Aldol condensation diastereoface selectivity

Discovery of a Remarkable Long-Range Effect on the Double Diastereoface Selectivity in an Aldol Condensation... 

Traditional models for diastereoface selectivity were first advanced by Cram and later by Felkin for predicting the stereochemical outcome of aldol reactions occurring between an enolate and a chiral aldehyde. [37] During our investigations directed toward a practical synthesis of dEpoB, we were pleased to discover an unanticipated bias in the relative diastereoface selectivity observed in the aldol condensation between the Z-lithium enolate B and aldehyde C, Scheme 2.6. The aldol reaction proceeds with the expected simple diastereoselectivity with the major product displaying the C6-C7 syn relationship shown in Scheme 2.7 (by ul addition) however, the C7-C8 relationship of the principal product was anti (by Ik addition). [38] Thus, the observed symanti relationship between C6-C7 C7-C8 in the aldol reaction between the Z-lithium enolate of 62 and aldehyde 63 was wholly unanticipated. These fortuitous results prompted us to investigate the cause for this unanticipated but fortunate occurrence. 

We next contemplated whether the unsaturation site could be encompassed in the context of a properly positioned benzo linkage. We were intrigued to discover that excellent diastereoface selectivity was obtained in the aldol condensation of the Z-lithium enolate with the benzyl-substituted formyl moiety, entry g. 

One of the first careful studies of the influence of chirality proximal to ketone enolates is illustrated in eq. [95] (113). Condensation of the enolate 126 (M = Li) with propanal (THF, -100 C) afforded a modest bias for the (5,i )-diastereomeric aldol adduct 127 (127 128 = 57 43). The influence of the metal center in this condensation has recently been examined. The boryl enolate 126 [M = B(n-C4H9)2l afforded a ratio 127 128 = 64 36 in pentane (-78°C) (6a, 113). Similar studies designed to probe the dependence of diastereoface selection on metal enolate structure have been carried out with metal enolates 129 (eq. [96], Table 32). 

Other related chiral erythro selective ketone enolates (iS -139 and (i )-139, readily prepared from (5)- and (i )-atrolactic acid, also exhibit good aldol diastereoface selection (3). From the data summarized in Table 34a, the influence of asymmetry in both condensation partners (entries C-F) has been amply demonstrated. The... 

Recently, the improved chiral ethyl ketone (5)-141, derived in three steps from (5)-mandelic acid, has been evaluated in the aldol process (115). Representative condensations of the derived (Z)-boron enolates (5)-142 with aldehydes are summarized in Table 34b, It is evident from the data that the nature of the boron ligand L plays a significant role in enolate diastereoface selection in this system. It is also noteworthy that the sense of asymmetric induction noted for the boron enolate (5)-142 is opposite to that observed for the lithium enolate (5)-139a and (5>139b derived from (S)-atrolactic acid (3) and the related lithium enolate 139. A detailed interpretation of these observations in terms of transition state steric effects (cf. Scheme 20) and chelation phenomena appears to be premature at this time. Further applications of (S )- 41 and (/ )-141 as chiral propionate enolate synthons for the aldol process have appeared in a 6-deoxyerythronolide B synthesis recently disclosed by Masamune (115b). 

The utility of chiral oxazoline enolates in asymmetric synthesis has elegantly been demonstrated by Myers (106,120). The stereoselective aldol condensations of these enolates have been examined in a hmited number of cases (eq. [107]) (32,121). Assuming that the enolate formed has the geometry indicated in 164 (120b), the diastereoselection observed for both the aldol condensation and the previously reported alkylations favors electrophile attack on the Re face as indicated. In contrast, the unsubstituted enolate 163b exhibits significantly poorer diastereoface selection with a range of aldehydes (eq. [108]) (121). 

The other aspect of the aldol condensation to be considered in using this reaction for the construction of compounds such as erythronolide-A is diastereoface selection. That is, in many cases one will want to carry out aldol condensations on aldehydes already having one or more chiral centers. The carbonyl faces in these molecules are diastereotopic, rather than enantiotopic, and there... 

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 order to test this concept as a way of controlling the problem of diastereoface selectivity in aldol condensations involving chiral aldehydes, we prepared the chiral ethyl ketone shown below, which is available in four straightforward steps from D-fructose. This compound shows modest inherent diastereoface... 

To capitalize on the concept of double stereodifferentiation as a method for enhancing mediocre diastereoface selectivity in aldol condensations of chiral aldehydes, we synthesized the chiral ethyl ketone shown below This compound shows good to excellent inherent diastereoface selectivity with achiral aldehydes The selectivity appears to increase dramatically with the steric demand of the group attached to the aldehyde carbonyl Thus, with pivalde-hyde and diacetaldehyde, only one aldol is produced The diastereoface selectivity in these two cases is at least 19 1 and 10 1, respectively (12)... 

B.i. Diastereoface Selectivity- -- - Heathcock defined three kinds of stereoselection for the aldol condensation simple diastereoselection, diastereoface selection, and double stereodifferentiation. 

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