Ring Junction Research Articles

Efficient and Divergent Total Synthesis of (-)-Epicoccin G and (-)-Rostratin A Enabled by Double C(sp3)-H Activation.

Dithiodiketopiperazines are complex polycyclic natural products possessing a variety of interesting biological activities. Despite their interest, relatively few total syntheses have been completed. We herein report the enantioselective, scalable, and divergent total synthesis of two symmetrical pentacyclic dithiodiketopiperazines, (-)-epicoccin G and (-)-rostratin A. A common intermediate was synthesized on a multigram scale from inexpensive, commercially available starting materials using an enantioselective organocatalytic epoxidation and a double C(sp3)-H activation as key steps, with the latter allowing the efficient simultaneous construction of the two five-membered rings. In addition to the cis,cis-fused target (-)-epiccocin G, the more challenging (-)-rostratin A, possessing two trans ring junctions, was obtained for the first time on a 500 mg scale through the optimization of each step and validation on multigram quantities. Both natural products were synthesized with high overall yields (13-20%). This study should facilitate access to this fascinating and yet understudied family of biologically active natural products.

Diastereoselective Methylation at the Congested β-Position of a Butenolide Ring: Studies toward the Synthesis of seco-Prezizaane-Type Sesquiterpenes.

We established a method for installing a methyl group at the β-position of a butenolide ring. The methylated position is located at the congested ring juncture of a 5,6,5-tricyclic lactone, which is common to neurotrophic seco-prezizaane-type sesquiterpenes. The samarium(II)-mediated conjugate addition of the halomethylsilyl ethers tethered to the proximal hydroxy groups efficiently formed the desired C-C bond. Subsequent fluoride-free Tamao oxidation and Barton-McCombie deoxygenation converted the resultant cyclic silyl ether into the corresponding methyl group.

Design and Characterization of Area-Efficient Trench Termination for 4H-SiC Devices

In this paper, the operation mechanism of trench termination is investigated through 2-D numeric simulation on Silvaco. It is found that in trench termination, the electric field is terminated by the accumulated holes at the outer trench sidewall. In order to ensure a high termination breakdown voltage, the trench is refilled with a combination of SiO2 and polyimide (PI). Through various 2-D numerical simulations, the impact of structural parameters on breakdown voltage has been discussed, namely, trench depth (TD), trench width (TW), and sidewall tilt angle. The 3-D simulations are also conducted to investigate the effect of round corner radius on the device breakdown voltage and electric field in the dielectrics. Based on these results, the trench termination is designed and then fabricated along with a p-i-n diode. The measurement results show that a $14~\mu \text{m}$ wide trench is sufficient to terminate a voltage of 1750V (>96% of the ideal planar breakdown). Comparing with conventional field limiting rings junction termination extension (FLR/JTE) technology, this trench termination can significantly reduce the termination length by a factor of 4. As a result, the area efficiency is largely improved from 62% to around 90% for a 2A device conducting at 1000 A/cm2. These results indicate that the SiC device price can be substantially lowered with such an area-efficient trench termination technology. Furthermore, the 168-h high-temperature reverse bias (HTRB) test under 1200 V and 175 °C shows the potential of this trench termination for long-term reliable operation. Finally, unclamped inductive switching (UIS) tests have been conducted on fabricated devices. Compared to commercial SiC junction barrier Schottky diodes with FLR, fabricated p-i-n diodes with trench termination show significant higher avalanche capability.

Stereoselective Convergent Synthesis of Tetrahydro-5 H-benzo[ c]fluorene via Nine-Membered Ring-Closing Metathesis and Transannular Acid-Mediated Cyclization/Nucleophilic Addition.

