Ireland-Claisen synthesis

The Ireland-Claisen reaction of ( )-vinylsilanes has been applied to the stereoselective synthesis of syn- and c/nti-2-substituted 3-silyl alkcnoic acids. a R-2-Alkyl-3-silyl acids are prepared by rearrangement of ( )-silyl ketene acetals which are generated in situ from the kinetically formed (Z)-enolate of the corresponding propionate ester40. Chelation directs the stereochemistry of enolization of heteroelement-substituted acetates in such a way that the syn-diastereomers are invariably formed on rearrangement403. 

Lewis acid catalysis of Ireland-Claisen rearrangements by TiCl4 has been observed.251 This methodology was employed in the synthesis of a novel type of anti-inflammatory drug candidate.252... 

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... 

Neier and coworkers have used a domino Diels-Alder/Ireland-Claisen process for the synthesis of (rac)-juvabione 4-46 and (rac)-epijuvabione [15]. Since neither the Diels-Alder reaction of the acetal 4-44 and methyl acrylate nor the sigmatropic rearrangement seemed to be stereoselective, these authors obtained the cyclohexene derivative 4-45 as a mixture of three diastereomers (Scheme 4.9). 

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. 

X.J. Wang, S.A. Hart, B. Xu, M.D. Mason, J.R. Goodell, F.A. Etzkorn, Serine-c/s-proline and Serine-frans-proline isosteres Stereoselective synthesis of (Z)- and ( )-alkene mimics by still-wittig and ireland-claisen rearrangements, J. Org. Chem. 

Schkeryantz and Pearson (59) reported a total synthesis of ( )-crinane (298) using an intramolecular azide-alkene cycloaddition (Scheme 9.59). The allylic acetate 294 was first subjected to an Ireland-Claisen rearrangement followed by reduction to give alcohol 295, which was then converted into the azide 296 using Mitsunobu conditions. Intramolecular cycloaddition of the azide 296 in refluxing toluene followed by extrusion of nitrogen gave the imine 297 in quantitative yield. On reduction with sodium cyanoborohydride and subsequent reaction with... 

Table T8. Synthesis of Methyl 2-Alkoxy-3.3-difluoro-4-oxoalkanoates 8 by Ireland-Claisen Rearrangement of 3,3-Difluoroallylic Alkoxyacetates 641...

Table 22. Synthesis of 2-(Trifluoromcthyl)alk-4-enoic Acids 18 by the Ireland-Claisen Rearrangement of Allylic 3,3.3-Trifluoropropionates I760...

The (panial) description of the synthesis and coupling of the live fragments starts with the cyclohexyl moiety C21—CM The first step involved the enantio- and diastereoselective Sharpless epoxidation of l,4-pentadien-3-ol described on p 126f The epoxide was converted m four steps to a 3-vinyl 6-lactone which gave a 3-cydohexenecarboxylate via Ireland-Claisen rearrangement (cf p 87) Uncatalysed hydroboration and oxidation (cf. p 131) yielded the desired muis-2-methoxycydohexanol which was protected as a silyl ether The methyl car-... 

Fig. 14.48. Ireland-CLaisen rearrangement of two 0-allyl-0-sityl ketene acetals. Trans-selective synthesis of disubsti-tuted and F-selective synthesis of trisubstituted alkenes.

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. 

H.-J. Altenbach, Ester Enolate Claisen Rearrangements , in Organic Synthesis Highlights (J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. ReiBig, Eds.), VCH, Weinheim, New York, 1991, 116-118. S. Pereira, M. Srebnik, The Ireland-Claisen Rearrangement, AldrichimicaActa 1993, 26, 17-29. 

Still and Schneider employed Ireland-Claisen rearrangement in the total synthesis of ( )-frullanolide (ll)6 (Scheme 1.3f). The key step of the synthesis is efficient Ireland-Claisen rearrangement of the P-pyrrolidinopropionate ester 12. The triethylsilylketene acetal rearranged in toluene at reflux and the pyrrolidine moiety was eliminated after stirring with a mixture of dimethyl sulfate and potassium carbonate in methanol to afford the a-substituted acrylic ester (13). Saponification followed by iodolactonization gave the iodolactone 14, which upon treatment with DBU led to ( )-frullanolide. 

In total synthesis of the structurally unique natural product calcimycin (15), Grieco and others used Ireland-Claisen rearrangement of the ester 17 to synthesize the key intermediate (18)7 (Scheme 1.3g). Monosilylation of the diol 16 followed by treatment with propionyl chloride in pyridine gave rise to the ester 17 in 90% yield. Treatment of 17 with LDA in THF at —78 C, subsequent addition of ferf-butyldimethylsilyl chloride in HMPA, and brief heating of the resulting silylketene acetal provided the corresponding silyl ester. Subsequent hydrolysis of the silyl ester and esterification with diazomethane gave 18 in 90% yield from 17. 

The C20 amino acid (2.V,3.S, 8.S, 9.S, 4/ , 6 )-3-amino-9-methoxy-2,6,8-tri-methyl-10-phenyldeca-4,6-dienoic acid (Adda 19) is a molecule of interest to biologists and organic chemists as a component of the hepatotoxic cyclic peptides called microcystins. Kim and Toogood used Ireland-Claisen rearrangement in their successful synthesis of Adda8 (Scheme 1.3h). The ester 20 underwent highly diastereoselective Ireland-Claisen rearrangement to provide the acid 21. Conversion of this acid to the phosphonium bromide 22 was achieved in nine... 

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. 

A new approach to the synthesis of Prelog-Djerassi Lactonic acid (1) is reported. A key step in this synthesis involves an Ireland-Claisen rearrangement/silicon-mediated fragmentation sequence to provide the carbon framework in (1). 

Scheme 3 Synthesis of intermediate for the Ireland-Claisen rearrangement...

The final approach was elegantly presented by Panek [44]. Several optically active ( )-crotylsilanes are available via stereoselective Ireland-Claisen rearrangement of enantiomerically pure vinylsilanes. Addition of the chiral crotylsilanes to acetals or to mixtures of aldehyde and trimethylsilyl methyl ether is effected by la to afford homoallylic ethers in exceedingly high diastereo- and enantioselectivity (Sch. 13). Occasionally a stoichiometric amount of la is required for allylation of aliphatic acetals, preserving the excellent level of asymmetric induction. The synthesis of (-F)-macbecin I involving triple use of the strategy imderscores the utility of the la-catalyzed asymmetric allylation [44c]. 

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. 

One key element of the total synthesis of (-)-dactylolide (-)- developed by McLeod et al. is a [3,3]-sigmatropic Ireland-Claisen rearrangement which allows the selective formation of the stereogenic centre at C-19. 

Recently, Claisen rearrangement of allyl-vinyl ether prepared from glycal ester with Tebbe reagent was reported [91]. In contrast to the Ireland-Claisen rearrangement, in principle, a non-enolizable ester can be employed (O Scheme 63). This method was applied for the synthesis of C-disaccharide. 

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