Enals Diels-Alder reactions

An endo-selective ionic Diels-Alder reaction of a,/f-enone and a,/f-enal acetals catalyzed by electrogenerated acid [99]... 

Lopez J. C., Lukacs G. Pyranose-Derived Dienes and Conjugated Enals. Preparation and Diels-Alder Cycloaddition Reactions ACS Symp. Ser. 1992 494 33-49 Keywords carbohydrate, befera-Diels-Alder reactions, stereoselectivity... 

Fig. 13 Diels-Alder reactions with enals catalyzed by 24...

Recently, catalytic asymmetric Diels-Alder reactions have been investigated. Yamamoto reported a Bronsted-acid-assistcd chiral (BLA) Lewis acid, prepared from (R)-3-(2-hydroxy-3-phcnylphenyl)-2,2 -dihydroxy-1,1 -binaphthyl and 3,5A(trifluoromethy I) - be nzeneboronic acid, that is effective in catalyzing the enantioselective Diels-Alder reaction between a,(3-enals and various dienes.62 The interesting aspect is the role of water, THF, and MS 4A in the preparation of the catalyst (Eq. 12.19). To prevent the trimerization of the boronic acid during the preparation of the catalyst, the chiral triol and the boronic acid were mixed under aqueous conditions and then dried. Using the catalyst prepared in this manner, a 99% ee was obtained in the Diels-Alder reaction... 

TABLE 5-2. Enantioselective Diels-Alder Reaction of Various a-Substituted a,/ -Enals with Cyclopentadiene Catalyzed by (R)-BLA 76a... 

An extensive review of the use of chiral Lewis acid catalysts in Diels-Alder cycloadditions has been presented. Brpnsted acid-assisted chiral Lewis acids have been shown to be highly efficient catalysts for the enantioselective Diels-Alder reactions of a- and /3-substituted-Q, /i-enals with numerous dienes. The chiral Lewis acid-catalysed Diels-Alder reaction between cyclopentadiene and alkenoyloxazolidi-nones can be catalysed by bis(oxazolone)magnesium catalysts. ... 

In a related transformation, Bode and co-workers have demonstrated the utility of homoenolate protonation in an azadiene Diels-Alder reaction catalyzed by aminoin-danol derived A-mesityl pre-catalyst 214 [118,119], The cyclization products 213 are obtained as a single diastereomer in excellent enantiomeric excess (Table 16). Electron-deficient enals are used in order to increase the electrophihcity and reactivity of the compounds. After protonation of the homoeneolate moiety, an inverse electron demand Diels-Alder is proposed to provide the desired cychzed product. 

Both a,p-unsaturated iminium species and enals react with 4-hydroxypyran-2-ones to give pyrano[43-h]pyranones in a formal [3+3] cycloaddition (Scheme 24) <99JOC690>. In the presence of butadienes, the malononitrile derivative 42 obtained from a 3-hydroxypyran-4-one undergoes a one-pot sequential intramolecular [S+2] pyranone - alkene cycloaddition and a Diels-Alder reaction to give the O-bridged tricyclic system 43 (Scheme 25) <99JOC966>. 

The reaction cannot be used with a,/3-enones or a,/ -enals because of a competitive Diels-Alder reaction induced by TiCl4. 

More recently, MacMillan has introduced the amine catalysts 42 and 45, readily available from L-phenylalanine, methylamine, and acetone or pivalaldehyde, respectively (Schemes 4.15 and 4.16). The broad potential of these materials in enan-tioselective organocatalysis was first proven in Diels-Alder reactions [28] and nitrone cydoadditions [29]. In 1,4-addition of C-nudeophiles MacMillan et al. later showed that Friedel-Crafts reactions of pyrroles with enals can be made highly enantioselective (Scheme 4.15) [30]. 

Conjugated dienes are needed for the Diels-Alder reaction (chapter 17) and Wittig disconnection 61 reveals that the choices here are more important. The easily prepared enals 62 would react with an unstabilised ylid 63 to give a Z-alkene but the conjugated allylic ylid 60 might give the -alkene. 

Stereospecificity, stereoselectivity and regioselectivity combined in Diels-Alder reactions give unprecedented control and you should now see why it is so important. The analgesic tilidine 47, effective in cases of severe pain, is an obvious Diels-Alder product.8 The regioselectivity is correctly ortho and the endo transition state 51 shows that the trans -enamine 49 is needed. This is the geometry we get when the enamine is made in the normal way from the enal 50 and Me2NH. 

