Aldol reaction using allylsilanes

Ab initio calculations on the reaction of enoxysilanes with formaldehyde have been used to characterize the electron-donating and -accepting strength of the different functions in the enoxysilane.92 This useful type of aldol reaction is also compared with the corresponding allylsilane version. 

Aldehydes undergo a Mukaiyama-aldol reaction followed by a Prins cyclization with the highly reactive allylsilane 329 to afford jy -2,6-tetrahydropyrans 330 that feature an oeo-methylene group at C-4 (Equation 140, Table 12). This Mukaiyama-aldol-Prins (MAP) cascade cyclization has been used to form a key bis-tetrahydropyran intermediate during the total synthesis of leucascandrolide A <2001JA8420>. Similarly, titanium tetrabromide mediated MAP reactions afford 4-bromo tetrahydropyrans <20030L3163>. 

Although the direct generation of titanium enolates is typically the most useful method of generating titanium enolates for aldol reactions, other methods have been described. Grubbs and Stille reported that titanium enolates could be generated by reaction of biscyclopentadienyltitanium al-kylidene complexes and acyl halides [93]. Oshima and coworkers reported the formation of titanium enolates from a-iodoketones with allylsilane and titanium tetrachloride [94]. Mukaiyama and coworkers reported the generation of titanium enolates from a-bromoketones on treatment with TiCh and copper powder [95]. 

In the pioneering works by Hosomi and Sakurai, a stoichiometric or substoichio-metric amount of TiCU, a conventional Lewis acid, was used for the carbonyl allylation with allylsilanes [106]. Davis and coworkers found that TMS borates such as Me3Si[BX(OTf)3] (X = OTf, Cl) enables an efficient, catalytic Hosomi-Sakurai allylation of aldehydes although (la) and Me3SiI show low catalytic activities (Scheme 9.41) [18, 107]. Ishihara and Yamamoto have demonstrated the utility of (lb) as Lewis acid catalyst of the carbonyl allylation as well as the Mukaiyama aldol reaction [15]. The silicon Lewis acid (lb), generated in situ by the reaction of allyltrimethylsilane with HNTf2, efficiently promotes the allylation of aldehydes and ketones with a loading of 0.5 mol% (Scheme 9.41). 

Soon after the first report of the aldol reaction of silyl enol ethers was disclosed, allylsilanes were reported to show similar reactivity toward aldehydes and ketones when activated by a stoichiometric amount of TiCU (Scheme 3-85). This synthetically important reaction has subsequently become the subject of many synthetic chemists and was improved extensively using various kinds of Lewis acid catalysts. Acyclic transition states are proposed to explain diastereoselectivities of the reaction depending on a Lewis acid and reaction conditions. Particularly, synclinal orientation of reactants is suggested to be more preferable rather than an antiperiplanar one particularly for ( )-allylsilanes based on molecular model studies (Scheme 3-86). High diastereoselectivity observed in the reaction of chiral allylsilanes with aldehydes is understood in terms of this transition state model which is based on the Felkin-type induction (Scheme 3-87). ... 

The most direct route to the 1,4-dicarbonyl equivalent required for the aldol condensation would be to couple the enol ether of an aldehyde with the enol ether of a ketone. However, this sequence proved impractical due to the hydrolytic instability of the ketone enol ether. Even after an extensive effort, the substrate for the electrolysis reaction could not be reproducibly prepared in high yield. These problems were readily avoided with the use of an allylsilane based... 

As we mentioned before, a classical Grignard reaction is formally described by the coupling of a covalent (albeit polarized) electrophile with an anionic nucleophile. Reactions shown in Scheme 2.41 (opposite) exemplify the alternative approach involving an interaction between cationic intermediates generated from carbonyl compounds (or their derivatives) under the action of Lewis acids and a purely covalent nucleophile, an allylsilane such as I09a or 109b. Similar electrophiles used in reactions with covalent silyl enolates such as 110 result in the formation of the aldol-Iike products (the Mukaiyama reaction ). 

Diastereoselective radical allylations have been studied in many different contexts, and a plethora of information exists regarding stereocontrol in these reactions. Allylations have been performed using the traditional trapping and )9-elimination sequence occurring typically with allylstannanes as well as a stepwise atom transfer/ elimination sequence found to occur with allylsilanes. Stereochemistry is commonly controlled through the use of chiral auxiliaries or by 1,2-induction, and functionalized anh -aldol and amino acid products are available using this established methodology. 

The 5-lactols and their acetylated derivatives (2, 8) are activated by acid to form oxonium cation intermediates (3, 9), which are attacked by nucleophiles to provide the substituted tetrahydropyrans with good stereoselectivity (Scheme 3) [13]. As the nucleophiles, allylsilane 4 (Hosomi-Sakurai reaction), silyl enol ethers 5 (Mukaiyama aldol) and EtaSiH (reduction) have frequently been used. Since the axial attack of the nucleophiles determines the product s... 

Nucleophilic addition to carbonyl compounds is the cornerstone of organic synthesis, highlighted by the classical examples of Grignard reactions, aldol condensation, LiA.lH4 reductions, and so on. However, when less reactive nucleophiles are employed, such as allylsilane [1], aUylstannane [1, 2], or CLSiR [3], activation is required. Here, we have a choice of activating either the electrophile or the nucleophile. Activation of the electrophile, that is, the carbonyl reactant, can be attained by coordination of a Lewis acid to the oxygen [4], which increases the electrophilicity of the carbonyl carbon and, consequently, the reactivity of the C=0 group. Alternatively, coordination of a Lewis base to the nucleophile can be assumed to increase its nucleophilicity, which should also allow the addition to occur [5]. Since only the coordinated species will react, the activator can be used in just a catalytic amounL provided that it can be regenerated after completion of the reaction and returned to the next catalytic cycle. Naturally, if the catalyst is chiral, preferential formation of one enantiomer of the product can be expected. 

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