Enantioselective Protonation of Enolates

Figure 3.3 Antibody 14D9 catalyzes the enantioselective protonation of enol ethers.

Chiral a-sulfinyl alcohols have proved useful in enantioselective protonation of enolates.Addition of lithium bromide enhances the ee in a number of cases, apparently via simultaneous coordination of lithium to the enolate and to the sulflnyl alcohol. 

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. 

Enantioselective Protonation of Enolates formed in situ from Enolate Precursors... 

Enantioselective Protonation of Enolates Generated in situ from Conjugated Unsaturated Carboxylates... 

C. Fehr, Enantioselective Protonation of Enolates and Ends , Angew. Chem. Int. Ed. Engl. 1996, 35, 2566-2587. 

Asensio and coworkers studied the effects of solvent, temperature, presence of lithium salts and proton acidity on the enantioselective protonation of enolates 230 to yield (/ )-2-methyl-1-tetralone (231, equation 58) with a-sulfinyl alcohols 232 and 1,2-sulhnyl thiols 233 . Stereoselectivity was generally enhanced when lithium bromide was present in the medium during enolization and also with the use of methylene chloride solutions. 

Overall, cinchona alkaloids, which are already powerful (organo)catalysts in most major chemical reactions, will be expected to be major players in the enantioselective protonations of enols/enolates. This will persuade the synthetic chemist to incorporate these methodologies with confidence in total syntheses. 

Enantioselective protonation of prochiral enols or enolates, which provides synthetic access to optically active carbonyl compounds, is an elegantly simple test reaction for enantioselective reagents and catalysts, for which a number of examples have been described [80]. The only reaction described with alkyl enol ethers concerns the highly enantioselective protonation of enol ethers such as 55 by catalytic antibody 14D9, an antibody raised against hapten 10 [81]. Antibody 14D9 has a practical turnover of /c-at = 0.4 for substrate 55 and produces... 

The. V-alkylation of ephedrine is a convenient method for obtaining tertiary amines which are useful as catalysts, e.g., for enantioselective addition of zinc alkyls to carbonyl compounds (Section D. 1.3.1.4.), and as molybdenum complexes for enantioselective epoxidation of allylic alcohols (Section D.4.5.2.2.). As the lithium salts, they are used as chiral bases, and in the free form for the enantioselective protonation of enolates (Section D.2.I.). As auxiliaries, such tertiary amines were used for electrophilic amination (Section D.7.I.), and carbanionic reactions, e.g., Michael additions (Sections D. 1.5.2.1. and D.1.5.2.4.). For the introduction of simple jV-substituents (CH3, F.t, I-Pr, Pretc.), reductive amination of the corresponding carbonyl compounds with Raney nickel is the method of choice13. For /V-substituents containing further functional groups, e.g., 6 and 7, direct alkylations of ephedrine and pseudoephedrine have both been applied14,15. 

The di-O-acylated tartaric acids, e.g., 40 42, are not only used for resolution of amines, but also as reagents for the enantioselective protonation of enolates (Section D.2.I.). They are prepared by the reaction of an excess of acid chloride (3-3.2 equivalents), e.g., benzoyl chloride, with tartaric acid at about 150°C. The di-O-acyl-tartanc anhydride is then hydrolyzed either with refluxing water for 30 minutes39 or with 5% water in acetone at lower temperature40-41. 

The effect of reaction conditions on the enantioselective protonation of enolates derived from dioxolanones and oxathiolanones (15) has been studied... 

Boronic acids and their derivatives are very popular as components of chiral Lewis acids and promoters for various reaction processes [481]. Indeed, the chiral acyloxyb-oranes and the oxazaborolidines (Section 1.2.3.5) described in Chapter 11 made a mark in organic synthesis. Recently, Ryu and Corey extended the apphcation of chiral oxaborolidinium catalysts to the cyanosilylation of aldehydes [482]. Chiral diaz-aborohdine salts were evaluated in the enantioselective protonation of enol ethers [145]. Likewise, a tartramide-derived dioxaborolane is key as a chiral promoter in the asymmetric cyclopropanation of allyhc alcohols [483]. More examples and details on the applications of boronic add derivatives as reaction promoters and catalysts are provided in Chapter 10. 

Scheme 12 Catalytic enantioselective protonation of enol silyl ethers...

SCHEME 31.7. Mechanism for the enantioselective protonation of enol 19 through an enolization process. 

SCHEME 31.45. Enol acetates as new type of substrates enantioselective protonation of enol... 

Aboulhoda SJ, Reiners I, Wilken J, Henin F, Muzart J. P-Amino tertiary cycloalkanols for the enantioselective protonation of enolic species produced by a palladium-induced cascade reaction. Tetrahedron Asymm. 1998 9 1847-1850. 

Fehr C. Enantioselective protonation of enolates in natural product synthesis. Chimia 1991 45 253-261. 

Asensio G, Aleman PA, Gil J, Domingo LR, Medio-Simon M. Stereoselection parameters and theoretical model in the enantioselective protonation of enolates with a-sulfinyl alcohols. J. Org. Chem. 1998 63 9342-9347. 

Asensio G, Gavina P, Cuenca A, Ramirez de Arellano MC, Domingo LR, Medio-Simon M. First synthesis of the chiral mixed O/S ligands, 1,2-sulfinyl thiols application as chiral proton sources in enantioselective protonations of enolates. Tetrahedron Asymm. 2000 11 3481-3493. 

Fehr C, Galindo J. Syntheses of the enantiomers of y-cyclo-geranic acid, -Y-cyclocitral, and a-damascone enantioselective protonation of enolates. Helv. Chim. Acta 1995 78 539-552. 

Beck EM, Hyde AM, Jacobsen EN. Chiral sulfinamide/ achiral sulfonic acid cocatalyzed enantioselective protonation of enol silanes. Org. Lett. 2011 13 4260-4263. 

Claraz A, Leroy J, Oudeyer S, Levacher V. Catalytic enantioselective protonation of enol trifluoroacetates by means of hydrogenocarbonates and cinchona alkaloids. J. Org. Chem. 2011 76 6457-r6463. 

Proton transfer processes are involved in many biochemical events and often play a key role in the catalytic activity of enzymes. Of particular interest, are enantioselective proton transfer processes frequently encountered in a number of biosynthetic sequences. Over the last few years, esterase and decarboxylase enzymes have appeared as appealing biocatalysts to achieve enantioselective protonation of enol acetates [1] and enantioselective decarboxylation of malonate derivatives [2] respectively. Conceptually, enantioselective protonation provides a simple... 

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