Meerwein-Eschenmoser Claisen rearrangement

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. 

Linton and Kozlowski have installed quaternary centers at oxindole C3 in enantioselective fashion via the Pd-catalyzed rearrangement of 2-allyloxy indoles (Scheme 2) [16]. For example, indole 7 underwent an enantioselective Meerwein-Eschenmoser-Claisen rearrangement in the presence of Pd(SbF6)2 and the chiral phosphinooxazoline ligand 8 to afford oxindole 9 in 89% yield and 89% ee. A two-point coordination of the chiral palladium catalyst to the C3 carbonyl and C2 oxygen (6-membered coordination system) has been proposed to rationalize the enantioselectivity of the transformation. Modest to good enantioselectivities were also observed for a series of bisphosphine chiral ligands. 

Scheme 2 Catalytic Meerwein-Eschenmoser-Claisen rearrangement...

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. 

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. 

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. 

Whereas cyclic allyhc alcohols of normal size can only yield (Z)acyclic allylic alcohols preferentially give ( )-isomers. Indeed, the Meerwein-Eschenmoser-Claisen rearrangement is an excellent method for the stereoselective formation of di- and trisubstituted (E)-double bonds in acyclic systems. The high diastereoselectivities observed (dr >95 5) can be explained by invoking a chair shaped transition state 35a or 36a (Scheme 7.15). This minimizes... 

Scheme 7.22 Simple diastereoselectivity in Meerwein-Eschenmoser-Claisen rearrangements.

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 Meerwein-Eschenmoser Claisen rearrangement is a variant of the Claisen process which is described by the thermal rearrangement of ketene... 

Parker has studied the regiochemical outcome of the Meerwein-Eschenmoser Claisen rearrangement in dialkenyl carbinols (296 and 297) and the realated propargyl-alkenyl carbinol (300) system. The less substituted alkene participated in the rearrangement (e.g., 298), and the process differentiated between an alkene and an alkyne resulting in the formation of enyne amide 301. ° ... 

The potential of the the Meerwein-Eschenmoser Claisen rearrangement was exploited by Muxfeldt and co-workers in the course of their studies of crimine alkaloid total synthesis. Allylic alcohol 302 was treated with 265 in refluxing dioxane resulting in a single diastereomer of y9-aryl amide 304. ° ... 

For an excellent review, see Gradl, S. N. Tiauner, D. The Meerwein-Eschenmoser-Claisen Rearrangement. In The Claisen Rearrangement - Methods and Applications-, Hiersemann, M., Nubbemeyer, U., Eds. Wiley-VCH Weinheim, 2007 pp 367-396. 

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