Felkin-Anh transition states

The lower diastereoselectivity found with aldehyde 15 (R = CH3) can be explained by the steric influence of the two methyl substituents in close vicinity to the stereogenic center, which probably diminishes the ability of the ether oxygen to coordinate. In contrast, a significant difference in the diastereoselectivity was found in the additions of phenyllithium and phenylmagnesium bromide to isopropylidene glyceraldehyde (17)58 (see also Section 1.3.1.3.6.). Presumably the diastereo-sclcctivity of the phenyllithium addition is determined by the ratio of chelation-controlled to nonchelation-controlled attack of the nucleophile, whereas in the case of phenylmagnesium bromide additional chelation with the / -ether oxygen may occur. Formation of the -chelate 19 stabilizes the Felkin-Anh transition state and therefore increases the proportion of the anZz -diastereomeric addition product. 

I-Oialkoxy carbonyl compounds are a special class of chiral alkoxy carbonyl compounds because they combine the structural features, and, therefore, also the stereochemical behavior, of 7-alkoxy and /i-alkoxy carbonyl compounds. Prediction of the stereochemical outcome of nucleophilic additions to these substrates is very difficult and often impossible. As exemplified with isopropylidene glyceraldehyde (Table 15), one of the most widely investigated a,/J-di-alkoxy carbonyl compoundsI0S, the predominant formation of the syn-diastereomer 2 may be attributed to the formation of the a-chelate 1 A. The opposite stereochemistry can be rationalized by assuming the Felkin-Anh-type transition state IB. Formation of the /(-chelate 1C, which stabilizes the Felkin-Anh transition state, also leads to the predominant formation of the atm -diastereomeric reaction product. 

Thus chelation control " may lead to either product, depending on the relative stabilities of the respective ot- and /(-chelates. In cases with predominant formation of the anri-diastereomer, it is often difficult to establish whether the formation of a /(-chelate or an open-chain Felkin - Anh transition state is responsible for the observed stereochemistry the decision usually rests on plausibility considerations. Thus, with regard to the results obtained for a-alkoxy carbonyl... 

Obviously, the nature of the organocopper reagent is an important factor with respect to the stereochemical outcome of the cuprate addition. This is nicely illustrated for the cuprate addition reaction of enoate 75 (Scheme 6.15). Here, lithium di-n-butylcuprate reacted as expected by way of the modified Felkin-Anh transition state 77 (compare also 52), which minimizes allylic A strain, to give the anti adduct 76 with excellent diastereoselectivity [30]. Conversely, the bulkier lithium bis-(methylallyl)cuprate preferentially yielded the syn diastereomer 78 [30, 31]. It can be argued that the bulkier cuprate reagent experiences pronounced repulsive interactions when approaching the enoate system past the alkyl side chain, as shown in transition state 77. Instead, preference is given to transition state 79, in which repulsive interactions to the nucleophile trajectory are minimized. 

Normant and Poisson prepared allenylzinc bromide reagents from TMS acetylenes along the lines of Epsztein and coworkers5, by sequential lithiation with s-BuLi to yield a lithiated species, and subsequent transmetallation with ZnBr2 (equation 35)27,28. Additions to racemic /J-silyloxy aldehydes proceed with low diastereoselectivity to afford mixtures of the anti,anti and anti,syn adducts (Table 17). The latter adducts are formed via an anti Felkin-Anh transition state. Additions to the racemic IV-benzylimine analogs, on the other hand, proceed with nearly complete Felkin-Anh diastereoselectivity to yield the anti,anti amino alcohol adducts (Table 18). 

Fig. 10.11. Addition of various hydride donors to 4-tert-butylcyclohexanone. With L-Selectride the equatorial approach (Formula A) is preferred, with sterically (less) demanding hydride donors the reaction proceeds axially via transition state B (cf. text and, particularly. Side Note 10.1). For comparison see the Felkin-Anh transition state C (in Figure 10.16 EWG = electron-withdrawing group).

Both in the Cram (Figure 10.16, left) and Felkin-Anh transition states (Figure 10.16, middle) a stabilizing orbital overlap occurs that was already encountered in connection with the discussion of Figure 10.13 there is a—in each case bonding—overlap between the o-MO assigned to the resulting C-Nu bond and... 

