Eight-membered Carbocycles Research Articles

Bidentate Lewis Acid-Catalyzed Inverse Electron-Demand Diels–Alder Reaction of Phthalazines and Cyclooctynes

AbstractHerein we report a method for facilitating the inverse-electron-demand Diels–Alder reaction of 1,2-diazines and cyclooctynes by utilizing a boron-based bidentate Lewis acid catalyst. Readily available electron-deficient and electron-rich phthalazines proved to be suitable substrates in this transformation. The described method enables the facile construction of diversely substituted polycyclic aromatic hydrocarbons fused to eight-membered carbocycles.

Synthesis of Eight-Membered Carbocycles by (I)/I(III)-Catalyzed Diene Cyclization

Synthesis of Eight-Membered Carbocycles by (I)/I(III)-Catalyzed Diene Cyclization

Divergent total synthesis of marine meroterpenoids (+)-dysidavarones A–C

Here, we report a concise and divergent enantioselective total synthesis of marine sesquiterpene quinone meroterpenoids (+)-dysidavarones A–C (1–3) using predysidavarone 6 as a key common intermediate. The highly strained and bridged eight-membered carbocycle of predysidavarone 6 was constructed by a one-pot intermolecular alkylation and intramolecular arylation of Wieland–Miescher ketone derivative 11 and benzyl bromide 12. The total synthesis of (+)-dysidavarones A–C (1–3) was achieved from predysidavarone 6 in a divergent manner by a late-stage introduction of the ethoxy group, which reveals the possible source of the ethoxy group within (+)-dysidavarones A–C (1–3) and provides a late-stage modifiable route for the synthesis of dysidavarone analogs for further anti-cancer activity evaluation.

Organocatalytic Enantioselective Thermal [4 + 4] Cycloadditions.

Chiral eight-membered carbocycles are important motifs in organic chemistry, natural product chemistry, chemical biology, and medicinal chemistry. The lack of synthetic methods toward their construction is a challenge preventing their rational design and stereoselective synthesis. The catalytic enantioselective [4 + 4] cycloaddition is one of the most straightforward and atom-economical methods to obtain chiral cyclooctadiene derivatives. We report the first organocatalytic asymmetric [4 + 4] cycloaddition of 9H-fluorene-1-carbaldehydes with electron-deficient dienes affording cyclooctadiene derivatives in good yields and with excellent control of peri-, diastereo-, and enantioselectivities. The reaction concept is based on the aminocatalytic formation of a polarized butadiene component incorporated into a cyclic extended π-system, with restricted conformational freedom, allowing for a stereocontrolled [4 + 4] cycloaddition. FMO analysis unveiled that the HOMO and LUMO of the two reacting partners resemble those of butadiene. The methodology allows for the construction of cyclooctadiene derivatives decorated with various functionalities. The cyclooctadienes were synthetically elaborated, allowing for structural diversity demonstrating their synthetic utility for the formation of, for example, chiral cyclobutene- or cyclooctane scaffolds. DFT computational studies shed light on the reaction mechanism identifying the preference for an initial but reversible [4 + 2] cycloaddition delivering an off-cycle catalyst resting state, from which catalyst elimination is not possible. The off-cycle catalyst-bound intermediate undergoes a retro-[4 + 2] cycloaddition, followed by a [4 + 4] cycloaddition generating a cycloadduct from which catalyst elimination is possible. The reaction pathway accounts for the observed peri-, diastereo-, and enantioselectivity of the organocatalytic [4 + 4] cycloaddition.

Mechanism and Stereochemistry of Rhodium-Catalyzed [5 + 2 + 1] Cycloaddition of Ene-Vinylcyclopropanes and Carbon Monoxide Revealed by Visual Kinetic Analysis and Quantum Chemical Calculations.

