Diastereoselectivity 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. 

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 practice, sequential treatment of chiral aldehyde 589 with the lithium enolate of P-(dimethylamino)propionate (597) followed by methyl iodide and then DBU, leads to esters 598 and 599 directly (anti. syn ratio=80 20) [100,187]. The predominance of the anti dia-stereomer (598) is predicted by the Felkin model. The tert-buty ester of 597 appears to be important, because analogous reaction with the corresponding methyl ester results in decreased diastereoselectivity (anti syn ratio = 65 35). 

Lodge, E. P. Heathcock, C. H. /. Am. Chem. Soc. 1987,109,3353 tested the theoretical models by determining diastereoselectivity in the addition of a lithium enolate to a series of chiral aldehydes. The results were in general agreement with the Anh-Eisenstein adaptation of the Felkin model, but the authors concluded that steric effects were as important as electronic effects (energy of the cr orbital) in determining the transition state for attack of the nucleophile on the carbonyl carbon atom. 

Other important molecules that are useful intermediates in the synthesis of natural products are chiral diols. anli-l,2-Diols of type 30 were obtained in good yields (75-85%) and moderate to good diastereoselectivity (76-96% de) by a nickel-catalyzed three-component addition of a-silyloxy aldehydes 27, alkynyl silanes 28a, and reduction with triisopropyl silane (29a) (Scheme 11.11) [31]. The diastereoselectivity of this process could be explained by the Felkin model. Alternatively, a chiral alkynyl derivative can control the outcome of the reaction. Thus, the coupling of optically active, oxazolidinone-derived ynamides, aldehydes, and silane as reducing agent led to the formation of y-siloxyenamide derivatives with diastereoselectivities up to 99% [32]. 

To account for tlie observed diastereoselectivity, a "modified" Felfcin-Anb model has been proposed [18], Jn analogy to tlie classical Felkin-Anb model, originally developed for tlie addition of otganometallic reagents to aldeliydes possessing a... 

In accord with the Felkin-Anh model, a-chiral ketones react more diastereoselectively than the corresponding aldehydes. Increasing steric demand of the acyl substituent increases the Cram selectivity. Due to the size of the acyl substituent, the incoming nucleophile is pushed towards the stereogenic center and therefore the diastereoface selection becomes more effective (see also Section 1.3.1.1.). Thus, addition of methyllithium to 4-methyl-4-phenyl-3-hexanonc (15) proceeds with higher diastercoselectivity than the addition of ethyllithium to 3-methyl-3-phenyl-2-pen-tanone (14)32. 

With a-alkyl-substituted chiral carbonyl compounds bearing an alkoxy group in the -position, the diastereoselectivity of nucleophilic addition reactions is influenced not only by steric factors, which can be described by the models of Cram and Felkin (see Section 1.3.1.1.), but also by a possible coordination of the nucleophile counterion with the /J-oxygen atom. Thus, coordination of the metal cation with the carbonyl oxygen and the /J-alkoxy substituent leads to a chelated transition state 1 which implies attack of the nucleophile from the least hindered side, opposite to the pseudoequatorial substituent R1. Therefore, the anb-diastereomer 2 should be formed in excess. With respect to the stereogenic center in the a-position, the predominant formation of the anft-diastereomer means that anti-Cram selectivity has occurred. 

Another model can be used to predict diastereoselectivity, which assumes reactant-like transition states and that the separation of the incoming group and any electronegative substituent at the a carbon is greatest. Transition state models 45 and 46 are used to predict diastereoselectivity in what is known as the Felkin Ahn model ... 

Usually, the diastereoselectivity in Michael additions is the one predicted by the Felkin-Anh model.57 However, it was discovered that in the case of the addition of highly hindered nucleophiles, as potassium phthalimide and succinimide, the major product has the opposite configuration to the one predicted by this model, because of the presence of steric hindrance interactions.58... 

Traditional models for diastereoface selectivity were first advanced by Cram and later by Felkin for predicting the stereochemical outcome of aldol reactions occurring between an enolate and a chiral aldehyde. [37] During our investigations directed toward a practical synthesis of dEpoB, we were pleased to discover an unanticipated bias in the relative diastereoface selectivity observed in the aldol condensation between the Z-lithium enolate B and aldehyde C, Scheme 2.6. The aldol reaction proceeds with the expected simple diastereoselectivity with the major product displaying the C6-C7 syn relationship shown in Scheme 2.7 (by ul addition) however, the C7-C8 relationship of the principal product was anti (by Ik addition). [38] Thus, the observed symanti relationship between C6-C7 C7-C8 in the aldol reaction between the Z-lithium enolate of 62 and aldehyde 63 was wholly unanticipated. These fortuitous results prompted us to investigate the cause for this unanticipated but fortunate occurrence. 

