Tricyclic Products Research Articles

Triflic acid-promoted Friedel–Crafts-type carbocyclization of alkenylated biphenyl derivatives: Synthesis and photophysical studies of novel 9,10-dihydrophenanthrenes

An efficient metal-free, triflic acid-promoted intramolecular Friedel–Crafts-type carbocyclization of alkenylated biphenyl derivatives is discussed. This method provides an elegant route for the construction of 9,10-dihydrophenanthrenes of biological significance in good to excellent yields. The carbocyclization reaction is likely to proceeds via activation of terminal CC bond of alkenylated biphenyl derivatives followed by subsequent aromatic electrophilic substitution to give desired carbocyclic products. Single crystal X-ray diffraction analysis of compound 10d revealed that the crystals are packed in AB-AB layer packing, where the molecules are aligned in anti-parallel fashion. Notably, all of the synthesized 9,10-dihydrophenanthrenes exhibited blue to greenish yellow fluorescence with λmax = 418–481 nm range. The stokes shift, quantum yield and optical band gap of tricyclic products were computed using their absorption and emission spectra. A significant positive solvatochromic effect was observed for 9,10-dihydrophenanthrene derivative 10l, which is a characteristic of ICT interactions.

Sesquiterpene Cyclase BcBOT2 Promotes the Unprecedented Wagner-Meerwein Rearrangement of the Methoxy Group.

Presilphiperfolan-8β-ol synthase (BcBOT2), a substrate-promiscuous sesquiterpene cyclase (STC) of fungal origin, is capable of converting two new farnesyl pyrophosphate (FPP) derivatives modified at C7 of farnesyl pyrophosphate (FPP) bearing either a hydroxymethyl group or a methoxymethyl group. These substrates were chosen based on a computationally generated model. Biotransformations yielded five new oxygenated terpenoids. Remarkably, the formation of one of these tricyclic products can only be explained by a cationically induced migration of the methoxy group, presumably via a Meerwein-salt intermediate, unprecedented in synthetic chemistry and biosynthesis. The results show the great principle and general potential of terpene cyclases for mechanistic studies of unusual cation chemistry and for the creation of new terpene skeletons.

Structure-Based Engineering of a Sesquiterpene Cyclase to Generate an Alcohol Product: Conversion of epi-Isozizaene Synthase into α-Bisabolol Synthase.

The sesquiterpene cyclase epi-isozizaene synthase (EIZS) from Streptomyces coelicolor catalyzes the metal-dependent conversion of farnesyl diphosphate (FPP) into the complex tricyclic product epi-isozizaene. This remarkable transformation is governed by an active site contour that serves as a template for catalysis, directing the conformations of multiple carbocation intermediates leading to the final product. Mutagenesis of residues defining the active site contour remolds its three-dimensional shape and reprograms the cyclization cascade to generate alternative cyclization products. In some cases, mutagenesis enables alternative chemistry to quench carbocation intermediates, e.g., through hydroxylation. Here, we combine structural and biochemical data from previously characterized EIZS mutants to design and prepare F95S-F198S EIZS, which converts EIZS into an α-bisabolol synthase with moderate fidelity (65% at 18 °C, 74% at 4 °C). We report the complete biochemical characterization of this double mutant as well as the 1.47 Å resolution X-ray crystal structure of its complex with three Mg2+ ions, inorganic pyrophosphate, and the benzyltriethylammonium cation, which partially mimics a carbocation intermediate. Most notably, the two mutations together create an active site contour that stabilizes the bisabolyl carbocation intermediate and positions a water molecule for the hydroxylation reaction. Structural comparison with a naturally occurring α-bisabolol synthase reveals common active site features that direct α-bisabolol generation. In showing that EIZS can be redesigned to generate a sesquiterpene alcohol product instead of a sesquiterpene hydrocarbon product, we have expanded the potential of EIZS as a platform for the development of designer cyclases that could be utilized in synthetic biology applications.

Hydrated [3+2] Cyclotelomerization of Butafulvenes to Create Multiple Contiguous Fully Substituted Carbon Centers.

