The Diels-Alder cycloaddition reaction of 1,l-dimethyl-1,3-butadiene derivatives received less attention until the discovery of the potent anticancer drug, taxol, in which the A-ring fragment can be constructed through the intermolecular Diels-Alder cycloaddition of the dienes with various dienophiles. Subsequent developments involve the intramolecular Diels-Alder cycloaddition of the dienes with α,β-unsaturated ketones to construct the A(B)-ring systems simultaneously. To explore the potential of the cycloaddition reaction, we initiated a program to study the reactivity of the dienes with different dienophiles, including α,β-unsaturated aldehydes, α,β-unsaturated ketones and acetylenic ketones, towards the Lewis acid-catalyzed intermolecular Diels-Alder cycloaddition reaction, which fo...[ Read more ]

The Diels-Alder cycloaddition reaction of 1,l-dimethyl-1,3-butadiene derivatives received less attention until the discovery of the potent anticancer drug, taxol, in which the A-ring fragment can be constructed through the intermolecular Diels-Alder cycloaddition of the dienes with various dienophiles. Subsequent developments involve the intramolecular Diels-Alder cycloaddition of the dienes with α,β-unsaturated ketones to construct the A(B)-ring systems simultaneously. To explore the potential of the cycloaddition reaction, we initiated a program to study the reactivity of the dienes with different dienophiles, including α,β-unsaturated aldehydes, α,β-unsaturated ketones and acetylenic ketones, towards the Lewis acid-catalyzed intermolecular Diels-Alder cycloaddition reaction, which forms the basis of this thesis.

The thesis begins with a brief introduction of the chemistry and biology of taxol. After a general introduction of the Diels-Alder cycloaddition reaction, the synthetic approaches to the A-ring of taxanes will be presented, followed by the intermolecular Diels-Alder cycloaddition of the dienes with α,β-unsaturated aldehydes. The reaction was found to work well with α-substituted acrolein derivatives to furnish the normal cycloadducts. However, the hetero-Diels-Alder cycloadducts, 3,6-dihydro-6,6-dimethyl-2H-pyran derivatives were formed when the reactions were performed with β-substituted acrolein derivatives. Experimental and theoretical studies (RHF/3-21G) conclude that the unusual findings should be attributed to the steric effect of the β alkyl substituents of the dienophiles on the highly asynchronous transition structure (during the cycloaddition), which is characteristic to the dienes.

The subsequent chapter describes the successful examples of intramolecular Diels-Alder cycloaddition reaction approaches towards the taxane skeleton. The later part of the chapter involves our studies on the intermolecular Diels-Alder cycloaddition reaction of the dienes with α,β-unsaturated ketones, which serves as a first example of the approach towards the construction of the B-seco taxoids. The reaction of the dienes with aryl vinyl ketones worked at -80 ℃ to provide the cycloadducts exclusively. For alkyl vinyl ketones, the unfavorable steric interaction between the l,l-dimethyl groups on the dienes and the alkyl substituent on the dienophiles necessarily makes the reactions take place at -40 ℃ and the cycloadducts were obtained together with the Michael addition products. A stepwise mechanism involving a zwitterionic intermediate is put forward to account for the experimental results.

The final chapter outlines a novel strategy for the formal synthesis of taxoids. The key reaction of the synthesis relies on the intermolecular Diels-Alder cycloaddition reaction of the dienes with acetylenic ketones. The strategy provides a convenient pathway for the introduction of the C-l hydroxyl group of taxol stereoselectively.