Asymmetric Induction - Carbonyl 1,2 Asymmetric Induction - Anti–Felkin Selectivity

Anti–Felkin Selectivity

Though the Cram and Felkin–Anh models differ in the conformers considered and other assumptions, they both attempt to explain the same basic phenomenon: the preferential addition of a nucleophile to the most sterically favored face of a carbonyl moiety. However, many examples exist of reactions that display stereoselectivity opposite of what is predicted by the basic tenets of the Cram and Felkin–Anh models. Although both of the models include attempts to explain these reversals, the products obtained are still referred to as "anti-Felkin" products. One of the most common examples of altered asymmetric induction selectivity requires an α-carbon substituted with a component with Lewis base character (i.e. O, N, S, P substituents). In this situation, if a Lewis acid such as Al-iPr₂ or Zn2+ is introduced, a bidentate chelation effect can be observed. This locks the carbonyl and the Lewis base substituent in an eclipsed conformation, and the nucleophile will then attack from the side with the smallest free α-carbon substituent. If the chelating R group is identified as the largest, this will result in an "anti-Felkin" product.

This stereoselective control was recognized and discussed in the first paper establishing the Cram model, causing Cram to assert that his model requires non-chelating conditions. An example of chelation control of a reaction can be seen here, from a 1987 paper that was the first to directly observe such a "Cram-chelate" intermediate, vindicating the model:

Here, the methyl titanium chloride forms a Cram-chelate. The methyl group then dissociates from titanium and attacks the carbonyl, leading to the anti-Felkin diastereomer.

A non-chelating electron-withdrawing substituent effect can also result in anti-Felkin selectivity. If a substituent on the α-carbon is sufficiently electron withdrawing, the nucleophile will add anti- relative to the electron withdrawing group, even if the substituent is not the largest of the 3 bonded to the α-carbon. Each model offers a slightly different explanation for this phenomenon. A polar effect was postulated by the Cornforth model and the original Felkin model, which placed the EWG substituent and incoming nucleophile anti- to each other in order to most effectively cancel the dipole moment of the transition structure.

This Newman projection illustrates the Cornforth and Felkin transition state that places the EWG anti- to the incoming nucleophile, regardless of its steric bulk relative to R_S and R_L.

The improved Felkin–Anh model, as discussed above, makes a more sophisticated assessment of the polar effect by considering molecular orbital interactions in the stabilization of the preferred transition state. A typical reaction illustrating the potential anti-Felkin selectivity of this effect, along with its proposed transition structure, is pictured below: