Diastereoselectivity, solvent effects

An analogous solvent effect was observed upon treatment of the chiral a-alkoxy aldehyde 11 with 2-lithio-4-methylfuran in the presence of zinc bromide. This highly diastereoselective addition reaction was the key step in a synthesis of the enantiomcrically pure C-10-C-20 fragment of the immunosuppressant KK 506139. 

Many mechanisms had been proposed in the past to rationalize this selectivity (tri-oxanes, perepoxide, exciplex, dipolar or biradical intermediates) however, it is now generally accepted that the reaction proceeds through an intermediate exciplex which has the structural requirements of a perepoxide. This assumption is supported by (a) the lack of stereoselectivity in the reactions with chiral oxazolines and tiglic acid esters (b) the comparison of the diastereoselectivity of dialkyl substituted acrylic esters with structurally similar non-functionalized aUtenes (c) the intermolecular isotope effects in the photooxygenation of methyl tiglate and (d) the solvent effects on regioselectivity. ... 

The Bayhs-Hillman reaction of optically pure azetidine-2,3-diones [235, 236] with methyl vinyl ketone in the presence of l,4-diazabicyclo[2.2.2]octane (DABCO) in acetonitrile at -20°C for 1 h have been reported to give functionalized allylic alcohols, having the p-lactam scaffold, in good yields (80%) and complete diastereoselectivity [237]. In terms of achieving good yields with a reasonable rate of reaction, 50 mol% of DABCO seemed to be the catalyst amount of choice for this reaction. No significant solvent effect was observed in the overall yield (Scheme 108). 

Solvent effects were found to be substantial for this [3+2] cycloaddition. Thus, the half-life of the thermal reaction of 21 with maleic anhydride at 105°C was reduced to 59 min in <73-MeN02 compared with 120 min in i/g-toluene. The authors proposed the key notion that a reactive, conformationally rigid metalated azomethine species 24 is responsible for the high diastereoselectivity observed in the reaction. 

Cationic ansa metallocenes can be utilized as chiral catalysts in Diels-Alder reactions. For example, in the presence of the cationic zirconocene complex [(ebthi)Zr(Ot-Bu) thf]+, the [4 + 2] cycloaddition of acrolein and cyclopentadiene proceeds efficiently to afford endo and exo cycloadducts (equation 71). In reactions in which methyl acrylate is used as the dienophile, cycloadditions occur with lower levels of enan-tioselection (23% ee), but with significantly higher degrees of diastereoselectivity (17 1 endo, exo). In these processes, recent studies demonstrated the great influence of chiral metallocene structure and the dramatic solvent effect. ... 

While the stereochemical outcome of the reactions with chiral (Z)-vinyl sulfoxides can be simply explained in terms of a reactive conformation, the outcome of reactions with chiral (f.)-vinyl sulfoxides cannot be satisfactorily explained. The latter reactions generally proceed with poorer selectivity and with either opposite or the same 7t-face selectivity compared to their Z counterparts94 95. Investigations with chiral (E)- and (Z)-vinyl (/Ci-sulfoxides 23 and ben-zylamine show, besides a solvent effect, that both reaction types proceed with similar diastereoselectivities. The reaction products are formed irreversibly and the extent of interconversion between the ( )- and (Z)-vinyl sulfoxide isomers is small (l-2%)96. 

A solvent effect on diastereoselectivity was also observed with other substrates (Table XVIII). Generally, when aromatic aldehydes (benzaldehyde, furfural, 2-thiophenecarbaldehyde) and benzaldehyde dimethyl acetal were used, the ratio of threo to erythro products increased in the following order... 

As shown in Scheme 34, a rather profound solvent effect on dienolate alkylation diastereoselectivity has been noted for the steroidal enone (71). Such large solvent effects have not been documented for other systems. Possible explanations based upon the position of the transition state along the reaction coordinate and/or specific solvation of the dienolate have been advanced to account for preferential axial alkylation in benzene and equatorial alkylation in t-butyl alcohol.However, in view of the fact that the degree of aggregation of the dienolate as well as the structure of the aggregates may be modified considerably in going from one solvent to the other, rationalization of the results is difficult. 

WL Adam, A. K. Smerz, Solvent effects in the regio- aird diastereoselective epoxidations of acyclic allylic alcohols by dimethyldioxirane Hydrogen bonding as evidence for a dipolar transition state, J. Org. Chem. 61 (1996) 3506. 

An improvement in aldol diastereoselection for a given boron ligand is obtained when less polar solvents are employed, presumably due to transition state compression in nonpolar solvents. This solvent effect is also significant in enolate chirality transfer in asymmetric aldol reactions. 

Table 4.3 lists selected examples where exceptionally high stereoselection has been encountered. Solvent effects play an important role in achieving high selectivity. For example the >99% diastereoselectivities for the addition of... 

Michael reactions. The ester group exerts profound influences on the steric course of the reaction. Thus diastereocontrol is possible by changing solvent, enolate counterion, and activating group at the a-carbon of the acceptor. The phenylthio group increases reactivity, but electron-withdrawing substituents at this position tend to erode the diastereoselectivity. Temperature effects are also dramatic. 

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