Intramolecular Diels-Alder Reaction Research Articles

Umpolung Reactivity of Ynamides: An Unconventional [1,3]-Sulfonyl and [1,5]-Sulfinyl Migration Cascade.

A regioselective sulfonyl/sulfinyl migration cycloisomerization cascade of alkyne-tethered ynamides is developed in the presence of XPhosgold catalyst. This reaction is the first example of a general [1,3]-sulfonyl migration from the nitrogen center to the β-carbon atom of ynamides, followed by umpolung 5-endo-dig cyclization of the ynamide α-carbon atom to the gold-activated alkyne, and final deaurative [1,5]-sulfinylation. This process allows the synthesis of peripherally decorated unconventional 4-sulfinylated pyrroles with broad scope from N-propargyl-tethered ynamides. In contrast, N-homopropargyl-tethered ynamides undergo intramolecular tetradehydro Diels-Alder reaction to provide 2,3-dihydro-benzo[f]indole derivatives. Control experiments and density-functional theory studies were used to study the reaction pathways.

Intramolecular Diels-Alder Cycloaddition Approach toward the cis-Fused Δ5,6-Hexahydroisoindol-1-one Core of Cytochalasins.

Synthesis of the cis-fused Δ5,6-hexahydroisoindol-1-one core of cytochalasins B2-B5, K, Z8, Z9, Z12-Z15, and Z17 has been established starting from an intramolecular Diels-Alder reaction of the amide-tethered (8 E)-1,3,8-nonatriene. The trans-fused 5/6-bicyclic adduct was then subjected to highly stereoselective C9-β-hydroxylation and epimerization of the C7-α-OH group.

Total Syntheses and Determination of Absolute Configurations of Cep-212 and Cep-210, Predicted Biosynthetic Intermediates of Tetrodotoxin Isolated from Toxic Newt.

Total syntheses of Cep-212 and Cep-210, predicted biosynthetic intermediates of tetrodotoxin isolated from the Japanese toxic newt, have been accomplished from geraniol by an intramolecular hetero Diels-Alder reaction as a key step in a highly stereoselective manner. The success of these syntheses enabled us to determine their absolute configurations by using a chiral normal-phase HPLC/MS analysis of the bis-dinitrobenzene derivative of natural Cep-212 and reference derivatives prepared from chemically synthesized enantiomers.

Genome-Mined Diels-Alderase Catalyzes Formation of the cis-Octahydrodecalins of Varicidin A and B.

Pericyclases are an emerging family of enzymes catalyzing pericyclic reactions. A class of lipocalin-like enzymes recently characterized as Diels-Alderases (DAses) catalyze decalin formation through intramolecular Diels-Alder (IMDA) reactions between electron-rich dienes and electron-deficient dienophiles. Using this class of enzyme as a beacon for genome mining, we discovered a biosynthetic gene cluster from Penicillium variabile and identified that it encodes for the biosynthesis of varicidin A (1), a new antifungal natural product containing a cis-octahydrodecalin core. Biochemical analysis reveals a carboxylative deactivation strategy used in varicidin biosynthesis to suppress the nonenzymatic IMDA reaction of an early acyclic intermediate that favors trans-decalin formation. A P450 oxidizes the reactive intermediate to yield a relatively unreactive combination of an electron-deficient diene and an electron-deficient dienophile. The DAse PvhB catalyzes the final stage IMDA on the carboxylated intermediate to form the cis-decalin that is important for the antifungal activity.

Mechanistic study on the intramolecular oxa-[4 + 2] cycloaddition of substituted o-divinylbenzenes.

This paper reports a detailed computational study of the mechanisms of formation of oxacyclic derivatives from substituted o-divinylbenzenes by a photoinduced intramolecular oxa-[4 + 2] cycloaddition. The reaction mechanism and chemoselectivity of trans, trans- and cis, trans-substituted ortho-divinylbenzene were studied. Detailed density functional theory calculations show that the reaction system proceeds through two main steps: light-active intramolecular cyclization and Diels-Alder reactions of C=O. Trans, trans-products of cycloaddition of substituted o-divinylbenzenes are more favored than cis, trans-products. Compared with different substituents, the cycloaddition reaction of phenyl ketone has a relatively low activation barrier, and the strong electron-withdrawing group on the benzene ring is more favorable for the intramolecular cycloaddition reaction of substituted o-divinylbenzenes.

A chiral auxiliary-based synthesis of the C5–C17 trans-decalin framework of anthracimycin

Intramolecular Diels–Alder [4 + 2] cycloaddition using a chiral Evans oxazolidinone auxiliary affords the trans-decalin framework of the potent antibiotic anthracimycin.

