Enantioselectivity protonation reactions

The molecular mechanism of the enantioselective protonation reaction by antibody 14D9 was revealed by a crystal structure analysis [19[. A catalytic carboxyl group AspH 101 was found at the bottom of the catalytic pocket and found to be necessary for catalysis by mutagenesis to Asn or Ala. The mechanism or protonation involves an overall syn addition of water to the enol ether in a chiral binding pocket ensuring complete enantioselectivity (Figure 3.4). 

Related enantioselective protonation reactions based on the use of thiophenol as a nucleophile have also been reported by Kumar et al. these reactions led to enantioselectivity of 45-51% ee [9]. For example in the presence of 20 mol% quinine 11 the adduct 10 was synthesized in 85% yield and with 46% ee (Scheme 9.3, Eq. b). Reaction product 10 has subsequently been used as an intermediate in the synthesis of (S)-naproxen, 12, which was obtained in 85% ee (after recrystallization). 

Enantioselective protonation reactions are not limited to dienols, however, but also function well with simple enols, e.g. the aryl enol 23. The aryl enol 23 was... 

Unlike lactic acid, mandelic acid (7) occurs in nature only in small amounts and is therefore more expensive. Formerly, it was obtained by resolution of the racemate with a chiral base, such as l-phenylethylamines or ephedrine6, but enantioselective reductions of a-oxo-a-phenylacetic acid by chemical or biochemical methods have become feasible (Section D.2.3.I.). Esters of mandelic acid, e.g.. 8. can be prepared by any convenient esterification technique (see. for example, refs 7 and 46) and have been used for enantioselective protonation reactions (Sections C. and D.2.I.). Similar to the corresponding lactic esters, fumaric acid derivatives 9 are obtained from the mandelic esters and used as chiral dienophiles in diastereoselective Diels Alder reactions (Section D. 1.6.1.1.1.2.2.1.). 

Vedejs and coworker succeeded in a kinetically controlled enantioselective protonation reaction, in which a-lithiated methylbenzylphosphine oxide was treated with -BuLi at -78°C and, subsequently, with a chiral camphor-derived amine to achieve protonation [Eq. (28)] [81]. Thereafter, Warren and coworkers... 

Cheon CH, Yamamoto H. A Br0nsted acid catalyst for the enantioselective protonation reaction. J. Am. Chem. Soc. 2008 130 9246-9247. 

Morita M, Drouin L, Motoki R, Kimura Y, Fujimori I, Kanai M, Shibasaki M. Two methods for catalytic generation of reactive enolates promoted by a chiral poly Gd complex application to catalytic enantioselective protonation reactions. J. Am. Chem. Soc. 2009 131 3858-3859. 

Larhed et al. investigated enantioselective Heck reactions with 2,3-dihydrofuran as alkene [86]. In the coupling with phenyl triflate, conditions previously reported by Pfaltz [87] were attempted under microwave irradiation. Interestingly, the catalytic system Pd2(dba)3/(4S)-4-t-butyl-2-[2-(diphenylphosphanyl)phenyl]-4,5-dihydro-l,3-oxazole, identified by the Swiss team, was found suitable for high-temperature microwave-assisted enantioselective Heck reactions (Scheme 76). Using a proton sponge as a base and benzene as a solvent gave the best conversions (Scheme 76). At tempera-... 

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]. 

Enantioselective protonation of silyl enol ethers using a SnCl4-BINOL system has been developed (Scheme 83). 45 This Lewis-acid-assisted chiral Bronsted acid (LBA) is a highly effective chiral proton donor. In further studies, combined use of a catalytic amount of SnCl4, a BINOL derivative, and a stoichiometric amount of an achiral proton source is found to be effective for the reaction.346 347... 

The efficiency with which modified Cinchona alkaloids catalyze conjugate additions of a-substituted a-cyanoacetates highlights the nitrile group s stereoselective role with the catalyst. Deng et al. [60] utilized this observation to develop a one-step construction of chiral acyclic adducts that have non-adjacent, 1,3-tertiary-quatemary stereocenters. Based on their mechanistic studies and proposed transition state model, the bifimctional nature of the quinoline C(6 )-OH Cinchona alkaloids could induce a tandem conjugate addition-protonation reaction to create the tertiary and quaternary stereocenters in an enantioselective and diastereoselective manner (Scheme 18). 

Cycloheptanones attained better enantioselectivity values than their six-membered analogs and the use of alkyl-substituted silyl enol ethers resulted in only moderate enantioselectivities. Indeed, replacement of P=0 by P=S or P=Se in the phospho-ramide catalyst led to improved results in terms of reactivity as well as enantioselectivity. The catalyst loading could be decreased to 0.05 mol% without a deleterious effect on the enantioselectivity (one example). Optimization experiments revealed the critical influence of the achiral proton source on the reactivity and enantioselectivity. This observation suggests a two-step mechanism for the protonation reaction (Scheme 71). 

