Intramolecular Diels-Alder Reaction Research Articles

Approach to the Core Structure of Signermycin B.

Among the natural tetramic acids with a decalinoyl part, signermycin B is unique because it contains a cis-decalin. In this paper, we demonstrate that the cis-decalin section of signermycin B can be accessed by an anionic oxy-Cope rearrangement. The substrate, a tricyclic dienol was prepared by an intramolecular Diels-Alder reaction of a masked ortho-benzoquinone, generated by oxidation of an α-methoxyphenol in presence of cis-2-hexenol. After a superfluous bromine on the cycloadduct was removed, reaction of the tricyclic ketone with isopropenylmagnesium bromide led to the tricyclic trienol that underwent the oxy-Cope rearrangement to a cis-decalinone. While we could show, that introduction of the 4-ethyl substituent (signermycin B numbering) is possible by enolate alkylation, the 4-epi-isomer was formed.

Rapid access to divergent fused polycycles via one-pot A3 coupling and intramolecular Diels-Alder reaction.

Divergent nitrogen-containing fused polycyclic ring systems are constructed from simple starting materials via a one-pot aldehyde-alkyne-amine (A3) coupling and intramolecular Diels-Alder reaction. This domino reaction directly furnishes linear 5/5/5 and 5/5/6, or nonlinear 5/5/6/5, polycyclic rings containing an oxa-bridged fused 5/5 bicycle and a 1,6-enyne substructure. One-step derivation of the oxa-bridged 5/5 bicycle leads to a polyfunctionalized 5/5 bicycle with tetrahydrofuran fused back-to-back to pyrroline or a 6/5 bicycle with the hexahydro-1H-isoindole structure, while cycloisomerizing the enyne substructure adds an extra fused 5-membered ring to afford functionalized linear 5/5/5/5 or 5/5/5/5/5 fused ring systems from selected substrates. In addition, the one-pot product can be designed so that the alkyne moiety is hydroalkoxylated to form an additional heterocyle in a linear 5/5/5/6 or nonlinear 5/5/6/5/5 ring system. This diversity-oriented synthetic approach thus allows rapid access to an under-explored structural space for discovery of new biological or non-biological activities or functions.

Competing Domino Knoevenagel-Cyclization Sequences with N-Arylcinnamylamines.

Domino Knoevenagel-cyclization reactions of N-arylcinnamylamines were carried out with active methylene reagents, which took place with five competing cyclization mechanisms: intramolecular hetero Diels-Alder reaction, stepwise polar [2 + 2] cycloaddition, styryl or aza-Diels-Alder reactions followed by rearomatization, and [1,5]-hydride shift-6-endo cyclization. In the stepwise aza-Diels-Alder reaction, the N-vinylpyridinium moiety acted as an azadiene, producing a condensed heterocycle with tetrahydroquinolizinium and tetrahydroquiniline subunits. Antiproliferative activity with low micromolar IC50 values was identified for some of the novel scaffolds.

Evaluation of Retro-Aldol vs Retro-Carbonyl-Ene Mechanistic Pathways in a Complexity-Generating C-C Bond Fragmentation.

We report an experimental and computational investigation of the likely mechanism of a cascade reaction. The reaction involves an intramolecular Diels-Alder reaction, followed by a C-C bond cleavage, to afford a complex bridged bicyclic product. As multiple reaction pathways could be envisioned for the latter step, the mechanism of the C-C bond cleavage step was investigated. Two reasonable reaction pathways were evaluated. Both computations and experiments indicate that the C-C bond cleavage step proceeds by a retro-carbonyl-ene pathway rather than a retro-aldol pathway. This report underscores the synergy between computational and experimental studies and establishes the mechanism of an interesting complexity-generating transformation.

Asymmetric Total Synthesis of (+)-Verrubenzospirolactone and (+)-Capillobenzopyranol.

