Enantioselective enols/enolates/enamines

When either or both of the reaction components has a chiral substituent, the reaction can be enantioselective (only one of the four diastereomers formed predominantly), and this has been accomplished a number of times. Enantioselective addition has also been achieved by the use of a chiral catalyst and by using optically active enamines instead of enolates. Chiral imines have also been used. ... 

The optically active Schiff bases containing intramolecular hydrogen bonds are of major interest because of their use as ligands for complexes employed as catalysts in enantioselective reactions or model compounds in studies of enzymatic reactions. In the studies of intramolecularly hydrogen bonded Schiff bases, the NMR spectroscopy is widely used and allows detection of the presence of proton transfer equilibrium and determination of the mole fraction of tautomers [21]. Literature gives a few names of tautomers in equilibrium. The OH-tautomer has been also known as OH-, enol- or imine-form, while NH tautomer as NH-, keto-, enamine-, or proton-transferred form. More detail information concerning the application of NMR spectroscopy for investigation of proton transfer equilibrium in Schiff bases is presented in reviews.42-44... 

Much like the enol systems discussed in Sect. 6.1, enamines are predictably difficult substrates for most iridium asymmetric hydrogenation catalysts. Both substrate and product contain basic functionahties which may act as inhibitors to the catalyst. Extended aromatic enamines such as indoles may be even more difficult substrates for asymmetric hydrogenation with an additional energetic barrier to overcome. Initial reports by Andersson indicated a very difficult reaction indeed (Table 14) [75]. Higher enantioselectivities were later reported by Baeza and Pfaltz (Table 14) [76]. 

Unstabilized enolates react with allylic carbonates in the presence of metalacyclic iridium-phosphoramidite catalysts. Although ketones and aldehydes have not yet been used directly as pronucleophiles with this catalyst system, silyl enol ethers [80] and enamines [81] react with linear allylic carbonates to form, after workup, p-branched, y-8 unsaturated ketones (Scheme 13). Both methods form products in high yield, branched selectivity, and enantioselectivity for a range of cinnamyl and alkyl-substituted allylic carbonates. However, the silyl enol ethers derived from aliphatic ketones reacted in lower yields than enamines derived from the same ketones. 

Enantioselective -Functionalization of Aldehydes and Ketones The direct and enantiosective functionalization of enolates or enolate equivalents with carbon-, nitrogen-, oxygen-, sulfur- or halogen-centered electrophiles represents a powerful transformation of chemical synthesis and of fundamental importance to modem practitioners of asymmetric molecule constmction. Independent studies from List, J0rgensen, Cordova, Hayashi, and MacMiUan have demonstrated the power of enamine catalysis, developing catalytic enantioselective reactions such as... 

Enamines, reaction with quinones, 20, 3 Enantioselective aldol reactions, 67, 1 allylation and crotylation, 73, 1 Ene reaction, in photosensitized oxygenation, 20, 2 Enolates ... 

List gave the first examples of the proline-catalyzed direct asymmetric three-component Mannich reactions of ketones, aldehydes, and amines (Scheme 14) [35], This was the first organocatalytic asymmetric Mannich reaction. These reactions do not require enolate equivalents or preformed imine equivalent. Both a-substituted and a-unsubstituted aldehydes gave the corresponding p-amino ketones 40 in good to excellent yield and with enantiomeric excesses up to 91%. The aldol addition and condensation products were observed as side products in this reaction. The application of their reaction to the highly enantioselective synthesis of 1,2-amino alcohols was also presented [36]. A plausible mechanism of the proline-catalyzed three-component Mannich reaction is shown in Fig. 2. The ketone reacts with proline to give an enamine 41. In a second pre-equilib-... 

The enantioselective total synthesis of 1 commences with the formation of the enamine of morpholine and cyclohexane-1,2-dione (6), which actually exists almost entirely in the enolic form. Constant removal of water shifts the equilibrium to the side of the product. 2-Siloxyaniline 7, " which can be easily prepared from 2-aminophe-nol, reacts with the morpholine enamine in an acid-catalyzed transamination to give enamine 8. 

Among the methodologies listed in the introduction to generate the key enol/enolate intermediate, the enantioselective protonations of metal enolates, the so-called preformed enolates, or of their substitutes such as enamines or enol ethers have known, by far, the most intensive research development (Scheme 7.2). 

Scheme 7.2 Enols, enolates, and enamines for enantioselective protonations.

Since the seminal work of Lucette Duhamel [3] in 1976 describing what is the first direct asymmetric protonation of an enolate (in fact its enamine analogue), it is only in 1992 that Takeuchi et al. successfully used a cinchona alkaloid for the enantioselective protonation of a particular samarium enediolate under mild conditions [4], Samarium diodide reduced benzil 1 into the corresponding enediolate 2, which was then enantioselectively protonated by quinidine 3 at room temperature, affording (R)-benzoin 4 in 91% ee (Scheme 7.3). The presence of molecular oxygen was necessary to obtain high selectivities. However, the procedure was not catalytic as 3 equiv of quinidine 3 were needed. Moreover, only one substrate was described showing the limits of this procedure. 

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. 

The third subsection of this chapter discusses the a-funtionalisation of aldehydes and ketones. a-Oxidation, amination and halogenation have recently been achieved with high levels of enantioselectivity using enantiopure Lewis acids, or by generation of chiral nonracemic metal enolates, in the presence of a suitable electrophilic heteroatom source. Similar levels of selectivity in this transformation are obtained via the intermediacy of chiral enamines generated using organocatalysts. 

Chiral nonracemic a-hydoxylated ketones are commonly accessed by asymmetric epoxidation or dihydroxylation of enol ethers and this methodology is discussed in the relevant sections of this book. Another general method for the enantioselective a-oxygenation of ketones and aldehydes is by reaction of an electrophilic source of oxygen with chiral nonracemic enamines or enolates or in the presence of Lewis acids. 

MacMillan and co workers have significantly expanded the scope of this enamine-mediated procedure by the addition of stoichiometric amounts of oxidant that leads to the in situ formation of a radical cation (12.57). This intermediate then undergoes enantioselective radical-based addition with a range of unsaturated substrates (12.58). For example, a-allylation with allylsilanes such as (12.60) can be effected with high ee using CAN as oxidant in the presence of imidazohdinone (12.61) as catalyst, while an a-heteroarylation occurs using N-Boc pyrrole. Furthermore, an asymmetric a-enolation of a range of aldehydes can be achieved by addition of silyl enol ethers such as (12.64). 

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