Enolates enantioselective alkylation

Efficient enantioselective alkylations are known.In another method, enantio-selective alkylation can be achieved by using a chiral base to form the enolate. 

The synthesis in Scheme 13.49 features use of an enantioselective allylic boronate reagent derived from diisopropyl tartrate to establish the C(4) and C(5) stereochemistry. The ring is closed by an olefin metathesis reaction. The C(2) methyl group was introduced by alkylation of the lactone enolate. The alkylation is not stereoselective, but base-catalyzed epimerization favors the desired stereoisomer by 4 1. 

The efficient enantioselective alkylation of the P/y-unsaturated ester 39 was achieved1351 by use of the N-anthracenylmethyl catalyst 12 (R=benzyl, X=Br) together with CsOH-H20 under phase transfer conditions analogous to those in the alkylation of the O Donnell imine 23, as shown in Scheme 13. The enantioselectivity of the alkylation correlates with Hammett o constants, and the N,N-dimethylamino substituents in 39 showed the most effective enantioselectivity. The tight ion pair in which the enolate... 

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>. 

The indanone substrate was methylated in 94% enantiomeric excess, by the use of a chiral catalyst, N-(/>-(trifluoromethyl)benzyl)cinchoninium bromide, under phase transfer conditions.1468 In another method enantioselective alkylation can be achieved by using a chiral base to form the enolate.1469... 

Koga has continued his research program in the enantioselective alkylations of achiral lithium enolates using chiral ligands. Previous examples had provided excellent ee and yields for tertiary carbon centers ligand 6 has now been designed that allows formation of quaternary carbon centers with high ee [44]. 

In route 1 a racemate, rac-42, is used as the starting material. Deprotonation and enantioselective alkylation of the resulting enolate give the desired products of type 43. The alternative, second route is based on use of the glycinate 44 as starting material. Alkylation steps with different alkyl halides furnish the desired product 43. 

Besides the glycinate ester derivatives described above, other types of enolate-forming compounds have proved to be useful substrates for enantioselective alkylation reactions in the presence of cinchona alkaloids as chiral PTC catalysts. The Corey group reported the alkylation of enolizable carboxylic acid esters of type 57 in the presence of 25 as organocatalyst [69]. The alkylations furnished the desired a-substituted carboxylate 58 in yields of up to 83% and enantioselectivity up to 98% ee (Scheme 3.23). It should be added that high enantioselectivity in the range 94-98% ee was obtained with a broad variety of alkyl halides as alkylation agents. The product 58c is a versatile intermediate in the synthesis of an optically active tetra-hydropyran. 

An efficient and highly selective access to enantioenriched a-carbonyl all-carbon-substituted quaternary stereocentres has been provided by enantioselective alkylations of tributyltin enolates catalyzed by Cr(salen)Cl (13, M = Cr).33... 

Corey studied the X-ray crystal structures of cinchonidinium salts and has formulated a model which explains the highly enantioselective alkylation of the enolate of 3 [3]. This model accounts for the sense of asymmetric induction in this process and the importance of the size of the R1 substituent in the salts 1 and 2 the model can be used to rationalise other phase transfer catalysed processes involving similar catalysts. The enolate 37 is thought to be in close contact with the least hindered face of the tetrahedron formed by the four atoms surrounding the quaternary nitrogen atom (the rear face of this tetrahedron is blocked by the bulky 9-anthracenylmethyl group). Alkylation of the less hindered face of 37 leads to the observed enantiomer of the product (see Figure 1). 

In a similar fashion, Lectka et al 2X have developed the silver-catalyzed enantioselective alkylation of a-imino ester 378 by treatment with silyl enol ethers in the presence of AgSbF6 and (i )-BINAP, giving the amino acid derivatives 379 in good to high yields and enantioselectivities (Scheme 110). The analogous ene reaction of substrate 378 with 2-phenyl-propene afforded the corresponding unsaturated amino ester with 71% ee.322... 

Enantioselective alkylation of chiral amide enolates was investigated by Evans and Takacs77 and by Sonnet and Heath78, who used amide 42, formed by condensation of an optically active methylol with a substituted acetyl chloride (equation 14). 

Ferraris D, Young B, Cox C, Drury HI WJ, Dudding T, Lectka T (1998b) Diastereo- and enantioselective alkylation of alpha-imino esters with enol silanes catalyzed by (R)-Tol-BINAP-CuC10(4).(MeCN)(2). J Org Chem 63 6090-6091... 

Highly enantioselective alkylations a to acyclic diene complexes have been developed. Deprotonation of (91) with LDA to form an ester enolate, followed by reaction with iodomethane, gives the alkylated prodnct (92) in excellent yield with 82% ee (Scheme 153). Stereospecific remote alkylation was used in a synthesis toward macrolactin A (Scheme 154). In the synthetic seqnence, the primary... 

An intriguing enantioselective preparation of substituted quaternary 1,4-benzodiazepin-2-one scaffolds has been reported by Carlier et al. <03JA11482>. Enantioselective alkylation is used to prepare chiral products 64 (e.g. R = H R = Me, PhCH2 R = Me2CH) from non-racemic glycine-derived 1,4-benzodiazepinones. If the N1 substituent is sufficiently large (e.g. an isopropyl group) then the stereochemistry at the 3-position of the 3-substituted 1,4-benzodiazepinones is transmitted to the product despite the loss of chirality at C-3 on intermediate enolate anion formation. 

