related carbon skeletons derived from copalyl diphosphates (ent-CPP and syn-CPP). This large family contains over 1600 known members that can be categorized into 11 major structural types. Among them, more than three-quarters share a bridged bicyclo[3.2.1]octane subunit, which is also an important branching point in biosynthesis en route to the other types of bicyclic scaffolds, such as bicyclo[2.2.2]-, bicyclo[3.3.0]-, and tricyclo[3.2.1.0]octanes. Combined with the significance of its stereochemical importance in biological activity, the assembly of the bicyclo[3.2.1]octane skeletons is critical to the success of the whole synthesis blueprint toward tetracyclic diterpenoids. Although a number of inspiring methodologies have been disclosed, general approaches by the incorporation of innovative cascade reactions permitting access to diverse structural types of tetracyclic diterpenoids remain limited and in urgent demand.Because of the long-standing interest in the synthesis of bridged diterpenoids, we have recently developed two complementary types of oxidative dearomatization induced (ODI) cascade approaches to the rapid and efficient construction of bicyclo[3.2.1]octane skeletons. In this Account, we summarize our original synthesis design, methodology development, and the application of these two strategies in tetracyclic diterpenoid synthesis during the past few years in our laboratory.First, we detail our preliminary investigation of the ODI-[5 + 2] cycloaddition/pinacol rearrangement cascade reaction, which showed a wide scope of vinylphenol substrates and led to cyclopentane and cyclohexane-fused bicyclo[3.2.1]octanes in good yields with excellent dr values. Next, we describe the utilization of this ODI-[5 + 2] cascade reaction which resulted in the asymmetric total syntheses of four highly oxygenated ent-kauranoids. The strategy concerning accurate stereochemical control in the ODI-[5 + 2] cycloaddition was then successfully transplanted to the total syntheses of three stemaranoids, thus providing a straightforward and diastereoselective route to C9-ethano-bridged tetracyclic diterpenoids. To access more complex diterpenoid rhodomollanol A, we exploited two additional biomimetic rearrangements, namely, the retro-Dieckmann fragmentation/vinylogous Dieckmann cyclization cascade and the photo-Nazarov cyclization/intramolecular cycloetherification cascade. Taken together with the ODI-[5 + 2] cascade, the asymmetric total synthesis of the target molecule was realized, which shed light on the biogenetic pathway of the unprecedented rhodomollane-type carbon framework. Finally, we describe an ODI-Diels-Alder/Beckwith-Dowd cascade approach as a valuable supplement to the ODI-[5 + 2] cascade for the fabrication of cycloheptane-fused bicyclo[3.2.1]octane skeletons. Its versatility was also demonstrated by the total syntheses of two challenging grayanane diterpenoids. In view of the high functional-group compatibility and scalability, we anticipate that the two novel cascade approaches will find further use in the field of complex natural product synthesis.

Bridged-Selective Intramolecular Diels-Alder Reactions in the Synthesis of Bicyclo[2.2.2]octanes.

Regioselectivity for intramolecular Diels-Alder (IMDA) reactions of 6-acetoxy-6-alkenylcyclohexa-2,4-dien-1-ones that were formed by oxidation of 2-alkenylphenols with lead tetraacetate in acetic acid were studied. Bridged regioselectivity was observed in the IMDA reactions of 6-acetoxy-6-alkenylcyclohexa-2,4-dien-1-ones having a dienophile part which could conjugate with an aromatic group. Bridged seven- and eight-membered rings and bicyclo[2.2.2]octane skeletons were constructed by the present IMDA reactions. Density functional theory (DFT) calculations suggested that conjugation of the dienophile with neighboring aromatic groups lowered the highest occupied molecular orbital-lowest unoccupied molecular orbital (HOMO-LUMO) energy gap and preceded bridged [4 + 2] adducts.

