Protonation, catalytic enantioselective

Collins and co-workers have performed studies in the area of catalytic enantioselective Diels—Alder reactions, in which ansa-metallocenes (107, Eq. 6.17) were utilized as chiral catalysts [100], The cycloadditions were typically efficient (-90% yield), but proceeded with modest stereoselectivities (26—52% ee). The group IV metal catalyst used in the asymmetric Diels—Alder reaction was the cationic zirconocene complex (ebthi)Zr(OtBu)-THF (106, Eq. 6.17). Treatment of the dimethylzirconocene [101] 106 with one equivalent of t-butanol, followed by protonation with one equivalent of HEt3N -BPh4, resulted in the formation of the requisite chiral cationic complex (107),... 

Recently, we established that several proton acids catalyze the metal-free reduction of ketimines under hydrogen-transfer conditions with Hantzsch dihydropyridine as the hydrogen source.Additionally, we were able to demonstrate a catalytic enantioselective procedure of this new transformation by employing a chiral Br0nsted acid as catalyst.(see Chapter 4.1). 

The chemistry of asymmetric protonation of enols or enolates has further developed since the original review in Comprehensive Asymmetric Catalysis [1], Numbers of literature reports of new chiral proton sources have emerged and several reviews [2-6] cover the topics up to early 2001. This chapter concentrates on new examples of catalytic enantioselective protonation of prochiral metal enolates (Scheme 1). Compounds 1-41 [7-45] shown in Fig. 1 are the chiral proton sources or chiral catalysts reported since 1998 which have been employed for the asymmetric protonation of metal enolates. Some of these have been successfully utilized in the catalytic version. 

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... 

Our research group developed catalytic enantioselective protonations of preformed enolates of simple ketones with (S,S)-imide 23 or chiral imides 25 and 26 based on a similar concept [29]. For catalytic protonation of a lithium eno-late of 2-methylcyclohexanone, chiral imide 26, which possesses a chiral amide moiety, was superior to (S.S)-imide 23 as a chiral acid and the enolate was pro-tonated with up to 82% ee. 

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. 

Yamamoto et al. reported full research details on catalytic enantioselective protonation under acidic conditions in which prochiral trialkylsilyl enol ethers and ketene bis(trialkyl)silyl acetals were protonated by a catalytic amount of Lewis acid assisted Bronsted acid (LBA15 or 16) and a stoichiometric amount of 2,6-dimethylphenol as an achiral proton source [20]. 

Catalytic enantioselective protonations of metal enolates already published can be roughly classified into two methods carried out under basic conditions and acidic conditions. The process under basic conditions is, for example, the protonation of reactive metal enolates such as lithium enolates with a catalytic amount of chiral acid and an excess of achiral acid. The process under acidic conditions employs silyl enol ethers or ketene silyl acetals as substrates. Under the influence... 

The first example of catalytic enantioselective protonation of metal enolates was achieved by Fehr and coworkers (Scheme 3) [44]. They found the enantioselective addition of a lithium thiolate to ketene 41 in the presence of an equimolar amount of (-)-iV-isopropylephedrine (23) with up to 97% ee. Based on the results, they attempted the catalytic version for example, slow addition of p-chlo-rothiophenol to a mixture of ketene 41 (1 equiv) and lithium alkoxide of (-)-N-isopropylephedrine 23-Li (0.05 equiv) gave thiol ester 43 with 90% ee. First, the thiol is deprotonated by 23-Li to generate lithium p-chlorothiophenoxide and 23. The thiophenoxide adds to the ketene 41 leading to Z-thiol ester enolate which is presumed to react with the chiral amino alcohol 23 via a four-membered cyclic transition state 42 to form the product 43 and 23-Li. The hthium alkoxide 23-Li is reused in the catalytic cycle. The key to success in the catalytic process is that the rate of introduction of thiophenol to a mixture of the ketene 41 and 23-Li is kept low, avoiding the reaction of the thiol with the intermediate hthium enolate. 

Our research group independently found a catalytic enantioselective proto-nation of preformed enolate 47 with (S,S)-imide 30 founded on a similar concept (Scheme 5) [51]. The chiral imide 30, which has an asymmetric 2-oxazoline ring and is easily prepared from Kemp s triacid and optically active amino alcohol, is an efficient chiral proton source for asymmetric transformation of simple metal enolates into the corresponding optically active ketones [50]. When the lithium enolate 47 was treated with a stoichiometric amount of the imide 30, (K)-en-riched ketone 48 was produced with 87% ee. By a H-NMR experiment of a mixture of (S,S)-imide 30 and lithium bromide, the chiral imide 30 was found to form a complex rapidly with the lithium salt. We envisaged that a catalytic asym-... 

Proton transfer. Protonation of prostereogenic enolates with the y-hydroxyselenoxides, such as 1, sometimes gives excellent ee. The SnCl complex of a methyl ether of chiral BINOL can be used in catalytic amounts to protonate silyl enol ethers, affording ketones in high optical yields. A catalytic enantioselective deprotonation to form a bromoalkene is achieved by KH in the presence of A-methylephedrine. 