Previously, we developed a rhodium-catalyzed [5 + 2 + 1] cycloaddition of ene-vinylcyclopropanes (ene-VCPs) and carbon monoxide to synthesize eight-membered carbocycles. The efficiency of this reaction can be appreciated from its application in the synthesis of several natural products. Herein we report the results of a 15-year investigation into the mechanism of the [5 + 2 + 1] cycloaddition by applying visual kinetic analysis and high-level quantum chemical calculations at the DLPNO-CCSD(T)//BMK level. According to the kinetic measurements, the resting state of the catalyst possesses a dimeric structure (with two rhodium centers) whereas the active catalytic species is monomeric (with one rhodium center). The catalytic cycle consists of cyclopropane cleavage (the turnover-limiting step), alkene insertion, CO insertion, reductive elimination, and catalyst transfer steps. Other reaction pathways have also been considered but then have been ruled out. The steric origin of the diastereoselectivity (cis versus trans) was revealed by comparing the alkene insertion transition states. In addition, how the double-bond configuration of the VCPs (Z versus E) affects the substrate reactivity and the origins of chemoselectivity ([5 + 2 + 1] versus [5 + 2]) were also investigated. The present study will provide assistance in understanding other carbonylative annulations catalyzed by transition metals.

Synthesis of the eight-membered carbocycle of brachialactone by intramolecular Mizoroki-Heck reaction

A synthesis of the BC ring moiety of brachialactone, a fusicoccane-type diterpene isolated from the tropical forage grass Brachiaria humidicola and found to inhibit nitrification by soil microbes, is described. Several precursors including the C ring were synthesized from a known chiral cyclopentane, and then subjected to the conditions for the Mizoroki-Heck reaction. Substrates incorporating vinyl (R = H) or enone (R = COCH3) moieties and incorporating an S configuration at C-2 successfully underwent intramolecular Mizoroki-Heck reaction, giving the BC ring structure of brachialactone.

Tf2O-Mediated Cyclization of 7-Enamides: Bioinspired Construction of Fused Eight-Membered Carbocyclic Enimines and Enones.

In this paper, we document the construction of functionalized and fused eight-membered carbocycles by the triflic anhydride-mediated cyclization of 7-enamides. Taking advantage of the high electrophilicity of the nitrilium ion intermediates, generated in situ from secondary N-(2,6-dimethyl)anilides, the nonactivated, trisubstituted alkene-nitrilium cyclization reactions proceeded smoothly to afford nonconjugated β,γ-enimines (for fused 6/6/8 ring systems), conjugated α,β-enimines (for 6/5/8), or fused 5/8 ring systems in good yields. When the cyclization reactions were followed by one-pot acidic hydrolysis, the reaction led directly to the corresponding α,β-enones. For some substrates, the reaction afford an efficient access to pendent cyclic β,γ-enimines/enones.

Diastereoselective Construction of Eight-Membered Carbocycles through Palladium-Catalyzed C(sp3)-H Functionalization.

A palladium-catalyzed cross-coupling reaction of 2-alkylphenyl bromides with biphenylene has been developed. The reactions formed eight-membered carbocycles through C(sp3)-H activation and the formation of two C-C bonds, and the chiral products were obtained with excellent diastereoselectivity. The reaction provides a new strategy for the construction of eight-membered carbocycles, and the products represent a novel type of chiral scaffold.

Recent Advances in the Total Synthesis of Natural Products Containing Eight-Membered Carbocycles (2009-2019).

Natural products containing eight-membered carbocycles constitute a class of structurally intriguing and biologically important molecules such as the famous diterpenes taxol and vinigrol. Such natural products are being increasingly investigated because of their fascinating architectural features and potent medicinal properties. However, synthesis of natural products with cyclooctane moieties has proved to be highly challenging. This review highlights the recently completed total syntheses of natural products with eight-membered carbocycles with a focus on strategic considerations. A collection of 27 representative studies from the literature covering the decade from 2009 to 2019 is described in chronological order with relevant studies grouped together, including syntheses of the same natural product by different research groups using different strategies. Finally, a summary and outlook including a discussion of the major features of each strategy used in the syntheses are presented. This review illustrates the diversity and creativity in the elegant synthetic designs of eight-membered carbocycles. We hope this review will provide timely illumination and beneficial guidance for future synthetic efforts for organic chemists who are interested in this area.

