Mediated Enantioselective Protonations

In this chapter, we review the enantioselective proto nation of enols/enolates where the asymmetry is brought by cinchona alkaloids, either the natural products or some analogues. The cinchona alkaloids may act as a direct protonating agent of enolates or as an acid-base bifunctional catalyst by first deprotonating the substrate to generate the enolate and then, as an acid, by reprotonating the carbanion. 

Several methodologies have been developed to generate the prostereogenic intermediate necessary to achieve enantioselective protonation but all have in common a stable or transient species, enol or enolate, which is being protonated by a chiral proton source. In specific cases, it is difficult to determine the real structure of the intermediate obtained, enolate or enol or both, because of the lack of its characterization and precise mechanistic investigations. 

Enantioselective protonations can be categorized into five groups depending on the type of reaction and substrate used to generate the key prochiral 

In this chapter, all research works directly in relation with enantioselective protonations mediated by cinchona alkaloids are exemplified by schemes. Several publications related to this type of chemistry, but not using cinchona alkaloids, are mentioned for comparison purposes but are not illustrated. Therefore, the reader can easily differentiate the studies involving cinchona alkaloids from other publications of interest for a better overall view of the research field. 

---

Ohta H. Enzyme-mediated enantioselective protonation to enolates in an aqueous medium. Bull. Chem. Soc. Jpn. 1997 70 2895-2911. 

In 1999, Yamamoto reported the first example of an enantioselective biomime tic polyene cychzation using chiral LBAs as artificial cyclases. The LBA cyclase is believed to participate in the initial enantioselective protonation of the terminal isoprenyl group which induces concomitant diastereoselective cychzation [128]. Subsequent work by the Yamamoto group led to the development of LBA 52 as an artificial cyclase for hydroxypolyprenoids (Scheme 5.68) [129]. LBA 52 mediated cychzation of the the appropriate achiral hydroxypolypreniods permitting the short total syntheses of (-)-Chromazonarol, (-i-)-8-epi-puupehedione, and (-)-ll -deox-ytaondiol (not shown). 

Chiral CHdo-alcohols (Fig. 35D (R = Et), F and G) as proton source mediate the enantioselective protonation of Sm-enolates according to Scheme 31 [255]. The optimal molar ratio of DHPEX (Fig. 35G) and HMPA were about 0.7 and 0.6, respectively. Steric factors dominate the enantioselectivity of this reaction sequence when unsymmetrical dialkylketenes are used. High enantiomeric excesses were achieved when the difference between the bulkiness of the alkyl groups for a given substrate is large. The relationship between the enantioselectivity of the protonation and the E/Z selectivity of Sm-enolate formation which is dependent on type of alkyl substitiution was examined. 

Bach T, Aechtner T, Neumtiller B (2002b) Enantioselective Norrish-Yang cyclisation reactions of A-( )-oxo-a>-phenylaIkyl)-substituted imidazolidin-ones in solution and in the solid state. Chem Eur J 8 2464-2475 Bach T, Grosch B, Strassner T, Herdtweck E (2003) Enantioselective [6jt]-photocyclisation reaction of an acrylanilide mediated by a chiral host. Interplay between enantioselective ring closure and enantioselective protonation. J Org Chem 68 1107-1116... 

There are two distinct approaches for the enantioselective protonation of prostere-ogenic enolates those that use an enantiomerically pure Brpnsted acid , and those that use an enantiomerically pure mediator in combination with an achiral Brpnsted acid . High levels of enantiomeric excesses have been achieved using both approaches however, the former has become more popular. 

The nucleophilic addition on substituted ketenes is a well-known method to generate a prochiral enolate that can be further protonated by a chiral source of proton. Metallic nucleophiles are used under anhydrous conditions therefore, the optically pure source of proton must be added then (often in a stoichiometric amount) to control the protonation. In the case of a protic nucleophile, an alcohol, a thiol, or an amine, the chiral inductor is usually present at the beginning of the reaction since it also catalyzes the addition of the heteroatomic nucleophile before mediating the enantioselective protonation (Scheme 7.5). The use of a chiral tertiary amine as catalyst generates a zwitterionic intermediate B by nucleophilic addition on ketene A, followed by a rapid diastereoselective protonation of the enolate to acylammonium C, and then the release of the catalyst via its substitution by the nucleophile ends this reaction sequence. 

Pracejus and coworkers reported the first Michael addition/enantioselective protonation mediated by cinchona alkaloids [15]. The authors put a special emphasis on the requirement of using chiral P-N,N-dialkylamino alcohol to achieve significant inductions. The addition of benzyl thiol 16 on 2-phthalimidoacrylate 17 catalyzed by 5 mol% of quinidine 3 gave the best selectivity (Scheme 7.10). 

