One can view plants as a reference library of compounds waiting to be searched by a chemist who is looking for a particular property. Taxol, a complex polyoxygenated diterpene isolated from the Pacific Yew, Taxus brevifolia, was discovered during extensive screening of plant materials for antineoplastic agents during the late 1960s. Over the last two decades, interest in and research related to taxol has slowly grown to the point that the popular press now seems poised to scoop each new development. What was once an obscure compound, of interest only to the most masochistic of synthetic chemists and an equally small number of cellular biologists, has become one of the few organic compounds, which, like benzene and aspirin, is recognizable by name to the average citizen. In parallel, the scientific study of taxol has blossomed. Physicians are currently studying its effects on nearly every known neoplasm. Biologists are using taxol to study the mechanisms of cell function by observing the effects of its interactions with the cellular skeletal systems. Synthetic chemists, absorbed by the molecule's unique and sensitive structure and functionality, are exploring seemingly every available pathway for its synthesis. Indeed, the demand for taxol has risen so in the last five years that alternative sources to the extraction of T. brevifolia are being vigorously pursued. Because of the rapidly expanding scope of research in the multifaceted study of taxol, those who are interested in the field may find acquisition of a reasonable base of knowledge an arduous task. For this reason, this account attempts to bring together, for the first time, in a cogent overview the chemistry and biology of this unique molecule.

Chemistry and Biology of Taxol

The synthesis of carbocyclic eight-membered rings

Progress in the construction of cyclooctanoid systems: new approaches and applications to natural product syntheses.

Die Pflanzen konnten als Quelle von Verbindungen betrachtet werden, aus denen sich der Chemiker solche mit besonderen Eigenschaften heraussuchen kann. Taxol, ein komplexes, polyoxygeniertes Diterpen aus der Pazifischen Eibe, Taxus brevifolia, wurde in den spaten sechziger Jahren bei einer umfassenden Untersuchung pflanzlicher Stoffe auf antineoplastische Wirkstoffe entdeckt. In den vergangenen zwei Jahrzehnten sind das Interesse an Taxol und die damit verbundenen Forschungsarbeiten langsam an dem Punkt angelangt, an dem es scheint, das die Medien aufmerksam geworden sind und jede neue Entwicklung gespannt erwarten. Das, was einstmals eine weitgehend unbekannte Verbindung war, an der nur die masochistischsten unter den Synthesechemikern und eine ebenso kleine Zahl von Zellbiologen Interesse zeigten, ist heute eine der wenigen organischen Substanzen, die — wie etwa Benzol oder Aspirin — auch dem Durchschnittsburger, dem Namen nach bekannt sind. Die wissenschaftlichen Untersuchungen von Taxol haben sich in dieser Zeit enorm ausgeweitet: Arzte erforschen zur Zeit seine Wirkung auf nahezu jedes bekannte Neoplasma; Biologen untersuchen die Wechselwirkungen zwischen Taxol und Zellskelettsystemen, um auf diese Weise die Mechanismen zu ergrunden, nach denen Zellen funktionieren; Synthesechemiker, die von der einzigartigen und empfindlichen Struktur sowie von der Funktionalitat des Taxols gefesselt sind, arbeiten intensiv daran, einen synthetischen Zugang zu ihm zu finden. Die Nachfrage nach Taxol ist in der Tat in den letzten funf Jahren so stark gestiegen, das intensiv nach Quellen alternativ zur Extraktion von T. brevifolia gesucht wird. Da bei den vielfaltigen Arbeiten uber Taxol der Wissensumfang schnell zunimmt, mag es fur den in diesem Gebiet Interessierten schwierig sein, sich ein angemessenes Grundwissen anzueignen. Wir wollen in diesem Beitrag daher erstmalig versuchen, einen Uberblick sowohl uber die Chemie als auch uber die Biochemie dieser einzigartigen Verbindung zu geben.

