Julia indole synthesis

Other examples of sigmatropic rearrangements leading to indoles are presented in the next chapter, or more appropriately elsewhere in this monograph. 

Indole Ring Synthesis From Natural Products to Drug Discovery, First Edition. Gordon W. Gribble. 2016 John Wiley Sons, Ltd. Published 2016 by John Wiley Sons, Ltd. 

Nucleophilic cyclization is a common tactic in all branches of organic chemistry, and several indole ring syntheses, which are presented in Chapters 8 through 22, employ this reaction as the central theme in the synthesis. The Sugasawa indole synthesis (Chapter 22) uses both nucleophilic and electrophilic reactions. 

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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. 

Julia s synthesis of lysergic acid 2 jj based on internal nucleophilic trapping of a benzyne intermediate in the ring C-seco intermediate (A). As in an earlier approach, the synthesis proceeds via indoline derivatives and formation of the indole nucleus is deferred until the very end. ... 

Spirotryprostatin A 142 and B 143 are two powerfully bioactive indole alkaloids. Both compounds inhibit the cell cycle in the G2/M phase, and 143 shows cytotoxic activity on the growth of human leukemia cell lines. Meyers and Carreira reported a total synthesis of 143. The Kocienski modified Julia olefmation was used in the formation of trisubstituted olefin without scrambling at Ci8. The alkene 146 was prepared in 78% yield by reacting sulfone 145 with aldehyde 144. The final product 143 was obtained by four-step reaction from the intermediate 146. 

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