Keck asymmetric allylation

The formation of chiral secondary homoallylic alcohols via the enantioselective addition of allylic nucleophiles to aldehydes is an important tool in organic synthesis. An efficient way to achieve this transformation is to use allylic organometallic reagents in the presence of chiral Lewis acid catalysts. The most widely studied catalysts in the area 

The exact course of the mechanism of the allylation is not fully understood. The chiral Lewis acid presumably activates the aldehyde toward nucleophilic attack by the allyltributyltin. After loss of the tributyltin group, the 

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. 

The spongistatins are a family of architecturally complex bisspiroketal macrolides, which display extraordinary cytotoxicity. During the second generation synthesis of the ABCD subunit of spongistatin 1, A.B. Smith and coworkers utilized the Keck allylation to construct the Kishi epoxide. The allylation was carried out under standard conditions, using tributyl-(2-ethylallyl)-stannane as the allylstannane reactant. The desired product was formed in high yield and a diastereomeric ratio greater than 10 1. 

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

Related reactions Keck asymmetric allylation, Sakurai allylation ... 

Last year, a short enantioselective total synthesis of herbarumin III (42) in 11% overall yield was published the approach applied uses Keck s asymmetric allylation and Sharpless epoxidation to build the key fragment. Esterification with 5-hexenoic acid and a RCM was used to yield 42. Finally, another asymmetric synthesis of herbarumin III (42) was carried out using (R)-cyclohexylidene glyceraldehyde as the chiral template. The key steps of the synthesis were the enantioselective preparation of the... 

Keck reported an asymmetric allylation with a catalytic amount of chiral titanium catalyst [24]. The enantioselective addition of methallylstannane to aldehydes is promoted by a chiral catalyst 13 prepared from chiral BINOL and Ti(0-i-Pr)4 (Scheme 9.10). An example of asymmetric amplification was reported by using (R)-BINOL of 50% ee, and the degree of asymmetric amplification was dependent on the reaction temperature. Tagliavini also observed an asymmetric amplification in the enantioselective allylation with a BIN0L-Zr(0-i-Pr)2 catalyst [25]. 

Rhizoxin is a macrocyclic natural product possessing antibiotic and antifungal properties, and it also exhibits antitumor activity. G.E. Keck and co-workers described a synthetic approach for the construction of this natural product, where they utilized the catalytic asymmetric allylation method as a key strategic element to establish the C13 stereochemistry. ... 

Keck, G. E., Geraci, L. S. Catalytic asymmetric allylation (CAA) reactions. II. A new enantioselective allylation procedure. Tetrahedron Lett. 1993,34, 7827-7828. 

Keck, G. E., Krishnamurthy, D., Grier, M. C. Catalytic asymmetric allylation reactions. 3. Extension to methallylstannane, comparison of procedures, and observation of a nonlinear effect. J. Org. Chem. 1993, 58, 6543-6544. 

Keck, G. E., Yu, T. Catalytic Asymmetric Allylation Reactions Using BITIP Catalysis and 2-Substituted Allylstannanes as Surrogates for P-Keto Ester Dianions. Org. Lett. 1999,1, 289-291. 

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. 

Of the BINOL/BINAP-metal catalyst complexes, only the allylation procedure described by Keck using the BINOL-Ti(IV) catalyst 451 has been applied in the synthesis of natural products, presumably because it has the most substrate generality and the field is so new. In a preliminary report, Evans disclosed the synthesis of the 4-hydroxy buteneolide terminus 470 of mucocin, where he uses Keck s original catalytic asymmetric allylation procedure to effect conversion of aldehyde 469 to the homoallylic alcohol 470 in good yield and high diastereoselectivity (Scheme 11-36) [312]. 

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 s asymmetric allylation has been employed independently by two research groups in the construction of the C1-C14 and fragments of fhe paclilaxel-... 

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]. 

