Enantioselection, 67 protonation

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

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). 

Other organometallic compounds that are hydrolyzed by water are those of sodium, potassium, lithium, zinc, and so on, the ones high in the electromotive series. Enantioselective protonation of lithium enolates and cyclopropyllithium compounds have been reported. When the metal is less active, stronger acids are required. For example, R2Zn compounds react explosively with water, R2Cd slowly, and R2Hg not at all, though the latter can be cleaved with concentrated HCl. How-... 

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... 

Chiral tetrahydroisoquinoline derivatives can be obtained by diastereoselective or enatioselective protonation. Deprotonation of lactam 87 with n-BuLi followed by addition of H2O and NH4CI afforded 88 in 92% yield and 97% ee. The stereoselectivity was highly dependent upon the proton source. Further elaboration afforded tetrahydroisoquinoline 89 in >97% ee . The enantioselective protonation of 1-substituted tetrahydroisoquinoline 90 in the presence of chiral amine 91 proceeded in 90-95% yield and 83-86% ee. This methodology was used in an asymmetric synthesis of salsolidine <00SL1640>. 

Scheme 4.61 Enantioselective protonation of237/238, giving allene 239.

The HOPG (highly oriented pyrolytic graphite) carbon electrode chemically modified with (5[-phenylalanine at the basal surface led to 2% ee in the reduction of 4-acetylpyridine [377]. A cathode modified with a chiral poly(pyrrole) reduced 4-methylbenzophenone or acetophenone in DMF/LiBr and phenol as proton donor to 1-phenylethanol with up to 17% ee [382]. Alkyl aryl ketones have been reduced to the corresponding alcohols at a Hg cathode in DMF/water in the presence of (1R,2S)-A,A-dimethylephedrinium tetrafluorobo-rate (DET), producing (5 )-l-phenylethanol with 55% ee from acetophenone. Cyclovoltammetry supports an enantioselective protonation of the intermediate (PhCOH(CH3)) [383]. 

The keto radical is reduced and further protonated. The function of yohimbine-H+ is to catalyze the tautomerization and to enantioselectively protonate the final carbanion. It is also concluded that the hydrophobic yohimbine is enriched near the hydrophobic cathode surface. Quantum chemical calculations demonstrate that si protonation of the intermediate anion by yohimbine-H+ to give the (i )-dihydroproduct is energetically favored [389, 390]. Similarly, 3-methylinden-l-one in the presence of strychnine yields 71% 3-methylindan-1-one with 35% ee (S -enantiomer). 

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. 

The reactivity of lithium enolates has been explored in a theoretical study of the isomers of C2H30Li, such as the lithium enolate, the acyl lithium, and the a-lithio enol. Imides containing a chiral 2-oxazolidine have been employed for enantioselective protonation of prochiral enolates.A degree of kinetic control of the product E/Z-enolate ratio has been reported for the lithiation of 3,3-diphenylpropiomesitylene, using lithium amides/alkyls. " °... 

The favourable effect of lithium bromide on facial enantioselective protonation of methyl tetralone enolate by a-sulfinyl alcohols has been attributed to coordination of lithium to both enolate and sulfinyl alcohol followed by competition between diastere-omeric paths involving intramolecular proton transfer the proposed transition-state model is supported by results of PM3 semiempirical calculations. ... 

BINOL derivative SnCl4 complexes are useful not only as artificial cyclases but also as enantioselective protonation reagents for silyl enol ethers. " However, their exact structures have not been determined. SnCl4-free BINOL derivatives are... 

Monoalkyl ethers of (R,R) 1,2-bis[3,5-bis(trifluoromethyl)phenyl]ethanediol, 24, have been examined for the enantioselective protonation of silyl enol ethers and ketene disilyl acetals in the presence of SnCU (Scheme 12.21) [25]. The corresponding ketones and carboxylic acids have been isolated in quantitative yield. High enantioselectivities have been observed for the protonation of trimethylsilyl enol ethers derived from aromatic ketones and ketene bis(trimethylsilyl)acetals derived from 2-arylalkanoic acids. 

Mechanistically, the Brpnsted acid-catalyzed cascade hydrogenation of quinolines presumably proceeds via the formation of quinolinium ion 56 and subsequent 1,4-hydride addition (step 1) to afford enamine 57. Protonation (step 2) of the latter (57) followed by 1,2-hydride addition (step 3) to the intermediate iminium ion 58 yields tetrahydroquinolines 59 (Scheme 21). In the case of 2-substituted precursors enantioselectivity is induced by an asymmetric hydride transfer (step 3), whereas for 3-substituted ones asymmetric induction is achieved by an enantioselective proton transfer (step 2). 

Scheme 70 Enantioselective protonation of silyl enol ethers...

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). 

Enantioselective protonation of ketone metal enolates constitutes an important method for the preparation of optically active ketones. Fuji and coworkers have shown interest in the magnesium countercation in the enantioselective protonation of such enolates. Pertinent results are obtained with protonation of Mg(II) enolates of 2-alkyltetralones and carbamates derived from l,l -binaphtalene-2,2 -diol as chiral proton sources, as indicated in equation 82 and Table 11. 

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. 

The fir st examples of the highly enantioselective protonation of silyl enol ethers, such as (32), have been reported (68-94% ee), using a complex of SnCLt and the monomethyl ether of BINOL (i )-(33). hr this catalytic cycle, the active catalyst is reprotonated by a bulky phenol (Scheme 10).43... 

An unusually strong CD for open-chain ketones 141 was recently reported327. Ketones 141 were formed by hydrogenation of /J,y-unsaturated precursors (As not reported) which were obtained by enantioselective protonation of samarium enolates (Table 8). 

A chiral BINAP-diphosphine complexed to silver , with fluoride as counterion, catalyses the enantioselective protonation of TMS-enolates, giving ketones with a tertiary asymmetric a-carbon in up to 99% ee.294... 

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

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... 

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

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. 

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