Chiral enamines alkylation

Chiral enamines prepared from /f-oxo esters and the tcrt-butyl ester of (.V)-valine are lithiated by LDA (—78 °C, toluene or THF, 1 h)18 19. Both enantiomers of the alkylation product are obtained with a high degree of diastercoselectivity starting from one auxiliary when the reaction is performed under the addition of different ligands (see Table 6). Addition of one equivalent of hexamethylphosphoric triamide (1IMPA) causes coordination of the lithium atom and alkylation from the top side18. 

Simple alkylation of the chiral chelate complex leads to formation of chiral dialkylacetic acids (Scheme 109).3S5 388 Simpler chiral enamines can also be used. The formation of chiral propanoic acids results from a resolution of racemic alkyl halides by the interaction of a chiral lithiooxazoline, which recognizes and reacts with one enantiomer at the expense of the other (Scheme 110).389 The above aspects of the asymmetric carbon—carbon bond formation from chiral oxazolines have been reviewed by Meyers.390... 

The alkylation of the chiral enamine (172) by 3-nitrostyrenes gives diastereomerically pure Michael adducts (173) with high ee (Scheme 62).182 Comparable selectivities were observed with a-(methoxycar-bonyl)cinnamates as substrates.183 The same method was used for the enantioselective alkylation of -tetralones in the 3-position by p-nitrostyrenes.184... 

The final modes of enantioselective allyl alkylations catalyzed by palladium involve the use of chiral nucleophiles447 and chiral leaving groups.448-449 Chiral enamines were found to undergo allylation in 100% optical yield in an intramolecular case and in up to 50% optical yield in intermolecular reactions (equation 358). 

Nicewicz and MacMillan merged later photoredox catalysis and asymmetric organocatalysis to an efficient approach to the otherwise difficult asymmetric a-alkylation of aldehydes 118 by activated alkyl bromides 117 (Fig. 30) [183]. The concept of face differentiation at the a-position of aldehydes via chiral enamines 121 provides the basis for the method. This allows the formation of functionalized... 

The process of enamine alkylation has found widespread application in natural product synthesis188. Since the overall sequence involves the reaction of a nitrogen moiety with a ketone to form a reactive intermediate, modification of the process through the use of chiral enamine seemed ideal for asymmetric induction. Previous attempts to obtain stereochemical control were for a long time unsuccessful, because proper attention had not been directed to the involvement of two reactive conformations, interconvertible... 

In 1969 Yamada and coworkers reported the first in a series of investigations on the alkylation of chiral enamines, derived from L-proline esters, with methyl acrylate and acrylonitrile170. The enamines were prepared under the usual azeotropic conditions but were not distilled since this resulted in cyclization, by nucleophilic attack of the enamine on the ester function, or partial racemization171. Optical yields were found to be... 

The use of a chiral enamine (81) derived from ( )-2-methoxymethylpyrrolidine and an achiral ester (78 R = Me) again resulted in complete anti-diastereoselectivity and an enantiomeric excess in favour of 80 (R = Me) of 85%. A chiral enamine moiety was hence shown to have a stronger influence on the asymmetric induction compared to a chiral ester group174. To obtain maximum effect the concept of double stereodifferentiation175 was employed. That is, the chiral enamine (81 X = CH2, S) was alkylated with a chiral ester [78 R = ( + )-menthyl]. In this case the reaction proceeded with complete diastereoselectivity and complete enantioselectivity (de = ee 99.9%), and gave the pure products (l S, 2R)-80 [R = ( — )-menthyl, X = CH2] and (l R, 2R)-80 [R = ( + )-men-thyl, X = S] in quantitative yield174. 

The reaction of chiral enamine 81 (X = CH2) with / -nitrostyrenes has also been investigated by Seebach and coworkers118". Only one of the four possible enantiomeric-ally pure diastereomers was formed and a-alkylated cyclohexanones were obtained in 90% or greater optical purity (Scheme 73). Their configuration was deduced as (l R, 2S) by chemical methods and X-ray analysis. 

