Intramolecular Diels-Alder synthesis

Revision Problem 3 House fJ. Org. Chem., 1965, 3 1061) wanted to study intramolecular Diels-Alder reactions and wanted molecules Uke TM 396 in which n is 3 or 4, so that the product will have a 5 or 6 membered ring if the reaction works. It would obviously be a good thing if the synthesis can easily be modified to make other size rings as well. What do you suggest ... 

Two approaches to convergent steroid syntheses are based on the thermal opening of benzocyclobutenes to the o-quinodimethane derivatives (see p. 80 W. Oppolzer, 1978 A) and their stereoselective intramolecular Diels-Alder cyclizations. T, Kametani (1977 B, 1978) obtained (+ )-estradiol in a six-step synthesis. The final Diels-Alder reaction occurred regio- and stereoselectively in almost quantitative yield, presumably because the exo transition state given below is highly favored over the endo state in which rings A and D would stcrically inter-... 

A similar intramolecular Diels-Alder strategy was employed in an efficient synthesis to an appropriately functionalized hydrindanone nucleus (212). After functionalization, Diels-Alder cyclization, and appropriate functional group manipulation, this hydrindanone was converted into ( )-cortisone. The overall process afforded ( )-cortisone in a total of 18 chemical steps in approximately 3% yield. 

Diisocyanoadociane, a novel marine-derived diterpenoid, was analyzed retrosynthetically using the intramolecular Diels-Alder transform as T-goal concurrently with topological and stereochemical guidance. The enantioselective synthesis outlined below allowed assignment of absolute configuration. 

The chiral copper reagent 24 is an effective catalyst not only for intermolecular, hut also for intramolecular Diels-Alder reactions, as shown in the following schemes (Scheme 1.41, 1,42, 1.43). Synthetically useful octalin and decalin skeletons were synthesized in high enantio- and diastereoselectivity. The synthetic utility of this intramolecular Diels-Alder reaction has been demonstrated hy a short total synthesis of isopulo upone [23, 33d]. 

Numerous examples of intramolecular Diels-Alder reactions have been repor-ted especially from application in the synthesis of natural products, where stereoselectivity is of particular importance e.g. syntheses of steroids. " ... 

A domino reaction,in this case consisting of an inter- and an intramolecular Diels-Alder reaction, is a key step in the synthesis of the hydrocarbon pago-dane 30, reported by Prinzbach et al When the bis-diQnQ 27 is treated with maleic anhydride 4, an initial intermolecular reaction leads to the intermediate product 28, which cannot be isolated, but rather reacts intramolecularly to give the pagodane precursor 29 ... 

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]. 

The synthesis of highly substituted rigid tricyclic nitrogen heterocycles via a tandem four-component condensation (the Ugi reaction)/intramolecular Diels-Alder reaction was investigated in both solution and solid phase [24]. The Ugi reaction in MeOH (Scheme 4.2) involves the condensation of furylaldehydes 17, benzylamine 18, benzyl isocyanide 19 and maleic or fumaric acid derivatives 20, and provides the triene 21 which immediately undergoes an intramolecular Diels-Alder reaction, affording the cycloadduct 22 in a diastereoisomeric mixture with high yield. 

Intramolecular Diels-Alder reactions employing furan as the diene component are an effective step in the synthesis of many natural products, but difficulties are sometimes encountered due to the poor dienic character of the aromatic ring. Using CDs can help to overcome this problem. Thus, when 73 is heated in water at 89 °C for only 6h a 20% epimeric 1 2 mixture of 74 and 75 is... 

The intramolecular Diels-Alder reaction of 78 was investigated during the synthesis of isoquinoline alkaloids [65ij. No reaction occurred when solid-phase conditions were used (Florosil in DCM and CaCli) or when a variety of Lewis acids were employed (SnCU, BF3, RAICI2, Ti(z — Pr)4-TiCl4). A 56 % yield of 79 was obtained by carrying out the cycloaddition in toluene in a sealed tube at 200 °C. jS-CD catalysis in water under milder conditions (Equation 4.11) improved the conversion to 84 %. 

Stereoseiective synthesis of decaiines via tandem photooxidation-intramolecular Diels-Alder reactions of bis-furan [104]... 

MetzP. Snltonesin Organic Synthesis/. Prakt. Chem. /Chem. -Ztg. 1998 540 1-10 Keywords Intramolecular Diels-Alder reaction... 

Keywords enantiospecific synthesis, intramolecular Diels-Alder approaches... 

Yadav J. S. Synthesis of Antitumor Agents Pure Appl Chem. 1993 65 1349-1356 Keywords taxol skeleton, intramolecular Diels-Alder reaction... 

Thomas E. J. Cytochalasan Synthesis Macrocycle Formation Via Intramolecular Diels-Alder Reactions Acc. Chem. Res. 1991 24 229 235... 

