Zirconium-mediated synthesis of cyclobutenes and palladium-catalyzed reactions in the synthesis of natural products

Fang Liu, Purdue University

Abstract

Zirconium-mediated ene-yne cross-coupling reaction was successfully applied in the preparation of (Z)-1,4-diiodo-1-alkene derivatives, which upon treatment of BuLi generated 1,2-disubstituted cyclobutenes. The scope of this new methodology was general which enables us to introduce, in high yields, a variety of substitutes into the $\rm C\sb1$ and $\rm C\sb2$ positions of cyclobutene, including alkyl, aryl, alkenyl, and alkynyl groups. In all cases, the formation of $\beta$-elimination product was not detected which indicates the facile I-Li exchange and/or rapid intramolecular cyclialkylation process. The mechanism of the cyclialkylation of 4-halo-1-alkenylmetals was also investigated. Either of the two pathways, i.e., $\sigma$-cyclization and $\pi$-cyclization, could dominate the reaction depending on (i) steric hindrance on both reacting sites; and (ii) the nucleophilicity of the alkenylmetal bond. $\sigma$-Cyclization is favored in substrates with less steric hindrance and strong nucleophilic $\rm C\sb{sp2}$-metal bonds. On the other hand, $\pi$-cyclization is favored in sterically hindered and/or nucleophilic $\pi$-bond containing substrates. Furthermore, the regiochemical outcome in anti-hydroalumination of homopropargylic alcohols and their higher analogues followed by iodinolysis has been explored and proven to be useful in preparation of alkenyl iodides bearing free hydroxyl functional groups which could later be converted into other functional groups. High efficiency of Pd-catalyzed carbon-carbon bond formation reactions has been once again demonstrated in the total synthesis of freelingyne, a sesquiterpene from Eremophila freelingii. The synthesis was achieved with essentially full control of the alkene geometries in 7 steps from readily available (E)-3-iodo-2-methyl-2-propen-1-ol. The most distinguishing and novel feature of the synthesis involves the Pd-catalyzed cross coupling-lactonization tandem process in which it has been found to be critically important to exclude radical sources by either degassing via freeze-thaw cycles or addition of an antioxidant. Application of the carbopalladation-carbonylation cascade in the synthesis of fuscin has also been explored.

Degree

Ph.D.

Advisors

Negishi, Purdue University.

Subject Area

Organic chemistry|Microbiology

COinS