Pentacyclic Framework Research Articles

Total Synthesis of (-)-Aspidospermidine via an Enantioselective Palladium-Catalyzed Allylic Substitution Strategy.

A total synthesis of (-)-aspidospermidine via an enantioselective Pd-catalyzed allylic substitution strategy is reported. This represents the first application of a Pd-catalyzed allylic substitution with a 3-substituted indole derivative in the synthesis of Aspidosperma alkaloids. In our synthetic route, the allylic substitution reaction was the stereo defining step. The pentacyclic framework was then constructed in a fully diastereoselective sequence. This culminated in the shortest enantioselective synthesis of aspidospermidine reported to date, in seven linear steps.

Aromative Dephosphinidenation of a Bisphosphirane‐Fused Anthracene toward E−H (E=H, Si, N and P) Bond Activation

AbstractA bisphosphirane‐fused anthracene (5) was prepared by treatment of a sterically encumbered amino phosphorus dichloride (3) with MgA ⋅ THF3 (A=anthracene). X‐ray diffraction analysis revealed a pentacyclic framework consisting of 5 with two phosphirane rings fused to the anthracene in a trans‐fashion. Compound 5 has been shown to be an efficient phosphinidene synthon, readily liberating two transient phosphinidene units for subsequent downstream bond activation via the reductive elimination of anthracene under mild conditions. The formal oxidative addition of H2 and E−H (E=Si, N, P) bonds by the liberated phosphinidene provided diphosphine and substituted phosphines. Furthermore, phosphinidene transfer to alkenes and alkynes smoothly yielded the corresponding phosphiranes and phosphirenes. The mechanism of the H2 activation by 5 was investigated by density functional theory (DFT) calculations.

Aromative Dephosphinidenation of a Bisphosphirane-Fused Anthracene toward E-H (E=H, Si, N and P) Bond Activation.

A bisphosphirane-fused anthracene (5) was prepared by treatment of a sterically encumbered amino phosphorus dichloride (3) with MgA ⋅ THF3 (A=anthracene). X-ray diffraction analysis revealed a pentacyclic framework consisting of 5 with two phosphirane rings fused to the anthracene in a trans-fashion. Compound 5 has been shown to be an efficient phosphinidene synthon, readily liberating two transient phosphinidene units for subsequent downstream bond activation via the reductive elimination of anthracene under mild conditions. The formal oxidative addition of H2 and E-H (E=Si, N, P) bonds by the liberated phosphinidene provided diphosphine and substituted phosphines. Furthermore, phosphinidene transfer to alkenes and alkynes smoothly yielded the corresponding phosphiranes and phosphirenes. The mechanism of the H2 activation by 5 was investigated by density functional theory (DFT) calculations.

Photocatalytic Tricyclization of Enediynes for the Synthesis of Chromenoquinolines in Continuous Flow.

A photocatalyzed radical-initiated tricyclization of enediynes was developed to synthesize a range of hitherto unknown sulfonated chromenoquinolines with moderate to excellent yields under continuous operational conditions. The reaction mechanism involves a complex series of steps including alkyl radical capture by sulfur dioxide (SO2), radical addition, 6-exo-dig/6-exo-dig/6-endo-trig tricyclization, and single electron transfer (SET). This cascade of reactions results in the direct formation of a pentacyclic framework structure, along with the creation of up to three new rings and five chemical bonds in a single step. This photocatalytic protocol exhibits a diverse substrate scope, remarkable tolerance to functional groups, and scalable adaptability.

Unlocking Biradical Character in Diborepins.

Systems that possess open- and closed-shell behavior attract significant attention from researchers due to their inherent redox and charge transport properties. Herein, we report the synthesis of the first diborepin biradicals. They display tunable biradical character based on the steric and electronic profile of the stabilizing ligand and the resulting geometric deviation of the diborepin core from planarity. While there are numerous all-carbon-based biradical systems, boron-based biradical compounds are comparatively rare, particularly ones in which the radical sites are disjointed. Calculations using density functional theory (DFT) and multireference methods demonstrate that the fused diborepin scaffold exhibits high biradical character, up to 95%. Use of a nonsterically demanding diaminocarbene promotes the planarization of the pentacyclic framework, resulting in the synthetic realization of a diborepin containing a dibora-quinoidal core, which possesses a closed-shell ground state and thermally accessible triplet state. The biradicals were structurally authenticated and characterized by both solution and solid-state electron paramagnetic resonance (EPR) spectroscopy. Half-field transitions were observed at low temperatures (about 170 K), confirming the presence of the triplet state. Initial reactivity studies of the biradicals led to the isolation and structural characterization of bis(borepin hydride) and bis(borepin dianion).

Fully atom-economic access to spiro-cyclic skeletons through photoredox-induced hydrogen transfer/Giese addition/dearomative cyclization/protonation cascade

Amine-tethered spiro-cyclic skeletons were obtained through photo-induced 100%-atom-economic dearomatization, involving the cleavage of the α-C(sp3)–H of amines. Pentacyclic framework was achieved from pyridinyl ring within two steps.

