Tricyclic Framework Research Articles

Total Synthesis of Metaphanine and Oxoepistephamiersine

AbstractHerein, we report a concise and divergent synthesis of the complex hasubanan alkaloids metaphanine and oxoepistephamiersine from commercially available and inexpensive cyclohexanedione monoethylene acetal. Our synthesis features a palladium‐catalyzed cascade cyclization reaction to set the tricyclic carbon framework of the desired molecules, a regioselective Baeyer–Villiger oxidation followed by a MeNH2 triggered skeletal reorganization cascade to construct the benzannulated aza[4.4.3]propellane, and a strategically late‐stage regio‐/diastereoselective oxidative annulation of sp3 C−H bond to form the challenging THF ring system and hemiketal moiety in a single step. In addition, a highly enantioselective alkylation of cyclohexanedione monoethylene acetal paved the way for the asymmetric synthesis of target molecular.

Total Synthesis of Metaphanine and Oxoepistephamiersine.

Herein, we report a concise and divergent synthesis of the complex hasubanan alkaloids metaphanine and oxoepistephamiersine from commercially available and inexpensive cyclohexanedione monoethylene acetal. Our synthesis features a palladium-catalyzed cascade cyclization reaction to set the tricyclic carbon framework of the desired molecules, a regioselective Baeyer-Villiger oxidation followed by a MeNH2 triggered skeletal reorganization cascade to construct the benzannulated aza[4.4.3]propellane, and a strategically late-stage regio-/diastereoselective oxidative annulation of sp3 C-H bond to form the challenging THF ring system and hemiketal moiety in a single step. In addition, a highly enantioselective alkylation of cyclohexanedione monoethylene acetal paved the way for the asymmetric synthesis of target molecular.

Evaluation of the Stereochemical Lability of Benzo‐Cycloheptene‐Based Drugs Endowed with Potentially Modulable Planar Chirality

AbstractAn experimental and theoretical study was carried out to analyze the configurational lability possessed by some of the most common drugs endowed with a central non‐planar seven‐membered cycloheptadiene ring, which confers chirality to these compounds. In fact, the absence of planarity allows the existence of two enantiomeric species that can interconvert thanks to a ring overturning mechanism. The energy barrier that opposes the inversion of the chiral tricyclic scaffold characterizing such species, which is strongly dependent on the presence of appropriate substituents on the two external cycles, has been investigated through Dynamic‐HPLC and off‐column racemization techniques, as well as through assessments based on molecular modelling approaches. Interesting indications were obtained by making targeted structural changes to allow accurate control of the stereolability characterizing the tricyclic framework.

Enantioselective Synthesis of Octahydrofuranoindole Core of Aspidosperma Alkaloids via a Diels-Alder/Reduction/Fluoroetherification Reaction Sequence.

Herein, we disclose the enantioselective synthesis of novel tricyclic fluorooctahydrofuranoindole spirooxindoles bearing five contiguous stereocenters via an organocatalytic sequential Diels-Alder/Reduction/Fluoroetherifiction reaction strategy. The potential of the developed approach was witnessed by generating vast examples (up to 20 examples) of library molecules embedding natural product core with good yields and phenomenal diastereo- and enantioselectivities (up to 77 % overall yield, up to 99 % ee and 10 : 1 dr). The synthetic utility of our protocol was further demonstrated by synthesizing tricyclic iodooctahydroindole spirooxindole framework through sequential Diels-Alder/reduction/iodoetherification reaction in 65 % overall yield and excellent stereoselectivity (99 % ee and 4 : 1 dr).

Approach to Seven-Membered Carbocycles via a Lewis Acid Catalyzed Intramolecular Michael Addition of Allenone.

A straightforward strategy for constructing seven-membered carbocycles by employing a Lewis acid catalyzed intramolecular Michael addition of allenones is reported. It offers atom-economic access to synthetically important furan-fused bi- or tricyclic frameworks containing seven-membered carbocycles, which are widely found in natural products possessing various bioactivities. A number of seven-membered carbocycle-containing polycyclic frameworks bearing diverse functional groups were prepared in good to excellent yields. Furthermore, the application potential of this strategy was exemplified by the construction of the key skeletons of Caribenol A and Frondosin B.

