Enantioselective Total Synthesis of the Antimitotic Agent Paecilospirone

Download or read book Enantioselective Total Synthesis of the Antimitotic Agent Paecilospirone written by Tsz Ying Yuen and published by . This book was released on 2011 with total page 245 pages. Available in PDF, EPUB and Kindle. Book excerpt: "This thesis describes the first, enantioselective total synthesis of the marine natural product paecilospirone (1). Paecilospirone is a polyketide derived metabolite isolated from the marine fungus Paecilomyces sp. collected off the coast of Yap Island, Federated States of Micronesia. Structural assignment following anticancer bioassay subsequently revealed a novel spiro[chroman-2,1(3H)- isobenzofuran] core where an -hydroxyl group occupies the unusual axial position of the sixmembered tetrahydropyran ring. An efficient and flexible strategy was developed to provide access to the [5,6]-bisbenzannulated spiroacetal in a convergent manner. Three key fragments, bromide 162, aldehyde 120 and ketone 92, were synthesised using readily available starting materials. In particular, ketone 92 was obtained from the chiral pool, thus allowing the facile incorporation of enantioselectivity into the synthesis. The fragments were successfully coupled together using an aryllithiation addition and a diasteresoselective, anti-boron aldol reaction. Initial attempts at the late stage spiroacetalisation reaction focused on the acid-mediated cyclisation of MOM-protected ketone 112. However, upon spirocyclisation, 113 readily underwent elimination to afford the corresponding dehydrated products. The problem was exacerbated by the axial orientation of the oxygenated group positioned to the spirocentre and anti to a vicinal hydrogen atom, thus a revision in protecting group strategy was enforced whereby access to the spiroacetal core was envisioned using pH neutral conditions. Attention therefore focused on the model study of a dihydroxyketone equivalent (123) in which the alcohol groups were protected as allyl ethers. Accordingly, treatment of 123 with Pd(PPh3)4 in the presence of a range of silane addictives successfully furnished the desired spiroacetal 124, clearly demonstrating the synthetic utility of this method for the preparation of sensitive spiroacetal systems. Subjection of bis-allyl ketone 166 to the established reaction conditions ultimately led to the completion of the total synthesis of paecilospirone 1"--Abstract.