Diastereoselective Intramolecular Diels-Alder Reactions

The Diels-Alder reaction is a powerful transformation that can generate structural and stereochemical complexity in a single chemical operation. This is amply demonstrated by some of its ingenuous applications in total syntheses of natural products. The first example of an intramolecular Diels-Alder reaction seems only to have been reported, by Alder, in 1953 [29, 30, 46). After this surprisingly slow start in comparison with its intermo-lecular counterpart, countless applications of intramolecular Diels-Alder reactions have since appeared [28-31]. 

Marshall conducted a series of studies in which the influence of various substituents on the chains joining the diene and dienophile partners was ascertained in intramolecular cycloadditions. A notable observation was the significantly enhanced diastereoselectivity for the TBS-protected substrate 53 in comparison with its MOM-protected counterpart 52 (Equation 3) [47]. Although the reaction of 52 gave an equal distribution of products 54 and 56 (cir= 50 50), the TBS ether 53 provided only the syn diastereomer 55 (dr 95 5). 

17 Dids-Alder and Hetero-Diels-Alder Reactions 

Subtle conformational effects inherent to the functionality that link the reacting components can be critical to the successful implementation of a tethering strategy [30, 52-54], Oppolzer reported that urethane 73 underwent cycloaddition to give exclusively the syn diastereomer 76 (Equation 4) [52], It was proposed that the allylic interactions with the N-methoxycarbonyl in 74 would disfavor this conformation and that the reaction thus proceeded via transition state 75 [30], In contrast, the corresponding amide 77 exhibited no pronounced conformational bias and provided an equal distribution of cycloadducts 78 and 79 (dr=41 59. Equation 5) [52], 

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Metz has developed a highly diastereoselective intramolecular Diels-Alder reaction of furans with vinyl sulfonates [22]. When hydroxyfuran 10 a was esterified with vinylsulfonic acid chloride, the intermediate sulfonate spontaneously underwent cycloaddition to give sultone 11a, Eq. 9. In the same manner, (-)-llb was obtained from (i )-10b which was derived from L-valine. 

Another diastereoselective intramolecular Diels-Alder reaction of furan was studied by Keay wherein the methyl group in the tether of (—)—12 directed the facial selectivity of the cycloaddition. Equilibrating conditions using a catalytic amount of Lewis acid gave the tricyclic enone (—)-13, Eq. 10 [23]. 

Diastereoselective intramolecular Diels-Alder reactions of sugar-derived trienes. 

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]. 

High-pressure and thermally induced intramolecular Diels-Alder reactions of furfuryl fumarates. Influence of tether substituents on diastereoselectivity [74]... 

A one-pot, four-component process involving the in situ formation of an azadiene followed by an intermolecular or intramolecular Diels-Alder reaction for the synthesis of highly functionalized piperidone scaffolds has been reported [81]. The compounds were obtained in good yields and diastereoselectivities (Figure 5). 

METHOXYCARBONYL-1,1,6-TRIMETHYL-1,4,4a,5,6,7,8,8a-OCTAHYDRO-2,3-BENZOPYRONE, an intramolecular Diels-Alder reaction is responsible for the diastereoselectivity. The stereoselective 1,4-functionalization of 1,3-dienes is exemplified by a two-step process leading to cis- and trans-1-ACETOXY-4-(DICARBOMETHOXYMETHYL)-2-CYCLOHEXENE. The effectiveness of a silyl hydride in providing a means for erythro-directed reduction of a p-keto amide is applied in a route to ERYTHRO-1 -(3-HYDROXY-2-METHYL-3-PHENYL-PROPANOYLJPIPERIDINE. This is followed by an asymmetric synthesis based on a chiral bicyclic lactam leading to (R)-4-ETHYL-4-ALLYL-2-CYCLOHEXEN-1-ONE. The stereoselectivity with which acetoxy migration can operate to an adjacent radical center is reflected in the one-step reaction that gives rise to 1,3,4,6-TETRA-O-ACETYL-2-DEOXY-a-D-GLUCOPYRANOSE. 

DIASTEREOSELECTIVE FORMATION OF a-METHOXYCARBONYL LACTONES THROUGH AN INTRAMOLECULAR DIELS-ALDER REACTION (4RS,4aRS,6RS,8aRS)-, (4S,4aS,6S,8aS)- AND (4R,4aR,6R,8aR)-4-METHOXY-CARBONYL-1,1,6-TRIMETHYL-1,4,4a,5,6,7,8,8a-OCTAHYDRO-2,3-BENZOPYRONE [rac-5, (+)-5, and (-)-5]... 

The intramolecular Diels-Alder reactions of vinyl sulfoximines 270 (n = 1,2) have been studied by Craig.121,122 In all cases mixtures of four diastereomeric cycloadducts were formed. When n = 1 the major diastereoisomer was the transfused compound 271 (n = 1) while when n = 2 the major diastereoisomer was the cis-fused compound 273 (n = 2) The diastereoselectivity of these reactions when n = 1 were essentially independent of the nature of the N-substituent in 270, while when n = 2 thejV-2,4,6-triisopropylphenylsulfonyl (Tris) derivative gave the highest selectivity for 273. 

After having developed a reliable route to the enantiopure carboxylic acid 4a, we next turned our attention to gain access to the enantiopure decalin fragment. One of the most efficient approaches to this structural motif is the intramolecular Diels-Alder reaction. The first systematic studies in the racemic series were performed by Roush and co-workers in 1981 (Roush and Hall 1981). Evans (Evans et al. 1984, 1988) and Oppolzer (Oppolzer and Dupuis 1985) showed that chiral auxiliaries in combination with strong Lewis acids allowed the generation of the endo adducts with excellent diastereoselectivities (Scheme 5). Recently, chiral Lewis acid catalysts were successfully used by Evans (Evans et al. 1999) and Corey (Zhou et al. 2003). 

When ethylene glycol was used instead of (-)-hydroxybenzoin (step e) in the preparation of the silicon tether, the intramolecular Diels-Alder reaction of step h proceeded with reverse diastereoselectivity, affording a mixture corresponding to 6 7 in a 1 10 ratio. Give an explanation for this finding. 

They also reported the intramolecular version of this asymmetric Diels-Alder reaction [53]. ( , )-Trienecarboximides of type 45 derived from chiral oxazolidones undergo Me2AlCl-catalyzed intramolecular Diels-Alder reactions affording bicyclic compounds 46 with high endo and diastereoselectivity (endolexo = -100 1). The stereochemistry is controlled by the stereogenic center at C4 of the chiral auxiliary (Xc) (Sch. 29). 

P. Herczegh, M. Zseby, L. Sziligyi, Z. Dinya, and R. Bogn r, High diastereoselection in the intramolecular Diels-Alder reaction of sugar-based l,7(E, 9-decatrienes, Tetrahedron 45 5995 (1989). 

The diastereoselective MesAI-mediated intramolecular Diels-Alder reaction, a highly ( )-selective Takai olefination and a Suzuki coupling were the key steps in the enantioselective total synthesis of (-)-equisetin by K. Shishido et al. It should be noted that the type of T-U olefination utilized allowed the preparation of functionalized heterosubstituted ( )-alkenes. 

Under high pressure, intramolecular [2 + 4] cycloadditions of a methylenecyclopropane moiety without being activated by an electron-withdrawing group - can be achieved. Thus, furfuryl derivatives 3, with an allyl ether or allylamine type linkage to a methylenecyclopropane, undergo intramolecular Diels-Alder reactions at 10-12 kbar to yield interesting new spirocyclo-propane-annulated tricyclic compounds 4 diastereoselectively in excellent yields. 

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