The construction of multiple continuous fully substituted carbon centers, which serve as unique structural motif in natural products, is a challenging topic in organic synthesis. Herein, we report a hydrated [3+2] cyclotelomerization of butafulvenes to create contiguous fully substituted carbon backbone. In the presence of scandium triflate, all-carbon skeleton with spiro fused tricyclic ring can be constructed in high diastereoselectivity by utilizing butafulvene as the synthon. Mechanistic studies suggest that this atom-economic reaction probably proceeds through a synergistic process containing butafulvenes dimerization and nucleophilic attack by water. In addition, the tricyclic product can undergo a series of synthetic derivatizations, which highlights the potential applications of this strategy. The recyclability of Sc(OTf)3 has also been demonstrated to show its robust performance in this hydrated cyclotelomerization.

Hydrated [3+2] Cyclotelomerization of Butafulvenes to Create Multiple Contiguous Fully Substituted Carbon Centers

AbstractThe construction of multiple continuous fully substituted carbon centers, which serve as unique structural motif in natural products, is a challenging topic in organic synthesis. Herein, we report a hydrated [3+2] cyclotelomerization of butafulvenes to create contiguous fully substituted carbon backbone. In the presence of scandium triflate, all‐carbon skeleton with spiro fused tricyclic ring can be constructed in high diastereoselectivity by utilizing butafulvene as the synthon. Mechanistic studies suggest that this atom‐economic reaction probably proceeds through a synergistic process containing butafulvenes dimerization and nucleophilic attack by water. In addition, the tricyclic product can undergo a series of synthetic derivatizations, which highlights the potential applications of this strategy. The recyclability of Sc(OTf)3 has also been demonstrated to show its robust performance in this hydrated cyclotelomerization.

Enantioselective synthesis of tricyclic oxoquinolines via NHC-catalyzed Michael-aldol-lactamization-dehydration cascade.

The enantioselective synthesis of tricyclic oxoquinolines via NHC-catalyzed cascade reaction of enals with malonates bearing a 2-aminophenyl group is reported. The chiral α,β-unsaturated acylazoliums underwent a smooth Michael-aldol-lactamization-dehydration quadruple cascade with the amino malonate derivative to afford the desired tricyclic products.

Salicylaldehydes in Strecker Reaction: Synthesis of Tricyclic Benzofuro[2,3‐b]pyrazin‐2(1H)‐ones via One‐Pot Seven Domino Reactions

The current study reports the first Strecker reaction with salicylaldehydes as carbonyl compounds. This pseudo‐five‐component reaction involved two moles of salicylaldehyde, two moles of cyanide, and one mole of amine, which reacted together in ethanol at reflux conditions, resulting in the tricyclic products benzofuro[2,3‐b]pyrazin‐2(1H)‐one (4a‐v). The benzofuro[2,3‐b]pyrazin‐2(1H)‐one products were formed via one‐pot seven Domino reactions including the Strecker reaction/ intramolecular cyclization/ tautomerization of imine to enamine/ Strecker reaction/ intramolecular cyclization/ conversion of amidine to amide/ and aerobic oxidation.

Dithioallyl Cations in Stereoselective Dearomative (3 + 2) Cycloadditions of Benzofurans: Mechanism and Synthetic Applications.

A stereoselective dearomative cyclopentannulation of benzofurans is reported. A previously reported dearomative (3 + 2) cycloaddition of indoles with 1,4-dithiane-fused allyl cations was found to lack stereoselectivity when more substituted cyclopentene rings are targeted. However, for benzofuran substrates, excellent levels of stereoselectivity were observed for the same allyl cation reagents under very similar reaction conditions. In this full account, we provide a mechanistic rationale and some design principles that govern the stereoselectivity of the intriguing dearomative transformations using dithioallyl cations and demonstrate how the stereoselectivity depends on electronic factors of the starting materials. The stereoselective methodology is also applied in a straightforward dearomative synthesis of the tricyclic sesquiterpenoid natural product aplysin and its analogues, starting from a simple benzofuran.

Synthesis of Tricyclic Tetrazoles by Cascade Diazotization/Intramolecular Radical C-H Heteroarylation of Arenes.

