Felkin transition state

Diastereoface selection has been investigated in the addition of enolates to a-alkoxy aldehydes (93). In the absence of chelation phenomena, transition states A and B (Scheme 19), with the OR substituent aligned perpendicular to the carbonyl a plane (Rl = OR), are considered (Oc-or c-r transition state R2 Nu steric parameters dictate that predoniinant diastereoface selection from A will occur. In the presence of strongly chelating metals, the cyclic transition states C and D can be invoked (85), and the same R2 Nu control element predicts the opposite diastereoface selection via transition state D (98). The aldol diastereoface selection that has been observed for aldehydes 111 and 112 with lithium enolates 99, 100, and 101 (eqs. [81-84]) (93) can generally be rationalized by a consideration of the Felkin transition states A and B (88) illustrated in Scheme 19, where A is preferred on steric grounds. 

Aldehyde 13, readily prepared by a four step synthesis from L-threonine,3a-i5 was treated with the known (Z)-7-methoxyallylboronate 1412a,c. This reaction, as with other reactions of pinacol allylboronates, was relatively slow and required 24-48 h at room temperature to reach completion. It was, however, extremely selective ana provided homoallyl alcohol 15 in 70% yield with greater than 95% diastereoselectivity. The stereochemistiy of this compound was quickly verified by conversion to 3 as shown in Figure 7.3a We now believe that this reaction proceeds by way of the Conforth-like transition state depicted in Figure 7, and not by way of a Felkin transition state as suggested in our original ublication, since a serious nonbonded interaction exists between the (Z)-methoxyl group and the C(3) substituents of 13 in the Felkin transition state. A... 

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. 

Consider the two Felkin transition states 10 and 11. Obviously, if perpendicular attack is assumed, the intermolecular steric and torsional interactions between the nucleophile and the substrate are identical, all distances (Nu—O, Nu-R, Nu-S,... 

As measured by the energy difference between the two Felkin transition states. A negative value corresponds to the stereochemistry predicted by Cram s rule. 

It remains to explain why the Felkin transition states are the most stable. During the reaction, the major interaction occurs between the nucleophile s HOMO and the substrate s LUMO. Therefore, the most reactive conformation of the substrate is that with the lowest LUMO. This corresponds to the geometry in which the C2-L bond is parallel to the tt system, as there is then a good overlap between the orbital and the lowlying ac2-L orbital, leading to a stabilization of the LUMO. The nucleophile may attack this conformer in an antiperiplanar or synperiplanar stereochemistry. The latter is disfavoured for two reasons ... 

Once the most reactive substrate conformations are known, it remains to look for the best approach of the nucleophile. An anti attack is promoted by a favorable secondary overlap between the nucleophile and o (C L), which is shown by the double arrow. Syn attack is disfavored, both by a negative secondary overlap (wavy line) and by the eclipsed relationship between C L and Nu---C (Figure 6.6). To summarize, the Felkin transition states are favored because they correspond to the best trajectories for attacking the most reactive conformations. 

According to Bernardi et al.,109 for (E)-enoates with two y-hydrocarbon substituents, the dominant interaction is with the nucleophile. Therefore, the smallest substituent S should be put in the outside position. For (Z)-enoates, S should be put in the inside position.110 For y-alkoxy-(E)-enoates, a Felkin transition state may rationalize organolithium111 and alkoxyde112 additions, but does not explain the results for... 

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). 

The unsaturated linkage in enantiomerically pure a-methyl-. -y-unsaturated ketones (45) exerted a powerful stereochemical influence on their reduction with L-selectride, particularly when R is a tri-methylsilyl group. The anti homoallylic alcohols (46) were produced with uniformly excellent stereoselectivity (>93 7) via a Felkin transition state in which the double bond occupied the perpendicular position (equation 12). This Felkin selectivity was sufficient to overcome any chelation-mediated contribution in the reduction of a-vinyl-p-hydroxy ketones (47) to the, 2-syn diols (48) with LiEtsBH in THF at -78 °C (equation 13).58... 

Stereoselective reduction of a-alkyl-3-keto acid derivatives represents an attractive alternative to stereoselective aldol condensation. Complementary methods for pr uction of either diastereoisomer of a-alkyl-3-hydroxy amides from the corresponding a-alkyl-3-keto amides (53) have been developed. Zinc borohydride in ether at -78 C gave the syn isomer (54) with excellent selectivity ( 7 3) in high yield via a chelated transition state. A Felkin transition state with the amide in the perpendicular position accounted for reduction with potassium triethylborohydride in ether at 0 C to give the stereochemi-cally pure anti diastereoisomer (55). The combination of these methods with asymmetric acylation provided an effective solution to the asymmetric aldol problem (Scheme 6). In contrast, the reduction of a-methyl-3-keto esters with zinc borohydride was highly syn selective when the ketone was aromatic or a,3-unsaturated, but less reliable in aliphatic cases. Hydrosilylation also provided complete dia-stereocontrol (Scheme 7). The fluoride-mediated reaction was anti selective ( 8 2) while reduction in trifluoroacetic acid favored production of the syn isomer (>98 2). No loss of optical purity was observed under these mild conditions. 

The excellent diastereoselection of all three of these substrate-directed allylation reactions is consistent with reaction occurring through Felkin transition states analogous to 39 (Fig. 11-6). These examples illustrate the excellent stereochemical control opportunities that exist in ( )-crotylation reactions of a-methyl chiral aldehydes, especially when the -position is branched (as in the (7s)-crotylation of 25 and 32, see above). 

