Alkylations chiral bases

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

The diastereomers 251/ewf-251 and 252/ent-252 could be separated and were decom-plexed separately. From the fraction of 251/ewt-251,253 was obtained with 85% ee (e.r. = 92.5 7.5), and the fraction of 252/ent-252 yielded ewt-253 with 88% ee (e.r. = 6 94). A similar situation results from the reaction with tributyltin chloride or alkylation reagents, but the diastereomeric ratio is strongly dependent on the electrophile. The following conclusion is drawn from these and further experiments The enantiomeric ratio is determined by a selection of the chiral base between the diastereotopic methylene groups, since the benzylic carbanionic centres are labile, whereas the diastereomeric ratio results from the relative rate of the electrophile approach syn or anti with respect to the A-methyl group. One question remains—why are opposite d.r. values formed in the alkylation by methyl iodide and ethyl iodide ... 

Alkylation of Enolates Obtained by Deprotonation with a Chiral Base... 

Substituted 3,6-dialkoxy-2,5-dihydropyrazines are regioselectively metalated by strong alkyl-lithium bases, such as butyllithium, (l-methylpropyl)lithium, fcrf-butyllithium, or lithium diiso-propylamide, at the less substituted carbon atom (C5). Metalation proceeds at low temperatures (in general, below — 70 C) in THF as solvent. Electrophiles suitable for alkylation of the lithiated derivatives include alkyl iodides, bromides and chlorides, as well as alkyl methanesulfonates, 4-methylbenzenesulfonates and trifluoromethanesulfonates. The electrophile adds trans to the substituent at C2 in a highly stereoselective fashion, with typical diastereomeric excesses of greater than 90% (syn addition has been reported in only one case where a-methylphenyl alanine was used as chiral auxiliary and an alkyl trifluoromethanesulfonate as electrophile18). 

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... 

Recent advances include the use of new chiral bases, extention to substrates other than ketones, and trapping with electrophiles other than silylating reagents and aldehydes. Regarding alternate substrates and electrophiles, the Simpkins group reported alkylation of a prochiral diester with common alkyl halides with >98% ee [46]. Simpkins and coworkers have also demonstrated desym-metrization of cyclic imides, in this case with trapping by silyl groups [47]. 

Examination of Scheme 27 (22 total chiral auxiliaries employed) indicates that aryl chiral auxiliaries (as in 42) are more effective than alkyl chiral auxiliaries (as in 43) within zeolites. Replacing the phenyl part in 42 by the cyclohexyl moiety as in 43 had a dramatic effect on the observed stereoselectivity. The diastereoselectivity dropped from 80% to 29% in LiY. Replacing the phenyl group by the naphthyl group (44 another aryl chiral auxiliary) gave 70% de in LiY. Aryl chiral auxiliaries, 45 and 46 based on aminoalcohols gave 60% and 89% de, respectively. 

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). 

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... 

Keywords Phase transfer. Chiral ligand. Chiral base, Allylic alkylation. Cinchonine, Enolate alkylation. Asymmetric deprotonation. Asymmetric arylation. Radical alkylation... 

Alkylations of lithium enolates of ketones in the presence of chiral bases has been widely studied [77, 559, 1008], but disappointing results were often obtained. However, Koga and coworkers performed asymmetric alkylations of cyclohexanone and tetralone lithium enolates in toluene at low temperatures [108, 1017]. The enolates are generated from the Li amide of chiral diamine 2.4 (X = CH2. R = MeOCH2CH2OCH2CH2). The presence of LiBr is essential to observe a high enantioselectivity (Figure 5.8), and the involvment of mixed aggregates is implied. 

Chiral bases are also used in asymmetrical synthesis. An alkylation is shown in 10.57.132... 

The. V-alkylation of ephedrine is a convenient method for obtaining tertiary amines which are useful as catalysts, e.g., for enantioselective addition of zinc alkyls to carbonyl compounds (Section D. 1.3.1.4.), and as molybdenum complexes for enantioselective epoxidation of allylic alcohols (Section D.4.5.2.2.). As the lithium salts, they are used as chiral bases, and in the free form for the enantioselective protonation of enolates (Section D.2.I.). As auxiliaries, such tertiary amines were used for electrophilic amination (Section D.7.I.), and carbanionic reactions, e.g., Michael additions (Sections D. 1.5.2.1. and D.1.5.2.4.). For the introduction of simple jV-substituents (CH3, F.t, I-Pr, Pretc.), reductive amination of the corresponding carbonyl compounds with Raney nickel is the method of choice13. For /V-substituents containing further functional groups, e.g., 6 and 7, direct alkylations of ephedrine and pseudoephedrine have both been applied14,15. 

Usually, stirring the alkyl carbamate with 1.5 equiv. of the chiral base in diethyl ether, toluene or pentane at -78°C for 4 to 6 h gives the best results. THF is suitable only for non-enantioselective deprotonations, since it displaces (-)-sparteine at lithium [87]. The mechanistic features are discussed in Sect. 2.5.2. In order to demonstrate the scope of the reaction, a number of representative examples are collected in Eq. (40). A fair number of electrophiles have been introduced. 

The Michael reaction of 2-alkyl substituted 1,3-diketones with alkynones has been carried out by Jnrgensen using chiral base 124a as the most efficient catalyst (Scheme 6.14). Importantly, this reaction not only generates a quaternary stereocenter but also delivers a highly functionalized final product containing an a,p-unsaturated ketone side chain, suitable for further... 

Two other alkylations were based on readily-available chiral auxiharies. PhUippe Karoyan of the Universite Pierre et Marie Curie observed Tetrahedron Lett. 2008, 49, 4704) that the acylated Oppolzer camphor sultam 20 condensed with the Mannich reagent 21 to give 22 as a single diastereomer. Andrew G. Myers of Harvard University developed the pseudoephedrine chiral auxiliary of 23 to direct the construction of ternary alkylated centers. He has now established J. Am. Chem. Soc. 2008,130, 13231) that further alkylation gave 24, having a quaternary alkylated center, in high diastereomeric excess. 

Ando A, Shioiri T. Asymmetric synthesis using chiral bases— enantioselective a-alkylation of carboxylic acids. Chem. Commun. 1987 656-658. 

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