Asymmetric enamine formation

The synthesis of menthol is given in the reaction scheme, Figure 5. 6. The key reaction [2] is the enantioselective isomerisation of the allylamine to the asymmetric enamine. It is proposed that this reaction proceeds via an allylic intermediate, but it is not known whether the allyl formation is accompanied by a base-mediated proton abstraction or hydride formation. 

C-Nucleophiles have recently been added asymmetrically to azodicarboxylates as Michael-acceptors, resulting in a-amination of the nucleophilic component. Examples of this type of reaction, which is based on activation of the aldehyde or ketone component by enamine formation, are summarized in Scheme 4.27. Please note that this type of reaction is covered in more detail in chapter 7 of this book. 

Small chiral organic molecules may catalyze the asymmetric addition of ketones, and aldehydes to electron-deficient olefins, such as vinylidene acetones, nitroole-fins, enones, and vinyl sulfones. In this chapter we will describe the inter- and intramolecular reactions in which activation of the carbonyl compound takes place via enamine formation. 

Proline was among the first compounds to be tested in asymmetric conjugated reactions, both as a chiral ligand [8] and also as an organic catalyst [3]. The earliest asymmetric intermolecular Michael-type addition, in which proline catalyzed the reaction (arguably via enamine formation) was reported by Barbas and colleagues [9, 10] and by List and co-workers [11]. The reaction, which proceeded in high chemical yield (85-97%) and diastereoselectivity, albeit afforded near-racemic products in dimethyl sulfoxide (DMSO) [11] (Scheme 2.37). The enantio-selectivity of the addition was later ameliorated by Enders, who demonstrated that a small amount of methanol rather than DMSO was beneficial to the enantiose-lectivity of the addition reaction [12]. 

The deprotonation of an iminium ion (formula A in Figure 7.27) to give an enam-ine is reversible under the usual reaction conditions. Therefore, the most stable enam-ine possible is produced preferentially. Figure 7.28 emphasizes this using the example of an enamine formation from a-methylcyclohexanone (i.e., from an asymmetrical ketone). The enamine with the trisubstituted double bond is produced regioselectively and not the enamine with the tetrasubstituted double bond. Since the stability of olefins usually increases with an increasing degree of alkylation, this result is at first... 

The 3-component condensation for synthesis of 3-acy 1-4-ary 1-1,4-dihydropyridines from amines, (3-dicarbonyl compounds and enals proceeds from enamine formation, Michael reaction and cyclodehydration is amenable to asymmetric induction, such as using ent-octahydro-lB. ... 

An alternative and useful method for intramolecular conjugate addition when the Michael donor is a ketone is the formation of an enamine and its reaction with a Michael acceptor. This can be advantageous as enamine formation occurs under reversible conditions to allow the formation of the product of greatest thermodynamic stability. Treatment of the ketone 40 with pyrrolidine and acetic acid leads to the bicyclic product 41, formed by reaction of only one of the two possible regio-isomeric enamines (1.51). Such reactions can be carried out with less than one equivalent of the secondary amine and have recently been termed organo-catalysis (as opposed to Lewis acid catalysis with a metal salt). The use of chiral secondary amines can promote asymmetric induction (see Section 1.1.4). 

The scope of this chapter does not allow nor attempt a comprehensive account of all developed processes to date. A detailed summary, in particular of aldol, Mannich, or ot-functionalisation reactions, can be found in excellent reviews written on the topic." Barbas and List reported an asymmetric, direct, intermolecular aldol reaction of acetones and aldehydes (Scheme 5.4), presumably via enamine formation of proline and acetone. As compared to its metal-catalysed alternatives, no preformation of the respective enolate is required, a mode of action that mimics metal-free aldolase enzymes. ... 

In the previons section, secondary chiral amines were employed that give rise to enamine formation npon reaction with ketones or aldehydes. Chiral tertiary amines, unable to form enamines, are nevertheless capable of inducing enantioselectivity in case substrates are used that contain sufficiently acidic protons such as aldehydes, ketones or active methylene compounds [33]. The cinchona alkaloids, by far the most versatile source of Brpnsted base catalysts, have played a prominent role in various types of asymmetric organocatalytic reactions [34], which is also true for the Mannich reaction. 

The cross-aldol reaction between two aldehydes is a very difficult transformation. Since ahphatic aldehydes can act both as nucleophiles and as electrophiles, a successful cross-reaction requires two aldehydes with a significant difference in the rate of enamine formation (Scheme 3.20). (3-Hydroxy-aldehydes can be easily synthesized in an amine-catalyzed direct asymmetric cross-aldol reaction between two aldehydes only when one enolizable aldehyde is used and self-aldolization is somehow prevented. 

Retrosynthetically, the syntheses of both compounds build on the iridoid 264 as the key intermediate. The required cw-bicyclic skeleton was obtained successfully starting from the (-)-citronellol-derived aldehyde 265. First, an asymmetric enamine-activated a-oxygenation catalyzed by (7 )-proline (70) followed by a Homer-Wadsworth-Emmons (HWE) olefmation gave compound 267. Redox state manipulations and O-protection then result in the formation of the... 

