Taxane ring system

The answer is c. (Hardman, pp 1260—1262.) Paclitaxel is a large structural molecule that contains a 15 membered taxane ring system. This anti cancer agent is an alkaloid derived from the bark of the Pacific yew tree. Its chemotherapeutic action is related to the microtubules in the cell. Paclitaxel promotes microtubule assembly from dimers and causes microtubule stabilization by preventing depolymerization. As a consequence of these actions, the microtubules form disorganized bundles, which decreases... 

Previous work by Holton [15] on the synthesis of taxane ring systems, indicated that the preparation of the bicyclo[5.3.1]undecane skeleton lies basically on the work of Biichi on patchouli alcohol [16], which led him to the development of the so-called "epoxy alcohol fragmentation" [15a]. 

Aldol condensation. The final step in a synthesis of the tricyclic taxane ring system involves an intramolecular aldol condensation of 2. Treatment with the usual bases results in a retro Michael reaction, but the desired cyclization to 3 can be effected in 90% yield by use of bromomagnesium diisopropylamide (1) or isopropylcyclohexylamide. The hydroxy ketone undergoes retroaldolization in the presence of mild acids or bases, but can be reduced and stored as the corresponding stable diol. 

Scheme 15-4 Formation of the taxane ring system by tandem macrocyclisation-transannulation.

The medicinal chemistry of taxol indicates that there are three points for esterification on the parent taxane ring system. Both taxol and its active analog taxotere have positions 3 and 10 so occupied. The 7 OH can also be so derivatized to afford active compounds. However, an unesterified C-3 hydroxyl results in an inactive compound. Water-soluble derivatives of C-7 and C-2 have been synthsized as potential pro-drugs to circumvent the extremely poor solubility of the drug. 

Radical macrocyclization to taxane ring system. Treatment of the iodotrienone 1 with Bu.iSnH/AlBN provides two epimers (2 and 3) of the taxane ring system. The ring system 2 corresponds to that present in taxol, the natural alkaloid found in the bark of yew trees. 

Scheme 8. Diyl trapping toward taxane ring systems...

Chemically, diterpenoid taxanes consist of a 15-membered tricyclic taxane ring system... 

The C-7 hydroxyl group is in many ways the most accessible functional group on the taxane ring system, and is second in reactivity only to the C-2 hydroxyl group in the side chain. For this reason its chemistry has been studied fairly extensively, and many simple derivatives have been prepared. Thus the acetyl derivative 4.1.1.1 (140,141), benzoyl derivative 4.1.1.2 (142), glutaiyl derivative 4.1.1.3 (143), amino acid derivatives 4.1.1.4-4.1.1.6 (144), chloroacetyl derivative 4.1.1.7 (145), and a docosahexaenoic acid derivative 4.1.1.8 (146) have all been prepared and found to have comparable activity to taxol. 

The Holton synthesis of the structurally-analogous taxane ring system involves acid-catalyzed rearrangement upon epoxide opening of P-... 

INOC has been used for the synthesis of tncylic compounds havmg the taxane A/B ring system with an aromatic C nrg fEq. 8.68. ° ... 

Other applications of the [6 + 2]- and [6 + 4]-cycloaddition reactions in total synthesis have been reviewed.127 The two representative examples shown in Scheme 38 illustrate their use in the total synthesis of /3-cedrene and the taxane ABC ring system. The total synthesis of /3-cedrene utilized an intramolecular [6 + 2]-reaction128 to set up a tricyclic intermediate and the synthesis of the taxane ABC ring system is accomplished via a [6+ 4]-cycloaddition. 

Kuwajima s Synthesis of ( )-Taxusin. Two key transformations are involved in Kuwajima s synthesis30 (1) construction of the tricyclic taxane skeleton via cyclization of the eight-membered B ring between C-9 and C-10 and (2) subsequent installation of the C-19 methyl group onto the ring system. 

Cycloadditions of bisdienes. This reaction, catalyzed efficiently by Ni(COD)2-P(C6Hs)3 (usually 1 2), provides a useful route to the eight-membered ring system found in taxane diterpenes. 

In later work, Mioskowski and co-workers (320) used cyclohexenone 160 to prepare oxime 161 as part of a twofold nitrile oxide strategy to synthesize the basic taxol ring system. Cycloaddition of 161 was effected by means of sodium hypochlorite and gave tricyclic isoxazoline 162, which feamres rings A and C of taxol (320) (Scheme 6.79). Nagaoka and co-worker tried to apply a related intramolecular cycloaddition toward the synthesis of the taxane A/B ring but this approach failed, producing only the oxime derivative (248) (see Scheme 6.44, Section 6.3.1). 

Taxane-type substances possess a totally original skeleton which may be described as a diterpene composed of three [9.3.1.0 ] pentadecene rings (2). The nomenclature first proposed for this ring system was modified in 1969 (4,5), the accepted numbering of the carbon atoms now being that shown in Fig. 1. 

The desired cyclization leading to the six-membered ring was achieved by intramolecular photocycloaddition of dioxolenone 107 as shown in Scheme 26. Consecutive cleavage of the ketal followed by retroaldol reaction augmented the initial ring system by a C2 unit to trans-bicycle 108 (90). Attempts to apply this reaction principle to a trans-decalin system in order to reach a taxane skeleton failed (97). 

The nickel-catalyzed intramolecular [4 -I- 4] cycloaddition strategy has been successfully applied to the construction of both the ab and bc ring systems of the taxane diterpenes. These studies additionally served to establish the viability of this chemistry for the construction of angularly alkyl-substituted bicy-clo[6.4.0]dodecanes. In an example typical of this class of transformatiais (Scheme 16), cyclooctadiene (125) was produced with greater than 97% diastereoselectivity and in 92% chemical yield when tetraene... 

The taxane family of diteipenes with a unique tricyclic ring system has attracted interest in both the biological and chemical communities. Particularly, taxol (82) exhibits singular biological activity through its ability to promote microtubule assembly. It is a most promising antitumor agent, now in phase II clinical trials, obtained from the baik of the pacific yew tree. 

Holton s plan for the synthesis of the ab ring system of taxanes e.g. 83) involves fragmentation of an easily accessible tricyclic compound derived from patchouli alcohol. Hydroxy-directed epoxidation of the tertiary alcohol (84) (from patchino 90) gives an unstable substance which undergoes gmentation in situ to provide the keto alcohol (85 Scheme 29). 

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