Aldehyde diastereoface selection

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... 

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... 

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. 

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. 

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]... 

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. 

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). 

Boryl enolates prepared from A-propionylsultam reacted with aliphatic, aromatic and a,/Tunsaturated aldehydes to provide diastereomerically pure. qw-aldols (Equation (174), whereas the presence of TiCl4 caused complete reversal of the diastereoface selectivity giving anti-aldols (Equation (175)).676-678 Camphor-derived chiral boryl enolates 423 were highly reactive and highly anti-selective enolate synthon system in aldol addition reactions promoted by TiCl4 or SnCl4 co-catalyst (Equation (176)).679... 

Not much is currently known concerning diastereoselective addition of metal enolates to ketones 48,108), but selectivities are expected to be lower. In case of titanium enolates, several examples have been studied 77). The reaction shown in Equation 67 involves an ester-enolate21 and proceeds strictly in a 1,2 manner with 90% diastereoselectivity. The observation is significant because similar reactions with aldehydes are essentially stereo-random77). Also, the lithium analog of 203 affords a 1 1 mixture of diastereomers. Diastereoface-selectivity in Equation 67 is not an exception, because 203 adds to acetophenone and pinacolone to afford 85 15 and >76 24 diastereomer mixtures, respectively 77). Although stereochemical assignments have not been made in all cases, the acetophenone adduct was converted stereospecifically into the p-lactone which was decarboxylated to yield an 85 15 mixture of Z- and E-2-phenyi-2-butene 77). 

The second is referred to as diastereoface selection, that is, in many cases one carries out aldol reactions on aldehydes already having one or more chiral centers. The carbonyl faces in these molecules are diastereotopic rather then enantiotopic. 

Myers et al. found that silyl enolates derived from amides undergo a facile non-catalyzed aldol addition to aldehydes at or below ambient temperature [90]. In particular, the use of cyclic silyl enolate 27, derived from (S)-prolinol propionamide, realizes high levels of diastereoface-selection and simple diastereoselection (anti selectivity) (Scheme 10.27). It has been proposed that this non-catalyzed highly stereoselective reaction proceeds via attack of an aldehyde on 27 to produce a trigonal bipyramidal intermediate 29 in which the aldehyde is apically bound 29 then turns to another isomer 30 by pseudorotation and 30 is then converted into 28 through a six-membered boat-like transition state (rate-determining step). 

Introduction of a chiral auxihary into the silyl group of silyl enolates has been attempted [109-111]. The enantioselectivity of the reaction with binaphthyl-based silyl enolate 44 is, however, rather low [109]. Denmark et al. have reported that en-oxysilacyclobutane 45, bearing a chiral auxihary, adds to aldehydes without any catalyst to give the corresponding adducts with high diastereo- and diastereoface-selectivity [111]. 

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 ... 

Of course, in the other combination, neither reactant gets its way. In this case, the effective diastereoface selectivity shown by the aldehyde should be poorer than is seen in reactions of the same aldehyde with representative achiral enolates. 

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)... 

That is, in order for the phenomenon to be observed, both reactants must show inherent diastereoface selectivity in their reactions with achiral partners. If one of the reactants shows no inherent diastereoface selectivity in its reactions with achiral reactants, then mutual kinetic resolution will not be observed regardless of the stereoselectivity of the other reactant. For an example, consider the case of an enzyme which mediates some reaction, say reduction of the carbonyl group. We can let the enzyme be A and assume that, because of its uniquely-evolved molecular structure, it shows very high inherent diastereoface selectivity (thus, it will reduce prochiral carbonyl compounds to chiral alcohols with very high enantiomeric excess). For B, let us take a chiral aldehyde that shows no inherent diastereoface selectivity in its... 

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