Felkin-Anh’s model

The Li—F chelation is also useful for stereoselective reactions. In particular, chelation between lithium of enolates and a fluorine of a trifluoromethyl group results in conformational fixation of substrates, leading to markedly enhanced stereoselection. This concept has often been employed to achieve stereocontrol in fluorinated enolate chemistry. Morisawa reported Li—F chelation-controlled stereoselective a-hydroxylation of enolate of 40 [22]. The oxidant approaches from the less hindered side of the Li—F chelated enolate intermediate (41), affording anti-alcohol (42) exclusively (Scheme 3.11). The syn-alcohol (45) was prepared by NaBlrh reduction of ketoester (43) via a reaction course predicted by Felkin-Anh s model (44). 

The reaction with Me2AlCl follows a different pathway. If we apply the Felkin-Anh s model in this case the situation has to be entirely analogous to that depicted... 

The stereoselectivity of the addition of pinacolone enolsilane 1 to P-alkoxy aldehydes bearing two stereocenters depends on the ability of the metal to form intermediate chelates. Those metals that monocoordinate the carbonyl group form Fel-kin products and the stereochemistry of these aldols is predicted by the Felkin-Anh s model. For metals chelating both the carbonyl and alkoxy groups, anti-Felkin products are obtained. In these cases the cyclic-Cram s model has to be used to predict the stereochemical outcome of the reaction. Therefore, non-chelated (Felkin-Ahn) and chelated models (cyclic-Cram) have been successively applied to understand the stereochemistry of the final reaction products. 

Natural bond orbital analysis of early and late TSs has been carried out to explore the factors involved in tt-selectivity of nucleophilic addition to carbonyls.209 Cieplak s o —r o hyperconjugation hypothesis (where o is the incipient bond) is not supported by the results for early TSs, and evidence in favour of Felkin-Anh s o er hypothesis is weak. Late TSs are devoid of o 7r(t=() interactions here, the Cieplak model may be applicable. 

A possible transition state based on the Felkin-Anh model was shown in Scheme 23. Judging from the (2/ ,3R,4S)-configuration of the product 31a, the major product is likely formed via the Felkin TS 33 showing the Si face attack of the Rh-( )-enolate. This step could be the catalyst-controlled reaction with the chiral catalyst. According to the prochiral face discrimination in the phebox-Rh-catalyzed reductive aldol reaction with the linear substrate, the Re face attack of the Rh (fij-enolate in TS 34 is unfavorable. In the case of the (R)-aldehyde, the anri-Felkin-Anh s TS 35, which gives the (2R,3R,4R)-product 31b, takes the unfavorable conformation with the bulky phenyl group at the apical position. 

Control of the stereoselectivity in nucleophilic additions to the carbonyl group. Facial selectivity. Felkin Anh s and Cram s models. Reactivity of TMS enol ethers towards electrophiles. 

The issue of stereochemistry, on the other hand, is more ambiguous. A priori, an aldol condensation between compounds 3 and 4 could proceed with little or no selectivity for a particular aldol dia-stereoisomer. For the desired C-7 epimer (compound 2) to be produced preferentially, the crucial aldol condensation between compounds 3 and 4 would have to exhibit Cram-Felkin-Anh selectivity22 23 (see 3 + 4 - 2, Scheme 9). In light of observations made during the course of Kishi s lasalocid A synthesis,12 there was good reason to believe that the preferred stereochemical course for the projected aldol reaction between intermediates 3 and 4 would be consistent with a Cram-Felkin-Anh model. Thus, on the basis of the lasalocid A precedent, it was anticipated that compound 2 would emerge as the major product from an aldol coupling of intermediates 3 and 4. 

Cram s open-chain model 229 Cram s rule 229, 233 Cram chelate model 229 Cram cyclic model 229 Cram-Felkin-Anh model 191,207, 236 f 246 cubane 12,318 cyanoacetic acid 636 f. cyanohydrin, protected 145, 150 f. cyclic carbonate protection 541 f., 657, 659 f., 666, 670 cyclization -,6-endo 734 -, 5-exo 733 f. 

As outlined in Section D.2.3.5., the stereochemical outcome of the addition of nucleophilic reagents to chiral aldehydes or ketones is rationalized most plausibly by the Cram-Felkin-Anh model. On the other hand, the corresponding reactions of oxygen- or nitrogen-heterosub-stituted aldehydes or ketones may be interpreted either by the same transition state hypothesis or, alternatively, by Cram s cyclic model. 