The diene methyl ethers or acetates, constructed from the Li-Br exchange/addition reactions of 2-vinylbenzaldehydes and 2-(but-3-en-1-yl)bromoarenes followed by etherification or acetylation of the corresponding alcohols, smoothly underwent the ring-closing metathesis (RCM) by using Hoveyda-Grubbs II as a catalyst to provide the corresponding benzannulated ( Z)-cyclononenes as single products in good yields (up to 75%). The ensuing one-pot acid-mediated transannular cyclization/nucleophilic addition at C7 furnished the corresponding tetrahydro-5 H-benzo[ c]fluorenes as single stereoisomers with the exclusive cis stereochemistry at the ring junction (C5-C6) and trans at the site of nucleophilic attack (C6-C7) on the three contiguous stereogenic centers in good to excellent yield (up to 94%). The developed strategy was general; the reaction conditions were compatible with hydride, azide, and electron-rich aromatics as nucleophiles. In addition, various methoxylated benzannulated cyclononene acetates could be employed as substrates. Thus, tetrahydro-5 H-benzo[ c]fluorenes could be prepared in four steps from appropriately substituted bromoarenes and benzaldehydes in good yields (up to 56%) with excellent stereo- and regio-control.

Tetracoordinate Boron-Fused Double [5]Helicenes as Cathode Active Materials for Lithium Batteries.

Double [5]helicenes possessing two tetracoordinated boron atoms at the ring junctions were synthesized from glycine anhydride in three steps. The helicene with fluorine substituents on the boron atoms was employed as a cathode active material in a lithium battery to demonstrate moderate performance in the 1.8-3.5 V range with more than 63 mAh g-1 discharge capacity for 20 cycles and high Coulombic efficiency of over 90%.

Synthetic Studies on Enantioselective Total Synthesis of Cyathane Diterpenoids: Cyrneines A and B, Glaucopine C, and (+)-Allocyathin B2.

The details for the synthetic studies on enantioselective total synthesis of cyathane diterpenoids cyrneine A (1) and B (2), glaucopine C (3), and (+)-allocyathin B2 are presented. We established a mild Suzuki coupling for heavily substituted nonactivated cyclopentenyl triflates using a phosphinamide-derived palladacycle as precatalyst and a chelation-controlled highly regioselective Friedel-Crafts cyclization. The utilization of these two key reactions enabled a rapid construction of the 5-6-6 tricyclic skeleton. In the middle stage of the synthesis, a Birch reductive methylation, a modified Wolff-Kishner-Huang reduction, and a carbenoid-mediated ring expansion were employed as the key reactions to furnish the 5-6-7 tricyclic core bearing two antiorientated all-carbon quaternary stereocenters at the C6 and C9 ring junctions. By applying these key transformations, a more efficient total synthesis of cyrneine A and allocyathin B2, and the first total synthesis of cyrneine B and glaucopine C, were accomplished through a collective manner. The late-stage conversions involving a base-mediated double bond migration and a double bond migration/aerobic γ-CH oxidation cascade for the stereoselective synthesis of cyrneine B and glaucopine C were interesting.

Microwave-Assisted Stereoselective Heterocyclization to Novel Ring d-fused Arylpyrazolines in the Estrone Series.

Microwave-assisted syntheses of novel ring d-condensed 2-pyrazolines in the estrone series were efficiently carried out from steroidal α,β-enones and hydrazine derivatives. The ring-closure reaction of 16-benzylidene estrone 3-methyl ether with hydrazine in acetic acid resulted in a 2:1 diastereomeric mixture of two 16,17-cis fused pyrazolines, which is contrary to the former literature data for both stereoselectivity and product structure. However, the cyclization reactions of a mestranol-derived unsaturated ketone with different arylhydrazines in acidic ethanol furnished the heterocyclic products in good to excellent yields independently of the substituents present on the aromatic ring of the reagents applied. The MW conditions also permitted the ring-closure reaction with p-nitrophenylhydrazine which is unfavorable under conventional heating. Moreover, the transformations led to the heterocyclic compounds stereoselectively with a 16α,17α-cis ring junction without being susceptible to spontaneous and promoted oxidation to pyrazoles.

