Benzaldehyde kinetic stereoselection

Because of conflicting reports or inadequate controls, the question of kinetic or thermodynamic control of stereochemistry for reported Reformatsky reactions often has no satisfactory answer. Jacques and co-workers have concluded that Reformatsky reactions of benzaldehyde in refluxing benzene can be completed with kinetic stereoselection. The relatively high syn.anti ratios they observed, at least with small R groups (equation 36 and Table 4), are not those expected for equilibrated zinc chelates. 

The optimum approach to kinetic stereoselection in the Reformatsky reaction would appear to be the use of two-stage procedures, which allows the zinc aldolates to be formed at the lowest possible temperature. Gaudemar-Bardone and Gaudemar prepared a variety of zinc ester enolates in dimethoxymethane at 40 C which were then reacted at lower temperatures with benzaldehyde or with acetophenone (equation 38). Selected data from their study are shown in Table 5. If these data are the result of total kinetic control, as concluded by the authors, it is clear that the reactions exhibit only a modest kinetic stereoselectivity. 

In aldol condensations involving preformed lithium enolates and aldehydes, complete kinetic stereoselection is observed (as illustrated in Scheme 39). When is bulky (e.g. t-butyl or trimethylsilyl) the (Z)-enolate gives the erythro-aldol and the ( )-enolate gives the threo-aldol. When R is smaller, the stereoselectivity diminishes or disappears. In contrast, a tetra-alkylammonium enolate reacts with benzaldehyde with equally high but opposite kinetic stereoselectivity. 

Using preformed lithium enolates, complete kinetic stereoselection has been achieved. The kinetic enolate of 2,2-dimethyl-3-pentanone is exclusively the Z isomer it adds to benzaldehyde to give only the erythro aldol product.Similar... 

Evans Jr. and coworkers reported a similar olefination reaction employing spirooxyphosphoranes of type 66. Upon treatment with a strong base (LiHMDS) and subsequent addition of benzaldehyde, the reaction proceeded to form anionic P(VI) intermediates (67,6 -106 to -116 ppm) that decomposed at room temperature to form the corresponding olefins and spiropentaoxyphosphoranes [ 105]. The stereoselectivity (E Z ratio) of the double bond-forming reaction depended upon the conditions evidence indicated the possibility of kinetic or thermodynamic control (Scheme 21). 

Inagaki M, Hiratake J, Nishioka T, Oda J (1989) Kinetic resolution of racemic benzaldehyde cyanohydrin via stereoselective acetylation catalyzed by lipase in organic solvent. Bull Inst Chem Res, Kyoto Univ 67 132-135... 

Even when the retroaldol reaction is fairly facile, stereoisomer equilibration can be slow. This phenomenon is illustrated in Scheme 16. A solution of the lithium aldolate (243) and benzaldehyde equilibrates to (244) and p-anisaldehyde with a half-life of 15 min at 0 °C. However, the syn lithium aldolate (244) equilibrates with its anti diastereomer (246) with a half-life of approximately 8 h at room temperature. The reason for this apparent dichotomy is that enolate (245) is so stereoselective in its reactions with aldehydes. Since the kinetic syn.anti ratio is 98.7 1.3, the syn aldolate must dissociate approximately 75 times in order for one syn aldolate molecule to be converted into one anti aldolate molecule. Of course, for less stereoselective enolates, such as the cyclohexanone enolate referred to above, stereochemical isomerization will more nearly parallel the rate of actual aldol reversal. 

The enolates derived from cyclic ketones are necessarily Zi-isomers. The enolate of cyclohexanone reacts with benzaldehyde to give both possible stereoisomeric products under kinetically controlled conditions. The stereoselectivity is about 6 1 in favor of the anti isomer under optimum conditions. ... 

---