Aldehydes, chiral condensation with achiral enolates

We have examined a purely logical way in which the "Cram s rule problem" can be attacked — double stereodifferentiation. For example, either reactant in an aldol condensation can be chiral and exhibit diastereoface selectivity. Suppose we have an aldehyde which reacts with achiral enolates to give the two possible erythro adducts in a 10 1 ratio ... 

In general, a good level of predictability is now associated with the sense of asymmetric induction in aldol condensations of achiral enolates and chiral a-substituted aldehydes. At present, the perturba-... 

If stoichiometric quantities of the chiral auxiliary are used (i.e., if the chiral auxiliary is covalently bonded to the molecule bearing the prochiral centres) there are in principle three possible ways of achieving stereoselection in an aldol adduct i) condensation of a chiral aldehyde with an achiral enolate ii) condensation of an achiral aldehyde with a chiral enolate, and iii) condensation of two chiral components. Whereas Evans [14] adopted the second solution, Masamune studied the "double asymmetric induction" approach [22aj. In this context, the relevant work of Heathcock on "relative stereoselective induction" and the "Cram s rule problem" must be also considered [23]. The use of catalytic amounts of an external chiral auxiliary in order to create a local chiral environment, will not be considered here. 

Diastereomer analysis on the unpurified aldol adduct 52b revealed that the total syn anti diastereoselection was 400 1 whereas enantioselective induction in the syn products was 660 1. On the other hand, Evans in some complementary studies also found that in the condensation of the chiral aldehyde 53 with an achiral enolate 56a only a slight preference was noted for the anti-Cram aldol diastereomer 58a (58a 57a = 64 36). In the analogous condensation of the chiral enolate 56b. however, the yn-stereoselection was approximately the same (57b 58b > 400 1) as that noted for enolate 49 but with the opposite sense of asymmetric induction (Scheme 9.17). Therefore, it can be concluded that enolate chirality transfer in these systems strongly dominates the condensation process with chiral aldehydes. 

Asymmetric Aldol-Type Reaction. CAB complex (2) is an excellent catalyst for the Mukaiyama condensation of simple achiral enol silyl ethers of ketones with various aldehydes. The CAB-catalyzed aldol process allows the formation of adducts in a highly diastereo- and enantioselective manner (up to 96% ee) under mild reaction conditions (eqs 4 and 5). The reactions are catalytic 20 mol % of catalyst is sufficient for efficient conversion, and the chiral auxiliary can be recovered and reused. 

CAB 2, R = H, derived from monoacyloxytartaric acid and diborane is also an excellent catalyst (20 mol %) for the Mukaiyama condensation of simple enol silyl ethers of achiral ketones with various aldehydes. The reactivity of aldol-type reactions can, furthermore, be improved, without reducing the enantioselectivity, by use of 10-20 mol % of 2, R = 3,5-(CF3)2C6H3, prepared from 3,5-bis(trifluoromethyl)phenyl-boronic acid and a chiral tartaric acid derivative. The enantioselectivity could also be improved, without reducing the chemical yield, by using 20 mol % 2, R = o-PhOCgH4, prepared from o-phenoxyphenylboronic acid and chiral tartaric acid derivative. The CAB 2-catalyzed aldol process enables the formation of adducts in a highly diastereo- and enantioselective manner (up to 99 % ee) under mild reaction conditions [47a,c]. These reactions are catalytic, and the chiral source is recoverable and re-usable (Eq. 62). 

Boron reagents such as ( + )- or (-)-(Ipc)2BOTf are chiral promoters in aldol condensations. " Enolization of an achiral ketone with (Ipc)2BOTf forms a chiral enolate and thus imparts diastereofacial selectivity (DS) for condensation with a chiral aldehyde. If the ketone is chiral, the DS of the reagent may be matched or mismatched with the... 

The aldol condensation is a powerful tool for the stereoselective synthesis of acyclic molecules with contiguous chiral centers. The catalytic asymmetric aldol reaction of ( )-2-rerr-butyldimethylsiloxy-2-phenylacetaldehyde (121) with the achiral silyl enol ether 1-ethylthio-l-trimethylsilyloxyethene (134) in the presence of tin(II) trifluoride and the chiral promotor ( S)-l-methyl-2-[(7V-naphthylamino)methyl]pyrrolidine (135) in propionitrile at — 78 °C proceeds smoothly to give a 94 6 mixture of diastereomeric aldol adducts 136 and 137 in 85% yield (Scheme 32). When performed on ( S)-129 this same reaction affords in 85% yield a 96 4 mixture of diastereomers 138 and 139. It is noteworthy that the newly created chiral centers in both of the major diastereomers 136 and 138 has the S configuration, suggesting that the stereochemistry of the aldol reaction is controlled by the chiral promotor and not the chiral aldehydes. 

Heathcock and White" and Masamune et al." developed independently the double stereodifferentiation to enhance 1,2-diastereoselection in aldol condensations of chiral aldehydes. As shown in Scheme 8.32," Masamune et al. examined the effect of stereochemistry of an enolate and an aldehyde in asymmetric aldol reaction. Benzaldehyde, the achiral aldehyde, reacted with the chiral enolate S-207 to... 

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