Rhodium(II)-Catalyzed Desaturative [3+2] Tandem Cyclization of Arylcycloalkanes with β-Dicarbonyls.

Synthetically important scaffolds, fused tricyclic frameworks containing a 2,3-cyclo[b]dihydrofuran unit, play a crucial role in drug discovery. In this study, we demonstrate that rhodium(II)/N-fluorobenzenesulfonimide can catalyze the in situ generation of highly reactive alkene intermediates from commonly accessible alkanes, which undergo intermolecular [3+2] tandem cyclization with the simultaneously generated β-dicarbonyl radical to synthesize a series of fused tricyclic frameworks containing a 2,3-cyclo[b]dihydrofuran unit with a quaternary carbon center.

Regioselective Cyclic Iminium Formation of Ugi Advanced Intermediates: Rapid Access to 3,4-Dihydropyrazin-2(1H)-ones and Other Diverse Nitrogen-Containing Heterocycles

Herein, advanced intermediates were synthesized through Ugi four-component reactions of isocyanides, aldehydes, masked amino aldehyde, and carboxylic acids, including N-protected amino acids. The presence of a masked aldehyde enabled acid-mediated deprotection and subsequent cyclization via the carbonyl carbon and the amide nitrogen. Utilizing N-protected amino acid as a carboxylic acid component, Ugi intermediates could be cyclized from two possible directions to target 3,4-dihydropyrazin-2(1H)-ones. Cyclization to the amino terminus (westbound) and to the carboxyl terminus (eastbound) was demonstrated. Deliberate selection of building blocks drove the reaction regioselectively and yielded diverse heterocycles containing a 3,4-dihydropyrazin-2(1H)-one core, pyrazin-2(1H)-one, and piperazin-2-one, as well as a tricyclic framework with a 3D architecture, 2,3-dihydro-2,6-methanobenzo[h][1,3,6]triazonine-4,7(1H,5H)-dione, from Ugi adducts under mild reaction conditions. The latter bridged heterocycle was achieved diastereoselectively. The reported chemistry represents diversity-oriented synthesis. One common Ugi advanced intermediate was, without isolation, rapidly transformed into various nitrogen-containing heterocycles.

Asymmetric Total Synthesis of Illisimonin A.

The discovery of illisimonin A in 2017 extended the structural repertoire of the Illicium sesquiterpenoids─a class of natural products known for their high oxidation levels and neurotrophic properties─with a new carbon backbone combining the strained trans-pentalene and norbornane substructures. We report an asymmetric total synthesis of (-)-illisimonin A that traces its tricyclic carbon framework back to a spirocyclic precursor, generated by a tandem-Nazarov/ene cyclization. As crucial link between the spirocyclic key intermediate and illisimonin A, a novel approach for the synthesis of tricyclo[5.2.1.01,5]decanes via radical cyclization was explored. This approach was applied in a two-stage strategy consisting of Ti(III)-mediated cyclization and semipinacol rearrangement to access the natural product's carbon backbone. These key steps were combined with carefully orchestrated C-H oxidations to establish the dense oxidation pattern.

Enantioselective Total Synthesis of (+)-Penostatins A and C

A stereoselective and column-economic approach to (+)-penostatins A and C has been developed. The multisubstituted A ring and B/C rings in their unique tricyclic framework are constructed through a Diels-Alder reaction/ozonolysis sequence and an exo intramolecular hetero-Diels-Alder reaction with high chemo-, regio-, and stereoselectivity. Using this route, (+)-penostatins A and C can be synthesized in 19 and 20 steps, respectively, with a good overall yield involving only five or six column chromatographic purifications.

Synthetic Study of Dragmacidin E: Enantioselective Construction of the Seven-Membered Ring-Fused Indole Skeleton with Contiguous Stereocenters.

We developed an enantioselective synthetic method of constructing a seven-membered ring-fused indole skeleton with contiguous stereocenters for the synthesis of dragmacidin E. Introduction of chirality at the benzylic position was achieved by Ir-catalyzed asymmetric hydrogenation. After construction of the tricyclic molecular framework using Pd-catalyzed cascade cyclization, the tetrasubstituted carbon center was created using the Ag nitrene-mediated C-H amination reaction. The developed method provided access to the functionalized seven-membered ring-fused indole skeleton with a hydroxymethyl branch in the tetrasubstituted carbon.

