Ireland-Claisen ester rearrangement

Previously, Ireland-Claisen ester-enolate rearrangement of the corresponding a-propionyloxy-allylsilane led to model system 5.44 Therefore, elaboration to 4 via rearrangement of 15 was pursued. To complete our retrosynthetic analysis, a plausible route to 15 was devised, involving straightforward homologation of 2P,3a-disubstituted cyclohexanone 17 to cyclohexene-carboxaldehyde 16, which in turn undergoes silylanion addition and subsequent acylation (Eq. 8). 

The Claisen rearrangement, Cope rearrangement, and associated variants are powerful tools that can be used to create a number of new chiral centers in an expeditious manner, but the use of heavy metals, such as mercury, should be avoided. Of these reactions, the Ireland-Claisen ester enolate reaction provides the most versatile synthetic pathway with minimal scale up problems. 

An important variant is the rearrangement of silylketene acetals like 10 and 11 which are easily accessible from allyl esters 9. This so-called Ireland-Claisen rearrangement is a valuable carbon-carbon bond forming reaction that takes advantage of the fact that the reactants are first connected to each other by an ester linkage as in allyl esters 9, that are easy prepare. 

Entries 10 to 15 involve use of the Ireland-Claisen rearrangement in multistep syntheses. An interesting feature of Entry 11 is the presence of an unprotected ketone. The reaction was done by adding LDA to the ester, which was premixed with TMS-C1 and Et3N. The reaction generates the T-silyl ketene acetal, which rearranges through a chair TS. 

The synthesis in Scheme 13.44 is also based on a carbohydrate-derived starting material. It controlled the stereochemistry at C(2) by means of the stereoselectivity of the Ireland-Claisen rearrangement in Step A (see Section 6.4.2.3). The ester enolate was formed under conditions in which the T -enolate is expected to predominate. Heating the resulting silyl enol ether gave a 9 1 preference for the expected stereoisomer. The... 

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. 

Alkylidene cyclohexenes were synthesized stereoselectively from bis-allyl silylketene acetals derived from cyclohexenones93. As shown in equation 66, Ireland Claisen rearrangement of ester 133 gave only E-diene 136. Reaction of 133 with potassium... 

Rearrangement of allyl trimethylsilyl ketene acetal, prepared by reaction of allylic ester enolates with trimethylsilyl chloride, to yield Y,5-unsaturated carboxylic a-cids. The Ireland-Claisen rearrangement seems to be advantageous to the other variants of the Claisen rearrangement in terms of E/Z geometry control and mild conditions. 

Ireland-Claisen rearrangement as an alternative approach to the syn isomer with a high degree of diastereoselectivity was also examined. This reaction might be similar to the system of ester-enolate [2,3]-Wittig shift in the case of OR (R=protective group). 

Usually, one would expect that an acrylate ester would be prepared by the acylation of an alcohol with acryloyl chloride. Jonathan M.J. Williams of the University of Bath reports (Tetrahedron Lett. 44 5523,2003) that this acylation can also be effected with the mild combination of Ph,P and maleic anhydride. The acrylate esters so prepared are interesting as polymerization precursors, and as Diels-Alder dienophiles. The allylic acrylates invite tandem conjugate addition / Ireland Claisen rearrangement. 

To avoid the formation of ketenes by alkoxide elimination, ester enolates are often prepared at low temperatures. If unreactive alkyl halides are used, the addition of BU4NI to the reaction mixture can be beneficial [134]. Examples of the radical-mediated a-alkylation of support-bound a-haloesters are given in Table 5.4. Further methods for C-alkylating esters on insoluble supports include the Ireland-Claisen rearrangement of O-allyl ketene acetals (Entry 6, Table 13.16). Malonic esters and similar strongly C,H-acidic compounds have been C-alkylated with Merrifield resin [237,238]. 

The Ireland-Claisen rearrangement of a 2-fluoroallylic ester of 3-methylcrotonic acid followed by a tandem Cope rearrangement to prepare a 6-fluoroocta-2.6-dienoic acid,7 is given in Section 5.1.5.1. (see compound 11). 

Alkenyl-2-azetidinone systems could be converted to bicyclic (3-lactam carboxylic esters and hence carboxylic acids (Fig. 5) via tandem Ireland-Claisen rearrangement and subsequent alkene metathesis [250],... 

The immediate product of the rearrangement, a carboxylic acid silyl ester, cannot be isolated and is hydrolyzed during workup. The Ireland-Claisen Rearrangement thus offers ready access to chain-extended carboxylic acids. 

Silylene transfer to a -unsaturated esters produces oxasilacyclopentenes and provides a new method for regio- and stereo-selective formation of enolate that can undergo facile and selective Ireland-Claisen rearrangements and aldol addition reactions to provide products with multiple contiguous stereocenters and quaternary carbon centers (Scheme 37). 

As shown earlier (Figure 13.22), silyl ketene acetals can be prepared at -78 °C by the reaction of ester enolates with chlorosilanes. O-Allyl-O-silyl ketene acetals (A in Figure 14.48) are formed in this reaction if one employs allyl esters. Silyl ketene acetals of type A undergo [3,3]-rearrangements rapidly upon warming to room temperature. This variation of the Claisen rearrangement is referred to as the Ireland-Claisen rearrangement. 

Ireland-Claisen rearrangements obviously occur under much milder conditions than the classical Claisen rearrangements of Figures 14.46 and 14.47. Among other things, this is due to product development control. The rearranged product of a Claisen-Ireland rearrangement is an a-allylated silyl ester, and its C=0 bond is stabilized by ester resonance (=14 kcal/mol... 

The product of a Ireland-Claisen rearrangement is a silyl ester. However, silyl esters generally are so sensitive toward hydrolysis that one usually does not attempt to isolate them. Instead, the silyl esters are hydrolyzed completely during work-up. Thus, Ireland-Claisen rearrangements de facto afford carboxylic acids and, more specifically, they afford y,5-unsaturated carboxylic acids. 

Ireland-Claisen rearrangements frequently are used for the synthesis of alkenes. This works particularly well if the allyl ester is derived from a secondary allyl alcohol. In this case a stereogenic double bond is formed in the rearrangement. The examples in Figure 14.48 show that the alkene is mostly trans-configured if this C=C bond is 1,2-disubstituted and almost completely is-configured if it is trisubstituted. 

Figure 14.51 shows four Ireland-Claisen rearrangements that exhibit simple diastereose-lectivity (see Section 11.1.3 for a definition of the term). The substrates are two cis, trans-iso-meric propionic acid esters. The propionic acid esters in Figure 14.51 are derived from achiral allyl alcohols. This is different from the situation in Figure 14.50. However, these esters contain a stereogenic C=C double bond. Both the esters in Figure 14.51 can be converted into their 7 "-enolates with LDA inpureTHF (cf. Figure 13.16). Silylation affords the two T -con-figured O-allyl-O-silyl ketene acetals A and D, respectively. Alternatively, the two esters of Figure 14.51 can be converted into their Z -enolates with LDA in a mixture of THF and DMPU (cf. Figure 13.17). Treatment with rert-BuMe,SiCl then leads to the Z-isomers B and C of the O-allyl-O-silyl ketene acetals A and D, respectively.

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