A cascade diazotization/intramolecular radical C-H heteroarylation of 1-benzyloxy-5-aminotetrazoles and 1-phenethyl-5-aminotetrazoles as substrates using sodium nitrite and acetic acid without any heating, catalysis, irradiation, or electrolysis is reported. This one-pot reaction afforded the desired tricyclic tetrazole products in good yields (up to 94%) without isolation of the diazonium salt intermediate under mild reaction conditions.

Nucleophilicities of Cyclic α‐Diazo Carbonyl Compounds

AbstractThe one‐bond nucleophilic reactivities of seven cyclic α‐diazo carbonyl compounds in dichloromethane were determined by analyzing the kinetics of their reactions with benzhydrylium ions (one‐bond reference electrophiles) at 20 °C according to the Mayr‐Patz equation. Though not calibrated for pericyclic reactions, the identified nucleophilicities also reflect relative reactivities of the α‐diazo carbonyl compounds in 1,3‐dipolar cycloadditions with dimethyl acetylenedicarboxylate. These (3+2)‐cycloadditions primarily gave spirocyclic 3H‐pyrazoles, which underwent thermal [1,5]‐sigmatropic (van Alphen‐Hüttel) rearrangements to furnish 1H‐pyrazole‐fused tricyclic products.

Catalytic aza-Nazarov cyclization reactions to access α-methylene-γ-lactam heterocycles.

We have developed a catalytic aza-Nazarov reaction of N-acyliminium salts generated in situ from the reaction of a variety of cyclic and acyclic imines with α,β-unsaturated acyl chlorides to afford substituted α-methylene-γ-lactam heterocycles. The reactions proceed effectively in the presence of catalytic (20 mol %) amounts of AgOTf as an anion exchange agent or hydrogen-bond donors such as squaramides and thioureas as anion-binding organocatalysts. The aza-Nazarov cyclization of 3,4-dihydroisoquinolines with α,β-unsaturated acyl chlorides gives tricyclic lactam products 7 in up to 79% yield with full diastereocontrol (dr = >99:1). The use of acyclic imines in a similar catalytic aza-Nazarov reaction with 20 mol % of AgOTf results in the formation of α-methylene-γ-lactam heterocycles 19 in up to 76% yield and with good to high diastereoselectivities (4.3:1 to 16:1). We have demonstrated the scalability of the reaction with a gram-scale example. The relative stereochemistry of the α-methylene-γ-lactam products 19 has been determined via the single-crystal X-ray analysis of lactam 19l. In order to shed light on the details of the reaction mechanism, we have performed carefully designed mechanistic studies which consist of experiments on the effect of β-silicon stabilization, the alkene geometry of the α,β-unsaturated acyl chloride reactants, and adventitious water on the success of the catalytic aza-Nazarov reaction.

N-Heterocyclic Carbene-Catalyzed Aza-Michael-Mannich-Lactamization Cascade for the Enantioselective Synthesis of Pyrazoloquinolin-3-ones.

The enantioselective synthesis of functionalized pyrazoloquinolin-3-ones via N-heterocyclic carbene-catalyzed cascade reaction of α-bromoenals with 2-aminoaryl N-tosyl hydrazones is reported. The in situ-generated α,β-unsaturated acylazoliums underwent an aza-Michael-Mannich-lactamization sequence to afford the tricyclic products bearing three contiguous stereocenters, including a sterically demanding quaternary stereocenter with high enantioselectivity. The unprotected amine-triggered aza-Michael pathway over the competing amidation pathway is noteworthy.

Synthesis and characterization of sulfide/sulfone-containing 18-8-18-membered-ring ladder-type siloxanes.

Innovative macrocyclic 14-membered molecule (5) and tricyclic 18-8-18-membered-ring ladder-type siloxane-based compound (7), with sulfide units inserted in the backbone were prepared through B(C6F5)3-catalyzed Piers-Rubinsztajn reaction. Further oxidation of 5 and 7 with m-CPBA enables the synthesis of the novel sulfonyl-containing cyclic and ladder-type compound (8 and 9) in high yields. Both tricyclic ladder-type products (7 and 9) show superior thermostability and their well-defined syn-type structures were determined by X-ray crystallographic analysis. The compounds 7 and 9 may become promising building blocks for various new materials.

