Diastereomer interconversion

The asymmetric activation can be done by a chiral activator through in situ diastereomer interconversion of the tropos ligand of racemic catalysts (Scheme 8.22). One possible case is that selective complexation of a chiral activator with one enantiomer of a racemic catalyst occurs. The remaining enantiomeric catalyst may then isomerize and complex with the chiral activator leading to a single diastereomer (Scheme 8.22a). The other case is that nonselective complexation of a tropos catalyst with a chiral activator initially provides a 1 1 ratio of activated diastereomers, which would isomerize to the single diastereomeric activated complex (Scheme 8.22b). 

In Fig. 11, at high concentrations of ethylene carbonate, the rate constants ks[EC] and kR[EC] for insertion into the EBTHI zirconaaziridine 17q are much greater than kSSR and ksss and insertion occurs more rapidly than the equilibrium can be maintained. The product ratio reflects the equilibrium of 17q, where Keq is 17.2 (Eq. 32) [21]. Beak has called this limit a dynamic thermodynamic resolution pathway [66]. In contrast, at the lowest concentration of ethylene carbonate in Fig. 10, the first-order rate constants kSSR and ksss for diastereomer interconversion are comparable to the effective first-order rate constants for insertion. As Keq is known to be 17.2, ks/kR can be calculated the 53% ee of (S)-amino acid ester 19q (Scheme 9) implies that kslkR<0.19 (Eq. 33) and that the rate constant for insertion kR[EC] into the minor diastereomer is at least five times faster than ks[EC] into the major diastereomer. 

Figure 5 Diastereomer interconversion in TpRe(CO)(MeIm)(thiophene)...

In the literature [25, 26a,c-g], inverse kinetic isotope effects for the reductive elimination of alkanes from metal centers, which is the miaoscopic reverse of alkane activation by oxidative addition, have been explained by the presence of an a alkane intermediate. Recently, thermolysis of the diastereomerically pure complexes (R5),(5R)-[2,2-dimethylcyclopropyl) (Cp )-(PMe3)lrH] and (/ / ),(5 5)-[2,2-dimethylcyclopropyl)(Cp )(PMe3)IrH] (see Scheme VI.5) in CaDs has been shown [26h] to result in its interconversion to the other diastereomer. The analogous reaction of the deuterium-labeled complexes resulted additionally in scrambling of the deuterium from the a-position of the dimethylcyclopropyl ring to the metal hydride position. Diastereomer interconversion and isotopic scrambling occurred at similar rates and have been discussed in terms of a common intermediate mechanism involving a metal alkane complex (Scheme VI.5). 

Scheme VI.5. The alkane-complex intermediate mechanism proposed for deuterium-scrambling and diastereomer interconversion in the iridium complexes.

The oxidation of a-tocopherol (1) to dimers29,50 and trimers15,51 has been reported already in the early days of vitamin E chemistry, including standard procedures for near-quantitative preparation of these compounds. The formation generally proceeds via orf/zo-quinone methide 3 as the key intermediate. The dimerization of 3 into spiro dimer 9 is one of the most frequently occurring reactions in tocopherol chemistry, being almost ubiquitous as side reaction as soon as the o-QM 3 occurs as reaction intermediate. Early accounts proposed numerous incorrect structures,52 which found entry into review articles and thus survived in the literature until today.22 Also several different proposals as to the formation mechanisms of these compounds existed. Only recently, a consistent model of their formation pathways and interconversions as well as a complete NMR assignment of the different diastereomers was achieved.28... 

The spiro dimer of a-tocopherol (9, see also Fig. 6.4) is formed as mixture of two diastereomers by dimerization of the o-QM 3 in a hetero-Diels-Alder reaction with inverse electron demand. Both isomers are linked by a fluxion process (Fig. 6.22), which was proven by NMR spectroscopy.53 The detailed mechanism of the interconversion, which is catalyzed by acids, was proposed to be either stepwise or concerted.53-55... 

The methano-dimer of a-tocopherol (28)50 was formed by the reaction of o-QM 3 as an alkylating agent toward excess y-tocopherol. It is also the reduction product of the furano-spiro dimer 29, which by analogy to spiro dimer 9 occurred as two interconvertible diastereomers,28 see Fig. 6.23. However, the interconversion rate was found to be slower than in the case of spiro dimer 9. While the reduction of furano-spiro dimer 29 to methano-dimer 28 proceeded largely quantitatively and independently of the reductant, the products of the reverse reaction, oxidation of 28 to 29, depended on oxidant and reaction conditions, so that those two compounds do not constitute a reversible redox pair in contrast to 9 and 12. 