The first asymmetric total synthesis of (+)-verrubenzospirolactone (1), a distinctive highly fused benzosesquiterpenoid, characterized by a pentacyclic skeletal structure, is realized through a concise 10-step synthetic pathway with an impressive 22.8% overall yield. Notable highlights of this synthetic endeavor include (i) the introduction of a Ru-catalyzed ortho C-H activation step, (ii) the application of Pd-catalyzed asymmetric allylic alkylation to establish a pivotal stereocenter at C-3 with an excellent enantiomeric excess, (iii) B-alkyl Suzuki-Miyaura coupling to construct a Diels-Alder precursor, and, ultimately, (iv) the successful deployment of an intramolecular Diels-Alder reaction to complete the synthesis of (+)-verrubenzospirolactone without erosion of the enantiomeric excess.

One-Pot Reaction Sequence: N-Acylation/Pictet-Spengler Reaction/Intramolecular [4 + 2] Cycloaddition/Aromatization in the Synthesis of β-Carboline Alkaloid Analogues.

One-pot synthesis of tetrahydro-β-carbolines, fused with an isoindole core, was proposed starting from maleic anhydride and azomethines easily available from tryptamines and 3-(hetaryl)acroleins. This sequence includes four key steps: an acylation of the aldimine with maleic anhydride, a Pictet-Spengler cyclization, an intramolecular Diels-Alder reaction, and a concluding [1,3]-H shift. As a result, six- or seven-nuclear alkaloid-like heterocyclic systems, containing a benzo[1,2]indolizino[8,7-b]indole fragment annulated with furan, thiophene, or pyrrole, are formed in a diastereoselective manner.

Asymmetric Total Synthesis of Pedrolide.

The asymmetric total synthesis of pedrolide (>200 mg) with an unprecedented [5-5-5-6-6-3] hexacyclic core (pedrolane) was achieved. Its unique bicyclo[2.2.1]heptane ring system was efficiently constructed via an enantioselective ene reaction of cyclopentadiene followed by a Wittig reaction, isomerization, and a diastereoselective intramolecular Diels-Alder reaction cascade. The highly oxygenated carane [6-3] ring system was synthesized via a ring-closing metathesis reaction followed by an unusual free carbene cyclopropanation. Furthermore, the 12 contiguous stereocenters of pedrolide were installed diastereoselectively.

Total Synthesis of Icumazole A Using a Modified Cadiot-Chodkiewicz Coupling.

The first total synthesis of myxobacteria metabolite icumazole A (1) is reported. Key steps in the route include an organocatalyzed asymmetric self-aldol reaction followed by an acetate aldol reaction to form the stereotriad present in the oxazole moiety, an intramolecular Diels-Alder reaction to form the isochromanone, and an acetylide addition and selective methylation. The final steps involved a high-yielding modified Cadiot-Chodkiewicz coupling and stereoselective reduction to secure the Z,Z-diene and afford 1.

A one-pot telescopic synthesis of benzo[b]carbazoles and exploration of their liquid crystalline properties.

We describe a diversity-oriented one-pot telescopic synthesis of various benzo[b]carbazoles with the naphthannulation of indoles as the key step, enabled by an intramolecular furan-olefin Diels-Alder reaction. This strategy is general and efficient across a wide range of substrates. We applied this method to synthesize and characterize the first benzo[b]carbazole-based liquid crystalline materials, where the unique molecular design led to the formation of a rare nematic phase at room temperature.

Investing in entropy: the strategy of cucurbit[n]urils to accelerate the intramolecular Diels–Alder cycloaddition reaction of tertiary furfuryl amines

The “Circe effect” in supramolecular catalysis: the investment in entropy of CB[7] upon substrate binding accounts for the acceleration (kincluded/kbulk up to 104!) of the intramolecular Diels–Alder reaction of tertiary furfuryl amines.

