Palladium-catalyzed Negishi coupling and zirconium -catalyzed asymmetric carboalumination of alkenes (ZACA): Powerful tools in the synthesis of natural products

Zhihong Huang, Purdue University

Abstract

Pd-catalyzed Negishi coupling has been serving as one of the powerful methods for the construction of carbon-carbon bond since its first discovery in 1976. Many research groups have utilized Negishi coupling to synthesize various types of natural products or complex organic compounds as the pivotal step. To overcome a long-standing synthetic challenge of preparing ( Z)-trisubstituted alkenes using Pd-catalyzed cross-coupling, it is found that hydroboration of 1-bromo-1-alkynes, migratory insertion, and transmetallative iodinolysis in one-pot to synthesize (Z)-trisubstituted iodides is a highly efficient and stereoselective method, which proved to be excellent for the synthesis of some natural products containing (Z)-trisubstituted alkenes. As depicted in detail in chapter one, was the development of the above methodology and its application to the synthesis of fragments of discodermolide, (-)-callystatin A and archazolid A and B natural products, and most importantly, to the total synthesis of (6E,10Z)- O-Methylmyxalamide D, for the first time. As discussed in chapter two, the 1:1 mixture of DIBAL-H and Cp2 ZrCl2 in THF provides a convenient and genuine equivalent to HZrCp2Cl, which has been employed in hydrozirconation of alkynes-Pd-catalyzed Negishi coupling tandem processes for the synthesis of conjugated dienes, or polyenes. Zr-catalyzed Asymmetric Carboalumniation of Alkenes (ZACA) has emerged as an efficient and useful method for asymmetric synthesis of 2-methyl-1-alkanol, usually of 70–80% ee. Despite the high efficiency and high overall stereoselectivity (≥98% overall ee) for the synthesis of deoxypolypropionate units containing at least two chiral carbon centers, thanks to the chromatography separation of diastereoisomers, ZACA reaction thus far failed to produce those compounds of high stereoselectivity (≥98% ee) that contain only one chiral carbon center or even two chiral ones, which are unable to effectively interact for facile chromatographic separation. But nevertheless, lipase-catalyzed acetylation and ZACA synergy provides a good solution to this problem. Its synthetic power has been eloquently demonstrated through the synthesis of a certain type of natural products, as discussed in Chapter three.

Degree

Ph.D.

Advisors

Negishi, Purdue University.

Subject Area

Organic chemistry

COinS