Intramolecular Cyclization of 3,3‐Diarylpropenylamides of Electron‐Deficient Alkenes: Stereoselective Synthesis of Functionalized Hexahydrobenzo[f]isoindoles

Intramolecular Diels–Alder reactions of various 3,3‐diarylpropenylamides of electron‐deficient alkenes to give hexahydrobenzo[f]isoindoles were investigated. Reaction of 1,1,2‐ethenetricarboxylic acid 1,1‐diethyl ester with 3,3‐diaryl‐2‐propen‐1‐amines under the amide formation conditions gave the tricyclic compounds in sequential processes involving intramolecular Diels–Alder reaction. The reaction gave cis‐ and trans‐fused tricyclic compounds selectively, depending on the substituents on the benzene ring, reaction temperature and solvent. In the reaction with dissymmetrically substituted 3,3‐diaryl‐2‐propen‐1‐amines, trans‐substituted aryl group reacted mainly as a styrene component. Amides of electron‐deficient alkenic carboxylic acids such as fumarate do not undergo cyclization at room temperature sequentially and the reaction on heating gave trans‐fused hexahydrobenzo[f]isoindoles. The origin of the observed stereoselectivity has been examined by the DFT calculations.

Triple photochemical domino reaction of a tetrafluorostilbene terminating in double fluorine atom transfer

In domino reactions, the product formed in one step undergoes a subsequent transformation under identical reaction conditions. Owing to the spontaneous nature of these reactions, it is difficult to isolate the key intermediates, and these are thus usually presumed. Here we perform a photoinduced domino reaction consisting of three photochemical steps. First, oxidative photocyclisation of a tetrafluorostilbene derivative generates tetrafluoro[7]helicene, which readily undergoes a photoinduced intramolecular Diels–Alder reaction. The resulting product then undergoes a double fluorine atom transfer under the same photochemical conditions. As a result, the four originally adjacent fluorine atoms are separated into two pairs in the final product. One advantage of a photochemical domino process over a thermal one is that the process can be suspended and restarted. Hence, precise control of the irradiation time allows us to isolate the thermally stable intermediates and characterise them using X-ray crystallography, thus confirming the until-now putative domino process.

Asymmetric Total Synthesis and Biological Evaluation of (+)-Cycloclavine

The first total synthesis of natural (+)-cycloclavine uses a catalytic­ asymmetric cyclopropanation of allene, a regiospecific Pd-catalyzed­ enone formation, and two intramolecular Diels–Alder reactions for indole/indoline annulations. The binding properties of natural (+)- and unnatural (–)-cycloclavine on 16 CNS receptors revealed significant stereospecificity and unique binding profiles in comparison to LSD, psilocin, and DMT. Differential 5-HT affinities, as well as novel sigma­-1 receptor properties bode well for potential therapeutic developments of clavine alkaloid scaffolds.

Total Synthesis of epi-Trichosetin.

The natural 3-decalinoyltetramic acid epi-trichosetin was synthesized in ten steps starting from ( R)-(+)-citronellal using an intramolecular Diels-Alder reaction and a Lacey-Dieckmann cyclization as the key steps. The use of a 2-nitrobenzyl protecting group resulted in an efficient synthetic endgame. The natural product was obtained in 4.1% overall yield.

Collective total synthesis of botryanes

The collective total synthesis of a series of botryanes, which are an important group of sesquiterpene antibiotics isolated from the metabolites of the fungus Botrytis cinerea, has been reported. The highly functionalized hydrindane skeleton of the botryanes was efficiently synthesized via an unusual intramolecular Diels-Alder reaction, which was promoted by TsOH as a protic acid. The concise total synthesis of (±)-hypocrolide A with a challenging hexacyclic skeleton was accomplished in 8 steps from the readily available starting materials.

H-Bonding Mediated Asymmetric Intramolecular Diels-Alder Reaction in the Formal Synthesis of (+)-Aplykurodinone-1.

An asymmetric formal total synthesis of (+)-aplykurodinone-1 was achieved using a route, in which hydrogen bonding serves as a stereochemical control element governing the π-facial selectivity of intramolecular Diels-Alder (IMDA) reaction of an enone tethered 2-pyrone. In the IMDA process, the configuration at a stereogenic, hydroxyl bearing an α-carbon in the enone dienophile is conveyed in a highly effective manner through intramolecular hydrogen bonding with the enone carbonyl oxygen. The tricyclic lactone, generated in this process, was successfully converted to a late stage intermediate in Danishefsky's synthesis of aplykurodinone-1.

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.

Metal-Free Triple Annulation of Ene-Yne-Ketones with Isocyanides: Domino Access to Furan-Fused Heterocycles via Furoketenimine.

