Evans’ auxiliaries

ETP2 base, see phosphazene base 2 Evans auxiliary, see Darzens reaction 13 exo cyclization mode 272... 

The main disadvantages of Evans auxiliaries 22 and 23 are that they are expensive to purchase and inconvenient to prepare, as the preparation involves the reduction of (5 )-valine 24 to water-soluble (b )-valinol, which cannot be readily extracted to the organic phase. The isolation of this water-soluble vali-nol is difficult and requires a high vacuum distillation, which is not always practical, especially on an industrial scale. Therefore, an efficient synthesis of Evans chiral auxiliary 25 has been developed, as depicted in Scheme 2-1930 ... 

The chiral boron enolates generated from /V-acyl oxazolidones such as 7 and 8 (which were named Evans auxiliaries and have been extensively used in the a-alkylation reactions discussed in Chapter 2) have proved to be among the most popular boron enolates due to the ease of their preparation, removal, and recycling and to their excellent stereoselectivity.8... 

Double asymmetric induction (See section 1.5.3) can also be employed in aldol reactions. When chiral aldehyde 15 is treated with achiral boron-mediated enolate 14, a mixture of diastereomers is obtained in a ratio of 1.75 1. However, when the same aldehyde 15 is allowed to react with enolates derived from Evans auxiliary 8, a syn-aldol product 16 is obtained with very high stereo-... 

The Evans auxiliary is first removed reductively. As a result, N- Solution... 

Substrate for this kind of Evans auxiliary is the aminoacid (/ )-phenylalanine, which is reduced to the alcohol 23 and exposed either to carbon disulfide in combination with triethylamine and sodium hydroxide to synthesize 19 or to diethylcarbonate and potassium carbonate to form oxazolidin-2-one 24. 

Neri, C. Williams, J. M. J. New routes to chiral Evans auxiliaries by enzymatic desymmetrization and resolution strategies. Adv. Synth. Catal. 2003, 345, 835-848. 

Alternatively, diltiazem (30) has been prepared using the Evans auxiliary derivative 31 derived from L-valine (Scheme 23.7).55 After dehydration of the adduct from the condensation of 31 with anisaldehyde through the mesylate, the enol ether was formed with a Z E ratio of 4 1. This imide was then treated with 2-aminothiophenol in the presence of 0.1 equiv. 2-aminothiophenoxide with no change in the isomer ratio. The auxiliary was removed with trimethylaluminum, with concomitant formation of the lactam. After separation by crystallization, the correct diastereoisomer was converted to diltiazem in >99%ee. 

Lilly has used an Evans auxiliary in its synthesis of LY309887 (32), a dideazafolate antitumor agent (Scheme 23.8).2 The de of the key step, reaction of the titanium-derived enolate, was >98%. It was noted that the auxiliary could be recycled after cleavage with lithium borohydride. 

Unfike the Evans auxiliaries, however, removal of the super Quat auxiliary is easily accomplished upon treatment with either lithium hydroxide or lithium alkoxide. Thus, hydrolysis with LiOH affords the enantionmerically pure a-substituted carboxylic acid and near quantitative recovery of the chiral auxiliary (eq 8). 

The first successful asymmetric Diels-Alder reaction was the reaction of cyclopenta-diene with a chiral a,j8-unsaturated amide with Evans auxiliary by use of different Lewis acids [23]. The highest endo/exo selectivity was observed when ZrCl4 was used, although the enantioselectivity when ZrCU was employed was lower, in the ratio 7.2 1, whereas use of Et2AlCl under similar conditions gave a ratio of 17 1 (Eq. 23). 

What is the substrate that contains the Evans auxiliary ... 

After protection of the secondary alcohol with TBSOTf, the Evans auxiliary is cleaved under reductive conditions with LiBH4 to afford the primary alcohol, which is afterwards protected with TBSCl to form 25. 

After reductive cleavage of the Evans auxiliary, the resulting alcohol is TBS-protected employing TBSCl. This reagent is not reactive enough to react with secondary alcohols and thus selectively protects only the primary alcohol. 

The substituents of the oxazolidinone system Evans auxiliary) shield one face of the enolate. 

Typically, the product of an aldol reaction and its stereochemistry are predictable by using the formalism of the chair-like Zimmerman-Traxler transition state.However, if the formalism is used in this case, the stereochemistry of the product is predicted incorrectly. Using chelating metal ions (in this case zinc), favored transition states such as 31 should be formed. The heteroaryl substituent of aldehyde 8 is equatorially oriented and the substituents of the oxazolidinone auxiliary point outward. However, the favored transition state predicts the formation of the minor diastereomer epi-10. In transition state 32, the substituents of the Evans auxiliary point to the aldehyde, which destabilize this transition state and make it unfavored. The product predicted by this transition state is the major diastereomer 10, which is an astonishing result. 

Hintermann, T., Seebach, D. A useful modification of the Evans auxiliary. 4-lsopropyl-5,5-diphenyloxazolidin-2-one. Helv. Chim. Acta 1998, 81,2093-2126. 

A vinylogous Mukaiyama reaction, similar to that utilized in our synthesis, was employed to introduce the C-, stereocenter in Nicolaou s synthesis and also in the synthesis of preswinholide A reported by the Nakata group I53k One notable reaction in Nakata s synthesis of preswinholide A was the auxiliary-controlled aldol reaction shown in Scheme 9-31. Here the Evans auxiliary is used to couple two relatively complex fragments 91 and 92 to give 93. Unusually, this reaction was best performed using the lithium enolate of imide 91. 

Schering-Plough Corp, has used an oxazolidinone in its synthesis of the cholesterol adsorption inhibitor (+)-SCH 54016 (24) (Scheme 7) [51], Condensation of an acid chloride intermediate with the (7 )-phenylglycine-derived Evans auxiliary followed by reaction of the titanium enolate with -(4-methoxybenzyh-dene)anihne gave the intermediate 25. This was silylated and treated with TBAF, resulting in removal of the auxiliary and cyclization to form the 2-azetidinone ring. The stereochemistry was exclusively trans. The azetidinone was then converted to the bromide, followed by intramolecular alkylation to form SCH 50416 in > 99% ee. 

Diels-Alder PS-bound Evans auxiliary EtaAlCl [249]... 

Application of asymmetric alkylation with Evans auxiliaries Aldol Reactions with Evans Oxazolidinones The syn aldol reaction with boron enolates... 

Application of asymmetric alkylation with Evans auxiliaries... 

With a smaller Lewis acid (TiCI4) a slightly different open or extended transition state 115 is preferred leading predominantly to one syn-enantiomer 116. These variations on aldol reactions with the Evans auxiliaries allow the synthesis of almost any enantiomer in good yield. 

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