Felkin model asymmetric induction

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 ... 

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

If it is assumed that the Curtin-Hammett principle applies, one need only to compare the energies of the minima on the solid and dashed curves to be able to predict the structure of the major product. These curves also allow a direct comparison of Cram s, Cornforth s, Karabatsos s and Felkin s model for 1,2 asymmetric induction. Both Figures show the Felkin transition states lying close to the minima. The Corn-forth transition states (Fig. 3) are more than 4 kcal/mol higher and should contribute little to the formation of the final products assuming a Boltzmann distribution for the transition states, less than one molecule, out of a thousand, goes through them. Similarly, Fig. 4 shows the Cram and Karabatsos transition states to lie more than 2.7 kcal/mol above the Felkin transition states, which means that they account for less than 1% of the total yield. 

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. 

A DFT study of enolborane addition of o -heteroatom-substituted aldehydes has focused on the relevance of the Cornforth and polar Felkin-Anh (PKA) models for asymmetric induction.154 Using chiral substrates, MeCH(X)CHO, polar (X = F, Cl, (g) OMe) and less polar (X = SMe, NMe2, PMe2) substituents have been examined. The former favour Cornforth TS structures, the latter PKA. TS preferences have been correlated with the relative energy of the corresponding rotamer of the uncomplexed aldehyde. An in-depth study of addition of ( > and (Z)-enolborane nucleophiles to 2-methoxypropanal successfully predicts experimentally determined diastereofacial selectivities. 

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. 

The directed aldol reaction in the presence of TiC found many applications in natural product synthesis. Equation (7) shows an example of the aldol reaction utilized in the synthesis of tautomycin [46], in which many sensitive functional groups survived the reaction conditions. The production of the depicted single isomer after the titanium-mediated aldol reaction could be rationalized in terms of the chelation-controlled (anft-Felkin) reaction path [37]. A stereochemical model has been presented for merged 1,2- and 1,3-asymmetric induction in diastereoselective Mukaiyama aldol reaction and related processes [47]. 

In the Type II allylation reactions of a-methyl-/i-alkoxy aldehydes, the principles of 1,2- and 1,3-asymmetric induction both contribute to the reaetion diastereo-selectivity. Evans and co-workers have explained the stereoehemical outcome of these reactions in terms of a merged 1,2- and 1,3-asymmetric induction model [931- For example, the 2,3-anti aldehyde 135 reacts with allyl- and methallyltri-n-butylstannanes 98, generating the Felkin homoallylic alcohols 136 with >99 1 diastereoselectivity (Eq. (11.8)) [93]. 

Let us consider the nucleophilic addition to a carbonyl group adjacent to a stereogenic center. Following Anh-Felkin s modification of Crams s model for asymmetric induction, the reaction can follow either of the pathways shown in... 

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. 

This chapter begins with a detailed examination of the evolution of the theory of nucleophilic attack on a chiral aldehyde or ketone, from Cram s original rule of steric control of asymmetric induction to the Felkin-Anh-Heathcock formulation. Then follows a discussion of Cram s simpler rigid model (chelate rule), then carbonyl additions using chiral catalysts and chiral (nonenolate) nucleophiles. The chapter concludes with asymmetric 1,4-additions to conjugated carbonyls and azomethines. 

Although increases in the acidity of the aqueous solution were found not to impact on product stereoselectivity, salt effects can prove beneficial (5), presumably as a consequence of the increased internal pressure brought about in the system. The sense of asymmetric induction conforms to operation of the illustrated Cram-like transition state (Scheme 1). This working model is consistent with the nondirective effects brought on by the sterically bulky a-oxy (OBn, OTBS), a-thia (PhS, MeS), and a-amino (BnaN, isoindolyl) groups (9). Under the latter circumstances, chelation is not observed and ir-facial discrimination is achieved instead via Felkin-Anh transition states under the steric control of the substituents. The dimethylamino... 

A study of the stereochemical outcome of the addition of lithium enolates to a-alkoxyaldehydes has shown that the predominant product is not that predicted by application of Cram s cyclic model for asymmetric induction. Assuming the alkoxy-group to be the largest group a- to the aldehyde, the major product is that predicted by Felkin s model (Scheme 59). ... 

Discuss the factors behind selection of the reactive conformation in the Felkin-Ahn model for conversion of 53 to 54. How would Cornforth have rationalized this stereochemical result [For an interesting system where the Cornforth and Felkin-Ahn models predict different stereochemical results see Evans, D. A. Siska, S. J. Cee, V. J. Resurrecting the Cornforth Model for Carbonyl Addition Studies on the Origin of 1,2-Asymmetric Induction in Enolate Additions to Heteroatom-Substituted Aldehydes Andrew. Chem. Int. Ed. 2003, 42, 1761-1765] (CJH-5)... 

Show your understanding of the Cram and Felkin-Ahn models for asymmetric induction in carbonyl addition reactions by predicting (or rationalizing) the stereochemical course of the following reactions. (Calcimycin-3)... 

Asymmetric centers located at the a- and P-positions of the aldehyde influence the facial selectivity of the Sakurai reaction (1,2- and 1,3-asymmetric induction, respectively). 2-Phenylpropanal 52 is an example of a-methyl substituted aldehyde. It reacts with trimethylsilane to give mostly the syn adduct 53, as predicted by the Cram and Felkin-Anh models (Table 8). The selectivities are modest (< 2.7 1)... 

The asymmetric synthesis of (—)-denticulatin A (30) shows an interesting application of the boron aldol chemistry (Scheme 6) [23]. In a group-selective aldol reaction between the weso-aldehyde 27 and (5)-28, the hydroxyalde-hyde 29 was formed with > 90 % de, which spontaneously cyclized to the lactol 31. The configuration at the stereocenters of C-2 and C-3 in 29 is in accordance with the induction through the sultam auxiliary as well as with preference of an a-chiral aldehyde to react to the ant/-Felkin diastereomer in an aldol reaction which is controlled by the Zimmermann-Traxler model [24, 25]. 

Diastereoselectivity induced by chiral aldehydes the substrate plays an important role in the facial diastereoselection, particularly when there is an asymmetric center adjacent to the carbonyl group. In the general case, the approach of the allyltin is assumed to follow the Felkin-Anh model giving the syn adduct preferentially. This induction was used for the synthesis of natural products [186] even as complex as Ciguatoxin or Laulimalide [187]. 

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