Felkin induction

Panek and co-workers demonstrated that the reaction of (5)-2-benzyloxypropa-nal (17) with the allylic silane (5)-18 under the influence of Bp3-OEt2 gave the syn homoallylic alcohol 19 with excellent level of Felkin induction [35]. Interestingly, the high level of syn selectivity was also observed in the condensation of 17 and (/ )-18. On the other hand, the reaction of 17 with (5)-18 in the presence of TiCLj produced anti homoallylic alcohol 20 almost exclusively, whereas the reaction with (R)-18 promoted by TiCL afforded syn homoallylic alcohol 21. Presumably, the reactions proceeded through a Cram chelate transition state model... 

In our synthesis, iterative aldol reactions of dipropionate reagent (R)-18 allowed for the control of the C3-C10 stereocenters (Scheme 9-72) [89]. Hence, a tin-mediated, syn aldol reaction followed by an anti reduction of the aldol product afforded 270. Diol protection, benzyl ether deprotection and subsequent oxidation gave aldehyde 271 which reacted with the ( )-boron enolate of ketone (/ )-18 to afford anti aldol adduct 272. While the ketone provides the major bias for this reaction, it is an example of a matched reaction based on Felkin induction from the... 

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 ... 

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

Almost 50 years ago, Cram outlined a rule (Cram s rule), which proved to be fruitful in understanding, predicting, and controlling diastereoselectivity induced by a remote stereocenter [258,259], Numerous examples of 1,2 induction have confirmed over the time the predictive character of this rule [260], Afterwards, other important contributions of Felkin and coworkers and Anh... 

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. 

The first example of 1,2-asymmetric induction was reported by Yamamoto and cowork-ers with/V-propyIaldirn ines derived from a-phenylpropionaldehyde (equation 13). The reaction gave mainly the anti product135, consistent with a Felkin-Ahn addition. A 1,3-asymmetric induction took place with the imine prepared from 1-phenylethylamine and isovaleraldehyde, giving a somewhat lower 7 1 diastereoselectivity. 

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]. 

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]. 

An exhaustive compilation of examples of reduction of acyclic ketones with an adjacent chiral center appeared recently and is not reproduced here. Those methods that give excellent levels of asymmetric induction likely to be useful in synthesis are highlighted here. The results are collected according to the substrate being reduced rather than the reducing agent. Most of the examples can be rationalized by consideration of the Felkin transition state or, where appropriate, the chelated transition state (Section 1.1.2.1). 

Given this problem, the attachment of the butanone synthon to aldehyde 74 prior to the methyl ketone aldol reaction was then addressed. To ovenide the unexpected. vTface preference of aldehyde 74, a chiral reagent was required and an asymmetric. syn crotylboration followed by Wacker oxidation proved effective for generating methyl ketone 87. Based on the previous results, it was considered unlikely that a boron enolate would now add selectively to aldehyde 73. However, a Mukaiyama aldol reaction should favour the desired isomer based on induction from the aldehyde partner. In practice, reaction of the silyl enol ether derived from 87 with aldehyde 73, in the presence of BF3-OEt2, afforded the required Felkin adduct 88 with >97%ds (Scheme 9-29). This provides an excellent example of a stereoselective Mukaiyama aldol reaction uniting a complex ketone and aldehyde, and this key step then enabled the successful first synthesis of swinholide A. 

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]. 

As the size of the allylmetal reagent increases, 1,2-induction plays an increasingly important role. This is illustrated in Eqs. (11.10) and (11.11), where the ( -silyloxyallyl)stannane 113 gives high levels of stereoselectivity for the Felkin dia-stereomer 141 with the 2,3-anti aldehyde 135, but poor diastereoselectivity for the Felkin diastereomer 143 with the 2,3-syn aldehyde 138 (ratio = 59 32 9) [93]. Note that in this case the Felkin isomer 143 predominates vs the preferential formation of the anti-Felkin isomer in Eq. (11.9), thus highlighting the role of the steric demands of the reagent in determining the overall reaction stereoselectivity. 

The utility of BF3-OEt2, a monodentate Lewis acid, for acyclic stereocontrol in the Mukaiyama aldol reaction has been demonstrated by Evans et al. (Scheme 10.3) [27, 28]. The BF3-OEt2-mediated reaction of silyl enol ethers (SEE, ketone silyl enolates) with a-unsubstituted, /falkoxy aldehydes affords good 1,3-anti induction in the absence of internal aldehyde chelation. The 1,3-asymmetric induction can be reasonably explained by consideration of energetically favorable conformation 5 minimizing internal electrostatic and steric repulsion between the aldehyde carbonyl moiety and the /i-substituents. In the reaction with anti-substituted a-methyl-/ -alkoxy aldehydes, the additional stereocontrol (Felkin control) imparted by the a-substituent achieves uniformly high levels of 1,3-anti-diastereofacial selectivity. 

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