Eschenmoser amide acetal rearrangement

C. H. Heathcock, B. L. Finkelstein, E. T. Jarvi, P. A. Radel and C. R. Hadley, J. Org. Chem., 1988, 53, 1922. Even lower yields of the rearrangement product were obtained with the Eschenmoser amide acetal variant, retroaldolization being the principal competing process in this case. 

Claisen rearrangement of 3,4-unsaturated glycosides to C4-branched derivatives provided useful intermediates for the total synthesis of thromboxanes (Scheme 20). First reported independently by Corey et al. [41] and Hernandez [42],both the Eschenmoser amide acetal and the Johnson orthoester procedure afforded good results for the conversion of allylic alcohol 99 (R = Me, R = H) to the respective amide or ester 100. Corey et al. further transformed the former compound to lactone 101, previously described as a precursor for the total synthesis of thromboxane B2 (102). A number of further derivatives 100 (R = allyl, R = H or TBDMS, R = NMe2 or OEt) and its C2-epimer were prepared in a similar manner during later thromboxane synthetic studies [43,44]. 

Whereas Eschenmoser and Johnson variants of the Claisen rearrangement utilize an excess of amide acetal and orthoester precursors, respectively, for generation of the vinyl ether functionality, the Carroll... 

In 1964, Eschenmoser [5] discovered that the exchange between amide acetals and allylic alcohols observed by Meerwein [6] afforded after rearrangement of y,d-unsaturated amides (Scheme 6.1). 

Condensation with Amide Acetals or Ketene Acetals (Eschenmoser-CIaisen Rearrangement)... 

The most convenient and common way to carry out a Meerwein-Eschenmoser-Claisen rearrangement is by heating an aUylic alcohol with a ketene acetal or amide acetal (Schemes 7.3 and 7.4). In this chapter, these conditions are referred to as the Eschenmoser-CIaisen rearrangement per se. 

Scheme 7.4 Eschenmoser-Claisen rearrangement via condensation with amide acetals.

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. 

The Claisen rearrangements of amide acetals of allyl or crotyl alcohols are known as the Eschenmoser-Claisen rearrangements [78]. For example, E- and Z-isomers of 113 give 113a and 113b as major product, respectively [78]. 

N,O-acetal intermediate 172, y,<5-unsaturated amide 171. It is important to note that there is a correspondence between the stereochemistry at C-41 of the allylic alcohol substrate 173 and at C-37 of the amide product 171. Provided that the configuration of the hydroxyl-bearing carbon in 173 can be established as shown, then the subsequent suprafacial [3,3] sigmatropic rearrangement would ensure the stereospecific introduction of the C-37 side chain during the course of the Eschenmoser-Claisen rearrangement, stereochemistry is transferred from C-41 to C-37. Ketone 174, a potential intermediate for a synthesis of 173, could conceivably be fashioned in short order from epoxide 175. 

Sigmatropic rearrangement of A, 0-ketene acetals to yield Y,5-unsaturated amides. Since Eschenmoser was inspired by Meerwein s observations on the interchange of amide, the Eschenmoser-Claisen rearrangement is sometimes known as the Meerwein-Eschenmoser-Claisen rearrangement. 

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. 

Related to the orrAo-ester rearrangement is the Eschenmoser variation, which involves exchange of A, A -dimethylacetamide dimethyl acetal with an allylic alcohol and in situ rearrangement of the intermediate ketene 0-acetal to furnish the corresponding unsaturated amides. Again, transfer of stereochemistry from the allylic alcohol to the product is observed. ... 

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