Chiral imidazolidin-4-ones-chiral secondary amines-had already been successfully used in asymmetric synthesis before they started their own career as organo-catalysts [1]. They were deployed as chiral auxiliaries for alkylation processes [2], Michael additions [3], and aldol reactions [4], For syntheses of this class of catalyst see Reference [5]. The ability to activate both carbonyl compounds by enamine formation as well a, 3-unsaturated carbonyl compounds by intermediate formation of iminium ions makes imidazolidin-4-ones a valuable class of organocatalysts in both series. Thus, they can roughly be divided by their mode of activation into enamine [6] or iminium [7] catalysis (Scheme 4.1). These catalysts were successfully deployed in a wide range of several important enantioselective C-C bond formation and functionalization processes. Figure 4.1 shows the chiral imidazo-lidinones covered in this chapter. 

Class 1 aldolase mimics consist of amino acid catalysts that presumably activate the donor via enamine formation and the acceptor through a hydrogen bond with an acid functionality. Repotted hrst by Wiechert et al. and then by Hajos and Parrish,-proline was found to catalyze intramolecular asymmetric aldol reactions. However, the... 

Several methods for asymmetric C —C bond formation have been developed based on the 1,4-addition of chiral nonracemic azaenolates derived from optically active imines or enamines. These methods are closely related to the Enders and Schollkopf procedures. A notable advantage of all these methods is the ready removal of the auxiliary group. Two types of auxiliaries were generally used to prepare the Michael donor chiral ketones, such as camphor or 2-hydroxy-3-pinanone chiral amines, in particular 1-phenylethanamine, and amino alcohol and amino acid derivatives. 

Chapter 2 to 6 have introduced a variety of reactions such as asymmetric C-C bond formations (Chapters 2, 3, and 5), asymmetric oxidation reactions (Chapter 4), and asymmetric reduction reactions (Chapter 6). Such asymmetric reactions have been applied in several industrial processes, such as the asymmetric synthesis of l-DOPA, a drug for the treatment of Parkinson s disease, via Rh(DIPAMP)-catalyzed hydrogenation (Monsanto) the asymmetric synthesis of the cyclopropane component of cilastatin using a copper complex-catalyzed asymmetric cyclopropanation reaction (Sumitomo) and the industrial synthesis of menthol and citronellal through asymmetric isomerization of enamines and asymmetric hydrogenation reactions (Takasago). Now, the side chain of taxol can also be synthesized by several asymmetric approaches. 

Mechanistically, the Brpnsted acid-catalyzed cascade hydrogenation of quinolines presumably proceeds via the formation of quinolinium ion 56 and subsequent 1,4-hydride addition (step 1) to afford enamine 57. Protonation (step 2) of the latter (57) followed by 1,2-hydride addition (step 3) to the intermediate iminium ion 58 yields tetrahydroquinolines 59 (Scheme 21). In the case of 2-substituted precursors enantioselectivity is induced by an asymmetric hydride transfer (step 3), whereas for 3-substituted ones asymmetric induction is achieved by an enantioselective proton transfer (step 2). 

The stereoselective or stereospecific formation of these compounds and their interaction with butyllithium was studied with the help of NMR. Paquette and Freeman first applied asymmetric induction to the synthesis of four-membered rings, especially with the sulfene-enamine 2 -F 2 cycloaddition. The in situ generation of sulfene 68 by dehydrochlorination with butyllithium of the sulfonyl chloride allowed the formation of cycloadduct 69 in 88 % yield. In a variation, the sulfene may be generated by base-induced... 

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... 

Sawyer and Wibberley5 demonstrated that the product obtained by Singh et al.i2 in the reaction of 2-amino-4-methylpyridine and acetylacetone in polyphosphoric acid was not the naphthyridine but was instead the enamine of type 5, which was formed by hydrolysis of the pyrido[l,2-a]pyrimidinium salt (6) when the reaction mixture was neutralized. Formation of both isomeric pyrido[l,2-c<]pyrimidinium salts with asymmetric 1,3-diketones (R1 R2) was occasionally observed.3... 

The Zr-catalyzed asymmetric alkylation shown in Eq. (2) [8] illustrates two important principles (1) The catalytic asymmetric protocol can be readily applied to the synthesis of non-aryl imines to generate homochiral amines that cannot be prepared by any of the alternative imine or enamine hydrogenation protocols. (2) The catalytic amine synthesis involves a three-component process that includes the in situ formation of the imine substrate, followed by its asymmetric alkylation. This strategy can also be readily applied to the preparation of arylamines. The three-component enantioselective amine synthesis suggests that such a procedure maybe used to synthesize libraries of homochiral amines in a highly efficient and convenient fashion. 

The basicity of the amine nitrogen appears to be an important factor for an effective asymmetric induction. Phenyl substituents on the nitrogen atom greatly retard the reaction rate. Thus, /V-phenyl- and IV.lV-diphenylgeranylamine are inert at 40°C and 24 h reaction time. Few characteristic features are worth noting. If an allylamine is secondary, the product is the corresponding imine, a more stable valence tautomer of the enamine, which cannot be detected in the reaction mixture. The exclusive formation of an ( )-enamine regardless of the double-... 

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