Aldol reaction ephedrine

Another chiral auxiliary for controlling the absolute stereochemistry in Mukaiyama aldol reactions of chiral silyl ketene acetals has been derived from TV-methyl ephedrine.18 This has been successfully applied to the enantioselec-tive synthesis of various natural products19 such as a-methyl-/ -hydroxy esters (ee 91-94%),18,20 a-methyl-/Miydroxy aldehydes (91% ee),21 a-hydrazino and a-amino acids (78-91% ee),22 a-methyl-d-oxoesters (72-75% ee),20b cis- and trans-l1-lactams (70-96% ee),23 and carbapenem antibiotics.24... 

Other Applications. Chiral oxazaborolidines derived from ephedrine have also been used in asymmetric hydroborations, and as reagents to determine the enantiomeric purity of secondary alcohols. Chiral l,3,2-oxazaborolidin-5-ones derived from amino acids have been used as asymmetric catalysts for the Diels-Alder reaction,and the aldol reaction. ... 

The enolates of //-acylimidazolidinones derived from 1.131 generated from ephedrine 1.61 (R = H) are useful in asymmetric alkylations [447, 448] and aldol reactions [449, 450] and cuprate additions to the a,p-unsaturated acyl analogs have recently been described [451], These chiral auxiliaries are cleaved by MeONa/MeOH or LiEtBHj. Recently, Davies and coworkers have suggested the use of symmetrical AyV-diacyl-1,3-imidazolidin-2-ones 1.132, formed from diamines having a C2 axis of symmetry [452], for asymmetric aldol reactions [449]. Juaristi [453] has used peihydropyrimidin-4-ones for related purposes. 

These results are interpreted by the attack of the aldehyde on the least hindered side of the enolate 6.104, through a chair or twist-boat-like transition state [408] (see above). Both (S)- and (R)-chromium tricarbonyl complexes of 2-me-thoxyacetophenone have been prepared, and their boron enolates react selectively with MeCH=CHCHO, although further decomplexation was not carried out [1280]. Chiral aminonitrile 1.71 bearing the ephedrine skeleton [301] or men-thone-derived ketals [374] have been used as chiral auxiliaries in aldol reactions, but modest selectivities were obtained. 

Based on mechanistic studies and on the reasonable expectation that both the aldehyde carbonyl and the ephedrine NMe2 group tend to bind to TiCl4, which usually ligates two electron-donating molecules to form cis-octahedral six-coordinate complexes, the transition structure models shown below were proposed for the asymmetric aldol reaction. ... 

Hitchcock and covrorkers developed ephedrine-derived 3,4,5,6-tetrahydro-21-f-l,3,4-oxadiazin-2-one-based chiral auxiliary 141 and demonstrated its utility in aldol reactions [50]. It vas discovered that the aldehyde had to be present during enolization for reaction to occur, because of difficulties in enolization. Use of aromatic aldehydes resulted in good yield and good to excellent selectivity, as did aliphatic aldehydes vithout a-hydrogen atoms. This method is not useful for aldehydes bearing a-hydrogen atoms, because of self-condensation. 

Scheme 4.48 Evans aldol reaction of ephedrine-derived N-propionyloxazolidinone 51 and conversion of the adduct 213 into Weinreb amide 214 under cleavage of the auxiliary.

Several examples exist of the application of chiral natural N-compounds in base-catalyzed reactions. Thus, L-proline and cinchona alkaloids have been applied [35] in enantioselective aldol condensations and Michael addition. Techniques are available to heterogenize natural N-bases, such as ephedrine, by covalent binding to mesoporous ordered silica materials [36]. 

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