Diels-Alder Intermolecular

Acid chloride 5 is readily available from the known benzylic alcohol 6,4e but intermediate 4 is still rather complex. It was recognized that compound 4 could conceivably be formed in one step from 2-methoxyfuran (9)10 and iodotriflate 10. The latter compound was designed with the expectation that it could be converted to benzyne 8," a highly reactive species that could be intercepted in an intermolecular Diels-Alder reaction with 2-methoxyfuran (9) to give 7. The intermediacy of 7 is expected to be brief, for it should undergo facile conversion to the aromatized isomer 4 either in situ or during workup. 

The first examples of macrocyclization by enyne RCM were used in Shair s impressive biomimetic total synthesis of the cytotoxic marine natural product longithorone A (429) [180]. This unique compound features an unusual hep-tacyclic structure which, in addition to the stereogenic centers in rings A-E, is also chiral by atropisomerism arising from hindered rotation of quinone ring G through macrocycle F (Scheme 85). It was assumed that biosynthesis of 429 could occur via an intermolecular Diels-Alder reaction between [12]paracy-... 

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]. 

Asymmetric induction in the intermolecular Diels-Alder cycloaddition reactions can be achieved with chirally modified dienes and dienophiles as well as with chiral Lewis-acid catalysts [54-56]. 

The rates of intermolecular Diels-Alder reactions of hydrophobic dienes and dienophiles are significantly increased when the cycloadditions are performed in pure ethylene glycol (EG) [49a]. Some examples are illustrated in Scheme 6.30. This performance is due to the fact that the EG (i) forms extensive hydrogen bonding, (ii) is able to solubilize hydrophobic dienes and dienophiles, and (hi) forms molecular aggregations with the reactants. 

Aqueous intermolecular Diels-Alder chemistry vernolepin revisited [16e]... 

To avoid problems with the separation of regiomers, dimethyl acetylene dicarboxylate (DMAD) was chosen as a dienophile. The intermolecular Diels-Alder reactions were performed in refluxing dichlorobenzene (bp 132 °C), while the intramolecular reaction of alkyne tethered pyrazinone required a solvent with a higher boiling point (bromobenzene, bp 156 °C). In the case of 3-methoxy or 3-phenyl pyrazinones a mixture of pyridinones and pyridines was obtained, while for the alkyne tethered analogue only the di-hydrofuropyridinone was isolated as the single reaction product. 

The preparation of 1-substituted 4//,6//-dihydrothieno[3,4-c]fiu an 5,5-dioxide and some intermolecular Diels-Alder reactions with typical dienophiles (e.g., DMAD) were reported (Scheme 3, <96JCS(P1)2699>). 

Grieco utilized an aqueous intermolecular Diels-Alder reaction as the key step in forming the AB ring system of the potent cytotoxic sesquiterpene vernolepin. 87 Cycloaddition of sodium ( >3,5-hexa-dienoate with an a-substituted acrolein in water followed by direct reduction of the intermediate Diels-Alder adduct gave the desired product in 91% overall yield (Eq. 12.28). 

For clarification, individual transformations of independent functionalities in one molecule - also forming several bonds under the same reaction conditions -are not classified as domino reactions. The enantioselective total synthesis of (-)-chlorothricolide 0-4, as performed by Roush and coworkers [8], is a good example of tandem and domino processes (Scheme 0.1). I n the reaction of the acyclic substrate 0-1 in the presence of the chiral dienophile 0-2, intra- and intermolecular Diels-Alder reactions take place to give 0-3 as the main product. Unfortunately, the two reaction sites are independent from each other and the transformation cannot therefore be classified as a domino process. Nonetheless, it is a beautiful tandem reaction that allows the establishment of seven asymmetric centers in a single operation. 

So far, only those domino Knoevenagel/hetero-Diels-Alder reactions have been discussed where the cycloaddition takes place at an intramolecular mode however, the reaction can also be performed as a three-component transformation by applying an intermolecular Diels-Alder reaction. In this process again as the first step a Knoevenagel reaction of an aldehyde or a ketone with a 1,3-dicarbonyl compound occurs. However, the second step is now an intermolecular hetero-Diels-Alder reaction of the formed 1 -oxa-1,3 -butadiene with a dienophile in the reaction mixture. The scope of this type of reaction, and especially the possibility of obtaining highly diversified molecules, is even higher than in the case of the two-component transformation. The stereoselectivity of the cycloaddition step is found to be less pronounced, however. 

