Diastereomers equilibration

FIGURE 5. Double Michael adducts that undergo diastereomer equilibration via retro-Michael-Michael reactions. 

Norton and coworkers noticed significant differences in diastereoselectivity for formation of EBTHI zirconaaziridines 17m under kinetic vs thermodynamic conditions. In general, 17m was prepared by heating the (EBTHI)zirconium methyl amide complex at 70 °C (Scheme 3). Use of a 20-fold excess of carbonate, by accelerating insertion relative to diastereomer equilibration, permitted... 

The observations summarized in Table 8 have important preparative consequences. To achieve the highest possible ( )-alkene selectivity in a system that is capable of stereochemical equilibration, it is essential to provide sufficient time for oxaphosphetane equilibration below the decomposition temperature. This is best done by monitoring the diastereomer mixture using NMR methods to establish the temperature thresholds for diastereomer equilibration as well as for alkene formation from the more reactive cis-diastereomer. Once these temperatures are known, equilibration can be allowed to proceed below the temperature for (Z)-alkene formation until the optimum ratio of trans-cis oxaphosphetanes is obtained. Subsequent warming completes the optimized E-selective alkene synthesis in an equilibrating system (Table 7). 

This isomerization reaction leads to the buildup of a new stereogenic center. Therefore, addition of a chiral diphosphine may lead to the formation of an optically active product. Addition of the chiral bidentate diphosphine (5, -2,3-bis(diphenylphosphino)butane (5,S)-chiraphos) to a CHjCIj solution of the six-membered ring nickelacycle derived from glutaric anhydride leads to a mixture of diastereomers with a 16% diastereomeric excess favoring the R configuration (Scheme 5). However, on standing at 24 °C, the mixture of diastereomers equilibrates favoring the thermodynamically more stable S nickelacycle isomer with 52% diastereomeric excess. 

In order to test whether this high level of diastereoselectivity is due to the stereoselective formation of 35 A, or a consequence of rapid equilibration between 35 A and 35 B, both reagents were selectively prepared via the tributylstannanes 38. Treatment of either reagent with chloro-trimethylsilane led to a similar ratio of the diastereomers 36 A/36B, with the anti-diastereomer 36A predominant in both reactions. 

Interestingly, when R1 and R2 are hydrogens, the -configurated amino nitriles 1 arc obtained, whereas one or two methoxy substituents on the aromatic ring leads to (S)-diastereomers. This surprising effect is caused by the preferential crystallization of the (R)- or the (.S )-diastereomers, respectively. If the pure diastereomers of 1 are dissolved in methanol, equilibration occurs. On concentration, the optically pure diastereomer again crystallizes from the solution45. 

The submitters report obtaining 1.29 (12%) of the c/.v-diastereoisomer and 8.39 g (80%) of the trans-diastereoisomer. The submitters recommend that the purified diastereomers be stored in the freezer (-18°C). Both pure isomers slowly equilibrate to a 21 79 mixture of cis/trans isomers upon standing at ambient temperature for several weeks. 

However, upon dissolution, an epimerization of the anions can occur in the presence of acidic counter-ions. This is particularly true for 16a-16d [39]. The nature of the solvent (MeOH, CHCI3) plays a crucial role on the kinetics of epimerization and the position of the resulting equilibrium. For anions made with a 2R, 3R) tartaric backbone, a A configuration is always preferred in MeOH the selectivity, obtained after a slow equilibration, being independent of the nature of the ester alkyl chain (diastereomeric ratio (d.r.) 3 1). However, in chloroform, the A diastereomer is rapidly obtained and the selectivity is best if the ester side chain is sterically demanding (d.r. 2 1 to 9 1 from 16a to 16d) (Scheme 16). 

The reductive amination of ketones can be carried out under hydrogen pressure in the presence of palladium catalysts. However, if enantiopure Q -aminoketones are used, partial racemization of the intermediate a-amino imine can occur, owing to the equilibration with the corresponding enam-ine [102]. Asymmetric hydrogenation of racemic 2-amidocyclohexanones 218 with Raney nickel in ethanol gave a mixture of cis and trans 1,2-diamino cyclohexane derivatives 219 in unequal amounts, presumably because the enamines are intermediates, but with excellent enantioselectivity. The two diastereomers were easily separated and converted to the mono-protected cis- and trans- 1,2-diaminocyclohexanes 220. The receptor 221 has been also synthesized by this route [103] (Scheme 33). 

If one of two equilibrating diastereomers crystallizes out of solution, shifting the equilibrium in one direction, the process is referred to as an asymmetric transformation of the second kind lUPAC Compendium of Chemical Technology, 2nd Edition, Mc-Naught, A. D., Wilkinson, A., Eds. Blackwell Science, 1997. 

