Ketones asymmetric allylation

Enamines derived from ketones are allylated[79]. The intramolecular asymmetric allylation (chirality transfer) of cyclohexanone via its 5-proline ally ester enamine 120 proceeds to give o-allylcyclohexanone (121) with 98% ee[80,8l]. Low ee was observed in intermolecular allylation. Similarly, the asymmetric allylation of imines and hydrazones of aldehydes and ketones has been carried out[82]. 

Chapters 4-6 present an overview and a comparison between the various existing strategies for asymmetric epoxidation of unfunctionalized alkenes, a, (3-unsaturated ketones and allylic alcohols. 

Palladium(0)-catalyzed a-allylation of silyl ethers is a reaction which can be carried out with ketones as well as with aldehydes91. It is highly regiospecific when applied to ketones. a-Allylations can also be performed with enol acetates using allyl carbonates in the presence of catalytic amounts of palladium(O) complexes and (tributyl)methoxytin92,93. The steric course of the reaction has not been studied systematically but a high level of diastereoselectivity is expected and possibilities for asymmetric induction by the use of chiral auxiliaries are envisaged. 

Palladium-catalysed asymmetric a-allyl alkylation of acyclic ketones has been reported allyl enol carbonates of a wide range of ketones undergo allyl transfer in high yields and ees at room temperature.197... 

Sharpless asymmetric epoxidation of allylic alcohols, asymmetric epoxidation of conjugated ketones, asymmetric sulfoxidations catalyzed, or mediated, by chiral titanium complexes, and allylic oxidations are the main classes of oxidation where asymmetric amplification effects have been discovered. The various references are listed in Table 4 with the maximum amplification index observed. 

The allylation reaction between ketones and allylsilanes was achieved in 2005. Yamamoto and Wadamoto developed the asymmetric allylation reaction in the presence of AgF-Difluorphos (Scheme 9.6).12 The reaction of ketones and allyltrimethoxysilane in the presence of AgF and Difluorophos afforded the corresponding tertiary homoallyhc alcohols with high enantioselectivities. Additionally, a,(3-unsaturated ketones could be used as substrates, and this catalytic system could be applied for the asymmetric crotylation reaction to obtain anti adducts preferentially (Schemes 9.7 and 9.8). When a,p-unsaturated ketones were used as substrates, 1,2-addition products were obtained exclusively. As described before, the anti adducts were obtained predominately, regardless of the geometry of crotyltrimethoxysilane. 

Recently, Trost reported an efficient Pd-catalyzed asymmetric allylic alkylation of 1-tetralones [175] and a-arylketone 83 creating a quaternary center as exemplified by the synthesis of 84 (Scheme 7) [176]. Two a-heterocyclic ketones were also alkylated with similar results. Ferrocene-based ligands are effective in pro-... 

Catalytic asymmetric allylations of aldehydes or ketones are roughly classified into two methods, namely, those using chiral Lewis acid catalysts and those using chiral Lewis base catalysts. The former method uses less reactive allylsilanes or allylstannanes as the allyl source. The latter method requires allyltrichlorosi-lane or more reactive allylmetals. Both processes are applicable to the reactions with substituted allylmetal compounds or propargylation. 

Oxocarbenium ions bearing a chiral auxiliary are useful for asymmetric allylation with 10. For example, oxocarbenium ions generated from aldehydes and homochiral Me3Si ether 15 are allylated with high diastereoselectivity (Scheme 104,104a,104b rp e resultant homoallyl ethers can easily be converted into homoallyl alcohols without epimerization. This two-step procedure is applicable to enantioselective allylation of ketones.105,1053... 

Catalytic asymmetric allylation of aldehydes and ketones with allylsilanes can be achieved by using chiral Lewis acids, transition metal complexes, and Lewis bases. In recent years, much attention has been paid for the chiral Lewis base-catalyzed system using allyltrichlorosilanes. Advances in catalytic asymmetric carbonyl allylation have been described in detail in recent reviews.116,117,117a... 

Practical and efficient asymmetric allylation of aldehydes is successfully promoted by Lewis acid catalysts bearing chiral auxiliaries to afford high levels of enantioselectivity.165 The effective catalysts for asymmetric allylation to benzaldehyde are shown below (Scheme j) 166-176 The catalytic asymmetric allylation of ketones has proved to be a more challenging transformation owing to the significantly low reactivity compared to aldehydes. In 2002, a catalyst based on titanium complex was developed (Equation (51)).A ... 

Planar chiral phosphaferrocene-oxazolines (379) constitute another family of complexes that are usefiil as ligands in asymmetric catalysis. Preparation of these takes advantage of a modified Friedel-Crafts acylation of (373) and an unusual conversion of the resulting trifluoromethyl ketone into an amide that is then cyclized to an oxazoline. The diastereomeric complexes thus formed are chromatographically separable and are used in a palladium-catalyzed asymmetric allylic substitution. Modification of this complex by using the anion derived from 3,4-dimethyl-2-phenylphosphole gives more... 

