Eschenmoser reaction

Claisen-Eschenmoser Reaction (Eschenmoser-Claisen Rearrangement) Amides are produced after rearrangement with heating. 

Thioamides are strongly electrophilic and easily alkylated [368] at sulfur, yielding iminium salts in a quantitative yield. This property has often been used, notably for the Eschenmoser reaction (see Section 4.3.5). 

Keywords Thiocarbonyl compounds, Thiophilic addition, Cycloaddition reactions, Enethioli-sation, Eschenmoser reaction, Sigmatropic rearrangement. 

The alkylation of thioamides is currently used for the Eschenmoser reaction which is discussed later in this article. 

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]. 

Lhommet and his group [182] have tackled the difficult creation of tetra-substituted C-C double bonds through the Eschenmoser reaction. They found conditions to overcome the unfavourable alkylation with secondary a-bromo esters slow addition of triethylamine and triphenylphosphine to a solution of thiolactam and a-bromo ester. In this way the thioiminium salt was trapped as soon as it was formed. 

Methyl and 14/3-ethyl-4,5-epoxymorphinan derivatives have been examined 289 in the GPI and MTF assays. 14/3-Ethylmorphinone exhibited a very high level of agonist potency (117 x morphine). In another study 14-alkyl groups were introduced into 4,5-epoxymorphinans via a Claison-Eschenmoser reaction. 290 The 6-azido-14/3-methyl derivative 188 was 5000 x morphine (sc) in the MTF test and 189 had 104 x the antinociceptive potency of morphine. 

This type is a one-pot reaction widi all components present fix>m the beginning. The alcohol is first converted into an 5N-activated (HGA) species (43), which undergoes an OX displacement with the carboxylic acid to form the ester (equation 18). Two methods are known to fit into this general scheme the Mitsunobu reaction and die Vorbriiggen-Eschenmoser reaction. ... 

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. 

Several synthetic approaches toward the poison-dart frog alkaloids, including pumiliotoxin C (56), ge-phyrotoxin (57) and histrionicotoxin (58), have utilized the Eschenmoser reaction in a variety of distinct applications. These structurally related alkaloids are isolated from skin extracts of various Central and South American frogs in the Dendrohates genus and possess neurotoxic properties. Since their initial isolation and characterization, these toxins have attracted considerable attention for both their synthetic challenge and their interesting biological properties. ... 

Gephyrotoxin (57) is isolated from the frog Dendrohates histrionicus and possesses similar neurotoxic properties. Numerous chemical approaches have been developed to synthesize the parent compound and its hydrogenated analogs. Several of these approaches have incorporated the Eschenmoser reaction, each in a different application. 

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 first total synthesis of racemic histrionicotoxin (58), the parent structure in a family of related spirocyclic alkaloids isolated from the skins of Dendrobates histrionicus, utilized the Eschenmoser reaction to generate the anchor of what would become the enyne group extending from the a-position of the piperidine nucleus. The spirothiolactam intemiediate (77) was condensed with ethyl 2-bromoace-toacetate in the presence of sodium bicarbonate to produce (78) in good yield (Scheme 18). Prior to further reaction on the vinylogous carbamate, the pendent allylic acetate was elalx>rated to the enyne (79). Subsequent deacylation and enyne protection yielded spirobicycle (80), which gave a 1 1 mixture of isomers upon reduction. The desired diastereomer (81) was isolated and subsequently converted to racemic histrionicotoxin (58). 

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 synthesis of several analogs of the phosphodiesterase inhibitors PDE-I (134) and PDE-II (135) adapted the Eschenmoser reaction to perform a key cyclization that demonstrated its utility in constructing highly functionalized heterocycles. These tricyclic compounds are of additional interest because of their presence in the potent antitumor antibiotic CC-1065 (136). Cyclization of the pyrrolylthiopyrrolidi-none (137) to the tricyclic structure was achieved either by the Eschenmoser reaction or by the Knoeven-... 

The mitomycins are a class of antitumor antibiotics that has been the target of numerous synthetic efforts. The Eschenmoser reaction was a key coupling step in the synthesis of a mitomycin intermediate, apomitomycin (153). Thiopyrrolidinone (149) was alkylated with the aryl bromoacetate (150), and the intermediate a-thioiminium salt was heated with DBU (Scheme 32). The desired condensation product (151) was obtained in excellent yield, although epimerization about the pyrrolidine ring had occurred to produce a 1 1 mixture of the cis and trans substituted diastereomers. Note that, in contrast to a-alkyl-substituted electrophiles, which require conversion to triflates for complete thioamide alkylation, the more reactive benzylic bromide in (150) gave efficient alkylation. The key intermediate (151) was cy-clized in the presence of sodium hydride and copper(I) bromide to yield a single product (152) in nearly quantitative yield. Epimerization to the more stable trans isomer occurred under the cyclization conditions. This intermediate was readily converted to the final product (153). 

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