John Ward has functionalized an indane using method D in route to tetra-petalone A (46) (Fig. 4.24).25 The o-OBoc benzyl alcohol 44 undergoes addition with two equivalents of Grignard and affords after acidic workup the phenolic indane 45 in 73% yield. Because of steric effects, only one diastereomer is observed after hydrolysis of the enol ether and thermodynamic equilibration of the... 

Thus the triplet states of the two diastereomers react to yield different product distributions although this effect is far less marked for the triplet than for the singlet reaction, which is essentially stereospecific. The singlet reaction could be either concerted or due to an extremely shortlived biradical. Since the product distributions of the triple reaction of these two diastereomers are different, it is clear that cleavage must occur before complete equilibration. Thus the lifetime of the aliphatic ketone derived biradical must be considerably shorter than the corresponding biradical derived from an aryl ketone. 

After extensive experimentation, it was discovered that exposure of silyl ether (+)-97 to potassium trithiocarbonate and trifluoroacetic acid in dichloromethane affords a 25 7 1 mixture of endolendo endo/exo exo/exo bisdithiepanethione products, reflecting a ca. 5 1 preference for nucleophilic approach from the endo-face of each diketopiperazine moiety. Resubjection of the isolated bisdithiepanethione diastereomers to the original reaction conditions did not result in their equilibration, indicating that the products were a result of kinetic trapping. 

The diastereomeric pentacoordinated bromostannanes 49 and 50 were found to equilibrate at — 13°C in toluene to a mixture of diastereomers27. The composition of the equilibrium mixture is dependent upon the R substituent (Table 4). As the size of this group is increased, the equilibrium is shifted in favor of the sterically less congested diastereomer 49. 

Esterification of p-toluenesulfinic acid with (- )-menthol gives a mixture of two diastereomers, which equilibrate to the pure (-)-menthyl (S)-p-toluenesulfinate diastereomer in the presence of hydrochloric acid (80% yield). The report includes an improved procedure for reaction of 1 with CH,MgI to give (R)-( + )-methyl p-tolyl sulfoxide.1... 

It would be highly desirable to be able to correlate metal ion structure as well as the individual steric requirements of the specific substituents Ri, R2, and Ra with the equilibration studies cited above. Because of the numerous uncertainties associated with the data, however, only qualitative generalizations can be made. The higher-valent metal aldolate complexes (M = ZnL, MgL, AIL2), upon equilibration, appear to favor the threo diastereomer to a greater extent than the monovalent metal aldolates (M = Li, Na). With regard to... 

An additional important observation that (Z)-enolates exhibit erythro diastereoselection was made by Dubois and Fellmann (5b). Their investigation demonstrated that the magnesium enolate 24a (20°C, Et2 0) condensed with benzaldehyde under kinetic conditions to give exclusively the erythro diastereomer 25E (R3 = Ph, E T>95 5), and upon prolonged equilibration afforded the isomeric threo adduct (T E > 95 5) (eq. [ 15]). Heathcock has reported... 

Menthyl p-iodobenzenesulfinate 62 exists in two diastereomeric forms having [a]u + 46 and -146 (79,103). Herbrandson and Cusano (103) determined their absolute configurations on the basis of kinetic studies of the hydrogen chloride-catalyzed equilibration (+>62 (-)-62 and ethanolysis of both diastereomeric esters. They found that the equilibration reaction carried out in nitrobenzene at room temperature results in the formation of a mixture containing 59 3% of the dextrorotatory diastereomer. On the other hand, the rate of ethanolysis of the thermodynamically more stable (+)-62 isomer was found to be twice as large as that of the (->isomer. 

Otto, Sanders, and coworkers have utilized disulfide exchange to generate dynamic libraries of diastereomeric receptors [3]. DCLs made from a racenfic dithiol led to numerous cyclic structures including four cyclic tetramers, with the RR,RR,RR,RR diastereomer being the most stable (along with its all-5 enantiomer). Upon addition of N(CH3)J, the meso-diastereomer shown below was amplified 400-fold (Fig. 5.3). The structure of the diastereomer was confirmed by NMR and re-equilibration... 

Figure 2b shows the other extreme, whereby the rate of epimerization is fast relative to the rate of substitution. In this case, Curtin-Hammett kinetics apply, and the product ratio is determined by AAG. In the specific case of organolithium enantiomers that are rendered diastereomeric by virtue of an external chiral ligand, such a process may be termed a dynamic kinetic resolution. Both of these processes are also known by the more general term asymmetric transformation One should be careful to restrict the term resolution to a separation (either physical or dynamic) of enantiomers. An asymmetric transformation may also afford dynamic separation of equilibrating diastereomers, but such a process is not a resolution. "... 

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