Scheme 6.165 Enantioselective Strecker reactions catalyzed by biflinctional hydrogen-bonding guanidine organocatalyst 178. Catalytic action of 178 HCN hydrogen bonds to 178 and generates a guanidinium cyanide complex after protonation, which activates the aldimine through single hydrogen bonding and facilitates stereoselective cyanide attack and product formation.

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. 

L-Prolinethioamides (39, R = alkyl including chiral alkyl), prepared from proline and amines, are effective in acetone-benzaldehyde reactions.110 Mechanistic studies focused in particular on suppression of non-enantioselective side-reactions, and also on the role of the side-chain of the catalyst acting as hydrogen bond donor, especially as the thioamides (with their more acidic N—H protons) are more catalytic than their amide analogues. 

The Muzart group reported an organocatalytic protonation reaction based on an in situ-formation of the required enolate by photochemical tautomerization of the chiral ammonium enolate 26 as an initial step [21]. The ammonium ion in 26 functions as the chiral proton source. Subsequent esterification affords the desired car-boxylate 20 in up to 65% yield and enantioselectivity in the range 40-85% ee. An example is shown in Scheme 9.8. The best results were obtained by use of the secondary, N-isopropyl-substituted aminobornanol for formation of the chiral ammo-... 

A new catalytic cycle for the enantioselective protonation of cyclic ketone enolates with sulfinyl alcohols has been developed (Scheme 2)25 In this method, the achiral alcohol plays two roles it is involved in the turnover of the chiral proton source and also in the generation of a transient enolate through the reaction of its corresponding alkoxide with the enol trifluoroacetate precursor. Stereoselectivity was found highly dependent on the structure of the achiral alcohol. 

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. 

Enantioselective protonation. (R)- and (S)-a-Damascone (4) have been prepared by a Grignard reaction followed by enantioselective protonation with l1 and 2,3 both available from (-)- or (+ )-ephedrine. Thus protonation of the ketone enolate 3 with (+ )-l or (- )-2 furnishes (S)- or (R)-a-damascone (4), respectively. 

Desymmetrisation by enantioselective ortholithiation has been achieved with ferrocenylcarboxamides 434,187 and also (with chiral lithium amide bases) a number of chromium-arene complexes.188 The chromium arene complex 435, on treatment with s-BuLi-(-)-sparteine, gives 436 enantioselectively, and reaction with electrophiles leads to 437. However, further treatment with r-BuLi generates the doubly lithiated species 438, in which the new organolithium centre is more reactive than the old, which still carries the (-)-sparteine ligand. Reaction of 438 with an electrophile followed by protonation therefore gives ent-431.m... 

Several new catalytic asymmetric protonations of metal enolates under basic conditions have been published to date. In those processes, reactive metal enolates such as lithium enolates are usually protonated by a catalytic amount of chiral proton source and a stoichiometric amount of achiral proton source. Vedejs et al. reported a catalytic enantioselective protonation of amide enolates [35]. For example, when lithium enolate 43, generated from racemic amide 42 and s-BuLi, was treated with 0.1 equivalents of chiral aniline 31 followed by slow addition of 2 equivalents of ferf-butyl phenylacetate, (K)-enriched amide 42 was obtained with 94% ee (Scheme 2). In this reaction, various achiral acids were... 

Takeuchi and coworkers have achieved the catalytic enantioselective protonation of a samarium enolate 45 in the THF/FC-72 [F3C(CF2)4CF3] biphasic system using a C2-symmetric chiral diol 5 (DHPEX) or a fluorinated chiral alcohol 6 as a catalyst and a fluorinated achiral alcohol 46 (Scheme 3) [11]. The fluorinated biphasic system was more effective than THF alone, and enantioselectivities near maximum values were obtained in the reaction. In addition, it was unnecessary to add the achiral alcohol 46 slowly to the reaction mixture. 

Muzart and coworkers have reported a new catalytic enantioselective protonation of prochiral enolic species generated by palladium-induced cleavage of p-ketoesters or enol carbonates of a-alkylated 1-indanones and 1-tetralones [21 ]. Among the various (S)-p-aminocycloalkanols examined, 17 and 18 were effective chiral catalysts for the asymmetric reaction and (J )-enriched a-alkylated 1-indanones and 1-tetralones were obtained with up to 72% ee. In some cases, the reaction temperature affected the ee. 

Liang G, Trauner D (2004) Enantioselective Nazarov reactions through catalytic asymmetric proton transfer. J Am Chem Soc 126 9544—9545 Liu B, Feng X, Chen F, Zhang G, Cui X, Jiang Y (2001) Synlett 2001 1551 Liu H, Cun LF, Mi AQ, Jiang YZ, Gong LZ (2006) Enantioselective direct aza hetero-Diels-Alder reaction catalyzed by chiral Brpnsted acids. Org Lett 8 6023-6026... 

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... 

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