Circular current and induced force in a molecular ring junction

We consider bias-induced circular current in a molecular ring junction. It is natural to define circular current as a component of ring current that acts as a sole source of magnetic flux induced in the ring. Alternatively, the bias-induced circular current can also be determined from the magnetic response of the ring junction to an external flux in the zero-flux limit. This leads to determination of bias-induced circular current without actually calculating the bond currents. We also explore the possibility of circular current-induced force rupturing the covalent bonds in the ring leading to ultimate breakdown of the ring junction. Our calculations underscore the reliability problem posed by the current magnification effect in the molecular ring structures.

Synthesis of Tetracoordinate Boron-Fused Benzoaceanthrylene Analogs via Tandem Electrophilic C-H Borylation.

Benzoaceanthrylene analogs with tetracoordinate boron at the ring junction were synthesized through tandem electrophilic C-H borylation of 2,6-dinaphthylpyridine followed by nucleophilic substitution. Notably, the [5,6]-annulation occurred selectively over [6,6]-annulation with the assistance of nitrogen coordination of the pyridine ring. The X-ray crystallographic analysis revealed the polycyclic skeleton with a distorted tetracoordinate boron atom and a unique packing structure with intermolecular π-π interaction. The photophysical and electrochemical properties of these benzoaceanthrylene analogs were evaluated by UV-vis spectroscopy and differential pulse voltammetry. The electron affinity of the fluorine-substituted derivative is estimated to be 3.49 eV from the ionization potential and optical band gap. Thus, this derivative is expected to be a promising n-type semiconducting material.

Synthetic Access to Cyclopenta[a]inden-2(1H)-ones from Morita-Baylis-Hillman Products of 2-Alkynyl Benzaldehydes.

A new strategy for the synthesis of cyclopenta[a]inden-2(1H)-ones has been developed. An intramolecular Pauson–Khand reaction of the Morita–Baylis–Hillman (MBH) adducts, derived from 2-alkynyl benzaldehydes, provided the consequent novel cyclopenta[a]inden-2(1H)-ones bearing multifunctionalities including an ester group at the fused ring junction (tert-carbon center). The generality of this approach was illustrated by studying the several MBH derivatives containing diverse substitutions/functionalities.

Synthesis of 3-Azidopiperidine Skeleton Employing Ceric Ammonium Nitrate (CAN)-Mediated Regioselective Azidoalkoxylation of Enol Ether: Total Synthesis of D2 Receptor Agonist (±)-Quinagolide.

The total synthesis of (±)-quinagolide, which is a D2 receptor agonist, was accomplished via a ceric ammonium nitrate (CAN)-mediated regioselective azidoalkoxylation of enol ether route. Key features of the synthesis include Claisen rearrangement, PPTS (pyridinium p-toluenesulfonate)-catalyzed one-pot acetal deprotection, followed by a diastereoselective Henry reaction, which enables construction of the required trans ring junction and CAN-mediated regioselective azidoalkoxylation of enol ether. The PPTS-catalyzed intramolecular diastereoselective Henry reaction to fix three contiguous stereocenters on tetrahydronaphthalene and the first-of-its-kind synthesis of the 3-azidopiperidine skeleton, using a CAN-mediated regioselective azidoalkoxylation of enol ether, are important findings of the present work.

Total Synthesis of (±)-Prostratin

Summary Prostratin, a highly complex diterpene natural product, is a pre-clinical candidate in developing a cure for HIV-1 infection and also a potent and selective inhibitor of several tumors. Despite nearly 40 years of progress, prostratin and related natural products still present formidable challenges for synthetic chemists. Here, we report a total synthesis of (±)-prostratin that proceeds in 23 steps from cyclopentadiene. The synthetic strategy includes rapid assembly of the tricyclic core and highly controlled establishment of the densely functionalized C ring, featuring an array of stereoselective transformations including alkoxide-guided 1,4-additions and cyclopropane formation. This work should enable further explorations of chemical and biological spaces based on prostratin and related natural products.

