Asymmetric reactions benzylation

Chiral alcohols have also been used in an asymmetric synthesis of sulphoxides based on halogenation of sulphides. Johnson and coworkers have found319 that the reaction of benzyl p-tolyl sulphide with JV-chlorobenzotriazole (NCBT) followed by addition of (—) menthol and silver tetrafluoroborate afforded diastereoisomeric menthoxysulphonium salts 267 which, upon recrystallization and hydrolysis, gave benzyl p-tolyl sulphoxide with 87% optical purity (equation 145). More recently, Oae and coworkers reported320 that optically active diaryl sulphoxides (e.e. up to 20%) were formed either by hydrolysis or thermolysis of the corresponding diaryl menthoxysulphonium salts prepared in situ from diaryl sulphides using ( —) menthol and t-butyl hypochlorite. 

In a closely related reaction, asymmetric reduction of 3-(2V-benzyl-7V-methylamino)propiophenone using H2, [Rh(COD)Cl]2 and the chiral phosphine (2S,4S-(l-(A-methyl-carbamoyl)-4-(dicyclohexylphosphino)-2-[diphenylphosphino)methyl]-pyrrolidine ((2S,4S)-MCCPM), followed by debenzylation and addition of the alcohol to l-chloro-4-(trifluoromethyl)benzene gave (R)-fluoxetine (4-(/ )). ... 

The asymmetric benzylation of 16 was promoted by phosphonium salt 12 in moderate yield with encouraging levels of enantioselectivity when the catalyst loading was as low as 0.20 mol % (Table 7.1, entry 3). Further, a low temperature improved the enantiomeric excess to 50% ee (entry 5). A low enantiomeric excess obtained using the phosphonium salt 13 (entry 6) suggested a critical role for two mandelamide units in the catalytic efficiency of phosphonium salt 12. Unfortunately, this reaction proved to be highly substrate-sensitive, and other alkylating agents or different ester substituents in 16 afforded low enantioselectivities. 

The reactions of Grignard reagents with acyclic sugar derivatives have also been investigated as potential routes for the synthesis of compounds containing asymmetric, benzylic carbon atoms.22 W. A. 

Asymmetric benzylic functionalization using a chiral base can be achieved. For example, reaction of complex (58) with the chiral base (59) and methyl iodide produce complex (60) in high yield and enantiomeric excess (Scheme 100). Asymmetric benzylic alkylation can also be obtained using the chiral complex (62) derived from enantioselective deprotonation of (61) (Scheme 101). High enantiomeric excess is observed upon deprotonation and alkylation of isobenzothiophen complexes with a chiral base (Scheme 102). 

Asymmetric Michael Reactions. Asymmetric induction has been observed in Michael-type addition reactions that are catalyzed by chiral amines. The Ai-benzyl fluoride salt of quinine has been particularly successful since the fluoride ion serves as a base and the aminium ion as a source of chirality. Drastic improvements in optical purity (1-23%) have resulted by changing from quinine to the N-benzyl fluoride salt (eq 11). ... 

The most pertinent effects of ultrasound in solid-liquid reactions are mechanical, which are attributed to symmetrical and/or asymmetrical cavitation. Symmetrical cavitation (the type encountered in homogeneous systems) leads to localized areas of high temperatures and pressures and also to shock waves that can create microscopic turbulence (Elder, 1959). As a result, mass transfer rates are considerably enhanced. For example, Hagenson and Doraiswamy (1998) observed a twofold increase in the intrinsic mass transfer coefficient in the reaction between benzyl chloride (liquid) and sodium sulfide (solid). In addition, a decrease in particle size and therefore an increase in the interfacial surface area appears to be a common feature of ultrasound-assisted solid-liquid reactions (Suslick et al., 1987 Ratoarinoro et al., 1992, 1995 Hagenson and Doraiswamy, 1998). 

Benzylic alcohols are reactive in the presence of an acid as an activator. Asymmetric carbonylation of l-(6-methoxy-2-naphthyl)ethanol (20) by using DDPPI as a chiral ligand in the presence of CuCb and / -TsOH as activators afforded the methyl ester of (5)-naproxen (21) with 81 % ee [12], Benzyl alcohol was carbonylated to phenylacetic acid under somewhat harsh conditions in the presence of HI. Presumably the carbonylation of benzyl iodide, generated by the reaction of benzyl alcohol with HI, occurred. 1,2-Di(hydroxymethyl)benzene (22) was carbonylated to give 3-isochromanone 25 in 88 % yield. In this reaction, one of the benzylic alcohols is converted to benzylic iodide 23 and the lactone 25 was obtained via acylpalladium 24 [13]. 

