Intermolecular Diels—Alder synthesis

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]. 

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. 

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). 

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). 

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. 

Intermolecular Diels-Alder W. Oppolzer in COS, Ch. 4.1 hetero J. Hamer, 1,4-Cycloaddition Reactions, Academic Press, New York, 1967 D. L. Boger and S. M. Weinreb, Hetero Diels-Alder Methodology in Organic Synthesis, Academic Press, New York, 1967 B Weinreb in COS, Ch. 4.2 D. 

W. Oppolzer, Intermolecular Diels-Alder Reactions, in Comprehensive Organic Synthesis (B. M. Trost,... 

Kozikowski and Hasan (77JOC2039) used an intermolecular Diels-Alder reaction for the synthesis of the pyridocarbazole alkaloid ellipticine (456) (Scheme 57). Reaction of oxazolediene 454 with excess acetic acid at 145°C gave the pyridine 455 in 16% yield. Addition of methyllithium to cyanopy-ridine 455 followed by hydrolysis and cyclization with acetic acid afforded ellipticine (456). 

Boger and others (82JOC3761 82JOC3763 83JOC623 85JA5754) used this pyridine annulation for the formal total synthesis of antitumor, antibiotic streptonigrin (63) by an intermolecular Diels-Alder reaction between 1,2,4-... 

Oppolzer, W, Intermolecular Diels-Alder reactions. In Comprehensive Organic Synthesis, Trost, B M, Fleming, I, Paquette, L A, Eds., Pergamon Press, Oxford, pp. 315-399, 1991. 

The total synthesis of the rubrolone aglycon was accomplished in the laboratory of D.L. Boger as part of the ongoing research to explore the cycloaddition reaction of cyclopropenone ketals. The key step in the production of the seven-membered C-ring was the intermolecular Diels-Alder reaction of an electron-rich diene with the very strained dienophile. The cycloaddition took place in excellent yield (97%) and with complete disastereoselectivity. 

The critical step in the enantioselective and stereocontrolled total synthesis of eunicenone A by E.J. Corey et al. was the highly efficient chiral Lewis acid catalyzed intermolecular Diels-Alder cycloaddition reaction The diene component was mixed with 5 equivalents of 2-bromoacrolein and 0.5 equivalents of the chiral oxazaborolidine catalyst in CH2CI2 at -78 °C for 48h. The reaction gave 80% of the desired cycloadduct in 97% ee and the endolexo selectivity was 98 2. 

Certain functional groups can direct through hydrogen-bonding the outcome of the intermolecular Diels-Alder cycloaddition. This was the case in the key Diels-Alder cycloaddition step during the total synthesis of ( )-rishirilide B in the laboratory of S.J. Danishefsky. The diene was thermally generated in situ. 

Although this chapter is limited to intermolecular all-carbon reactions, the literature connected to this type of Diels-Alder reactions is still immense. The last general reviews about intermolecular Diels-Alder reactions date from nearly ten years ago - v During the past decade, several reviews were published dealing with specialized topics such as mechanistic aspects , specific dienes 2-35 dienophiles , applications in synthesis " ° and introduction of chirality by using chiral auxiliaries qj- chiral Lewis acids . ... 

Oppolzer W (1991) Intermolecular Diels-Alder Reactions. In Trost BM, Fleming I (eds) Comprehensive Organic Synthesis. Pergamon Press, Oxford, vol 5 chap 4.1 Carruthers W (1990) Cycloaddition Reactions in Organic Synthesis. Pergamon Press, New York... 

The Diels-Alder reaction with inverse electron demand has been one of the most intensively studied reactions of 1,2,4-triazines. In this reaction 1,2,4-triazines behave as electron-deficient dienes and react with electron-rich dienophiles to give, generally, pyridines (see Houben-Weyl, Vol. E7b, p 471 ff). [4 + 2] Cycloadditions of 1,2,4-triazines have been observed with alkenes, alkynes, strained double bonds, electron-rich double and triple bonds, but in a few cases also with electron-deficient alkynes C—N double and triple bonds can also be used as dienophiles. In addition to intermolecular Diels-Alder reactions, intramolecular [4 + 2] cycloaddition reactions of 1,2,4-triazines have also been studied and used for the synthesis of condensed heterocyclic systems. A review on the intermolecular Diels-Alder reaction was published by Boger and Weinreb 14 Sauer published a review on his studies in 1992,381 and E. C. Taylor published a summary of his own work on intramolecular Diels-Alder reactions in 1988.382... 

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