A new furoketenimine intermediate from the coupling of ene-yne-ketones and o-alkenyl arylisocyanides, which enables the efficient synthesis of a wide range of tetracyclic and pentacyclic furan-fused heterocycles in a one-pot domino process under catalyst-free conditions, is disclosed. Based on the control experiments, a cascade of 1,6-addition, cyclization, intramolecular Diels-Alder reaction, and oxidative aromatization was proposed for the mechanism.

Intramolecular Diels-Alder Reaction of a Silyl-Substituted Vinylimidazole en Route to the Fully Substituted Cyclopentane Core of Oroidin Dimers.

An intramolecular Diels-Alder reaction of a silyl-substituted vinylimidazole delivers a diastereomeric mixture of C4-silyl functionalized dihydrobenzimidazoles. Subsequent diastereoselective reduction and elaboration of the lactone gives rise to a polysubstituted tetrahydrobenzimidazole, which, upon oxidative rearrangement, affords a single spirofused imidazolone containing all of the relevant functionality for an approach to the oroidin dimers axinellamine, massadine, and palau'amine.

Divergent Annulative C–C Coupling of Indoles Initiated by Manganese-Catalyzed C–H Activation

Manganese(I)-catalyzed C–H activation of indoles and divergent annulative coupling with alkyne-tethered cyclohexadienones has been realized under operationally simple conditions. These annulation systems are under condition control. The coupling in the presence of BPh3 additive followed a C–H activation-alkyne insertion-Michael addition pathway, affording an exocyclic olefin attached to a tetrahydrofuran ring. In contrast, when Zn(OAc)2/PivOH additives were introduced, initial olefination en route to intramolecular Diels–Alder reaction and subsequent elimination of an alcohol was followed to deliver a fused six-membered ring. The selectivity stands in contrast to those reported using rhodium(III) and cobalt(III) catalysts, highlighting the unique reactivity and selectivity of manganese catalysts.

Divergent Diels-Alder Reactions in the Biosynthesis and Synthesis of Endiandric-Type Tetracycles: A Computational Study.

Endiandric acids and related polyketide natural products arise from polyene precursors and occur naturally as fused and bridged tetracycles. In some cases, the intramolecular Diels-Alder reactions that produce fused and bridged tetracycles result from a diene tether that may act as either a 4π or 2π component in the cycloaddition. To examine the preference for fused or bridged products, we applied density functional theory (using the M06-2X and B3LYP functionals) to reactants with various substituents for both fused and bridged transition states. Fused products were generally preferred except when disfavored by extreme steric hindrance (e.g., a tert-butyl group). These computational results are consistent with experimental data and suggest the existence of as-yet undiscovered natural products.

A novel entry to xanthones by an intramolecular Diels-Alder reaction involving 2-(1,2-dichlorovinyloxy) aryl dienones

A wide array of synthetic methods are described in the literature for the preparation of xanthones—a prominent class of tricyclic molecules that occur widely in nature. Majority of these reported methods involve linking the two aromatic rings and forming the central pyrone ring using a variety of classical and non-classical cyclization strategies. In a conceptually different approach, we describe here a new xanthone synthesis wherein both the pyrone and the second aromatic rings were forged in a single step by an intramolecular cycloaddition reaction involving 2-(1,2-dichlorovinyloxy) aryldienones.

Origin of the Thiopyrone CTP-431 "Unexpectedly" Isolated from the Marine Sponge Cacospongia mycofijiensis.

An intriguing hypothesis that latrunculin A, a well-known natural product, might have undergone transformation into the unprecedented thiopyrone CTP-431 upon long-term storage in methanol is advanced. Thus, opening of the hemiacetal of latrunculin A, followed by E1CB elimination, and dehydration would give a polyene that could undergo intramolecular Diels-Alder reaction, followed by methanolysis of the thiazolidinone ring and ring closure by intramolecular thiol addition to an enone. Experimental evidence that the novel thiazolidinone to thiopyrone rearrangement can occur is presented.

Gold(I)-Catalyzed Intramolecular Diels–Alder Reaction: Evolution of Trappable Intermediates via Asynchronous Transition States

In recent years allenes have been shown to be capable of exhibiting several modes of cycloadditions in the presence of transition metal catalysts that are otherwise unattainable for ethylene and acetylene. Herein, we predict that the [1 + 2]-cycloaddition pathway is accessible in a Au(I)-catalyzed reaction of allene with cis-1,3-butadiene. The electrophilicity of the central carbon of allene can be harnessed using a Au(I)-catalyst and -COOMe mediated stereoelectronics. A potential energy modification approach is applied to stabilize the diradicaloid intermediates. Our simulations establish that the product selectivity of the [4 + 2]- and [2 + 2]-pathways are steered by dynamical effects. Furthermore, a bioinspired version of this reaction is shown to afford an alternative synthetic pathway for proline and azepine analogs indicating rich prospects for thermal allene-butadienereactions in drug discovery.