ABSTRACT
The Taxol core was prepared in five steps via a key copper-catalyzed asymmetric conjugate addition trapping sequence. The use of a bromodiene-derived alkylzirconium nucleophile followed by trapping with POCl3/DMF gave a highly functionalized intermediate featuring a quaternary center in 69% yield with 92% ee. After 1,2-addition, Suzuki-Miyaura cross-coupling, allylic oxidation, and a type II intramolecular Diels-Alder reaction, the taxol core was obtained in 11% overall yield with 92% ee.
Subject(s)
Copper/chemistry , Organometallic Compounds/chemistry , Paclitaxel/chemical synthesis , Zirconium/chemistry , Catalysis , Cycloaddition Reaction , Molecular Structure , Paclitaxel/chemistryABSTRACT
Zirconium enolates, derived from copper-catalyzed asymmetric conjugate additions, are trapped with the Vilsmeier-Haack reagent. Asymmetric additions generate quaternary carbon centers with high enantioselectivity (generally â¼90% ee), and the enolates are converted to unsaturated ß-chloroaldehydes (41-57% yields). The reaction tolerates changes to the nucleophile, can be used to form five-, six-, or seven-membered ring products, and is scalable to 5 mmol, and the products are readily elaborated by condensation, cross coupling, and addition reactions.