Diels-Alder cycloaddition intramolecular

Ab initio Hartree-Fock and density functional theory calculations were performed to study the transition state geometry in intramolecular Diels-Alder cycloaddition of azoalkenes 55 to give 2-substituted 3,4,4u,5,6,7-hexahydro-8//-pyrido[l,2-ft]pyridazin-8-ones 56 (01MI7). 

The Diels-Alder cycloaddition is the best-known organic reaction that is widely used to construct, in a regio- and stereo-controlled way, a six-membered ring with up to four stereogenic centers. With the potential of forming carbon-carbon, carbon-heteroatom and heteroatom-heteroatom bonds, the reaction is a versatile synthetic tool for constructing simple and complex molecules [1], Scheme 1.1 illustrates two examples the synthesis of a small molecule such as the tricyclic compound 1 by intermolecular Diels-Alder reaction [2] and the construction of a complex compound, like 2, which is the key intermediate in the synthesis of (-)chlorothricolide 3, by a combination of an intermolecular and an intramolecular Diels-Alder cycloaddition [3]. 

Diels-Alder Reaction in Unconventional Reaction Media Intramolecular Diels-Alder cycloadditions of bis-diene substrates [94]... 

Scheme 1.16 Elaboration of dipolar cycloadduct 136 and Intramolecular Diels-Alder cycloaddition...

We became particularly interested in strychnine when we noticed that the tetracycle 21 (Scheme 4.6), which might be readily available by an intramolecular Diels-Alder cycloaddition of a tryptamine-derived aminodiene, contains much of the complexity of this popular alkaloid target. In fact, this tetracycle is common to many indole monoterpene alkaloids including members of the Strychnos, Aspidosperma, and... 

Although Wender s synthesis was completed prior to Hudlicky s, it was published later [65]. It utilized the technique of mefa-photocycloaddition of arenes that Wender developed into a general method of synthesis for both angular and linear triquinanes. The overall strategy was centered around an intramolecular Diels-Alder cycloaddition for construction of the internal six-membered ring of the target. 

A pyran ring is formed in the intramolecular Diels-Alder cycloaddition of alkene-tethered enantiopure (lS,2R)-l,2-dihydroxycyclohexa-3,5-diene-l-carboxylic acid derivatives (derived from the biodihydroxylation of benzoic acid). For the three cases illustrated in Scheme 6.246, Mihovilovic and colleagues found that moderate to high yields of the desired cycloadducts could be obtained by exposing a solution of the precursor to microwave irradiation at 135-210 °C for extended periods of time... 

Cycloaddition reactions of furans are still widely used as key steps in the construction of complex molecules including natural products. As an example, the intramolecular Diels-Alder cycloaddition of 2-amido substituted furans provides a useful tool for the synthesis of fused, nitrogen-containing poly-heterocycles. Thus, thermolysis of 3-substituted amidofuran produces tricyclic indolinone 39 as a 2 1 mixture of diastereomers via amidofuran cycloaddition-rearrangement methodology, which serves as a key intermediate in the total synthesis of ( )-dendrobine, a major component of the Chinese ornamental orchid Dendrobium nobile . 

Reaction of a-allenyl alcohol 147 with methanesulfonyl chloride and triethylamine in toluene at 190 °C, in a sealed tube, led to the tricyclic dihydropyrrolizin-4-one 149 in 35% yield. This transformation involves a domino mesylation/ intramolecular Diels-Alder cycloaddition via diene 148 (Scheme 29) <2002CC1472>. 

DFT calculations have been used to study the mechanistic pathway of the intramolecular Diels-Alder cycloaddition involved in the biosynthesis of natural products paraherquamide A and VM55599. The cycloaddition involves a dihydropyrolo[l,2- ]pyrazine as the azadiene and a standard alkene as the dienophile (Scheme 1). Analysis of the results reveals that these cycloadditions take place through concerted transition structures associated with [4+2]... 

The use of vinylallenes as the diene component in Diels-Alder reactions is very common, thus resulting in their ubiquitous use in natural product synthesis. A vinylal-lene has even been proposed by Schreiber and Kiessling [10] as a biogenetic intermediate in the synthesis of the skeleton of esperamicin A (32 —> 33). Their synthetic approach to esperamicin A (34) was modeled after this biogenetic proposal in which a Type II intramolecular Diels-Alder cycloaddition was used to gain access to the highly unsaturated bicyclic core of 34 (Scheme 19.8) [10]. 

Application to both Type I and Type II intramolecular Diels-Alder cycloaddition has also met with appreciable success, the most efficient catalyst for these reactions being imidazolidinone 21 (Scheme 7) [51, 52]. The power of the inttamolecular Diels-Alder reaction to produce complex carbocyclic ring structures from achiral precursors has frequently been exploited in synthesis to prepare a number of natural products via biomimetic routes. It is likely that the ability to accelerate these reactions using iminium ion catalysis will see significant application in the future. 

The pyrone ring then acts as the dienophile in the intramolecular Diels-Alder cycloaddition, which was conducted in a microwave oven. The final step of this synthesis is a high-temperature ester pyrolysis to introduce the exocyclic double bond of longifolene. 

