Asymmetric with allylic halide

Alkyl halides or alkyl sulfates, treated with the salts of sulhnic acids, give sul-fones. A palladium catalyzed reaction with a chiral complexing agent led to sul-fones with modest asymmetric induction.Alkyl sulhnates R SO—OR may be side products. " Sulfonic acids themselves can be used, if DBU (p. 1530) is pre-sent. Sulfonyl halides react with allylic halides in the presence of AICI3 Fe and wit benzyl hlaides in the presence of Sm/HgCla. " " Sulfones have also been prepared by treatment of alkyl halides with tosyUiydrazide. " ... 

The reactions of organocuprates with allylic halides and esters have been widely studied [624a]. The introduction of chiral leaving groups on the electrophile aUows useful levels of asymmetric induction. Gais and coworkers [519] have used chiral sulfoximines 1.150. Isomerization of these sulfoximines, followed by... 

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. ... 

Seebach and Naef1961 generated chiral enolates with asymmetric induction from a-heterosubstituted carboxylic acids. Reactions of these enolates with alkyl halides were found to be highly diastereoselective. Thus, the overall enantioselective a-alkyla-tion of chiral, non-racemic a-heterosubstituted carboxylic acids was realized. No external chiral auxiliary was necessary in order to produce the a-alkylated target molecules. Thus, (S)-proline was refluxed in a pentane solution of pivalaldehyde in the presence of an acid catalyst, with azeotropic removal of water. (197) was isolated as a single diastereomer by distillation. The enolate generated from (197) was allylated and produced (198) with ad.s. value >98 %. The substitution (197) ->(198) probably takes place with retention of configuration 196>. 

Primary allylic halides may be efficiently asymmetrically dihydroxylated in 40-98% ee. The products may be readily converted into epoxy alcohols in high yields, by treatment with NaOH in THF (equation 19)116. 

Catalyst screening experiments resulted in the discovery that copper(salen) complex 33 was a highly effective catalyst for the conversion of alanine derivative 16b into (f )-a-methyl phenylalanine 17 under the conditions shown in Scheme 8.16. The presence of just 1 mol% of catalyst 33 was sufficient to induce the formation of compound 17 with up to 92% ee and in >70% yield [33]. Allyl bromide, 1-chloromethylnaphthalene and ethyl iodide also reacted with substrate 16b to give the corresponding (H)-a-methyl a-amino acids in the presence of 2 mol % of complex 33 [34], Complex 33 also catalyzed the asymmetric mono-alkylation of glycine-derived substrate 34 by benzylic or allylic halides, to give (H)-a-amino acid derivatives 35 with 77-81% ee. and in greater than 90% yield, as shown in Scheme 8.17. 

The ability of allyltin halides to extend their coordination sphere allowed the preparation of chiral hypervalent complexes with diamine ligands, which have been efficient in the asymmetric synthesis of homoallylic alcohols with up to 82% ee100. Similarly, a chiral hypervalent allyltin was prepared from a low valent tin (II) catecholate, chiral dialkyl tartrate and ally lie halide101. The allylation of aldehydes and activated ketones proceeded with high enantiomeric excess. Allyltins prepared from Lappert s stannylene and allylic halides were shown to be efficient as well, although the Lewis acid character of the tin atom is much less marked in that case102,103. 

Asymmetric allylation is performed by chiral allylating reagents. The chiral allyltin generated in situ from benzodio-stannole [Sn(02C6H4)], allyl halide, chiral dialkyl tartrates and l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) reacts with aromatic aldehydes in the presence of copper salts to afford the chiral homoallyl alcohols (Equation (50)).164... 

Thiophene sulfonium salts have also been used for alkylation of phenols, thiophenols, and other nucleophiles (Equation 70) <2001T2871>. Ylides generated from THT and alkyl or allyl halides are known to react with aldehydes to form oxiranes. However, a modified procedure has been developed in which only a catalytic amount of THT is used for the preparation of vinyloxiranes from allyl bromides and aldehydes. In most of the cases, a m-/ra r-mixture of vinyloxiranes was obtained. Optically pure C2-symmetric /ra r-2,5-dimethyltetrahydrothiophene has also been used for the asymmetric version of this reaction, but the enantioselectivity was poor (25% ee) (Equation 71) <2003CC2074>. 

In accordance with this model one finds diastereoselectively anti products on reaction of aldehydes with ( )-allyl compounds, whereas allyl systems with the (Z)-configuration give mainly syn products and it is even possible to effect asymmetric induction. As the double bond of the product can be oxidatively cleaved to a CW3 group, the reaction can be regarded as a stereoselective aldol reaction, an aspect which explains the widespread interest in this type of reaction. With heterosubstituted allylic anions it is sometimes possible to effect predominantly y-attack with different electrophiles by the choice of the heteroatom.2 For instance it is well known that with sulfur substituents like —SR, —SOR or —SOjR the a-attack dominates, but doubly lithiated allenethiol possesses high y-reactivity and can be used as a homoenolate anion equivalent in reaction with electrophiles such as alkyl halides (Scheme 7). ... 

