S-trans rotamers

The use of chiral auxiliaries to induce (or even control) diastereoselectivity in the cycloaddition of nitrile oxides with achiral alkenes to give 5-substituted isoxazolines has been investigated by a number of groups. With chiral acrylates, this led mostly to low or modest diastereoselectivity, which was explained in terms of the conformational flexibility of the vinyl-CO linkage of the ester (Scheme 6.33) (179). In cycloadditions to chiral acrylates (or acrylamides), both the direction of the facial attack of the dipole as well as the conformational preference of the rotamers need to be controlled in order to achieve high diastereoselection. Although the attack from one sector of space may well be directed or hindered by the chiral auxiliary, a low diastereomer ratio would result due to competing attack to the respective 7i-faces of both the s-cis and s-trans rotamers of the acrylate or amide. 

The PES for rotation around the C—C bond of 58, M=Si, Ge (Figure 18) shows two minima the s-trans and the gauche, while the s-cis structure is a saddle point that connects two gauche enantiomers. The gauche rotamer is by ca 4333 and 3 kcal mol-1335 for 58, M = Si, Ge, respectively, less stable than the s-trans rotamer, an energy difference very similar to that in 1,3-butadiene. However, the rotation barrier about the central C—C bond in 58, M = Si and Ge, of ca 10-11 and 9.5 kcalmol-1, respectively, is... 

The stereochemical course of these reactions was also explained by assuming an exo approach of dipole to the vinyl sulfoxide in s-trans conformation, which in this case would be the less destabilized by electrostatic repulsions (Scheme 95). A similar stereochemical course would explain the results obtained in the reactions of nitrone 194 with (Z)-vinyl sulfoxides 13 (Scheme 96) [159a]. With these dipolarophiles, the exo selectivity is complete, and the 7r-facial selectivity is very high (de 82-98 %) and depends on the size of the R group, which must be responsible for the shifting the conformational equilibrium around the C-S bond toward the s-trans rotamer. The major adduct exo(t)-202 (R = Me) was transformed into the enantiomerically pure piperidine alkaloid (-l-)-sedridine. 

Few examples have been reported demonstrating enantioselective cyclization methodology. One known example, however, is similar to the diastereoselective cyclization of 175, which uses a menthol-derived chiral auxiliary and a bulky aluminum Lewis acid (see Eq. (13.55)). The enantioselective variant simply utilizes an achiral template 188 in conjunction with a bulky chiral binol-derived aluminum Lewis acid 189 (Eq. (13.59)) [75]. Once again the steric bulk of the chiral aluminum Lewis acid complex favors the s-trans rotamer of the acceptor olefin. Facial selectivity of the radical addition can then be controlled by the chiral Lewis acid. The highest selectivity (48% ee) was achieved with 4 equivalents of chiral Lewis acid, providing a yield of 63%. 

Success in diastereoselective Lewis acid-mediated conjugate radical additions using chiral oxazolidinones led Sibi and Porter to evaluate enantioselective variants. Based on previous work from their laboratories as well as information in the literature (control of the s-cis vs s-trans rotamer of the enoate), they surmised that a bidentate Lewis acid in combination with an achiral oxazolidinone template and a chiral ligand would be a good starting point to probe enantioselective conjugate radical additions (Scheme 2). 

As the origin of the occurrence of the quantum chain process in the isomerization of the dienes and trienes above, energy transfer from their excited triplet states to their ground states of the s-cis form was proposed. Compared to s-trans rotamers, s-cis rotamers have lower triplet energies and are more readily excited, although less populated in the ground state. For example, the following reaction may proceed [82] ... 

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