Hydroxy amides resolution

Figure 18.25. Dynamic kinetic resolution of racemic y-hydroxy amides 67.

Fransson, A. B. L., Boren, L., Pamies, O., and Backvall, J. 2005. Kinetic resolution and chemoenzymatic dynamic kinetic resolution of functionalized y-hydroxy amides. J. Org. Chem., 70(1) 2582-2587. 

In some cases the resolution of the diastereomeric amides on silica gel is sufficiently large to achieve preparative separation. The preparative separation of diastereomeric hydroxy amides has proved useful in supplying quantities of enantiomerically pure lactones (eq 5). ... 

The same successful procedure applies to other hydroxy compounds such as hydroxy lactones [202], hydroxy amides [203], and hydroxy phosphonic acids [204,205]. The results of these enantioselective resolutions are presented in Scheme 44. 

Scheme 44 Resolution of hydroxy lactones, hydroxy amides, and hydroxy phosphonamides.

The enzymatically catalyzed kinetic resolution of amino alcohols has been established on the multi-ton scale by BASF [7] (Scheme 7.14). Initial studies gave poor selectivity for the unprotected alcohols, as the resolution of trows-2-aminocyclopen-tanol (racemic 28) gave the amine (S,S) 29 and the amide (R,R) 30 in 25% . When the hydroxy functionality was protected as an ether, then resolution of racemic benzyl ether 31 proceeds with high to the give the amine (S,S) 32 and the RR amide 33 with >99.5 and 93 % respectively [33, 34]. 

The application of antibiotics as chiral selectors has resulted in the successful resolution of almost all types of neutral, acidic, and basic racemic molecule. These antibiotics have been used for the enantiomeric resolution of amino acids, their derivatives, peptides, alcohols, and other pharmaceuticals. The selectivities of the most commonly used antibiotic-based (vancomycin, teicoplanin, and ristocetin A) CSPs varied from one racemate to another and are given in Table 1. Vancomycin was used for the chiral resolution of amino acids, amines, amides, imides, cyclic amines, amino alcohols, hydantoins, barbiturates, oxazolidinones, acids, profens, and other pharmaceuticals. Teicoplanin was found to be excellent chiral selector for the enantiomeric resolution of amino acids, amino alcohols, imides, peptides, hydantoins, a-hydroxy and halo acids, and oxazolidinones, whereas ristocetin A is capable of chiral resolution of amino acids, imides, amino... 

Hydroxy-N-methylmorphinan was also found to bind to opioid receptors), but its analgesic activity in the MW assay was of doubtful significance. Related morphinan-6-ones were synthesized via 3-methoxyphenylethyl-amide(76,77) (e.g., Scheme 3.10). Resolution at the 2-benzyltetrahydroiso-quinoline stage afforded (-)-2-hydroxy-N-methylmorphinan-6-one (75a) and the corresponding methyl ether (75b). Neither compound exhibited significant MHP activity,(50) with the ether being only about i x morphine. The (+)-enantiomorphs were prepared in a similar manner.<50)... 

Such requirements very well meet especially when a-amino acids and a-hydroxy acids are separated. It is interesting that resolution of amino acids racemates could be easily obtained for a-amino acids possessing a free carboxyl group. In case of esterification, amidation, elimination, reduction, or substitution of carboxylic group, resolution was poorer or there was no resolution. 

Resolution of a,a-disubstituted a-amino acids (but also of a,a-disubstituted a-hydroxy acids [51]) can also be performed on their esters. We have used pig liver esterase (PLE) for resolution of a variety of a,a-disubstituted esters. Although all substrates tested are hydrolyzed, only for a-substituted phenylglycine esters (17, X = NH2) and a-substituted mandelic esters (17, X = OH) reasonable enanlioselectivities are observed for hydrolysis of the (S) enantiomer (E = 2-114) [44]. For these types of amino acids and hydroxy acids the PLE resolution forms a valuable extension of the M. neoaurum resolution technology, since the corresponding racemic amides are hydrolyzed sluggishly (Scheme 8). The PLE resolution of a-allylphenylglycine ethyl ester has been applied in the synthesis of D-a-phenylproline (vide infra). 

L-a-Amino acids have been prepared by the resolution of racemic a-amino acid amide by the L-specific aminopeptidase from Pseudomonas putida ATCC 12633 [7]. Enzyme from R putida ATCC 12633 cannot be used to resolve a-alkyl-substituted amino acid amides 103. Aminoamidase from Mycobacterium neoaurum ATCC 25795 has been used in the preparation of L-a-alkyl amino acid 104 (Fig. 34) and D-amide of a-alkyl-substituted amino acids by enzjmaatic resolution process using racemic a-alkyl amino acid amide as a substrate [169,179]. Amidase from Ochrobactrum anthropi catalyzed the resolution of a,a-disubsituted amino acids, iV-hydroxy amino acids, and a-hydroxy acid amides. The resolution process could lead to the production of chiral amino acids or amides in 50% yield. Recently, amino acid racemases have been used to get 100% yield of chiral amino acids [179]. 

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