Lycorine is an alkaloid that has attracted attention from both the synthetic community and pharmacologists. Prior synthetic approaches have included inter-and intramolecular Diels-Alder cycloaddition. Based on a similar retrosynthetic disconnection, Padwa and co-workers (106,109) chose to use a push-pull carbonyl ylide cycloaddition with a disubstituted pyrrolidinone core to generate a tricyclic substrate. The major difference for this synthetic smdy was the availability of a labile proton a to the carbonyl moiety (Scheme 4.53). 

MRS Nicolaou 2000A Martin 1999. Biogenetic intramolecular Diels-Alder cycloaddition Baldwin 1999... 

Stocking, E.M. Sanz-Cervera, J.F. Williams, R.M. (2000) Total synthesis of VM55599. Utilization of an intramolecular Diels-Alder cycloaddition of potential biogenetic relevance. J. Am. Chan. Soc., 122, 1675-83. 

Mesoionic oxazolium-5-oxides 49 react with aminomalonic ester to give pyrrolidinones 50 as the major or exclusive products <99H(50)71> and the oxazolamine 51 is converted by sodium acetate in acetic acid into the hydantoin 52 <99JHC283>. The intramolecular Diels-Alder cycloaddition of the oxazole 53 and related compounds has been used as a route to substituted isoquinolines <99JOC3595>. ... 

The ability of related acylhydrazones 94 (Scheme 24), derived from a,/3-unsaturated aldehydes, to participate in intramolecular Diels-Alder cycloaddition reactions has been proven to occur by Gilchrist and coworkers (91TL125). They reported that azadiene 94 (n = 1) cyclized to 95, whereas compound 94 (n = 0) did not undergo intramolecular cycload-... 

There are times that it is important to run the Grubbs reaction under equilibrating conditions. In the course of a synthesis of ophirin 12, Michael Crimmins of the University of North Carolina observed (J. Am. Chem. Soc. 2004,126, 10264) that metathesis of 8 under the usual conditions gave mainly the undesired cyclic dimer. At elevated temperature, the dimer re-entered the equilibrium, leading to the desired 9 as the major (15 1) product. The oxonene ring system of 10 then directed the intramolecular Diels-Alder cycloaddition, leading to 12. 

There is an excellent recent review on intramolecular dipolar cycloadditions.1 Reviews on mechanistic aspects of intermolecular 1,3-dipolar cycloadditions abound2 and a treatise on intramolecular Diels-Alder cycloadditions is available.3... 

The Lewis acid-promoted tandem inter[4 + 2]/intra[3 + 2]-cycloaddition of the (fumaroyloxy)nitroalkene (124) with the chiral /i-silylvinyl ether (125) is the key step in the total synthesis of (+)-crotanecine (126), the necine base of a number of pyrrolizidine alkaloids (Scheme 46).237 The tandem inter[4 + 2]/intra[3 + 2]-cycload-ditions of nitroalkenes (127) with dipolarophiles attached to the /f-carbon of a vinyl ether (128) provides a method of asymmetric synthesis of highly functionalized aminocyclopentanes (129) (Scheme 47).238 trans-2-( 1 -Methyl-phenylethyl)cyclohex-anol has been developed as a new auxiliary in tandem 4 + 2/3 + 2-cycloadditions of nitroalkenes.239 The scope and limitations of the bridged mode tandem inter-[4 + 2]/intra[3 + 2]-cycloadditions involving simple penta-1,4-dienes are described in detail.240 A tandem intermolecular/intramolecular Diels-Alder cycloaddition was successfiilly used to synthesize a B/C cA-fused taxane nucleus (130) in 50% overall... 

DCC/DMAP mediated esterification of 2-butynoic acid using (+)-(/ )-89 followed by intramolecular Diels-Alder cycloaddition of the resulting ester in refluxing n-decane [cone. 0.07 M] provided the tricyclic lactone (+)-47 in 60% overall yield [Scheme 21]. Epoxidation of (+)-47 using m-CPBA led to P-epoxy lactone (+)-48 in 64% yield. The P-epoxy lactone (+)-48 is highly crystalline, unlike the racemic form. 

FCyclodextrin also catalyzes the intramolecular Diels-Alder cycloaddition of the I urane I in water at 89 lo give 2 in 91% yield. In the absence of the catalyst, the yield... 

Polycyclic Systems via l-MCR and Intramolecular Diels-Alder Cycloaddition... 

The first example of a tandem Ugi-4CR/intramolecular Diels-Alder reaction was reported by Paulvannan at Affimax [95], who obtained precursors for intramolecular Diels-Alder cycloadditions by an Ugi-4CR between furan-2-carboxaldehydes, monoamides or monoesters of fumaric or maleic acids, benzylamine, and benzyl isocyanide. The Ugi-4CR adducts 172 were never isolated since they underwent... 

Scheme 2.63. Tricyclic lactams via Ugi 4-CC/intramolecular Diels-Alder cycloaddition.

DFT calculations on the intramolecular Diels-Alder reaction of penta-l,3-dienyl acrylates predict stereoselectivities that are in good agreement with the experimen- (g) tal results.85 Another DFT study at the B3LYP/6-31G(d) level of the intramolecular Diels-Alder cycloaddition of 5-vinylcyclohexa-1,3-dienes has been reported. Reaction rates are influenced by dienophile twisting and substituent effects.86 The intramolecular dehydro-Diels-Alder reactions of ynamides (79) provides a new synthesis of benzo[fc]-, tetrahydrobenzo[fc]-, naphtho[l,2-/j -, and dibenzo[a,c]carbazoles... 

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