The addition of a hydride donor to an a-chiral aldehyde with an O or an N atom in the a position or to an analogous ketone takes place through the so-called Felkin-Anh transition state provided that the heteroatom at C-a is not incorporated in a five-membered chelate ring together with the O atom of the carbonyl group. This transition state is also shown in Figure 10.16 (center Nu = H ), both as a Newman projection and in the sawhorse... 

Grignard reagents and a-chiral aldehydes that contain a dialkylamino group at their stereocenter, as does compound A of Figure 10.42, react selectively via the Felkin-Anh transition state of Figure 10.16 (Nu = Ph ). The N atom in substrate A is tertiary and sufficiently hindered by the two benzyl substituents that it cannot be incorporated into a chelate. 

Fig. 8.8. Addition of different hydride donors to 4-tert-butylcyclohexanone. For L-Selectride the equatorial attack is preferred (formula A), whereas for sterically undemanding hydride donors the axial attack via transition state B is preferred. For easier comparison the Felkin-Anh transition state C (from Fig. 8.11 EWG, electron-withdrawing group).

In the explanation favored today, the reason for this stereoelectronic effect is as follows The electronically preferred direction of attack of a hydride donor on the 0=0 double bond of cyclohexanone is the direction in which two of the C—H bonds at the neighboring a positions are exactly opposite the trajectory of the approaching nucleophile. Only the axial C—H bonds in the a positions can be in such an antiperiplanar position while the equatorial C—H bonds cannot. Moreover, these axial C—H bonds are antiperiplanar with regard to the trajectory of the H nucleophile only if the nucleophile attacks via a transition state B, that is, axially (what was to be shown). The antiperiplanarity of the two axial C—H bonds in the a positions is reminiscent of the antiperiplanarity of the electron-withdrawing group in the a position relative to the nucleophile in the Felkin-Anh transition state (formula C in Fig. 8.8 cf. Fig. 8.11, middle row). 

The substrate control of the diastereoselectivity, which originates from aldehyde B and makes a Felkin-Anh transition state preferred in the attack of the phosphonate ion on the C=0 double bond (compare Figure 8.11, middle). 

The O-silylated allylindium shows moderate //////-selectivity, via the Felkin-Anh transition state, while the hydroxy-bearing allylindium exhibits. //-selectivity by dual coordination of indium intramolecularly to the hydroxy group and intermolecularly to the aldehyde (Scheme 20).133 With the CH2OH now locked below the developing chair, the R substituent could become the key factor. The easy accessibility of the aldehyde in 15 leads to the highly preferred formation of 1,4-syn products relative to 16 (Scheme 21). 

When hydroxy bromide 20 is subjected to the typical coupling conditions, neither 3- nor 2-PyCHO shows high diastereoselectivity (Scheme 25). The low-level stereochemical bias toward 3-PyCHO can be accounted for in terms of the Felkin-Anh transition states 21. When 2-PyCHO is involved, the intramolecular chelation option 22 is favored over 23, despite the obvious steric congestion associated with the onset of intermolecular chelation in both transition states. 

Indium-promoted addition of (Z)-2-(bromomethyl)-2-butenoate to ct-protected hydroxy aldehydes in water results in the selective formation of diastereomer 37 of the possible four stereoisomers 36-39 via the Felkin-Anh transition state (Scheme 40).170... 

How will this aldehyde (which can be made from the amino acid serine) read with nucleophiles such as lithiated alkynes Consider a Felkin-Anh transition state again, we know that the nitrogen, being electronegative, will lie perpendicular to the carbonyl group in the most reactive conformation, so we need only consider these two. The least hindered direction of attack is shown, and that indeed gives the required product. 

Although this is the only chapter in which stereoelectronics appears in the title, you will soon recognize the similarity between the ideas we cover here and concepts like the stereospecificity of E2 elimination reactions (Chapter 19), the Karplus relationship (Chapter 32), the Felkin-Anh transition state (Chapter 33), and the conformational requirements for rearrangement (Chapter 37) and fragmentation (Chapter 38) reactions. 

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