Conformations, anti substituent effects

These calculations show that, if vinyl alcohol and vinyl thiol indeed mainly exist in planar syn conformations, as previously stated, the situation can be very different when halogen substituents are present. In some cases, the anti conformation is more or less out-of-plane staggered and can become more stable than the syn one. The general trends of substituent effects can be discussed by molecular orbitals analysis and electrostatic interactions. The results are subject to experimental confirmation, at least in the case of enols since their conformers can be prepared by the action of singlet oxygen atom on substituted ethylen, and trapped in low temperature matrices. 

These data may be interpreted using the four-conformer model shown in Figure 4.10. Simply put, both steric and electronic effects determine the favored anti substituent. Thus in the methoxy series (Figure 4.10a), conformers A and B are favored when R is methyl, ethyl, or isopropyl, and attack is favored via conformer... 

For this case and many others, the Felkin model was established unequivocally to be energetically preferred, and a variety of details and interpretations were provided. In addition to the role of torsional and steric effects, Anh and Eisenstein found that the most electronegative substituent-that with the lowest-lying a LUMO-would take the conformation anti to the attacking nucleophile. This model and its rationale are now universally known as the Felkin-Anh model. A variety of refinements and extensions occurred in following decades, such as the location of actual transition... 

Reasonable predictions for the shift values for trans-decalin can be based on the simple substituent effects outlined in Chapter 1 and the stereochemical considerations mentioned above. Thus, the bridgehead carbons would be predicted to absorb at 45.3 (27.3, + 24.0 for three additional P substituents, and -6.0 for a 3 carbon with four p substituents, 43.7 obs.). Similarly, the prediction for C-2 would be 35.3 (27.3 + 8.0), 34.3 observed, and for C-3 would be 27.3 (26.9 obs.) since there are no additional a or P substituents relative to cyclohexane and the y carbons are anti, not gauche. There is a small upfield shift, typically 0.5 for an anti, y carbon, but in most cases this effect is too small to be of significant use in st eochemical predictions. The situation with cis-decalin is more complicated because of the superposition of two equal energy conformations. Nonetheless, the shifts observed are understandable once this factor is combined with stereochemical considerations to be detailed in Chapter 3. 

As mentioned before, compounds with a C-3 -F down (i.e., compound 1) are anti-HIV effective. This is particularly true for the case in which the base equals thymine or uracil (Table 1). The C-2 -F up substituent found in 2 is equally consistent with anti-HIV activity. However, inversion at either one of these two centers results in the complete disappearance of antiviral activity. One can invoke the aforementioned gauche effect between fluorine and the furanose oxygen to explain why in both active templates of 1 and 2 the S conformation is favored in solution. The inactivity of the inverted conformers, on the other hand, could be explained... 

Syn elimination and the syn-anti dichotomy have also been found in open-chain systems, though to a lesser extent than in medium-ring compounds. For example, in the conversion of 3-hexyl-4-d-trimethylammonium ion to 3-hexene with potassium ec-butoxide, 67% of the reaction followed the syn-anti dichotomy. In general syn elimination in open-chain systems is only important in cases where certain types of steric effect are present. One such type is compounds in which substituents are found on both the P and the y carbons (the unprimed letter refers to the branch in which the elimination takes place). The factors that cause these results are not completely understood, but the following conformational effects have been proposed as a partial explanation. The two anti- and two syn-periplanar conformations are, for a quaternary ammonium salt ... 

Heteroatom substituents also introduce polar effects. In the case of a-alkoxy aldehydes the preferred TS appears to be F and G for the E- and Z-enolates, respectively. These differ from the normal Felkin TS for nucleophilic addition. The reactant conformation is believed to be determined by minimization of dipolar repulsion between the alkoxy substituent and the carbonyl group.96 This model predicts higher 3,4-anti ratios for Z-enolates, and this is observed. 

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