Diels-Alder-cascade

In their pioneering work on the catalytic carbopalladation reaction of 1,2-heptadiene with phenyl iodide in the presence of a suitable base, Shimizu and Tsuji observed the formation of the corresponding substituted 1,3-dienes 62 via a / -hydride elimination from the 7z>allyl intermediate 61 [61]. Based on these observations, a three-component Heck-Diels-Alder cascade process has been developed by Grigg and co-workers [73]. A wide variety of aryl and heteroaryl iodides were used for the intermolecular reaction with dimethylallene to afford the corresponding 1,3-dienes. These subsequently react in situ with N-methylmaleimide to give the bicyclic adducts 63 (Scheme 8.30). 

Chung has used a combined PK/Diels-Alder cascade reaction to synthesize [5.5.5.6] fenestranes and triquinanes. The first products (181) were obtained in high yield from diendiynes 180 upon reaction with dicobalt octacarbonyl (5%) under 30 atm of CO at 130 °C. The authors think it is more probable that the Diels-Alder reaction occurs after the PKR instead that the diene reacts first with the closer triple bond to form a 1,4-cyclohexadiene that would undergo the PKR (Scheme 53) [ 170]. 

Furans are also useful 4ji components for tandem Ugi condensation/intra-molecular Diels-Alder cascade reactions. For example, stirring a methanolic mixture of compounds 127-129 and benzylamine at rt provided the Ugi condensation product 130 that underwent a subsequent intramolecular Diels-Alder cycloaddition to furnish 131 in 70-90% yield (Scheme 23) (99TL1851). This methodology also allowed for a solid phase synthesis by using an ArgoGel-Rink resin as the amine component, providing cycloadducts 131 (after cleavage from the resin) in ca. 90-95% yields. 

If the oxidation is performed in the presence of an external dienophile, the respective products of [4+2] cycloaddition are formed [351-356]. Typical examples are illustrated by a one-pot synthesis of several silyl bicyclic alkenes 283 by intermolecular Diels-Alder reactions of 4-trimethylsilyl substituted masked o-benzoquinones 282 generated by oxidation of the corresponding 2-methoxyphenols 281 [351] and by the hypervalent iodine-mediated oxidative dearomatization/Diels-Alder cascade reaction of phenols 284 with allyl alcohol affording polycyclic acetals 285 (Scheme 3.118) [352]. This hypervalent iodine-promoted tandem phenolic oxidation/Diels-Alder reaction has been utilized in the stereoselective synthesis of the bacchopetiolone carbocyclic core [353]. 

The MacMillan group expanded the scope of their organocatalytic Diels— Alder cascade in 2013 to complete an elegant, highly efficient nine step enantioselective synthesis of (—)-vincorine (18). ... 

Double and even triple Heck-Diels-Alder cascade reactions involving bicyclopropyli-dene and 1,4-diiodo- or 1,3,5-triiodobenzene, respectively, have been accomplished. In these sequences, the carbopaUadation across the highly strained alkene is followed by a cyclopropyhnethyl to homoallyl rearrangement with concomitant /3-hydride elimination to yield an allylidenecyclopropane, which subsequently undergoes a smooth [4 + 2] cycloaddition to furnish the spiro[5.2]octene moiety (Scheme 4). ... 

Recently, MacMillan reported a nine-step enantioselective total synthesis of (+)-minflensine via the key step reaction of organocatalytic Diels-Alder-cascade cyclization. Scheme 3.43 [58],... 

The fused tricyclic system of hirsutellones A-C, embodied by 125, was generated by a concise and stereoselective intramolecular epoxide opening/Diels-Alder cascade reaction of epoxide... 

Scheme 8.5 Preferred Heck coupling with the tetrasubstituted alkene bicyclopropylidene (16) (a) single, (b) double, and (c) triple Heck-Diels-Alder cascade reactions [121, 122].