The combination of two successive [4+2] cycloadditions has already been described by Diels and Alder [la] for the reaction of dimethyl acetylenedicarboxylate with an excess of furan. A beautiful, more modern, example is the synthesis of pagodane (4-5) by Prinzbach [2], in which an intermolecular Diels-Alder reaction of 4-1 and 4-2 to give 4-3 is followed by an intramolecular cycloaddition. The obtained 4-4 is then transformed into 4-5 (Scheme 4.1). 

The readily available enantiopure acyclic hydroxy 2-sulfinyl butadiene 585 undergoes a highly face-selective Diels-Alder cycloaddition with PTAD to generate the densely functionalized cycloadduct 586 (Equation 84). The complete reversal of facial selectivity is observed when sulfonyl derivative 587 is treated with PTAD under identical conditions (Equation 85). These results demonstrate that the sulfinyl functionality is not just synthetically useful but also an extremely powerful element of stereocontrol for intermolecular Diels-Alder cycloadditions. On the other hand, the corresponding ( , )-hydroxy-2-sulfinyldienes treated with PTAD affords the cycloadducts in high yield but with moderate 7i-facial selectivity <1998CC409, 2005CEJ5136>. 

Lipids from marine products have been studied less frequently. The detection of co-(o-alkylphenyl)alkanoic acids with 16,18 and 20 carbon atoms together with isoprenoid fatty acids (4,8,12-trimethyltetradecanoic acid and phytanic acid) and substantial quantities of bones from fish and molluscs has provided evidence for the processing of marine animal products in vessels [58 60]. C16, C18, and C20 co-(o-alkylphenyl)alkanoic acids are presumed to be formed during the heating of tri-unsaturated fatty acids (C16 3, C18 3 and C20 3), fatty acyl components of marine lipids, involving alkali isomerization, pericyclic (intermolecular Diels-Alder reaction) and aromatization reactions. 

Apart from its application in intermolecular Diels-Alder reactions, chiral acyloxy boron (CAB) can also be used to effect intramolecular Diels-Alder reactions with excellent stereoselectivity (Scheme 5-45).73... 

The thermal ring opening of the cyclobutene in the heterocycle (339) led also to cyclohexene derivatives (340) through intermolecular Diels-Alder reaction 119). 

Several other intramolecular reactions showed only slight rate accelerations or retardations (VanderJagt et al., 1970). Of potential synthetic use, it has been found that both intramolecular and intermolecular Diels-Alder reactions can be catalysed by /3-CD (Sternbach and Rossana, 1982 Breslow and Guo, 1988). 

In an approach by Jung and Nishimura, the assembly of the dysidiolide decalin skeleton 54 was deemed possible via an intermolecular Diels-Alder reaction between cydohexene 52 and dienophile 53 [14]. Based on precedent established by Wulff et al. [15] [where Z = C(OCH3)=Cr(CO)5], the cycloaddition should give predominantly the exo isomer as shown (Scheme 19.12). However, all attempts to effect the cydoad-dition simply gave recovery of starting material. It was reasoned that steric hindrance was to blame. The steric hindrance assodated with the dienophile was decreased by replacing one of the methyl groups with another double bond in the... 

The key reaction in Jung et al. s proposed assembly of Plaunol B (81a) and C (81b) was an intermolecular Diels-Alder reaction between a diene and an allenic lactone that should give the exo-methylene group in the natural product (Scheme 19.16) [20], The phenyl-substituted lactone 83 was prepared as a model for the eventual furan lactone of the plaunols. Cydoaddition of 82 possessing a TBS enol ether and... 

Intramolecular Diels—Alder reactions without prior 1,4-addition of oxygen (cf. previous section) have similarly been postulated for a number of [2.2]paracyclophane analogs. When [2](2,5)furano[2](l,4)naphthalen-ophane (42) is heated in excess dimethyl acetylenedicarboxylate at 100 °C, a polycyclic compound of structure 134 is formed. The mechanism of formation of 134 is most probably as follows 101> the furan moiety reacts as active diene component in an intermolecular Diels—Alder reaction to give 135. This is followed by further intramolecular 1,4-addition with the unsubstituted naphthalene ring as diene component to give the product 133, which has been isolated. 

Asatone (110 Scheme 25), a neolignan, was quickly assembled by capitalizing upon the ability of a nucleophilic solvent to intercept the intermediate cation formed upon the electrooxidation of (108) in this instance the conjugated 1,3-diene (109) was produced. This result contrasts with the oxidation of 4,5-dimethoxyphenol (101) (Scheme 23) wherein the nonconjugated 1,4-diene (102) was generated. Diene (109) served admirably as both the diene and the dienophile in an intermolecular Diels-Alder reaction leading to asatone (110) [51]. 