Most recently, Sun and co-workers [31] reported the first direct enantioselective hydrosilylation of prochiral IH-indoles by combined Brpnsted acid/Lewis base activation. The key factor for this methodology is the addition of one equivalent of water to react with HSiCH to generate a strong Brpnsted acid, HCl. In this way the reaction proceeds through the generation of electrophilic indolenium ions by C3 protonation with the in situ-formed HCl, accompanied by subsequent chiral Lewis base-mediated enantioselective hydrosilylation with HSiCH (Scheme 15.7). 

The direct asymmetric reduction of unprotected l//-indoles to chiral indolines with up to 93% ee progressed via electrophilic indolenium ions formed by C(3) protonation by in situ generated HCl the chiral Lewis base (149) then mediated enantioselective hydride transfer from HSiCl3. ... 

Takeuchi S, Miyoshi N, Ohgo Y. Asymmetric synthesis of ketones by Sml2-mediated allylation or benzylation of ketenes followed by enantioselective protonation. Chem. Lett. 1992 21 551-554. 

Nakamura Y, Takeuchi S, Ohgo Y, Yamaoka M, Yoshida A, Mikami K. Sml2-mediated reductive enolization of a-hetero-substituted ketones and enantioselective protonation. Tetrahedron Lett. 1997 38 2709-2712. 

Poisson T, Dalla V, Marsais F, Dupas G, Oudeyer S, Levacher V. Organocatalytic enantioselective protonation of silyl enolates mediated by cinchona alkaloids and a latent source of HP. Angew. Chem. Lnt. Ed. 2007 46 7090-7093. 

Chemical catalysts for transfer hydrogenation have been known for many decades [2e]. The most commonly used are heterogeneous catalysts such as Pd/C, or Raney Ni, which are able to mediate for example the reduction of alkenes by dehydrogenation of an alkane present in high concentration. Cyclohexene, cyclo-hexadiene and dihydronaphthalene are commonly used as hydrogen donors since the byproducts are aromatic and therefore more difficult to reduce. The heterogeneous reaction is useful for simple non-chiral reductions, but attempts at the enantioselective reaction have failed because the mechanism seems to occur via a radical (two-proton and two-electron) mechanism that makes it unsuitable for enantioselective reactions [2 c]. 

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. 

The highly selective abstraction of one of the enantiotopic protons in carbamates due to the presence of (—)-sparteine dnring the metalation step, onthned in equation 11, proved itself to be a particularly fruitful concept in the context of chiral economy Thus the protocol permits one to convert a prochiral snbstrate into a non-racemic product in remarkable enantioselectivity. Usually, metalated carbamates like 21 generated by this method react with electrophiles under retention of confignration (eqnation 70). In the metalation step, mediated by (—)-sparteine, the pro-5 proton is removed predominantly, and reaction products 169 are obtained in >95% ee as a rnle (eqnation 70) . ... 

Modest enantioselectivity was observed for the P-replacement reaction catalyzed by 33-36 bilayer membranes [45]. D-Tryptophan formation prevailed over that of the l-form in 50-55 % ee regardless of chirality of the substrate, serine. Conversely, no enantioselectivity was observed when the 32 vesicle was used in place of 33. This suggested that the imidazolyl group of 33 might exercise stereospecific acid catalysis in the protonation of the prochiral carboanion intermediate. The enantioselectivity was also modest (ca. 30% ee) when the P-replacement reaction was mediated by the co-vesicle formed with 37,32, and an additional peptide lipid having (S)-binaphthol moieties (35) in the presence of Cu(n) ions. 

Heterobimetallic catalysis mediated by LnMB complexes (Structures 2 and 22) represents the first highly efficient asymmetric catalytic approach to both a-hydro and c-amino phosphonates [112], The highly enantioselective hydrophosphonylation of aldehydes [170] and acyclic and cyclic imines [171] has been achieved. The proposed catalytic cycle for the hydrophosphonylation of acyclic imines is shown representatively in Scheme 10. Potassium dimethyl phosphite is initially generated by the deprotonation of dimethyl phosphite with LnPB and immediately coordinates to the rare earth metal center via the oxygen. This adduct then produces with the incoming imine an optically active potassium salt of the a-amino phosphonate, which leads via proton-exchange reaction to an a-amino phosphonate and LnPB. 

The enantioselective biomimetic total synthesis of the alkaloid (+)-aristotelone was accomplished by C.H. Heathcock and co-workers." The synthetic sequence commenced with a Hg(N03)2-mediated Ritter reaction between (1S)-(-)-P-pinene and 3-indolylacetonitrile. Upon protonation, the pinene underwent a Wagner-Meerwein rearrangement to generate a tertiary carbocation which reacted with the cyano group. The initially formed imine product was reduced to the corresponding amine by sodium borohydride in methanol. 

---