Benzyl derivatives asymmetric reactions

Allylic silanes react with aldehydes, in the presence of Lewis acids, to give an allyl-substituted alcohol. In the case of benzylic silanes, this addition reaction has been induced with Mg(C104)2 under photochemical conditions. The addition of chiral additives leads to the alcohol with good asymmetric induction. In a related reaction, allylic silanes react with acyl halides to produce the corresponding carbonyl derivative. The reaction of phenyl chloroformate, trimethylallylsilane, and AICI3, for example, gave phenyl but-3-enoate. ... 

Introduction. (5)-4-Benzyl-2,2,5,5-tetramethyloxazolidine is used as a chirality-controlling auxiliary. Its amide derivatives preferentially occupy the syn conformation so that one of the u-facial reaction sites of the amide moiety becomes sterically less hindered. This chiral auxiliary will be especially useful for the asymmetric reactions which have to be performed in the absence of metallic additives. 

Relatively limited work on profene synthesis via carbonylation of benzyl-X derivatives has been reported from university groups. One exception is the stero-selective carbonylation of racemic benzylic bromides. The asymmetric reaction toward enantiomerically pure profenes could a priori proceed either by a kinetic resolution or by true asymmetric induction via the intermediacy of a trigonal substrate. Results from Arzoumanian et al. [35] strongly suggest that the carbonylation of 1-methylbenzyl bromide with oxazaphospholene-palladium complexes is a kinetic resolution process with a discriminative slow oxidative addition step. Best enantiomeric excess is about 64 % ee at 9 % chemical yield. Another possible way to synthesize enantiomerically pure profenes is to start from optically pure benzyl derivatives. Baird et al. investigated the carboxylation of optically active benzyl carbonates with palladium catalysts. The enantiomeric excess was only modest [36]. Thus, the development of an efficient catalytic asymmetric carbonylation of C-X derivatives is still an existing challenge. 

A few years ago Cahard reported a series of studies on the use of immobilized cinchona alkaloid derivatives in asymmetric reactions with phase-transfer catalysts [17[. Two types of polymer-supported ammonium salts of cinchona alkaloids (types A and B in Scheme 8.4) were prepared from PS, and their activity was evaluated. The enantioselectivity was found to depend heavily on the alkaloid immobilized, with the type B catalysts usually giving better results than the type A catalysts. By performing the reaction in toluene at -50 °C in the presence of an excess of solid cesium hydroxide and 0.1 mol equiv of catalyst 10, benzylation of the tert-butyl glycinate-derived benzophenone imine afforded the expected (S)-product in 67% yield with 94% ee, a value very close to that observed with the nonsupported catalyst. (Scheme 8.4, Equation b) Unfortunately-and again, inexplicably-the pseudoenantiomer of 10 proved to be much less stereoselective, affording the R)-product in only 23% ee. No mention of catalyst recycling was reported [18]. 

Since cbiral sulfur ylides racemize rapidly, they are generally prepared in situ from chiral sulfides and halides. The first example of asymmetric epoxidation was reported in 1989, using camphor-derived chiral sulfonium ylides with moderate yields and ee (< 41%) Since then, much effort has been made in tbe asymmetric epoxidation using sucb a strategy without a significant breakthrough. In one example, the reaction between benzaldehyde and benzyl bromide in the presence of one equivalent of camphor-derived sulfide 47 furnished epoxide 48 in high diastereoselectivity (trans cis = 96 4) with moderate enantioselectivity in the case of the trans isomer (56% ee). ... 

The asymmetric synthesis of 2,3-diamino acids can be accomplished by the addition of chiral enolates to prochiral imines. For example, reaction of morpholine-2-one 103, derived from (S)-phenylglycinol, with N-benzyl ben-zaldimine in the presence of pyridine and para-toluenesulfonic acid at high... 

Hanessian reported the synthesis of enantiomerically pure or highly enriched allylglycine and its chain-substituted analogs from the reaction of the sultam derivatives of O-benzyl glyoxylic acid oxime with ally he bromides in the presence of zinc powder in aqueous ammonium chloride (Eq. 11.41).72 Brown noticed the critical importance of water in the asymmetric allylboration of /V-trimethylsilyIbcnzaldimines with B-allyldiisopinocampheylborane.73 The reaction required one equivalent of water to proceed (Eq. 11.42). 

Various kinds of chiral acyclic nitrones have been devised, and they have been used extensively in 1,3-dipolar cycloaddition reactions, which are documented in recent reviews.63 Typical chiral acyclic nitrones that have been used in asymmetric cycloadditions are illustrated in Scheme 8.15. Several recent applications of these chiral nitrones to organic synthesis are presented here. For example, the addition of the sodium enolate of methyl acetate to IV-benzyl nitrone derived from D-glyceraldehyde affords the 3-substituted isoxazolin-5-one with a high syn selectivity. Further elaboration leads to the preparation of the isoxazolidine nucleoside analog in enantiomerically pure form (Eq. 8.52).78... 

