Synthesis of taxoid analogues via tether controlled cycloaddition reactions.

Abstract

The syntheses of potential Taxol$\sp\circler$ analogues 35 and 57-b are described. The route selected employed a planar group (aromatic ring or a double bond) in the tether to facilitate the key step, an intramolecular Diels-Alder reaction. This approach afforded the tricyclic core of 35 in an efficient and direct manner. The Diels-Alder precursor 33 was synthesized from 3-methylbenzyl alcohol, acrolein, and (Z)-1-iodo-2-p-methoxybenzyloxymethyl-1,3-butadiene (15). The cyclization of alcohol 33 proceeded readily under oxidative conditions at room temperature to afford the cis-fused ring system 35. The tetracyclic nucleus of 57-b was prepared by an intermolecular Diels-Alder reaction of cyclopentadiene with intermediate 56-a. It was found that the bicyclic core of ketone 56-a could be generated by an intramolecular Diels-Alder reaction in which a tether containing a double bond behaved as a planar control unit. The precursor 54 was synthesized successfully from (Z)-2-butene-1,4-diol, vinylmagnesium bromide, and (Z)-1-iodo-2-methoxymethyl-1,3-buta-diene (22). The intramolecular Diels-Alder cycloaddition of alcohol 54 occurred under oxidative conditions at room temperature and afforded a mixture of diastereomers, of which the major product was the cis-fused ring system 56-a. Collectively these studies have provided new routes to complex ring systems and have demonstrated that improved reactivity and stereochemical control can be derived from appropriately selected tether control groups.