Amino alcohols chiral purity

Asymmetric [1,3 dipolar cycloaddition.2 This sulfoxide reacts with C-phenyl-N-methylnitrone (2) to form optically active 4-(p-tolylsulhnyl)-isoxazoIiilines (3a and 3b), which differ only in chirality of the S=0 group. The optical purity was shown to be no less than 80% by conversion to the amino alcohol 4. The absolute configuration... 

Cellulose was the first sorbent for which the resolution of racemic amino acids was demonstrated [23]. From this beginning, derivatives such as microcrystalline triacetylcellulose and /3-cyclodextrin bonded to silica were developed. The most popular sorbent for the control of optical purity is a reversed-phase silica gel impregnated with a chiral selector (a proline derivative) and copper (II) ions. Separations are possible if the analytes of interest form chelate complexes with the copper ions such as D,L-Dopa and D.L-penicillamine [24], Silica gel has also been impregnated with (-) brucine for resolving enantiomeric mixtures of amino acids [25] and a number of amino alcohol adrenergic blockers were resolved with another chiral selector [26]. A worthwhile review on enantiomer separations by TLC has been published [27],... 

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 slow nucleophilic addition of dialkylzinc reagents to aldehydes can be accelerated by chiral amino alcohols, producing secondary alcohols of high enantiomeric purity. The catalysis and stereochemistry can be interpreted satisfactorily in terms of a six-membered cyclic transition state assembly [46,47], In the absence of amino alcohol, dialkylzincs and benzaldehyde have weak donor-acceptor-type interactions. When amino alcohol and dialkylzinc are mixed, the zinc atom acts as a Lewis acid and activates the carbonyl of the aldehyde. Zinc in this amino alcohol-zinc complex is regarded as a kind of chirally modified Lewis acid. Various kinds of polymer-supported chiral amino alcohol have recently been prepared and used as ligands in dialkylzinc alkylation of aldehydes. 

Itsuno s amino alcohol (70), prepared from L-valine, is an extremely efficient auxiliary for enantioselective reduction of aryl alkyl ketones using BH3. The corresponding alcohols are obtained in up to 100% ee using BH3 and 0.5 equiv. of (70) in THF at 30 °C. Reduction of dialkyl ketones affords (R)-carbinols in 55-73% ee. Halomethyl t-butyl ketones are also converted to the corresponding (5)-carbinols in high optical purity (Scheme 15). Immobilized amino alcohol (70) permits reduction in a continuous flow system. 1-Phenylpentanol of 90% ee was prepared by this catalytic process in almost 1000% chemical yield based on the quantity of chiral auxiliary used. ... 

An asymmetric synthesis of amino alcohols by asymmetric addition of Grignard reagents to chiral a-bromoglycine esters provides a convenient synthesis of a-amino esters (Scheme 4.8, [99]). Hydrolysis of the product ester produces racemized amino acids, but reduction affords amino alcohols that can be subsequently oxidized to the amino acids with no loss of enantiomeric purity. Note that in the proposed transition structure, the phenyl effectively shields the Re face (toward the viewer) of the imine, which is chelated to the carbonyl by magnesium halide formed in the dehydrohalogenation. 

Individual amino acids show considerable differences in their propensity for racemization. This is exceptionally pronounced in derivatives of S-benzyl-cysteine, 0-benzyl-serine and S-cyanoalanine. The role of the substituent on the jS-carbon atom is not obvious. Early assumptions of j8-elimination, that is the reversible elimination-addition of benzyl mercaptane, benzyl alcohol or HCN, were not supported by the extensive studies of J. Kovacs. This example shows, however, that the azlactone mechanism, while it appears to be the most important pathway of racemization, is not the only process which leads to diminished chiral purity. For instance it is reasonable to consider that... 

Several different measures of the diastereoselectivity can be given. Just as for e.e., we can define the diastereomeric excess (d.e.) of a reaction as the proportion of the major diastereomer produced less that of the minor one. In examples such as the one here, where one new stereogenic unit is formed in a diastereoselective reaction, this is the preferred measure of selectivity. While it does not have the same correlation with optical purity as e.e., it does have the advantage that if the original stereogenic unit(s) are removed, as, for example, by removal of the chiral auxiliary in a second-generation method (see chapter 5), the e.e. of the final product correlates directly with the d.e. of the initial product. Thus if the mixture of (56) and (57) was decarboxylated, the e.e. of the resulting amino alcohol would be equal to the d.e. of (56)/(57). 

After 18 rounds of evolution and the introduction of at least 35 mutations, the volumetric activity of the mutant was increased 4000-fold and this allowed a process having a space-time yield greater than 360 gp, d L/d. The optical purity of the desired product was higher than 99.5%. As a result of this extensive protein engineering study, several new and usefiil HHDHs became commercially accessible. The synthetic applicability of these HHDHs was demonstrated on several examples in the past [30,82-85]. Kosjek and coworkers published the resolution of 2,2-disubstituted epoxides 50 via biocatalytic azidolysis and subsequent synthesis of chiral amino alcohols 52 and aziridines 53 containing a tertiary center (Scheme 9.17) [86]. 

The chiral Mn-salen catalysts have successfully been used in pharmaceutical industry processes. For example, enantioselective epoxidation of indene 43 under Jacobsen et al. s conditions provided epoxide 44 in 71% yield and 84—86% ee. It was reported that both yield and enantiose-lectivity were increased by adding 4-phenylpyridine N-oxide (PPNO) as co-oxidant in the system. A modified Ritter reaction converted indene oxide 44 into the c -amino alcohol 46. The enantiomeric purity of 46 was enhanced to >99% ee by formation of the corresponding L-tartrate salt followed by recrystallization. Amino alcohol 46 was identified as a critical component of the highly effective HIV protease inhibitor Indinavir 47 developed by Merck (White-house Station, NJ) (Scheme 35.12). ... 

Soai developed the/5-amino alcohol N,N-dibutylnorephedrine (DBNE, 159) which is readily available in both enantiomeric forms (Scheme 2.18) [99]. This ligand generates a catalyst for the addition of Et2Zn to both aliphatic and aromatic aldehydes with excellent optical purity ( 90%). As an example of the high stereocontrol induced by the chiral catalyst, either enantiomer of DBNE overrules the induction by the stereocenter in the a-chiral aldehyde 158 to furnish the diastereomeric products 160 and 161, respectively, with impressive stereoselectivity [100]. 

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