Enantiomers stereospecific

The stereochemistry of drugs and precursors can be vital in determining synthetic routes. Horvever, since enantiomers are nearly chemically identical, standard chromatographic methods cannot separate them. To effect a chromatographic separation of enantiomers, stereospecific interactions have to be incorporated. As described in Chapter 5, the use of chiral stationary phases is one method of discriminating enantiomers while capillary electrokinetic chromatography (MEKC) using chiral cy-clodextrins is another. Both of these protocols have been applied to methamphetamine and related compounds and precursors, substances that will be discussed in detail later in the chapter. 

Even though the ris-aconitate substrate is achiral, only the (2P.35) enantiomer of the product is formed. We ll look at the reason for this stereospecificity in Section 9.14. 

Figure 2.3 An example of a stereospecific biotransformation resolution of bicyclic lactams. A and Ai are an enantiomer pair as are B and Bi.

The stereospecificity of the biological oxidation reactions has been exploited in the preparation of optically active sulphoxides. One enantiomer of the sulphoxide is oxidized to the sulphone faster than the other and so there is an excess of one enantiomeric sulphoxide after partial reaction has occurred164. 

Allylic alcohols can be converted to epoxy-alcohols with tert-butylhydroperoxide on molecular sieves, or with peroxy acids. Epoxidation of allylic alcohols can also be done with high enantioselectivity. In the Sharpless asymmetric epoxidation,allylic alcohols are converted to optically active epoxides in better than 90% ee, by treatment with r-BuOOH, titanium tetraisopropoxide and optically active diethyl tartrate. The Ti(OCHMe2)4 and diethyl tartrate can be present in catalytic amounts (15-lOmol %) if molecular sieves are present. Polymer-supported catalysts have also been reported. Since both (-t-) and ( —) diethyl tartrate are readily available, and the reaction is stereospecific, either enantiomer of the product can be prepared. The method has been successful for a wide range of primary allylic alcohols, where the double bond is mono-, di-, tri-, and tetrasubstituted. This procedure, in which an optically active catalyst is used to induce asymmetry, has proved to be one of the most important methods of asymmetric synthesis, and has been used to prepare a large number of optically active natural products and other compounds. The mechanism of the Sharpless epoxidation is believed to involve attack on the substrate by a compound formed from the titanium alkoxide and the diethyl tartrate to produce a complex that also contains the substrate and the r-BuOOH. ... 

The combined use of the oxidation of a free phosphine [99] and stereospecific reduction of the phosphine oxide [74] was employed for the synthesis of (R,R)-f-Bu-BisP from (S,S)-BisP itseLf. Specifically, (S,S)-BisP was deboronated (TfOH/KOH), oxidized (HjOj), and reduced (MeOTf/LiAlH4) [74], producing, unfortunately, low yields of the desired counter-enantiomer. 

Therefore, the fact that the reaction proceeds through a syn addition is not important for predicting the products. If the reaction had been an anti addition, we would have obtained the same products. In fact, if the reaction had not been stereospecific at all, we still would have obtained the same two products (the pair of enantiomers above). 

Using synthetic enantiomers, we found that anatoxin-a is highly stereospecific with the (+) isomer having 150-fold greater potency than the (-) isomer (Figure 2) 19). The semi-rigid nature of anatoxin-a undoubtedly facilitates its stereospecificity. 

Sulfoxides without amino or carboxyl groups have also been resolved. Compound 3 was separated into enantiomers via salt formation between the phosphonic acid group and quinine . Separation of these diastereomeric salts was achieved by fractional crystallization from acetone. Upon passage through an acidic ion exchange column, each salt was converted to the free acid 3. Finally, the tetra-ammonium salt of each enantiomer of 3 was methylated with methyl iodide to give sulfoxide 4. The levorotatory enantiomer was shown to be completely optically pure by the use of chiral shift reagents and by comparison with a sample prepared by stereospecific synthesis (see Section II.B.l). The dextrorotatory enantiomer was found to be 70% optically pure. 