Synthesis of the 5/6 fused-spiro tricyclic framework of manginoid A

We developed a concise, ten-step route to the 5/6 fused-spiro tricyclic framework (A/B/C rings) of manginoid A from the starting materials cyclopentenone and 1,3-cyclohexanedione. Michael addition and subsequent Mukaiyama aldol reaction introduced two side chains at the α,β-positions of cyclopentenone. Tsuji–Trost allylation of this cyclopentenone moiety and 1,3-cyclohexanedione afforded a key intermediate. A late-stage Michael addition formed the spiro-fused tricyclic framework.

Synthetic Studies to Fused 5/5/6‐Tricyclic Frameworks: Access to Presilphiperfolanol Analogues and A, B, C‐Ring System of Lycopodium Alkaloids and Cyclopiane Diterpenes

AbstractHerein, we describe new synthetic approaches to fused 5/5/6‐carbocyclic frameworks present in various polycyclic natural products such as presilphiperfolanols, lycopodium alkaloids, and cyclopiane diterpenes. Our work features, a strategically introduced hydroxy group at thetert‐carbon center of the tricyclic system which is present in presilphiperfolanols. In addition, one presilphiperfolanol analogue is reported to show the potential of strategies disclosed in this work. All the new compounds are characterized by high‐resolution NMR spectral data. The structures of critical compounds were confirmed by various chemical transformations and further supported by single‐crystal X‐ray diffraction data. Overall, our approach is simple and rely on readily available starting materials and involves a tandem‐metathesis sequence. The synthetic studies disclosed here are applicable to the synthesis of natural products and to design medicinally important targets.

Total Synthesis and Anti-inflammatory Activity of Stemoamide-Type Alkaloids Including Totally Substituted Butenolides and Pyrroles

AbstractTotally substituted butenolide including two tetrasubstituted olefins is a distinct structural motif seen in Stemona alkaloids, but efficient methods for its synthesis are not well developed. As an ongoing program aimed at the collective total synthesis of the stemoamide group, we report a stereodivergent method to give either (E)- or (Z)-totally substituted butenolide from the same intermediate. While AgOTf­-mediated elimination via an E1-type mechanism results in the formation of the kinetic (Z)-tetrasubstituted olefin, subsequent TfOH-mediated isomerization gives the thermodynamic (E)-tetrasubstituted olefin. The pyrrole ring is another important structure found in Stemona alkaloids. The direct oxidation of pyrrolidine rings with MnO2 and careful purification gives the pyrrole groups without isomerization of the stereocenter in the lactone group. These two methods enabled us to synthesize a series of stemoamide-type alkaloids including tricyclic, tetracyclic, and pentacyclic frameworks. The anti-inflammatory activities by inhibition of iNOS expression in macrophage cell line RAW264.7 indicate that the most potent anti-inflammatory compounds without cytotoxicity are protostemonines, which consist of pentacyclic frameworks including the totally substituted butenolide.

Total Synthesis of (+)-Alstonlarsine A.

An enantioselective total synthesis of (+)-alstonlarsine A (1), a monoterpenoid indole alkaloid possessing a unique pentacyclic skeleton as well as a rare biological activity, is achieved. The key step is an efficient domino sequence, comprising enamine formation followed by an inverse-electron-demand intramolecular dearomative Diels-Alder cycloaddition for the construction of 9-azatricyclo[4.3.1.03,8 ]decane core. The key intermediate for this domino sequence was synthesized by a newly developed methodology, relying on indole C(2) -H bond functionalization, combined with intramolecular Horner-Wadsworth-Emmons reaction. This tactical combination offers a new general entry into other (privileged) tricyclic frameworks possessing indole ring fused to 6-, 7- or 8-membered rings.