Scheme 1.9 Asymmetric benzylic C-H bond insertion reactions of Rh2(S-DOSP)4 carbenoids reported by Davies.

Scheme 1.10 Total synthesis of (+)-imperanene and (-)-a-conidendrin via asymmetric benzylic C—H bond insertion reactions reported by Davies.

In 1996, Katsuki and co-workers studied asymmetric benzylic oxidation reactions by using Mn(salen) complexes. However, the best result they obtained was just 29% yield and 64% ee when 1,1-dimethylindane was used as the substrate and C25 as catalyst (Scheme 1.60). Later, they further enhanced the enantioselective control to 90% ee by changing the catalyst to C26, albeit the yield is only 24.5%. ... 

The asymmetric benzylation of enolates derived from the phosphono-propanoamide (206) bearing (S)-a-methylbenzylamine (MBA) moiety easily obtained in a two step reaction from (205), has been examined by Ordonez (Scheme 73). Surprisingly, a reversal of the 7i-facial diastereoselectivity was observed by a change of the kind and number of equivalents of the lithium base. The reaction of the lithium enolate obtained using 2.0 equiv of LDA, LiHMDS or LTMP followed by benzylation with benzyl bromide afforded the (7 ,5)-diastereoisomer (207a), whereas the use of >2.5 equiv of the lithium base (LDA, LiHMDS or LTMP) gave the (5,5)-diastereoisomer... 

Cram s pioneering work had a significant impact in the design of new chiral crown ethers as phase-transfer catalysts. Koga synthesized a series of C2-symmetric chiral crown ethers 2-4 from optically active diols, and systematically investigated their performance in the asymmetric conjugate addition of methyl phenylacetate to methyl acrylate [8]. Recently, a novel BINOL-based aza-crown ether 5 was developed by Jaszay et al. [9], which was proved to be effective for the asymmetric conjugate addition reaction. Takizawa and coworkers applied a chiral spiro crown ether 6 to the asymmetric benzylation... 

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 [2 + 2] cycloaddition reaction of A -benzyl-l,4-dihydropyridine 34b with acrylonitrile, followed by catalytic reduction gave two pairs of diastereoisomeric amides 36 and 37 with a low diastereomeric excess, probably due to the large distance between the asymmetric center and the site of acrylonitrile attack. Compounds 36 and 37 were resolved into the four individual diastereoisomers (ca 5% for compound 36 and 15% for 37) [97JCR(M)321], Irradiation of 1,4-dibenzyl-1,4,5,6-tetrahydropyridine 38 in the presence of 29 gave two stereoisomers. 

Until this work, the reactions between the benzyl sulfonium ylide and ketones to give trisubstituted epoxides had not previously been used in asymmetric sulfur ylide-mediated epoxidation. It was found that good selectivities were obtained with cyclic ketones (Entry 6), but lower diastereo- and enantioselectivities resulted with acyclic ketones (Entries 7 and 8), which still remain challenging substrates for sulfur ylide-mediated epoxidation. In addition they showed that aryl-vinyl epoxides could also be synthesized with the aid of a,P-unsaturated sulfonium salts lOa-b (Scheme 1.4). 

Following Uskokovic s seminal quinine synthesis [40], Jacobsen has very recently reported the first catalytic asymmetric synthesis of quinine and quinidine. The stereospecific construction of the bicyclic framework, introducing the relative and absolute stereochemistry at the Cg- and expositions, was achieved by way of the enantiomerically enriched trans epoxide 87, prepared from olefin 86 by SAD (AD-mix (3) and subsequent one-pot cyclization of the corresponding diol [2b], The key intramolecular SN2 reaction between the Ni- and the Cg-positions was accomplished by removal of the benzyl carbamate with Et2AlCl/thioanisole and subsequent thermal cyclization to give the desired quinudidine skeleton (Scheme 8.22) [41],... 

Asymmetric alcoholyses catalyzed by lipases have been employed for the resolution of lactones with high enantioselectivity. The racemic P-lactone (oxetan-2-one) illustrated in Figure 6.21 was resolved by a lipase-catalyzed alcoholysis to give the corresponding (2S,3 S)-hydroxy benzyl ester and the remaining (3R,4R)-lactone [68]. Tropic acid lactone was resolved by a similar procedure [69]. These reactions are promoted by releasing the strain in the four-membered ring. 

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. ... 

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... 

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