Inverse electron demand Diels-Alder reactions also have applications in biological systems. Fox reported that electron poor tetrazine diene 39 successfully forms a bioconjugate with the protein thioredoxin modified to contain a rara-cyclooctene (38). In an example of this Diels-Alder reaction in the absence of thioredoxin, tetrazine 39 combines with /ra -cyclooctene to yield cycloadduct 40 in quantitative yield. Like the synthesis of 37 described above, this reaction proceeds via a Diels-Alder/retro Diels-Alder cascade with elimination of N2. The reaction works well in organic solvents, water, and cellular media with 41 generated as the final product in protic solvents. ... 

In a spectacular final sequence during his synthesis of haouamine A, Baran employed an intramolecular Diels-Alder reaction with alkyne dienophile 133 to yield cycloadduct 134. This material then underwent a retro Diels-Alder reaction (producing carbon dioxide) followed by ester hydrolysis to afford haouamine A. This Diels-Alder/retro-Diels-Alder cascade is remarkable since the benzene ring formed in this sequenee is not planar. 

The final type of intramolecular Diels-Alder reaction that finds wide use in natural product total syntheses is the transannular process. Danishefsky exploited the power of this transformation during an oxidative dearomatization/transannular Diels-Alder cascade in his synthesis of 11-0-debenzoyltashironin. Deslongchamps produced the tricyclic core of cassaine via a transannular intramolecular Diels-Alder reaction. The tricyclic c/5-decalin with appended macrocycle framework of superstolide A is also available using this strategy. Roush demonstrated the effectiveness of this approach by heating 140 in toluene to yield cycloadduct 141 that was transformed into superstolide A in four more steps. ... 

In the course of biomimetic total synthesis of gambogin, Nicolaou reported a dramatic rate acceleration in water of the Claisen rearrangement of 138 to 139 (Scheme 5.45). ° In ds-benzene at 100°C there was no detectable reaction, while in dy-DMF and MeOH the rearrangement was complete in 30 min. The use of water (MeOH/HyO 1 1) reduced the reaction time in half The authors also report the first examples of a Claisen-Diels-Alder cascade sequence (140 141 142) accelerated by aqueous medium. In this case, the beneficial effect of water with respect to dy-DMF was even greater. 

Scheme 7.7 Rhodium-catalyzed [2-1-2-1-2] cycloadditioii/[4-l-2] Diels-Alder cascade.

Various cyclohexadienes can be obtained through the rhodium-catalyzed cyclotrimerization of 1,6-diynes with alkenes [12] or 1,6-enynes with alkynes [13], Valorization of these cyclohexadienes was reported with the development of original tandem [2-I-2-I-2] cycloaddition/[4-l-2] Diels-Alder cascades. For example, Tanaka and coworkers recently achieved the construction of bridged polycyclic lactam products, by performing a [2-1-2-1-2] cycloaddition/[4-l-2] Diels-Alder cascade between... 

Scheme 7.30 Double organocatalyzed Diels-Alder cascade.

Reports depicting organocascades involving more than one Diels-Alder reaction are scarce. However, under imidazolidinone catalysis, achiral dendralenes and enals as dienophiles are able to undergo a double Diels-Alder cascade with high efficiency and enantioselectivities (Scheme 7.30) [48]. 

In 2013, the group of Liu reported the first total synthesis of bolivanine through a Diels-Alder/intramolecular hetero-Diels-Alder cascade sequence, which allowed... 

Yuan, C., Du, B., Yang, L., Liu, B. (2013). Bioinspired total synthesis of bohvianine a Diels—Alder/intramolecular Hetero-Diels—Alder cascade approach. Journal of the American Chemical Society, 135, 9291-9294. 

Substituted cyclopentenones were indeed obtained from the Claisen-metathesis tandem [165] and there are also reports on a metathesis-Nazarov [166] and a metathesis-Diels-Alder cascade [167]. 

SCHEME 21.2. Claisen/Diels-Alder cascade for the synthesis of 1-O-methyllateriflorone. 

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