Ephedrine-derived ligands

Scheme 3.4 Ephedrine-derived S/N ligands for addition of ZnEt2 to benzaldehyde.

High degrees of enantioselectivity have been observed when alkylzinc reagents react with aldehydes in the presence of chiral ligands.120 Among several compounds that have been used as ligands are exo - (dime th y I a m i no )no rb o rn c o I (A)121 122 123 124 and diphenyl(l-methyl-pyrrolin-2-yl)methanol (B) as well as ephedrine derivatives C and D. 

In the last section several oxazaphospholidine oxides, obtained by oxidation of the P(III) precursor with t-BuOOH, have already been described. There is also one report by Juge and co-workers in which they prepare oxazaphospholidine oxides and sulfides by in situ deboronation/oxidation of oxazaphospholidine boranes. This section illustrates some more derivatives, prepared directly from P(V) species and ephedrine. Chronologically, these types of compounds were studied earlier than the corresponding P(III) counterparts. Nowadays oxazaphospholidine boranes, not oxides, are the most important precursors used to prepare enantiopure phosphorus ligands. However, apart from historic interest, ephedrine-derived oxazaphospholidine oxides, sulfides and selenides occupy an important place in the study of phosphorus stereochemistry and conformational analysis. Only a few examples are described here. 

Brunner and Hammer in 1984, who employed Co(acac)2 combined with a chiral C2-symmetric diamine ligand which provided enantioselectivities of up to 66% ee. Later in 1988, Soai et al developed the first asymmetric conjugate additions performed under chiral nickel(ii) catalysis/ The process, which involved dieth-ylzinc addition to chalcones, provided the corresponding 1,4-products in low to moderate enantioselectivities (<55% ee) by using an ephedrine derivative as the chiral ligand, as shown in Scheme 2.1 (first equation). Soon after, better enantioselectivities of up to 90% ee were achieved by the same authors using Ni(acac)2 as the nickel source instead of NiBr2, bipyridine as additive, and acetonitrile as solvent (Scheme 2.1, second equation). ... 

Chiral benzophospholanes are an interesting class of compounds with potential appUca-tions as chiral ligands in enantioselective reactions. These reactions can be promoted by palladium complexes however, the selectivity is moderate [1]. An alternate approach used an ephedrine-derived auxiliary (Scheme 4.192) [330], One of the keys to the synthesis was the use of ether as the solvent. Other solvents such as THF were not as effective. The final step in the synthesis involved loss of the chiral auxiliary and formation of the borane-protected l-phenyl-2-ox-a-l-phosphindane. The yield and selectivity of the process were outstanding (96%, 97.5% ee). 

Grigg and co-workers (383) found that chiral cobalt and manganese complexes are capable of inducing enantioselectivity in 1,3-dipolar cycloadditions of azomethine ylides derived from arylidene imines of glycine (Scheme 12.91). This work was published in 1991 and is the first example of a metal-catalyzed asymmetric 1,3-dipolar cycloaddition. The reaction of the azomethine yhde 284a with methyl acrylate 285 required a stoichiometric amount of cobalt and 2 equiv of the chiral ephedrine ligand. Up to 96% ee was obtained for the 1,3-dipolar cycloaddition product 286a. 

On the other hand, enantioselective conjugate addition to 2-cyclohexenone with lithium dibutylcuprates (having a noncova-lently bound chiral phosphorus ligand derived from ephedrine) affords 3-butylcyclohexanone with up to 76% ee (eq 14). ... 

ReO(Tp)(r]2-N-X)] have been synthesized from the reaction of [ReOCl2(Tp)] with chiral bidentate ligands in which r 2-N-X = alcoholates or amidates derived from (lS,2/ )-ephedrine, (I. S, 2.S )-diphcriylcthylcricdiamine, and L-proline. These chiral-at-Re complexes have been fully characterized by NMR, IR, circular dichroism, polarimetry, and X-ray crystallography, and have been found to be stable and resistant to oxo-transfer when subjected to harsh conditions.216... 

The first attempt to use a chiral ligand to modify borane was Kagan s attempt at enantioselective reduction of acetophenone using amphetamine-borane and desoxy-ephedrine-borane in 1969 [18]. However, both reagents afforded 1-phenyl ethanol in <5% ee. The most successful borane-derived reagents are oxazaborolidines, introduced by Hirao in 1981, developed by Itsuno, and further developed by Corey several years later (reviews [19,20]). Figure 7.2 illustrates several of the Hirao-Itsuno and Corey oxazaborolidines that have been evaluated to date. All of these examples are derived from amino acids by reduction or Grignard addition. Hirao... 

Enantioselective addition of Bu2CuLi to enones. Preliminary results indicate that the phosphorus derivative 1 of ephedrine can serve as a chiral ligand for dibutyl-cupratcs. The ligand (+) is obtained by reaction of (—)-ephedrine with HMPA. Highest enantioselectivity is obtained by use of two equiv. of 1 for one equiv. of the cuprate... 

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