Endo-versus exo-addition

As with regioselectivity, the issue of endo- versus exo-selectivity in aqueous Diels-Alder reactions (simple diastereoselectivity) is also under FMO control. However, the unique solvent properties of water lead to an enhancement of endo-selectivity that goes beyond well-known solvent polarity effects. For example, Breslow s group looked at the endo/exo product ratios for the reaction of cyclopentadiene and several dienophiles (Table 1.5) [39, 

A dramatic increase in the endo/exo ratios (as well as reaction rates - see section 1.2) was observed for all four dienophiles studied on going from organic to aqueous reaction media (entries 1-3 in Table 1.5). The selectivity enhancements in entry 3 must be ascribed to the water, since these two-phase reactions did not exhibit the same selectivity (and rate) profiles as the reactions in neat cyclopentadiene (entry 1). It was suggested that the preference for endo attack in water was the result of a polar medium effect plus a hydrophobic effect that favored the more compact endo transition state. 

Breslow also noted that the presence of detergents such as sodium dodecyl-sulfate and cetyltrimethylammonium bromide (data not shown) had little effect on the product ratios of these aqueous Diels-Alder reactions. These results suggest that the increased endo/exo ratios and rates measured for a series of similar Diels-Alder reactions in aqueous detergent solutions by Sauer and co-workers may not be due to micellar effects as proposed [41]. Further support for Breslow s hydrophobic solvent effect hypothesis came from a study of Diels-Alder reactions of cyclopentadiene and a series of maleate and fumarate derivatives by Schneider and Sangwan [42]. They found a better correlation between the endo/exo product ratios for these reactions and solvophobicity parameters for various solvent systems as opposed to polarity effects alone. Subsequently, Cativiela et al. noted that a dual model (solvophobicity and polarity effects) can satisfactorily account 

Entry Reaction medium Reactant Butenone Methyl Dimethyl Methyl  

Grieco s group reported the effects of water on the reaction of diene 3.18 and a-formylenone 3.19 in their first publication on aqueous Diels-Alder chemistry (Table 1.6) [44]  

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