Studies toward (-)-gymnodimine: concise routes to the spirocyclic and tetrahydrofuran moieties

[formula: see text] (-)-Gymnodimine is a member of a unique class of potent marine toxins possessing imines within a spirocylic array. Herein we report the synthesis of the tetrahydrofuran fragment and a strategy toward the spirocyclic imine fragment of this family of toxins. Key reactions include an asymmetric anti-aldol reaction to set the stereochemistry of the tetrahydrofuran and a formal, intermolecular Diels-Alder reaction involving an alpha-methylene-delta-lactam and a dienyne.     

Studies towards a postulated biomimetic Diels-Alder reaction for the synthesis of himgravine

The possible role of an iminium ion mediated Diels-Alder reaction on the biosynthetic pathway to himgravinc is discussed. The results of a preliminary investigation of a related oxycarbenium ion mediated Diels-Alder reaction are reported and are in accord with the stereochemistry of the natural product.     

High Pressure Diels-Alder Reaction of Furan and Methyl Acrylate

The stereochemistry of the high pressure-induced Diels-Alder reaction of furan and methyl acrylate can be altered by varying the reaction temperature. Changes in solvent, reagent stoichiometry, or reaction pressure had no effect upon the stereochemistry of the cycloaddition.     

A concise synthesis of the functionalized [5-7-6] tricyclic skeleton of guanacastepene A

The six membered ring of guanacastepene A was constructed by a Diels-Alder reaction of 1,1,4-trisubstituted diene to set up the correct relative stereochemistry at the C8 quaternary center and the remote C5 stereocenter. In 10 efficient steps from the Diels-Alder adduct 9, the desired highly functionalized [5-7-6] tricyclic skeleton 2 was synthesized. Key steps involve trimethylsilyl chloride (TMSCl) assisted Michael addition to form enol ether and the usage of the enol ether in the following intramolecular Mukaiyama aldol reaction to form the middle seven membered ring of guanacastepene A.     

Concise synthesis of the core bicyclo[2.2.2]diazaoctane ring common to asperparaline, paraherquamide, and stephacidin alkaloids

A versatile synthesis of the bicyclo[2.2.2]diazaoctane core structure of asperparaline, brevianamide, paraherquamide, and stephacidin natural products is demonstrated. This convergent synthesis relies on an intramolecular hetero Diels-Alder reaction to construct the key tetracycle from a diketopiperazine derived azadiene; which in turn was formed from prolinamide and a pyruvic acid derivative. The stereochemical outcome of the Diels-Alder reaction was found to favor the brevianamide stereochemistry.     

Studies on the method of total synthesis of koumine: I. 4-Substituted 1,2-dihydropyridine derivatives and their function as a conjugated diene in Diels-Alder reaction

A route to the total synthesis of koumine has been suggested. Five 4-substituted 1, 2-d hydropyridine derivatives, which are supposed to be a conjugated diene of Diels-Alder reaction to produce the isoquinuclidine ring of koumine, have been synthesized. Only two of them were found to be able to undergo the Diels-Alder reaction. The stereochemistry of the reaction product has also been examined.     

Total synthesis of (+/-)-stemodinone via an efficient ring-exchange strategy

A total synthesis of (+/-)-stemodinone, a tetracyclic stemodane diterpene, from the known tricyclic methyl olefin 11 is described. The key steps involve an efficient ring-exchange reaction and palladium(0)-catalyzed lactone migration. The ring-exchange strategy for controlling the stereochemistry was based on an initial Diels-Alder reaction to form a new ring followed by cleavage of the original ring. Cleavage of the original ring of the Diels-Alder adduct 9 was achieved by an initial regio- and chemoselective Baeyer-Villiger oxidation followed by the Pd(0)-catalyzed lactone-migration reaction reported by us.     

Total synthesis of amaminol A: establishment of the absolute stereochemistry

The first synthetic route to amaminol A with use of an organocatalytic intramolecular Diels-Alder reaction is reported. The absolute stereochemistry is proven with a crystallographic image of a cyclic carbamate of amaminol A.     

