Taxane synthesis

Jayasinghe, L. R. Datta, A. Ali, S. M. Zygmunt, J. Vander Velde, D. G. Georg, G. I. Structure-activity studies of antitumor taxanes synthesis of novel C-13 side chain homologated taxol and taxotere analogs. J. Med. Chem., 1994, 37 2981-2984. 

Jayasinghe LR, Datta A, Ali SM, Zygmunt J, Vander Velde DG, Georg GI (1994) Structure-Activity Studies of Antitumor Taxanes Synthesis of Novel C-13 Side Chain Homologated Taxol and Taxotere Analogs. J Med Chem 37 2981... 

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. ° ... 

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>. 

Entries 10 to 14 show reactions involving acetals. Interestingly, Entry 10 shows much-reduced stereoselectivity compared to the corresponding reaction of the aldehyde (The BF3-catalyzed reaction of the aldehyde is reported to be 24 1 in favor of the anti product ref. 80, p. 91). There are no stereochemical issues in Entries 11 or 12. Entry 13, involving two cyclic reactants, gave a 2 1 mixture of stereoisomers. Entry Mis a step in a synthesis directed toward the taxane group of diterpenes. Four stereoisomeric products were produced, including the Z E isomers at the new enone double bond. 

This reaction can be used in synthesis of medium-sized rings by cleavage of specific bonds. An example of this reaction pattern can be seen in a fragmentation used to construct the ring structure found in the taxane group of diterpenes. 

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. 

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. 

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]. 

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). ... 

Novel polycyclic heterocyclic systems including the isoxazoline ring were described. Thus, oximes 191 and 193 in the presence of sodium hypochlorite afforded heterocycles 192 or 194, respectively (equations 83 and 84). Intramolecular cycloaddition of nitrile oxide was used in the synthesis of the A-ring fragments of la,25-dihydrovitamin D3 and taxane diterpenoids, sulphur-containing isoxazoles, fluoro-substituted aminocyclopentanols and aminocyclopentitols . New gem- and vic-disubstituted effects in such cyclization reactions have been reviewed by Jung. ... 

Nagaoka and co-worker (248) sought to apply an intramolecular cycloaddition for the synthesis of the taxane A/B rings, starting with the nitro derivative 37... 

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). 

---