Stereocontrol in Diels-Alder cycloaddition

D. Horton and D. Koh, Stereocontrol in Diels-Alder cycloaddition to aneainratnd sugars Reactivities of acyclic seven-carbon trims dfenophttea derived hoot aldopeotoees, Carbohydr. Res. 250 249 (1993). 

Posner G. H. Stereocontrolled Synthesis of Functionalized Cyclohexenes Via Diels-Alder Cycloadditions of 2-Pyrones and 2-Pyridones-Applications to Synthesis of Physiologically Active Compounds in Stereocontrolled Org. Synth. 1994 177, Ed. Trost B. M., Pb. Blackwell Oxford... 

The readily available enantiopure acyclic hydroxy 2-sulfinyl butadiene 585 undergoes a highly face-selective Diels-Alder cycloaddition with PTAD to generate the densely functionalized cycloadduct 586 (Equation 84). The complete reversal of facial selectivity is observed when sulfonyl derivative 587 is treated with PTAD under identical conditions (Equation 85). These results demonstrate that the sulfinyl functionality is not just synthetically useful but also an extremely powerful element of stereocontrol for intermolecular Diels-Alder cycloadditions. On the other hand, the corresponding ( , )-hydroxy-2-sulfinyldienes treated with PTAD affords the cycloadducts in high yield but with moderate 7i-facial selectivity <1998CC409, 2005CEJ5136>. 

Molecular electrostatic potentials have been used to explain the regioselectivity exhibited in the Diels-Alder cycloaddition reactions between 1-trimethylsilyloxy-butadiene and the quinones 5-formyl-8-methyl-1,4-naphthoquinone, 5-methoxy-7-methyl-1,4-phenanthrenequinone, and 5,6,7-trimethyl-1,4-phenanthrenequinone.128 The intramolecular Diels-Alder reaction of masked o-benzoquinones (123) with a variety of dienes provides adducts (124) which rearrange to functionalized ris-decal ins (125) with complete stereocontrol of up to five stereocentres. This methodology ... 

The critical step in the enantioselective and stereocontrolled total synthesis of eunicenone A by E.J. Corey et al. was the highly efficient chiral Lewis acid catalyzed intermolecular Diels-Alder cycloaddition reaction The diene component was mixed with 5 equivalents of 2-bromoacrolein and 0.5 equivalents of the chiral oxazaborolidine catalyst in CH2CI2 at -78 °C for 48h. The reaction gave 80% of the desired cycloadduct in 97% ee and the endolexo selectivity was 98 2. 

Much of the early scientific work of the late Aleksander Zamojski focused on the total synthesis of racemic monosaccharides, based on stereocontrolled reactions of substituted dihydropyrans obtained by Diels—Alder cycloaddition. His article in Volume 40 of this series details many of his early studies in this area. His colleagues Jarosz and Chmielewski (Warsaw) here offer a broad insight into Zamojski s contributions, which later extended into chiral structures, higher sugars, and oligosaccharides. 

In combination with Cu(II) and Cu(I) salts, the polymer-anchored, enantio-merically pure bisoxazoHnes showed only poor enantioselectivity in the Diels-Alder cycloaddition between N-acryloyloxazolidinone and cyclopentadiene (up to 45% ee). Better stereocontrol was found in the cyclopropanations of styrene and 1,1-diphenylethylene with ethyl diazoacetate (up to 93% ee) and in the ene reactions between ethyl glyoxalate and a-methylstyrene or methylenecyclohexane (up to 95% ee), which was comparable to the structurally related, unsupported ligands. Only a slight decrease in activity and in stereocontrol was observed upon recovery and recycling of the catalyst. The catalytic transformations were as efEdent as if performed with the corresponding catalysts supported on insoluble polymers. 

The intramolecular aza Diels-Alder cycloaddition is also a valuable tool for the synthesis of alkaloids as demonstrated by the stereocontrolled synthesis of ( )-lepadifor-mine 137 (Scheme 41.29). This tricyclic alkaloid has been isolated from several species of Clavenia and Polycitoridae sea squirts and is moderately cytotoxic toward various tumor cell lines and effective to block potassium ion channels. Initial attempts to perform the aza Diels-Alder reaction with the racemic imino-diene t-butyl ester 134 in toluene at temperatures up to 165°C did not lead to the observation of any cycloadducts but to double bonds isomerization products. The corresponding free carboxylic acid only suffered decarboxylation. The addition of trifluoroacetic acid to generate an imminium species was also unsuccessful. 

Okamura and Nakatani [65] revealed that the cycloaddition of 3-hydroxy-2-py-rone 107 with electron deficient dienophiles such as simple a,p-unsaturated aldehydes form the endo adduct under base catalysis. The reaction proceeds under NEtj, but demonstrates superior selectivity with Cinchona alkaloids. More recently, Deng et al. [66], through use of modified Cinchona alkaloids, expanded the dienophile pool in the Diels-Alder reaction of 3-hydroxy-2-pyrone 107 with a,p-unsaturated ketones. The mechanistic insight reveals that the bifunctional Cinchona alkaloid catalyst, via multiple hydrogen bonding, raises the HOMO of the 2-pyrone while lowering the LUMO of the dienophile with simultaneous stereocontrol over the substrates (Scheme 22). 

The carbo- and hetero-Diels-Alder reactions are excellent for the constmction of six-membered ring systems and are probably the most commonly applied cycloaddition. The 1,3-dipolar cycloaddition complements the Diels-Alder reaction in a number of ways. 1,3-Dipolar cycloadditions are more efficient for the introduction of heteroatoms and are the preferred method for the stereocontrolled constmction of five-membered heterocycles (1 ). The asymmetric reactions of 1,3-dipoles has been reviewed extensively by us in 1998 (5), and recently, Karlsson and Hogberg reviewed the progress in the area from 1997 and until now (6). Asymmetric metal-catalyzed 1,3-dipolar cycloadditions have also been separately reviewed by us (7-9). Other recent reviews on special topics in asymmetric 1,3-dipolar cycloadditions have appeared. These include reactions of nitrones (10), reactions of cyclic nitrones (11), the progress in 1996-1997 (12), 1,3-dipolar cycloadditions with chiral allyl alcohol derivatives (13) and others (14,15). 

Although a number of multistep procedures are available for the introduction of five-membered carbocycles, their direct formation in a thermal cycloaddition is rare.6 Interest in the potential application of such a three-carbon + two-carbon cyclopentane cycloaddition has been derived from the expectation that such a process could prove to be an effective complement to the four-carbon + two-carbon Diels-Alder reaction which is used extensively in the regio- and stereocontrol led preparation of functionalized six-membered carbocycles. 

If nitroalkenes are employed as heterodienes in hetero Diels-Alder reactions instead of nitrosoalkenes, cyclic nitrones are formed. These cycloadducts undergo numerous subsequent reactions, and especially the combination of this hetero Diels-Alder reaction with a 1,3-dipolar cycloaddition is an extremely powerful tool for the synthesis of polycyclic alkaloids. This domino [4+ 2]/[3+ 2] cycloaddition chemistry has been comprehensively reviewed by Denmark and Thorarensen very recently, and this review also covers many hetero Diels-Alder reactions of nitroalkenes being not part of this sequential transformation [5]. Therefore the present article will focus on some selected examples which might highlight the advanced state of the art concerning stereocontrol of these reactions. On the other hand, an insight shall be given into the multitude of polycyclic structures accessible by means of nitroalkene cycloaddition chemistry. 

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