The key step in all these transformations is without doubt the reaction of l-lithio-l,3-dithianes with organic halides and epoxides. The alkylation usually proceeds extremely rapidly with primary alkyl iodides (-78 C, 0.2 h) and with allylic and benzylic halides - - (Scheme 59, entry a) but is much slower with secondary alkyl iodides and bromides. The reaction is best carried out at low temperature in order to obtain good yields by lowering the competitive elimination reaction it has been found to proceed with inversion of the configuration at the asymmetric carbon when optically active alkyl halides are used. ... 

Chiral malonate esters have been used successfully in asymmetric cyclopropanations, as shown by the example in Scheme 6.39, part of a total synthesis of steroids such as estrone [143,144]. The key step in this sequence is an intramolecular Sn2 alkylation of the monosubstituted malonate. The rationale for the diastereoselec-tivity is shown in the illustrated transition structure. Note that the enolate has C2 symmetry, so it doesn t matter which face of the enolate is considered. The illustrated conformation has the ester residues syn to the enolate oxygens to relieve Al>3 strain, with the enolate oxygens and the carbinol methines eclipsed. The allyl halide moiety is oriented away from the dimethylphenyl substituent, exposing the alkene Re face to the enolate. The crude selectivity is about 90% as determined by conversion to the dimethyl ester and comparison of optical rotations [143], but a single diastereomer may be isolated in 67% yield by preparative HPLC [144], This reaction deserves special note because it was conducted on a reasonably large scale ... 

Allylation. Allyl halides are converted to allyltitanium compounds by r-PrMgBr/jr-PrOj Ti, which can be used for allylation of carbonyl compounds and aldimines. With imines derived from a chiral a-phenethylamine, the reaction is highly diastereoselective following the Cram pattern exhibiting a 1,3-asymmetric induction. 

Asymmetric PTC is an important method in the synthesis of a-alkyl and a-amino acids. Belokon et al. [7] reported that the compound (47 ,57 )-2,2-dimethyl-Q ,Q ,Q , Q -tetra-phenyl-l,3-dioxolane-4,5-dimethanol (TADDOL) was used to catalyze the C-alkylation of C-H acids with alkyl halides to the asymmetric synthesis of a-methyl-substituted a-amino acids under PTC conditions. The alkylations of the substrate C-H acids with benzyl bromide or allyl bromide were conducted in dry toluene at ambient temperature with NaH or solid NaOH as base and TADDOL as a chiral promoter. The type of base is important in the asymmetric C-alkylation of C-H acids. 

The catalytic asymmetric allylation of aldehydes is another reaction that has received a great deal of attention. Both allylstannes and the less reactive allylsilanes undergo addition to aldehydes with high ee in the presence of enantiomerically pure Lewis acids and Lewis bases and asymmetric versions of the chromium-catalysed Kishi-Nozaki-Hiyama reaction utilising allyl halides have recently been developed. 

In 2011, Palomo [114] reported the first enamine-mediated direct asymmetric a-alkylation of aldehydes with electron-deficient allylic halides, in which the key C—C bond-formation proceeds via an 8 2 pathway. The reaction is efficiently catalyzed by co-catalysts system diphenylprolinol derivative/DMAP or DABCO... 

The first example of asymmetric thio-Claisen rearrangement based on axial chirality has been described by our group and involves atropisomeric thioanilides bearing an ortbo-tert-butyl group [132]. These axially chiral thioamides were subjected to LDA deprotonation followed by S-allylation with various allyl halides. 

The reaction was originally performed using a stoichiometric amount of the oxidant OSO4, with attendant problems of toxicity and cost.P2] The appeal of the method was greatly enhanced by the discovery that the asymmetric oxidation worked just as well under the more modem catalytic conditions, with only a trace of osmium tetroxide and(V-methylmorpholine(V-oxide (68) as the reoxidant. P3] The method is tolerant of a wide variety of functional groups (esters, allylic halides) and, unlike the Sharpless oxidation, has no need of an allylic hydroxyl group as an internal ligand. [ 4]... 

Reactions of racemic as well as optically pure 2 -carbonyl-/ -lactams with indium and allyl halides offer a convenient asymmetric entry into densely functionalized hydroxy-/ -lactams, with good regio- and stereocontrol (Eq. 4.29). A highly stereoselective indium allylation was used for asymmetric synthesis of a highly functionalized THE derivative (Eq. 4.30). ... 

Nickel catalysts with optically active ligands, e.g. (49), couple optically active Grignard reagents with vinyl halides in up to 32.9% enantiomeric excess.A Pd/neomenthyldiphenyl phosphine catalyst achieves only a modest 12% e.e. in the allylation of PhZnCl with allylic acetates.Chelating asymmetric... 

The j -BuLi-(—)-sparteine combination is widely used in enan-tioinductive organic reactions. 4.H7-i22 Benzylic asymmetric alkylation may thus be achieved by subsequent treatment with alkyl halides, alkyl tosylates, and allyl tosylates 1,3-Oxathiane derivatives shown in eq 50 may be lithiated and quenched with electrophiles. An interesting aspect of this reaction is the equatorial stereoselectivity, which is independent of the size of the electrophile introduced. ... 

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