Diastereoface selectivity, in the

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

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... 

In general, diastereoface selectivity in the allylic sulfoxide-to-sulfenate Mislow-Evans rearrangement is possible in cases such as 74 (Scheme 18.19). having the sulfoxide attached to a chiral center, or with substrates of type 75, where the alkene faces are rendered diastereotopic by a structural element distal from the allyl sulfoxide. These diastereoselective... 

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. 

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

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). 

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. 

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). 

Asymmetric Diels-Alder reactions. Chiral a,p-unsaturated N-acyl oxazolidones exhibit high diastereoface selection in Diels-Alder reactions, particularly those conducted in the presence of diethylaluminum chloride (1.2 equiv.). 

In the epoxidation of racemic secondary alcohols, there are two stereochemical problems to be considered (i) differentiation of enantiomers (kinetic resolution) and (ii) diastereoface selection in epoxidation. 

The stereosequences indicate site stereochemical control with chain migratory insertions, which result in site isomerization and occasional reversal in diastereoface selectivity. With the zirconocene, the activity was found to be 56 kg PP/mmol Zr. Even cyclic olefins such as cyclobutene, cyclopentene, or norbomene could be polymerized with the chiral catalysts to high melting polymers (mp > 400°C) . ... 

Superposition of the [2,3] Wittig framework onto a rigid carbocyclic template can provide an asymmetric environment which results in diastereoface selectivity for the rearrangement. Thus, the (—[-camphor derived tertiary ether 3 undergoes sigmatropic rearrangement with concurrent induced diastereoselection29. 

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... 

For the homolytic mode of formation of the Co - C bond in coenzyme Bi2 (2) the structure [51] and reactivity of cob(II)alamin (23) gave crucial information. The radicaloid 23 has a pentacoordinated Co(II) center and is considered to fulfill all the structural criteria of a highly efficient radical trap (see Fig. 10), since its reactions with alkyl radicals occur with negligible restructuring of the DMB-nucleotide coordinated cobalt-corrin moiety [51]. From this it is understandable that the remarkably high reaction rate of 23 with alkyl radicals (such as the 5 -deoxy-5 -adenosyl radical) and the diastere-ospecificity for the reaction to occur at the j8-face, are both consistent and explainable due to the structure of cob(II)alamin. The coordination of the DMB-nucleotide in 23 controls the (a/j8)-diastereoface selectivity (in both a kinetic and thermodynamic sense) in alkylation reactions at the Co(II) center. 

Keck has documented a set of examples of chelation-controlled allylations of / -alkoxy-substituted aldehydes such as 117 (Scheme 5.20) [91]. The coupling constants in the H-NMR spectrum of the species generated upon mixing TiCl4 and 117 are consistent with the formation of a chelate 119 in which the cyclohexyl substituent occupies a pseudoaxial position. The allylation of 119 from the diastereoface opposite to the axially dispositioned cyclohexyl group accounts for the observed induction (120/121 = 96 1). The lack of selectivity in the allylation of 118 (122/123 = 1 1.1) is consistent with the relevance of chelation control in the previous example, as TBS ethers generally fail to participate in chelate formation. 

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