Thirsk, Carl Edward (2003) Stereoselective routes to the total synthesis of the polyene macrolide viridenomycin. Doctoral thesis, Durham University.
Viridenomycin 11 is a polyene macrolide possessing a wealth of biological activity. As part of an ongoing program examining the stereoselective synthesis of polyene natural products, a strategy was explored to effect the total synthesis of viridenomycin 11.As a consequence of the adopted retrosynthetic strategy, the project was naturally divided into three main areas: efforts directed towards the southern (E, E, E, Z)-tetraene 210, towards the northern (E, Z, Z)-triene 209, and towards the core cyclopentenone 211.Both polyenic sections 209 and 210 were tackled with a view to utilizing palladium-coupling methodology developed in the group, whereby vinylboronates of type 122 undergo Heck coupling with alkenyl halides, affording polyenyl boronates that may then be converted into polyenyl iodides via stereoselective iodo-deboronation. The geometry of the new double bond is determined by the order of reagent addition during the iodo-deboronation. Vinylboronates such as 122 may thus be regarded as a vinyl dianion equivalent, permitting ready access to either alkene geometry, and allowing a polyene chain to be built up via an iterative process. Efforts towards 209 gave rise to a surprising reaction, in which it was discovered that iodoacrylates 214 are problematic Heck coupling partners due to a propensity to undergo novel Michael addition-elimination reactions with most amine bases, instead affording amino acrylates in excellent yields.Efforts towards 210 called for the development of new and robust methods for the elaboration of the amino acid phenylglycine, providing gready improved procedures for its conversion to the corresponding N-protected β-amino alcohol, N-protected β-amino-O-sulfonylates, N -protected β -amino iodides and N-protected β-amino nitriles, all valuable synthetic intermediates in their own right. An advanced synthon en route to 210 was prepared by Heck coupling of (Z)-iodide 214 with vinylboronate 272, representing a considerable in-road into the synthesis of this fragment. Markedly different chemistry was required to synthesize 211. Its retrosynthetic strategy called for a stereoselective aldol reaction, and as a consequence of this work it was found that novel oxazaborolidinone mediated Mukaiyama aldol additions between diene 4-(ferr-butoxy)-2,4-bis[(trimethylsilyl)oxy]-l,3-butadienyl methyl ether 335 and a wide range of electrophiles gave aldol products in isolated yields of up to 90%.
|Item Type:||Thesis (Doctoral)|
|Award:||Doctor of Philosophy|
|Copyright:||Copyright of this thesis is held by the author|
|Deposited On:||09 Sep 2011 10:02|