Felkin selectivity

As shown in Scheme 8, the synthesis of aldehyde 45 was achieved in eight steps utilizing the common precursor 31 [46-48], Remarkably, the Mukaiyama aldol addition of silyl enol ether 46 to aldehyde 47 proceeded with anti-Felkin selectivity, which was attributed to involvement of the Weinreb amide and aldehyde carbonyl... 

The unsaturated linkage in enantiomerically pure a-methyl-. -y-unsaturated ketones (45) exerted a powerful stereochemical influence on their reduction with L-selectride, particularly when R is a tri-methylsilyl group. The anti homoallylic alcohols (46) were produced with uniformly excellent stereoselectivity (>93 7) via a Felkin transition state in which the double bond occupied the perpendicular position (equation 12). This Felkin selectivity was sufficient to overcome any chelation-mediated contribution in the reduction of a-vinyl-p-hydroxy ketones (47) to the, 2-syn diols (48) with LiEtsBH in THF at -78 °C (equation 13).58... 

The Mukaiyama aldol reaction of ethyl ketones can lead to the controlled introduction of two adjacent stereocenters. While enolate geometry may not be trans-fened faithfully to the relative stereochemistry of the aldol product syn versus anti), stereoconvergent reactions are possible. In the example shown in Scheme 9-5, it should be noted that 7i-facial control from the chiral aldehyde is strong as both products 7 and 8 arise from Felkin selectivity [5]. 

Our synthesis of (9S)-dihydroerythronolide A, which constitutes a formal synthesis of erythronolideA (226), depends on a key aldol reaction between the racemic aldehyde 244 and imide auxiliary 245 (Scheme 9-66) [84]. In this reaction, the auxiliary overrides any aldehyde facial bias, thus leading to an equimolar mixture of separable syn adducts 246 and 247. These two compounds were then processed separately and together provide five of the ten necessary stereocenters of erythronolideA (C9 will be oxidized). This synthesis also features the thioalkyla-tion of silyl enol ether 248 giving ketone 249, a process which can be compared with the Mukaiyama addition to aldehydes. Presumably, Felkin selectivity controls the Cii stereocenter while the mixture of C12 epimers was not detrimental as epi-merization could be effected in the subsequent elimination step. 

The completion of the synthesis of ebelactone A required an anti aldol reaction of a suitable three-carbon unit to proceed with and-Felkin selectivity, i.e. a mismatched reaction. Conversion of thioester 280 into its ( )-enol borinate and reaction with aldehyde 279 gave two anti aldol adducts, unfortunately with little stereochemical preference. The minor isomer 281 from this reaction was used in the successful synthesis of ebelactone A (274), and the same chemistry, now using thioester 282, was employed to complete the first synthesis of ebelactone B (275). 

The reaction of both ( )- and (Z)-butenylindium bromides with a-alkoxy aldehydes has been examined to assess the direction and sense of both relative and internal stereoinduction. (Scheme 10-100). High selectivities for the 2>A-synlA,5-anti diastereomers are observed in the reaction of the Z-2-(bromomethyl)-2-butenoate (293) with ehiral aldehydes 294. The stereochemical outcome of the reaction is believed to result from reaction through transition structure xxvi. As the size of the R substituent increases only modest erosion of the coupling diastereoselectiv-ities is observed. This is reminiscent of the anti-Felkin selectivity observed with (Z)-2-butenylboronates with chiral aldehydes (Section 10.4.2.1). 

These aldols have all had just one chiral centre in the starting material. Should there be more than one, double diastereomeric induction produces matched and mismatched pairs of substrates and reagents, perfectly illustrated by the Evans aldol method applied to the syn and anti aldol products 205 themselves derived from asymmetric aldol reactions. The extra chiral centre, though carrying just a methyl group, has a big effect on the result. The absolute stereochemistry of the OPMB group is the same in both anti-205 and yvn-205 but the stereoselectivity achieved is very different. The matched case favours Felkin selectivity as well as transition state 201 but, with the mismatched pair, the two are at cross purposes. It is interesting than 1,2-control does not dominate in this case.33... 

In the presence of zinc bromide (ZnBr2), the nucleophilic addition of 2-fliryllithium to 167 proceeds in a highly stereoselective manner to afford the a /-adduct 170. This observed high stereoselectivity has been attributed to enhanced Felkin selectivity due to the chelation effect... 

The extreme buUdness of these aluminum reagents is able to control the addition reaction of carbonyl compounds by complexation which will or can lead to unexpected stereoselectivity. When MAD was mixed with the carbonyl compound of 4-tert-butylcyclohexanone, a stable 1 1 complex was formed. This complex was treated with methyllithium at low temperature to yield an equatorial alcohol almost exclusively. The observed stereochemical outcome was opposite that of the product from reaction of cyclohexanone with methyllithium. The equatorial selectivity achieved with MAD was found to be almost perfect [11, 12], Furthermore, if the same reaction conditions are applied to chiral aldehydes, a fi-Felkin selectivities are observed [12] (Scheme 5). 

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