Lithium enolates Claisen rearrangement

It has been shown that the Claisen rearrangement of lithium enolates of amino acid enynol esters allows the synthesis of very sensitive y, 5-unsaturated amino acids with conjugated enyne side chains.The chelate-enolate Claisen rearrangement has also been applied to the synthesis of unsaturated polyhydroxylated amino acids, polyhydroxylated piperidines, and unsaturated peptides. ... 

Ester enolate Claisen rearrangement (4, 307- K)8 6, 276-277 7, 209-210). Lithium hexamethyldisilazide is comparable to LDA in combination with HMPT for stereoselective Claisen rearrangement of ester cnolates. ... 

Claisen rearrangement. The ester enolate Claisen rearrangement of allyl esters of protected amino acids proceeds after replacing the lithium ion with Zn. 

It is possible to treat ketones with allyl alcohol and an acid catalyst to give y,5-unsaturated ketones directly, presumably by initial formation of the vinylic ethers, and then Claisen rearrangement.In an analogous procedure, the enolates (126) of allylic esters [formed by treatment of the esters with lithium isopropylcyclohex-... 

The ester 7-1 gives alternative stereoisomers when subjected to Claisen rearrangement as the lithium enolate or as the silyl ketene acetal. Analyze the respective transition structures and develop a rationale to explain these results. 

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. 

The aldol reaction is an addition of metal enolates to aldehydes or ketones to form P-hydroxy carbonyl compounds.1 The simplest aldol reaction would be the reaction of acetaldehyde lithium enolate with formaldehyde (Scheme 2.1). As the transition state of this reaction involves six atoms, the aldol reaction is another example where a six-membered transition state is presumed to be operating. The transition state of the aldol reaction is very similar to those of Claisen and Cope rearrangements, and therefore the remarkable facility of the lithium enolate reaction is attributed to the stability of an aromatic transition state.2... 

The quaternary center was constructed stereospecifically by Claisen rearrangement (Scheme 46). The necessary enol ether was obtained by reaction of the secondary alcohol of 399 with ethyl vinyl ether and mercuric acetate. To change the polarity of the endocyclic double bond, the unsaturated ketone was reduced with lithium aluminum hydride to the allylic alcohol, 400, at low temperature. Then, prolonged heating with xylene led to the aldehyde, 401. Protection of the secondary alcohol was achieved by bromoether formation with W-bromosuccinimide in acetonitrile before the aldehyde of 402 was reacted with methyllithium. The epimeric mixture of secondary alcohols was protected as acetates 403. Then, the cyclic ketone... 

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-... 

A remarkably facile tandem 1,4-conjugate addition Claisen rearrangement is observed by utilizing the copper enolate derived by addition of lithium dimethylcop-per to 2-(allyloxy)-2-cyclohexenone. The resultant hydroxy ketone is obtained as a single stereoisomer in nearly quantitative yield. 

The N=C double bond of anils can be a part of 1,5-diene systems that are able to undergo the aza-Claisen rearrangement (see Section III.A.2.b). Such asymmetric isomerization of allylic imidoester enolates 115 was observed upon deprotonation with lithium diethylamide to give the amides 116 in moderate yields but with good stereoselectivity195 (equation 47). 

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)... 

A bimetallic intermediate formed with the bidentate quinine or quinidine ligand, coordinating to the lithium enolate that undergoes Claisen rearrangement to afford the enantioenriched products, was proposed (Figure 4.2). 

This is true also of allylic esters 182 so that the geometry of both alkenes involved in the Claisen-Cope rearrangement can be controlled if the lithium enolate is trapped by silylation to give 183. Drawing the rearrangement in the chair conformation 183a — 184 gives a predictable diastereoisomer of the product 185. 

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 contrast to chelation-controlled anionic Claisen rearrangements of /(-hydroxy esters [where chelation control only allows the formation of (i -lithium enolates see p 3420], all four diastereomeric A-crotylic a-hydroxy ketene dithioacetals can be prepared either by deprotona-... 

Claisen rearrangement. The quenching of the lithium enolates derived from allylic acetates results in enol phosphates, which show a higher propensity for Claisen rearrangement than ketene silyl ethers. The mixed anhydride products can be used directly to generate carboxylic acid derivatives. 

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