Enantiomeric inversion

Members of the 2-APA class of NSAIDs have the potential for in vivo enantiomeric inversion, whereby the R-enantiomer (distomer) may be inverted to the active antipode, the S-enantiomer (eutomer). The S-enantiomer... 

Mehvar, R. Jamali, F. Pharmacokinetic analysis of the enantiomeric inversion of chiral nonsteroidal antiinflammatory drugs. Pharm. Res. 1988, 5, 76 79. 

N.m.r. spectroscopy has been used to study enantiomeric inversions of a series of tetrahedral chelates of zinc(ii), cadmium(ii), and lead(ii). The rates of inversion depend on the nature of the metal, the donor atoms, and the structure and substituents of the chelate rings. An intramolecular diagonal-twist mechanism is suggested. Rapid complex formation kinetics between zinc(ii) and the glycine zwitterion and pada (pyridine-2-azo-p-dimethylaniline) have been studied using relaxation methods. 

Although unsynunetrically substituted amines are chiral, the configuration is not stable because of rapid inversion at nitrogen. The activation energy for pyramidal inversion at phosphorus is much higher than at nitrogen, and many optically active phosphines have been prepared. The barrier to inversion is usually in the range of 30-3S kcal/mol so that enantiomerically pure phosphines are stable at room temperature but racemize by inversion at elevated tempeiatuies. Asymmetrically substituted tetracoordinate phosphorus compounds such as phosphonium salts and phosphine oxides are also chiral. Scheme 2.1 includes some examples of chiral phosphorus compounds. 

Whereas the barrier for pyramidal inversion is low for second-row elements, the heavier elements have much higher barriers to inversion. The preferred bonding angle at trivalent phosphorus and sulfur is about 100°, and thus a greater distortion is required to reach a planar transition state. Typical barriers for trisubstituted phosphines are BOSS kcal/mol, whereas for sulfoxides the barriers are about 35-45 kcal/mol. Many phosphines and sulfoxides have been isolated in enantiomerically enriched form, and they undergo racemization by pyramidal inversion only at high temperature. ... 

Each of the following molecules might be resolved into two enantiomers if 1) the molecule s preferred geometry is chiral, and 2) the molecule s enantiomeric forms do not readily interconvert (this interconversion is called configuration inversion ). 

The major application of the Mitsunobu reaction is the conversion of a chiral secondary alcohol 1 into an ester 3 with concomitant inversion of configuration at the secondary carbon center. In a second step the ester can be hydrolyzed to yield the inverted alcohol 4, which is enantiomeric to 1. By using appropriate nucleophiles, alcohols can be converted to other classes of compounds—e.g. azides, amines or ethers. 

The conclusion that SN1 reactions on enantiomerically pure substrates should give racemic products is nearly, but not exactly, what is found. In fact, few S jl displacements occur with complete racemization. Most give a minor (0%-20%) excess of inversion. The reaction of (J )-6-cbloro 2,6 dimethyloctane with I420, for example, leads to an alcohol product that is approximately 80% racemized and 20% inverted (80% R,S + 20% S is equivalent to 40% R + 60% S). 

One consequence of tetrahedral geometry is that an amine with three different substituents on nitrogen is chiral, as we saw in Section 9.12. Unlike chiral carbon compounds, however, chiral amines can t usually be resolved because the two enantiomeric forms rapidly interconvert by a pyramidal inversion, much as an alkyl halide inverts in an Sfg2 reaction. Pyramidal inversion occurs by a momentary rehybridization of the nitrogen atom to planar, sp2 geometry, followed by rehybridization of the planar intermediate to tetrahedral, 5p3 geometry... 

Figure 24.1 Pyramidal inversion rapidly interconverts the two mirror-image (enantiomeric) forms of an amine.

Primary 1-lithio-2-alkenyl diisopropylcarbamates are not configurationally stable in solution. However, under properly selected conditions, the ( )-sparteine complex of the 5-enantiomer crystallizes, leading to a second-order asymmetric transformation6 77-78 132. The suspension is converted to the tri(isopropoxy)titanium derivative with inversion of the configuration, which is shown to have enantiomeric purities up to 94% (Section D.l.3.3.3.8.2.3.). 

The a-substitution of enantiomerically enriched (-)-sparteine complexes of lithioalkenyl carbamates with methyl chloroformate76 or carbon dioxide77, in a manner contrary to a former assumption 76, proceeds with inversion of the configuration 131 131, leading to optically active 3-alkenoic acid esters. 

