Felkin-Anh mode

The mismatched R/S pairing could lead to the anti,syn adduct through transition state C and the syn,anti adduct via D (Scheme 9.30). The former pathway entails non-Felkin-Anh addition but anti disposed methyl and aldehyde substituents. Transition state D proceeds through the Felkin-Anh mode of carbonyl addition but requires eclipsing of the methyl and aldehyde substituents. This interaction is the more costly one and thus disfavors the syn,anti adduct. 

The importance of this approach to 33 lies in the fact that enolization of l-phenyl-2-butanone does not give pure 33 under kinetic or thermodynamic conditions. Moreover, if the acylsilane possesses a stereogenic center in the a-position, the addition occurs according to the Felkin-Anh mode. ... 

As described above, the reactions of Grignaid or organolithium reagents to a-hydroxy- or a-amino-carbonyls can proceed with extremely high stereoselectivities (>99 1) when cyclic chelation control is in effect. However, attempts to generate products arising from the Cram-Felkin-Anh mode of addition exclusively have been much less successful. Hiese products are available by the use of conditions which favor nonchelation-controlled processes however, until recently, the selectivities of these reactions (up to 80-90%) never reached those observed in cyclic chelation control additions. 

Similar selectivities (>99 1) are observed in the cyclic chelation controlled reaction of a-benzyloxy carbonyls such as (4a equation 4) with Grignard reagents. However when the a-hydroxy group is protected as a silyl ether (4b), the selectivities observed in the addition reaction diminish (60 40), or reverse (10 90 Table 3). The nonchelating nature of a silyl group, as well as its steric bulk, are responsible for this change in selectivity. In the case of (4b), nucleophilic addition via the Felkin-Anh model effectively competes with the cyclic-chelation control mode of addition. 

Addition of HMPA to the reaction mixture to suppress chelation causes a reversal in the stereoselectivity, yielding (9) as the dominant product. Similar trends in the addition of ethyl metallics to (7) are report. Use of conditions expected to enhance chelation produces (8) as the major product (9) is formed predominantly when chelation is inhibited (Table 4). The proposed modes of addition according to chelation control, yielding (8), and Felkin-Anh models, yielding (9), are shown in Figures 6 and 7. 

Diene-aldehyde cycloadditions in which the carbohydrate contains the formyl group were studied at high pressure by Jurczak and co-workers (55). Cycloaddition of 1-methoxybutadiene to aldehyde 59 at 20 kbar and 53° C occurred to give 60 with complete stereoselectivity. When the reaction was carried out at 11 kbar in the presence of Eu(fod)3 as a catalyst, a 98 2 ratio of the cycloadducts was obtained in which 60 was the major product. The diastereoselectivity of the reaction is consistent with a Felkin-Anh transition state in which the diene approaches the formyl group from the less hindered face, in the endo mode. 

In the Felkin model (5), the important steric interactions involve R1 and R rather than the carbonyl oxygen as assumed by Cram (2-4) and also Karabat-sos (6). On this basis, the preferred mode of attack is 4 + 5 yielding 6, the least strained of six possible staggered conformations (three staggered conformations are possible for each of the diastereoisomers 2 and 3 6 is equivalent to the least strained conformation of 2). Recently, Anh and Eisenstein (7) have concluded from their ab initio calculations that the transition 4+ 5 6 does indeed correspond to the minimum energy transition state. 

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