Isomers, erythro/threo

Owing to the fully reversible equilibrium nature of the aldol addition process, enzymes with low diastereoselectivity will typically lead to a thermodynamically controlled mixture of erythro/threo-isomers that are difficult to separate. The thermodynamic origin of poor threo/erythro selectivity has most recently been turned to an asset by the design of a diastereoselective dynamic kinetic resolution process by coupling of L-ThrA and a diastereoselective L-tyrosine decarboxylase (Figure 10.47)... 

Enol lactones are assumed to form from iV-methylisoquinolinium salts as a result of a Hofmann-type degradation process. This P elimination is a highly stereospecific reaction in which Z isomers are produced from precursors of erythro configuration and isomers from threo diastereomers(5,97). This fact seems to suggest that syn rather than the more usual anti elimination takes place. Examination of models indicates, however, that there is a preferred conformation in which the C-8 hydrogen is in the syn and coplanar position to the quaternary nitrogen. This hypothesis was proved correct in experiments carried out in vitro (5,14,15,91-94). 

Erythro/threo Terms derived from carbohydrate nomenclature used to describe the relative configuration at adjacent stereocenters. Erythro refers to a configuration with identical or similar substituents on the same side of the vertical chain in Fischer projection. Conversely, a threo isomer has these substituents on opposite sides. These terms came from the nomenclature of two carbohydrate compounds, threose and erythrose (see Fig. 1-35). 

Epoxidation of allyl alcohols can generate two isomers, the threo- and erythro-epoxides (Schemes 11 and 12). Control of the relative amounts of the two isomers... 

The aldol condensation of benzaldehyde with the thioacetamide carbanion (RCHCSNRV), derived from the desilylation of the silyl-thioether with tetra-/i-buty-lammonium fluoride, is stereoselective at—80°C producing the erythro isomer of the p-hydroxy thioamide preferentially (Scheme 6.18, R = Me, erythro threo 95 5) via a conformationally mobile intermediate. However, when R is bulky, a greater amount of the threo isomer is formed. Predictably, as the reaction temperature is raised, so the stereoselectively decreases. This procedure contrasts with the corresponding condensation catalysed by titanium salts, where the complexed intermediate produces the threo isomer [47, 48],... 

Dihydromuscimol (49) is a conformationally restricted analogue of the physiologically important neurotransmitter y-aminobutyric acid (GABA) and has been prepared using the cycloaddition of dibromoformaldoxime to A-Boc-allylamine followed by N-deprotection with sodium hydroxide (Scheme 6.52) (278). The individual enantiomers of dihydromuscimol were obtained by reaction of the bromonitrile oxide with (5)-( + )-l,2-0-isopropylidene-3-butene-l,2-diol, followed by separation of the diastereoisomeric mixture (erythro/threo 76 24), hydrolysis of respective isomers, and transformation of the glycol moiety into an amino group (279). 

Methylphenidate possesses two asymmetric carbon moieties, giving rise to four optical isomers d-threo, /-threo, d-erythro, and /-erythro (Patrick et ah, 1987). There is stereoselectivity in receptor site binding and its relationship to response. The standard preparation is comprised of the threo racemate as it appears to be the central nervous system (CNS) active form (Patrick et ah, 1987 Hubbard et ah, 1989). In addition, in rats, the d-methylphenidate isomer shows greater reuptake inhibition of DA and NE than the /-isomer (Patrick et ah, 1987). D-Methylphenidate is now available under the brand name Focalin. 

At the instant Pasteur recognized the existence of stereoisomers (objects), he also accepted the existence of stereoprocesses (operations). For the notion of isomer carries with it criteria of distinguishability among these is the possibility that a given isomer can be formed, separated, or altered in a way which differentiates it from other isomers. This applies equally to isomers with many properties in common, e.g. optical antipodes, or to those with essentially all different properties, e.g. cis-trans, syn-anti, gauche-anti, erythro-threo, or axial-equatorial pairs. Now, the stereo-path may be part of an overall conversion which, if described in some detail, we term a mechanism. Our present task is to attempt to understand those elementary or single-step processes by which stereochemical choices are made. 

A characteristic feature of some of these reactions is the dependence of their efficiency on the basicity of the radical anion [108], The differences are especially manifested in non-polar solvents, where the CIP are expected to dominate. Some of these cleavage processes are more efficient than expected, based on the thermodynamic evaluations of the unassisted fragmentation (Sect. 3.2). Also a stereochemical preference for cleavage is observed for erythro isomers as compared to the threo isomers (Scheme 6). In benzene erythro/threo selectivity is high, being highest for the relatively basic radical anion of dicyanonaphthalene and lowest for the relatively nonbasic radical anion of thioindigo. The stereochemical preference disappears in acetonitrile if biphenyl is used as a co-sensitizer [108]. 

In general, (//////-elimination will result in an erythro dj pair giving the cis isomer, and the threo d,l pair results in the trans isomer. The threo isomer, however, tends to react significantly faster than the erythro isomer. Taking the... 

Figure 5.3f shows an example 2D HMQC-TOCSY spectrum of a syringyl-rich poplar acetylated MWL, in which the predominance of the eryt/tro-isomers is clearly revealed, particularly in the correlation with C-a ( 75 ppm). The Ca-Cp correlation clusters for erythro- and t/treo-isomers and for syringyl and guaiacyl units are beautifully disperse in a 2D INADEQUATE spectrum [50], A plot of model shifts for all 16 of the P-ether combinations (erythro/threo, syringyl/guaiacyl, and etheri-fied/free-phenolic), correlated well with major features of the contour complex, on the same spectrum. 

The concentrations of erythro and threo aldols as a function of time are presented in Figure 1 (a) for a relatively nonpolar solvent (90 10 THF-MeOH) and in Figure 1(b) for a polar solvent (pure MeOH). In the nonpolar solvent the threo aldol is formed more rapidly than the erythro isomer. However, as a result of the reversibility of the system, its concentration peaks and then diminishes to eventually reach an equilibrium value. In pure MeOH, on the other hand, the erythro. threo equilibrium composition is maintained throughout the reaction. Thus, the reaction is under thermodynamic control in the polar solvent and under kinetic control in the less polar one. 

RCHO % erythro-threo % ee Conf n. Major Isomer [a]jj (CHCI3)... 

Interestingly, regardless of the configuration of the enol ethers, the erythro isomer always predominated erythro threo = 80/20 to > 95/< 5). Aromatic and a, ff-unsatu-rated aldehydes always provided higher diastereo- erythro threo > 94 6) and enantio-... 

Cram s model does not always predict the stereochemical result of kinetically controlled reductions with aluminum isopropoxide (Cram and Greene, 1953). For example, i -(—)-3-cyclohexyl-2-butanone is reduced to predominantly ZR,2R-erythro carbinol (erythro/threo = 1.9). Apparently special steric forces are important in this reduction. Recent work (Shiner and Whittaker, 1963) has shown that aluminum isopropoxide is trimeric or tet-rameric. It is therefore conceivable that some hydride transfers will involve Al(OR)3 units that are not coordinated to the carbonyl groups they reduce. These transfers may occur preferentially from the side opposite that exposed to a coordinated Al(OR).3 unit. Such competitive mechanistic pathways might well yield an isomer ratio not in agreement with that produced by less complex reducing agents. 

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