Dao et al.36 have shown that for racemic S(+)-2-aminobutane-gossy-polone-imine lowering temperature to 280 K has slowed the interconversion of the diastereomers. 

Further complications may arise with the larger amino acids such as isoleucine, where the R side-chain itself contains a chiral carbon atom [R = CH3CH2C H(CH)3, where the asterisk denotes the second chiral centre]. This molecule is an example of a diastereomer - a molecule with more than one chiral centre. Diastereomers have different physical and chemical properties, and their interconversion is more complicated, and is termed epimerization. 

In general the syn,syn complex is the most stable isomer but it is in equilibrium with the other three diastereomers (Scheme 17.3). The interconversion between the jt-complexes proceeds via the less stable rj-complexes and is rather slow. Usually more than one Jt-allyl intermediate is present in the reaction mixture, which makes chirality transfer from an enantiomerically enriched allene to the product complicated. 

SCHEME 1. Conformational map of the RcRn and RcSn diastereomers of /V-ethyl-iV-methyl-2-aminobutane (EMAB). Interconversions among conformers within dashed boxes are fast on the NMR time scale at 104 K. Those between dashed boxes occur via rotations about the methine carbon-nitrogen bond with barriers which are DNMR-visible. The interconversion between the solid boxes occurs via nitrogen inversion (disstereomeric interconversion). The values in parentheses are MM2-80 results. Reprinted with permission from Reference 71. Copyright (1988) American Chemical Society... 

In the first of four chapters in this volume of Topics in Stereochemistry, Michinori Oki presents a comprehensive review of atropisomerism with special reference to the literature of the past two decades. The review summarizes restricted rotation about sp2-sp2, sp2-sp, and sp3-sp3 bonds and it concludes with an analysis of reactions of isolated rotational isomers. It places particular emphasis on the magnitude of rotation barriers as a function of structure (incidentally identifying some of the largest barriers yet measured to conformer interconversion) and on the isolation of stable single-bond rotational diastereomers. 

As the last example in equation 44 demonstrates, synthetically interesting enantioen-richments can be achieved from configurationally labile 1-phenylselanylalkyllithium compounds . It has been shown that the e.r. in aldehyde addition roughly corresponds with the d.r., and it has been concluded that the interconversion of diastereomers is slower than the addition step " . 

The stereochemistry of 1,3-dipolar cycloadditions of azomethine ylides with alkenes is more complex. In this reaction, up to four new chiral centers can be formed and up to eight different diastereomers may be obtained (Scheme 12.4). There are three different types of diastereoselectivity to be considered, of which the two are connected. First, the relative geometry of the terminal substituents of the azomethine ylide determine whether the products have 2,5-cis or 2,5-trans conformation. Most frequently the azomethine ylide exists in one preferred configuration or it shifts between two different forms. The addition process can proceed in either an endo or an exo fashion, but the possible ( ,Z) interconversion of the azomethine ylide confuses these terms to some extent. The endo-isomers obtained from the ( , )-azomethine ylide are identical to the exo-isomers obtained from the (Z,Z)-isomer. Finally, the azomethine ylide can add to either face of the alkene, which is described as diastereofacial selectivity if one or both of the substrates are chiral or as enantioselectivity if the substrates are achiral. 

The interconnection of configuration and conformation and their joint influence on NMR spectral parameters is of particular importance for acyclic aliphatic diastereomers, since these molecules are conformationally flexible and can adopt a large number of rotamers. Energy barriers for conformational interconversions are often small and can be overcome easily and frequently at... 

Medium-sized and large ring systems often show complicated conformational interconversions involving pseudorotations in one or even more conformational families. This makes stereochemical assignments in diastereomers rather difficult. Thus, very few systematic studies have been published. The situation is improved if such rings are embedded in polycyclic systems, or if they contain double bonds, which leads to restricted conformational mobility. An example is the differentiation of diastereomeric 2,3-dihydro-lf/-benzo[6]azepines 1 on the basis of y-gauche effects and on d(13C) and 3/H H values640. 

When an appropriate chiral phosphine ligand and proper reaction conditions are chosen, high enantioselectivity is achieved. If a diphosphine ligand of C2 symmetry is used, two diastereomers of the enamide coordination complex can be produced because the olefin can interact with either the re face or the si face. This interaction leads to enantiomeric phenylalanine products via diastereomeric Rh(III) complexes. The initial substrate-Rh complex formation is reversible, but interconversion of the diastereomeric olefin complexes may occur by an intramolecular mechanism involving an olefin-dissociated, oxygen-coordinated species (18h). Under ordinary conditions, this step has higher activation enthalpies than the subsequent oxidative addition of H2, which is the first... 

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