Intramolecular Diels-Alder Cycloaddition Research Articles

Microwave-assisted tandem Wittig–intramolecular Diels–Alder cycloaddition. Product distribution and stereochemical assignment

The IMDA cycloadditions of 10 different ester-tethered 1,3,8-nonatrienes have been examined under controlled microwave heating (MeCN, 180 °C, 30 min), giving 90–99% yields, and the stereochemical outcome of the exo and endo adducts established together with X-ray crystal structural analysis. A microwave-assisted tandem Wittig–IMDA cycloaddition protocol has been established for a modular synthesis of the bicyclic lactones starting from α-bromoacetates of 2,4-pentadien-1-ols and α-oxo carbonyl compounds in the presence of PPh 3 and 2,6-lutidine (MeCN, 180 °C, 30 min). The overall yields of the tandem reactions are 68–80% and the stereoselectivity of the major adducts formed from E-substituted 1,3,8-nonatriene is the same as that observed for the purified 1,3,8-nonatrienes.

Evaluation of possible intramolecular [4+2] cycloaddition routes for assembling the central tetracyclic core of the potent marine antiinflammatory agent mangicol A

A plan for enantioselective construction of the mangicol A framework by means of intramolecular Diels–Alder cycloaddition is outlined. First to be assembled is the enantiopure cyclopentenecarboxylic acid 16. Of the several approaches targeting the 1,3-diene component 56, only that involving palladium-catalyzed enyne cyclization proved successful. Following the coupling of 16 to 56, we were unable to bring about any detectable level of (4π+2π) cycloaddition. Activation of the diene by incorporation of an OSiEt 3 substituent on a terminal sp 2-hybridized center likewise proved unsuccessful. Further facilitation was sought in the form of cyclopentenonecarboxylate 66. However, thermal activation, Lewis acid catalysis, and high-pressure conditions proved ineffective and did not lead to C–C bond formation. These studies serve to underscore the extent to which steric complications can complicate matters and the extent to which they must be skirted to arrive at the title compound.

1-[(E)-Butadienylsulfonyl]-3,3-dimethylbut-2-yl methacrylate

The title compound, C14H22O4S, was synthesized as a precursor for intramolecular Diels–Alder cycloaddition reactions. The (E)-buta-1,3-dienyl and methacrylate ester systems adopt an s–trans conformation in the solid state, with the two π units in both cases being almost coplanar.

Alkyne hydrosilylation catalyzed by a cationic ruthenium complex: efficient and general trans addition.

The complex [Cp*Ru(MeCN)3]PF6 is shown to catalyze the hydrosilylation of a wide range of alkynes. Terminal alkynes afford access to alpha-vinylsilane products with good regioselectivity. Deuterium labeling studies indicate a clean trans addition process is at work. The same complex is active in internal alkyne hydrosilylation, where absolute selectivity for the trans addition process is maintained. Several internal alkyne substrate classes, including propargylic alcohols and alpha,beta-alkynyl carbonyl compounds, allow regioselective vinylsilane formation. The tolerance of a wide range of silanes is noteworthy, including alkyl-, aryl-, alkoxy-, and halosilanes. This advantage is demonstrated in the direct synthesis of triene substrates for silicon-tethered intramolecular Diels-Alder cycloadditions.

Establishing the absolute configuration of the asbestinins: enantioselective total synthesis of 11-acetoxy-4-deoxyasbestinin D.

A highly stereoselective synthesis of 11-acetoxy-4-deoxyasbestinin D (1) has been completed in 26 linear steps. The synthesis hinges on a selective glycolate aldol addition to establish the C-2 stereocenter, a ring-closing metathesis reaction to complete the oxonene, and an intramolecular Diels-Alder cycloaddition to establish the relative configuration at C-1, C-10, and C-14. This initial total synthesis of an asbestinin also serves to confirm the absolute configuration of this subclass of the C-2-C-11-cyclized cembranoid natural products.

