Ireland-Claisen rearrangement control

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. 

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 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... 

Asymmetric Ireland-Claisen Rearrangements. Chiral enolates derived from the boron complex (5) and allyl esters rearrange with excellent selectivity upon warming to —20 °C for a period of 1-2 weeks (eqs 9 and 10). As discussed above, the geometry of the intermediate enolate can be controlled by appropriate choice of base and solvent, thus allowing access to either syn or anti configuration in the product The reaction can be completed in 2-4 days with little erosion in selectivity when run at 4 °C. 

Application of Claisen methodology led to a number of successful total syntheses of natural compounds. Thromboxane B2 has been synthesized from a 4,5-unsaturated sugar derived from D-glucose [126]. The Ireland-Claisen rearrangement [127] is also the key reaction used to control the introduction of the right wing of pseudomonic acids [128]. 

In addition, an important feature of the Ireland-Claisen rearrangement is the option of controlling the enolate geometry through judicious choice of the reaction conditions. ... 

TBS-protection, a second, boron-mediated, syn aldol reaction led to the formation of 277 with 95% ds. In this case, ketone 278 controlled the stereochemical outcome of the reaction, and chiral ligands on boron were not required. A simple steric model accounts for this selectivity (see Scheme 9-11), and a titanium-mediated aldol reaction would be expected to give the same product. Following elaboration, including an Ireland-Claisen rearrangement, aldehyde 279 was prepared. 

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]. 

This method also allows a two-directional chain elongation with considerable structural flexibility. Thus, double Ireland-Claisen rearrangement of the symmetrical bis(propanoate) 21 gives meso, a]]-syn 23 in 86% d.r. together with complete control of the alkene geometry446. 

Hydroxyethylene dipeptidc isosteres 35, which are of interest as transition state analogs, e.g., in renin inhibitors where they replace the scissile dipeptide unit (Leu-Val) of angiotensinogen, the natural substrate of renin, can be obtained from optically active acid 32 via iodolactoniza-tion in several steps. The synthesis of 32 is achieved using an Ireland - Claisen rearrangement as the key step which allows complete control of the three stereogenic centers44. For a stereocontrolled synthesis of peptide bond isosteres via Claisen rearrangements see also ref 448. 

The stereoselectivity of the Ireland-Claisen rearrangement is controlled by the configuration of the double bonds in both the allylic alcohol and the silyl ketene acetal. The chair TS model predicts that the configuration at the newly formed C-C bond will be determined by the E- or Z-configuration of the silyl ketene acetal. 

Allylic alcohol 846 is instrumental in controlling the stereochemistry in the synthesis of (+ )-roccellaric acid (864) [231] (Scheme 115). The key step is an Ireland-Claisen rearrangement of propionate 861, which produces 862 as a mixture of isomers (epimeric at the methyl group). The minor diastereomer is removed at the lactone stage (863). Debenzylation and oxidation of the alcohol to an acid furnishes the natural product. 

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. 

Kuwajima and Aoki first reported a 1,4-addition/Ireland-Claisen rearrangement sequence (Scheme 4.56) [57]. Cu-catalyzed addition of MeMgBr to a series of allyl acrylates yielded the desired pentenoic acids, albeit in modest diastereoselectivity. The low diastereoselectivity almost certainly reflected a lack of control of enolate geometry. 

Tab. 5.2.5 Auxiliary-controlled Ireland-Claisen rearrangements of esters 20.

Several applications of the chelation-controlled Ireland-Claisen rearrangement in natural product syntheses were reported by Burke et al. The syntheses of a series of bicyclic bilactone natural products such as ethisoUde and related structures started with an epimeric mixture ofj8-hydroxy-a-methylene lactone 57 (Scheme 5.2.18) [31]. 

Very recently, Hong et al. [48] used the chelation-controlled Ireland-Claisen rearrangement of 89 in their synthesis of carbovir analogues 91. Herein, again the ring was closed via ring-closing metathesis. 

---