Synthesis of the B-ring of FR182877. Investigation of the reactions of 6-fumaryl 1,3,8-nonatrienes

Investigation of the intramolecular Diels-Alder reactions of 6-fumaryl 1,3,8-nonatrienes, substituted at the C5 by a vinyl group, to afford the B-ring of FR182877 are reported. The synthesis of the required 1,3,8-nonatriene was achieved quickly and in high yield. 6-Fumaryl 1,3,8-nonatrienes substituted at the C5 by a vinyl group were found to undergo competing tandem sigmatropic rearrangement/Diels-Alder cyclisation when heated under standard Diels-Alder cyclisation conditions. This rearrangement became the exclusive pathway when the reaction was performed in the presence of a Lewis acid. As expected from modeling studies, the major intramolecular Diels-Alder cyclisation product was the desired exo-trans adduct, which was required for the synthesis of FR182877. Intrigued by the rearrangements, a number of alterations were made to the 1,3,8-nonatriene. Replacement of the fumaryl group by an acetyl group resulted in the diminished reactivity of the 1,3,8-nonatriene with neither rearrangements nor cycloadditions observed. Variation of the C5 substituent was found to be very important in determining the π-diastereoselectivity of the Diels-Alder cyclisation.     

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

The bicyclo[4.3.0]nonane (C₁₁-C₂₁) 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.     

A concise synthesis of d,l-brevianamide B via a biomimetically-inspired IMDA construction

A concise synthesis of brevianamide B has been accomplished using a biomimetically-inspired intramolecular Diels-Alder reaction to diastereoselectively form the characteristic bicyclo[2.2.2]diazooctane core.     

Synthetic studies toward nortriterpenoids of schisandraceae family. Approach to the construction of functionalized C/D and A/B ring units of micrandilactone C and rubrifloradilactone B

Construction of 6/7 fused bicycles featuring C/D rings of micrandilactone C and rubrifloradilactone B is reported through IMDA reaction of properly designed substrates. Also a route to the construction of a tricycle having A/B ring of nortriterpenoids of schisandra family is reported using RCM and a bromonium ion initiated cycloetherification reaction as the key steps.     

Microwave-mediated intramolecular Diels-Alder cyclization of biodihydroxylated benzoic acid derivatives

The synthetic utility of biodihydroxylated benzoic acid derivatives for the construction of bridge bicyclo scaffolds was investigated. Biodihydroxylation of benzoic acid using Ralstonia eutropha B9 gave (1S,2R)-1,2-dihydroxycyclohexa-3,5-diene-1-carboxylic acid (DCD) in high optical purity (>95% ee). Protection of the intermediate and subsequent functional group transformation gave the required cyclization precursors in moderate to excellent overall yields. Subsequent intramolecular Diels-Alder cyclization of biodihydroxylated benzoic acid derivatives was carried out using either thermal or microwave conditions. Enantiomerically pure products with five chiral centers were obtained in 4-6 steps from achiral starting material.     

A Study of Intramolecular Diels-Alder Reactions of Allylamino Dienenitriles

The intramolecular Diels-Alder reactions of 2-allylanilino 3,5-heptadienenitriles (3) produced equimolar amounts of perhydroisoindoles 4 and 5, the structures of which were determined by spectral methods, but also by X-ray diffraction of 4a.     

Syntheses and optical properties of stable 8-alkylidene-bacteriochlorins mimicking the molecular structures of natural bacteriochlorophylls-b and g

We prepared bacteriochlorophyll(BChl)-b and g models by Diels-Alder reactions of 8-vinyl-chlorophylls with tetracyanoethylene. The resulting 8-alkylidene-bacteriochlorins with various substituent groups at the 3-position had the same π-conjugate as BChls-b/g. While the natural pigments isomerized by addition of an acid to afford the corresponding chlorins, the synthetic models were stable under the acidic conditions due to dialkylation at the 7-position. These BChl-b/g models are useful for investigating the optical properties of relatively unstable BChls-b/g.     

Angular hydroxymethyl directed intramolecular Diels-Alder approach for the stereo- and regioselective synthesis of pimaraditerpenes

The stereo- and regioselective synthetic route to pimaraditerpenes, employing an angular hydroxymethyl directed intramolecular Diels-Alder reaction of the decaline intermediate, has been developed. This synthetic approach allows prompt access to both natural pimaraditerpenes and the unnatural regioisomers, which would be potentially new anti-inflammatory pimaraditerpenes.     