Another total synthesis of elisapterosin B (27), as well as colombiasin A (36) was reported by the Rychnovsky group [39]. The underlying concept of this approach was the proposed biosynthetic pathway shown in Scheme 8. Thus, the authors decided to prepare the putative metabolite 46 in 0-methylated form 128 and subject it to Lewis acid conditions in the hope that cyclization might occur to either 27 or 36, or both. The required precursor 128 would stem from an intermolecular Diels-Alder reaction between diene 129 and quinone 130 (Scheme 20). 

The retrosynthetic concept of the Nicolaou group is shown in Scheme 22. The target molecule 36 is disconnected via an IMDA cyclization of the diene quinone precursor 138, which would be generated from the tetraline derivative 139 using Wittig chemistry followed by aromatic oxidation. A Claisen-type rearrangement would provide access to 139 whereby the side chain required for the rearrangement of 140 would be introduced by 0-acylation. The core of 141 would be formed via an intermolecular Diels-Alder reaction between diene 142 andp-benzoquinone 130 [42]. 

In a rather elegant approach towards colombiasin A (36) Flynn et al. [47] would access the tetracyclic carbon skeleton through an enantioselective intermolecular Diels-Alder sulfoxide elimination-intramolecular Diels-Alder (DA-E-IMDA) sequence between double-diene 166 and quinone 167 (Scheme 26). A key element of the proposed approach would be the chiral sulfoxy group in 167 which controls both the regio and facial selectivity of the intermolecular Diels-Alder reaction and eliminates generation of the dienophile for the IMDA reaction. 

Few examples of the preparation of six-membered heteroaromatic compounds using Fischer-type carbene complexes have been reported [224,251,381]. One intriguing pyridine synthesis, reported by de Meijere, is sketched in Figure 2.35. In this sequence a (2-aminovinyl)carbene complex first rearranges to yield a complexed 1 -azadiene, which undergoes intermolecular Diels-Alder reaction with phenylacetylene. Elimination of ethanol from the initially formed adduct leads to the final pyridine. 

The Diels-Alder reaction outlined above is a typical example of the way in which axially chiral allenes, accessible through 1,6-addition, can be utilized to generate new stereogenic centers in a selective fashion. This transfer of chirality is also possible by means of intermolecular Diels-Alder reactions of vinylallenes [30], aldol reactions of allenyl enolates [31], and Ireland-Claisen rearrangements of silyl allenylketene acetals [32]. 

A semiempirical AMI study of the inverse-electron-demand Diels-Alder reaction of 4-substituted 6-nitrobenzofurans with enol ethers and enamines favours a stepwise mechanism involving short-lived diradical intermediates. The inverse-electron-demand intermolecular Diels-Alder reactions of 3,6-bis(trifluoromethyl)-l,2,4,5-tetra-zine with acyclic and cyclic dienophiles followed by the elimination of N2 produce 4,5-dihydropyridazines, which cycloadd further to yield cage compounds. The preparation of jS-carbolines (90) via an intramolecular inverse-electron-demand Diels-Alder... 

However, when pyridyliminophosphorane (306a) is treated with phenyl isocyanate or isothiocyanate (Scheme 110), mixed carbodiimides are obtained, which are capable of an intermolecular Diels-Alder reaction resulting in triazine 308. The cycloaddition occurs specifically with one C = N double bond of the carbodiimide serving as the dienophile (77ZC371). 

An intermolecular Diels-Alder reaction of the A-sulfinyl diene 116, prepared from amino diene 115, gave a 1 2 mixture of epimers of 1-... 

Bicyclopropylidene (1) does not undergo an intermolecular Diels-Alder reaction with furan and 2-methoxyfuran even under high pressure. Intramolecular cycloadditions of compounds 160 with a furan tethered to bicyclopropylidene, however, were easily brought about under high pressure (10 kbar) and gave cycloadducts 161 stereoselectively in yields ranging from 32 to 95% (Scheme 35) [58]. 

Scheme 8.8 Thermal intermolecular Diels-Alder reactions.

Subsequently to the intermolecular Diels-Alder reaction, a new diene is produced which can then be utilized in a second cycloaddition process. The feasibility of the second Diels-Alder process was demonstrated by the thermal cycloaddition of 44 with a variety of dienophiles to afford the cycloadducts 47 in high yields, albeit with moderate diastereoselectivity (Scheme 8.8). Additional investigations will be necessary to delineate further the scope and limitations of this rapid increase in molecular complexity. 

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