Eschenmoser-sulfide-contraction reaction

The synthesis of thiiranes with subsequent elimination of sulfur is an important procedure for the creation of C=C bonds, especially for sterically crowded systems (47,48), in analogy to the Eschenmoser-sulfide-contraction reaction (116). The spontaneous elimination of sulfur was observed in the rhodium-catalyzed reaction of diazo compound 62, which gave rise to the formation of cyclopentenone derivative 63 (117) (Scheme 5.24). A synthesis of indolizomycin was published by Danishefsky and co-workers (118) and involved a similar annulation step. In this case, however, the desulfurization reaction was achieved by treatment with Raney Ni. 

A third application of the Eschenmoser reaction in the synthesis of racemic perhydrogephyrotoxin (76) is based on an extension of the chemistry developed during the pumiliotoxin C synthesis. - Beginning with the bicyclic thiolactam (73), the sulfide-contraction reaction was used to append to the decahydro-isoquinoline a functionalized five-carbon side chain that would later be cyclized and become the a-hy-droxyethylpyrrolidine portion of the molecule. Alkylation of the thiolactam (73) with methyl 5-bromolevulinate followed by treatment with the Eschenmoser dual base-thiophile reagent (28) produced the vinylogous carbamate (74) in 81% yield from the starting thiolactam (73 Scheme 17). Reduction of the vinylogous amide (74), followed by equilibration of the amino ketones in the presence of... 

The Eschenmoser reaction is extremely useful for the conversion of amides into enaminoesters via the thioamide reaction with a-haloesters, and triphenylphosphine mediated sulfide contraction, and we are fortunate that Shiosaki has published a thorough review on this topic [180]. The accompanying scheme shows a typical example for which an organometallic route with a lithium or a zinc enolate was not successful [181]. 

A pair of geometric isomers about the alkene can result from the condensation process. Eschenmoser demonstrated that sulfide contraction on the secondary thiolactam produced exclusively the (Z)-isomer (equation 3). Other studies have indicated sole formation of the ( )-isomer using tertiary thiolactams and bromoacetates or a mixture of isomers when a-substituted electrophiles were employed (vide infra). However, most synthetic applications of the Eschenmoser reaction have not stringently identified the geometry about the resulting alkene since the double bond is later reduced or equilibrated in the final product. A systematic investigation to identify factors that may influence the stereochemical outcome has not been reported. 

The Eschenmoser reaction was applied a second time as one of the methods to introduce the -butyl appendage. The alkylated a-amino ester (97) was oxidized to the monosubstituted thiolactam (98), and introduction of the butyl side chain, via sulfide contraction as described above, yielded a mixture of vinylogous carbamates (99). Treatment of the carbamates (99) under transfer hydrogenolysis conditions yielded the optically pure dialkylpyrroline (100), another component of the ant trail pheromone. Subsequent reduction of the pyrroline with platinum afforded the optically pure ds-2,5-dialkyl-substituted pyrrolidine (101). Other pyrrolidine-containing alkaloids have been prepared by similar approaches involving the Eschenmoser reaction. ... 

The preparation of substituted five- and six-membered lactones served as a model system to examine the feasibility of this novel ring-forming strategy. A hydroxythioamide (168) was allowed to react with chloroacetyl chloride, and the resulting a-chloro ester (169) was treated with sodium iodide and the Eschenmoser dual base-thiophile reagent (28) to afford the cyclic enamino lactone (170) in high yield (Scheme 35). No epimerization of the lactone was observed. Likewise, the five-membered enamino lactone (172) resulted from reaction of the hydroxythioamide (171) with chloroacetyl chloride followed by sulfide contraction. 

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