Carbonyl compounds asymmetric protonation

E Emori, T. Arai, H. Sasai, M Shibasaki, A Catalytic Michael Addition of Thiols to a, -Unsaturated Carbonyl Compounds Asymmetric Protonations, J. Am Chem Soc 1998,120, 4043-4044. 

Emori E, Aral T, Sasai H, Shihasaki M. A catalytic Michael addition of thiols to a,p-unsaturated carbonyl compounds asymmetric Michael additions and asymmetric protonations. J. Am. Chem. Soc. 1998 120 4043 044. 

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. 

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. 

Heterobimetallic asymmetric complexes developed by Shibasaki et al. are known as effective catalysts for asymmetric Michael additions. They achieved a catalytic asymmetric protonation in Michael additions of thiols to a,P-unsaturated carbonyl compounds using LaNa3tris(binaphthoxide) and SmNa3tris(binaphthoxide) complexes (SmSB) 37 [42]. For instance, treatment of thioester 48 with 4-fert-butyl(thiophenol) and 0.1 equivalents of (P)-SmSB 37 (Ln=Sm) in CH2C12 at -78°C gave the adduct 49 in 93% ee and in 86% yield (Scheme 4). The high enantiomeric ratio is considered to be attributable to an... 

Tetradentate chiral proton donors have been used for the asymmetric protonation of samarium enolates formed by the Sml2 reduction of a-heteroatom-substituted carbonyl compounds. For example, Takeuchi examined the reduction of a-heterosubstituted cyclohexanone 12 using Sml2 and the BINOL-derived chiral proton source 13.41 Ketone 14 was obtained in good yield and high enantiomeric excess (Scheme 2.11). Coordination of the proton source to samarium is key to the success of the transformation.41... 

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]. 

The asymmetric synthesis of a-hydroxymethyl carbonyl compounds is currently the subject of considerable interest because of their versatility as dual-function chiral synthons. There have been no reports of successful enantioselective hydroxymethylations of prochiral metal enolates with formaldehyde because of the instability and small steric size of gaseous formaldehyde. The author and Yamamoto et al. developed the enantioselective alkoxymethylation of silyl enol ethers by introducing suitable carbon-electrophiles in place of the activated-protons of LBA [142]. 

In addition to investigations this important class of compound may also be studied by means of MAS NMR spectroscopy. In fact we have shown that sharp resonances may be obtained from solid state MAS NMR of molecular hydrido carbonyl complexes without recourse either to the multiple pulse methods [22] or to isotopic dilution [23]. This is due to the fact that in these compounds the protons are intramolecularly diluted. We considered again H20s3(CO)io which crystallizes with one molecule as the asymmetric unit, as determined by a neutron diffraction study [24], and displays an interproton distance of 2.38 A. This interproton distance affords a dipolar coupling constant of 8.91 kHz. Now, rotation of the sample at 8.1 kHz allows... 

Reactions of chiral allylic boranes with carbonyl compounds Reactions of chiral allyl boranes with imines Asymmetric Addition of Carbon Nucleophiles to Ketones Addition of alkyl lithiums to ketones Asymmetric epoxidation with chiral sulfur ylids Asymmetric Nucleophilic Attack by Chiral Alcohols Deracemisation of arylpropionic acids Deracemisation of a-halo acids Asymmetric Conjugate Addition of Nitrogen Nucleophiles An asymmetric synthesis of thienamycin Asymmetric Protonation... 

Asymmetric protonation of enols or enolates is an efficient route as is asymmetric alkylation of enolates to prepare carbonyl compounds which possess a tertiary asymmetric carbon at the a-position (Scheme 1). Numerous successful methods have been developed and applied to organic synthesis. Several reviews of asymmetric protonation have been pubHshed [1,2,3,4,5] and the most recent... 

The aza-Morita-Baylis-HiUman reaction is known to be a useful and atom-economical C-C bond-forming reaction of electron-deficient alkenes with imines usually catalyzed by Lewis bases [202]. It formally involves a sequence of reactions including a Michael addition, a Mannich reaction, a proton transfer, and a retro-Michael reaction ( -elimination). Although there are many reports in the field of the enantioselective aza-Morita-Baylis-Hilhnan reaction, only rare examples of asymmetric domino reactions initiated by this reaction have been reported. In 2010, Sasai et al. [203] developed the first organocatalyzed asymmetric domino aza-Morita-Baylis-Hillman/aza-Michael reaction of a,p-unsaturated carbonyl compounds with N-tosylimines, allowing an easy access to chiral cis-1,3-disubstituted isoindolines as single diastereomers. The process was induced by a Hg-BINOL-derived catalyst and provided these products in high yields and enantioselectivities, as shown in Scheme 10.18. 

Catalytic enantioselective protonation of prochiral ketone enolates is a beneficial route to optically active carbonyl compounds possessing a tertiary asymmetric carbon at the a-position. In the asymmetric protonation of trimethylsilyl enolates with methanol, BINAP-AgF has been found to act as a chiral catalyst [90,91], which is also known to catalyze asymmetric allylation of aldehydes with allylic trimethoxysilanes [42] as well as asymmetric aldol reaction with trimethoxysilyl enolates [54]. This protonation can be most effectively performed using 6 mol% ofBINAP and 10 mol% of... 

Sodeoka and co-workers " reported on an interesting access to (3-amino carbonyl compounds thanks to a palladium-catalyzed 1,4-addition of amine salts 79a-b followed by asymmetric protonation (Scheme 31.28). Once again, BINAP was found to be the ligand of choice providing the corresponding p-amino carbonyl compounds 80a-d in up... 

Hustedt and Pfeil in 1961 noticed the difference in sensitivity toward the presence of protic solvents between the asymmetrical synthesis induced by cinchona cations and by the enzyme [74]. In the years thereafter Pfeil and co-workers published several important contributions to the synthetic usefulness of the enzyme. They found that the presence of the tightly but not covalently bound FAD molecule in the enzyme is essential, both for its stability and for its activity. The apoenzyme is catalytically inactive, but activity can be fully regenerated by addition of FAD in its oxidized form [28]. A reaction scheme was proposed for the asymmetrical synthesis as depicted in Scheme 2, in which the carbonyl compound first forms a complex with the chiral catalyst. This complex then reacts in a rate-determining step with a cyanide ion. In a third, fast, step the complexed cyanohydrin anion is protonated by HCN. 

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