The Ketosynthase Domain Controls Chain Length in Mushroom Oligocyclic Polyketide Synthases.

The nonreducing iterative type I polyketide synthases (NR-PKSs) CoPKS1 and CoPKS4 of the webcap mushroom Cortinarius odorifer share 88 % identical amino acids. CoPKS1 almost exclusively produces a tricyclic octaketide product, atrochrysone carboxylic acid, whereas CoPKS4 shows simultaneous hepta- and octaketide synthase activity and also produces the bicyclic heptaketide 6-hydroxymusizin. To identify the region(s) controlling chain length, four chimeric enzyme variants were constructed and assayed for activity in Aspergillus niger as heterologous expression platform. We provide evidence that the β-ketoacyl synthase (KS) domain determines chain length in these mushroom NR-PKSs, even though their KS domains differ in only ten amino acids. A unique proline-rich linker connecting the acyl carrier protein with the thioesterase domain varies most between these two enzymes but is not involved in chain length control.

Conversion of lignin oil and hemicellulose derivative into high-density jet fuel

Synthesizing high-density fuel from lignocellulose can not only achieve green and low-carbon development, but also expand the feedstock source of hydrocarbon fuel. Here, we reported a route of producing high-density fuel from lignin oil and hemicellulose derivative cyclopentanol through alkylation and hydrodeoxygenation. HY with SiO2/Al2O3 molar ratio of 5.3 was screened as the alkylation catalyst in the reaction of model phenolic compounds and mixtures, and the reaction conditions were optimized to achieve conversion of phenolic compounds higher than 87% and selectivity of bicyclic and tricyclic products higher than 99%. Then two phenolic pools simulating the composition of two typic lignin oils were studied to validate the alkylation and analyze the competition mechanism of phenolic compounds in mixture system. Finally, real lignin oil from depolymerized of beech powder was tested, and notably 80% of phenolic monomers in the oil were converted into fuel precursor. After hydrodeoxygenation, the alkylated product was converted to fuel blend with a density of 0.91 g/mL at 20 °C and a freezing point lower than −60 °C, very promising as high density fuel. This work provides a facile and energy-efficient way of synthesizing high-performance jet fuel directly from lignocellulosic derivatives, which decreases processing energy consumption and improve the utilization rate of feedstock.

A Tandem Prins/Friedel‐Crafts Cyclization Strategy for the Stereoselective Synthesis of Hexahydro‐2H‐benzo[g]chromenes

AbstractA tandem Prins/Friedel‐Crafts cascade strategy has been developed for the synthesis of hexahydro‐2H‐benzo[g]chromene derivatives. Under action of equimolecular amount of BF3 etherate, δ,ϵ‐unsaturated alcohols and arylacetaldehydes are coupled to form oxocarbenium ion intermediates, which are captured by the alkene moiety through a favored six‐membered transition state. The Prins‐cyclization resultant tertiary carbenium ions undergo consecutive intramolecular Friedel–Crafts cyclization to create the tricyclic products. This process enables a tandem formation of three new chemical bonds in one single operation with high yields and stereoselectivity in most cases. When cyclic substituents are involved, a variety of spiro derivatives could also be synthesized successfully, which further proved the robustness of this methodology.

How a 10-epi-Cubebol Synthase Avoids Premature Reaction Quenching to Form a Tricyclic Product at High Purity.

