Paclitaxel 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 paclitaxel can be prepared in the laboratory and cannot be categorized as particularly efficient. The primary goal of the present effort is to develop a more abbreviated route to paclitaxel by addressing at least two central rearrangements, which we have demonstrated in 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 some of these concepts, has already been completed. Our protocol will rely on D-camphor, an inexpensive enantiomerically pure commodity chemical, to produce the targeted compounds in their proper absolute configuration. Emphasis is to be placed on brevity; consequently, very reasonable regiocontrol and the minimum number of protection/deprotection maneuvers are to be developed. Flexibility shall also be paramount, such that minor changes in methodology will allow for the adaptation of our intermediates to arrival at several targeted end-products. Our first priority is to arrive at paclitaxel. As the most expeditious route is being made evident, real time will be concurrently devoted to preparing important congeners not available by degradation of the natural product. These include, but are not limited to, the 1-deoxy, D-homo-, 2-desmethyl, and 12-methylene derivatives, in addition to the D-ring invertomer and the C-nor isomer.
| Paquette, Leo A; Lo, Ho Yin; Hofferberth, John E et al. (2003) A delicate balance of energetics. Subtleties associated with alpha-ketol-based bridge migration to afford 9-keto-10beta-p-methoxybenzyloxytaxanes. J Org Chem 68:2276-81 |
| Paquette, Leo A; Lo, Ho Yin (2003) Chemical modification of a highly functionalized taxane. The consequences of an absent bridgehead double bond on oxetane D-ring construction. J Org Chem 68:2282-9 |
| Paquette, Leo A; Hofferberth, John E (2003) Effect of 9,10-cyclic acetal stereochemistry on feasible operation of the alpha-ketol rearrangement in highly functionalized paclitaxel (Taxol) precursors. J Org Chem 68:2266-75 |
| Hofferberth, J E; Lo, H Y; Paquette, L A (2001) Stereospecific anionically promoted transannular hydride shifts in medium-ring hydroxy ketones. Probe of their reversibility and the potential for regiocontrol. Org Lett 3:1777-80 |
