Diastereofacial preference studies

The poor diastereoselectivity of the reactions of chiral aldehydes and achiral allylboronates appeared to be a problem that could be solved by recourse to the strategy of double asymmetric synthesis.f Our studies thus moved into this new arena of asymmetric synthesis, our objective being the development of a chiral allylboron reagent capable of controlling the stereochemical outcome of reactions with chiral aldehydes independent of any diastereofacial preference on the part of the carbonyl reaction partner. 

In the interest of asymmetric synthesis, there has been a considerable effort to develop chiral ketones, esters and amides that will undergo aldol reactions with high diastereofacial preference. One such reagent is ketone (181), available in three steps from (S)-f-butylglycine. [For a discussion of the use of the racemic version of ketone (181) for aldol reactions, see ref. 57d, pp. 181-184.] Aldol reactions of several different enolates of (181) have been studied with benzaldehyde (Scheme 11 Table 20).The... 

Chiral amides (222) and (223) and imides (224) and (225) have also been studied as reagents for asymmetric aldol reactions. These reagents show excellent diastereofacial preferences as their boron and zirconium enolates, but generally show poor selectivity as their lithium enolates. The reader is referred to other chapters in this volume for a discussion of these and related reagents. 

Chiral a-methyl aldehydes (43) show exceptional diastereofacial preferences in their Lewis acid mediated reactions with enol silanes (equation i6) 2i 25c-26-64 selected data are reported in Table 8. The reason for this selectivity may be due to an approach trajectory of the nucleophile closer to the stereocenter when the carbonyl group is bound to the Lewis acid. Additions to chiral a-alkoxy aldehyde (48) were studied with both nonstereogenic (equation 17 Table 9) and stereogenic enol silanes (equation 18 Table 10). (Stereogenic and nonstereogenic are defined according to Mislow and Siegel.) ... 

Regio- and diastereoselectivity in 1,3-dipolar cycloadditions of nitrile oxides to 4-substituted cyclopent-2-enones was studied (238, 239). The reactions are always regioselective, while the diastereofacial selectivity depends on the nature of the substituents. Thus, 4-hydroxy-4-methylcyclopent-2-enone (75) gives preferably adducts 76a, the 76a 76b ratio warying from 65 35 to 85 15 (Scheme 1.22). 

Systematic study on the diastereofacial selectivity in the intramolecular photocycloaddition of alkenes to chiral dioxinones was recently reported by Haddad and coworkers129 on compounds of type 298. Preferred pyramidalization in the direction of the less exposed side (the axial methyl at the acetal center) described in structure 298b, and first bond formation at this position (found to be the case in dioxinones 143 and 146, Scheme 31), are essential features for obtaining selective photocycloadditions of alkenes to chiral dioxinones from this side, leading to the kinetically favored products. In such cases the preferred approach is not necessarily from the more exposed side (Figure 6). 

A DFT study of enolborane addition of o -heteroatom-substituted aldehydes has focused on the relevance of the Cornforth and polar Felkin-Anh (PKA) models for asymmetric induction.154 Using chiral substrates, MeCH(X)CHO, polar (X = F, Cl, (g) OMe) and less polar (X = SMe, NMe2, PMe2) substituents have been examined. The former favour Cornforth TS structures, the latter PKA. TS preferences have been correlated with the relative energy of the corresponding rotamer of the uncomplexed aldehyde. An in-depth study of addition of ( > and (Z)-enolborane nucleophiles to 2-methoxypropanal successfully predicts experimentally determined diastereofacial selectivities. 

To achieve high stereoselectivity applicable to any aldehyde in the cyclocondensation reaction the use of double diastereofacial selectivity has been investigated. These studies revealed an interesting relationship between the chiral catalyst used in the reaction and the chiral auxiliary. Contrary to the notion that the selectivity of a chiral diene and chiral dienophile are enhanced only in a matched pair, the interactivity of a chiral catalyst with a chiral diene where the two individual components have an opposite facial preference seems to give a high degree of asymmetric induction in the cyclocondensation reaction. ... 

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