Terpenes are the largest class of natural products and are attractive targets in the fuel, fragrance, pharmaceutical, and flavor industries. Harvesting terpenes from natural sources is environmentally intensive and often gives low yields and purities, requiring further downstream processing. Engineered terpene synthases (TSs) offer a solution to these problems, but the low sequence identity and high promiscuity among TSs are major challenges for targeted engineering. Rational design of TSs requires identification of key structural and chemical motifs that steer product outcomes. Producing the sesquiterpenoid 10-epi-cubebol from farnesyl pyrophosphate (FPP) requires many steps and some of Nature’s most difficult chemistry. 10-epi-Cubebol synthase from Sorangium cellulosum (ScCubS) guides a highly reactive carbocationic substrate through this pathway, preventing early quenching and ensuring correct stereochemistry at every stage. The cyclizations carried out by ScCubS potentially represent significant evolutionary expansions in the chemical space accessible by TSs. Here, we present the high-resolution crystal structure of ScCubS in complex with both a trinuclear magnesium cluster and pyrophosphate. Computational modeling, experiment, and bioinformatic analysis identified residues important in steering the reaction chemistry. We show that S206 is crucial in 10-epi-cubebol synthesis by enlisting the nearby F211 to shape the active site contour and prevent the formation of early escape cadalane products. We also show that N327 and F104 control the distribution between several early-stage cations and whether the final product is derived from the germacrane, cadalane, or cubebane hydrocarbon scaffold. Using these insights, we reengineered ScCubS so that its main product was germacradien-4-ol, which derives from the germacrane, rather than the cubebane, scaffold. Our work emphasizes that mechanistic understanding of cation stabilization in TSs can be used to guide catalytic outcomes.

Cycloaddition of 4-Acyl-1H-pyrrole-2,3-diones Fused at [e]-Side and Cyanamides: Divergent Approach to 4H-1,3-Oxazines.

4-Acyl-1H-pyrrole-2,3-diones fused at [e]-side with a heterocyclic moiety are suitable platforms for the development of a hetero-Diels–Alder-reaction-based, diversity-oriented approaches to series of skeletally diverse heterocycles. These platforms are known to react as oxa-dienes with dienophiles to form angular 6/6/5/6-tetracyclic alkaloid-like heterocycles and are also prone to decarbonylation at high temperatures resulting in generation of acyl(imidoyl)ketenes, bidentate aza- and oxa-dienes, which can react with dienophiles to form skeletally diverse products (angular tricyclic products or heterocyclic ensembles). Based on these features, we have developed an approach to two series of skeletally diverse 4H-1,3-oxazines (tetracyclic alkaloid-like 4H-1,3-oxazines and 5-heteryl-4H-1,3-oxazines) via a hetero-Diels–Alder reaction of 4-acyl-1H-pyrrole-2,3-diones fused at [e]-side with cyanamides. The products of these transformations are of interest for drug discovery, since compounds bearing 4H-1,3-oxazine moiety are extensively studied for inhibitory activities against anticancer targets.

Alcohol-Incorporating Diels-Alder Dimerization of In Situ Formed ortho-Quinamine via Co-Nitrenoid Insertion.

We disclose herein a Cp*Co(III)(LX)-catalyzed dearomative Diels-Alder dimerization of 2,6-disubstituted phenyl azidoformates. Upon the postulated cobalt-nitrenoid insertion into the neighboring ortho-carbon, the key intermediate of ortho-quinamine was generated for the subsequent dimeric cycloaddition process. A series of experimental and computational studies suggested that the quinolinol ligand of the cobalt catalyst plays a crucial role in the alcoholic solvent incorporation into the o-quinamine moiety, thereby enabling the Diels-Alder dimerization to furnish the bridged tricyclic bisamidation products.

Transannular Approach to 2,3-Dihydropyrrolo[1,2-b]isoquinolin-5(1H)-ones through Brønsted Acid-Catalyzed Amidohalogenation.

A transannular approach has been developed for the construction of pyrrolo[1,2-b]isoquinolinones starting from benzo-fused nine-membered enelactams. This process takes place in the presence of a halogenating agent and under Brønsted acid catalysis and proceeds via a transannular amidohalogenation, followed by elimination. The reaction has been found to be wide in scope, enabling the formation of a variety of tricyclic products in good overall yield, regardless of the substitution pattern in the initial lactam substrate. The reaction has also been applied to the total synthesis of a reported topoisomerase I inhibitor and to the formal synthesis of rosettacin. Further extension of this methodology allows the preparation of 10-iodopyrrolo[1,2-b]isoquinolinones by using an excess of halogenating agent and these compounds can be further manipulated through standard Suzuki coupling chemistry into a variety of 10-aryl-substituted pyrrolo[1,2-b]isoquinolinones.