If a chiral aldehyde, e.g., methyl (27 ,4S)-4-formyl-2-methylpentanoate (syn-1) is attacked by an achiral enolate (see Section 1.3.4.3.1.), the induced stereoselectivity is directed by the aldehyde ( inherent aldehyde selectivity ). Predictions of the stereochemical outcome are possible (at least for 1,2- and 1,3-induction) based on the Cram—Felkin Anh model or Cram s cyclic model (see Sections 1.3.4.3.1. and 1.3.4.3.2.). If, however, the enantiomerically pure aldehyde 1 is allowed to react with both enantiomers of the boron enolate l-rerr-butyldimethylsilyloxy-2-dibutylboranyloxy-1-cyclohexyl-2-butene (2), it must be expected that the diastereofacial selec-tivitics of the aldehyde and enolate will be consonant in one of the combinations ( matched pair 29), but will be dissonant in the other combination ( mismatched pair 29). This would lead to different ratios of the adducts 3a/3b and 4a/4b. 

A and B differ in the angle which the trajectory of the nucleophile forms with the plane of the olefin. For obtuse angles, the Felkin-Anh model is preferred, as the steric crowding outside the olefin has to be minimized (attack from the side of S). In contrast, B (Houk model)41 is superior for acute angles (minimal steric crowding inside the olefin). 

Figure 6.8 Felkin s model according to Anh-Eisenstein41 (22) and Cieplak81 (23).

Recall that the Felkin-Anh model predicts the preferred approach of a nucleophile to a carbonyl group bearing a chiral centre. The model places the most bulky group on the chiral centre (L) perpendicular to the plane of the carbonyl and its substituent (R), and the least bulky group on the chiral centre (S) adjacent to the carbonyl substituent (R). The nucleophile then prefers to approach the carbonyl past the smallest substituent on the chiral centre. 

Felkin s model relied on reducing steric interactions and strain energy about the carbonyl group. Anh and Eisenstein, however, supplied an alternative reason for the preferred transition-state conformation. The dominant orbital interaction in this reaction is between the highest occupied molecular orbital (HOMO) of the nucleophile and the lowest unoccupied molecular orbital (LUMO) of the carbonyl... 

Hetero-Diels-Alder reactions starting with unsaturated compounds with heteroatom-carbon or heteroatom-heteroatom multiple bond(s) are also enhanced by Lewis acids [374-381]. Aldehydes and imines work as dienophiles under the influence of TiCU- Electron-rich dienes are generally a preferable partner, as shown in Eq. (149), in which the product was obtained virtually as a single isomer [382,383]. The importance of the choice of the Lewis acid in determining the stereochemical outcome of the reaction is illustrated in Eq. (150) [384]. The notion of chelation and of Felkin-Anh models, respectively, is valid for these Diels-Alder reactions. Diastereoi-somers other than those shown in Eq. (150) were not detected. The stereochemistry of the product in Eq. (149) could be also explained by the chelation model. 

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. 

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. 

D. Kaneno and S. Tomoda, Origin of facial diastereoselection in 2-adamantyl cations. Theoretical evidence against the Felkin-Anh and the Cieplak models, Tetrahedron Lett., 45 (2004) 4559 1562. 

The Felkin-Anh Model [CP2, G5, M5, N2, N5, NNl, WHl, WH2, WP2, WTl] The attack of a hydride H on a prochiral carbonyl group can be accomplished either on the Re or Si face of the carbonyl, leading to a pair of diastereomers, as shown in the models in Figure 3.10. In these models L represents the most bulky group, P the most polar, and S the smallest group. Initially Cram [CA2] proposed model 3.18 to interpret the formation of the major isomer. This is called Cram in Figure 3.10, and the other isomer is labeled anti-Cram. ... 

Furthermore, when the R and R" groups are too bulky, chelation becomes unlikely. With either Li(s-Bu)3BH or DIBAH, the reaction yields the product expected from the Felkin-Anh model [SS2], as shown in Figure 3.40. Similar results are observed in the reduction of 2-fluoro-2-trifluoromethyl-3-hydroxy-ketones [IY3]. 

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