Ireland-Claisen rearrangements, enolates, lithium

Further variations of the Claisen rearrangement protocol were also utilized for the synthesis of allenic amino acid derivatives. Whereas the Ireland-Claisen rearrangement led to unsatisfactory results [133b], a number of variously substituted a-allenic a-amino acids were prepared by Kazmaier [135] by chelate-controlled Claisen rearrangement of ester enolates (Scheme 18.47). For example, deprotonation of the propargylic ester 147 with 2 equiv. of lithium diisopropylamide and transmetallation with zinc chloride furnished the chelate complex 148, which underwent a highly syn-stereoselective rearrangement to the amino acid derivative 149. 

Addition of lithium enolate (56) to trifluorocrotonate (55) proceeded smoothly in almost quantitative yields with excellent stereoselectivity. The intramolecular chelation in 57 retards the retro-aldol reaction. On the other hand, nonfluorinated crotonate (59) provided 60 in a poor yield because of the faster retro-aldol reaction [26]. The stereochemistry of the chelated intermediate (57) was proven by trapping 57 as its ketenesilylacetal (61). Pd-catalyzed Ireland-Claisen rearrangement of 61 proceeded stereospecifically to give a single stereoisomer (62), suggesting a rigid control of the three consecutive stereocenters (Scheme 3.12) [27]. 

In 1972, Ireland and Mueller reported the transformation that has come to be known as the Ireland-Claisen rearrangement (Scheme 4.2) [1]. Use of a lithium dialkylamide base allowed for efficient low temperature enolization of the allyUc ester. They found that sUylation of the ester enolate suppressed side reactions such as decomposition via the ketene pathway and Claisen-type condensations. Although this first reported Ireland-Claisen rearrangement was presumably dia-stereoselective vide infra, Section 4.6.1), the stereochemistry of the alkyl groups was not an issue in its application to the synthesis of dihydrojasmone. 

Takano et al. used the Ireland-Claisen rearrangement of an allyl lactate in the total synthesis of calcitriol lactone (Scheme 4.76) [74]. The rearrangement proceeded with a 6.7 1 diastereoselectivity via O-silylation of the intermediate li-che-lated Z-enolate. Takano noted that the corresponding benzyl ether gave significantly lower de (70%) than the PMB ether. This is presumably due to the PMB ether s greater Lewis basicity and hence its greater propensity to coordinate a lithium cation. 

The sequential Michael addition/Ireland-Claisen reactions proceed with high diastereoselectivity in one pot. Preparation of the lithium enolate 68 with LDA in THF at —78 °C followed by the addition of the allylic ester acceptor 67 leads to the smooth conjugate addition, whose stereoselectivity was more than 98% diastereomeric excess. The ketene silyl acetal 70, which was formed by the trapping of the Michael addition intermediate 69 with TMSCl, underwent Ireland-Claisen rearrangement in the presence of PdCl2(PhCN)2... 

This method was further improved when it was found that readily available allyl esters of the general formula 493 could also be involved in Claisen rearrangements via intermediate formation of ketene derivatives such as lithium enolates 494 or trimethylsilyl ketene acetals 495 (the Ireland-Claisen variant" ). Moreover, rearrangement of these substrates into unsaturated acids 496 occurred easily at room temperature or below. This was in striking contrast to all previous versions of the Claisen rearrangement, which required heating at elevated temperatures (140-160 °C). The Ireland (silyl ketene acetal) variant of... 

In 1972, a further brilliant improvement on the Claisen rearrangement was realized by Ireland and co-woikers. Ester enolization wiA lithium dialkylamide bases, followed by silylation with TMS-Cl, generated reactive silyl ketene acetals at -78 °C or lower temperatures. Sigmatropic rearrangement to easily hydrolyzable 7,8-unsaturated silyl esters occurred at ambient tempontures (15 16 17 equa-... 

The ability of charged substituents to accelerate the 3,3-sigmatropic reiarrangement of allyl vinyl ethers (the Claisen rearrangement) has also been documented. The effect of oxyanion substituents on the rate and course of aliphatic Claisen rearrangements has been the subject of particular attention. " In 1972, Ireland and Mueller reported that the lithium enolate derivatives of allyl esters undergo rapid and effi-... 

Claisen rearrangement of allyl esters. Ireland and Mueller6 report that lithium enolates of allyl esters rearrange rapidly at room temperature or slightly above to the corresponding y,<5-unsaturated acids. Thus the allyl ester (1) is converted into the lithium enolate (2) by treatment with lithium isopropylcyclohexylamide in THF at —78°. The solution of (2) is then allowed to warm to 25° for 10 min. The y,S-unsaturated acid (3)... 

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