Enantioselectivity reversal

Karlsson, C., Wikstrom, H., Armstrong, D. W, and Owens, P. K. (2000). Enantioselective reversed-phase and non-aqueous capillary electrochromatography using a teicoplanin chiral stationary phase.. Chromatogr. A 897(1-2, 3), 349-363. 

Scheme 5 Enantioselectivity reversal in the Soai reaction in the presence of the chiral catalyst DMNE and the achiral additive DBAE...

As a first assumption to explain the unexpected enantioselectivity reversal, Lutz et al. proposed that the chiral and achiral additives interact to form a new dimeric species that catalyzes the formation of the opposite enantiomer of the chiral catalyst [65]. As described in a later section, the interaction between the chiral additive and the reaction product of the Soai reaction could represent a second possibility to explain the phenomenon of enantioselectivity reversal. 

According to Lutz et al. [65], the mixed aggregate XY is assumed to promote the product with opposite configuration to that of the chiral catalyst X alone, i.e., in the present example the S product. The kinetic steps denoted in Scheme 9, together with the minimal or alternative kinetic model, can give rise to a simulation of the experimentally observed enantioselectivity reversal. 

In the second option, additive-product interactions are assumed. These can lead to the reproduction of enantioselectivity reversal by considering only one additive. The driving force for the enantioselectivity reversal in this case originates from a competition between kinetic steps that give rise to the product R on one hand and to the product S on the other. Due to mutual inhibition, as expressed by the minimal or alternative kinetic model, i.e., R + S++RS (k2, /t3), a process that gives rise to the formation of R is in some way equivalent to an inhibition of the S formation and vice versa. Due to additive-product... 

As we have already shown [82], these two equilibria alone can be sufficient to cause the enantioselectivity reversal if very special kinetic properties such as the slower formation of the thermodynamically more stable dimer are considered. A more general situation is given when the pro-R additive is additionally allowed to display catalytic properties in the formation of the Soai products such as ... 

The simplest situation occurs if X is highly stereoselective regarding the formation of R and if it shows an overwhelming preference to form the XR over the XS dimer. In this case, the competition between k 6 and k ]0 alone gives rise to the enantioselectivity reversal. Here, R is inhibited by the process X + R-o-XR but promoted by A + Z + X R + X. In this particular case, a stepwise transition between the two optically active states can be obtained by simulation within a certain range of the involved rate parameters when the concentration of the additive is gradually increased. A more general case where all the realistic processes are operative is shown in Fig. 7. 

Fig. 8 Early time evolution of the R and S Soai reaction products on both sides of the stepwise transition as shown in Fig. 7. a R-trapping is dominant giving rise to enantioselectivity reversal (pro-R catalyst [X]0 = 1.55 x 10 3 M) b R-catalysis is dominant resulting in the preservation of enantioselectivity (pro-R catalyst [X]o = 1.95 x 10-3). Same initial conditions and rate parameters as in Fig. 7...

Further attempts by introducing Y + R and Y + S interactions showed that both the enantioselectivity reversal in the presence of competing chiral or achiral catalysts as well as the experimentally observed variation of the transition step as a function of the structure of the chiral catalyst can be addressed by the same approach [82],... 

The effect of enantioselectivity reversal serves as an additional experimental observation that gives a possible clue for the reaction mechanism. By the proposed additive-product interactions it was predicted that even poor stereoselectivity and discriminating capability of the catalytic additive can give rise to enantioselectivity reversal. This also gives a possible kinetic explanation for the effect of miscellaneous chiral additives in the Soai reaction and their role as potent chiral initiators. 

While phenyl- and terf-butyl-substituted catalysts conferred similar degrees of enantioselectivity, the phenyl catalyst proved much more reactive. Interestingly, enantioselectivity reversed when the tert-butyl ligand replaced the phenyl ligand in the bis(oxazoline) copper (II) catalysts [23]. 

To the best of our knowledge, this phenomenon is tmprecedented in catalytic asymmetric synthesis. In addition to our previous results [56, 57] of the enantioselectivity reversal based on the addition of achiral catalyst, these results should be possibly understood that the heterochiral aggregate acts as the catalytic species in the enantioselective dialkylzinc addition to the aldehydes. 

The ratio of yy -epoxide (shown above) to ant -eipoxide is 10—25 1 with TYZORTPT catalysis, whereas vanadjdacetylacetonate is less selective and y -chloroperoxybenzoic acid gives the reverse 1 25 ratio. It is supposed that TYZOR TPT esterifies the free hydroxyl, then coordinates with the peroxide to favor yy -epoxidation (135). This procedure is related to that for enantioselective epoxidation of other allyflc alcohols in 9—95% enantiomeric excess (135). 

