Lewis acid-catalyzed diene-aldehyde cyclocondensation reaction

The synthetic value of this reaction has been enhanced by the development of a wide range of methodologies for glycal synthesis from 0-acylatcd glycosyl halides1 or from noncarbohydrate precursors. By use of the Lewis acid-catalyzed diene-aldehyde cyclocondensation reaction, glycals of natural and non-natural sugars can be obtained (Scheme 4).31... 

Scheme 4. Synthesis of glycals by Lewis acid-catalyzed diene-aldehyde cyclocondensation reaction (P-R2 gluco series a-R2 galacto series).

Myles DC, Danishefsky S, Schutte G. Development of a fully synthetic stereoselective route to 6-deoxyerythronohde B by reiterative applications of the Lewis acid catalyzed diene aldehyde cyclocondensation reaction a remarkable instance of diastereofacial selectivity. J. Org. Chem. 1990 55 1636-1648. 

The Lewis acid catalyzed diene-aldehyde cyclocondensation (LACDAC) reaction is a fast procedure to obtain dihydropyrones such as 28.4... 

A particularly elegant example is the application of Danishefsky s diene [107] to the total synthesis of carbohydrates and carbohydrate derivatives. While it was known that activated aldehydes undergo cycloaddition with electron-rich dienes, the process was not efficient with typical aldehydes under thermal conditions. A major breakthrough was realized [108] with the development of the Lewis acid-catalyzed diene-aldehyde cyclocondensation (LACDAC) reaction, which provided a new strategy for the synthesis of carbohydrates and other polyoxygenated natural products (Scheme 1.4) [109],... 

The major development in the Lewis acid catalyzed reaction came in 1981 when Danishefsky and coworkers reported that ZnCh and BF3-OEt2 catalyze the cyclocondensation of silyloxy dienes with unactivated aldehydes. The use of these Lewis acid catalysts permits a variety of simple aldehydes to be used in the reaction (Table 2). Danishefsky also critically evaluated the mechanism and stereochemistry of the cyclocondensation reaction with a series of dienes, aldehydes and catalysts. These studies resulted in conditions to control the relative and absolute stereochemistry of the reaction and allowed the use of this chemistry in natural product synthesis. 

Lewis acid catalysts increase the reactivity of dienophiles in Diels-Alder reactions by complexing to basic sites on the dienophile. ° The Lewis acid lowers the LUMO of the adjacent ir-system, which strengthens the overlap between the LUMO of the dienophile and the HOMO of the diene. In 1979 Scheeren reported that ZnCh catalyzes the cyclocondensation reaction of unactivated aldehydes with l-methoxy-3-(trimethylsilyloxy)-l,3-butadiene. Experimental details of this reaction, however, were not fully documented. In 1982 Scheeren also reported the use of aluminum alkoxydichlorides as catalysts... 

Since the investigations which used ZnCb and BF3-OEt2 as catalysts, other Lewis acids have been shown to catalyze the cyclocondensation reaction. MgBr2, for example, was used by Pearson and Danishefsky to add the power of chelation control to the reaction. When chiral a-alkoxy aldehydes are condensed with dienes under the influence of MgBr2, products derived from an ACF transition state predominate. The chelation of the metal by the a-alkoxy group of the aldehyde forces the aldehyde side chain to occupy the same side of the aldehyde as the metal. The diene, therefore, can attack the aldehyde from the least hindered exo face giving rise to the trans-KC product (Scheme 5). When an aldehyde is used that cannot form a chelate to the metal (such as benzaldehyde) syn (endo) selectivity is observed. 

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