Transition-Metal-Catalyzed Cycloadditions for the Synthesis of Eight-Membered Carbocycles: an Update from 2010 to 2020

Transition-Metal-Catalyzed Cycloadditions for the Synthesis of Eight-Membered Carbocycles: an Update from 2010 to 2020

Construction of seven- and eight-membered carbocycles by Lewis acid catalyzed C(sp3)-H bond functionalization.

We achieved a concise construction of seven- and eight-membered carbocycles via Lewis acid catalyzed C(sp3)-H bond functionalization. In these reactions, a quite rare [1,6 (or 7)]-hydride shift/cyclization process proceeded smoothly to afford seven- and eight-membered carbocycles with good chemical yields starting from substrates with high conformational freedom.

Mn(i)-Catalyzed nucleophilic addition/ring expansion via C-H activation and C-C cleavage.

Mn(i)-Catalyzed synthesis of seven- or eight-membered carbocycles is disclosed via C-H activation of heteroarenes and coupling with alkyne-functionalized 1,3-cyclopentadiones or 1,3-cyclohexadiones. This n to n + 2 (n = 5, 6) ring expansion reaction proceeded via a C-H alkenylation/carbonyl addition/retro-Aldol cascade. Structurally diverse mid-sized carbocycles were constructed via cleavage of both C-H and C-C bonds in a single operation.

Design and Synthesis of Thermal Contracting Polymer with Unique Eight-Membered Carbocycle Unit

It is uncommon for a solid substance to expand upon cooling and contract upon heating. In this work, we synthesized a carbocycle monomer that contains 1,2:5,6-dibenzocyclooctadiene (DBCOD) unit and...

Synthesis of distorted nanographenes containing seven- and eight-membered carbocycles.

This feature article focuses on the bottom-up approaches (solution-phase) based on organic synthesis for the preparation of saddle-shaped distorted polycyclic aromatic hydrocarbons (PAHs). We summarise the recent progress on the synthetic strategies followed to obtain well-defined nanographenes containing heptagonal and octagonal carbocycles, highlighting the novel strategy developed by our group together with our recent contributions in the area of distorted aromatics. The presence of seven- or eight-membered rings induces a saddle-shape curvature in the planar network pushing the structure out of the plane, which influences the physical properties exhibited. Some brief details on the optical and electronic properties of these curved nanostructures are also discussed.

P-5 8員環閉環を基盤としたグリコシルホスファチジルイノシトールの生合成を阻害するセスタテルペン YW3699の合成研究(ポスター発表の部)

P-5 8員環閉環を基盤としたグリコシルホスファチジルイノシトールの生合成を阻害するセスタテルペン YW3699の合成研究(ポスター発表の部)

Syntheses of non-aromatic medium and large rings synthesized via phenylnitrenium ions

We describe the preparation of m- and p-substituted phenyl azides which, on treatment with trifluoromethanesulfonic acid in chloroform (and only in one case, after adding trifluoroacetic acid) at 0°C, gives rise to the intermediate phenylnitrenium ions that undergo intramolecular cyclization to give six-, eight-membered carbocycles, and ten-membered heterocycles. Intramolecular cyclization of 1-(4-azidophenyl)-4-phenylbutane (3b) gives direct access to the 1,2,3,4-tetrahydronaphthalene lignan scaffold with a good yield. When the same reaction is carried out on 1-(3-azidophenyl)-4-phenylbutane (3a), the meta isomer of 3b, the 3-aminodibenzo[a,c]cyclooctadiene is obtained with a modest yield. When an ethoxycarbonyl group is introduced at position two of the butene chain [16a, as an E/Z mixture (1/4)], the ethyl 3-aminobenzo[a,c]octatriene carboxylate was the major compound, and the 10-membered heterocycle the minor one, both derived from (E)-16a. Finally, when a methyl group is located at the para position of the azido group [(E)-16b], cyclization involves the carbon atom ortho to the nitrogen atom and the ethyl 4-methyl-1-tosylaminobenzo[a,c]octatriene carboxylate is the only compound obtained, after treatment with tosyl chloride. With all these structural changes, we have switched over from the formation of mixtures of compounds to the regioselective formation of the target molecule, suggesting the corresponding mechanism of reaction and expanding the knowledge of this type of reaction.

