DIRHODIUM(II) CARBOXAMIDATE CATALYSTS AS LEWIS ACIDS FOR THE HETERO-DIELS-ALDER REACTION.
DIRHODIUM(II) CARBOXAMIDATE CATALYSTS AS LEWIS ACIDS FOR THE HETERO-DIELS-ALDER REACTION.
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Date
2004-12-14
Authors
Valenzuela, Marcela Victoria
Advisor
Doyle, Michael P
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Abstract
The hetero-Diels-Alder reaction between an aldehyde and a diene provides access to dihydropyrans which are precursors in the chemical synthesis of biologically active natural products. Lewis acid catalysts increase reactivity by activating the carbonyl group of the aldehyde dienophile towards addition. Chiral dirhodium(II) carboxamidates are highly selective Lewis acids that have high turnover numbers in the hetero-Diels-Alder reaction. The reaction between aromatic aldehydes with Danishefsky's diene in the presence of only 0.01 mol % catalyst afforded the corresponding dihydropyran products in high enantioselectivities and yields.
Optimization of reaction conditions led to the discovery that the amount of dihydropyran formed increased at elevated temperatures while maintaining stereoselectivities as high as 98 % ee for aromatic aldehydes extending from p-nitro- to p-methoxy-benzaldehyde. Aldehydes with electron-donating substituents required longer reaction times in comparison to those having electron withdrawing substituents. Reactions with aliphatic aldehydes were sluggish in comparison to aromatic aldehydes, however enantioselectivities as high as 86 % were achieved.
A detailed kinetic analysis of the hetero-Diels-Alder reaction, which has not been previously reported, was performed to gain insight into the mechanistic pathway for the dirhodium(II) catalyzed hetero-Diels-Alder reaction. Both the equilibrium constants for the association between catalyst and aldehyde and the rates of reaction for various para-substituted aldehydes were determined. Kinetic investigations revealed a pronounced electronic influence on the rate of reaction giving a Hammett ρ value of +1.9 (versus σ+). The reaction rate for p-nitrobenzaldehyde is 20 times faster than p-chlorobenzaldehyde which is 36 times faster than p-anisaldehyde. Aldehydes with higher equilibrium constants for coordination with dirhodium(II) catalyst undergo slower rates of cycloaddition. Detailed kinetic studies established that inhibition of the catalyst by reactant aldehyde is apparent. In addition, reactions exhibit first order dependence on aldehyde and diene, and variable dependence on catalyst.
The dimethyl analogue of the Danishefsky's diene, 1-methoxy-2-methyl-3-trimethylsilyolxy-1,3-pentadiene, reacted with nitro-substituted aromatic aldehydes to form exclusively the cis-dihydropyran in high selectivity and yield. The approach of the diene to the catalyst-aldehyde complex is influenced by substitution on the incoming diene. Furthermore, substitution on the diene affects the rate of reaction with p-nitrobenzaldehyde. The diastereoselectivity with aromatic aldehydes other than nitro- substituted aldehydes was optimized; however, long reaction times were necessary to obtain high conversion.