Synthesis Julia reaction

Nucleophilic additions to carbonyl groups lead to alcohols which on dehydration, furnish alkenes70,71. This two-step protocol has been extremely useful for diene and polyene synthesis with wide variation in the carbonyl substrate and the nucleophilic addendum. Diene synthesis using aldol-type condensation as well as phenyl sulphonyl carbanion (the Julia reaction) are also discussed in this section. 

The olefination based upon the reaction of benzothiazolyl- and phenyltetra-zolyl sulfones with carbonyl compounds is widely used in the target-oriented synthesis. In order to illustrate the reaction scope, yields and stereoselectivities, in this section we present selected examples of these reactions. The examples include reactions of saturated sulfones with saturated aldehydes, saturated sulfones with o, j6-unsaturated carbonyl compounds, -unsaturated sulfones with saturated aldehydes, and /l,y-imsaturated sulfones with a, -unsaturated aldehydes. The emphasis is given to recent work. A complete account of earlier applications of the modified Julia reaction has been given in the Blakemore review [98]. 

In a study on vitamin D2 synthesis [ 124], a sterically very hindered sulfone 273 (Scheme 90) with the axially oriented sulfonyl group was transformed into an anion (NaHMDS) and subjected to reaction with diene-aldehyde 274 used in excess. After deprotection, vitamin D2 275 and its unstable C7-C8 Z-isomer 276, were obtained in 70% yield, ratio of 72/28, respectively. Some BT-sulfone 277 generated by epimerization of 273 was also isolated. An attempt to carry out the reaction with the reverse allotment of the fimctional groups (sulfone 278 with ketone 279) failed. With regard to the isomer ratio 275 and 276, it is of interest that the classical Julia reaction of phenylsuhbne corresponding to 277 and aldehyde 274 occurs with somewhat lower selectivity towards the -isomer [125]. 

Among the different methods for the synthesis of alkenes, none matches the versatility of carbonyl olefination.290 It has been extensively studied since the discovery of the Wittig reaction,291292 and a wide variety of approaches to transform carbonyl compounds into alkenes have been developed. Besides the classical Julia reaction,94 the most generally applicable methods for direct olefination of carbonyl compounds include the Wittig,291,293,294 Homer-Wittig,295,293,296 Homer-Wadsworth-Emmons,297,298,293 Peterson,299 301 Johnson,302 and Julia-Kocienski303,304 reactions. All of these methods involve the addition of a... 

The critical three double bonds present in the anthelmintic ivermectin were introduced via the Wadsworth-Emmons or Julia reactions. The Mukaiyama procedure was used to construct 16-membered lactones. These analogs differ from ivermectin in lacking the diol system at C5 and C7, the alkyl substituents at C24 and C25, the oxymethylene fragment at Cs, and by replacement of the disaccharide at C13. A variation of this procedure was also successful in the synthesis of analogs of the miticidal milbemycin D. The biological activity of the synthetic analogs was inferior when compared to that of the naturally occurring compounds. 

The last group of reactions uses ring opening of carbonyl or 1-hydroxyalkyl substituted cyclopropanes, which operate as a -synthons. d -Synthons, e.g. hydroxide or halides, yield 1,4-disubstituted products (E. Wenkert, 1970 A). (1-Hydroxyalkyl)- and (1-haloalkyl)-cyclopropanes are rearranged to homoallylic halides, e.g. in Julia s method of terpene synthesis (M. Julia, 1961, 1974 S.F. Brady, I968 J.P. McCormick, 1975). 

Another category Ic indole synthesis involves cyclization of a-anilino aldehydes or ketones under the influence of protonic or Lewis acids. This corresponds to retro.synthetic path d in Scheme 4.1. Considerable work on such reactions was done in the early 1960s by Julia and co-workers. The most successful examples involved alkylation of anilines with y-haloacetoacetic esters or amides. For example, heating IV-substituted anilines with ethyl 4-bromoacetoacetate followed by cyclization w ith ZnClj gave indole-3-acetate esterfi]. Additional examples are given in Table 4.3. 

The reaction of the phenylsulphinyl allylic lithium a-carbanion 342 with oxiranes was found by Guittet and Julia to give, after rearrangement and desulphurization, dihydroxy-dienes 343427 (equation 197). Demoute and coworkers have described the alkylation reaction of a very sophisticated 2-alkenyl sulphoxide 344 as a part of the total synthesis of a juvenile hormone 345428 (equation 198). Since the allylic sulphoxide carbanion has an ambident character, the alkylation may occur sometimes also at the y-position. This direction of alkylation is observed in the case of acyclic allylic sulphoxide anions 346, and results in the formation of the corresponding allylic sulphoxide 347 and vinylic sulphoxide 348423 (equation 199). 

Julia and coworkers have utilized the sulphenylation reaction in the synthesis of / , y-unsaturated dithiocarboxylates 494, via the reaction sequence shown in equation 298557. 

Julia and Paris120 described an olefin synthesis, based on the use of a sulphonyl group which directs the formation of a carbon-carbon bond. Subsequent reductive elimination with sodium amalgam leads to the alkene, as outlined in equation (50). The reaction sequence is similar in principle to an olefin synthesis first developed by Cornforth121. The yields of all steps are generally above 80%. 

A second paper161 describes the use of the same base in either THF or t-butanol for the elimination of a-acetoxy phenyl sulphones as outlined in equation (68), in essence a reaction sequence very similar to the Julia olefin synthesis (Section III.B.3) except in the method by which the sulphonyl group is finally removed. 

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