Isosteroidal alkaloids from the bulbs of Fritillaria tortifolia

Three new isosteroidal alkaloids, frititorines A-C (1–3), were isolated from the bulbs of Fritillaria tortifolia, together with ten known ones (4–13). Their structures were elucidated by extensive spectroscopic analyses, chemical methods, and single-crystal X-ray crystallographic analysis. Compound 1 is the first 5β-cevanine alkaloid with a cis A/B ring junction from the Fritillaria genus. Compound 2 is the first example of glycosylated isosteroidal alkaloid N-oxide. Compound 1 showed significant relaxant effect on Ach-induced tracheal contraction with pA2 and EC50 values equivalent to those of aminophylline.

The Role of Ortho-dearomatization Reaction in Constructing Spirocyclic Scaffolds with an All-carbon Ring Junction

Background: Spiro skeleton is an important structural motif in natural products, usually accounting for their formidable architectures and remarkable biological profiles. Recent advances demonstrated that a diverse range of scenarios held the promise for the assembly of spirocenter based on ortho-dearomatization strategy. In this article, we describe the latest development of ortho-dearomatization reaction in constructing spirocyclic scaffolds with an all-carbon ring junction from a methodological standpoint. Objective: The review focuses on recent progress in the area of ortho-dearomatization reaction in constructing spirocyclic scaffolds with an all-carbon ring junction. Conclusion: In summary, we have summarized the capability of ortho-dearomatization reaction to construct spirocyclic skeleton, a common structural pattern found at the core of numerous natural products with broad structural diversities and important bioactivities. Success in this area will benefit not only the area of synthetic chemistry through methodological development, but also medicinal chemistry and chemical biology by providing access to rapid assembly of bioactive compounds’ core scaffolds.

Selective Divergent Synthesis of Indanols, Indanones, and Indenes via Acid-Mediated Cyclization of (Z)- and (E)-(2-Stilbenyl)methanols and Its Application for the Synthesis of Paucifloral F Derivatives

Starting from bromo/iodobenzaldehyde derivatives, the corresponding ( Z)- and ( E)-(2-stilbenyl)methanols could be prepared in 2-5 steps via Pd-catalyzed cross-coupling reactions (Sonogashira and Heck reactions) followed by aryllithium/aryl Grignard addition. For the ( E)-stilbenes, subsequent acid-mediated cyclization using p-TsOH immobilized on silica (PTS-Si) at low temperatures furnished the 2,3- trans-1-indanols with complete stereocontrol at the C2-C3. Further oxidization of the alcohol provided the indanones, which are structurally related to the natural product paucifloral F. At higher temperatures, 1,2- and 2,3-disubstituted indenes could be selectively prepared in good to excellent yields. On the other hand, the ( Z)-stilbenes, under similar conditions (PTS-Si), did not give the indanols; only the 1,2-disubstituted indenes could be obtained. To gain further insights into the stereochemistry at C2-C3 for the ( Z)-stilbenes, hydride or azide was employed as a nucleophile; the corresponding indane products were obtained with the cis stereochemistry at the C2-C3. Thus, the ( Z)- or ( E)-olefin geometry of the substrate directed the stereoselective indanyl cyclization to furnish the cis or trans at the C2-C3 ring junction, respectively, while reaction conditions controlled the selectivity of the product types.

Topological quantum computation based on chiral Majorana fermions

The chiral Majorana fermion is a massless self-conjugate fermion which can arise as the edge state of certain 2D topological matters. It has been theoretically predicted and experimentally observed in a hybrid device of a quantum anomalous Hall insulator and a conventional superconductor. Its closely related cousin, the Majorana zero mode in the bulk of the corresponding topological matter, is known to be applicable in topological quantum computations. Here we show that the propagation of chiral Majorana fermions leads to the same unitary transformation as that in the braiding of Majorana zero modes and propose a platform to perform quantum computation with chiral Majorana fermions. A Corbino ring junction of the hybrid device can use quantum coherent chiral Majorana fermions to implement the Hadamard gate and the phase gate, and the junction conductance yields a natural readout for the qubit state.

