Diels-Alder sequence

Scheme 3.80. Domino cyclization/1,5-hydrogen shift/hetero-Diels-Alder sequence.

Jacobi and coworkers used an oxy-Cope/Diels-Alder sequence to synthesize the tumor inhibitor gnididione (4-234) [80]. A similar sequence was also used by Kraus and coworkers for the synthesis of 11-deoxydaunomycinone (4-235) [81]. 

An interesting entry to functionalized dihydropyrans has been intensively studied by Tietze in the 1990s using a three-component domino-Knoevenagel Hetero-Diels-Alder sequence. The overall transformation involves the transient formation of an activated heterodienophile by condensation of simple aldehydes with 1,3-dicarbonyls such as barbituric acids [127], Meldrum s acid [128], or activated carbonyls. In situ cycloaddition with electron-rich alkenes furnished the expected functionalized dihydropyrans. Two recent examples concern the reactivity of 1,4-benzoquinones and pyrazolones as 1,3-dicarbonyl equivalents under microwave irradiation. In the first case, a new three-component catalyst-free efficient one-pot transformation was proposed for the synthesis of pyrano-1,4-benzoquinone scaffolds [129]. In this synthetic method, 2,5-dihydroxy-3-undecyl-1,4-benzoquinone, paraformaldehyde, and alkenes were suspended in ethanol and placed under microwave irradiations to lead regioselectively the corresponding pyrano-l,4-benzoquinone derivatives (Scheme 38). The total regioselectivity was... 

Dehydrogenation of A2-imidazolines (416 Z = NR) gives imidazoles, but requires quite high temperatures and a catalyst such as nickel or platinum. Alternatively, hydrogen acceptors such as sulfur or selenium can be used (70AHC( 12)103). A2-Imidazoline derivatives (417) are thermally converted into imidazoles (418) by a retro-Diels-Alder sequence (93JOC3387). 

Scheme 5.49. Enantioselective Domino-Knoevenagel-Diels-Alder-sequence catalyzed by proline 245 or DMTC 251.

In this transformation two new C-C-rr-bonds are formed from three different components. The enantioselectivity of this reaction is generally low (< 5%). With cyclic ketones the corresponding products were obtained as single diastereomers. It is proposed that this reaction involves a Knoevenagel-hetero-Diels-Alder sequence where proline utilizes both iminium and enamine catalysis (Scheme 9.20). 

Microwave-assisted Diels-Alder reactions of 9-substituted anthracenes with 2-acetamidoacrylate in DMF generate conformationally constrained bicyclic bisaryl a-amino acid derivatives with high regioselectivity.138 The Sc(OTf)3-catalysed Diels-Alder reaction of anthracenes with methyl vinyl ketone does not proceed via an electron-transfer process from anthracenes to the MVK-Sc(OTf)3 complex.139 (-)-(/ )-9-(l,2-Dimethoxyethyl)anthracene has been used as a chiral template in the Diels-Alder/retro-Diels-Alder sequence for the synthesis of a,j3-unsaturated lactams.140... 

A more advanced, direct route to the core structure of CP-263,114 (me-1) has recently been published by Wood et al., who used carbon-based fragmentation after a phenolic oxidation/ intramolecular Diels-Alder sequence [10], In addition, various cycloadditions for the synthesis of the central bicyclic skeleton have been established [11], Further methods to construct the bicyclic backbone by means of a Diels-Alder reaction [12] and by an exciting multi-step domino reaction [13] are introduced in the next sections, in the context of the total syntheses of the phomoidrides by Nicolaou and Shair, respectively [14]. 

The convenient generation of bicyclo[2.2.2]octenones through the use of ortho-quinol derivatives in Diels-Alder reactions recently inspired Wood and co-workers in their studies toward the total synthesis of CP-263,114 (110) [148]. They relied on the Wessely-Yates tandem oxidative acetoxylation/intramolecular Diels-Alder sequence to build bicyclo[2.2.2]octenones such as 114 en route to advanced isotwistane intermediates such as 111b, which could eventually be fragmented to furnish the carbocyclic core of 110 (i.e. 111a —> 110, Figure 29) [149-153],... 

Snider et al. have synthesised the antiinsectan ( )-leporin [496] 7-26 using the domino-Knoevenagel-hetero Diels-Alder sequence. The intermediate 1-oxa-1,3-butadiene 7-25 was formed in situ by condensation of the pyridone 7-23 and the dienal 7-24. Subsequently, a hetero Diels-Alder reaction occurred accompanied by minor side reactions. Thus, the desired cycloadduct 7-27 was formed only in moderate yield as 5 1 mixture with its trans-fused diastereomer (Fig. 7-6). Functionalisation of the nitrogen atom yielded the natural product. A similar reaction sequence occurred in the synthesis of the structurally related free radical scavenger ( )-pyridoxatin, however, in this approach the hetero Diels-Alder reaction represented only a side reaction competing with the desired intramolecular ene reaction [497]. 

