Eschenmoser-Claisen rearrangement reaction

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

In an attempt to achieve an enantioselective Eschenmoser-Claisen rearrangement with amide salts 6, (2R,5R)-l-(fluoroacetyl)-2,5-dimethylpyrrolidine was methylated to give chiral 6d. 5 Reaction of 6d with the lithium salt of (fj-crotyl alcohol gives amide 7d as a mixture of diastereomers, in which the. vj rt-isomers predominate. 

The reaction outlined in O Scheme 59 is an example of a variant of the Claisen rearrangement of allyl ketene aminal (so-called Eschenmoser-Claisen rearrangement) [87], The reaction dose not require an acid catalyst glycal was just heated with dimethylacetamide dimethyl acetal to form ketene aminal, which underwent the sigmatropic rearrangement to form the corresponding )/,5-unsaturated amide. 

During the asymmetric total synthesis of (+)-pravastatin by A.R. Daniewski et al., one of the stereocenters was introduced with the Eschenmoser-Claisen rearrangement. The tertiary alcohol intermediate was heated in neat N,N-dimethylacetamide dimethyl acetal at 130 °C for 48h, during which time the by-product methanol was distilled out of the reaction mixture to afford the desired amide in 92% yield. 

Related reactions Carroll rearrangement, Claisen-lreland rearrangement, Eschenmoser-Claisen rearrangement, Johnson-Claisen rearrangement ... 

Reaction of 25 with LiAIH4 stereoselectively reduced the enone system in a 1,2-fashion as well as the amide carbonyl to give 26. Eschenmoser Claisen rearrangement [30] of 26 afforded the desired rearranged product 27 in 49% yield. The major side product in the rearrangement was diene 28 (32%), and it was found that... 

The synthesis of three fragments 278, 282, and 285 for the C21-C42 bottom segment is summarized in Scheme 41. The Eschenmoser-Claisen rearrangement of amido acetal of 276, which was prepared via 2-bromocyclohexenone by Corey s asymmetric reduction, afforded amide 277. Functional group manipulation including chain elongation provided Evans-type amide 278. The Evans aldol reaction of boron enolate of 279 with aldehyde 280 stereoselectively afforded 281, which was converted into aldehyde 282 through a sequence of seven steps... 

The allylic alcohol was subjected to an Eschenmoser-Claisen rearrangement with dimethylacetamide dimethylacetal to introduce the C14 substituent in a stereoselective manner. Reduction of the amide to the corresponding aldehyde with phenyl silane in the presence of Ti(0/Pr)4 was followed by an acid-promoted closure of the C-ring of codeine. In order to prevent N-oxidation, the amine was converted to the corresponding tosylamide, via debenzylation and treatment with tosyl chloride, before the allylic alcohol was introduced by the reaction of the alkene with selenium dioxide (65). The stereochemistry of the C6 hydroxy functionality was corrected by applying the well-known oxidation/reduction protocol [46, 60] before the benzylic double bond was reductively removed under Birch conditions. Codeine (2) was obtained in 17 steps with an overall yield of approximately 0.6%. 

Scheme 13.30 Sequential Johnson-Claisen and Eschenmoser-Claisen rearrangements. Scheme 13.31 Double Ireland-Claisen rearrangement reactions.

The Eschenmoser-Claisen rearrangement is a closely related transformation which delivers carboxylic amide rather than ester products, via the intermediacy of the analogous ketene aminals. Scheme 13.30 depicts the reaction of a cyclic, unsaturated antz-1,2-diol which was... 

Erdmann (see Volhard-Erdmann Cyclization) Erlenmeyer-Plochl Azlactone and Amino Acid Synthesis Eschenmoser Coupling Reaction Eschenmoser Fragmentation Eschenmoser-Claisen Rearrangement Eschenmoser-Tanabe Fragmentation Eschweiler-Clarke Reaction Etard Reaction... 

The Meerwein-Eschenmoser-Claisen rearrangement is one of the most useful pericyclic reactions. In its basic form, it involves the conversion of an allylic alcohol 1 to a ketene N, 0-acetal 2, which undergoes rapid [3,3]-sigmatropic rearrangement to yield a y,d-unsaturated amide 3 (Scheme 7.1). In accordance with the general electronic effects observed in Claisen rearrangements, the presence of an electron-donating amino substituent on the ketene acetal intermediate substantially increases the rate of the pericydic step. 