Asymmetric Diels-AUer reactions The observation that simple acyloxy-boranes such as H2BOCOCH=CH2, prepared by reaction of BH3 with acrylic acid, can serve as Lewis acid catalysts for reactions of the a,P-unsaturated acids with cyclopentadiene (15, 2) has been extended to the preparation of chiral acyloxy-boranes derived from tartaric acid. The complex formulated as 3, prepared by reaction of BH3 with the monoacylated tartaric acid 2, catalyzes asymmetric Diels-Alder reactions of a,P-enals with cyclopentadiene with high enantioselectivity. The process is applicable to various dienes and aldehydes with enantioselectivities generally of 80-97 % ee. 

A comparison of the relevant transition states of the intramolecular Diels-Alder reaction can explain the observed configuration of the products 76 and 77. In the case of 76 (n = 0), the diene moiety is more likely to approach from underneath the enal face in an "endo manner (the Alder rule) because of a steric interaction with the phenyl group. The other structures 77 that contain a longer side chain (n = 1) allow the approach from both beneath and above the enal face, but NOE analyses of the isolated products 77 revealed that the diene approaches the dienophile from the top. Thus, in both systems, the trans-fused endo-configuration is preferred because of steric interactions with the phenyl substituents and the nitro group (Enders et al. 2007b). 

He M, Bode JW (2005) Catalytic synthesis of y-lactams via direct annulations of enals and N-sulfonylimines. Qrg Lett 7 3131-3134 He M, Struble JR, Bode JW (2006) Highly enantioselective azadiene Diels-Alder reactions catalyzed by chiral N-heterocyclic carbenes. J Am Chem Soc 128 8418-8420... 

Most chiral organoboron Lewis acids reported to date are based on an organoborane that is attached to a chiral organic moiety such as a diol, aminoalcohol, or other readily available chiral substrates.Organoboron derivatives recently used as catalysts in enantioselective Diels-Alder reactions include the family of chiral acyloxyboranes (CAB) with (196) and (197) as representative examples and various cyclic boronic esters such as (198) and (199). An interesting system that combines the favorable Lewis acid properties of fluorinated arylboranes with a chiral Bronsted acid has been developed by Ishihara and Yamamoto. The Bronsted acid-assisted chiral Lewis acids (BLA) (200) was found to be highly effective in enantioselective cycloadditions of Q ,jS-enals with various dienes. The presence of the Bronsted acid functionality leads to significant acceleration of the reaction. 

Asymmetric Diels-Alder Reaction of Unsaturated Aldehydes . The boron atom of acyloxyborane is activated by the electron-withdrawing acyloxy groups, and consequently acyloxyborane derivatives are sufficiently Lewis acidic to catalyze certain reactions. Thus, asymmetric Diels-Alder reactions of a,p-enals with dienes using (1) as a Lewis acid catalyst have been developed. For example, the reaction of cyclopentadiene and methacrolein gives the adduct in 85% yield (endo exo= 11 89) and 96% ee (major exo isomer) (eq 3). Some additional examples are listed in Figure 1. The a-substituent on the dienophile increases the enantioselectivity, while p-substitution dramatically decreases the selectivity. In the case of a substrate having substituents in both a- and p-positions, high enantioselectivity is observed thus the a-substituent effect overcomes that of the p-substituent. 

The readily prepared and air-stable complex trans 4, catalyzes Diels-Alder reactions between 1,3-dienes and a,]3-unsaturated methyl ketones or enals. Nitro-methane is the best solvent, and rate accelerations are up to a factor of 10 compared to the uncatalyzed reaction and up to 10 compared to catalysis by trifluoroacetic acid (Scheme 10.20) [34]. 

C2-chiral bidentate fluoroarylphosphinite ligands, efficiently catalyze the asymmetric Diels-Alder reaction between enals and 1,3-dienes [36], Electronic factors apart, the catalyst creates a chiral contour that favors enal coordination, and subsequently this was extended to Ru Lewis acids [37]. These are stable at room temperature, and can be recycled almost quantitatively after the reaction. The immediate catalyst precursor, Ru(Cp)(BIPHOP-F)I is readily available via a one-pot synthesis from Ru3(CO)i2. Although the Ru-catalysts were at first not quite as active as the Fe analogues and produced lower asymmetric induction than the Fe analogues, structural data showed the way to improve the situation (Scheme 10.21). 

This CAB has also been applied to the enantioselective Diels-Alder reaction of a-bromo-a,/3-enals with dienes [10]. a-Bromo-a,/3-enals are useful dienophiles in the Diels-Alder process because of the exceptional synthetic versatility of the resulting adducts e.g., an important intermediate for prostaglandin synthesis [17a]. In the presence of 10 mol % 2, R = H, a-bromoacrolein and cyclopentadiene in dichloro-methane undergo a smooth Diels-Alder reaction to give the (5)-bromo aldehyde in quantitative yield, 95 % ee and 94 6 exolendo CHO) diastereoselectivity (Eq. 11). Similar results are obtained for the catalyst 2, R = o-PhOCgHj, in propionitrile quantitative yield, 98 % ee ((5) enantiomer major), 94 6 exolendo CHO) diastereoselectivity (Eq. 11). Other examples are listed below. 

The boron-substituent-dependent enantioselectivity of CAB-catalyzed Diels-Alder reactions has been studied as a first step toward obtaining mechanistic information on the sp -sp conformational preferences in a, d-enals, where the possibility of s-cis or s-trans conformers exists in the transition-state assembly of Diels-Alder reaction catalyzed by Lewis acid [12]. a-Substituted a,P-ena s (e.g. methacrolein) favors an s-trans conformation in the transition-state assembly irrespective of the steric features of the boron substituent. On the other hand, the sp -sp conformational preference of a-unsubstituted a,/3-enals (acrolein and crotonaldehyde) can be reversed by altering the structure of the boron substituent an s-trans conformation is preferred when the substituent on the boron is small (H, C=CBu), whereas an s-cis conformation is preferred when the substituent is bulky (o-PhOC(jH4). 

We have also studied the solution conformations of CAB-complexed methacrolein and crotonaldehyde by use of NOE measurements (Table 1) [12]. These results are in agreement with the transition-state preference for the s-trans or s-cis conformation of a,/8-enals, on the basis of the enantioselectivity of the aldol and Diels-Alder reactions catalyzed by CAB. Finally, it has been established that the effective shielding of the si face of the CAB-coordinated a, -enal arises from /r-stacking of the 2,6-diisopropoxy-benzene ring and the coordinated aldehyde. 

An extremely useful enantioselective Diels-Alder reaction which uses a super-reactive cationic oxazaborinane catalyst was recently reported by Corey and co-workers (Eq. 25) [25]. This strong chiral Lewis acid promotes the Diels-Alder reaction between reactive and unreactive dienes and dienophiles. With tetrabromoborate as a counter-ion, good enantioselectivities were achieved in the reaction of cyclopenta-diene with several a,/3-enals. With tetrakis[3,5-bis(trifluoromethyl)phenyl]borate as a counter-ion, the reaction of isoprene and a-bromoacrolein at -94 °C gave the desired cycloadduct in 90 % yield and 96 % ee. 

The absolute stereo-preference in the Diels-Alder reaction can be easily understood in terms of the most favorable transition-state assembly 5, in which an attractive donor-acceptor interaction favors coordination of the dienophile at the face of boron which is cis to the 2-hydroxyphenyl substituent. At this time, the conformation of a,y3-enal has a strong s-trans preference. We believe that the coordination of a proton of the 2-hydroxyphenyl group with an oxygen of the adjacent B-O bond in complex 5 plays an important role in asymmetric induction this hydrogen-bonding interaction via a Brpnsted acid would cause the Lewis acidity of boron and the jr-basicity of the phenoxy moiety to increase, and the transition-state assembly 5 would be stabilized. The jr-basic phenoxy moiety and the jr-acidic dienophile could then assume a parallel orientation at the ideal separation (3 A) for donor-acceptor interaction. In this conformation, the hydroxyphenyl group blocks the si face of the dienophile, leaving the re face open to approach by diene. 

The absolute stereochemical course of the enantioselective Diels-Alder reactions can be rationalized on the basis of the mechanistic model previously described for the reaction of a,/3-enals and cyclopentadiene with a catalyst in which a formyl CH - O hydrogen-bond provides additional organization of the transition state [25,35]. On the basis of that analysis, there are two possible approaches of cyclopentadiene to the... 

Although they are often considered as poorer ligands than diphosphines, they lead also to very efficient and attractive enantioselective catalytic systems as exemplified here. As recent examples, diphosphinites 19 and 20 have been involved successfully in hydrogenation of olefins (mostly itaconate derivatives and enamides, up to > 99.9 % ee) ([84-89] and functionalized ketones (21) (up to 86 % ee) [90], hydrocyanation (19) [91], standard Pd-mediated allylic alkylation (20) [92] (up to 86% ee) [93], and Diels-Alder reaction between a,/l-enals and dienes (eq. (4) 99 % ee) [94]. 

Table 1-5. Asymmetric Diels-Alder reaction of a, ff-enal with cyclopentadiene catalyzed by CAB.")...

Diels-Alder-based strategy (Scheme 18).90 An analogous route has also been explored by Miller et a/.91 who obtained the acetoxy-aldehyde (152) from the Diels-Alder reaction of 3-methylbuta-l,3-dienyl acetate with 2-methylprop-2-enal. Cyclization of (152) with sodium hydride gave the coumarin derivative (153). Unfortunately, cyclization of the corresponding methyl ketone (154) yielded the chromanone derivative (155) and not the methyl analogue of (153). 

Azadienes 24 are easily made from amines and enals such as 23. The Diels-Alder reaction of 24 with maleic anhydride looks very attractive 25 and you might expect 26 to be the product. 

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