Enamines chiral intermediates

The domino process probably involves the chiral enamine intermediate 2-817 formed by reaction of ketone 2-813 with 2-815. With regard to the subsequent cy-doaddition step of 2-817 with the Knoevenagel condensation product 2-816, it is interesting to note that only a normal Diels-Alder process operates with the 1,3-bu-tadiene moiety in 2-817 and not a hetero-Diels-Alder reaction with the 1-oxa-l,3-butadiene moiety in 2-816. The formed spirocydic ketones 2-818/2-819 can be used in natural products synthesis and in medidnal chemistry [410]. They have also been used in the preparation of exotic amino adds these were used to modify the physical properties and biological activities of peptides, peptidomimetics, and proteins... 

Fig. 2.5 Electronic and steric interactions in the approach of the electrophilic heteroatom (Het) to the nucleophilic carbon atom in the chiral enamine intermediate.

J0rgensen and Juhl reported the first organocatalytic enantioselective inverse-electron-demand hetero-Diels-Alder reaction of aldehydes (e.g., 71) and enones (e.g., 72) with excellent diastereo- and enantioselectivity. Scheme 3.26 [41], The reaction utilizes a chiral enamine intermediate as an alkene in catalytic asymmetric cycloaddition reactions. 

It is proposed that efficient shielding of the 5t-face of the chiral iminium intermediate by the bulky aryl groups of the catalyst leads to a stereoselective Re-facial nucleophilic conjugate attack on the electrophilic P-carbon by the amino group of 163 (Scheme 1.70). Then the chiral enamine intermediate generated performs a 3-exo-tet nucleophilic attack on the now electrophilic nitrogen atom, and acetic acid is released. The intramolecular ring closure pushes the equilibrium in the forward direction and makes this step irreversible. 

Abstract The reversible reaction of primary or secondary amines with enolizable aldehydes or ketones affords nncleophilic intermediates, enamines. With chiral amines, catalytic enantioselective reactions via enamine intermediates become possible. In this review, structure-activity relationships and the scope as well as cnrrent limitations of enamine catalysis are discnssed. 

The highly enantioselective direct conjugate addition of ketones to nitroalkenes has been promoted by a chiral primary amine-thiourea catalyst (7).31 The observed anti diastereoselectivity has suggested participation of a (Z)-enamine intermediate, given (g) the complementary diastereoselectivity obtained in analogous reactions involving (E)-enamines generated from secondary amine catalysts. 

Chiral amines (both primary and secondary amines) and amino acids have been used as catalysts for aldol reactions, Mannich-type reactions, and other reactions that proceed through enamine intermediates. An enamine-based catalytic cycle is shown in Scheme 2.1. The catalytic cycle includes formation of an iminium intermediate between a donor carbonyl compound and the amine-containing catalyst, the formation of an enamine intermediate from the iminium, C-C bond forma-... 

The direct activation and transformation of a C-H bond adjacent to a carbonyl group into a C-Het bond can take place via a variety of mechanisms, depending on the organocatalyst applied. When secondary amines are used as the catalyst, the first step is the formation of an enamine intermediate, as presented in the mechanism as outlined in Scheme 2.25. The enamine is formed by reaction of the carbonyl compound with the amine, leading to an iminium intermediate, which is then converted to the enamine intermediate by cleavage of the C-H bond. This enamine has a nucleophilic carbon atom which reacts with the electrophilic heteroatom, leading to formation of the new C-Het bond. The optically active product and the chiral amine are released after hydrolysis. 

Using chirally tritiated samples of the protoberberine (67) it has been established that hydroxylation of (67) to give (68) occurs with loss of the 13-pro-R hydrogen atom, i.e. normal retention of configuration, and does not involve an enamine intermediate since tritium is not lost from C-14 during the course of this biotransformation.62 It is to be noted that similar results, associated with C-13, have been observed61 for narcotine (63) and chelidonine (62) biosynthesis, except that here the 13-pro-S proton is removed. 

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... 

Suitable enamines can react with (ethoxycarbonyl)nitrene, generated from ethyl 7V-(4-nitrophenylsulphoxy)carbamate, giving relatively unstable aziridines103. Diaster-eoselective attack of this nitrene on the double bond of chiral enamine 98 and opening of the intermediate aziridine (197) afforded enantiomerically enriched 2-ethoxycarbony-laminocyclohexanone 198104,105 (equation 42). 

B. Chiral Synthesis with Enzymes that Utilize Enamines Intermediates. . 1295... 

The process mechanism as shown in Figure 2.23 consists of an initial activation of the aldehyde (66) by the catalyst [(5)-67] with the formation of the corresponding chiral enamine, which then, selectively, adds to nitroalkene (65) in a Michael-type reaction. The following hydrolysis liberates the catalyst, which forms the iminium ion of the a,(3-unsaturated aldehyde (62) to accomplish the conjugate addition with the nitroalkane A. In the third step, another enamine activation of the intermediate B leads to an intramolecular aldol condensation via C. Finally, the hydrolysis of it returns the catalyst and releases the desired chiral tetra-substituted cyclohexene carbaldehyde (68). 

The Aldol reaction is one of the most powerful methods for creating the C-C bond. Typical conditions involve the formation of an enolate, usually with a stoichiometric equivalent of base. Stereoinduction is nsnally accomplished with chiral enolates, aldehydes, or auxiliaries.Nature, however, is much more efficient, having created enzymes that both catalyze the aldol reaction and produce stereospecific product. These enzymes, called aldolases, are of two types. The type II aldolases make use of a zinc enolate. Of interest for this section are the type I aldolases, which make use of enamine intermediates. Sketched in Scheme 6.6 is... 

The intermediate in this reaction could be either the prostereogenic enolate or the chiral enamine formed in situ. In an attempt to distinguish between these pathways, the chiral enamine prepared from methyl (S)-prolinate was allowed to react with methyl A-phenylseleno-(S)-prolinate. The isolated 2-phenyl-2-phenylselenopropanal had the same enantiomeric excess as that obtained in the direct a-selenenylation of racemic 2-phenylpropanal. This result clearly indicates that the intermediacy of the chiral enamine cannot be excluded7. 

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%. 

We (Novartis) reported ] an enantioselective synthesis of (2S,2 71)- zyf/iro-methylphenidate (3) utilizing Evans (S)-4-benzyl-2-oxazolidinone chiral auxiliary to control the diastereofacial selectivity in the hydrogenation of enamine intermediate (65 Scheme 16). Acylation of (S)-4-benzyl-V-phenylace-tyl-2-oxazolidinone (61) with the mixed anhydride 63, followed by deprotection of the V-Boc group with TFA, and neutralization of the reaction mixture with NaHCOs afforded the enamine intermediate 65. Hydrogenation of enamine 65 with 10% Pd-C in ethyl acetate furnished 66 in 95% yield with an excellent diastereoselectivity (97 5). Treatment of 66 with methanol in the presence of EnR afforded the desired... 

Enamines react with ethoxycarbonylnitrene to give N-substituted a-amino ketones via an aziridine intermediate (Scheme 186). Using chiral enamines the a-amino ketone can be obtained in relatively high optical yield (77% ee) but low chemical yield... 

Tandem conjugate addition ofenolates and aldol reactions Tandem conjugate addition of chiral amines and aldol reactions Part III - Intermediate is an Unstable Imine or Enamine Intermediate Would Be Formed by Amide Condensation... 

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