Thiophene-containing products of the Ugi reaction in an oxidation-triggered IMDA/aromatization cascade: a simple access to 3-oxoisoindolines

A novel approach to skeletally diverse 3-oxoisoindolines has been developed which includes preparation of Ugi adducts containing thiophene and fumaric acid residues. When treated with excess m-CPBA at room temperature, these precursors undergo a simple oxidative cycloaddition/aromatization transformation and the corresponding 3-oxoisoindoline products are isolated in fair chemical yield over two steps. The second step is thought to include S-oxidation/IMDA/S-oxidation/SO₂ extrusion/aromatization events.     

Synthetic studies toward the cytotoxic norditerpene (+)-harringtonolide: setting up key-stereogenic centers of the cyclohexane ring D

The pivotal stereogenic centers of the asymmetric cycle D of (+)-harringtonolide were installed by functionalization of an enantiomerically pure IMDA cycloadduct, constructed from the chiral pool. The chiral 1,3-dioxane template used to direct the IMDA reaction was unraveled in an acidic medium, through spectacular hydrolysis of the acetal and concomitant lactone ring contraction. The central cyclohexene was selectively epoxidized either on the β- or on the α-side depending on the substitution pattern. The reactivity of several epoxide intermediates was challenged toward the construction of the oxygenated bridges of harringtonolide. We found one of them suitable for an access to another natural product, tetrodecamycin, which shares a similar substitution pattern as harringtonolide. Alternatively, functionalization led to set up key-stereocenters, en route to the asymmetric total synthesis of harringtonolide. The reactivity of the epoxide intermediates gave helpful insight for future work on this total synthesis.     

Effect of ring fusion stereochemistry on double bond geometry. Unexpected formation of nine-membered cyclic ether with E-configurated double bond through RCM

Formation of a nine-membered cyclic ether with E-configurated double bond was observed during construction of 5-9-5 tricycles through RCM of dienes. Ring fusion stereochemistry in the products oxonenes was found to have profound influence on the olefin geometry. cis-anti-cis 5-9-5 tricycle was obtained with Z-configurated olefin while cis-syn-cis 5-9-5 system was obtained with E- as well as Z-configurated double bond with the former predominating.     

Intramolecular Diels-Alder Reactions of Furans with Allenyl Ethers. Formation of Indanone and Tetralone

The intramolecular Diels-Alder reactions of the furans 3 , 11a and 11b produced indanone 6 and tetralones 14a and 14b respectively, presumably via the corresponding allenyl ethers 4 , 12a and 12b and the intramolecular cycloadducts 5 , 13a and 13b .     

Michael reaction,VI. Effect of carbonyl compounds on the stereochemistry and mechanism of the reaction

Zusammenfassung Die Stereochemie einer zweistufigen Gleichgewichts-Michael-Reaktion zwischen Dialkylamiden der Phenylessigsäure und Methylestern oder Dialkylamiden der Zimtsäure wird von den neutralen Carbonylverbindungen stark beeinflußt. Dieser Effekt kann mit der Zerstörung einer intramolekularen Chelatstruktur des Addukts und der darauffolgenden Bildung einer offenen Metallform mit einem dem neutralen Addukt ähnlichenerythro-threo-Verhältnis erklärt werden. Die Zunahme der elektrischen Leitfähigkeit des Reaktionsgemisches stützt diese Vorstellung.Es wird ein über das Chelat verlaufender Mechanismus im nichtpolaren Medium postuliert. Dieser Mechanismus ist in guter Übereinstimmung sowohl mit der geringen Stereoselektivität (bei kinetischer Kontrolle) als auch mit dem Einfluß der Lösungsmittel auf die Stereochemie.

---

Michael reaction, VI. Effect of carbonyl compounds on the stereochemistry and mechanism of the reaction

The equilibrium stereochemical result of the two-stepMichael reaction between phenylacetic acid dialkylamides and methyl cinnamate or cinnamic acid dialkylamides is affected by the neutral carbonyl compounds taking part in the synthesis. This effect is explained by breakdown of the intramolecular chelate structure of the reaction adduct and appearance of an open metal form with isomeric partitioning close to that of the neutral adduct. This is further supported by the increased electroconductivity of the reaction mixtures. A chelate mechanism for the reaction in nonpolar medium is postulated which is in good agreement with the low stereoselectivity under kinetic conditions as well as with the effect of the polarity of the solvent on the kinetic stereochemical result.

