Chiral enamine asymmetric

The modification of chiral enamines enables the asymmetric nitro-olefination of oxyin-doles, as shown in Eq. 4.98.124 An enantioselective synthesis of (-)-psudophyrnaminol is accomplished using this reaction. 

Node and Fuji have developed a new chiral synthesis of various alkaloids using chiral nitroalkene, (S)-(-)-2-methyl-2-(2 -nitrovinyl)-S-valerolactone. Scheme 8.11 shows a total synthesis of (-)-physostigmine, a principal alkaloid of the Calabar bean.53 The key nitroalkene is prepared by asymmetric nitroolefination of a-methyl-8-lactone using a chiral enamine (see... 

Upon irradiation with ultraviolet light Fischer chromium-carbene complexes 16 react as if they were ketenes, although evidence for the generation of free ketenes has not been observed (see Section 1.4.2.). Photocycloadditions of these complexes onto chiral enamines show significant asymmetric induction.22... 

Asymmetric allylation.n The chiral enamine 1, derived from the allyl ester of (S)-proline, when treated with this Pd(0) complex at 25° in various solvents provides (S)-( — )-2-allylcyclohexanone (2) in 80-100% ee, the highest enantio-selectivity being observed in CHC13. 

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... 

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... 

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. 

Chiral enamine derivatives have also been used as electron-rich alkenes. The oxazoline derivative 17 reacted with benzaldehyde to yield the two stereoiso-meric oxetanes 18a and 18b with a diastereomeric excess of 67% (Scheme 5) [12]. A significantly higher diastereoselectivity was observed in the case of the reaction of the pyrrolidine derivatives 19 where the enamine function is localized inside the five membered ring [13]. Then the oxetane 20a (R — n-Cgil g) was used in an asymmetric synthesis of the antifungal alkaloid (+ )-preussin. The approach of the 3n,7T excited ketone preferentially occurred syn with respect to... 

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... 

The stereoselective allylation of aldehydes was reported to proceed with allyltrifluorosilanes in the presence of (S)-proline. The reaction involves pentacoordinate silicate intermediates. Optical yields up to 30% are achieved in the copper-catalyzed ally lie ace-toxylation of cyclohexene with (S)-proline as a chiral ligand. The intramolecular asymmetric palladium-catalyzed allylation of aldehydes, including allylating functionality in the molecules, via chiral enamines prepared from (5)-proline esters has been reported (eq 15). The most promising result was reached with the (S)-proline allyl ester derivative (36). Upon treatment with Tetrakis(triphenylphosphine)palladium(0) and PPh3 in THF, the chiral enamine (36) undergoes an intramolecular allylation to afford an a-allyl hemiacetal (37). After an oxidation step the optically active lactones (38) with up to 84% ee were isolated in high chemical yields. The same authors have also reported sucessful palladium-catalyzed asymmetric allylations of chiral allylic (S)-proline ester enamines" and amides with enantiomeric excesses up to 100%. 

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... 

Two representative organocatalytic reaction systems can be considered for nucleophilic a-substitution of carbonyl compounds, the issue of this chapter. One involves the in situ formation of a chiral enamine through covalent bond between organo-catalyst (mainly a chiral secondary amine such as proline) and substrate (mainly an aldehyde), followed by asymmetric formation of new bond between the a-carbon of carbonyl compound and electrophile. Detachment of organocatalyst provides optically active a-substituted carbonyl compound, and the free organocatalyst then participates in another catalytic cycle (Figure 6.1a) [2]. 

Optically active aldehydes are desirable synthetic precursors for the construction of chiral carbon skeltones in organic synthesis. Several methods had been devised for the synthesis of optically active aldehydes employing chiral enamines chiral imines or chiral hydrazone however, little was known about the asymmetric synthesis of chiral aldehyde having a functional group in the same molecule... 

Asymmetric induction has been observed in some of these cycloaddition reactions with the use of chiral enamines ". For example, reaction of L-proline derived enamines (e.g. 95) with methyl vinyl ketone (equation 17) afforded, after hydrolysis, chiral cyclohexenones (e.g. 96) with optical yields up to 50%. ... 

High asymmetric induction was reported in the cycloaddition of 2-sulfonyldienes with chiral enamines. For example, reaction of 2-phenylsulfonyl-l,3-pentadiene (146) with enamine I47 leads to adduct 148 as only one diastereoisomer (equation 29) for which the absolute stereochemistry was determined by X-ray diffraction. 

Stork and coworkers [624e] have introduced enamines as a nucleophilic substitute of enols, and a few asymmetric aldol reactions have been performed with enamines. Scolastico and coworkers [1311] have reacted morpholine enamines with chiral oxazolidine 1.84 (EWG = Ts), and in some cases they obtained higher sdectivities than those obtained from enoxysilanes ( 6.9.3) (Figure 6.102). Chiral enamines derived from pyrrolidine 1.64 (R = MeOCI ) react with acyliminoesters of chiral alcohols at -100°C [1313], Double diastereodifferentiation is at work so that from matched reagents, for example the pyrrolidine enamine and iminoester 6.126 shown in Figure 6.102, P-keto-a-aminoesters are obtained with a high diastereo- and enantioselectivity. The esters of either enantiomer of menthol or of achiral alcohols give mediocre asymmetric induction. 

As chiral auxiliary. Asymmetric Michael addition of -keto esters is achievable via the chiral enamines. The stereoselectivity is dependent on solvent and additives. 

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