RETRACTED: Biomimetic approach to Galbulimina type I alkaloids

On treatment with trifluoroacetic acid the tetraene precursor 23 underwent Boc deprotection, condensation and an iminium ion accelerated intramolecular Diels-Alder cycloaddition resulting in an iminium species 12, which was further converted into himbacine 1, himbeline 3 and himandravine 4, three out of four Galbulimina type I alkaloids thus providing strong evidence for the proposed biogenesis of this important family of alkaloids.

A Novel Intramolecular Diels—Alder Cyclization Involving Indoloazepines.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Efficient synthesis of new 11-thiasteroids and their oxides and dioxides

We show that our strategy, involving the use of an intramolecular Diels–Alder cycloaddition of o-xylylenes as the key step, can be applied efficiently to sulphur molecules. The synthesis of sulfoxide and sulfone derivatives is described and the vinyl group of those latters is oxidized, using the Wacker process, in good yields. Moreover, X-ray crystal structures of thiasteroids 11a and 12a matching the trans- anti-trans ring configuration of natural products are reported.

Ring Fission of Chiral Cyclic Acetals Plus Intramolecular [4 + 2] Cycloaddition: A Sequential Access to Medium‐Size Lactones. Application to the Synthesis of Carbasugars.

AbstractFor Abstract see ChemInform Abstract in Full Text.

First total synthesis of 3-aza-11-thia-1,3,5(10)-trieno steroids

The first total synthesis of 3-aza-11-thia-1,3,5(10)-trieno steroids was achieved via an intramolecular Diels–Alder cycloaddition of o-quinodimethanes as the key step.

Sequential Aminodiene Diels−Alder Approach to the Ergoline Skeleton

Through a novel sequence of aminodiene Diels-Alder reactions, several substituted amidofurans were readily converted to tricyclic ketones in good yield. The formation of the tricyclic ketone system is the result of a ring opening and dehydration of a transient oxabicyclic adduct formed by an intramolecular Diels-Alder cycloaddition of an amidofuran with a cyclohexenone moiety tethered such that it participates in the cycloaddition as the 2pi component. A convenient way to construct the cyclohexenone is to make use of some aminodiene chemistry developed by Rawal. An angular carbomethoxy group is required in order to activate the olefin toward cycloaddition with Rawal's diene. The presence of this activating group not only prevents the isomerization of the advanced ergoline intermediate to a naphthalene but can also be leveraged for an oxidation to provide Uhle's ketone (13). The easily formed Kornfeld ketone analogue 25 was readily transformed into the corresponding triflate 41 by the action of triflic anhydride and a base. Oxidative addition of vinyl triflate 41 to Pd(0) and the ability of the resulting vinyl palladium species to undergo cross-coupling with terminal alkynes prompted us to devise an expeditious route to lysergic acid. Unfortunately, our inability to carry out a regioselective Heck reaction using vinyl triflate 41 and the methylene amino acrylate ester 48 thwarted the completion of the synthesis of lysergic acid.

A short approach to the bicyclo[4.3.0]nonane fragment of stawamycin

The bicyclo[4.3.0]nonane (C 11–C 21) fragment of stawamycin has been prepared by a sequence involving 11 steps (10% overall yield) from methyl ( R)-(−)-3-hydroxy-2-methylpropionate. Key steps are a Pd-catalysed Stille coupling reaction between a vinyl iodide and a vinyl stannane followed by an intramolecular Diels–Alder cycloaddition reaction to give the desired adduct as the major isomer in 21% overall yield.

Enantioselective Synthesis of the Tricyclic Core of GKK1032, Novel Antibiotic Anti-Tumor Agents, by Employing an Intramolecular Diels-Alder Cycloaddition Strategy

An efficient and enantioselective synthesis of a deca­hydrofluorene nucleus, the tricyclic core (ABC-ring system) of GKK1032s, novel antimicrobial and anti-tumor agents, was achieved using a highly diastereoselective intramolecular Diels-­Alder (IMDA) reaction. The substrate for the IMDA reaction was synthesized through intermolecular Diels-Alder reaction of ­Kitahara-Danishefsky’s diene and an enone derived from enulose to construct the functionalized C-ring. CuCl-promoted Stille coupling of a vinyl iodide and a vinylstannane installed the requisite triene side chain.