Besides stereoselective alkylations of glycine-derived enolates, enantioselective construction of chiral quaternary carbon centers from a-amino acids is one of the most challenging topics in current organic synthesis , since nonproteinogenic a,a-disubstituted amino acids often show a remarkable influence on the conformation of peptides. Moreover, they can act as enzyme inhibitors or as building blocks for the synthesis of a wide range of natural products . 

Enantioselective Alkylations and Catalytic Asymmetric Alkylations. a-Substitution of a carbonyl-containing substrate via generation of an enolate ion followed by subsequent reaction with an electrophile remains one of the most fundamental transformations in synthetic organic chemistry. A more recent advance to this type of transformation is the ability to perform this... 

In an extension of this methodology, it has been demonstrated that in some cases the enantioselective alkylation of lithium enolates can be achieved by means of a catalytic amount of 1. As in the stoichiometric version (vide supra), the reaction conditions play a crucial role in determining the yield and % ee. One fundamental modification in the catalytic version is the addition of two equiv of an achiral bidentate amine [e.g. tetramethylethylenediamine (TMEDA) or Al,lV,7V, A -tetramethy-Ipropylene diamine (TMPDA)] to trap the large excess of lithium bromide present at the beginning of the reaction. This catalytic asymmetric variant is illustrated by the reaction of the lithium enolate of 1-tetralone with a variety of electrophiles (eq 7). In this example, the optimal reaction conditions were determined to be 0.05 equiv of 1,2.0 equiv of TMPDA, and 10.0 equiv of the alkyl halide. 

Efficient enantioselective alkylations are known.In another method enantio-selective alkylation can be achieved by using a chiral base to form the enolate. Alternatively, a chiral auxiliary can be attached. Many auxiliaries are based on the use of chiral amides ° or esters.Subsequent formation of the enolate anion allows alkylation to proceed with high enantioselectivity. A subsequent step is... 

Enantioselective alkylation of amides. Two laboratories1 2 have used (S)-prolinol as the chiral auxiliary for a synthesis of chiral amides. Alkylation of the enolate of the amide 1 (prepared with LDA or t-butyllithium) proceeds with pronounced... 

Lectka and co-workers have simultaneously developed similar phosphine-transition metal catalysts for the same transformation [54a, 54b, 54c, 54d]. These researchers were interested in testing the reactivity of a-imino esters toward enol silane nucleophiles upon chelation with a late transition metal (Ag(I), Cu(I), Ni(II), and Pd(II)) as a means of substrate activation. This ultimately led to the development of a catalytic, enantioselective alkylation of a-imino esters with enol silanes in up to 98% ee and in high chemical yields (Scheme 28). 

Enantioselective Alkylation via Cyclopropanation of Silyl Enol Ethers... 

Reissig and coworkers have devised an indirect method of enantioselective alkylation of ketones via cyclopropanation of silyl enol ethers in the presence of the chiral copper catalyst 16, followed by ring opening to provide the substituted ketones. Overall, the transformation corresponds to alkylation of ketones using methyl diazoacetate as the electrophile. Enantioselectivities up to 88% were realized in the cyclopropanation of aryl substituted olefins, Eq. (20) [63,64]. 

Scheme 3.25. Enantioselective alkylation of lithium enolate/secondary amine/lithium bromide complexes by interligand asymmetric induction [148,149].

The enantioselective alkylation of A-protected a-amino esters has been studied with many chiral catalysts, including spirocyclic ammonium salt 10A, while (lOB) containing two binaphthyl components is an effective mediator for alkylation of protected glycine under phase-transfer conditions.p-f-Boc-amino acid derivatized with (-l-)-pseu-doephedrine enables enantioselective alkylation of the ensuing amides. - Note the enolate derived from 11 remains chiral, alkylation products are produced in high ee. ... 

Defined quaternary centers can also be constructed a to ketones, by enantioselective alkylation. Eric N. Jacobsen of Harvard University has found (J. Am. Cliem. Soc. 2005, 127, 62) that tin enolates work particularly well with his Cr salen catalyst. A variety of activated alkylation agents give high ee from the alkylation. It works well for 5-, 6- and 7-membered rings. 

The most common nucleophiles employed in the allylic alkylation are soft species such as malonate esters. However, Trost and Schroeder have discovered that high ees can be achieved in the addition of cyclic lithium enolates using ligand (10.54) with one equivalent of trimethyltin chloride, which may act to soften the nucleophilic species by transmetaUation to the tin enolate. Enantioselective additions of nonstabilised ketone enolates can also be achieved using an alternate palladium-catalysed decarboxylation protocol. In this approach an allyl 3-ketoester (10.72) or allyl vinyl carbonate (10.73) undergoes decarboxylation in the presence of Pd(0) to... 

Enolates with Chiral Auxiliaries. Enantioselective alkylation of carbonyl derivatives encompassing chiral auxiliaries constitutes an important synthetic process. The anions derived from aldehydes, acyclic ketones, and cyclic ketones with (S)-l-Amino-2-methoxymethylpyrrolidine (SAMP) are used to obtain alkylated products in good to excellent yields and high enan-tioselectivity (e.g. eq 21). ... 

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