In reactions of a-methyl chiral aldehydes with achiral (Z)-crotylboronates, the anti-Felkin adduct (cf. 107b) is favored (for further discussion see Section 11.2) [3, 65]. In the double asymmetric reaction of 97b and (S,S)-213, the anti,syn-di-propionate 107b is obtained with high selectivity (selectivity=95 5). The stereochemistry of 107b is consistent with product formation via the matched anti-Felkin transition state 247. Finally, the, vyn,5y -dipropionate 106c is obtained as the major product from the mismatched reaction of the TBDPS-protected aldehyde 97c with (f ,R)-(Z)-213 this reaction, however, is not sufficiently stereoselective to be synthetically useful (selectivity = 64 36). The mismatched transition state... 

Marshall s chiral allenylmetal reagents have been utilized in double asymmetric reactions with chiral aldehydes for the synthesis of polypropionate natural products. All four dipropionate diastereomers are accessible from the reactions of chiral allenylmetal reagents with a-chiraI-y5-alkoxy aldehydes 97 (153, 158, 276, 277]. The BF3-OEt2-catalyzed addition of allylstannane (l )-218a to aldehyde 97a occurs in high yield and diastereoselectivity to give the xyn.syn-dipropionate 395, presumably through either the synclinal or antiperiplanar Felkin transition states 396 and 397 (Eq. (11.31)). 

Finally, the 5jn,ann -dipropionate 402 is best obtained through the reactions of the TBDPS-protected aldehyde 97c with the allenylindium (or allenylzinc) reagent (R)-392, formed in situ from mesylate (5 )-389. The diastereoselectivity of this reaction is best rationalized through the cyclic Felkin transition state 403, where the aldehyde alkyl group and the Me group of the allene adopt an anti relationship in the transition state (Eq. (11.34)). 

Double asymmetric reactions between [7-(alkoxy)allyl]stannanes 230 and the a-benzyloxy aldehyde 55 exhibited clear matched and mismatched behavior [168]. With BF3 OEt2 catalysis, the matched double asymmetric reaction between (R)-230a and aldehyde (S)-55 generates exclusively the syn,anti adduct 425 (Eq. (11.40)). Formation of 425 can be rationalized through either the antiperipla-nar, Felkin transition state 426 (as proposed by Marshall) or the synclinal Felkin transition state 427. 

The L-talo and L-gulo adducts 447 and 449 were obtained with very high stereoselectivity (no other diastereomers reported) from the reaction of aldehyde 444 with the [y-(alkoxy)allyl]indium reagents generated from (5)-230a and (R)-230a, respectively. In these double asymmetric reactions, reagent control is clearly dominant. The stereochemistry of adduct 447 is rationalized by the Felkin transition state 448 while the stereochemistry of adduct 449 is rationalized by the anti-Felkin transition state 450 [275]. 

Consider the two Felkin transition states 10 and 11. Obviously, if perpendicular attack is assumed, the intermolecular steric and torsional interactions between the nucleophile and the substrate are identical, all distances (Nu-0, Nu-R, Nu-S, Nu-M) being the same in 10 and 11. The discrimination can come only from intramolecular interactions in the substrate, which is rather surprising for a bimolecular reaction. In their original paper Felkin and his coworkers postulated that the interactions of substituents M and S are stronger with R than with 0. It is not clear why this should be so, as the predominance of R over O must hold even for R = H. Nevertheless, this hypothesis allows the correct prediction of the stereochemistry, agrees well with the observation that selectivity increases with the bulkiness of R, and for these reasons, has not been questioned. 

In 1977, Anh [23] used ab initio methods to evaluate the energies of all the postulated transition structures (Figures 4.2 - 4.4) for the reaction of 2-methyl-butanal and 2-chloropropanal (the former to test the Cram, Karabatsos, and Felkin models, and the latter to test the Felkin and Comforth models). The nucleophile was H , located 1.5A from the carbonyl carbon, at a 90° angle, on each face of the carbonyl. Rotation of the C1-C2 carbon-carbon bond then provided an energy trace which included structures close to all of the previously proposed conformational models. The results for both compounds clearly showed the Felkin transition states to be the lowest energy conformers for attack on either face of the carbonyl. Inclusion of a proton or lithium ion, coordinated to the oxygen, produced similar results. It therefore appeared that Felkin s notion of attack antiperiplanar to the large substituent was correct. 

Dipropionates are available through the reaction of the (. -and (2)-crotylboronates 2 and 3 with a-methyl-P-hydroxy aldehydes. The syn,anti-dipropionate 43a emerges as the major product with 97 3 selectivity from the matched crotylation reaction of aldehyde 40a with (R,R)-2. This is the intrinsically favored adduct, and its formation can be rationalized via the Felkin transition state F. The antAanh-dipropionate 44b is the major adduct (selectivity = 90 10) of the mismatched reaction of aldehyde 40b and 2. Its formation can be rationalized via anti-Felkin transition state G and is an example of a reagent-controlled reaction. 

In reactions of a-methyl chiral aldehydes with (.. -enolates and Type (2)-crotylmetal reagents like 3, the anti-Felkin addition product is favored due to unfavorable syn-pentane interactions in the Felkin transition state. Thus, in the matched reaction, the (S,5)-3 reagent reacts with aldehyde 40a to provide the anh, syn-dipropionate 45 with 95 5 selectivity. The stereochemical outcome of the reaction can be rationalized by anti-Felkin transition state H, where the nucleophile must approach near the methyl substituent. The mismatched reaction between aldehyde 40b and (R,R)-3 provides a mixture of dipropionates where the syn,syn-dipropionate 46 is only modestly favored (64 36 = sum of all other diastereomers). Transition state I, that rationalizes the formation of the major product, is less favorable as the nucleophile must approach the carbonyl carbon past the larger R substituent. 

Scheme 23 Proposed mechanism via Felkin transition state...

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