In 1999 Trost and Schroder reported on the first asymmetric allylic alkylation of nonstabilized ketone enolates of 2-substituted cyclohexanone derivatives, e.g. 2-methyl-1-tetralone (45), by using a catalytic amount of a chiral palladium complex formed from TT-allylpaUadium chloride dimer and the chiral cyclohexyldiamine derivative 47 (equation 14). The addition of tin chloride helped to soften the lithium enolate by transmetala-tion and a slight increase in enantioselectivity and yield for the alkylated product 46 was observed. Besides allyl acetate also linearly substituted or 1,3-dialkyl substituted allylic carbonates functioned well as electrophiles. A variety of cyclohexanones or cyclopen-tanones could be employed as nucleophiles with comparable results . Hon, Dai and coworkers reported comparable results for 45, using ferrocene-modified chiral ligands similar to 47. Their results were comparable to those obtained by Trost. 

This methodology has been used to provide efficient protocols for the asymmetric allylic alkylation of p-keto esters, ketone enolates, barbituric acid derivatives, and nitroalkanes. Several natural products and analogs have been accessed using asymmetric desymmetrization of substrates with carbon nucleophiles. The palladium-catalyzed reaction of a dibenzoate with a sulfonylsuccinimide gave an advanced intermediate in the synthesis of L-showdomycin (eq 3). ... 

A considerable success has been realized for asymmetric hydrogenation of functionalized alkenes since the discovery of BINAP-Ru complexes in the mid-1980s [5]. The details are described in each of the following substrates, enamides, alkenyl esters and ethers, a,/3- and /3,y-unsaturated carboxylic acids, a,/3-unsaturated esters and ketones, and allylic and homoallylic alcohols. 

On the other hand, unsaturated aldehydes and ketones were obtained using allylic alcohols as alkene components [68]. Similarly, allyl f-butyldimethylsilyl ether and N-allylamides gave silyl enol ethers [69] and enamides [70], respectively. The ruthenium-catalyzed alkene-alkyne coupling was successfully combined with the palladium-catalyzed intramolecular asymmetric allylic alkylation [71] to provide a novel one-pot heterocyclization method [72]. 

Several enantioselective approaches to vitamin E (1), based on resolution of the products, the use of enantiopure natural building blocks, auxiliary controlled reactions and asymmetric oxidations have been described. In addition, a palladium-catalyzed asymmetric allylic alkylation reaction to build up the chiral chroman framework has been employed by Trost. Tietze and coworkers have developed asymmetric syntheses of the chiral chroman moiety using either the selective ally-lation of an alkyl methyl ketone or a Sharpless dihydroxylation as the key step. However, none of these methods is efficient enough for an industrial approach. ... 

The resulting derivatives were applied with success in the standard asymmetric allylic alkylation (up to 97 % ee) [134, 136] or in transformations involving either specific allylic substrates (2-cycloalkenyl derivatives, up to >99% ee) [135, 137], unsymmetrical substrates (monosubstituted allyl acetate, up to 83% ee) [140], or especial nucleophiles (nitroalkanes [141], iminoesters [138 a], or diketones [139, 140, 142]). Such ligands were also effective in the formation of quaternary chiral carbon through allylic substitution (eq. (6)) [138, 143], deracemiza-tion of vinyl epoxides (up to 99% ee) [144], or alkylation of ketone enolates [138 b], and deracemization of allylic derivatives [145]. 

The asymmetric allylation of unfunctionalized aliphatic ketones has also been described (Scheme 10-23) [43]. Simple aliphatic ketones are treated with a mixture of the trimethylsilyl ether of norpseudoephedrine (58), two equivalents of allyltrimethylsilane, and a catalytic amount of triflic acid. The homoallylic ethers... 

The use of C2-symmetric 1,2- and 1,3-diols as chiral auxiliaries is a reliable method for asymmetric allylation of acetals [382]. Acyclic acetals derived from homochiral 1-phenylethanol undergo the Hosomi-Sakurai allylation with high diastereoselectivity [383]. Tietze et al. have, on the other hand, reported that the TMSOTf-catalyzed successive acetalization-allylation reaction of aliphatic aldehydes with homochiral silyl ethers 123 and allyltrimethylsilane gives the corresponding homoallyl ethers with complete diastereocontrol these ethers can be readily converted into enantiomerically pure homoallyl alcohols without epimerization (Scheme 10.135) [384]. This method is applicable to asymmetric allylation of methyl ketones [385]. 

Allylation of ketones is a fundamental and important transformation, and therefore, efficient catalysts promoting addition of allylstannanes to ketones have been investigated [89]. Enantioselective allylation of ketones is a very challenging topic. It has been disclosed that asymmetric allylation of ketones with allylstannanes was promoted by addition of BINOL/TiCl2(OiPr)2 catalyst [90] or by premixing of BINOL with tetraallyltin [91]. In these reactions, however, enantioselectivity was not sufficient for practical purposes (acetophenone <65% ee). It was recently discovered that acetophenone was allylated by a mixture of tetraallyltin and an alkyl-triallyltin in the presence of monothiobinaphthol to furnish the desired chiral homoallyl alcohol with high enantioselectivity (Scheme 12.35) [92]. 

Reactions of chiral allylic boranes with carbonyl compounds Reactions of chiral allyl boranes with imines Asymmetric Addition of Carbon Nucleophiles to Ketones Addition of alkyl lithiums to ketones Asymmetric epoxidation with chiral sulfur ylids Asymmetric Nucleophilic Attack by Chiral Alcohols Deracemisation of arylpropionic acids Deracemisation of a-halo acids Asymmetric Conjugate Addition of Nitrogen Nucleophiles An asymmetric synthesis of thienamycin Asymmetric Protonation... 

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