While stoichiometric amounts of base were used in the nitronate anion protonations, catalytic amounts of concave macrocycles 156,157 and 159 were found to influence the addition of alcohols to diphenylketene. The chiral concave macrocycle 161 catalyzed the addition of l -l-phenylethanol 20% faster than the addition of the S-enantiomer to the ketene thus demonstrating the enantioselectivity of the concave reagent [8]. 

These experiments also enabled the discovery of catalytic enantioselective protonation. [46] Highly ( )- enriched, pure hthium enolate (98 2) was obtained hy a Grignard reaction, addition of chlorotrimethylsilane, fractional distillation and treatment with methyllithium. For the stereoselective protonation, 0.2-0.3 equivalents of isopropylephedrine were sufficient, because this was re-... 

Shibasaki further developed a direct catalytic enantioselective conjugate addition of terminal allqmes to a,p-unsaturated thioamides under proton-transfer conditions (Scheme 2.26). The combined use of chiral... 

Catalytic enantioselective protonation of a-oxygenated ester enolates has been achieved via a phospha-Brook rearrangement, using a simple phosphite and a cinchona catalyst the process converts R R-C=0 R R C H-0P(0)(0Ar)2." ... 

Aminoindole 166 was found to undergo a catalytic, enantioselective aza-Claisen rearrangement upon heating in toluene with chiral phosphoric acid 168 to afford 2,3-disubstituted indole 167. A variety of substituents were competent under the reaction conditions and both yields and ee s were excellent in most examples. It was proposed that the rearrangement was accelerated and transferred high enantioselectivity by an arene CH—O interaction between the C2 proton and the phosphate counterion of 168 (13JA16380). 

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... 

Shibasaki and Kanai developed a catalytic enantioselective nitrile aldol reaction using CuOf-Bu-DTBM-SEGPHOS complex as a catalyst (Fig. 3) [27] (for other reports of direct catalytic nitrile aldol reactions, see [31, 32]). Despite moderate enantioselectivity, it is noteworthy that chemoselective generatimi of an enolate equivalent (copper ketene imide 6 in Fig. 4) is possible from acetonitrile in the presence of aldehydes containing more acidic a-protons. The pATa values of a-protons of acetonitrile and aliphatic aldehydes are 31.3 and ca. 23 (in DMSO), respectively. Key for the selective deprotonation from acetonitrile is the chemoselective interaction between soft Cu(I) and soft nitrile, which selectively acidifies a-protons of acetonitrile (Fig. 4, 5). 

Catalytic Enantioselective Protonation Using Chiral Poly Gadolinium Complexes... 

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

In the context of catalytic enantioselective conjugate additions, preformed enolates play two different roles as enolates, mainly those of silicon, they add to Michael acceptors under activation by a catalyst. On the other hand, enolates are involved in a second different function as intermediates, if any nucleophile reacts with a,P-unsaturated carbonyl compounds they may be quenched by protonation or reaction with different electrophiles in a stereoselective manner. 

In 2009, the catalytic enantioselective semipinacol rearrangement of 2-oxo allylic alcohols 83 was detailed by Zhang et al., leading to enantioenriched spiro-ethers 84 in a single operation (Scheme 2.24). They found that both phosphoric acids 5b and silver phosphate 5i were optimal catalysts, while the latter probably underwent silver-proton exchange with hydroxyl group of subsnates in the catalytic procedure [35],... 

Encouraged by their preliminary results, Fehr and coworkers developed the first catalytic enantioselective protonation in the course of the enantioselective synthesis of... 

This approach is based on the kinetic of the protonation step indeed, the chiral enol-enolate hybrid should react faster than the uncomplexed enolate as well as faster than the achiral enolate complex, resulting from the complexa-tion of the achiral proton source with the Li enolate. To address these difficulties, Fehr and co-workers described an elegant and efficient catalytic enantioselective protonation using 20 mol% of (—)-//-E and 0.85 equiv of phenyl-2-propanone 23. This process affords the corresponding saturated (S)-a-damascone (5)-24) with 94% yield and excellent enantioselectivity (94% ee). It should be noted that this catalytic process might also be used for the enantioselective protonation of the key thioester (50-20, which could be obtained with 98% ee using 50 mol% of ( )-//-E. 

SCHEME 31.26. Mechanism of catalytic enantioselective protonation of Rh enolate. 

Mohr JT, Nishimata T, Beheima DC, Stoltz BM. Catalytic enantioselective decarboxylative protonation. J. Am. Chem. Soc. 2006 128 11348-11349. 

Yanagisawa A, Kikuchi T, Watanabe T, Kuribayasahi T, Yamamoto H. Catalytic enantioselective protonation of simple enolate with chiral imide. Synlett 1995 372-374. 

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