A novel intramolecular Diels–Alder cyclization involving indoloazepines

The reaction of indoloazepines 1 and α,β-unsaturated aldehydes in reflux toluene led to tetracyclic compounds 2. The key to this reaction was an intramolecular Diels–Alder cycloaddition by the indoloacrylate (dienophile)–dienamine (diene) intermediates generated in situ.

Cycloaddition Chemistry of 2-Vinyl-Substituted Indoles and Related Heteroaromatic Systems

[reaction: see text] The intramolecular Diels-Alder cycloaddition reaction (IMDAF) of several N-phenylsulfonylindolyl-substituted furanyl carbamates containing a tethered pi-bond on the indole ring were examined as an approach to the iboga alkaloid catharanthine. Only in the case where the tethered pi-bond contained two carbomethoxy groups did the [4 + 2]-cycloaddition occur. Push-pull dipoles generated from the Rh(II)-catalyzed reaction of diazo imides, on the other hand, undergo successful intramolecular 1,3-dipolar cycloaddition across both alkenyl and heteroaromatic pi-bonds to provide novel pentacyclic compounds in good yield and in a stereocontrolled fashion. The facility of the cycloaddition was found to be critically dependent on conformational factors in the transition state. Ligand substitution in the rhodium(II) catalyst markedly altered the product ratio between [3 + 2]-cycloaddition and intramolecular C-H insertion. The variation in reactivity reflects the difference in electrophilicity between the various rhodium carbenoid intermediates. Intramolecular C-H insertion is enhanced with the more electrophilic carbene generated using Rh(II) perfluorobutyrate.

Intramolecular Diels−Alder Cycloadditions of Fulvenes. Application to the Kigelinol, Neoamphilectane, and Kempane Skeletons

A variety of polycyclic ring skeletons (e.g., kigelinol, neoamphilectane, and kempene systems) can be prepared rapidly via intramolecular Diels-Alder cycloadditions (IMDA) of fulvenes. The length of the tethers and the diversity of the substituents on the fulvene core dictate the nature of the IMDA pathway. [reaction: see text]

Biomimetic Total Synthesis of (+)-Himbacine

On treatment with trifluoroacetic acid butenolide 14 undergoes N-Boc deprotection and condensation followed by an iminium ion activated intramolecular Diels-Alder cycloaddition to give the (+)-himbacine precursor 11 on reductive work up. Compound 11 was converted into (+)-himbacine in four synthetic steps. [reaction: see text]

Synthetic Studies Aimed at (‐)‐Cochleamycin A. Evaluation of Late‐Stage Macrocyclization Alternatives.

AbstractFor Abstract see ChemInform Abstract in Full Text.

IMDA Reactions of β,δ-Diketoester-Substituted 1,7,9-Undecatrienes: Application­ in the Formal Synthesis of Solanapyrone D

In this paper we describe the synthesis of β,δ-diketoester substituted 1,7,9-undecatrienes and their intramolecular Diels-Alder (IMDA) cycloadditions under thermal and acid-catalysed conditions. Application of this chemistry in the synthesis of a solanapyrone D precursor is reported.

Ring fission of chiral cyclic acetals plus intramolecular [4 + 2] cycloaddition: a sequential access to medium-size lactones. Application to the synthesis of carbasugars

A set of alpha,beta-unsaturated cyclic acetals were reacted with t-butyllithium in THF. A conjugate elimination took place, triggering a ketal ring cleavage when two eq. of TMEDA were added to the medium. The lithium alcoholate thus obtained could be trapped in situ by 2,2,2-trifluoroethyl acrylate. The resulting acryloyl (1Z,3E)-dienyl ether was then submitted to an intramolecular Diels-Alder cycloaddition under high pressure (12 kbar, 50 degrees C). Depending on the structure of the linkage between the diene and the acrylate, the expected ("fused") lactones were obtained with total endo- or exo-selectivities and high to complete diastereoselectivities. A remarkable inversion of selectivity, from endo to exo, with respect to the stereochemical elements of the tether could be observed in these cases. A five step diastereoselective transformation of two of the resulting nine-membered ring lactones into modified carbasugars was finally achieved in 23% overall yield.