Relationship between PAH4 formation and thermal reaction products in model lipids and possible pathways of PAHs formation

Lipids are closely related to the generation of PAHs during food thermal processing. During heating, lipids mainly triglycerides undergo hydrolysis, oxidation and decomposition. The relationship between the various products and the formation of PAHs is still unclear. This paper investigated the effect of different lipid standards on PAH4 production, and explored their thermal stability and reaction products to delve into nature of the differences in PAH4 production. Fatty acids were more prone to generate PAH4 than glycerides. The higher the degree of esterification of glycerides, the higher its thermal stability and the lower the content of PAH4 generated, implying that hydrolysis of glycerides promoted the generation of PAH4. In addition, there was a positive correlation between unsaturation in lipids and the PAH4 production. After heat treatment, hydroperoxides, unsaturated fatty alcohols and aldehydes, alkenes and aromatic substances were abundant in oleic acid and linoleic acid which produced the most PAH4. Thermal decomposition of lipid hydroperoxides was the pathway for the generation of conjugated hydrocarbon radicals, alcohols, aldehydes, and alkenes. The intramolecular cyclization and Diels-Alder reaction acted as ring-forming reactions, with consequent dehydrogenation, decarboxylation, side-chain breaks and radical reorganization, ultimately facilitating the amplification of the aromatic rings and the formation of PAHs.

Synthesis of Cytotoxic Quino[4,3-b]carbazole Frameworks through an Intramolecular Diels-Alder Reaction.

An intramolecular Diels-Alder reaction of positionally isomeric indole-2/3-phenylvinyl-N-alkynylated (N-phenylsulfonyl)amines has been successfully exploited for the synthesis of quino[4,3-b]carbazole and its analogues. This reaction proceeds through a [4 + 2] cycloaddition followed by elimination and deprotection of phenylsulfonyl units to afford the quinocarbazoles in moderate to good yields. The reaction features a broad substrate scope and remarkable functional group forbearance. A preliminary in vitro cytotoxicity evaluation of representative quino[4,3-b]carbazoles was performed against NCI-H460 human cancer cell culture. Among the quino[4,3-b]carbazoles evaluated, five of the fluorine-containing quinocarbazoles displayed nano molar range (0.8-2.0 nm) GI50 values. The UV-vis and fluorescence spectral studies of representative quinocarbazoles were also performed. Like ellipticine, four of the quinocarbazoles displayed dual emissions confirming the existence of p-quinonoid like tautomeric forms in a polar protic solvent.

Steglich Esterification of Activated Cinnamyl Cinnamate Derivatives and Computational Studies of Intramolecular Diels-Alder for Lignan Synthesis

A ryltetralin and arylnaphthalene lignans consisting of methylenedioxy or trimethoxy groups, such as podophyllotoxin and phyllanthusmin C, are known to have effective anticancer properties. The synthesis of these compounds can be achieved through intramolecular Diels-Alder reactions on cinnamyl cinnamate ester derivatives. Furthermore, this ester is commonly synthesized through an esterification reaction between cinnamoyl halide and cinnamyl alcohol. In this study, cinnamyl cinnamate only produced a 41% yield, while a nearly quantitative yield of 98% was obtained using the Steglich reaction with N,N’-dicyclohexylcarbodiimide and 4-dimethylaminopyridine. This reaction was used to synthesize eight cinnamyl cinnamate ester derivatives, which consisted of methylenedioxy and trimethoxy groups, following a combinatorial synthesis. 3,4-Methylenedioxy- and 3,4,5-trimethoxycinnamyl alcohols were obtained by reducing methyl 3,4-methylenedioxycinnamate and 3,4,5-trimethoxycinnamic acid, respectively. The results showed that the ester yields were excellent, except for the ester derivatives of 3,4,5-trimethoxycinnamyl alcohol. This alcohol was unstable during column chromatography, leading to the direct esterification of the crude reduction products. A side product with Rf adjacent to the ester was obtained, thereby reducing the ester yield. The identification of this by-product and the intramolecular Diels-Alder reaction on the products obtained were described in this study. Computational studies showed that transforming reactants into products led to the production of one intermediate compound and two transition states (TS). Each TS represented the intramolecular Diels-Alder cycloaddition reaction and migration of [1,3]-hydrogen. Thermodynamic studies consistently revealed that a solvent environment could effectively reduce the activation energy associated with a chemical process.