Total Synthesis of (+)‐Alstonlarsine A

An enantioselective total synthesis of (+)-alstonlarsine A (1), a monoterpenoid indole alkaloid possessing a unique pentacyclic skeleton as well as a rare biological activity, is achieved. The key step is an efficient domino sequence, comprising enamine formation followed by an inverse-electron-demand intramolecular dearomative Diels–Alder cycloaddition for the construction of 9-azatricyclo[4.3.1.03,8]decane core. The key intermediate for this domino sequence was synthesized by a newly developed methodology, relying on indole C(2)-H bond functionalization, combined with intramolecular Horner–Wadsworth–Emmons reaction. This tactical combination offers a new general entry into other (privileged) tricyclic frameworks possessing indole ring fused to 6-, 7- or 8-membered rings.

Cyclocarbonylation of Allenyl Glyoxylate Strategy to Build the Tricyclic Core of Cyclocalopin A.

An approach for the construction of the tricyclic framework of naturally occurring cyclocalopin A is described. The establishment of the crucial intermediate α-methylene bis-γ,δ-lactone involves a [2 + 2 + 1]-cyclocarbonylation of newly introduced allenyl glyoxylate via direct methods using Mo(CO)6 or sequential reaction pathways. The sequential reaction route involved a stannylative cyclization by Pd(0) catalyst, bromination of an vinyl stannane moiety, and final cyclocarbonylation by palladium catalysis to provide the bis-γ,δ-lactone. The feasibility of forming the spiro-system by an exo-selective [4 + 2]-cycloaddition was accomplished.

Synthesis of the 5/6 Fused-Spiro Tricyclic Framework of Manginoid a

Synthesis of the 5/6 Fused-Spiro Tricyclic Framework of Manginoid a

Cyanomethylation of 2,3,4,9-tetrahydro-1H-carbazol-1-one based on using two different reagents: Antioxidant activity and DFT studies

C-2 and C-6 monoalkyl nitrile substituted reactant (1), which constitute the tricyclic framework of carbazole derivatives along with the substructure of the Strychnos alkaloids family, have been synthesized by using different bases to produce substitution reactions. In addition, the antioxidant capacity of the synthesized compound by the CUPRAC (cupric reducing antioxidant capacity) method was evaluated and the obtained TEAC (Trolox equivalent antioxidant capacity) coefficient implied that product (2) has antioxidant feature. The B3LYP/6-311G(d,p) level calculations were performed in the gas phase, and the optimized geometries obtained from these calculations were used for the solvation media calculations. The SMD variation of the IEFPCM (polarized continuum model) was used to conduct the quantum chemical calculations in the solvent environment such as CHCl3, CH3OH, and H2O (water, ε=78.4). Also, the NMR chemical shifts of the products were calculated using GIAO (Gauge-Independent Atomic Orbital) approach and compared with the corresponding experimental data. The TD-DFT calculations disclosed that the observed peaks for both products were attributed to the n→ π* and π→ π* excitations. Moreover, NBO analysis revealed that the n→ π* and π→ π* interactions have a great importance for lowering the stabilization energy for all compounds. Also, the FMO (Frontier Moleular Orbital) analyses implied that the product P2 would prefer the intermolecular interactions would rather than the intramolecular interactions.

Controlling the Gold(I)-Catalyzed 1,5-Allenene Reaction: Construction of Fused Rings with Excellent Diastereoselectivity.

In the present study, the gold(I)-catalyzed reaction of 1,5-allenenes was controlled in such a way that instead of a [2 + 3] cycloaddition, a 5-exo-cyclization with the formation of a carbocation occurred. The latter could be trapped with both oxygen and carbon nucleophiles. In the investigated system, fused tricyclic frameworks with three contiguous stereocenters with excellent chemo- and diastereoselectivity in up to 95% yield were obtained.

Synthesis of a Bicyclo[2.2.1]heptane Skeleton with Two Oxy-Functionalized Bridgehead Carbons via the Diels-Alder Reaction.

We describe a synthetic method for a bicyclo[2.2.1]heptane skeleton with two oxy-functionalized bridgehead carbons. This method involves an intermolecular Diels-Alder reaction using 5,5-disubstituted 1,4-bis(silyloxy)-1,3-cyclopentadienes, the diene structure of which has never been synthesized. Furthermore, the intramolecular Diels-Alder reaction using a diene bearing a dienophile moiety at the C-5 position can provide a tricyclic carbon framework that includes the bicyclo[2.2.1]heptane skeleton. The novel bicyclo[2.2.1]heptane derivatives could be utilized as versatile building blocks for organic synthetic chemistry.