Taxane skeleton

Formation of a 6-hydroxydihydropyran-3-one by the oxidative rearrangement of a furan followed by its conversion to a pyrylium ylide forms part of a synthesis of the taxane skeleton <96T14081>. 

These authors have also used an iodotrienedione in this process, but this led to the desired taxane skeleton in only 25 % yield. 

Scheme 3.21. Domino radical macro-cyclization/transannular-cyclization procedure for the synthesis of the taxane skeleton.

An impressive combination of two Diels-Alder reactions is also described by Winkler [4] for the synthesis of the taxane skeleton, though two different Lewis acids must be used for the two cycloadditions. Thus, it does not strictly match the definition of a domino reaction. 

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. 

A -tritylaziridine-2-(5)-carboxaldehyde. The application of a novel, sequential, trans-acetalation oxonium ene cyclization has delivered a stereoselective synthesis of the C-aromatic taxane skeleton, and a combinatorial sequence of the regioselective propiolate-ene, catalytic enantioselective epoxidation and carbonyl-ene cyclization reactions has been used to complete the synthesis of the A-ring of a vitamin D hybrid analogue. 

Medium sized carbocycle synthesis Ring contracting [1,2]-Wittig rearrangement Yadav and Ravishankar have demonstrated that the Wittig rearrangement of the cyclic substrate 32 is useful for the construction of the taxane skeleton 33, albeit in low yield (equation 17). ... 

The [6+4] cycloaddition reaction was applied to the construction of a taxane skeleton [76], Adduct 314 was obtained by the reaction of complex 312 with diene... 

Lange, G.L., Decicco, C.P., Willson, J., and Strickland, L.A. (1989) Ring expansions of [2 + 2] photoadducts. Potential applications in the synthesis of triquinane and taxane skeletons. Journal of Organic Chemistry, 54, 1805—1810. 

Somewhat better yields are obtained in the construction of the taxane skeleton 120 from 119.87... 

Since the first review by Lythgoe (7), which appeared in this treatise in 1968, the subject of taxane-type molecules has developed predominantly around taxol (1), discovered in 1971 by Wani et al. (2). This is clearly borne out by the 1985 review by Suffness and Cordell (i), also in The Alkaloids, wherein the chemistry and pharmacology of taxol are the principal subjects. Since then, the major part of the work concerned with this family of substances has centered almost exclusively on (1) hemisyntheses based on the taxol molecule and on deacetylbac-catin III (2) total synthesis of the taxane skeleton as well as certain polyfunctional derivatives, and (3) development of the pharmacology of taxol and its derivatives. 

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). 

Besides the investigations treated so far concerning the synthesis of the taxane skeleton, some groups have also reported on the synthesis of particular building blocks. Synthesis of the taxol side chain 30 (57) has already been introduced in Section V,B. A Swedish group presented an enantiospecific synthesis of a functionalized ring A derivative 105,106). Starting from L-arabinose, 136 (Scheme 33) was made in 20 steps and could be transformed by three further steps into 137. 

Despite the existence of a large number of taxol derivatives, only taxol itself has given rise at present to significant pharmacological and biological studies. However, some work employing the mixture taxol—cephalomannine 115) (more easily extracted from the bark of T. baccata than taxol itself) as well as derivatives having a xylose residue attached to the taxane skeleton may be cited 116). 

An oxetane ring in a taxane skeleton was successfully opened with TiC, despite the presence of many functional groups in the same molecule (Eq. 288) [649]. 

The (2R,3S)-phenylisoserine side-chain at position 13 of the taxane skeleton in the anti-cancer drug taxol (from the yew tree) is essential to its action. 

Additions to Cyclohexenones. Intramolecular additions in cyclohexene systems also provide access to natural products. Thus the photocyclization of enone (27) affords the adduct (28) which is suggested as a route to the nortaxane or taxane skeleton. Intramolecular reaction of the enone (29) affords two products (30, 70%) and (31, 14%). The identity of the major products was determined by X-ray crystallography and is the result of hemiacetalisation of the original (2-f-2)-adduct (32). The minor product (31) is formed from the major by a yie TTo-Aldol reaction. ... 

Several approaches to the taxane skeleton (97) have been published recently (see also reference 9). All have involved (2+2)- cycloaddition of the type reported by Berkowitz et ai. who have added cyclopentene and cyclohexene to the enone (98) to yield the cycloadducts (99). Successful addition of the alkene (lOO) to the same enone yields the ring-opened adduct (101). In a similar fashion the intramolecular addition of the enone (102) affords a (2+2)-adduct which can be treated with base to provide a route to the skeleton of the same natural product. ... 

The Taxane Diterpenes.— The taxane skeleton represents an alternative mode of cyclisation of the macrocyclic diterpene hydrocarbon. Seven new taxane derivatives have been isolatedfrom Taxus baccata and characterised on the basis of spectroscopic and other data. Their structures are summarised in the following formulae (136a—g). In addition, the structure of baccatin-III (137), one of a group of complex esters isolated from the same source, has been com-pleted. The application of the olefin Octant rule to the taxane A double bond leads to the absolute configuration of these diterpenes. 

Several approaches to the synthesis of taxol and the taxane skeleton have employed Shapiro reactions.25 An interesting route to the taxol A-ring that illustrates the utility of dianion functionalization prior to alkene generation was recently described by Koskinen.256 As shown below, treatment of tosylhydrazone 48 with 2.2 equiv of n-BuLi... 

The Nef reaction has also been used in the construction of the 7-deoxy-ABC ring taxane skeleton. As shown below, conjugate reduction of nitroalkene 41 with NaBFU followed by oxidation of the resulting nitronate salt with K2CO3/H2O2 provided tetracycle 42 in 60% yield.24 These reaction conditions are sufficiently mild to tolerate the presence of ketone and silyl ether functional groups in the molecule. 

The naturally occurring diterpenoids with the taxane skeleton are the typical constituents of 7ax s. The constituents of the yew became the active subject of phytochemical and synthetic work since the discovery of terpenes belonging to the taxane group (8-10). 

A number of taxoids isolated from different Taxus species, on structural reinvestigation were found to contain a rearranged nortaxoid skeleton or 11(15—>V)-abeo taxoids, as they are more correctly described (133,160,161) and not a taxane skeleton as originally proposed. Brevifoliol (181) was the first natural taxoid with 11(15—>l)-afoeotaxane skeleton which was initially assigned a normal taxane skeleton (162) but was later corrected to the... 

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