Alkenes, trisubstituted Julia coupling

The Julia coupling has also been successfully utilized for the synthesis of more complex alkenes. There are limitations to the application of the method to tri- and tetra-substituted alkenes, since the addition of the sulfone anion to a highly substituted ketone forms a -alkoxy sulfone that is difficult to trap and isolate. There is a tendency for highly substituted p-alkoxy sulfones to revert back to the ketone sulfone. There have been several recent examples of the synthesis of trisubstituted ( )-alkenes worthy of note. 

Most recently, the immunosuppressive agent FK-S06 (416) has been the target of total synthesis. To date several approaches to the trisubstituted alkene region at C-19 and C-20 have appeared. These preliminary studies allow the comparison between the Warren phosphine oxide approach and the Julia coupling. In the first total synthesis of FK-S06, Jones and coworkers at Merck formed the the alkene deprotonadon of the phosphine oxide (418) and condensation with the aldehyde (417). The hydroxy-phosphine oxides were formed in a ratio of 1 1 in 77% yield. The less polar diastereomer was treat with base to obtain the ( )-alkene (419) in 32% overall yield from the aldehyde (equation 96). Danishefsky utilized the Julia coupling for the formation of the trisubstituted alkene region. The sulfone anion (420) was treated with isobu raldehyde as a model, followed by acetylation and reductive elimination to... 

In Hanessian s approach to avermectin discussed in Section 3.1.11.4.1, the Julia coupling was used for the trisubstituted alkene and the diene portion of the molecule. The sulfone (439) was deprotonated with Bu"Li and the aldehyde (440) added to it to obtain a 47% yield (77% based on recovered sulfone) of -hydroxy sulfones (equation 103). The alcohol was converted to the chloride and the reductive cleavage carried out with sodium amalgam in 35% yield. The desired diene was the only detectable isomer (441). From the examples cited, it is apparent that the synthesis of ( , )-dienes by the Julia coupling is an extremely successful process, in terms of both yield and selectivity. 

Formation of the vinyl sulfone from the B-hydroxy sulfone followed by displacement with a Grignard reagent or cuprate is an alternative to the Julia coupling sequence for trisubstituted alkenes see ref. 272a. 

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