Felkin model ketone reduction

Hydrosilylation provided a novel alternative reduction of a-oxy ketones (29) with tunable dia-stereoselectivity (Scheme 3). Fluoride-catalyzed reduction with phenyldimethylsilane in HMPA provided the jyn-alcohols (28) with high selectivity (87 13-96 4). The absence of a coordinating cation and the bulkiness of the reducing species combined to favor the Felkin model for these reductions. Conversely, reduction in trifluoroacetic acid proceeded via a proton-bridged cyclic transition state to give the anti products (30 84 16-99 1), These complementary methods constitute a powerful tool in stereoselective synthesis. 

The presence of a chiral acetal, aminal or oxathiane in the vicinity of a carbonyl group can direct the reduction of a ketone toward a diastereoisomeric alcohol, whether or not chelation is operative. For example, the LiAlHf or Li 5-BU3BH reductions shown in Figure 6.13 give predominantly the diastereoisomer predicted by the Felkin-Ahn model while reductions with DIBAL or LiAlH4/MgBr2 give predominantly the diastereoisomer predicted by the chelation model [87,94, 213, 226],... 

Acyclic Ketones. The stereochemistry of the reduction of acyclic aldehydes and ketones is a function of the substitution on the adjacent carbon atom and can be predicted on the basis of the Felkin conformational model of the TS,63 which is based on a combination of steric and stereoelectronic effects. 

Another interesting variation on the Felkin-Anh model is the reduction of ketones with very bulky a-substituents phenyl (38), cyclohexyl (39), and f-butyl... 

Prediction for the reduction of cyclic ketones on the basis of the Cram, Karabatsos and Felkin-Ahn models is usually unreliable and a simple model has yet to emerge. 

Furthermore, when the R and R" groups are too bulky, chelation becomes unlikely. With either Li(s-Bu)3BH or DIBAH, the reaction yields the product expected from the Felkin-Anh model [SS2], as shown in Figure 3.40. Similar results are observed in the reduction of 2-fluoro-2-trifluoromethyl-3-hydroxy-ketones [IY3]. 

The Felkin-Ahn and Cram models are best applied to acyclic systems. Problems arise when any of these models are used to predict the products generated by the reduction of cyclic ketones. These problems will be analyzed and new models for predicting diastereoselectivity in the reduction of cyclic molecules will be discussed in Section 4.7.C. 

Addition of -butylmagnesium bromide to 624 followed by Swem oxidation affords the ketone 642. Zinc borohydride addition occurs with almost exclusive anri-selectivity (>99 1), leading to 646 in accordance with an a-coordinated transition-state model in which the r -face of the carbonyl is exposed to the reagent. Presumably the MOM-ethers display a crown ether effect to facilitate a-chelation. In marked contrast, L-Selectride shows excellent 5y -selectivity to provide 645 (92 8), consistent with a j5-chelation and/or Felkin— Anh model. The a ri-adduct 646 is converted in five steps to ketone 647, which undergoes a similar highly selective hydride reduction with zinc borohydride to yield the anti,syn,syn-alcohol 648 (96 4). This product is converted in six steps to the r n5-(2i ,57 )-pyrroline 649, which undergoes a Wacker oxidation followed by catalytic reduction to (— )-indolizidine 195B (650) and its C-5 epimer (86 14) (Scheme 142). 

Dimethyl(phenyl)silane reduces aldehyde and ketone carbonyls with the aid of fluoride ion or acid. a-Acylpropionamides, 1-aminoethyl ketones, and 1-alkoxyethyl ketones are readily converted into the corresponding -hydroxy amides, o -amino alcohols, and a-alkoxy alcohols, respectively. The stereoselectivity is complementary and generally high erythro (or syn) isomers are obtained with trifluoroacetic acid (TFA), whereas threo (or anti) isomers are obtained with fluoride ion activator (eq 1). The erythro selectivity in the acid-promoted carbonyl reduction is ascribed to a proton-bridged Cram s cyclic transition state. On the other hand, the threo selectivity in the fluoride-mediated reduction is explained in terms of the Felkin-Anh t) e model, wherein a penta-or hexacoordinated fluorosilicate is involved. No epimerization at the chiral center is observed during the reaction. 

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