Comforth model

In the absence of chelation, comparison of the destabilizing syw-pentane interactions recently encouraged Evans and coworkers to use the Comforth model to justify the exalted 3,4-anti selectivity observed for a series of chiral a-oxygenated aldehydes reacting with the Z(O) boron and lithium enolates of 2-methyl-3-pentanone (Scheme 117)568. Comple-mentarily, the corresponding E(O) isomers showed, as expected, a striking difference in their 2,3-selectivities, while the 3,4 anti-selectivity was lowered in both cases a finding inconsistent with the PFA model. 

SCHEME 117. Comparative chair-like transition states using the polar Felkin-Anh and Comforth models for Z(O)568... 

Another stereochemical aspect of these Diels-Alder reactions which has been studied by the Vedejs group is the facial selectivity in cycloadditions of chiral thioaldehydes. For instance, thioaldehyde (184), generated by the photochemical method, added to cyclopentadiene to give exo adducts (185) and (186) Jong with endo isomers (187) and (188) (Scheme 24). As was the case for achiral thioaldehydes, the endo adducts predominated (-9 1). The facial selectivity obtained can be rationalized via a Felkin-Anh or Comforth model for asymmetric induction. 

Less acidic than Ti and Zi chloroderivatives, MeTi(OPr )3 perfoims chelation-controlled addition to chiral alkoxy ketones as well as or better than organomagnesium compounds, but fails to chelate to aldehydes or hindered ketones. Should the formation of a cyclic chelation intermediate be forbidden, the reaction is subject to nonchelation control, according to Ae Felkin-Anh (or Comforth) model. Under these circumstances, the ratio of the diastereomeric products is inverted in favor of the anti-Cram product(s). In the case of benzil (83 Scheme 7) this can be accounted for by the unlikely formation of a cyclic intermediate such as (85), and thus the preferential intermediacy of the open chain intermediate (86) that leads to the threo compound (88). This view is substantiated by the fact that replacement of titanium with zirconium, which is characterized by longer M—O bonds, restores the possibility of having a cyclic intermediate and, as a consequence, leads to the erythro meso) compound (87) thus paralleling the action of Mg and Li complexes. 

In 1977, Anh [23] used ab initio methods to evaluate the energies of all the postulated transition structures (Figures 4.2 - 4.4) for the reaction of 2-methyl-butanal and 2-chloropropanal (the former to test the Cram, Karabatsos, and Felkin models, and the latter to test the Felkin and Comforth models). The nucleophile was H , located 1.5A from the carbonyl carbon, at a 90° angle, on each face of the carbonyl. Rotation of the C1-C2 carbon-carbon bond then provided an energy trace which included structures close to all of the previously proposed conformational models. The results for both compounds clearly showed the Felkin transition states to be the lowest energy conformers for attack on either face of the carbonyl. Inclusion of a proton or lithium ion, coordinated to the oxygen, produced similar results. It therefore appeared that Felkin s notion of attack antiperiplanar to the large substituent was correct. 

If the aldehyde carries a chelating substituent (e.g., BnO-) in the a-position, as in 58, other models, such as the chelation or Comforth models may applyThe latter is used with Lewis acids incapable of forming chelates, e.g., BF3. The most stable conformer is the one in which dipoles are antiparallel to each other (61), and the nucleophile attacks from the least hindered face. 

Thus, 2-benzyloxyaldehyde 63 provides the syn adduct 64 with good selectivities when using SnCU, in line with the chelation model (Table 9). In contrast, BF3 promotes the anti stereoselection predicted by the Comforth model, but in modest excess. TiCU gives undesired, chlorinated products. Chelation control is also feasible in the case of a-methoxycyclohexa-none 66 where the nucleophile attacks from the equatorial face. The approach from the axial face is hindered by the two axial hydrogens. ... 

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