The chiral enamine (84) has been shown to react with / -nitrostyrenes to give a mixture of mainly the 3- together with some of the 1-alkylated tetralone on hydrolysis. The main product (85) was shown to be greater than 90% diasteromerically pure and of 75-99% optical purity, and to have the (l R, 3 S)-configuration118ft (Scheme 74). 

An enantioselective radical substitition (termed SOMO activation ) involving pyrroles has been reported <07SCI582>. For example, treatment of pyrrole 58 with octanal 59 and chiral amine 60 in the presence of CAN gave chiral 2-alkylated pyrrole 61. The mechanism included the formation of an enamine radical. A radical alkylation of 3-substituted pyrroles with xanthates produced 2,3-disubstituted pyrroles regioselectively <07TL4515>. 

Asymmetric alkylation of a-alkyl-P-keto esters. The sense of asymmetric alkylation of the chiral enamines prepared from (S)-valine /-butyl ester with a-alkyl-P-keto esters is markedly controlled by the solvent. Thus alkylation of the anion 1, prepared with LDA in toluene, with CH,I in the presence of HMPT (1 equiv.) results in (R)-2 in 99% ee, whereas alkylation in THF (2 equiv.) results in (S)-2 in 92% ee. The effect of HMPT is general for a variety of electrophiles depending on the electrophile, dioxolane... 

Alkylations and Allylations. The asymmetric alkylation of chiral enamines derived from (S)-proline esters has been disclosed. The a-alkylation of cyclohexanone proceeds with an optical purity of 59%. (5)-Proline catalyzes the alkylation of xanthopurpurin (34) by 2-hydroxytetrahydropyran yielding... 

When the nitrogen of the substrate contains a chiral R group, both the Stork enamine synthesis and the enamine salt method can be used to perform enantiose-lective syntheses. The use of A-proline can generate a chiral enamine in situ, thus allowing alkylation to occur, giving alkylated product with good enantioselec-tivity,. The reaction has been done intramolecularly. ... 

Chiral enamines may be prepared by condensation of ketones with enantioenriched 5ec-amines. The C2-symmetric rran5-2,5-dimethylpyrrolidine is a frequently used chiral auxiliary for the preparation of enantiomeric enamines. Alkylation of chiral enamines followed by hydrolysis is an effective method for the enantioselective alkylation of ketones. ... 

Alkylation of aldehydes with enol silyl ethers is accomplished on oxidation of the latter species with CAN. By forming chiral enamines from the aldehydes and the imidazolidinone 20 in situ the reaction furnishes optically active products. ... 

In the light of highly successful results with the alkylation of hydrazones, attention has been focussed upon the potential of chiral enamines. Excellent yields of chiral -[2-(trimethylsilyl-... 

Hiemstra (2007) eliminated the competing enamine alkylation pathway by cyclization of unsubstituted A -tritylsulfenyltryptamines 173 with aliphatic and aromatic aldehydes (RiCHO) in the presence (20 mol %) of a related chiral phosphoric Brensted acid catalyst The yields (70-... 

Metallation and alkylation of chiral enamines (15) lead to 2-alkylcycloalk-anones with high enantiomeric purity (Scheme 39). The basis for the efficient enantioselective alkylation rests with the rigidity of the lithioenamine induced... 

The acceptor properties of nitro-alkenes are well known and have been utilised for the asymmetric synthesis of a-alkylated cyclohexanones via Michael addition of chiral enamines to (3-nitro-styrenes, the conjugate addition of... 

Conversion of a ketone into the corresponding chiral hydrazone derivative (19) enables alkylation to beachieved with high (<87%)enantioselectivity (Scheme 24). Even more impressive, enantioselective alkylations are observed when the chiral enamine (18) is metalated and treated with alkyl halide. ... 

There are many more enantioselective processes in which optically active products are obtained by the use of an optically active reagent, which can subsequently be recovered. For example, ketones can be converted to enamines or imines using chiral amines. Alkylation gives optically active ketone and the amine can be recovered after the normal hydrolytic workup. Table 11.2 records some examples of amines which have been used and the level of enantiomeric excess which has been achieved. Section 1.9 can be consulted for a review of the mechanism of these alkylation reactions. 

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