ChemInform Abstract: Rhodium‐Catalyzed [5 + 2 + 1] Cycloaddition of Ene‐Vinylcyclopropanes and CO: Reaction Design, Development, Application in Natural Product Synthesis, and Inspiration for Developing New Reactions for Synthesis of Eight‐Membered Carbocycles

AbstractReview: 66 refs.

Rhodium-catalyzed [5 + 2 + 1] cycloaddition of ene-vinylcyclopropanes and CO: reaction design, development, application in natural product synthesis, and inspiration for developing new reactions for synthesis of eight-membered carbocycles.

Practical syntheses of natural products and their analogues with eight-membered carbocyclic skeletons are important for medicinal and biological investigations. However, methods and strategies to construct the eight-membered carbocycles are limited. Therefore, developing new methods to synthesize the eight-membered carbocycles is highly desired. In this Account, we describe our development of three rhodium-catalyzed cycloadditions for the construction of the eight-membered carbocycles, which have great potential in addressing the challenges in the synthesis of medium-sized ring systems. The first reaction described in this Account is our computationally designed rhodium-catalyzed two-component [5 + 2 + 1] cycloaddition of ene-vinylcyclopropanes (ene-VCPs) and CO for the diastereoselective construction of bi- and tricyclic cyclooctenones. The design of this reaction is based on the hypothesis that the C(sp(3))-C(sp(3)) reductive elimination of the eight-membered rhodacycle intermediate generated from the rhodium-catalyzed cyclopropane cleavage and alkene insertion, giving Wender's [5 + 2] cycloadduct, is not easy. Under CO atmosphere, CO insertion may occur rapidly, converting the eight-membered rhodacycle into a nine-membered rhodacycle, which then undergoes an easy C(sp(2))-C(sp(3)) reductive elimination process and furnishes the [5 + 2 + 1] product. This hypothesis was supported by our preliminary DFT studies and also served as inspiration for the development of two [7 + 1] cycloadditions: the [7 + 1] cycloaddition of buta-1,3-dienylcyclopropanes (BDCPs) and CO for the construction of cyclooctadienones, and the benzo/[7 + 1] cycloaddition of cyclopropyl-benzocyclobutenes (CP-BCBs) and CO to synthesize the benzocyclooctenones. The efficiency of these rhodium-catalyzed cycloadditions can be revealed by the application in natural product synthesis. Two eight-membered ring-containing natural products, (±)-asterisca-3(15),6-diene and (+)-asteriscanolide, have been synthesized using the [5 + 2 + 1] cycloaddition as the key step. In the latter case, excellent asymmetric induction was obtained using a chiral substrate. The efficiency of the [5 + 2 + 1] reaction was further demonstrated by the synthesis of four sesquiterpene natural products, (±)-pentalenene, (+)-hirsutene, (±)-1-desoxyhypnophilin, and (±)-hirsutic acid C, containing linear or branched triquinane skeletons utilizing the tandem or stepwise [5 + 2 + 1] cycloaddition/aldol reaction strategy. With the success of [5 + 2 + 1] cycloaddition in natural product synthesis, application of the [7 + 1] and benzo/[7 + 1] cycloadditions in target- and function-oriented syntheses can be envisioned.

ChemInform Abstract: Chemoenzymatic Routes to Polyoxygenated Cyclooctenones Related to the Eastern Hemisphere of the Macrolactam Tripartilactam.

AbstractReaction sequences are reported to synthesize eight‐membered carbocycles such as (IV), starting from the enzymatically‐derived enantiopure cis‐diol (I).

Use of RCM Reactions for Construction of Eight-Membered Carbocycles and Introduction of a Hydroxy Group at the Juncture between Five- and Eight-Membered Carbocycles

Model studies for total synthesis of YW3699 were carried out in order to introduce a hydroxy group at the ring juncture between 5- and 8-membered carbocycles. The five-membered ring part, hydrazone, and aldehyde with a cyclohexane ring were connected by the Shapiro reaction, followed by conversion to diketones, which were treated with IBX to afford hydroxylated models.