Ireland variant, of the Claisen rearrangement

The Ireland variant of the Claisen rearrangement relies on the generation of the vinyl moiety of the double unsaturated system by enolization of an ester. The principle of this technique is given in Scheme 11.42 and it allows the transformation of allylic alcohol 177 into 180 via ester 178 and the ketene acetal 179. Application of this chemistry to the construction of the chiral quaternary carbon atom of the zaragozic acid core is shown in Scheme 11.47 [142]. Additional examples of this rearrangement are found in Section 11.5.2.2. 

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. 

Since its introduction in 1972, the Ireland silyl ester enolate variant of the Claisen rearrangement has become increasingly popular in organic synthesis. Areas of successful applications include the polyether... 

Most [3,3]-sigmatropic rearrangements take place thermally, and the Cope, oxy-Cope and Claisen rearrangements are among the most important rearrangements in this class. Important variants of the Claisen rearrangement include the Johnson modification via orthoesters, the Eschenmoser modification via ketene N,O-acetals, the Ireland modification via ketene silylacetals and the Corey modification via boron ester enolates [696], The aza-Claisen rearrangement has also seen... 

The Ireland variation is, without doubt, the most important method among the variants of the Claisen rearrangement. The modification consists of the rearrangement of an allyl ester in the form of an ester enolate or silyl ketene acetal to give a y.d-unsaturated acid40 41-80,87 88. 

More recently, several variations of the Claisen rearrangement have been reported that also possess some of the features of the Ireland variant, including the amide Claisen, S,S- and N,S-ketene acetal Claisen and the zwitterionic Qaisen rearrangements [2]. This review will focus on the Ireland variant of the Qaisen rearrangement in which a sUyl ketene acetal is an intermediate, although mention will be made of boron ketene acetals where appropriate. 

In spite of the impressive variety of studies on the Ireland-Claisen rearrangement, several significant Hmitations to the reaction remain. A general solution to the problem of stereocontrolled formation of Cl,Cl-disubstituted silyl ketene acetals has yet to be reported. There is as yet no general catalytic enantioselective variant of the Claisen rearrangement There are as yet no reports of stereoselective generation of acyclic tetrasubstituted alkenes. 

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... 

The Claisen rearrangement of bis-allyl vinyl ethers and related systems has been studied by several groups [98]. Modest to high levels of regioselectivity were obtained in the parent Claisen as well as Johnson, Eschenmoser and Ireland variants of the reaction. Parker and Farmar applied the ester enolate variant of the Ireland-Claisen rearrangement of a bis-aUylic ester to the synthesis of biflora-4,10(19),15-triene, using the rearrangement to install the 1,3-diene component for a subsequent intramolecular Diels-Alder reaction [99]. 

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. 

Corey and Lee [696] have recently proposed a variant of the Ireland-Claisen rearrangement that uses boron enolates of allylic esters derived from 2.62. The E-crotyi (Re = Me) or E-cinnamyl (Rz = Ph) derivatives could be selectively transformed into the Z- or E-boron enolates 10.46 at low temperature (Figure 10.16). The rearrangements take place at about 0°C, and the Z-enolates lead vay selectively to anti acids 10.47 with an excellent enantiomeric excess while the E-enolates lead to syn acids 10.48, with an interesting selectivity if R = Me or Et (Figure 10.16). In most cases, the enantiomeric excesses are excellent however, when the reaction is conducted with ally] esters (R = H), the ee s are a little bit lower (74 - 84%). These results are interpreted via a chair transition state that minimizes steric interactions [696],... 

Fujisawa et al. used a glycolate variant of the Ireland-Claisen rearrangement to generate the expected syn product with high diastereoselectivity (Scheme 4.84) [79]. Peterson olefination of the )5-hydroxysilane gave either the 2E,4Ej- or (2Z,4 )-dienes when basic or Lewis acidic conditions were used, respectively. 

This section is devoted to illustrating the manifold applications of the Ireland-Claisen rearrangement in natural products synthesis. The examples were generally chosen because they illustrate the first example of a particular variant of the Ireland-Claisen rearrangement to natural products synthesis. 

Burke et al. employed a cyclic variant of the glycolate Ireland-Claisen rearrangement in the asymmetric synthesis of (-I-)-breynolide (Scheme 4.128) [122]. The rearrangement of the Z-silyl ketene acetal via a boat transition state generated the C3,C4 stereochemistry of the natural product in high yield and stereoselectivity. 

Knight and co-workers reported the use of a ring contraction variant of the Ire-land-Claisen rearrangement to prepare the [5.3.0] ring system of the dictyols (Scheme 4.145) [140]. Rearrangement of the bicyclic lactone under typical Ireland conditions resulted in formation of the bicycUc skeleton of the dictyols. 

The conversion of an aUyUc ester to the corresponding pentenoic acid is formally an isomerization. From an atom economy standpoint [145], the Ireland-Claisen rearrangement suffers from the need for stoichiometric (or superstoichio-metric) base and silylating reagent A truly catalytic variant of the rearrangement would constitute a significant advance. 

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. 

Another interesting variant of Claisen rearrangement has been introduced by Ireland [149], and used by his group in carbohydrate chemistry. The starting compound is again an allylic alcohol that is esterified by a suitable carboxylic acid. This ester is enolized in basic medium, and quenching of the intermediate enolate at low temperature gives a ketene silyl... 

Since introduction of the Ireland-Claisen rearrangement in 1972, the Ireland variant has become increasingly popular in organic synthesis [66]. Although excess Ic with appropriate base is often employed as selective silylating agent, the role of residual trialkylsilyl triflate and base has not been detailed. Illustrated here are some examples of silyl triflate-mediated rearrangement which can be conducted under milder conditions. 

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