Rh(I)-catalyzed ring opening of an IMDAF-derived oxabicyclo cycloadduct as the key step in the synthesis of (+/-)-epi-zephyranthine.

[reaction: see text] A new strategy for epi-zephyranthine has been developed that is based in part on an extraordinarily facile intramolecular Diels-Alder reaction of a 2-imido-substituted furan. By using a Rh(I)-catalyzed ring opening of the resulting oxabicyclic adduct, the cis-diol stereochemistry of epi-zephyranthine was established.     

Synthesis and chemistry of bridgehead allylsilanes. Stereoselective reactions with aldehydes

A type II intramolecular Diels-Alder reaction provides access to bicyclo[5.3.1] ring systems with an imbedded bridgehead allylsilane. The Lewis acid catalyzed reactions of these compounds with aldehydes proceed efficiently and with control of stereochemistry. [reaction: see text]     

Intramolecular Diels-Alder reactions of optically active allenic ketones: chirality transfer in the preparation of substituted oxa-bridged octalones

The intramolecular Diels-Alder reaction of allenic ketones containing a furyl unit (IMDAF) to generate oxatricyclic systems in good yields is described. The alkene dienophiles 1ab give poor yields of the cycloadducts 2ab, presumably due to the facile retro Diels-Alder reaction. However, the analogous allenic dienophile 7 afforded the desired cycloadduct 8 in 91% yield on treatment with dimethylaluminum chloride. When the allene bears an alkyl substituent on the terminal carbon, complete diastereoselectivity is seen in the IMDAF, e.g. cyclization of 14 gave only the cycloadduct 15 in 80% yield presumably due to greater steric hindrance in the transition state II as compared to that in I. Finally we report complete chirality transfer of the stereochemistry of an allene to the carbon framework of the oxatricyclic system. Thus, the optically active allenic ketone 20 afforded only the desired cycloadduct 21 with the correct absolute stereochemistry needed for the synthesis of the arisugacin class of natural products.     

Stereoselective total synthesis and stereochemistry of diplodiatoxin,a mycotoxin from diplodia maydis

The stereochemistry of diplodiatoxin has been deduced, and the assumed stereostructure has been confirmed by the synthesis using highly stereocontrolled strategy, in which the intramolecular Diels-Alder reaction of a(E, E, E)-triene is involved.     

Diazapolycyclic compounds—XIII : Reactions of diazaquinone adducts with N-bromosuccinimide

The action of N-bromosuccinimide on adducts obtained by Diels-Alder reaction of benzo(g)phthalazin-1,4-dione with substituted 1,3-butadienes is reported. Different addition or substitution products are formed depending on the solvent and reaction conditions. The stereochemistry of the most interesting among these compounds has been studied, and a possible mechanism for their formation is proposed.     

Biomimetic macrocycle-forming Diels-Alder reaction of an iminium dienophile: synthetic studies directed toward gymnodimine

The macrocyclic core of gymnodimine has been constructed via an intramolecular Diels-Alder reaction of an alpha,beta-unsaturated iminium dienophile in water. The cycloaddition furnished a single exo-product, along with two endo-products. Through X-ray analysis of a suitable derivative, the stereochemistry of the exo-product was established, thereby demonstrating that its stereochemistry matches that of gymnodimine. In contrast, macrocyclization of an analogous alpha,beta-unsaturated ketone dienophile gave only undesired endo-products. Interestingly, the imine dienophile shows remarkable stability in water. [reaction: see text]     

o-Thioquinones on [2.2]paracyclophanes: an example of totally stereocontrolled hetero Diels-Alder reactions

The reaction of 4-hydroxy[2.2]paracyclophane with phthalimidesulfenyl chloride allowed the preparation of a suitable precursor for a paracyclophane-o-thioquinone. This species participates in an inverse electron demand hetero Diels-Alder reaction with different electron-rich alkenes to give the expected benzoxathiin cycloadducts with complete control of regio- and stereochemistry.     

