Diastereoface selection

In accord with the Felkin-Anh model, a-chiral ketones react more diastereoselectively than the corresponding aldehydes. Increasing steric demand of the acyl substituent increases the Cram selectivity. Due to the size of the acyl substituent, the incoming nucleophile is pushed towards the stereogenic center and therefore the diastereoface selection becomes more effective (see also Section 1.3.1.1.). Thus, addition of methyllithium to 4-methyl-4-phenyl-3-hexanonc (15) proceeds with higher diastercoselectivity than the addition of ethyllithium to 3-methyl-3-phenyl-2-pen-tanone (14)32. 

In a chiral aldehyde or a chiral ketone, the carbonyl faces are diastereotopic. Thus, the addition of an enolate leads to the formation of at least one stereogenic center. An effective transfer of chirality from the stereogenic center to the diastereoface is highly desirable. In most cases of diastereoface selection of this type, the chiral aldehyde or ketone was used in the racemic form, especially in early investigations. However, from the point of view of an HPC synthesis, it is indispensable to use enantiomerically pure carbonyl compounds. Therefore, this section emphasizes those aldol reactions which are performed with enantiomerically pure aldehydes. 

Highly diastereoface selective Michael additions to chiral cycloalkenones and lactones have been developed264. The selectivity is, in general, due to the shielding of one of the diastereotopic faces by a substituent R at the stereogenic center in the y- or -position (steric effect). 

This enolate can then react with a plethora of electrophiles, setting a new stereocenter by a diastereoface-selective reaction. The simplest electrophile to trap enolate 71 is H" ", which can, for example, originate from methanol [89] or diphenyl acetaldehyde (as a readily enolizable aldehyde) [90] leading to the acy-lated catalyst species (Fig. 38). The free catalyst is regenerated by acyl-group transfer to methanol(ate) or the aldehyde-derived enolate, producing methyl or enolesters 72/73 in good yields and enantioselectivities. 

Figure 5-3. Diastereoface selection in the cycloaddition process. Reprinted with permission by Am. Chem. Soc., Ref. 4.

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. 

Our discoveries using aldehyde 63 (Table 2.1, formula II) and related congeners were unique in that our substrate aldehydes lack the typical resident protected alcohol derivative that is usually involved in fashioning anti diastereoface selectivity. [41]... 

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. 

Dale, Sir Henry 77 Delay 77 Delay, Jean 77 delocalized orbitals 233 Deniker, Pierre 77 Density Functional Theory 55,228,241,271,278 deposition conditions 168 design of the Sawatzky-Kay apparatus 152 Dess-Martin oxidation 11 detailed atomic-level representation 92 determinant 279 diastereoface selectivity 22,... 

Recently, the issue of aldehyde diastereoface selection has been examined for the enolates 99 to 103 (2,26,33,64). For these substituted enolates, aldol diastereoselection has been demonstrated to... 

Remote steric effects have also been noted to play an unanticipated role in the sense of asymmetric induction. This is apparent from related condensations carried out on aldehydes 106 (26) and 107 (eqs. [76]-[78]) (26,92). Other examples illustrating the influence of remote structural perturbations on the carbonyl addition process have been observed in these laboratories. The addition of the lithio benzoxazole 110 to aldehyde 108 proceeded with good Cram diastereoface selection (95a), whereas the same nucleophilic addition to aldehyde 109 was stereorandom (95b). 

Diastereoface selection has been investigated in the addition of enolates to a-alkoxy aldehydes (93). In the absence of chelation phenomena, transition states A and B (Scheme 19), with the OR substituent aligned perpendicular to the carbonyl a plane (Rl = OR), are considered (Oc-or c-r transition state R2 Nu steric parameters dictate that predoniinant diastereoface selection from A will occur. In the presence of strongly chelating metals, the cyclic transition states C and D can be invoked (85), and the same R2 Nu control element predicts the opposite diastereoface selection via transition state D (98). The aldol diastereoface selection that has been observed for aldehydes 111 and 112 with lithium enolates 99, 100, and 101 (eqs. [81-84]) (93) can generally be rationalized by a consideration of the Felkin transition states A and B (88) illustrated in Scheme 19, where A is preferred on steric grounds. 

Ester Erythro-Threo Ratio Diastereoface Selection"... 

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). 

One possible explanation for the diastereoface selection (AAGt -78°C 3 kcal/mol) observed for these chiral enolates is illustrated in Scheme 23. In the respective aldol transition states derived from conformers A and B leading to erythro diastereomers A and B, it may be assumed that developing imide resonance (118) will lock the chiral auxiliary in one of the in-plane conformations illustrated in products A or B. Based on an examination of models, it is projected that developing CHj R, allyhc strain steric interaction (37) disfavors that transition state leading to A. These steric considerations are largely attenuated in the transition state leading to the observed erythro adduct B. ... 

It should also be noted that there is a strong conformational bias for only one of the product chelate conformers. For example, erythro chelate D should be strongly disfavored by both 1,3-diaxial Rj L and CH3 Xq steric control elements. Consequently, it is assumed that the transition states leading to either adduct will reflect this conformational bias. Further support for these projections stems from the observations that the chiral acetate enolates derived from 149a exhibit only poor diastereoface selection. In these cases the developing Rj CH3 interaction leading to diastereomer A is absent. Similar transition state allylic strain considerations also appear to be important with the zirconium enolates, which are discussed below. 

The preceding discussion clearly demonstrates the important role that metal-centered steric effects can exert on enolate diastereoface selection in the aldol process. A recent publication from this laboratory provides an additional example of the importance of this... 

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 Importance of Enolate Substitution in Aldol Diastereoface Selection ... 

The observation that aldehyde diastereoface selection is interrelated with allylborane geometry has important implications for the related aldol processes. The reactions of (-)-180a and (-)-180b with both enantiomers of aldehyde 181 revealed both consonant and dissonant double stereodifferentiation. For the Cram-selective ( )-crotyl... 

The correlation between allylboronic ester stereochemistry and aldehyde diastereoface selection stands in contrast to the behavior of stereochemicaUy defined lithium enolates, which generally exhibit a preference for the Cram mode of addition to chiral aldehydes from either enolate geometry (cf, eqs. [72]-[77]). The stereochemical... 

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