Rhabdaprovidines D–G, Four New 6,6,5-Tricyclic Terpenoids from the Vietnamese Sponge Rhabdastrella providentiae

Four new 6,6,5-tricyclic terpenoids, named rhabdaprovidines D-G (1–4), were isolated from the Vietnamese sponge Rhabdastrella providentiae. The structures of 1–4 were elucidated by extensive analysis of HR-ESI-MS and NMR spectroscopy. The absolute stereochemistry of compounds 3 and 4 were determined by both experimental and theoretical calculated circular dichroism (CD) spectra. Compounds 1, 2, and 4 contained trans-syn-trans 6,6,5-tricyclic nucleus meanwhile compound 3 possessed trans-syn-cis ring junction. Compound 4 displayed novel structure by the presence of five rings and nine chiral carbon centers in the isomalabaricane triterpene backbone.

Phytochemical and Biological Investigation of Narcissus pseudonarcissus Cultivated in Egypt

A phytochemical investigation of the alkaloidal content of the bulbs of Narcissus pseudonarcissus cultivated in Egypt resulted in the isolation of the alkaloid; 9-O-demethyl-7-O-methyllycorenine (5) in addition to the eight known alkaloids; homolycorine (1), 7-O-methyloduline (2), 7-O-methyllycorenine (3), hippeastrine (4), 9-O-demethylhomolycorine (6), galanthamine (7), haemanthamine (8) and lycorine. Structural determination of the isolated alkaloids was established by different spectral analyses (UV, MS, NMR and 2D-NMR). The isolation of 9-O-demethyl-7-O-methyllycorenine (5) is reported here for the first time from family Amaryllidaceae. The chemotaxonomic significance of the isolated alkaloids was also studied; six of the isolated alkaloids belong to the homolycorine series which is a distinctive feature for the section Pseudonarcissi. The alkaloids of the homolycorine series are absent from some tribes of the Amaryllidaceae, such as the Amaryllideae or Hemantheae. Moreover, all the Narcissus alkaloids of the homolycorine series display a B/C ring junction with a cis stereochemistry Furthermore, the antimicrobial activity of some isolated alkaloids has been studied. It is noteworthy that this is the first phytochemical and biological investigation to be carried out on the Amaryllidaceae plant N. pseudonarcissus grown in Egypt.

Histidine N(τ)-cyclized macrocycles as a new genre of polo-like kinase 1 polo-box domain-binding inhibitors

Transition toward peptide mimetics of reduced size is an important objective of peptide macrocyclization. We have previously shown that PLH∗SpT (2a) (where H∗ indicates the presence of a –(CH2)8Ph group at the N(π) position and pT indicates phosphothreonine) is an extremely high affinity ligand of the polo-like kinase 1 (Plk1) polo-box domain (PBD). Herein we report that C-terminal macrocyclization of 2a employing N(π),N(τ)-bis-alkylated His residues as ring junctions can be achieved in a very direct fashion. The resulting macrocycles are highly potent in biochemical assays and maintain good target selectivity for the Plk1 PBD versus the PBDs of Plk2 and Plk3. Importantly, as exemplified by 5d, our current approach permits deletion of the N-terminal “Pro-Leu” motif to yield tripeptide ligands with decreased molecular weight, which retain high affinity and show improved target selectivity. These findings could fundamentally impact the future development of peptide macrocycles in general and Plk1 PBD-binding peptide mimetics in particular.

Total synthesis of (+)-trans- dihydronarciclasine from (+)-7-azabicyclo[2.2.1]heptanone

A concise asymmetric total synthesis of Amaryllidaceae alkaloid (+)-trans-dihydronarciclasine is accomplished starting from optically pure 7-azabicyclo[2.2.1]heptanone scaffold in 13 linear steps. Key features of the strategy include substrate-directed stereoselective installation of the trans B-C ring junction and regioselective Wacker-type internal olefin oxidation to provide a rapid access to all hydroxyl functionalities over the key cyclohexane ring in a stereocontrolled manner.