Total synthesis of 8,12-iso-iPF3alpha-VI, an EPA-derived isoprostane: stereoselective introduction of the fifth asymmetric center

[reaction: see text] A new and stereoselective approach for the synthesis of all-syn isoprostanes is reported. This method, which is based on acid-catalyzed Diels-Alder reaction, allows the introduction of the side chain with a predetermined stereochemistry of the hydroxy group. The first total synthesis of an eicosapentaenoic acid (EPA)-derived iP, 8,12-iso-iPF3alpha-VI 10, was performed using this approach.     

Experimental and theoretical studies of Diels-Alder dimerization of 1,2,3,4,5-pentachlorocyclopentadiene and of Diels-Alder cycloaddition of polychlorinated cyclopentadienes to norbornadiene

Diels-Alder cyclodimerization of 1,2,3,4,5-pentachlorocyclopentadiene (1) affords 2a as the exclusive reaction product. Diels-Alder cycloaddition of 1 to norbornadiene also proceeds stereoselectively to produce a single [4+2] cycloadduct, 4c. The structures of 2a and 4c were established unequivocally via application of single crystal X-ray crystallographic techniques. The origins of the observed diastereofacial selectivity in each of these cycloaddition processes have been investigated by application of semiempirical (AM1 Hamiltonian) and ab initio (Hartree-Fock 3-21G*) calculations. The computational results thereby obtained, which are based upon consideration of the kinetically favored transition state for each of the two cycloaddition reactions studied, are consistent with experiment. These semiempirical and ab initio methods also have been used to investigate the mechanisms of the Diels-Alder reactions that have been used to prepare aldrin and isodrin (7 and 8, respectively). The results thereby obtained suggest that isodrin formation via Diels-Alder cycloaddition of cyclopentadiene to 1,2,3,4,7,7-hexachloronorbornadiene proceeds with kinetic control of product stereochemistry.     

Imino Diels-Alder-Based Construction of a Piperidine A-Ring Unit for Total Synthesis of the Marine Hepatotoxin Cylindrospermopsin

The synthesis of a piperidine A-ring precursor to the alkaloid cylindrospermopsin (1) is described. The initial approach to the A-ring precursor focused on the imino Diels-Alder reaction of diene 8 with ethyl (N-tosylimino)acetate (9) to form the cycloadduct 10 as a single stereoisomer. However, all attempts to convert ester 10 to a requisite diene such as 5 were unsuccessful. An alternative strategy involved the Diels-Alder cycloaddition of N-tosylimine 9 with oxygenated diene 19 under either thermal or Lewis acid-catalyzed conditions to produce a mixture of cis and trans enones 20 and 21. Although the undesired cis-enone 20 was the major product under all reaction conditions, it could be converted to the desired trans enone 21 by acid-catalyzed isomerization. Copper-mediated conjugate addition of vinylmagnesium bromide to cis-enone 20 followed by stereoselective ketone reduction with L-Selectride produced alcohol 23, whose structure was confirmed by X-ray crystallography. Similarly, trans-enone 21 was converted to alcohol 25 whose structure and stereochemistry were also established by X-ray analysis. Alcohol 25 was then protected as the silyl ether 26, which was hydroborated at the terminal olefin to produce primary alcohol ester 28having the stereochemistry and functionality needed for cylindrospermopsin.     

Bridging with Pyrroudines

The synthesis of benzodicyclicpyrrolidines 7 and 9 of specific stereochemistry such as N-Substituted-2,3-dimethyl-1,4-endo or exo-(3′,4′-pyrrolidine)-1,4-dihydronaphthalene is described. These have analgesic activity. The precursors 3, 4, 5, and 6 and a novel Diels-Alder reaction are discussed.     

Meldrum's acid-derived thione dienophile in a convergent and stereoselective synthesis of a tetracyclic quassinoid intermediate

An advanced intermediate toward anti-cancer quassinoids has been synthesized using a quadruple diene-transmissive [4+2]-cycloaddition strategy. High convergence is achieved thanks to a regio- and stereoselective hetero-Diels-Alder reaction using a thione. The relative stereochemistry of the final Diels-Alder adduct was controlled by tethered substituents introduced via a highly syn- and gamma-selective vinylogous Mukaiyama aldol.