Felkin control

Based on these results, Kalesse et al. applied the vinylogous Mukaiyama aldol reaction in their total synthesis of ratjadone [33, 34]. In the synthesis of the C14-C24 segment (A-fragment), the vinylogous aldol reaction was used together with different Lewis acids to achieve the addition of this diacetate syn-thon in a diastereoselective manner under Felkin control (Scheme 23). 

Addition of crotyltri-n-butyltin (5 11, 143) to chiral a-alkoxy aldehydes (6) presents a more complicated situation, since four products are possible. Products 7 and 8 result from chelation-controlled diastereofacial selectivity products 9 and 10 are products of Cram-Felkin control. In the reaction catalyzed by BF, etherate the major products are 7 and 9 in the ratio 67 33. Use of TiCl4 or MgBr, results in formation of only 7 and 8. With the former catalyst the 7/8 ratio is 63 37 with the latter, 92.5 7.5. The almost exclusive formation of 7 is consistent with the known ryn-stereoselectivity in the reaction of 5 with achiral aldehydes. 

The sterochemistry of additions of allyltri-n-butyltin (1) and crotyltri-n-butyltin (5) with 3-alkoxy aldehydes is more complex. In the allyltin reactions, useful diastereofacial selectivity is observed only with TiCU (4.6 1) or SnCU (9 1). Optimum stereoselectivity in the reaction of the p-alkoxy aldehyde 11 with 5 is observed in the reaction catalyzed by BF, etherate, which results mainly in the product of Cram-Felkin control (equation I). The highest chelation-controlled selectivity in reactions of 5 with the p-benzyloxy aldehyde 12 is obtained with MgBr, (equation II). 

There is an important lesson to be learnt here. The principles we have been explaining ar generally true but in any individual case the result may not follow the principle. This is particular true of Felkin control with aldehydes as H and O are not that different in size. You should first app the principle (here Felkin control) and then check the result. You should not be ashamed if you g this one wrong. 

An anti aldol reaction with Felkin control was now needed to couple the two spiroacetal fragments and generate the correct stereochemistry at C15 and C f, of the spongistatins. A study of the individual fragments indicated that while the enolate showed little facial selectivity, the aldehyde component had a considerable bias for the desired Felkin product. Best results were obtained with the lithium-mediated aldol coupling, which gave adduct 104 in good yield and acceptable selectivity [56 c]. 

The utility of BF3-OEt2, a monodentate Lewis acid, for acyclic stereocontrol in the Mukaiyama aldol reaction has been demonstrated by Evans et al. (Scheme 10.3) [27, 28]. The BF3-OEt2-mediated reaction of silyl enol ethers (SEE, ketone silyl enolates) with a-unsubstituted, /falkoxy aldehydes affords good 1,3-anti induction in the absence of internal aldehyde chelation. The 1,3-asymmetric induction can be reasonably explained by consideration of energetically favorable conformation 5 minimizing internal electrostatic and steric repulsion between the aldehyde carbonyl moiety and the /i-substituents. In the reaction with anti-substituted a-methyl-/ -alkoxy aldehydes, the additional stereocontrol (Felkin control) imparted by the a-substituent achieves uniformly high levels of 1,3-anti-diastereofacial selectivity. 

The Eu-catalyzed aldol reactions of chiral a-siloxy and a-alkoxy aldehydes with KSA show high levels of diastereocontrol, the sense depending on the nature of the a-substituent (Scheme 10.20) [68]. The stereoselectivity with the a-siloxy aldehyde can be explained by an antiperiplanar transition state merged with Felkin control, whereas reaction of fhe a-alkoxy aldehyde would proceed mainly via a synchnal transition state involving chelation of the substrate and coordination of fhe acetal alkoxy group of KSA. 

Felkin control over reactions of nucleophiles with carbonyl compounds Role of electronegative substituents... 

Now coupling to the simpler allyl silane 169 with the same Lewis acid but also with MeOSiMe3 gives the new alcohol as its methyl ether 170. Once again control is from silicon as the aldehyde has no neighbouring chiral centre to exert Felkin control. New chiral centres at C-10 and C-ll are created. 

The silyloxy aldehyde 1 was prepared from the ester 9 by reduction with Dibal. Felkin-controlled 1,2-addition of the allyl stannane 2 established the relative configuration of the secondary alcohol of 3, that was then used to control the relative configuration of the new alcohol in 10. Addition of the crotyl horane 12 to the derived aldehyde 11 also proceeded with high diastereocontrol. 

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