Highly chemoselective oxidative dimerization of indolosesquiterpene alkaloids: a biomimetic approach to dixiamycin.

Dimeric indolosesquiterpene alkaloids, typically N-N- and C-N-linked xiamycin dimers, feature a pentacyclic framework with four contiguous stereogenic centers at the periphery of a trans-decalin scaffold to which a carbazole unit is attached. In comparison with actual biosynthetic dixiamycin derivatives, we designed C-C-linked xiamycin dimers, aiming to use them as a powerful tool to create unique scaffolds as drug candidates. In this work, we disclose the first synthetic route to access a C-C dimeric indolosesquiterpene skeleton, featuring a hypervalent iodine (PIFA)-catalyzed oxidative dimerization reaction in a single-step operation with overwhelming control over the chemoselectivity and regioselectivity. This strategy has been successfully applied to the synthesis of a C-C dimer of xiamycin A (3) and xiamycin A methyl ester (15) that demonstrates a new synthetic pathway for dimeric indolosesquiterpene alkaloids.

A new class of potent liver injury protective compounds: Structural elucidation, total synthesis and bioactivity study.

A new class of potent liver injury protective compounds, phychetins A-D (1-4) featuring an unique 6/6/5/6/5 pentacyclic framework, were isolated and structurally characterized from a Chinese medicinal plant Phyllanthus franchetianus. Compounds 2-4 are three pairs of enantiomers that were initially obtained in a racemic manner, and were further separated by chiral HPLC preparation. Compounds 1-4 were proposed to be originated biosynthetically from a coexisting lignan via an intramolecular Friedel-Crafts reaction as the key step. A bioinspired total synthesis strategy was thus designated, and allowed the effective syntheses of compounds 2-4 in high yields. Some of compounds exhibited significant anti-inflammatory activities invitro via suppressing the production of pro-inflammatory cytokine IL-1β. Notably, compound 4, the most active enantiomeric pair invitro, displayed prominent potent protecting activity against liver injury at a low dose of 3mg/kg in mice, which could serve as a promising lead for the development of acute liver injury therapeutic agent.

A Convergent Total Synthesis of (+)-Ineleganolide.

We report the total synthesis of the furanobutenolide-derived diterpenoid (+)-ineleganolide. The synthetic approach relies on a convergent strategy based on the coupling of two enantioenriched fragments, which are derived from (-)-linalool and (+)-norcarvone, respectively. A high-yielding, one-step Michael addition and aldol cascade furnishes a pentacyclic framework as a single diastereomer, thereby overcoming previous challenges in controlling stereochemistry. The endgame features an O2-facilitated C-H oxidation and a samarium diiodide-induced semipinacol rearrangement to furnish the highly rigid central seven-membered ring.

Cucurbitane triterpenes from Hemsleya chinensis tubers and their anti-inflammatory activities

Six new cucurbitane-type triterpenes, hemchinins A-F (1–6), together with thirteen known ones (7–19) were isolated from ethyl acetate extraction of Hemsleya chinensis tubers. Compounds 1–2 were a group of cucurbitane triterpenes possessing an infrequent pentacyclic framework. Their structures were established by comprehensive UV, IR, HRMS, 1D/2D NMR, and ECD analyses. Bioassay results showed that most isolated compounds exhibited anti-inflammatory actions, in which compounds 13 and 15 exhibited stronger activities at 6.25 μM, with NO inhibition rates of 49.00 ± 0.05% and 48.40 ± 0.10%, respectively.

Construction of a Pentacyclic Framework Enabled by Nickel Catalysis.

We present a novel nickel-catalyzed reaction of indole-tethered 2-alkynylphenol esters with various (hetero)aryl boronic acids, resulting in the synthesis of diversely functionalized pentacyclic benzofurocyclohepta[b]indole derivatives. This unprecedented cascade reaction involves the arylative cyclization of alkynes, nucleophilic attack of the indole moiety on the oxonium ion intermediate, 1,2-alkyl group migration, and aromatization. The synthesized molecules exhibit exceptional cytotoxicity against multiple cancer cell lines while maintaining biocompatibility toward healthy cells.

Practical synthesis of phthalascidin and zalypsis antitumor agents

The first total synthesis of zalypsis and the practical synthesis of phthalascidin (Pt-650) are achieved through the Pictet-Spengler cyclization coupling strategy. The direct iodination of the primary alcohol in trihydroxyl intermediate 26 followed by SN2 reaction with potassium phthalimide is employed to rapidly introduce the required amino functionality at C-22 on the pentacyclic framework. By the approaches, the two antitumor agents can be obtained from sesamol or N-Cbz-l-tyrosine with ca. 8%-10% overall yield.

Synthesis of Pentacyclic Framework of Herquline A.

