Felkin models

A further improvement of the theory of 1,2-asymmetric induction was introduced by Felkin15. Neither Cram s open-chain model nor the Karabatsos model is able to explain why the stereoselectivity increases when either the incoming nucleophile R2e or the substituent at the carbonyl group (R1) increases in bulk. To explain these experimental observations the following assumptions are made for the Felkin model ... 

Figure 7. Realistic nucleophile approach Felkin model.

A modified Cram model 7 and/or Felkin model 8 is proposed for the 1.2-asymmetric induction on chiral imines. 

In the ( )-series, e.g., ( )-5-benzyloxy-3-hexen-2-one, the ano-compound 3a was the major isomer. This can be rationalized based on the Felkin model ... 

If the substituents are nonpolar, such as an alkyl or aryl group, the control is exerted mainly by steric effects. In particular, for a-substituted aldehydes, the Felkin TS model can be taken as the starting point for analysis, in combination with the cyclic TS. (See Section 2.4.1.3, Part A to review the Felkin model.) The analysis and prediction of the direction of the preferred reaction depends on the same principles as for simple diastereoselectivity and are done by consideration of the attractive and repulsive interactions in the presumed TS. In the Felkin model for nucleophilic addition to carbonyl centers the larger a-substituent is aligned anti to the approaching enolate and yields the 3,4-syn product. If reaction occurs by an alternative approach, the stereochemistry is reversed, and this is called an anti-Felkin approach. 

A study of the lithium enolate of pinacolone with several a-phenyl aldehydes gave results generally consistent with the Felkin model. Steric, rather than electronic, effects determine the conformational equilibria.77 If the alkyl group is branched, it occupies the large position. Thus, the f-butyl group occupies the large position, not the phenyl. 

E- and Z-silyl thioketene acetals give the 2,3-anti product. The 3,4-syn ratio is 50 1, and is consistent with the Felkin model. When this nucleophile reacts with 2-benzyloxypropanal (Entry 8), a chelation product results. The facial selectivity with respect to the methyl group is now reversed. Both isomers of the silyl thioketene acetal give mainly the 2,3-syn-3A-syn product. The ratio is higher than 30 1 for the Z-enolate but only 3 1 for the F-enolate. 

Entry 5 is a case in which the a- and (3-substituents reinforce the stereoselectivity, as shown below. The largest substituent is perpendicular to the carbonyl, as in the Felkin model. When this conformation is incorporated into the TS, with the a-methyl... 

With chiral aldehydes, reagent approach is generally consistent with a Felkin model.163 This preference can be reinforced or opposed by the effect of other stereocenters. For example, the addition of allyl stannane to l,4-dimethyl-3-(4-methoxybenzyloxy)pentanal is strongly in accord with the Felkin model for the anti stereoisomer but is anti-Felkin for the syn isomer. 

The presence of a stereogenic center on the aldehyde can strongly inlinence the diastereoselectivity in allylboration reactions, especially if this center is in the a-position. Predictive rules for nucleophilic addition on snch a-snbstitnted carbonyl substrates such as the Felkin model are not always snitable for closed transition structures.For a-substituted aldehydes devoid of a polar substituent, Roush has established that the minimization of ganche-ganche ( syn-pentane ) interactions can overrule the influence of stereoelectronic effects. This model is valid for any 3-monosubstituted allylic boron reagent. For example, althongh crotylboronate (E)-7 adds to aldehyde 39 to afford as the major prodnct the diastereomer predicted by the Felkin model (Scheme 2), " it is proposed that the dominant factor is rather the minimization of syn-pentane interactions between the Y-snbstitnents of the allyl unit and the a-carbon of the aldehyde. With this... 

In the Felkin model (5), the important steric interactions involve R1 and R rather than the carbonyl oxygen as assumed by Cram (2-4) and also Karabat-sos (6). On this basis, the preferred mode of attack is 4 + 5 yielding 6, the least strained of six possible staggered conformations (three staggered conformations are possible for each of the diastereoisomers 2 and 3 6 is equivalent to the least strained conformation of 2). Recently, Anh and Eisenstein (7) have concluded from their ab initio calculations that the transition 4+ 5 6 does indeed correspond to the minimum energy transition state. 

That dipolar effect may be substantial is shown by a series of results which agree better with the Cornforth than with the Felkin model.96 Some very interesting results... 

For reactions not under chelating conditions, Evans and co-workers proposed a merger of the Felkin (1,2) model and a polar (1,3) model. Thus, Ca is arranged according to the Felkin model with the L group anti to the nucleophile. The C Cp bond is staggered and the polar substituent X on Cfj is oriented in the direction opposite to the C=0 group ... 

Hydrosilylation provided a novel alternative reduction of a-oxy ketones (29) with tunable dia-stereoselectivity (Scheme 3). Fluoride-catalyzed reduction with phenyldimethylsilane in HMPA provided the jyn-alcohols (28) with high selectivity (87 13-96 4). The absence of a coordinating cation and the bulkiness of the reducing species combined to favor the Felkin model for these reductions. Conversely, reduction in trifluoroacetic acid proceeded via a proton-bridged cyclic transition state to give the anti products (30 84 16-99 1), These complementary methods constitute a powerful tool in stereoselective synthesis. 

Figure 6-5. The Felkin model for nucleophilic attack at acyclic carbonyfs.

C2-catalyzed process is a remarkable reversal of this typical Cram-Felkin stereoselectivity of the aldol, to a disfavored and energetically more demanding anti-Cram-Felkin model. 

Like the N- m e t h y I - 2 - ad a m a n ta n o ne species above, 5-aza-2-adamantanone N-oxide exhibits axial selectivity by a margin of 96 4 on reduction with NaBH4 in isopropanol. Cieplak model predicts axial selectivity for the overall electron-attracting character of the N+-0 bond. The Anh-Felkin model fails as it is opposite of the Cieplak model in concept and allows attack of a nucleophile anti to the more electron-deficient bond on the a carbon. The computed 3D structures of 5-aza-2-adamantanone N-oxide and its protonated derivative are shown in Fig. 12. 

The Cieplak model fails as it predicts axial attack for the electron-attracting nature of the boron atom. For the same reason, however, the Anh-Felkin model succeeds in predicting the equatorial selection. Houk s TS model also succeeds in predicting the equatorial preference. Since D2 is 4° larger than D1 in 5-bora-2-adamantanone, less destabilizing interactions in the TS for equatorial attack over those in the TS for axial attack are expected. The computed 3D structures of 5-bora-2-adamantanonc and its above derivatives are shown in Fig. 13. 

Felkin model for asymmetric induction if one uses the order of ligand preferences for the anti position MeO > Bu > Ph > Pr > Et > Me > H. Note that the major isomers produced in reactions of the a-meth-oxy aldehydes (Table 17, entries 5-9) are not those expected from a chelation-controlled process. 

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