STRUCTURE AND SYNTHETIC CHALLENGES

Key features of the structure of Taxol (Figure 1) that require careful consideration by the synthetic chemist attempting a total synthesis are, the sterically congested double bond containing 'A' ring, the central eight membered 'B' ring and the oxetane 'D' ring. The high degree of oxygenation present in a range of oxidation states, coupled with the 9 asymmetric centres means that Taxol presents an interesting challenge to synthetic chemists.

Additional problems arise from the lability of the oxetane 'D' ring which has been shown to open under acidic or nucleophilic conditions. This raises the question of whether to have the oxetane present initially or to treat it as a functional group to be introduced at a later stage. If left unprotected the C7 hydroxyl can epimerise through a retro-aldol process involving the C9 carboxyl and for this reason many synthetic approaches introduce the oxygenation at C9 at a late stage. The central 'B' ring represents a challenge as the formation of an eight membered ring is disfavoured both by enthalpic and entropic factors and the geminal dimethyl functionality at C15 only serves to exacerbate this problem.

Two main strategies for the synthesis of the 'B' ring have emerged, namely cyclisation of an acyclic precursor, or ring expansion of the bicyclic derivative. One feature common to many syntheses is the late stage introduction of the C13 oxygenation via an allylic oxidation process.

Despite all the potential pitfalls the challenge of total synthesis has been met, with the publication of four total syntheses to date, along with numerous other elegant approaches to the molecule.

SUMMARY OF THE TOTAL SYNTHESES TO DATE

Four total syntheses have been completed to date, with K.C. Nicolaou and R.A. Holton publishing virtually concurrently in early 1994. The next synthesis to be published was that of S.J Danishefsky in 1995, and finally P.A Wender published in 1997. Throughout the following section the molecules have been numbered using the scheme used for the parent Taxol .

Nicolaou's synthesis

Holton's synthesis

Danishefsky's synthesis

Wender's synthesis

In the four total syntheses to date two clearly different strategies have been demonstrated. Thus, Nicolaou and Danishefsky both utilised a convergent approach to form the 'B' ring by an intramolecular cyclisation whereas both Holton and Wender used linear routes, with the central 'ABC' ring system being formed by the fragmentation of the highly strained bicyclic systems. A common feature of all the syntheses is the use of a C1, C2 cyclic carbonate to introduce the hydroxybenzoate functionality. In the two convergent syntheses the carbonate also has the added advantage of preorganising the structure for cyclisation.

Of the two convergent syntheses Danishefsky's has many advantages; the oxetane 'D' ring is carried throughout the synthesis and the readily available starting material is enantiomerically pure, therefore there is no need for the late stage resolution. Also of note is the relatively high (49%) yield for the formation of the 'B' ring. In Nicolaou's synthesis the formation of the 'B' ring whilst impressive is also the lowest yielding (23%) step in the sequence. The main disadvantage in Danishefsky's approach is the arduous manipulation needed to cleave the C10, C10' methylene, lowering the efficiency of the overall process.

As stated earlier the two linear approaches rely on the relief of strain in fused bicyclic systems to generate the 'B' ring. Once the 'AB' ring system is in place, Holton's strategy for adding the 'C' ring is far more efficient than that of Wender.

TAXOL ANALOGUES

The best known analogue to date is Taxotere (Figure 2), N-debenzoyl-N-tert-butoxycarbonly-10-decetyl Taxol, which was first synthesised by Portier et al. and has also been been approved for clinical trials.

The structure of taxotere differs from taxol due to:-

• A tert-butoxycarbonyl group instead of benzoyl group on the taxol side chain.
• A hydroxyl group instead of the acetoyl group on the taxol B ring.

Taxotere is currently undergoing clinical trials. Patients experience side effects such as hair loss, mouth sores, and low white blood cell counts. Taxotere® is being developed by Rhone-Poulenc Rorer, inside sources have revealed that industrial-scale production of Taxotere has already begun.

The main advantages of Taxotere over Taxol are as follows:-

• Taxotere is easier to administer to patients due to it's better solubility in water.
• Taxotere is more potent anticancer agent than Taxol against a variety of tumours. A recent Phase II study reported the highest ever antitumour activity in patients with breast cancer.

http://www.ch.ic.ac.uk/local/projects/farmer/

C.A.L LANE : Synthesis studies towards Taxol (Thesis, Imperial College 1997)

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