Since its original discovery, the Meerwein-Eschenmoser-Claisen rearrangement has proven to be a reUable reaction with considerable scope. Apart from the aUylic and benzylic systems [4-6] shown below, propargylic alcohols [7,8] and aUenyl... 

Apart from its practicahty, the synthetic value of the Meerwein-Eschenmoser-Claisen rearrangement Ues in its abihty to overcome considerable sterical hindrance, for instance the establishment of quaternary stereocenters (Fig. 7.1). The reaction allows for chirahty transfer starting from readily accessible enantiomeri-caUy pure allyhc and propargyhc alcohols to afford amides with carbon-based... 

From a retrosynthetic point of view, the Meerwein-Eschenmoser-Claisen rearrangement shares the basic Claisen retron, a y,<5-unsaturated carbonyl compound, with other variants of the reaction. More specifically, its retron consists of a two-carbon chain branching off an allyhc stereocenter and terminating in an amide or a functional group derived thereof Such a motif can be readily identified in numerous natural products and other synthetic targets. 

Several variants of the Meerwein-Eschenmoser-Claisen rearrangement have been reported, which mostly differ in the way the ketene N,0-acetal intermediate is formed. Following a review of this aspect, the regjo- and stereoselectivity of the reaction is discussed. Finally, the usefulness of the reaction in the synthesis of complex target molecules is highlighted using selected examples, mostly from natural product syntheses. 

In addition to its wide substrate scope and functional group compatibility, the Meerwein-Eschenmoser-Claisen rearrangement is marked by high regio- and stereoselectivity, notably in the case of acydic substrates. In fact, the reaction provides some of the best examples for acyclic stereocontrol reported in the literature. 

The Meerwein-Eschenmoser-Claisen rearrangement, in particular the Eschen-moser amide acetal version, has been extensively applied toward the synthesis of natural products and other complex target molecules. The literature is replete with cases where the reaction provided the only way to place a substituent in a sterically hindered environment. The following paragraphs provide selected examples of its use and also serve to highlight the further synthetic transformation of the unsaturated N,N-dimethylamides normally obtained. Perhaps the only drawback of the Eschenmoser-Claisen rearrangement is the stabiUty of these amides, whose hydrolysis and reduction requires relatively harsh conditions. However, electrophilic activation via the y,(5-double bond can be used to manipulate this functionality. 

Danishefsky et al. took recourse to an Eschenmoser-Claisen rearrangement in a total synthesis ofgelsemine (Scheme 7.26) [54]. Although the implementation of the reaction required the subsequent removal of one carbon, it proved to be the only viable way to install the spirocycHc stereocenter. A variety of alternative [2,3]-and [3,3]-sigmatropic rearrangements were found to be unsuccessful. Treatment of allylic alcohol 70 with DMADMA furnished amide 71, which underwent condensation with the nearby benzyl carbamate to yield lactam 73 upon purification on silica gel in 45% overall yield. The unusual byproduct 72 could be recycled to 70 by treatment with aqueous acid. 

Somewhat ironically, the Eschenmoser-Claisen rearrangement was not employed in Woodward s and Eschenmoser s synthesis of Vitamin 8,2, for which it was initially developed [79]. However, the reaction figured prominently in Mulzer s approach toward the molecule (cf. Scheme 7.5) [15] and has found extensive applications in Montforfs studies on bacterial chlorines [80-82]. For instance, in a synthesis of heme dl, a twofold Eschenmoser-Claisen rearrangement was used to convert porphyrin 102 into chlorin 103, setting the quaternary stereocenters of the target (Scheme 7.35) [83]. 

Finally, the Eschenmoser-Claisen rearrangement has found appUcations in drug synthesis. Mulzer s synthesis of the antidepressant (J )-rolipram serves as an example (Scheme 7.36) [84]. Rearrangement of chiral cinnamyl alcohol 104 gave unsaturated amide 105 with Uttle erosion of optical purity. Ozonolysis and reduction afforded alcohol 106 and set the stage for a subsequent Mitsunobu reaction with hydrazoic acid. Reduction of the azide function followed by intramolecular transamidation gave y-lactam 107, which was converted into (R)-rolipram in two straightforward steps. 

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