Ireland-Claisen rearrangement examples

The stereochemistry of Ireland-Claisen rearrangements of cyclic compounds is sometimes indicative of reaction through a boat TS. For example, the major product from 2-cyclohexenyl propanoate is formed through a boat TS.244... 

The Diels-Alder reaction outlined above is a typical example of the utilization of axially chiral allenes, accessible through 1,6-addition or other methods, to generate selectively new stereogenic centers. This transfer of chirality is also possible via in-termolecular Diels-Alder reactions of vinylallenes [57], aldol reactions of allenyl eno-lates [19f] and Ireland-Claisen rearrangements of silyl allenylketene acetals [58]. Furthermore, it has been utilized recently in the diastereoselective oxidation of titanium allenyl enolates (formed by deprotonation of /3-allenecarboxylates of type 65 and transmetalation with titanocene dichloride) with dimethyl dioxirane (DMDO) [25, 59] and in subsequent acid- or gold-catalyzed cycloisomerization reactions of a-hydroxyallenes into 2,5-dihydrofurans (cf. Chapter 15) [25, 59, 60],... 

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. 

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]. 

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. 

Danishefsky and coworkers have demonstrated the conversion of lactones to carbocycles by the 3,3-sigmatropic shift of silylketene acetals. Jq the total synthesis of the Fusarium toxin equisetin, for example, keto lactone (138) was converted to its bissilyl derivative (139) by reaction with 2 equiv. of LDA and an excess of TMS-Cl. In situ thermolysis of ketene acetal (1 ) led to a very smooth transformation into ester (140), which was carried on to equisetin (Scheme 26). This methodology was also applied by Schreiber and Smith in the preparation of the cyclohexyl moiety of the immunosuppressive agent FK-506. Ireland-Claisen rearrangement of silylketene acetal (142), prepared by treatment with TBDMS-OTf and triethylamine at low temperature, provided, after hydrolysis of the silyl ester, the carboxylic acid (143) in 71% overall yield (Scheme 27). The strict translation of configuration via a boatlike transition state is typical for this permutation. 

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. 

Example 6, chirality-transferring Ireland-Claisen rearrangement"... 

Schemes 13.13 and 13.14 show examples of Ireland-Claisen rearrangements of substrates possessing cyclic allylic motifs. In Scheme 13.13. a glycal-derived substrate is used this transformation has become established as a useful method for the generation of C-glycosides...

Inanaga et al. reported the first example of a nucleophileotalyzed Ireland-Claisen rearrangement (Scheme 4.11) [12]. Conjugate addition of tricyclohexyl-phosphine to aUyl acrylates generated intermediate phosphonium allyl sUyl ketene acetals, which underwent rearrangement to yield a-substituted acrylates after elimination of the phosphine. 

The C4 stereocenter dominates the stereochemical outcome of the Ireland-Claisen rearrangements in appropriately substituted allyl silyl ketene acetals. For substrates lacking a C4 stereocenter, other more remote stereocenters may play a significant role in the stereochemical outcome. There are comparatively few cases of remote stereocontrol, so most examples will be described in this section. The stereocenters will be discussed based on their location relative to the allyl silyl ketene acetal. Carbons a to the Cl carbon will be designated Cl, alpha to C4, C4 and so on (Fig. 4.1). 

Also in 1993, Hauske and JuUn reported a similar Ireland-Claisen rearrangement of an acyclic C6 carbamate (Scheme 4.35) [39]. The authors examined three different silyl ketene acetals in the rearrangement, although no experimental details were provided. AU three examples apparently proceeded with complete facial selectivity with respect to the allyUc alkene to afford the syn stereochemistry between the aUyl group and the NHBoc group in the conformation shown. The same rationale for facial selectivity can be applied as for Mulzer s results in the previous scheme. The reason for the low C2,C3 synjanti diastereoselectivity in the propionate example was not addressed. A lack of control of enolate geometry or post-rearrangement epimerization are both possible. 

The earliest examples of Ireland-Claisen rearrangements of allyl silyl ketene acetals bearing a stereocenter at C6 were reported by Cha and Lewis in 1984 (Scheme 4.36) [40]. In contrast to the nitrogen C6 substituents, oxygen substituents exhibited considerably less facial bias. Rearrangements of the acetate esters of either the Eor Z alkenes gave only 1.3 1 and 1.4 1 C3,C6 anti.syn ratios, respectively. 

Since the Ireland-Claisen rearrangement typically begins with deprotonation of an allyhc ester, the scope of the reaction is potentially Hmited by the presence of other acidic protons in the molecule. Several examples of selective deprotonation of esters in the presence of other carbon acids have been reported. 

With the exception of the above example, post-rearrangement epimerization is generally an undesired side reaction. McIntosh et al. found that Ireland-Claisen rearrangement of some his-allyUc esters using excess KHMDS and TlPSOTf led to... 

Bartlett et al. reported the first example of an Ireland-Claisen rearrangement of an aUyhc glycolate in 1982 (Scheme 4.68) [66]. Treatment of crotyl glycolate with 2.25 equivalents of LICA and TMSCl in THF gave 50% yield of the 2-hydroxy-pen-tenoic acids with essentially no stereoselectivity. 

In 1980 Danishefsky et al. reported the first examples of Ireland-Claisen rearrangements of vinyl lactones to afford carbocyclic carboxyUc adds (Scheme 4.89) [82]. Treatment of 6-vinyl pentanoHdes under standard Ireland conditions and heating of the reaction mixture to 105 °C afforded the rearranged adds in generally good yields. The products necessarily arose from a boat transition state, since the chair transition states would be exceptionally strained. 

Funk et al. reported an early example of lieterocycle synthesis via a ring contraction of a azalactone via an Ireland-Claisen rearrangement (Scheme 4.99) [87]. Since the lactone was 10-membered, the rearrangement occurred exclusively via the boat transition state to afford the cis piperidine diastereomer. The product was elaborated in several steps to a protected version of meroquinene, an intermediate in cinchona alkaloid syntheses. 

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. 

Kuwajima reported one example of an Ireland-Claisen rearrangement of a pro-pargyl acrylate that was initiated by Cu(I)-catalyzed conjugate addition of MeMgBr (Scheme 147) [57]. 

Meanwhile, the Ireland-Claisen rearrangement of protected a-hydroxy aUylic esters found various applications in natural product syntheses, what clearly underlines the potential of this synthetic protocol. Several examples are described by Kallmerten et al. For example, rearrangement of (Z)-configured ester 35 gave rise to the required anti rearrangement product 36, which was converted in five steps into the dilactone 37, a precursor of the antifungal metabolite avenaciolide (Scheme 5.2.11) [23]. 

In contrast to the a-oxy- or a-amino-substituted allylic esters, not many examples for a-thio substituted substrates and their application in Claisen rearrangements are described so far (Scheme 5.2.63). Lythegoe et al. applied the Ireland-Claisen rearrangement to the synthesis of a-mercapto acids such as 199 starting from allylic esters 198 [116]. 199 was oxidized and further converted into a,j8-unsaturat-ed esters or subjected to an oxidative degradation. Jones et al. used the Ireland-Claisen rearrangement of 200 in their syntheses of thietan oxides [117]. 

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