Homoallylic alcohols Keck allylation reaction

A. Furstner and co-workers devised an efficient synthesis of (-)-gloeosporone, a fungal germination inhibitor. They utilized the Keck asymmetric allylation method to create the 7(R>homoallylic alcohol subunit. The reaction of the substrate aldehyde in the presence of the in situ generated catalyst provided the product with high yield and as the only diastereomer. It is important to note that it was essential to use freshly distilled Ti(/-OPr)4 for the preparation of the catalyst in order to get high enantioselectivity and reproducible results. 

A convergent, stereocontrolled total synthesis of the microtubule-stabilizing macrolides, epothilones A and B was achieved in the iaboratory of S.J. Danishefsky. During their investigations, they examined several approaches to construct these natural products. One possible strategy to introduce the Cl 5-hydroxyl group in an enantioselective fashion was to use Keck s asymmetric allylation method. Under standard conditions, the reaction provided the desired homoallylic alcohol in good yield and excellent enantioselectivity. 

Keck asymmetric allylation The reaction of aldehydes with allyltributylstannane in the presence of Lewis acid catalysts to form homoallylic alcohols. 236... 

The transmetallation or the metal-metal exchange reaction of an allylic tin species with an electrophile was first observed in 1970 [77]. The possibility that transmetallation may play a role in the Lewis acid-promoted reaction of allylstannanes with aldehydes was initially discussed by Tagliavini [78], Keck [79], Yamamoto [71b, 80], and Maruyama [81]. It is believed that upon transmetallation with either SnCU or TiCl4, the addition of an allylstannane and aldehyde will occur via a cyclic, six-membered transition structure. The reaction occurs by coordination of the aldehyde carbonyl with the Lewis acidic trichlorotin or trichlorotitanium reagent, thus affording the anti homoallylic alcohol (Scheme 10-42). 

Keck [89a-c], Tagliavini [89d,e], and Yu [89f] have extensively studied the BINOL-Ti- or binol-Zr promoted reactions of achiral aldehydes with allylstan-nanes. The initial studies employed BINOL and either Ti(Oi-Pr)4 or TiCl2(0/-Pr)2 as the Lewis acid promoter in the reaction of achiral aldehydes with allyltributyl-stannane. The reaction affords good yields of the desired homoallylic alcohol with a high degree of enantioselectivity even with as little as 10 mol% of the chiral catalyst (Scheme 10-49) [89a]. The rate and turnover of the catalytic, asymmetric allylation reaction have also been optimized. It was found that when /-PrSSiMe3 is added to the reaction, a rate acceleration occurs, allowing as little as 1-2% of the catalyst to be used [89 fj. 

Using Keck s original catalytic allylation procedure, Danishefsky and co-workers converted aldehyde 474 to the homoallylic alcohol 475 (conditions A, Scheme 11-38, 60% yield, >95% ee) used in their total synthesis of epothilones A and B [314], Asymmetric allylation with a stoichiometric amount of Brown s reagent, [(-)-lpc]2BAll (195), however, was higher yielding and required a shorter reaction time (conditions B, Scheme 11-38, 83% yield, >95% ee). 

Keck examined allylations with enriched mixtures of E- and Z-2-butenylstannanes 9 and several simple aldehydes 10. i Reactions were generally selective for production of the. yyn-homoallylic alcohols 11, and diastereoselectivity was enhanced by higher proportions of the -2-butenylstannanes (Scheme 5.2.3). The analysis recognizes three staggered rearrangements 13, 14 and 15, which may contribute to the formation of syn-W. The preference of one transition state over another is dependent on non-bonded interactions and especially the interactions introduced by Lewis acid complexation. 

Keck almost simultaneously reported two procedures using chiral titanium catalysts 6A and 6B for the enantioselective addition of allyltributyltin to aldehydes [11]. In the first procedure, the catalyst 6A is prepared from a 1 1 mixture of (R)-binaphthol and titanium tetraisopropoxide. The second procedure for the preparation of 6B, in contrast, requires a 2 1 mixture of BINOL, Ti(0 Pr)4, and a catalytic amount of CF3SO3H or CF3CO2H. Using 10 mol % of the catalyst 6A or 6B, a variety of aromatic, aliphatic, and a,P-unsaturated aldehydes are efficiently transformed into the corresponding optically active homoallylic alcohols with high enantioselectivity. An improved procedure was later published for the catalytic asymmetric allylation reactions using the 2 1 BINOL/Ti catalytic system [12]. 

The Keck reaction is the allylation of a carbonyl compound performed with an allylstannane and mediated by a Lewis acid. The reaction product is a homoallylic alcohol. 

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