Eschenmoser-Claisen amide acetal rearrangement

Eschenmoser, A. Helv. Chim. Acta 1964, 47, 2425-2429. Albert Eschenmoser (Switzerland, 1925—) is known for his work on, among many others, the monumental total synthesis of Vitamin Bn with R. B. Woodward in 1973. He now holds dual appointments at both ETH Zurich and the Scripps Research Institute in La Jolla, CA. 

In Comprehensive Organic Synthesis Trost, B. M. Fleming, I., Eds. Perga-mon, 1991, Vol. 5, 827-873. (Review). 

Williams, D. R. Nag, P. P. Claisen and Related Rearrangements. In Name Reactions for Homologations-Part II Li, J. J., Corey, E. J., Eds. WUey Sons Hohoken, NJ, 2009, pp 60-68. (Review). 

Meerwein, H. Florian, W. Schon, N. Stopp, G. Justus Liebigs Ann. Chem. 1961, 641, 

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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. 

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... 

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. 

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... 

Cyclopentenol derivatives show similar behavior. Combination of an ethenyl-substimted substrate with dimethylacetamide dimethyl acetal under thermal conditions gave the product of Eschenmoser-Claisen rearrangement, with delivery of the C—C bond taking place in a syn fashion with respect to the ethenyl group (Schem j3A5). The product amide was converted via iodolactonization into the bicyclic lactone, demonstrating the utility of the rearrangement product in subsequent transformations. ... 

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. 

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. 

Both Parsons [49] and Mulzer [50, 51] used related Eschenmoser-Claisen rearrangements to set a benzylic quaternary stereocenter in their approach to morphine alkaloids (Scheme 7.25) [5, 52, 53]. Reduction of cyclohexenone 65 followed by Eschenmoser-Claisen rearrangement gave unsaturated amide 66, which was subsequently converted into a known precursor of morphine (Scheme 7.24, Eq. 1). Treatment of the acid sensitive phenanthrenol 67 with dimethylacetamide dimethyl acetal (4) afforded amide 68 comprising the entire carbon skeleton of the morphine (Eq. 2). The amide was subsequently reduced to a primary alcohol (69) using lithium triethylborohydride (Super-Hydride), the most suited reagent to perform this task. Previous total syntheses of the alkaloid were intercepted at the stage of dehydrocodeinone. 

In the light of the emergence of morpholine amides as substitutes of Weinreb amides, a direct incorporation of the former in the Eschenmoser-Claisen product is strategically attractive for synthesis. Traimer and coworker have treated allylic alcohol 290 with jV,jV-morpholine acetal 289 at high temperature, generating in situ the ketene iV, 0-acetal which smoothly rearranged to morpholine amide 291. ° ... 

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]. 

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]. 

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