TUMOR REMISSION--TAXOL AND CLOSE ANALOGS VIA SYNTHESIS

点击翻译按钮获取中文摘要

DESCRIPTION: Taxol and its close structural relatives represent very demanding targets for the implementation of de novo synthetic tactics. This is a consequence of their high structural complexity and abundant stereochemical detail. The routes developed to the present time were designed primarily to demonstrate that taxol can be prepared in the laboratory. None can be categorized as particularly efficient. Seemingly the best way to improve overall synthetic efficiency is to reduce the number of requisite steps and utilize highly efficient processes. The primary goal of the present effort is to develop an abbreviated route to taxol by addressing at least two central rearrangements, which have been demonstrated highly functionalized settings to be capable of meeting the stated needs. The approach is therefore one designed around the tactic of elaborating the entire taxane ring system early by submitting simple 1,2-adducts of D-camphor derivatives to sequential charge-accelerated oxy-Cope and alpha-ketol rearrangements alongside new, specifically tailored reactions. A synthesis of taxusin, which takes advantage of many of these concepts, has been completed. The protocol will rely heavily on the use of D-camphor, an inexpensive, enantiomerically pure commodity isolated from the camphor tree, in order to produce the targeted compounds in their proper absolute configuration. Emphasis is to be placed on brevity; consequently, very reasonable regiocontrol and a minimum of protection/deprotection maneuvers are to be deployed. Flexibility will also be paramount, such that minor changes in methodology will allow for adaptation of the intermediates to arrival at several targeted end-products. The first priority is to arrive at taxol. Once the route to taxol is made evident and is progressing well, real time will be devoted to structural modifications. The ancillary objectives will include the preparation of 1-deoxytaxol and its alpha-oxetanyl isomer where the D ring is fused to the alpha-surface of the framework.