The asymmetric hydrosilylation that has been most extensively studied so far is the palladium-catalyzed hydrosilylation of styrene derivatives with trichlorosilane. This is mainly due to the easy manipulation of this reaction, which usually proceeds with perfect regioselectivity in giving benzylic silanes, 1-aryl-1-silylethanes. This regioselectivity is ascribed to the formation of stable 7t-benzylpalladium intermediates (Scheme 3).1,S Sa It is known that bisphosphine-palladium complexes are catalytically much less active than monophosphine-palladium complexes, and, hence, asymmetric synthesis has been attempted by use of chiral monodentate phosphine ligands. In the first report published in 1972, menthyldiphenylphosphine 4a and neomenthyldiphenylphosphine 4b have been used for the palladium-catalyzed reaction of styrene 1 with trichlorosilane. The reactions gave l-(trichlorosilyl)-l-phenylethane 2 with 34% and 22% ee, respectively (entries 1 and 2 in Table l).22 23... 

Murray and colleagues199 developed some 2,5-diketopiperazines as new chiral auxiliaries and examined their asymmetric induction in the Diels-Alder reactions of their A-acryloyl derivatives with several dienes. Some of their results with dienophile 320 have been summarized in Table 19 (equation 89). When the benzyl group on 320 was substituted by an isopropyl or /-butyl group, the diastereofacial selectivity dropped dramatically. It was proposed that tv-tt stacking between the phenyl group and the electron-poor double bond provided a more selective shielding of one face of the double bond in this special case. 

Durst and co-workers (309) investigated in detail the stereochemistry of deuteration and methylation of carbanions derived from optically active (+)-(5)-benzyl methyl sulfoxide 34 and (+)-(i )-benzyl t-butyl sulfoxide 290. The reactions, which allowed the extent of asymmetric induction on the a-carbon atom as well as the stereochemistry of deuteration and methylation to be determined, are summarized in Schemes 30 and 31. 

Although Helmchen et al. showed that asymmetric iridium-catalyzed allylic substitution could be achieved, the scope of the reactions catalyzed by iridium complexes of the PHOX ligands was limited. Thus, they evaluated reactions catalyzed by complexes generated from [lr(COD)Cl]2 and the dimethylamine-derived phosphoramidite monophos (Scheme 8) [45,51]. Although selectivity for the branched isomer from addition of malonate nucleophiles to allylic acetates was excellent, the highest enantiomeric excess obtained was 86%. This enantiomeric excess was obtained from a reaction of racemic branched allylic acetate. The enantiomeric excess was lower when linear allylic acetates were used. This system catalyzed addition of the hthium salts of A-benzyl sulfonamides to aUylic acetates, but the product of the reaction between this reagent and an alkyl-substituted linear aUylic acetate was formed with an enantiomeric excess of 13%. 

Asymmetric allylic oxidation and benzylic oxidation (Kharasch-PSosnovsky reaction) are important synthetic strategies for constructing chiral C—O bonds via C—H bond activation.In the mid-1990s, the asymmetric Kharasch-Sosnovsky reaction was first studied by using chiral C2-symmetric bis(oxazoline)s. " Later various chiral ligands, based mainly on oxazoline derivatives and proline derivatives, were used in such asymmetric oxidation. Although many efforts have been made to improve the enantioselective Kharasch-Sosnovsky oxidation reaction, most cases suffered from low to moderate enantioselectivities or low reactivities. 

Cross coupling between an aryl halide and an activated alkyl halide, catalysed by the nickel system, is achieved by controlling the rate of addition of the alkyl halide to the reaction mixture. When the aryl halide is present in excess, it reacts preferentially with the Ni(o) intermediate whereas the Ni(l) intermediate reacts more rapidly with an activated alkyl halide. Thus continuous slow addition of the alkyl halide to the electrochemical cell already charged with the aryl halide ensures that the alkyl-aryl coupled compound becomes the major product. Activated alkyl halides include benzyl chloride, a-chloroketones, a-chloroesters and amides, a-chloro-nitriles and vinyl chlorides [202, 203, 204], Asymmetric induction during the coupling step occurs with over 90 % distereomeric excess from reactions with amides such as 62, derived from enantiomerically pure (-)-ephedrine, even when 62 is a mixture of diastereoisomcrs prepared from a racemic a-chloroacid. Metiha-nolysis of the amide product affords the chiral ester 63 and chiral ephedrine is recoverable [205]. 

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