Lipshutz and coworkers synthesized an optically active BINOL analog by copper-catalyzed intramolecular biaryl coupling and applied the complex with Ti(0 Pr)4 7 to Keck s asymmetric allylation [23]. In the reaction with benzalde-hyde or cyclohexanecarboxaldehyde, almost identical results were obtained with regard to both yields of isolated product and enantiomeric excesses. 

The use of titanium catalysts formed from (S)- or (/ )-binaphthol 1.44 and H(Oi-Pr)4 or Ti(0/-Pr)2Cl2 has been proposed by Keck, Umani-Ronchi and their cowoikers [1218-1221] for the asymmetric allylation of aldehydes with CH2=C(R)CH2SnBu3 (R = H,Me). These reactions occur near room temperature in the presence of molecular sieves, and excellent yields and enantiomeric excesses are obtained (Figure 6.53). 

Since Keck s original disclosure in 1993 many groups have been interested in expanding the scope of the reaction with a variety of chiral catalysts. These catalytic systems have, in general, moderated the reaction conditions and increased enantioselectivity. This section attempts to present the scope and limitations of many of those systems in an effort to assist in choosing the best system for asymmetric allylation of a specific substrate. 

With this strategy in mind, Keck s construction of the 2,6-cii-tetrahydropyran unit commenced with the asymmetric allylation [185] of aldehyde 2.275 with allystannane 2.276 promoted by BEMOL titanium tetraisopropoxide (BITIP) to furnish the homoaUyl alcohol 2.274 (95 %, 95 % ee) [186]. The formation of the key 2,6- s-tetrahydropyran 2.277 was accomplished by the Hosomi-Sakurai-Prins cychzation in the presence of TMSOTf in 85 % yield as a single diaste-reomer. SUyl deprotection and oxidation, followed by Homer-Wadsworth-Em-mons olefination proceeded to provide 2.278, which was further elongated to the phosphonoacetate 2.279. Exposure of the resulting phosphonoacetate to NaHMDS after desilylation and subsequent oxidation afforded the macrocycle 2.280 via the Homer-Wadsworth-Emmons olefination protocol. 

Asymmetric allylation of aldehydes or ketones using allylstannane reagents is useful for the preparation of chiral homallyl alcohols. Chiral Lewis acids such as BINOL-Ti complexes are effective. This asymmetric synthesis is called the Keck allylation. " The chiral organocatalysts achieves diastereoselective allylation also albeit in a moderate enantiomeric excess. " For example, an aldehyde readily available from S-malic acid reacts with an allylstannane in the presence of an in situ generated Ti (R)-B1N0L 2 complex to provide the corresponding (-)-alcohol in 70% yield in ca 18 1 diastereoselectivity (Scheme 3-214). ... 

Asymmetric amplification has been observed in organotin-catalyzed C-C bond formation. Keck, for example, discovered that allylation of aldehydes with... 

K. Barry Sharpless (bom 1941) received his PhD in 1968 at Stanford University. Since 1990 he is W. M. Keck Professor of Chemistry at the Scripps Research Institute in La Jolla, USA. Among several other important discoveries. Sharpless developed catalysts for asymmetric oxidations. In 1980 he achieved the catalytic asymmetirc oxidation of allylic alcohols to chiral epoxides by utilizing titanium complexes with chiral ligands (e. g. Section 3.3.2). One of the many applications of chiral epoxides is the use of the epoxide (R)-glycidol for pharmaceutical production of beta-blockers. Sharpless received the Nobel prize for chemistry in 2001 together with Knowles and Noyori. 

Keck and Tagliavani reported within months of each other the asymmetric ally-lation reactions with allyltri-n-butylstannane and various aldehydes with BINOL-Ti(IV) catalysts 451 and 452, respectively [289, 2901. Although the two catalysts give similar yields and enantioselectivities with a range of aldehydes, the diiso-propoxide catalyst 451 has been used more extensively. Keck and co-workers have shown that a variety of aldehydes react with allyl and methallyltri-n-butyl-stannane in modest to excellent yield and with good to excellent enantioselection using (/ )-451 as the catalyst (Table 11-25) [289, 296, 2971. 

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