Enols protonation, asymmetric

In an asymmetric p-diketone there should be a preference by the enol proton for one of the carbonyls over the other and attempts have been made to determine which it is by C-nmr spectroscopy (Shapet ko et al., 1975 Lazaar and Bauer, 1983). With the additional help of O-nmr spectroscopy it has been possible to demonstrate convincingly that the enol group prefers the carbonyl with a p-group in the following order CF3 > Ph > Bu > Me (Geraldes et al., 1990). 

Recent developments in enantioselective protonation of enolates and enols have been reviewed, illustrating the reactions utility in asymmetric synthesis of carbonyl compounds with pharmaceutical or other industrial applications.150 Enolate protonation may require use of an auxiliary in stoichiometric amount, but it is typically readily recoverable. In contrast, the chiral reagent is not consumed in protonation of enols, so a catalytic quantity may suffice. Another variant is the protonation of a complex of the enolate and the auxiliary by an achiral proton source. Differentiation of these three possibilities may be difficult, due to reversible proton exchange reactions. 

Only recently, Shibasaki et al. reported on the application of a Sm-Na-(R)-BINOL-complex as catalyst in a reaction cascade consisting of an a.symmetric Michael addition of thiols to a,fS- xn-saturated carbonyl compounds followed by an asymmetric enolate protonation [20]. 

A number of other asymmetric enolate protonation reactions have been described using chiral proton sources in the synthesis of a-aryl cyclohexanones. These include the stoichiometric use of chiral diols [68] and a-sulfinyl alcohols [69]. Other catalytic approaches involve the use of a BlNAP-AgF complex with MeOH as the achiral proton source, [70] a chiral sulfonamide/achiral sulfonic acid system [71,72] and a cationic BINAP-Au complex which also was extended to acyclic tertiary a-aryl ketones [73]. Enantioenriched 2-aryl-cyclohexanones have also been accessed by oxidative kinetic resolution of secondary alcohols, kinetic resolution of racemic 2-arylcyclohexanones via an asymmetric Bayer-Villiger oxidation [74] and by arylation with diaryhodonium salts and desymmetrisation with a chiral Li-base [75]. 

As with many asymmetric processes, there are three ways to control absolute stereochemistry in the Nazarov cyclization Asymmetry transfer, the use of chiral auxiliaries, or asymmetric catalysis. It is important to realize, however, that there are two distinct processes operating that determine the stereochemistry of the product. To control the absolute stereochemistry of the p-carbon atom(s), it is necessary to control the sense of conrotation, clockwise or counterclockwise (torquoselectivity, see Section 3.4.3). To control the absolute stereochemistry of the a-carbon atom however, it is necessary to control the facial selectivity for enol protonation. 

Ojjpolzer W, Kingma AJ, Poli G. Asymmetric 1,4-additions of Gilman reagents to a,p-disubstituted ( )-enoylsul-tams/enolate protonations. Tetrahedron 1989 45 479-488. 

The low-temperature method is effective not only in the kinetic resolution of alcohols but also in the enantioface-selective asymmetric protonation of enol acetate of 2-methylcyclohexanone (15) giving (f )-2-methylcyclohexanone (16). The reaction in H2O at 30°C gave 28% ee (98% conv.), which was improved up to 77% ee (82% conv.) by the reaction using hpase PS-C 11 in /-Pt20 and ethanol at 0°C. Acceleration of the reaction with lipase PS-C 11 made this reaction possible because this reaction required a long reaction time. The temperature effect is shown in Fig. 14. The regular temperature effect was not observed. The protons may be supplied from H2O, methanol, or ethanol, whose bulkiness is important. 

Whilst the addition of a chiral NHC to a ketene generates a chiral azolium enolate directly, a number of alternative strategies have been developed that allow asymmetric reactions to proceed via an enol or enolate intermediate. For example, Rovis and co-workers have shown that chiral azolium enolate species 225 can be generated from a,a-dihaloaldehydes 222, with enantioselective protonation and subsequent esterification generating a-chloroesters 224 in excellent ee (84-93% ee). Notably, in this process a bulky acidic phenol 223 is used as a buffer alongside an excess of an altemativephenoliccomponentto minimise productepimerisation (Scheme 12.48). An extension of this approach allows the synthesis of enantiomericaUy emiched a-chloro-amides (80% ee) [87]. 