Enantioselective Total Syntheses of Cassane Furanoditerpenoids and Their Stimulation of Cellular Respiration in Brown Adipocytes.

We report the first and enantioselective total syntheses of (+)-1-deacetylcaesalmin C, (+)-δ-caesalpin, (+)-norcaesalpinin MC, and (+)-norcaesalpinin P. Salient features of the synthetic strategy are an exo-selective intramolecular Diels-Alder reaction of a furanoquinone monoketal and subsequent chemoselective reduction of the resulting pentacyclic furfuryl ketal, furnishing a keystone intermediate. The latter enables access to the collection of natural products through implementation of stereoselective oxidations. Having accessed the cassane furanoditerpenoids, we unveil previously unknown bioactivity: (+)-1-deacetylcaesalmin C stimulates respiration in brown adipocytes, which has been suggested to play a central role in treatment of obesity.

Exploring the Mechanism of the Intramolecular Diels-Alder Reaction of (2E,4Z,6Z)-2(allyloxy)cycloocta-2,4,6-trien-1-one Using Bonding Evolution Theory.

In the present work, the bond breaking/forming events along the intramolecular Diels-Alder (IMDA) reaction of (2E,4Z,6Z)-2(allyloxy)cycloocta-2,4,6-trien-1-one have been revealed within bonding evolution theory (BET) at the density functional theory level, using the M05-2X functional with the cc-pVTZ basis set. Prior to achieving this task, the energy profiles and stationary points at the potential energy surface (PES) have been characterized. The analysis of the results finds that this rearrangement can proceed along three alternative reaction pathways (a-c). Paths a and b involve two steps, while path c is a one-step process. The first step in path b is kinetically favored, and leads to the formation of an intermediate step, Int-b. Further evolution from Int-b leads mainly to 3-b1. However, 2 is the thermodynamically preferred product and is obtained at high temperatures, in agreement with the experimental observations. Regarding the BET analysis along path b, the breaking/forming process is described by four structural stability domains (SSDs) during the first step, which can be summarized as follows: (1) the breaking of the C-O bond with the transfer of its population to the lone pair (V(O)), (2) the reorganization of the electron density with the creation of two V(C) basins, and (3) the formation of a new C-C single bond via the merger of the two previous V(C) basins. Finally, the conversion of Int-b (via TS2-b1) occurs via the reorganization of the electron density during the first stage (the creation of different pseudoradical centers on the carbon atoms as a result of the depopulation of the C-C double bond involved in the formation of new single bonds), while the last stage corresponds to the non-concerted formation of the two new C-C bonds via the disappearance of the population of the four pseudoradical centers formed in the previous stage. On the other hand, along path a, the first step displays three SSDs, associated with the depopulation of the V(C2,C3) and V(C6,C7) basins, the appearance of the new monosynaptic basins V(C2) and V(C7), and finally the merging of these new monosynaptic basins through the creation of the C2-C7 single bond. The second step is described by a series of five SSDs, that account for the reorganization of the electron density within Int-a via the creation of four pseudoradical centers on the C12, C13, C3 and C6 carbon atoms. The last two SSDs deal with the formation of two C-C bonds via the merging of the monosynaptic basins formed in the previous domains.

Enantioselective Total Synthesis of (-)-Zygadenine.

