Felkin-ANH conformation

When the medium-sized group is a methyl group, and when the substituent cis to it is a hydrogen atom, as in the trans alkene -5.146, it appears that the Felkin-Anh conformation for the transition structure 5.147, with the medium-sized group inside, is still the lowest in energy in spite of the A1,3 allylic interaction, and attack... 

Only with the small methyl radical does alkene 60 react via its A -strain con-former 63A, which has a slightly lower energy than the Felkin-Anh conformer 63B. 

After recrystallization from hexane, the major diastereomer is obtained in a 71 % yield. Although interpretation of the steric course of the reaction is difficult25, the preferred formation of the (6S )-diastereomer may be rationalized in terms of an imine conformation which is favored according to the Felkin-Anh model (vicinal C-O orthogonal to C = N)26 and by chelation21. 

Normally, additions depicted by model C lead to the highest asymmetric induction. The antiperiplanar effect of OR substituents can be very efficient in the Houk model B ( , , , , ) however it plays no role in model C. Furthermore, the Houk model B must be considered in all cycloaddition-like reactions. The Felkin-Anh model A is operative for nucleophilic additions other than cuprate additions ( ). The epoxidation reactions are unique as they demonstrate the activation of one diastereoface by a hydroxy group which forms a hydrogen bridge to the reagent ( Henbest phenomenon ). The stereochemical outcome may thus be interpreted in terms of the reactive conformations 1 and 2 where the hydroxy function is perpendicular to the olefinic plane and has an optimal activating effect. 

The stereochemical outcome can be rationalized by considering the approach of the aldehyde to the preferred conformation of the allylindium. The approach of the aldehyde is postulated to be in antiperiplanar to the OPG group as for the Felkin-Anh model. The allylindium prefers to adopt the conformation 12 rather than 13, where the 1,3-allylic strain with R is minimized and the steric interaction with the aldehyde is also reduced (Scheme 18). The facial selection with respect to the aldehyde is determined by the aldehyde residue (R ) to occupy in the least sterically demanding position, away from the substituted allylic carbon. The carbonyl allylation then proceeds via a six-membered chairlike transition state, in which the aldehyde substitutent attains an equatorial position, to afford the 1,4-syn product. 

With Nu = Et we have the right product and, more importantly, we can be pretty sure it is for the right reason this model of the way a nucleophile attacks a carbonyl compound, called the Felkin-Anh model, is supported by theoretical calculations and numerous experimental results. Notice that we don t have to decide which is the lower energy of the two conformations this is not necessary because the attack in black will occur even if the conformer on the left is the minor one in the mixture. 

How will this aldehyde (which can be made from the amino acid serine) read with nucleophiles such as lithiated alkynes Consider a Felkin-Anh transition state again, we know that the nitrogen, being electronegative, will lie perpendicular to the carbonyl group in the most reactive conformation, so we need only consider these two. The least hindered direction of attack is shown, and that indeed gives the required product. 

Although this is the only chapter in which stereoelectronics appears in the title, you will soon recognize the similarity between the ideas we cover here and concepts like the stereospecificity of E2 elimination reactions (Chapter 19), the Karplus relationship (Chapter 32), the Felkin-Anh transition state (Chapter 33), and the conformational requirements for rearrangement (Chapter 37) and fragmentation (Chapter 38) reactions. 

There is one further complication, but this time easily resolved, well understood, and supported by high-level calculations. When the electronegative element coordinates to a metal that can simultaneously coordinate to, and activate, the carbonyl group, the conformation will be that of a ring 5.90. The attack from the less hindered side, opposite to the group R, is then relatively easily predicted, and is the opposite of that predicted from the Felkin-Anh rule. It has long been known as chelation control. 

Stereoselectivities observed in the reactions of the a-chiral acylsilanes are explained by consideration of the the Felkin-Anh model. The conformers depicted in Figures 9 and 10 are predicted to be those through which nucleophilic addition occurs. The sterically demanding TMS group apparently differentiates between the a-hydrogen (S) and the a-methyl (M) substituents. This preference for the conformation in Figure 9 results in a highly stereoselective reaction. 

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