Diels-Alder reactions of enal

Scheme 7.67 NHC-catalyzed asymmetric formal Diels-Alder reaction of enals with a,p-unsaturated imines reported by Bode.

Scheme 7.71 NHC-catalyzed inverse electron demand Diels-Alder reaction of enals and enones reported by Bode.

Thereafter, the group disclosed NHC-catalysed highly enantioselective Diels-Alder reactions of enals and ketoenones to afford synthetically valuable dihydropyrones 103 in excellent yields and with outstanding stereoselectivities (Scheme 20.45). ... 

In 2006, Bode and coworkers reported the first enantioselective inverse-electron-demand hetero-Diels-Alder reaction of enals 130 with a,(i-unsaturated imines 131 under the catalysis of carbene precatalyst 123 in combination with Hiinig s base [59]. A broad range of substrates were well tolerated to afford synthetically important dihydropyridinone products 132 in good yields with remarkable enantioselec-tivities (Scheme 38.38). The need to introduce electron-withdrawing groups for enals only lies within the increased electrophilicity of these substrates, which enhances the rate of their reaction with the nucleophilic catalysts. The observed... 

In addition to the LUMO-lowering activated enantioselective Diels-Alder reactions of enals, MacMillan s group revealed that this catalytic strategy was also amenable to [3 -I- 2] cycloadditions between nitrones and a, 3-unsaturated aldehydes to provide isoxa-zolidines in high yields, moderate diastereoselectivity, and moderate enantioselectivity... 

Asymmetric Diels-Alder reaction represents one of the earliest successful organo-catalytic reactions [46, 60], Thongh extraordinary progresses have been achieved in this field, there are qnite a few challenges remained to be addressed. For example, the reactions have been limited with enals and successful examples with enones are rare the exo/endo selectivity is generally poor in many cases and a great number of a-substituted enals remain difficult substrates. Chiral primary amine such as 124 has been attempted in the Diels-Alder reactions of enals and cyclopentadiene. Though the reaction scope is quite limited, notable improvements on endo/exo ratio was obtained (Scheme 5.32) [61]. 

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

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. ... 

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. 

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. 

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. 

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. 

Scheme 7.24 Stereoselective Diels-Alder reaction of 2-vinyl indoles with trans-enals catalysed by prolinol Im.

Several other groups have further studied the Diels-Alder reaction of cyclopentadiene and 2-enals using different catalytic systems [8-10]. Hayashi and co-workers [11] successfully employed the Hayashi-Jprgensen prolinol salts 11... 

SCHEME 6.2. Secondary amine catalyzed Diels-Alder reactions of 2-enals with cyclopentadiene. 

The asymmetric Diels-Alder reaction of a,(3-unsaturated ketones have met much less success, most likely due to the lower reactivity of ketones in iminium ion formation compared to the corresponding 2-enals. This setback was overcome by MacMillan in 2002 when they extended the scope of their Diels-Alder protocol to include a,(3-unsaturated ketones using the more reactive imidazolidinone salt 16 as... 

Stereoselectivity in Hetero Diels-Alder Reactions of a-Enals,... 

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