Felkin-Ahn transition state

Addition of (TMS)3SiH to a-chiral ( )-alkene 7 was found to take place with a complete Michael-type regioselectivity (Reaction 5.8) [26]. A complete syn stereoselectivity was observed for R = Me, and it was rationalized in terms of Felkin-Ahn transition state 8, which favours the syn product similar to nucleophilic addition. 

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. 

Fio. 4. Houk s transition state model (a) and the Felkin-Ahn transition state model (b) for the reaction of the dioxolane (48) with nitrile oxides. 

As a Stereochemical Prohe in Nucleophilic Additions. Historically, the more synthetically available enantiomer, (4R)-2,2-dimethyl-l,3-dioxolane-4-carhoxaldehyde, has been the compound of choice to probe stereochemistry in nucleophilic additions. Nevertheless, several studies have employed the (45)-aldeh-yde as a substrate. In analogy to its enantiomer, the reagent exhibits a moderate si enantiofacial preference for the addition of nucleophiles at the carbonyl, affording anti products. This preference for addition is predicted by Felkin-Ahn transition-state analysis, and stands in contrast to that predicted by the Cram chelate model. Thus addition of the lithium (Z)-enolate shown (eq 1) to the reagent affords an 81 19 ratio of products with the 3,4-anti relationship predominating as a result of preferential si-face addition, while the 2,3-syn relationship in each of the diastere-omers is ascribed to a Zimmerman-Traxler-type chair transition state in the aldol reaction. ... 

These results can be understood on the basis of a Felkin-Ahn transition state arrangement for the BF3 experiments and a chelation transition state arrangement with MgBt2 as the promoter. The matched transition states are pictured in Fig. 12. The latter additions are strongly substrate-controlled, which accounts for the formation of (Z) products as the minor adducts. Evidently the methyl substituent is an efficient facially directing group in the chelated aldehyde substrate. 

Adjacent stereocenters influence the mode of addition of nucleophiles such as hydrides and organometallic reagents to acyclic ketones. The Felkin-Ahn transition state provides a predictive model that is general when steric effects are dominant. Other factors must be considered when polar or chelating substituents are present. 

A -(a-Carboxyalkyl)tryptamines can be prepared by alkylation of a-amino acid ester by tryptophyl bromide. The chirality of the amino acid unit directs diastereo-selectivity in the range of 70-98% for cyclization with a variety of aromatic aldehydes. The best selectivity is obtained with relatively bulky amino acid substituents, as for valine and isoleucine. The reactions appear to occur under kinetic control and the stereoselectivity is consistent with the sterically preferred Felkin-Ahn transition state [336]. 

Stereoselective Carbonyl Reductions. L-selectride reduction of U-acyl-Y-lactones has been shown to furnish the syn-reduction products in good yield and high diastereoselection which may be hydrolysed to threo-diols. The stereochemistry appears to be largely independent of the size of the acyl group and is in accord with reduction following the Felkin-Ahn transition-state model (Scheme 2). ... 

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 ... 

Substrate control This refers to the addition of an achiral enolate (or allyl metal reagent) to a chiral aldehyde (generally bearing a chiral center at the a-position). In this case, diastereoselectivity is determined by transition state preference according to Cram-Felkin-Ahn considerations.2... 

The mechanism of reduction of cyclic ketones by LiAlH4 and NaBH4 is quite different. The LiAlH4 reduction involves reactant-like transition states (Scheme 6.18) and NaBH4 reductions involve product-like transition states (Scheme 6.19). The LiAlH4 reductions favour equatorial attack if bulky axial groups are present at C-3 and C-5 because of steric factors. Some non-steric factors which also favour equatorial attack can be explained by Felkin-Ahn rationalization on the basis of either torsional strain or the need for antiperiplanarity. 

Felkin-Ahn/Cornforth (anti) product is predominant with MgBr2 as a consequence of strong solvent-Lewis acid association at the expense of chelation. The same trend is observed with the a-OTBS derivative and MgBr2 owing to the diminished capacity of TBS ethers to complex with MgBr2- Probable transition states for these additions are depicted in Fig. 2. 

Significantly higher diastereoselectivity was observed in reactions with a-branched aldehydes as illustrated in Eq. (34) [54]. Here the (5)-a-methyl-/3-OMOM aldehyde substrate is matched with the (f )-a-OMOM stannane in a Felkin-Ahn acyclic transition state to afford the syn, syn adduct almost exclusively. 

The foregoing addition reaction is strongly reagent-directed. Both (S)- and (R)-2-benzyloxypropanal afford adducts with high diastereoselectivity (Eq. 51). With the former the product might arise by Felkin-Ahn addition whereas a chelation controlled transition state could account for the latter. 

The geometry of the aldol transition state was interpreted in terms of the variation in mode of the aldehyde/catalyst complexation [Felkin-Ahn (nonchelating) model versus chelating model] and size of KSA. The same complex efficiently catalyzes the Michael reaction of a,/9-unsaturated ketones with KSA [124],... 

The a r/-addition is in agreement with the classical open-chain Felkin-Ahn <82JA7162> transition state model A whereas the iyn-addition can be explained by model B that is formed by intramolecular... 

The most intensely studied aldol addition mechanisms are those beUeved to proceed through closed transition structures, which are best understood within the Zimmerman-Traxler paradigm (Fig. 5) [Id]. Superposition of this construct on the Felkin-Ahn model for carbonyl addition reactions allows for the construction of transition-state models impressive in their abiUty to account for many of the stereochemical features of aldol additions [50a, 50b, 50c, 51]. Moreover, consideration of dipole effects along with remote non-bonding interactions in the transition-state have imparted additional sophistication to the analysis of this reaction and provide a bedrock of information that may be integrated into the further development and refinement of the corresponding catalytic processes [52a, 52b]. One of the most powerful features of the Zimmerman-Traxler model in its application to diastereoselective additions of chiral enolates to aldehydes is the correlation of enolate geometry (Z- versus E-) with simple di-astereoselectivity in the products syn versus anti). Consequently, the analyses of catalytic, enantioselective variants that display such stereospecificity often invoke closed, cyclic structures. Further studies of these systems are warranted, since it is not clear to what extent such models, which have evolved in the context of diastereoselective aldol additions via chiral auxiliary control, are applicable in the Lewis acid-catalyzed addition of enol silanes and aldehydes. 

The Cram selectivity is consistent with Felkin-Ahn addition, as shown in Figure 8a, with the large phenyl substituent controlling the organometallic approach. In addition, Yamamoto et a/. have proposed more detailed chair-like transition state models shown in Figures 8b and 8c to account for the un-... 

The issues that remain under discussion are (1) the relative importance of the acceptor (Felkin-Ahn) or donor (Cieplak) hyperconjugation capacity of a substituents (2) the relative importance of electrostatic effects and (3) the role of reactant pyramidalization in transmitting the substituent effects. Arguments have been offered regarding the importance of electrostatic effects in all the systems we have discussed. Consideration of electrostatic effects appears to be important in the analysis of stereoselective reduction of cyclic ketones. Orbital interactions (hyperconjugation) are also involved, but whether they are primarily ground state (e.g., reactant pyramidalization) or transition state (e.g., orbital stabilization) effects is uncertain. 

Felkin and Ahn proposed an alternative model that gave somewhat better results in these systems.279,280 The model was based on several assumptions. (1) the transition states are reactant-like (2) the previous... 

In each case, draw the transition state for the Cram, Karabatsos and Felkin-Ahn models of the reaction of each molecule with (l)MeMgBr (2) PhMgCl (3) CH3C C -Na+ (4) EtLi (5) 2-lithio-l,3-dithiane... 

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