The carbonyl group in a ketone or aldehyde is an extremely versatile vehicle for the introduction of functionality. Reaction can occur at the carbonyl carbon atom using the carbonyl group as an electrophile or through enolate formation upon removal of an acidic proton at the adjacent carbon atom. Although the carbonyl group is an integral part of the nucleophile, a carbonyl compound can also be considered as an enophile when involved in an asymmetric carbonyl-ene reaction or dienophile in an asymmetric hetero Diels-Alder reaction. These two types of reaction are discussed in the next three chapters. 

The pyrrolobenzodiazepine-5,11 -diones II have been utilized in asymmetric syntheses of both the cis- and tra i-decahydro-quinoline alkaloids (Schemes 21 and 22). For example, reduction of 100 with 4.4 equiv. of potassium in the presence of 2 equiv. of t-BuOH, followed by protonation of the resulting enolate with NH4CI at —78 °C gave the cA-fused tetra-hydrobenzene derivative 101.Amide-directed hydrogenation of 101 gave the hexahydrobenzene derivative with diastereo-selectivity greater than 99 1. Removal of the chiral auxiliary and adjustment of the oxidation state provided aldehyde 103 which was efficiently converted to the poison frog alkaloid (+)-pumiliotoxin C. 

A new chiral proton source (111), based on an asymmetric 2-oxazoline ring, has been found to be capable of effecting asymmetric protonation of simple prochiral metal enolates (112) to give corresponding ketones (113) which need not bear polar groups. 

Catalytic asymmetric protonation of a prochiral amide enolate by a chiral diamine (10mol%) has been achieved through careful optimization of the proton-shuttle conditions which must apply. ... 

Thereafter, Yamamoto reported the first metal-free Bronsted add catalyzed asymmetric protonahon reachons of silyl enol ethers using chiral Bronsted acid 13c in the presence of achiral Bronsted add media (Scheme 5.34) [61]. Importantly, replacement of sulfur and selenium into the N-triflyl phosphoramide increases both reactivihes and enanhoselectivihes for the protonation reaction. 

For a short review on asymmetric protonation of enol derivatives, see Yanagisawa, A. Ishihara, K. Yamamoto, H. Synlett 1997, 411 20. 

The two methyl groups in the olefin-copper(I) complex 26 are crucial for asymmetric induction. The 150° dihedral angle between the a- and /3-protons of the magnesium enolate 27 provides valuable information to determine the stereochemical effects on the a center. The two magnesium enolates 27 and 28 are reversibly temperature-dependent. Enolate 27 is the major component at 253 K, while enolate 28 becomes the major component at 293 K. Therefore, temperature lower than ca 256 K is required to obtain high stereoselectivity. 

Attempts to achieve an asymmetric 1,3-proton shift reaction of (/ )-33, obtained from ethyl 3,3,3-trifhioro-2-oxopropanoate and (f )-l-phenylethanamine in 81 % yield, resulted in conversion into 34 in 89% yield, but without any reliably delectable enantiomeric excess.26 Even at 10% conversion, the Shiff base 34 formed is completely racemic. Imine 34 undergoes isotopic exchange in triethylamine/methanoI-r/4 at a rate 10 times slower than the isomerization of 33 to 34. The authors reason that if a 1.3-proton shift mechanism is operating, some enantiomeric excess would have to be observable in product 34 at low conversion. Since this is not the ease, a 1,5-proton shift to the carbonyl oxygen, via stabilized anion 37, to form achiral intermediate enol 38, was proposed.26... 

The heterobimetallic multifunctional complexes LnSB developed by Shibasaki and Sasai described above are excellent catalysts for the Michael addition of thiols [40]. Thus, phenyl-methanethiol reacted with cycloalkenones in the presence of (R)-LSB (LaNa3tris(binaphthox-ide)) (10 mol %) in toluene-THF (60 1) at -40°C, to give the adduct with up to 90% ee. A proposed catalytic cycle for this reaction is shown in Figure 8D.9. Because the multifunctional catalyst still has the internal naphthol proton after deprotonation of the thiol (bold-H in I and II), this acidic proton in the chiral environment can serve as the source of asymmetric protonation of the intermediary enolate, which is coordinated to the catalyst II. In fact, the Michael addition of 4-/en-butylbenzcnethiol to ethyl thiomethacrylate afforded the product with up to 93% ee using (R)-SmSB as catalyst. The catalyst loading could be reduced to 2 mol % without affecting enantioselectivity of the reaction. 

Reviews have featured asymmetric protonations of enol derivatives133 and of enolates and enols.134 Highly enantiofacial protonation of prochiral lithium enolates has been achieved using chiral /J-hydroxy sulfoxides.135... 

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