These examples demonstrate that a selective Heck-Diels-Alder sequence with two different alkenes is only possible either in a stepwise manner, if an alkene reacts much faster in the Heck reaction than in the subsequent cycloaddition so that the 1,3-diene can be isolated, or as a real cascade reaction if one alkene is more reactive and thus selectively reacts as a coupling partner, whereas the other one is a better dienophile. Both concepts have been used by Kollar et al. for the annelation of cyclohexene rings onto the steroidal skeleton 26 (Scheme 4) [28-30]. At 60 °C the cycloaddition was sufficiently suppressed so that the Heck coupling product 29 could be isolated and subsequently subjected to Diels-Alder reactions with different dienophiles. For a domino reaction with both methyl acrylate and dimethyl fumarate (28) present in the reaction mixture, the conditions had to be precisely adjusted so that the mixed products 31 and 32 were formed predominantly along with only small amounts of the products of a twofold reaction of either 27 (R = CC Me) or 28 with 26. These conditions also proved suitable for a cascade reaction of 26 involving allyl alcohol 27 (R = CH2OH) or allyl acetate 27 (R = CH2OAc) and dimethyl fumarate (28). 

Enders D, Htittl MRM, Runsink J, Raabe G, Wendt B (2007b) Organocatalytic one pot asymmetric synthesis of functionalized tricyclic carbon skeletons via a triple cascade/Diels-Alder sequence. Angew Chem 119 471... 

Scheme 7.28. DMP-induced domino oxidation/hetero-Diels-Alder sequence.

Pizzirani D, Robert M, Recanatini M (2007) Domino Knoevenagel/Diels-Alder sequence coupled to Suzuki reaction a valuable synthetic platform for chemical biology. Tetrahedron Lett 48 7120-7124... 

The Lewis acid-promoted carbonyl-ene reaction of enantiomerically pure 4-oxoazetidine-2-carbaldehydes gave homoallylic alcohols, which have been used for the diastereoselective preparation of fused bicyclic, tricyclic and tetracyclic p-lactams of non-conventional structure 49 and 50, using tandem one-pot radical addition/cyclization or elimination-intramolecular Diels-Alder sequences <03JOC3106>. 

Por a competitive retro-Diels-Alder-Diels-Alder sequence in the attempted Ireland-Claisen rearrangement of a perhydroindane ring system, see S. D. Burke, D. M. Armistead and K. Shankaran, Tetrahedron Lett., 1986, 27, 6295. 

The unparalleled employ of five Diels Alder reactions (3 normal, 2 retro) in the Kende "isobenzofuran" route (Eq.3) provides a fitting conclusion to the discussion of Diels Alder sequences. Although a 1 1 mixture of regiolsomers is produced, the yield of 8c is 17% based on 75a. 

The first of these synthetic efforts arises from work of the Vedejs group at Wisconsin and is depicted in Scheme 3.3. °° The overall strategy employs the well-documented Diels-Alder sequence for stereocontrol in the cyclohexane ring and a [2,3] sigmatropic rearrangement for construction of the 11-membered carbocyclic rings of cytochalasin D (51) and zygosporin G (52). 

The 3- and 4-isomers are more readily aromatized than 2-imidazolines which are cyclic amidines and hence resonance stabilized (see CHEC-I) <80AHC(27)24l>. Heating in decahn, however, transformed (127) into a 2-substituted imidazole by a retro-Diels-Alder sequence (Equation (45))... 

A tandem Claisen/Diels-Alder sequence was recently used to construct the tricyclic structure found in a series of Garcinia natural products, represented by more-llin. On heating at 140 °C, acrylate ester 113 underwent an initial [3,3]-sigmatropic rearrangement to provide intermediate 114 (Scheme 20) (020L909). A subsequent intramolecular Diels-Alder cycloaddition then produced 115 in 92% yield. 

A novel tandem Pictet-Spengler/intramolecular Diels-Alder sequence has been used to prepare carboline derivatives. Reaction of imine 137 with maleic anhydride in CH2CI2 provided cycloadduct 140 in 60-80% yields (Scheme 25) (02TL203). The... 

Cycloaddition. Cyclic Fischer carbene complexes are generated from o-ethynylaryl carbonyl compounds with the title reagent at room temperature. When enol ethers or enamines are present, a Diels-Alder reaction-retro-Diels-Alder sequence occurs to furnish substituted naphthalenes (7 examples, 54—84%). 

The synthetic utility of oxazoles as azadienes was further advanced when Grigg and co-workers reported that the Diels-Alder reactions of oxazoles with alkynes provided furans via a tandem Diels-Alder retro-Diels-Alder sequence. Thus 5-ethoxy-4-substituted oxazoles 119 reacted with dimethyl acetylenedicar-boxylate in cold ether to yield 2-ethoxy-3,4-furandicarboxylic acid dimethyl ester 121 in >50% yield (Fig. 3.33). In this case, the intermediate cycloaddition adduct 120 extrudes a molecule of hydrogen cyanide or a nitrile derived from the C-4 substituent of the oxazole, via a retro-Diels-Alder reaction to provide a substituted... 

---