     

Investigations of the stereoselectivity of the intramolecular Diels-Alder reaction of a spiculoic acid model system

Model linear precursors to the spiculoic acids were prepared and underwent thermally induced IMDA reactions. The configuration of C5 in the stereotriad was found to dominate any inherent endo/exo selectivity of the IMDA reaction. The isomer (2E,5S)-20 underwent the IMDA to give the spiculoic acid stereochemistry in 84% yield and 94% ds. The required stereotriads were synthesised using stereoselective substrate-controlled aldol reactions; an anti-boron aldol reaction, controlled by the π-facial preference of (S)-2-benzoyloxypentan-3-one ((S)-27) led to (5R)-(22) and a syn-titanium aldol reaction, under the stereocontrol of a chiral N-acylthiazolidinethione (42) led to (5S)-(22). Chain extension using standard Wittig, HWE and ‘modified’ Julia olefinations installed the diene and dienophile components giving the linear precursors to the IMDA reactions.     

Epimerization and kinetic protonation as factors determining the stereochemistry of the Michael reaction

Summary Model compounds in which the only possibility for isomerization is epimerization were synthesized. They undergo isomerization under the conditions widely used in the Michael addition. Conclusions are drawn as to the possibilities for epimerization or kinetic protonation in the actual Michael adducts.

---

Epimerisierung und kinetische Protonierung als Faktoren der Stereochemie der Michael-Reaktion

Zusammenfassung Modellverbindungen, bei denen nur eine C-2 Epimerisierung möglich ist, wurden synthetisiert und einer Isomerisierung bei verschiedenen Reaktionsbedingungen unterworfen. Die Epimerisierung und kinetische Protonierung der Michaeladdukte wird diskutiert.

     

A mechanistic study on the intramolecular ionic Diels-Alder reaction of 2-methyl-3,9,11-tridecatriene-2-ol and 2,11-dimethyl-1,3,9,11-dodecatetraene

Intramolecular ionic Diels-Alder reaction of 2-methyl-3,9,11-tridecatriene-2-ol (1) was studied under acidic conditions. Treatment of 2-methyl-3,9,11-tridecatriene-2-ol (1) with trifluoromethanesulfonic acid yielded 7-methyl-8-isopropenyl-1,2,3,4,4aR^∗,7R^∗,8R^∗,8aS^∗-octahydronaphthalene (4) and (1Z)-1-((E)-but-2-enylidene)-2-(2-methylpropenyl)cyclohexane (5) through regioselective intramolecular ionic Diels-Alder reaction. The reaction appeared to proceed partly through a stepwise mechanism involving a carbocation intermediate. However, a concerted pathway rather than a stepwise one is suggested to be involved in the acid-catalyzed intramolecular Diels-Alder reaction of 2,11-dimethyl-1,3,9,11-dodecatetraene (13).     

A new approach to the bicyclo[4.3.0] ring system of natural products from the liverwort: total synthesis of (±)-chiloscyphone and (±)-isochiloscyphone

Construction of the tricyclic derivative 5, a common intermediate for the synthesis of sesquiterpenoids 1-4, was accomplished by using the intramolecular Diels-Alder reaction. Availability of 5 was demonstrated by effective total synthesis of chiloscyphone 1 and isochiloscyphone 2.     

Synthetic studies of GKK1032s: the asymmetric synthesis of the decahydrofluorene skeleton via a novel cyclization of silyl enol ether and sequential retro Diels-Alder and intramolecular Diels-Alder reactions

GKK1032s, which were isolated from the culture broth of Penicillium sp. GKK1032, exhibit antitumor activity. We constructed the fully elaborated decahydrofluorene skeleton of GKK1032s. The C-ring was constructed by intramolecular cyclization reaction between a chiral epoxide and silyl enol ether, and the dienophile moiety was introduced concurrently. In addition, the AB-rings were stereoselectively constructed using novel sequential retro Diels-Alder (DA) and intramolecular Diels-Alder (IMDA) reactions. Several further modifications of the IMDA adduct were carried out, leading to the asymmetric synthesis of the desired hydroxyester including nine stereo centers.     

Expedient synthesis of highly substituted α-pyrones from Baylis-Hillman adducts and their conversion to poly-substituted aromatics

An efficient synthetic protocol of fully substituted α-pyrones has been developed starting from the Baylis-Hillman adducts. Subsequent Diels-Alder reaction of the α-pyrones and DMAD produced poly-substituted aromatic compounds in high yields.     

First total syntheses of (±)-3-aza-11-selena and (±)-3-aza-11-tellura steroids

An efficient synthesis of 11-selena and 11-tellura steroids bearing a pyridine as an A ring was achieved via an intramolecular Diels-Alder cycloaddition of o-quinodimethanes, which were generated from a 3-azabicyclo[4.2.0]octa-1,3,5-trien-7-one ketal. The major isomer matches the trans-anti-trans ring configuration of natural products. Finally, the vinyl groups of the synthesized 11-hetero steroids have been oxidized by the Wacker process in good yields. The characteristic ¹H and ¹³C NMR spectroscopic features of the synthesized compounds are reported.