Rapid Access to Oxabicyclo[2.2.2]octane Skeleton through Cu(I)‐Catalyzed Generation and Trapping of Vinyl‐o‐quinodimethanes (Vinyl‐o‐QDMs)†

Summary of main observation and conclusionA Cu(I)‐catalyzed three‐component reaction of terminal enynals/enynones, diazo compounds, and alkenes has been developed. With this method, a series of oxabicyclo[2.2.2]octanes were effectively synthesized in high yields under mild reaction conditions. This transformation is proposed to proceed through trapping of the cyclic vinyl‐o‐quinodimethanes (vinyl‐o‐QDMs) species, which were generated from terminal enynals/enynones and diazo compounds by alkenes. The obvious advantages of wide substrate scopes, mild reaction conditions, and high seteroselectivity and atom efficiency make this reaction highly appealing for construction of highly rigid [2.2.2]octane skeleton.

Total Synthesis of (-)-Gardmultimine A.

The first total synthesis of Gardneria oxindole alkaloid (-)-gardmultimine A has been achieved in 19 steps from d-tryptophan in a fully stereocontrolled manner. This synthesis features (1) an Ir-catalyzed regioselective C-H borylation/oxidation sequence to introduce the C12 methoxyl group, (2) a stereocontrolled oxidative rearrangement of indole to construct the spirooxindole motif, and (3) an Au(I)-catalyzed transannular Conia-ene-type 6-exo-dig cyclization to establish the azabicyclo[2.2.2]octane skeleton and the exocyclic E-alkene with exclusive stereoselectivity.

Total Synthesis of (-)-Rhodomollanol A.

An asymmetric approach for the first total synthesis of (-)-rhodomollanol A, a highly oxidized diterpenoid, is described. The efficient synthetic strategy features three key transformations: (1) an oxidative dearomatization-induced (5 + 2) cycloaddition/pinacol-type 1,2-acyl migration cascade to build up the bicyclo[3.2.1]octane skeleton; (2) a retro-Dieckmann fragmentation/vinylogous Dieckmann cyclization cascade to assemble the bicyclo[3.3.0]octane subunit; and (3) a photo-Nazarov cyclization/intramolecular cycloetherification cascade to forge the 7-oxabicyclo[4.2.1]nonane core structure of the natural product.

Synthesis of 17-Deacetoxyl Chromodorolide B Based on a Gold-Catalyzed Alkoxycyclization Reaction.

A novel strategy to construct the highly oxidized 3-oxabicyclo[3.3.0]octane skeleton was developed via a gold-catalyzed cascade cyclization with 2,7-dioxabicyclo[3.2.0]hept-3-ene as the substrate. We utilized this methodology as the key reaction to synthesize 17-deacetoxyl chromodorolide B.

Terpenoid Cyclization by SAM-Dependent C-Methyl Transferase

Serratia plymuthica 4Rx13 emits the unique hydrocarbon sodorifen (C16H26) in which every carbon of the bicyclo[3.2.1]octane skeleton carries a methyl unit. Biosynthesis of this homosesquiterpene depends on a gene cluster comprising four genes, an isopentenyl pyrophosphate (PP) isomerase, a deoxyxylulose-5-phosphate synthase, a methyltransferase (MT), and a terpene synthase. The latter two enzymes are required and sufficient for the noncanonical biosynthesis of sodorifen.

Acetyl- and butyrylcholinesterase inhibitory activity of selected photochemicallysynthesized polycycles

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the main cause of dementia in the elderly population. Since the treatment of AD has been associated with the activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), their inhibitors remain the main focus of AD investigations. In this study we evaluated cholinesterase inhibitory activity of 14 bicyclo[3.2.1]octene/octadiene derivatives and naturally occurring sesquiterpene alcohol cedrol. These 14 compounds have been efficiently and ecologically prepared by a photochemical approach in batch photochemical reactors. Various compounds with the bicyclo[3.2.1]octene skeleton have already been successfully evaluated for treatment of central nervous system disorders and AD. Among the tested polycyclic derivatives, compounds 4-[(9$S)$-tricyclo[6.3.1.0$^{2,7}$]dodeca-2,4,6,10-tetraen-9-yl]pyridine (\textbf{3}) and (11$S)$-11-(4-chlorophenyl)-12-[($E)$-2-(4-chlorophenyl)ethenyl]tricyclo[6.3.1.0$^{2,7}$]dodeca-2,4,6,9-tetraene (\textbf{6}) showed the best inhibitory activity on BChE (IC$_{50}$ = 8.8 $\mu $M) and AChE (IC$_{50}$ = 17.5 $\mu $M), respectively.