Due to the presence of the a-methyl groups, these agents exist as optical isomers. Both isomers usually produce DOM-like effects, and the R (-)isomers constitute the eutomeric series. In this regard then, the effects of these agents are stereoselective, but not stereospecific. In general, the R (-)isomers are twice as potent as their racemates and about 5 to 8 times more potent than their S (- )enantiomers. Some representative data are provided in table 1. 

The synthesis in Scheme 13.21 starts with a lactone that is available in enantiomer-ically pure form. It was first subjected to an enolate alkylation that was stereocontrolled by the convex shape of the cis ring junction (Step A). A stereospecific Pd-mediated allylic substitution followed by LiAlH4 reduction generated the first key intermediate (Step B). This compound was oxidized with NaI04, converted to the methyl ester, and subjected to a base-catalyzed conjugation. After oxidation of the primary alcohol to an aldehyde, a Wittig-Horner olefination completed the side chain. 

A qualitatively new approach to the surface pretreatment of solid electrodes is their chemical modification, which means a controlled attachment of suitable redox-active molecules to the electrode surface. The anchored surface molecules act as charge mediators between the elctrode and a substance in the electrolyte. A great effort in this respect was triggered in 1975 when Miller et al. attached the optically active methylester of phenylalanine by covalent bonding to a carbon electrode via the surface oxygen functionalities (cf. Fig. 5.27). Thus prepared, so-called chiral electrode showed stereospecific reduction of 4-acetylpyridine and ethylph-enylglyoxylate (but the product actually contained only a slight excess of one enantiomer). 

Pyranopyrroloimidazoles have been prepared stereospecifically by an intramolecular 1,3-dipolar cycloaddition reaction. Either enantiomer of the imidazoline derivative 176 (the -enantiomer is shown) may react with the bromoacetyl-containing acrylate dipolarophile 177, in the presence of l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), to give the diastereomerically pure tricyclic product 178 in moderate yield (Equation 15). This reaction involves quaternization of the imidazole N, reaction of the quaternary salt with base to give the 1,3-dipole, which can then react, intramolecularly and stereospecifically, with the tethered dipolarophile <1997TL1647>. 

The kind of enantiomer [d-(-)- or l-(+)-] synthesized in the formation of the C4 intermediate varies. The acetoacetyl-CoA reductase (EC 1.1.1.36), which is NADPH-dependent, stereoselectively reduces acetoacetyl-CoA to d-(-)-3-hydroxybutyryl-CoA (R. eutropha [15]). The NADH-dependent reductase catalyzes the reduction of acetoacetyl-CoA to L-(+)-3-hydroxybutyryl-CoA. Afterwards two stereospecific crotonyl-CoA hydratases, l-(+)- and D-(-)-speci-fic, convert the L-(+)-3-hydroxybutyryl-CoA into the D-(-)-isomer (Rhodo-spirillum rubrum [16]). 

Our first investigations of the stereospecific aggregation of molecules in a monolayer involved the use of a novel chiral surfactant, AT-(a-methylbenzyl)stearamide, spread on aqueous acid subphases (Arnett and Thompson, 1981 Arnett et al, 1982). This surfactant was chosen for study because of the potential for strong hydrogen bonding between enantiomers, which should in theory yield closely packed aggregates in a film system. 

It is also encouraging that the calculations reproduce the stereospecificity of the two enantiomers of Tla. Here the predicted binding free energy difference is 2.1 kcal/mol in favor of the 5-enantiomer while the experimental difference is roughly 1.4 kcal/mol. The structures of these... 

Syntheses of naphthyridone derivatives follow the same procedures as those of quinolones, except that substituted 2-aminopyridines (Gould-Jacobs modification) or substituted nicotinic ester/nicotinoyl chloride are used instead of anilines or o-halobenzoic acid derivatives. Most of the recently introduced quinolone antibacterials possess bicyclic or chiral amino moieties at the C-7 position, which result in the formation of enantiomeric mixtures. In general, one of the enantiomers is the active isomer, therefore the stereospecific synthesis and enantiomeric purity of these amino moieties before proceeding to the final step of nucleophilic substitution at the C-7 position of quinolone is of prime importance. The enantiomeric purity of other quinolones such as ofloxacin (a racemic mixture) plays a major role in the improvement of the antibacterial efficacy and pharmacokinetics of these enan-... 

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