The Veratrum alkaloids are highly complex steroidal alkaloids characterized by their intricate structural and stereochemical features and exhibit a diverse range of pharmacological activities. A new synthetic pathway has been developed to access this family of natural products, which enabled the first total synthesis of (-)-zygadenine. This synthetic route entails the construction of a hexacyclic carbon skeleton through a stereoselective intramolecular Diels-Alder reaction, followed by a radical cyclization. Subsequently, a meticulously designed sequence of redox manipulations was optimized to achieve the de novo synthesis of this highly oxidized Veratrum alkaloid.

Cis-Decalin-containing tetramic acids as inhibitors of insect steroidogenic glutathione S-transferase Noppera-bo.

Decalin-containing tetramic acid is a bioactive scaffold primarily produced by filamentous fungi. The structural diversity of this group of compounds is generated by characteristic enzymes of fungal biosynthetic pathways, including polyketide synthase/nonribosomal peptide synthetase hybrid enzymes and decalin synthase, which are responsible for the construction of a linear polyenoyl tetramic acid structure and stereoselective decalin formation via the intramolecular Diels-Alder reaction, respectively. Compounds that differed only in the decalin configuration were collected from genetically engineered mutants derived from decalin-containing tetramic acid-producing fungi and used for a structure-activity relationship study. Our evaluation of biological activities, such as cytotoxicity against several cancer cell lines and antibacterial, antifungal, antimalarial, and mitochondrial inhibitory activities, demonstrated that the activity for each assay varies depending on the decalin configurations. In addition to these known biological activities, we revealed that the compounds showed inhibitory activity against the insect steroidogenic glutathione S-transferase Noppera-bo. Engineering the decalin configurations would be useful not only to find derivatives with better biological activities but also to discover overlooked biological activities.

Robust Synthesis of Terpenoid Scaffolds under Mn(I)-Catalysis.

The 6/6/5-fused tricyclic scaffold is a central feature of structurally complex terpenoid natural products. A step-economical cascade transformation that leads to a complex molecular skeleton is regarded as a sustainable methodology. Therefore, we report the first Mn(I)-catalyzed C(sp2)-H chemoselective in situ dienylation and diastereoselective intramolecular Diels-Alder reaction using iso-pentadienyl carbonate to access 6/6/5-fused tricyclic scaffolds. To the best of our knowledge, there is no such report thus far to utilize iso-pentadienyl carbonate as a substrate in C-H activation catalysis. Extensive mechanistic studies, such as the isolation of catalytically active organo-manganese(I) complexes, 1,3-dienyl-intermediates, and isotopic labeling experiments have supported the proposed mechanism of this cascade reaction.

Total Syntheses of Cinchona Alkaloids via Photoredox-Catalyzed Deoxygenative Arylation.

Metallaphotoredox-enabled deoxygenative arylation of alcohols is a recently developed robust synthetic strategy for sp2-sp3 coupling by MacMillan. Inspired by this method, we report herein its first utilization in natural product total synthesis through realizing the coupling of 4-bromo-quinoline or 4-bromo-6-methoxyquinoline with quincorine or quincoridine, respectively. The alcohols were de novo synthesized in racemic form by a key step of the intramolecular Diels-Alder reaction or in an enantioselective manner by Ir/amine dual-catalyzed allylation. All members of the cinchona alkaloids could be prepared efficiently.

Oxa-di-π-methane Rearrangement of a Substrate Embodying the Platencin Core Provides the Decahydro-1H-cyclopenta[c]indene Framework Associated with Various Diterpenes and Certain Lycopodium Alkaloids

AbstractA chemoenzymatic approach to the title framework is reported. The reaction sequence starts with the whole-cell biotransformation of iodobenzene and the conversion of the resulting homochiral metabolite into a triene that engages in an intramolecular Diels–Alder reaction and so affording an adduct embodying the platencin core. Application of an oxa-di-π-methane rearrangement to a derivative of this core affords a cyclopropannulated form of the target framework; the latter is then obtained through a TMSI-mediated cleavage of the three-membered ring. A strategy for the assembly of the enantiomeric framework is also described.