Synthesis of 8-Oxabicyclo[3.2.1]octanes by TiCl4-Mediated Reactions of 3-Alkoxycyclobutanones and Allenylsilanes

1-Substituted allenylsilanes reacted with 3-alkoxycyclobutanones in the presence of TiCl4 to afford 8-oxabicyclo[3.2.1]octan-3-ones stereoselectively. Nucleophilic attack of allenylsilanes to a 1,4-zwitterionic intermediate formed from 3-alkoxycyclobutanones and TiCl4­ followed by 1,2-silyl migration, five-membered cyclization with an alkoxy group, and seven-membered cyclization of titanium enolate was proposed. Deuteration and one-pot Peterson olefination suggested that alkyl titanium species were formed after cyclization to 8-oxabi­cyclo[3.2.1]octane skeletons.

Asperidines A–C, pyrrolidine and piperidine derivatives from the soil-derived fungus Aspergillus sclerotiorum PSU-RSPG178

One new pyrrolidine derivative, asperidine A (1), and two new piperidine derivatives, asperidines B (2) and C (3), were isolated from the soil-derived fungus Aspergillus sclerotiorum PSU-RSPG178 together with two known alkaloids. Compound 3 possessed an unprecedented 7-oxa-1-azabicyclo[3.2.1]octane skeleton with four chiral centers. Their structures were determined by spectroscopic evidence. The absolute configurations of compounds 2 and 3 were established using Mosher’s method and further confirmed for compound 3 by X-ray crystallographic data. Compound 2 dose-dependently inhibited the CFTR-mediated chloride secretion in T84 cells with an IC50 value of 0.96 μM whereas 3 displayed the same activity with the IC50 value of 58.62 μM. Compounds 2 and 3 also significantly reduced intracellular ROS under both normal and H2O2-treated conditions compared with their respective controls in a dose-dependent manner without cytotoxic effect on Caco-2 cells. In addition, compound 3 was inactive against noncancerous Vero cells whereas compound 2 was considered to be inactive with the IC50 value of >10 μM.

Cerrenins A-C, cerapicane and isohirsutane sesquiterpenoids from the endophytic fungus Cerrena sp

One new cerapicane cerrenin A (1), and two new isohirsutane sesquiterpenoids cerrenins B and C (2 and 3), were isolated from the broth extract of Cerrena sp. A593. Cerrenin A featured a rare cage-like bicyclo[3.2.1]octane skeleton, and cerrenin B represented the rearranged triquinane-type sesquiterpenoid. Their structures were extensively elucidated by NMR spectroscopic analysis with the absolute configuration determined by X-ray crystallography and ECD calculations. The anti-cancer activity for all the compounds were evaluated, and their plausible biosynthetic relationships involving fascinating carbon skeleton rearrangements were also suggested.

Asymmetric epoxidation of enones using cumyl hydroperoxide and in situ generated zinc complexes of chiral pyrrolidinyl alcohols

The homogeneous asymmetric epoxidation of a range of enones was carried out using cumyl hydroperoxide, diethylzinc, and chiral pyrrolidinyl alcohol-containing ligands to afford the corresponding epoxy ketones with enantioselectivities of ≤97% ee. Examination of the enantioselectivities obtained in the asymmetric epoxidation of enones using a range of chiral ligands indicated that synergy between the sterically bulky bicyclo[2.2.2]octane skeleton and the substituents attached to the carbinol moiety played an important role in determining the reaction enantioselectivity. The position and nature of the substituent on the aromatic ring of the enone also had a pronounced effect on the observed enantioselectivity.