The highly strained bowl-shaped pentacyclic structure of herquline A has rendered it one of the most difficult problems in organic synthesis yet to be solved. The challenges associated with the synthesis of herquline A have been well documented in four Ph.D. dissertations and in multiple reports regarding syntheses of its structurally simpler congeners. Herein, we report the construction of the pentacyclic core of herquline A that contains both N10-C2 and C3-C3' bonds. The key for success was the development of the tandem aza-Michael addition/enolate capture protocol that set the stage for subsequent palladium catalyzed C3(sp2 )-C3'(sp2 ) coupling reaction. Ensuing oxidative dearomatization of the left aryl ring allowed the formation of the pentacyclic diketone core of herquline A.

Asymmetric Total Synthesis of Phomarol

Asymmetric Total Synthesis of Phomarol

Enantioselective Total Synthesis of Pentacyclic Proaporphine Alkaloid (−)‐Misramine

AbstractAn enantioselective total synthesis of pentacyclic proaporphine alkaloid (−)‐misramine has been achieved. The synthetic route features a Pictet‐Spengler cyclization to construct the fused B and C rings and a sequence of Baeyer‐Villiger oxidation, Pinnick oxidation, and pinacol‐type cyclization to install the α‐hydroxy ketal moiety. The absolute configuration of the pentacyclic framework was elucidated by X‐ray single‐crystal analyses of (−)‐11‐demethoxymisramine.magnified image

Unsymmetrically-Substituted 5,12-dihydrodibenzo[b,f][1,4]diazocine-6,11-dione Scaffold-A Useful Tool for Bioactive Molecules Design.

Unsymmetrically N-substituted and N,N’-disubstituted 5,12-dihydrodibenzo [b,f][1,4]diazocine-6,11-diones were synthesized in the new protocol. The desired modifications of the dibenzodiazocine scaffold were introduced at the stages of proper selection of building blocks as well as post-cyclization modifications with alkylation or acylation agents, expanding the structural diversity and possible applications of synthesized molecules. The extension of developed method resulted in the synthesis of novel: tricyclic 5,10-dihydrobenzo[b]thieno[3,4-f][1,4]diazocine-4,11-dione scaffold and fused pentacyclic framework possessing two benzodiazocine rings within its structure. Additionally, the unprecedented rearrangement of 5,12-dihydrodibenzo[b,f][1,4]diazocine-6,11-diones to 2-(2-aminophenyl)isoindoline-1,3-diones was observed under the basic conditions in the presence of sodium hydride for secondary dilactams. The structures of nine synthesized products have been established by single-crystal X-ray diffraction analysis. Detailed crystallographic analysis of the investigated tri- and pentacyclic systems has shed more light on their structural features. One cell line derived from non-cancerous cells (EUFA30—human fibroblasts) and three tumor cells (U87—human primary glioblastoma, HeLa—cervix adenocarcinoma, BICR18—laryngeal squamous cell carcinoma) were used to determine the cytotoxic effect of the newly synthesized compounds. Although these compounds showed a relatively weak cytotoxic effect, the framework obtained for 5,12-dihydrodibenzo[b,f][1,4]diazocine-6,11-dione could serve as a convenient privilege structure for the design and development of novel bioactive molecules suitable for drug design, development and optimization programs.

Domino intermolecular and intramolecular Diels-Alder reaction sequence for expedient construction of a pentacyclic framework

Abstract We have successfully constructed a complex pentacyclic framework through a Domino sequence of inter and intramolecular Diels-Alder reactions performed in one pot using easily accessible substrates such as 2-((anthracen-9-ylmethoxy)methyl)furan and DMAD.

Synthetic studies towards (–)-deserpidine: Total synthesis of the stereoisomer and derivative of (–)-deserpidine

The asymmetric synthesis of 16,17,20-epi-deserpidine and a derivative of (–)-deserpidine has been achieved. Key features in the assembly of the pentacyclic framework include a visible-light photocatalytic intra-/inter-/intramolecular radical cascade reaction to construct the tetracyclic ABCD ring system in one-pot and an intramolecularaldol reaction to forge the cyclohexane E ring.

Total Synthesis of (-)-Ambiguine P.

Described is a concise total synthesis of (-)-ambiguine P, a cycloheptane-containing member of the hapalindole alkaloids. The challenging pentacyclic framework of the natural product was assembled rapidly via a [4 + 3] cycloaddition reaction-inspired strategy, and the tertiary hydroxy group was introduced by an NBS-mediated bromination-nucleophilic substitution sequence.

Total Synthesis of Pentacyclic (-)-Ambiguine P Using Sequential Indole Functionalizations.

The first synthesis of a pentacyclic ambiguine (ambiguine P) is reported. The synthesis takes advantage of sequential alkylations of an indole core to rapidly construct the pentacyclic framework of the natural product. Key to the success of the synthesis was the use of a Nicholas reaction to alkylate at C2, crafting a fused seven-membered ring that is characteristic of the pentacyclic ambiguines, as well as the use of an amide-directed functionalization at C12 to set a requisite quaternary center. A versatile late-stage intermediate was prepared that may be applicable to the synthesis of the other pentacyclic ambiguines.