Similar stereoselectivities are achieved in the allylation of enantiomerically pure proline-derived a-oxoamides47. l-Bromo-3-methy]-2-butcne reacts with clean allylic inversion. Since pinacol-type coupling products are also produced under the reaction conditions, this was taken as evidence for a radical addition mechanism47. 

When the latter adduct (R = CFI3), purified by chromatography, is treated with sodium azide (inversion of configuration) and subsequently subjected to alkaline hydrolysis and hydrogenation, the enantiomerically pure 2-amino-3-hydroxycarboxylic acid results102 ... 

The reported preparations of enantiomerically pure chiral iron-acyl complexes have relied upon resolutions of diastereomers. One route1415 (see also Houben-Weyl, Vol. 13/9 a, p 421) employs a resolution of the diastereomeric acylmenlhyloxy complexes (Fe/ )-3 and (FeS )-3 prepared via nucleophilic attack of the chiral menlhyloxide ion of 2 at a carbon monoxide of the iron cation of 1. Subsequent nucleophilic displacement of menthyloxide occurs with inversion at iron to generate the enantiomerically pure iron-acyl complexes (i>)-4 and (f )-4. 

Under inversion of the configuration at sulfur, enantiomerically pure 4,5-dihydro-2-[(7 )-sulfinylmethyl)]oxazoles (e.g 2) are obtained from metalaled 4,5-dihydrooxazoles and (-)-menthyl (5,)-4-methylbenzenesulfinate31. 

The enantiomerically pure isobomeol allyl sulfoxide derivatives (17 ,2Y,3/ ,4S )-1,7,7-tri-methyl-3-[(S)- or -(/ )-2-propenylsulfmyl]bicyclo[2.2.1]heptan-2-ol are thermally more stable inversion of configuration at sulfur, S -> / , occurs at 135-145 °C. Their lithio derivatives give exclusively y-1,4-adducts with 2-cyclopentenone19. 

H H non-bonded interactions are of great importance in organic compoimds, and thus it was of interest to attempt to investigate H H non-bonded potential functions via the determination of a steric isotope effect in the configurational inversion of an unsubstituted biaryl. In view of the extensive work of Harris and her co-workers in the 1,1 -binaphthyl series (see, for example, Badar et al., 1965 Cooke and Harris, 1963), and since the parent compound is one of the simplest hydrocarbons that may be obtained in enantiomeric forms, the determination of the isotope effect in the inversion of l,l -binaphthyl-2,2 -d2 (9) was... 

An enantioconvergent transformation leads to a single enantiomeric product from a racemate [51]. Each enantiomer is transformed via independent pathways by the same catalyst or by two different catalysts (Figure 6.6). For example, the hydrolysis of epoxides may proceed with high regio- and stereoselectivity vdth inversion or retention of configuration. Several enantioconvergent transformations of epoxides are reported in the last section of this chapter. 

In recent studies, we found that primary and secondary amines, alone or somehow faster in the presence of the soft Lewis acid Ag+ (refs. 7-9) substitute the bromine in (S)-2-bromopropanamides, in an organic solvent, at room temperature, and yield N-alkyl-, and N,N -dialky 1-aminopropanamides, with inversion of configuration and high enantiomeric excess. Conversely, in the presence of silver oxide (Ag20), much faster reactions occur with retention of configuration, giving... 

Stereoinversion Stereoinversion can be achieved either using a chemoenzymatic approach or a purely biocatalytic method. As an example of the former case, deracemization of secondary alcohols via enzymatic hydrolysis of their acetates may be mentioned. Thus, after the first step, kinetic resolution of a racemate, the enantiomeric alcohol resulting from hydrolysis of the fast reacting enantiomer of the substrate is chemically transformed into an activated ester, for example, by mesylation. The mixture of both esters is then subjected to basic hydrolysis. Each hydrolysis proceeds with different stereochemistry - the acetate is hydrolyzed with retention of configuration due to the attack of the hydroxy anion on the carbonyl carbon, and the mesylate - with inversion as a result of the attack of the hydroxy anion on the stereogenic carbon atom. As a result, a single enantiomer of the secondary alcohol is obtained (Scheme 5.12) [8, 50a]. 

The enantiomerization of phenoxyalkanoic acids containing a chiral side chain has been studied in soil using (Buser and Muller 1997). It was shown that there was an equilibrium between the R- and S- enantiomers of 2-(4-chloro-2-methylphenoxy)propionic acid (MCPP) and 2-(2,4-dichlorophenoxy)propionic acid (DCPP) with an equilibrium constant favoring the herbicidally active f -enantiomer. The exchange reactions proceeded with both retention and inversion of configuration at the chiral sites. 

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