Bicyclic (Alkyl)(amino)carbenes (BICAACs): Stable Carbenes More Ambiphilic than CAACs.

A straightforward strategy allows for the synthesis of storable bicyclic (alkyl)(amino)carbenes (BICAACs), which feature enhanced σ-donating and π-accepting properties compared to monocyclic (alkyl)(amino)carbenes (CAACs). Due to the bicyclo[2.2.2]octane skeleton, the steric environment around the carbene center is different from that of CAACs and similar to that observed in classical N-heterocyclic carbenes. The different electronic properties of BICAACs as compared to CAACs allow for ligand exchange reactions not only at a metal center, but also at main group elements.

Asymmetric Cascade Assembly of 1,2-Diaza-1,3-dienes and α,β-Unsaturated Aldehydes via Dienamine Activation.

A cascade vinylogous 1,6-Michael addition/1,4-proton shift/aza-Michael addition/hemiaminal formation sequence of 1,2-diaza-1,3-dienes and β-substituted 2-butenals has been developed under the influence of dienamine activation of a chiral secondary amine. This method exhibits high regio- and chemoselectivity and provides an efficient and straightforward approach to bicyclic l,8-diazabicyclo[3.3.0]octane skeletons with a tetrasubstituted stereogenic center with fair to excellent enantioselectivity.

Photoinduced Intermolecular [4+2] Cycloaddition Reaction for Construction of Benzobicyclo[2.2.2]octane Skeletons

A novel and efficient method for the synthesis of highly substituted benzobicyclo[2.2.2]octane skeletons has been explored. Under UV-light irradiation, o-divinylbenzenes underwent a pericyclic reaction to form the cyclic o-quinodimethane intermediates which were subsequently reacted with olefins through [4+2] addition to construct the benzobicyclo[2.2.2]octane skeletons in mild conditions. Gram scale reactions demonstrated the synthetic potential application of this protocol.

Divergent Total Synthesis of Atisane-Type Diterpenoids.

Atisane-type diterpenoids are the principal constituent of tetracyclic C20 -diterpenoids, widely isolated from the plant kingdom with varying degrees of structural complexity and pharmacological activity. The tetracarbocyclic system with the unique bicyclo[2.2.2]octane skeleton of this natural product family has generated interest within the synthetic community. Divergent total synthesis is an effective tactic to synthesize several atisane-type diterpenoids using structural interconversion from a common intermediate. This account summarizes the divergent total synthesis of atisane-type diterpenoids.

ChemInform Abstract: Synthetic Approaches to Construct the 6,8‐DOBCO Framework in Natural Products

AbstractReview: [58 refs.

Tadehaginosides A-J, Phenylpropanoid Glucosides from Tadehagi triquetrum, Enhance Glucose Uptake via the Upregulation of PPARγ and GLUT-4 in C2C12 Myotubes.

Ten new phenylpropanoid glucosides, tadehaginosides A-J (1-10), and the known compound tadehaginoside (11) were obtained from Tadehagi triquetrum. These phenylpropanoid glucosides were structurally characterized through extensive physical and chemical analyses. Compounds 1 and 2 represent the first set of dimeric derivatives of tadehaginoside with an unusual bicyclo[2.2.2]octene skeleton, whereas compounds 3 and 4 contain a unique cyclobutane basic core in their carbon scaffolds. The effects of these compounds on glucose uptake in C2C12 myotubes were evaluated. Compounds 3-11, particularly 4, significantly increased the basal and insulin-elicited glucose uptake. The results from molecular docking, luciferase analyses, and ELISA indicated that the increased glucose uptake may be due to increases in peroxisome proliferator-activated receptor γ (PPARγ) activity and glucose transporter-4 (GLUT-4) expression. These results indicate that the isolated phenylpropanoid glucosides, particularly compound 4, have the potential to be developed into antidiabetic compounds.