One interesting phenomenon was the effect of the boron substituent on enantioselectivity. The stereochemistry of the reaction of a-substituted a,/ -unsatu-rated aldehydes was completely independent of the steric features of the boron substituents, probably because of a preference for the s-trans conformation in the transition state in all cases. On the other hand, the stereochemistry of the reaction of cyclopentadiene with a-unsubstituted a,/ -unsaturated aldehydes was dramatically reversed on altering the structure of the boron substituents, because the stable conformation changed from s-cis to s-trans, resulting in production of the opposite enantiomer. It should be noted that selective cycloadditions of a-unsubsti-tuted a,/ -unsaturated aldehydes are rarer than those of a-substituted a,/ -unsatu-... 

For imines, a-imino esters with an N-p-methoxyphenyl substituent (21b) also reacted with Danishefsky s diene in the presence of 10 mol% of CUCIO4-T0I-BINAP to give the corresponding adduct in high yield with good enantiomeric excess (Scheme 5.10). Remarkably, reverse enantioselectivity was observed when the a-imino esters 21a and 21b were used. This notable selectivity was explained by as-... 

A rather unexpected discovery was made in connection to these investigations [49]. When the 1,3-dipolar cycloaddition reaction of la with 19b mediated by catalyst 20 (X=I) was performed in the absence of MS 4 A a remarkable reversal of enantioselectivity was observed as the opposite enantiomer of ench-21 was obtained (Table 6.1, entries 1 and 2). This had not been observed for enantioselective catalytic reactions before and the role of molecular sieves cannot simply be ascribed to the removal of water by the MS, since the application of MS 4 A that were presaturated with water, also induced the reversal of enantioselectivity (Table 6.1, entries 3 and 4). Recently, Desimoni et al. also found that in addition to the presence of MS in the MgX2-Ph-BOX-catalyzed 1,3-dipolar addition shown in Scheme 6.17, the counter-ion for the magnesium catalyst also strongly affect the absolute stereoselectivity of the reac-... 

Enantioselectivities were found to change sharply depending upon the reaction conditions including catalyst structure, reaction temperature, solvent, and additives. Some representative examples of such selectivity dependence are listed in Scheme 7.42. The thiol adduct was formed with 79% ee (81% yield) when the reaction was catalyzed by the J ,J -DBFOX/Ph aqua nickel(II) complex at room temperature in dichloromethane. Reactions using either the anhydrous complex or the aqua complex with MS 4 A gave a racemic adduct, however, indicating that the aqua complex should be more favored than the anhydrous complex in thiol conjugate additions. Slow addition of thiophenol to the dichloromethane solution of 3-crotonoyl-2-oxazolidinone was ineffective for enantioselectivity. Enantioselectivity was dramatically lowered and reversed to -17% ee in the reaction at -78 °C. A similar tendency was observed in the reactions in diethyl ether and THF. For example, a satisfactory enantioselectivity (80% ee) was observed in the reaction in THF at room temperature, while the selectivity almost disappeared (7% ee) at 0°C. 

R,R-DBFOX/Ph 250 reaction course 303 regioselectivity 216 retro-Diels-Alder reaction 29 reversal of enantioselectivity 224 rhodium... 

Temperature can also be used to optimize enantioselectivity in SFC. The selectivity of most CSPs increases as temperature decreases. For this reason, most chiral separations in SFC are performed at ambient or subambient temperatures [50, 74]. Subambient temperatures are particularly useful for compounds having low conformational stability [75]. Stringham and Blackwell explored the concept of entropically driven separations [76]. As temperature increased, enantioselectivity decreased until the enantiomers co-eluted at the isoelution temperature. Further increases in temperature resulted in reversal of elution order of the enantiomers. The temperature limitations of the CSP should be considered before working at elevated temperatures. 

There are four main factors that affect the enantioselectivity of sulfur ylide-mediated reactions i) the lone-pair selectivity of the sulfonium salt formation, ii) the conformation of the resulting ylide, iii) the face selectivity of the ylide, and iv) betaine reversibility. 

The fourth factor becomes an issue when anti betaine formation is reversible or partially reversible. This can occur with more hindered or more stable ylides. In these cases the enantiodifferentiating step becomes either the bond rotation or the ring-closure step (Scheme 1.12), and as a result the observed enantioselectivities are generally lower (Entry 5, Table 1.5 the electron-deficient aromatic ylide gives lower enantioselectivity). However the use of protic solvents (Entry 6, Table 1.5) or lithium salts has been shown to reduce reversibility in betaine formation and can result in increased enantioselectivities in these cases [13]. Although protic solvents give low yields and so are not practically useful, lithium salts do not suffer this drawback. [18]... 

Addition of (R,S)-9 to the aromatic benzaldehyde proceeded with higher enantiosclcctivity than the addition of the diastereomeric reagent (S,S)-9. The reverse is true for additions to aliphatic aldehydes. Thus, the highest enantioselectivity of 92% ee was observed in the addition of (R,R)- 9 to cyclohexanccarboxaldehyde. The low chemical yields of most addition reactions can be improved by addition of the Lewis acid diethylaluminum ethoxide. The presence of the Lewis acid solely enhanced the chemical yield without changing the enantioselectivity of the addition reactions. 

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