Alkenations Julia coupling

A study carried out by Kocienski and Lythgoe flrst demonstrated the trans selectivity of the Julia coupling process. The authors found the i uctive elimination could best be carried out with the acet-oxy or benzoyloxy sulfones. If the lithio sulfone derivative is used for addition to the carbonyl, the reaction can be worked up with acetic anhydride or benzoyl chloride to obtain the alkene precursor. In cases where enolization of the carbonyl is a complication, the magnesium derivative can frequently be used successfully. A modification of the reductive elimination was found to be most effective. Methanol, ethyl acetate/methanol or THF/methanol were the solvents of choice and a temperature of -20 C was effective at suppressing the undesired elimination of the acetoxy group to produce the vinyl sulfone. With these modifications of the original procedure, the ability of the reaction to produce dienes as well as rran.r-disubstituted alkenes was demonstrated, llie diastereoisomeric erythro- and threo-acetoxy sulfones could be separated and it was demonstrated that both isomers were converted to the rrans-alkene. It... 

The ( )-disubstituted alkene has been extensively studied with several applications of the Julia coupling attempted. The first synthesis of the natural product was accomplish by Kozikowski. In tltis t roach, the aldehyde (386) was reacted with 2 equiv. of the Wittig reagent (387) to produce (388), with an ( ) (Z) ratio of 40 (equation 89 no yield given). This first synthesis establishes the baseline... 

Keck attempted to apply the Julia coupling to the synthesis of pseudomonic acid Despite the success of the sulfone (393) in reactions with simple aldehydes, only modest yields of the desired coupling were observed. This problem was solved by reversing the aldehyde (395) and sulfone components (394), as shown in Scheme 55. The anion was formed with LDA in THF and condensed with the aldehyde. The P-hydroxysulfone was converted to the mesylate, and the reduction and simultaneous deprotection of the benzylglycoside was carried out with lithium and ammonia to produce the ( )-alkene (396), in 37% overall yield with excellent selectivity. 

Williams carried out a Julia coupling similar to the Keck example. With the removal of the acetal functionality, the coupling step of the Julia reaction was efficient, but the usual reductive elimination procedure failed. As an alternative to the acetylation and reductive elimination procedure, the P-sulfo-nyl xanthate was formed by quenching the addition reaction with carbon disulfide and methyl iodide. Reductive elimination was then carried out with tri-n-butyltin hydride to yield the desired ( )-alkene (399) in an 85 15 ratio with the (Z)-alkene in 83% overall yield (equation 91). 

These four examples of the successful application of the Julia coupling in natural product synthesis indicate the sensitivity of various substrates to the anionic conditions. The solutions, interchanging the aldehyde and sulfone portions, modification of the substrate or altering the reductive elimination conditions, are all techniques that can enable the successful use of the Julia coupling for ( )-alkene synthesis. 

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. 

Table 18 Julia Coupling to Produce ( j-Disubstituted Alkenes ...

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 a more direct comparison of the phosphine oxide elimination with the sulfone, Schreiber employed a identical system to Danishefsky, but used the phosphine oxide (422). Reaction with isobutyralde-hyde and subsequent elimination resulted in a 1 1 mixture of the ( )- and (Z)-alkenes (421 equation 98). It appears from the more complex example of the Merck synthesis and from this example, that the Julia coupling proceeds with higher ( )-selectivity, in similar yield. 

The diene pcntions of avermectin and milbemycin have been synthesized by application of the Julia coupling. For the total synthesis of milbemycin 3s by Baker and coworkers, the aromatic ring was incorporated as the aldehyde (431) and the spiroketal portion added as the sulfone (430 equation 100). The overall yield was 70-80% of the ( , )-alkene (432), exclusively. The identical bond disconnection was studied by Kocienski, but with the aldehyde (433) and sulfone (434) components reversed (equation 101). The anion was formed with LDA and, following functionalization and reductive elimination, the alkene was isolated in 39% yield in a 5 1 ratio of the ( )- and (Z)-isomers (435). 

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. 

In a study by Wicha directed to the synthesis of prostaglandins from the Corey lactone, the use of BFs-EtaO to catalyze the addition of the lithium sulfone anion (470) to aldehydes was demonstrated (equation 109). The use of Lewis acid catalysis results in significantly improved yields for the addition component of the Julia coupling. In this example, the addition of either the lithium or the magnesium sulfone anion proceeded in low yield. With the addition of BF3-Et20, the p-hydroxy sulfone can either be isolated, or directly converted to an alkene in one pot. This sequence was originally developed to deal with the specific problem of a-hydroxy aldehydes, and the difficulty of sulfone anion addition to these adducts. Other problems with addition of the sulfone adduct may be amenable to this solution as well. 

A second application of the use of Lewis acid catalysis in the Julia coupling can be found in the synthesis of trans-Biiktnt isosteres of dipeptides (478 Scheme 62). Initially, attempts to couple aldehydes derived from amino acids (473) resulted in poor overall yield of the alkene. This difficulty was solved by reversing the substituents, and introducing the amino acid portion as the anion of sulfone (476) to the chiral aldehyde (477). The dianion of the sulfone was formed and to it were added 2 equiv. of aldehyde and 1 equiv. of diisobutylaluminum methoxide. The resulting p-hydroxy sulfone was t en on to the reductive elimination step to produce the desired ( )-alkene (478), in 74% overall yield. 

See ref. 272a for an excellent discussion of all aspects of the Julia coupling, as well as additional examples of ( )-di- and -tri-substituted alkenes, and ( , )-dienes. 

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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