Intramolecular Diels-Alder reaction of substituted fiirans has been investigated as a route to the synthesis of isoquinoline alkaloids. Tetrahydroisoquinoline 81 was prepared from furan 80 in 40% yield <95JCS(P1)2393>. 

Zndo Selectivity Example The inlra-molecular Diels-Alder reaction was used to make (19) needed for a synthesis of the natural product torreyol. The intermediate (IS) could not be isolated as oxidation of alcohol (17) gave (19) directly. The intramolecular Diels-Alder must be very efficient. 

Sparks, S.M., Gutierrez, A.J., Shea, K.f (2003) Preparation of Perhydroisoquinolines Via the Intramolecular Diels-Alder Reaction of N-3,5-Hexadienoyl Ethyl Acrylimidates A Formal Synthesis of ( )-Reserpine. Journal of Organic Chemistry, 68, 5274-5285. 

The tricyclic compound 20-C, a potential intermediate for alkaloid synthesis, has been prepared by an intramolecular Diels-Alder reaction of the ketone obtained by deprotection and oxidation of 20-B. Compound 20-B was prepared from 20-A using alkyne-ethene metathesis chemistry. Show the mechanistic steps involved in conversion of 20-A to 20-B. 

Another enantiospecific synthesis of longifolene shown in Scheme 13.32 used an intramolecular Diels-Alder reaction as a key step. An alcohol intermediate was resolved in sequence B by formation and separation of a menthyl carbonate. After oxidation, the dihydropyrone ring was introduced by 7-addition of the ester enolate of methyl 3-methylbutenoate, followed by cyclization. 

Roush and coworkers developed a new one-pot sequence consisting of an intramolecular Diels-Alder- and an intramolecular vinylogous Morita-Baylis-Hillman-cyclization for the synthesis of spinosyns [31]. These compounds are poly-ketide natural products possessing extraordinary insecticidal activity. 

For the synthesis of estradiol methyl ether 4-319, the cydobutene derivative 4-317 was heated to give the orthoquinonedimethane 4-318 which cydized in an intramolecular Diels-Alder reaction [109]. The thermally permitted, conrotatory elec-trocyclic ring-opening of benzocyclobutenes [110] with subsequent intramolecular cycloaddition also allowed the formation of numerous complex frameworks (Scheme 4.70). 

Recently, Mander and coworkers [122] reported the total synthesis of sordaricin (4-347), the aglycone of the potent antifungal diterpene sordarin which was first isolated in 1971 from the ascomycete Sordaria araneosa. Two approaches were explored the first method utilized a possible biogenetic Diels-Alder reaction the second was based on a domino retro-Diels-Alder/intramolecular Diels-Alder process. Thus, heating of 4-348 led, with extrusion of cyclopentadiene, to a 1,3-butadiene as intermediate which underwent an intramolecular Diels-Alder reaction to give the desired 4-349 as the main product, together with a small amount of 4-350 (Scheme 4.77). 

A NiCl2/CrCl2-mediated domino process of the chiral aldehyde 6/4-81 iodotriene 6/4-82 was used for the synthesis of (-)-ircinianin (6/4-79) and (+)-wistarin (6/4-80), as described by Uenishi and colleagues (Scheme 6/4.19) [299]. After the coupling to give 6/4-83, an intramolecular Diels-Alder reaction occurred at room temperature, leading to the desired cyclic product 6/4-84 in 60% yield. 

For the total synthesis of heliophenanthrone, the Dyker group has recently used a platinum-catalyzed cyclization of an o-alkynylbenzaldehyde leading to an isoben-zopyrylium cation which underwent a subsequent intramolecular Diels-Alder reaction to give a diastereomeric mixture of the tricyclic structure [319]. 

Another synthesis using in situ-prepared o-benzoquinones has been reported by Liao and coworkers [45]. These authors observed that oxidation of 2-methoxy-phenols 7-92 with DAIB in the presence of unsaturated alcohols 7-93 furnish transient o-benzoquinone monoacetal intermediates, which easily undergo an intramolecular Diels-Alder reaction to provide bicyclo[2.2.2]octenones 7-94 with high regio- and stereoselectivity, as well as in acceptable yields (Scheme 7.25). 

The oxidative formation of p-benzoquinones from anilides such as 7-108 was used for the synthesis of the core scaffold of the natural products elisabethin A (7-106) and pseudopterosin A aglycone (7-107) (Scheme 7.30). Exposure of anilide 7-108 to DMP [53] led to the formation of the o-imidoquinone 7-109, which underwent an intramolecular Diels-Alder reaction to give 7-110 in 28% yield after hydration. In a competitive pathway, the p-quinone 7-111 is also formed from 7-108, which on heating in toluene again underwent an intramolecular Diels-Alder reaction to give cycloadduct 7-112 in 25% overall yield. Hydrolysis of 7-112 furnished the carbocyclic skeleton 7-113 of elisabethin A (7-106). 

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