Johnson-Claisen rearrange

Johnson-Claisen Rearrangement (Johnson Orthoester Rearrangement)... 

The Johnson Claisen rearrangement,31 also called the ortho ester Claisen rearrangement, involves the reaction of an allylic alcohol with an ortho ester, often triethyl orthoacetate, in the presence of a carboxylic acid such as propionic acid, usually at temperatures between 120 and 140 JC (Scheme 3).1 The intermediate kctcnc acetal rearranges stereoselectively. 

Table 16. Synthesis of 4-Substiluled Ethyl 3,3-Difluoroalk-4-enoates 2 by Johnson-Claisen Rearrangement...

The fact that the two terminal fluorines do enhance the rate of Claisen rearrangement is demonstrated by the Johnson-Claisen rearrangement of tnonofluoroallylic alcohol 3, which gives only a 41 % yield of /f-fluoro ester 4 after 48 hours at 140 C.2y... 

In contrast, monofluoroallylic alcohol (S)-5 undergoes the Johnson-Claisen rearrangement in good yield after 7 hours at 130 C.33 The primary fluoride 6 is produced as the -isomer and with good 1,3-chiral transfer as the 7 -enantiomer. This ester is a key intermediate in the synthesis of 3 -fluoroapionuclcosides. 

More recently, Kitazume and co-workers found that allylic alcohols 7 undergo the Johnson Claisen rearrangement in higher yields when the reaction is run in a sealed tube at 130 C for 12 hours.35 Under these conditions. (/ )-7 is converted into 8 with high E stereoselectivity and complete 1,3-chiral transfer. 

In one study, the Johnson-Claisen rearrangement was carried out with tripropyl a-fluoroor-thoacetate to give 2-fluoroalk-4-enoates 18 in moderate yields.37 2,3-Disubstituted ester 18d is formed in a diastereomeric ratio of nearly 1 1. 

DFT studies on the facial selectivities of six Johnson-Claisen rearrangements (Scheme 5) analogous to those used in the synthesis of gelsemine have reproduced experimental results in five out of the six cases, but have predicted formation of the same product (21) in all six reactions. The selectivity in these cases has been attributed to a combination of steric repulsions between vinylic proton H(l) and allylic proton H(7) or H(14), and electrostatic attractions between C(l) and the oxetane hydrogens C(5)-H and C(16)-H. Both of these factors, however, apparently predicted the non-observed product in the conversion of (22) into (23)22... 

Other indirect evidence for the existence of a six-membered transition state in the Johnson-Claisen rearrangement is found in Daub et al. s experiments3 (Scheme 1.2c). When cinnamyl alcohol was heated with triethylorthopro-pionate in the presence of an acid catalyst, the products were obtained... 

The increased syn/anti selectivity observed in the Johnson-Claisen rearrangement of the ketene acetal from the trisubstituted alkene is an indication that the reaction goes through a six-membered chairlike transition state4 (Scheme 1.2d). Transition state B is disfavored compared to state A, due to the developing 1,3-diaxial interactions between the two methyl groups in the transition state. 

The preference for a chairlike transition state in the Johnson-Claisen rearrangement is supported by further Houk et al. s computational studies (Scheme 1.2e).5 For the rearrangement of the parent methyl ketene acetal, chairlike transition state A is favored over boatlike transition state B by 2.3 kcal/mol. 

Johnson et al. used their newly developed orthoester Claisen reaction to achieve a highly stereoselective total synthesis of aM-trans squalene (5)1 (Scheme 1.20. The diene diol 6 underwent Johnson-Claisen rearrangement when it was heated with ethyl orthoacetate in the presence of propionic acid for 3 h at 138 C. The diene dialdehyde 7, obtained by treatment of the resulting ester with lithium aluminum hydride followed by oxidation with Collins reagent, reacted with 2-propenyllithium to give the tetraene diol 8. The tetraene dialdehyde 9, which... 

Pearson and Hembre synthesized a key intermediate (19) using the Johnson-Claisen rearrangement protocol in the total synthesis of the indolizidine... 

NR2 Eschenmoser-Claisen rearrangement R" = OR Johnson-Claisen rearrangement... 

During the total synthesis of the pentacyclic sesquiterpene dilactone (+)-merrilactone A by S.J. Danishefsky et al., a two-carbon unit was introduced at C9 by a Johnson-Claisen rearrangement. This high yielding transformation was carried out in the presence of catalytic 2,2-dimethyl propanoic acid at 135 °C using mesitylene as the solvent. A mixture of diastereomeric esters were formed, which were later hydrolyzed and subjected to iodolactonization to form the second lactone ring present in merrilactone A. The natural product was synthesized in 20 steps with an overall yield of 10.7%. 

The C7 quaternary stereocenter of (+)-gelsemine was established utilizing a Johnson-Claisen rearrangement by S.J. Danishefsky and co-workers.The starting stereoisomeric allylic alcohols were individually subjected to the rearrangement conditions, and each gave rise to the same Y,5-unsaturated ester. 

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