Asymmetric Ireland-Claisen rearrangement

Synthetic highlights on the pathway to the optimized leads 1-3 provide instructive examples of the intensive engagement of batch-wise synthetic chemistry at a relative early stage of lead optimization for future NDEs, as presented in Fig. 1.2. 

With the availability of an efficient method for the synthesis of enantiomerically pure (3S)-4, a multidisciplinary team at Merck Sharp and Dohme Research and 

According to Corey s early study, the E/Z ratio in this reaction is usually over 90 10, and for transformation of 8-10 it reaches 99 1 [23]. Since in this rearrangement, the terminal C=CH2 bond is formed, no diastereoselectivity around the unsaturated C=C bond can be expected. To optimize the yield and e.e. of 10, the authors modified the original protocol so that addition of the ester 8 to the bromoborane catalyst in step iv was carried out at 78°C, and after 1 h stirring at this temperature, the reaction was continued at ambient temperature for 16 h [22]. Following this protocol, approx. 80% yield of the (2/ ,3S)- -isomer of 10 with 

6 Hydroboration of the Terminal C=C Bond Anti-Markovnikov Hydratation 

Reagents and conditions / BnBr, K2C03.DMF II. BFI, THF, TFIF, then ifiTBSOTf, 2,6-lutidine, DCM, - 78 X  

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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. 

Chiral Auxiliary Mediated Asymmetric Ireland-Claisen Rearrangements 4.6.6.1 Chiral Clycolates... 

To date the most general chiral auxiliary mediated asymmetric Ireland-Claisen rearrangement is that of Corey et al. (Scheme 4.44) [47]. They found that treatment of crotyl propionates and related esters afforded good yields, diastereoselectivities and enantioselectivities of the pentenoic acid products. The rearrangements also occurred at significantly lower temperature than the silyl ketene acetals. A key advantage of the chemistry is that the chiral auxiliary attachment, Ireland-Claisen rearrangement, and auxiliary removal all occur in one pot. 

Corey et al. used the asymmetric Ireland-Claisen rearrangement in the synthesis of j8-elemene (Scheme 4.131) [124], Rearrangement of the Z-(0)-B-ketene acetal via the chair transition state afforded the trienic acid in good yield with complete diastereo- and enantioselectivity. 

Synthetic highlights Racemization and enantiomerization are two consequences of configurational instability. Enantiomerically enriched 3-amino-1,4-BZDs have been generated via crystallization-induced asymmetric transformation. Enantiomerically pure target products have been obtained by asymmetric Ireland-Claisen rearrangement, highly enantioselective rearrangement of prochiral allylic esters to 1,2-disubstituted carboxylic acids and hydroboration of the terminal C=C bond, an efficient anti-Markovnikov hydratation process. 

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]. 

As mentioned for the Ireland-Claisen rearrangement, asymmetric Claisen rearrangement reactions are well known.Chiral Lewis acids have been designed for... 

Konno, T. Kitazume, T. Synthesis of trifluoromethylated compounds with four consecutive asymmetric centers via sequential [3,3]-Ireland-Claisen rearrangement and iodolacto-nization. Tetrahedron Asymmetry 1997, 8, 223-230. 

In the Pd(II) catalyzed Ireland-Claisen rearrangement reported by Yamazaki et al. mentioned previously (cf. Scheme 4.9) a pronounced stereochemical effect was noted due to the Cl CF3 group (Scheme 4.25) [8]. The rearrangement apparently occurred via the Z-silyl ketene acetal and exhibited high 1,2-asymmetric induction. The lowest energy conformation about the Cl-CT bond should have the... 

Fleming and Betson reported that Ireland-Claisen rearrangement of either the E-or Z-silyl ketene acetals bearing a stereocenter at Cl possessing a TBDPS group gave moderate (R = i-Pr) to excellent (R = Me, Ph) 1,2-asymmetric induction (Scheme 4.32) [34]. The transition states were proposed to adopt a conformation with the CT hydro-... 

Djerassi and Shu observed no asymmetric induction in the Ireland-Claisen rearrangement of a steroid derived crotyl ester possessing an all-carbon stereocenter in the Cl" position (Scheme 4.39) [41]. In the case of the Z-sUyl ketene acetal, aU four possible isomers were obtained in a 7 7 1 1 ratio, with the major products being the expected syn isomers. 

Parsons et al. employed an allyl silane Ireland-Claisen rearrangement as a route to 1,3-dienes (Scheme 4.83) [78]. Rearrangement of the allyl silane was followed by acid induced fragmentation of the y5-epoxy aUyl silane to give the diene with high alkene stereoselectivity. The asymmetric induction at C2 of the pente-noic acid was surprisingly low for this type of Claisen rearrangement. 

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. 

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