Double diastereodifferentiation

Indeed, the combination of the aldehyde 1 with the (S)-enolate 2 delivers the diastereomers 3a and 3b in excellent selectivity (>100 1, matched pair ). On the other hand, a 1 30 ratio of 4 a/4 b is found in the corresponding reaction of the (2 )-enolate 2. Although the selectivity in the latter case ( mismatched pair ) is distinctly lower, the reliability of this chiral enolate 2 provides a degree of induced stereoselectivity which is sufficient for practical applications ( double diastereodifferentiation )29. The stereochemical outcome is largely determined by the chirality of the enolate in that the (S)-enolate 2 attacks the aldehyde almost exclusively from the Re-face whereas the (/ -enolate adds preferably to the Si-face of the carbonyl group in the aldehyde. 

The Brpnsted acid-assisted chiral Lewis acid (BLA) 28, prepared from a 1 2 molar ratio mixture of a trialkylborate and optically pure binaphthol, is also an excellent chiral promoter for the aza Diels-Alder reaction of imines with Danishefsky dienes (Eqs 44 and 45). Enantioselectivity and double diastereodifferentiation in reactions employing chiral 28 are slightly better than those using chiral 27 [41]. 

Double diastereodifferentiation (using enantiomerically pure reagents and substrates) can enhance diastereoselectivity if we have a matched case, but can erode it if we have the mismatched case. 

Up to this point, the discussion has focused on the existence of just a single stereogenic center or asymmetry element on the substrate, the reagent or the catalyst. However, reacting systems may include more stereocenters or asymmetry elements located either on the same partner or on other components. The presence of the added elements of asymmetry can influence the relative energies of the various transition states and either augment or erode the diastereodifferentiation observed when a similar reaction is performed in the presence of a single asymmetry element. For the sake of simplicity, only the case of double diastereodifferentiation will be considered here. Two possibilities arise ... 

Double diastereodifferentiation also occurs in kinetic resolution of racemates. Indeed, a chiral reagent will be matched with one of the enantiomers, which will react faster because the matched transition state is lower in energy than the mismatched one [127],... 

If the aldehyde is chiral, double diastereodifferentiation ( 1.6) is expected, and the stereoselectivity depends upon matching or mismatching of the partners. Brown [702], Corey [734], Roush [718, 720, 721] and their coworkers as well as Ganesh and Nicholas [1203] have prepared homoallylic alcohols with excellent diastereo- and enantiomeric excesses (Figure 6.45). 

Stork and coworkers [624e] have introduced enamines as a nucleophilic substitute of enols, and a few asymmetric aldol reactions have been performed with enamines. Scolastico and coworkers [1311] have reacted morpholine enamines with chiral oxazolidine 1.84 (EWG = Ts), and in some cases they obtained higher sdectivities than those obtained from enoxysilanes ( 6.9.3) (Figure 6.102). Chiral enamines derived from pyrrolidine 1.64 (R = MeOCI ) react with acyliminoesters of chiral alcohols at -100°C [1313], Double diastereodifferentiation is at work so that from matched reagents, for example the pyrrolidine enamine and iminoester 6.126 shown in Figure 6.102, P-keto-a-aminoesters are obtained with a high diastereo- and enantioselectivity. The esters of either enantiomer of menthol or of achiral alcohols give mediocre asymmetric induction. 

Asymmetric dihydroxylation of olefins bearing chiral substituents can take place with double diastereodifferentiation ( 1.6), so that matched and mismatched pairs will be observed [498, 753, 762],... 

These complexes also catalyze the enantioselective cyclopropanation of monosubstituted alkynes with bulky diazoesters [939, 1497] (Figure 7.87). Attempts at double diastereodifferentiation ( 1.6) have been carried out in the reaction of styrene with diazoesters of chiral alcohols under chiral Rh-3.61 complexes catalysis [939,1501], but disappointing selectivities were observed. 

Scheme 7.2. Double diastereodifferentiation in solid-phase aldol reactions toward spiroketal synthesis.

Control of stereoselectivity and double diastereodifferentiation was further investigated using resin-bound p-enolate 4 and both enantiomers of chiral aldehyde 8. After a sequence of aldol reaction as described previously, alcohol protection, and DDQ-mediated spiroketalization, reactions with aldehyde 8a(25) provided pure single diastereoisomer of the spiroketal 9. However, the reaction of 4 with aldehyde 8b(2l ) yielded 10 as the major diastereomer along with minor inseparable isomers (Scheme 7.2). Thus, although in both aldol reactions of the chiral enolate 4 with the enantiomeric aldehydes 8a and 8b the anti-aldol adduct is formed as the major product, the combination of 4 and 8a represents the matched case and the combination of 4 and 8b the mismatched case. 

In investigations of double diastereodifferentiating Mukaiyama aldol reactions, Evans demonstrated that the coupling of end silane 195 either to aldehyde 196 or to aldehyde 198 affords the Felkin products 197 and 199, respectively, with excellent diastereoselectivity (Scheme 4.21) [36]. Because of the involvement of open transition states in these aldol reactions, no direct correlation was found between the starting end silane geometry and the observed simply selectivity (syn versus anti). This contrasts with the simple diastereoselectivity typically observed for cis- and trans-metal enolates that react through cyclic Zimmerman-Traxler transition states. By this strategy, the addition of enol silane 201 to 200 provided an advanced intermediate 202 in the synthesis of 6-deoxyerythronolide B (187, Scheme 4.22) [97]. 

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