In related experiments, it was reported that reduction with sodium borohydride of acyl intermediate 43 forms the a,/f-unsaturated product 42 in excellent stereoselectivity and in 58-84% yield [59]. The diastereoselectivity of the reduction was predicted by the Felkin-Anh model (Fig. 7) (Scheme 15). 

Murakami and Taguchi utilized a diastereoselective Grignard addition to a substituted-chiral oxazoline aldehyde 524 (Scheme 8.170) in an improved stereoselective synthesis of D-n7 o-phytosphingosine. The good stereoselectivity observed for 525 can be rationalized by a Felkin-Ahn transition state model although a chelation control mechanism could not be mled out. 

A systematic study of methyl ketone aldol additions with a-alkoxy and o ,/5-bisalkoxy aldehydes has been undertaken, under non-chelating conditions.130 With a single a-alkoxy stereocentre, diastereoselectivity generally follows Cornforth/polar Felkin-Anh models. With an additional /5-alkoxy stereocentre, 7r-facial selectivity is dramatically dependent on the relative configuration at a- and /3-centres if they are anti, high de results, but not if they are syn. A model for such acyclic stereocontrol is proposed in which the /5-alkoxy substituent determines the position in space of the a-alkoxy relative to the carbonyl, thus determining the n-facial selectivity. 

Diastereoselective addition of organometallic reagents to a-chiral aldehydes usually follows the Cram s rule or Felkin-Ahn model. However, the sense ot the Odiastereoselectivity in the catalysed addition of dialkylzinc to a-chiral aldehydes is determined not by the chirality of aldehyde but by the configuration of the chiral catalysts. By choosing the appropriate enantiomer of the chiral catalyst, one can obtain the desired diastereomer from the diastereoselective addition of dialkylzincs to a-chiral aldehydes.18 Either of the diastereomers of protected chiral 1,2-diols and 1,3-diols is synthesized using the appropriate enantiomer of the chiral catalysts [(15,2f )-l, (R,R)-15, and their enantiomers] from the addition of diorganozincs to protected a-hydroxy-19 and P-hydroxyaldehydes (Scheme 12.3).20... 

Allylic a-carbamoyloxy sulfones 358 have been lithiated with n-BuLi and reacted with chiral a-oxy and a-amino aldehydes 359 in the presence of titanium tetraisopropoxide to provide enones 360 with high diastereoselectivity, according to the Felkin-Anh model, after a-elimination of lithium p-tolylsulfinate (Scheme 94)530 532. 

Addition of intermediate 719 to protected a-amino aldehydes1035 1041,1042 gave the corresponding adducts, for instance compounds 7271035 in good awh -diastereoselectivity (95 5) according to the Felkin-Anh model (Scheme 191). Chiral a-amino ketones758,783, 1043,1045 a so underwent diastereoselective addition of compound 719 to provide the... 

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]. 

There is a dichotomy in the sense of syn-anti diastereofacial preference, dictated by the bulkiness of the migrating group [94]. The sterically demanding silyl group results in syn diastereofacial preference but the less demanding proton leads to anti preference (Sch. 35). The anti diastereoselectivity in carbonyl-ene reactions can be explained by the Felkin-Anh-like cyclic transition-state model (Ti) (Sch. 36). In the aldol reaction, by contrast, the now inside-crowded transition state (Ti ) is less favorable than Tg, because of steric repulsion between the trimethylsilyl group and the inside methyl group of aldehyde (Ti ). The syn-diastereofacial selectivity is, therefore, visualized in terms of the anti-Felkin-like cyclic transition-state model (T2 )-... 

Fig. 6.1. Modified" Felkin-Arh model to account for the observed diastereoselectivity ir conjugate addition reactions to y-chiral Michael acceptors.

The computational support for Felkin s torsional strain model and its success in interpretation of experimental diastereoselectivities has led to its widespread adoption. It appears to be the preeminent open transition state involved in reductions when chelation is not important. Complementary selectivity observed in reductions that do involve chelation may be understood in terms of Cram s cyclic model. 

Threo diastereoselectivity is consistent with a chelation-controlled (Cram cyclic model) organolithium addition (Figure 8a). Since five-membered chelation of lithium is tenuous, an alternative six-membered chelate involving the dimethylamino nitrogen atom of the thermodynamically less stable (Z)-hydrazone (in equilibrium with the ( )-isomer) cannot be discounted. The trityl ether (entry 4, Table 9) eliminates the chelation effect of the oxygen atom such that the erythro diastereomer predominates (via normal Felkin-Ahn addition) (Figure 8b). 

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