Chemie und Biologie von Taxol

Recent applications of anionic oxy-cope rearrangements

The phenomenon of atropisomerism is critically examined in the tricyclic E, syn, up enolates derived from anionic oxy-Cope rearrangement of 1-vinyl-2-cyclohexenyl-7,7-dimethyl-exo-norbornan-2-ols, as well as the ketones derived from their protonation and methylation. In all cases studied, the [3,3] sigmatropic shift proceeds with 100% stereoselectivity via the endo-chair transition-state option. The E and syn stereochemistry is established during chirality transfer at this stage. The «oxygen-up» conformation stems directly from the structural features inherent in the starting alcohols. In the unsubstituted example and with certain substitution pattrerns in the original cyclohexene ring, the E, syn, up enolates are seen to be thermodynamically unstable relative to their E, syn, down atropisomers, such that products results exclusively by electrophilic capture of the latter. By suitable substitution, the barrier to this preequilibrium can be sufficiently heightened so that products resulting from the E, syn, up species can be obtained

Impact of substituent modifications on the atropselectivity characteristics of an anionic oxy-Cope ring expansion

The feasibility of the titled reactions for the rapid, enantioselective synthesis of cis-tricyclo[9.3.1.03,8]pentadecane precursors to taxusin and taxol has been examined. The catalysts most well suited to inducing the appropriate 1,2-shifts have been identified. To a great extent, the rearrangement products are formed as a direct consequence of appropriate structural features (kinetic phenomenon) and strain minimization (thermodynamic driving force). Complementary MM2 calculations of the global minimum in each series provided indications that were completely in line with the experimental observations. Sophisticated NMR studies and X-ray crystallographic determinations were coordinated to remove any ambiguity of product structure and solid-state conformation.

An Enantioselective Approach to the Taxanes: Direct access to functionalized cis‐tricyclo[9.3.1.03,8]pentadecanes via α‐hydroxy ketone and Wagner‐Meerwein rearrangements

The key elements associated with the synthetic elaboration of functionalized trans-tricyclo-[9.3.1.03,8]pentadecanes carrying either a bridgehead H or OH substituent are detailed. Starting with 12, a ketone available in two steps from (R)-2-oxo-7,7-dimethyl-l-vinylbicyclo[2.2.1]heptane, it proved possible to introduce trans-B/C ring juncture configuration as in 16 in five steps. This advanced intermediate constitutes the point of bifurcation. The pathway to taxusin precursor 23 was attained by stereospecific osmylation, reduction, and pinacol-like 1,2-Wagner-Meerwein rearrangement within acetoxy mesylate 22c. Still more abbreviated is the route to 32, which again takes advantage of the osmylation step but proceeds, forward without reduction of the rear carbonyl group. Once hydroxy diketone 31 is produced, equilibration in the presence of (t-BuO)3Al results in complete conversion to 32. The many stereoselective transformations developed in the course of this study, in combination with the several thermodynamic questions that have been clarified, are expected to be highly serviceable as more advanced thrusts toward taxusin and taxol are mounted.

Setting the Bridgehead Oxidation Level in trans‐Tricyclo[9.3.1.03,8]pentadecanes as a Prelude to the Dual Synthesis of Taxol and Taxusin

Stereocontrolled Oxygenation of Camphor Derivatives as a Prelude to the Complete .beta.-Ring Functionalization of Potential Precursors to Taxol and Structural Analogs Thereof

Steven W. Elmore

Papers

Impact of substituent modifications on the atropselectivity characteristics of an anionic oxy-Cope ring expansion

An Enantioselective Approach to the Taxanes: Direct access to functionalized cis‐tricyclo[9.3.1.03,8]pentadecanes via α‐hydroxy ketone and Wagner‐Meerwein rearrangements

Setting the Bridgehead Oxidation Level in trans‐Tricyclo[9.3.1.03,8]pentadecanes as a Prelude to the Dual Synthesis of Taxol and Taxusin

Stereocontrolled Oxygenation of Camphor Derivatives as a Prelude to the Complete .beta.-Ring Functionalization of Potential Precursors to Taxol and Structural Analogs Thereof

A convenient means for controlling the oxidation level of bridgehead carbon C-1 in functionalized tricyclo[9.3.1.03,8]pentadecanes