Asymmetric Deprotonation-Protonation

Alonso et al. (2005) described anion-radical proton abstraction from prochiral organic acids. If the anion radicals were formed from homochiral predecessors, asymmetric deprotonation can be reached. However, low reactivity of the anion radical is required Slow proton transfer, that is, high activation energy of the reaction discriminates well between diastereoselective transition states. 

Asynunetric Deprotonation/Protonation of Ketones. Lithium amides of chiral amines have been used for performing asymmetric deprotonations of symmetrically substituted (prochiral) ketones. The resulting optically active enols orenol derivatives (most frequently enol silanes) are highly versatile synthetic intermediates. Particularly useful for this purpose are chiral amines possessing Cj symmetry, such as (1). For example, reaction of 4-r-butylcyclohexanone with the lithium amide of (R,R)-(1) (readily prepared in situ by treatment of (1) with n-Butyllithium) is highly stereoselective the resulting enol silyl ether possesses an 88% ee (eq 4). ... 

Various processess (asymmetric protonation or asymmetric deprotonation) which are in principle strictly stoichiometric with respect to the chiral reagent have been transformed into catalytic processes by the addition of an achiral reagent or an achiral ligand. 

Asymmetric deprotonation of a prochiral compound having a sufficiently acidic C-H bond can be performed by a lithium amide generated from an enantio-pure secondary amine or by an organolithium reagent in the presence of a chiral tertiary amine [557, 559]. A chiral mixed aggregate is usually formed [77, 81, 974], and the reaction of this intermediate with electrophiles (including proton sources) can lead to a predominant enantiomer. 

Asymmetric induction in these reactions occurs either in the first deprotonation step [Eq. (la)] or in a postdeprotonation step [1] [(Eq. (lb)]. When the enantioselection occms in the deprotonation step, a proton is stereoselectively removed by a chiral base from a prochiral substrate to provide a configuration-ally stable enantioemiched carbanion, which reacts with an electrophile giving an enantioenriched product. This enantiodetermining pathway is termed asymmetric deprotonation . In fact, reactions of a-oxy and a-amino carban-ions are often controlled through an asynunetric deprotonation pathway (Fig. 2) [1,2]. 

Deprotonation-protonation is an alternative choice for asymmetric induction. Deprotonation of the meso-phospholane oxide with s-BuLi-(-)-sparteine and subsequent protonation with acetic acid afforded trans-phospholane oxide with 45 % ee together with the recovered raeso-phospholane oxide (Table 8) [80]. 

The use of enantiomerically pure bases to catalyse asymmetric deprotonations is an exciting idea that has been shown to be technically feasible. The major difficulty is that the catalytic base must be continuously deprotonated under the reaction conditions. In order to be effective, whatever achiral base provides the continuous deprotonation must not directly deprotonate the substrate. This is conceptually similar to catalytic protonation reactions, which are described in more detail in the next section. 

The asymmetric deprotonation of carbamates can be extended beyond pyrrolidines. Beak, for example, disclosed metalation of benzylamine 60 and alkylation of the resulting carbanion with methyl triflate to furnish 61 in 98 % ee (Scheme 13.10) [55]. Subsequent proton abstraction from 61 was effected with u-BuLi in the presence of TMEDA, followed by stereospecific alkylation with allyl triflate. Following removal of the p-methoxybenzyl group (CAN), the trisubstituted carbamate 62 was isolated in 97 % ee. 

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>. 

Coordination of ammonia or a substituted ammonia to a metal ion alters markedly the N — H dissociation rate (see See. 6.4.2). Since also proton dissoeiation of complexed ammines is base-catalyzed, then exchange can be made quite slow in an aeid medium. Thus, in a eoordinated system of the type 12, containing an asymmetric nitrogen atom (and this is the only potential souree of optical activity), there is every chance for a successful resolution in acid conditions, since inversion is expected only after deprotonation. It was not until 1966 that this was suc-eessfully performed, however, using the complex ion 12. A number of Co(III), Pt(II) and Pt(IV) complexes containing sarcosine or secondary amines have been resolved and their raeemizations studied.Asymmetrie nitrogen centers appear eonfined to d and d ... 

The asymmetric (—)-sparteine-mediated deprotonation of alkyl carbamates was unprecedented until discovered in 1990 °. For the first time, protected 1-alkanols could be transformed generally to the corresponding carbanionic species by a simple deprotonation protocol. Moreover, an efficient differentiation between enantiotopic protons in the substrate took place and the extent of stereoselection could be stored in a chiral ion pair, bearing the chiral information at the carbanionic centre. 

Only three PBP complexes of Fe(III) with acyclic ligands from the class of bis(acylhydrazone) of dap have been structurally characterized at present (41,49,53) and this prompted studies in that direction. Both direct and template synthesis afforded the complex [Fe(Hdapsox) Cl2] - 1/2H20 (9) with a monoanionic H2dapsox ligand (7). Protonation of the coordinated ligand was unsuccessful even upon addition of HC1 to the reaction mixture (Scheme 5). In spite of asymmetrical mono-deprotonation, the ligand was symmetrically pentadentately... 

The heterobimetallic multifunctional complexes LnSB developed by Shibasaki and Sasai described above are excellent catalysts for the Michael addition of thiols [40]. Thus, phenyl-methanethiol reacted with cycloalkenones in the presence of (R)-LSB (LaNa3tris(binaphthox-ide)) (10 mol %) in toluene-THF (60 1) at -40°C, to give the adduct with up to 90% ee. A proposed catalytic cycle for this reaction is shown in Figure 8D.9. Because the multifunctional catalyst still has the internal naphthol proton after deprotonation of the thiol (bold-H in I and II), this acidic proton in the chiral environment can serve as the source of asymmetric protonation of the intermediary enolate, which is coordinated to the catalyst II. In fact, the Michael addition of 4-/en-butylbenzcnethiol to ethyl thiomethacrylate afforded the product with up to 93% ee using (R)-SmSB as catalyst. The catalyst loading could be reduced to 2 mol % without affecting enantioselectivity of the reaction. 

Asymmetric protonations. Deprotonation (LDA) of the imine (2b) obtained from racemic 2-methylcyclohexanone and lb followed by protonation with ethanol and hydrolysis gives (S)-2-methylcyclohexane (3) in 90% ee. The enantioselectivity depends in part on the R group when R = H (2a), (R)-3 is formed in 22% ee. When (-butyl alcohol is used as the proton source, completely inactive 3 is obtained by the same sequence. No enantioselectivity is observed in protonation of the lithioenamine of 2-methylcyclohexanone and nonsupported la.2... 

Taddol has been widely used as a chiral auxiliary or chiral ligand in asymmetric catalysis [17], and in 1997 Belokon first showed that it could also function as an effective solid-liquid phase-transfer catalyst [18]. The initial reaction studied by Belokon was the asymmetric Michael addition of nickel complex 11a to methyl methacrylate to give y-methyl glutamate precursors 12 and 13 (Scheme 8.7). It was found that only the disodium salt of Taddol 14 acted as a catalyst, and both the enantio- and diastereos-electivity were modest [20% ee and 65% diastereomeric excess (de) in favor of 12 when 10 mol % of Taddol was used]. The enantioselectivity could be increased (to 28%) by using a stoichiometric amount of Taddol, but the diastereoselectivity decreased (to 40%) under these conditions due to deprotonation of the remaining acidic proton in products 12 and 13. Nevertheless, diastereomers 12 and 13 could be separated and the ee-value of complex 12 increased to >85% by recrystallization, thus providing enantiomerically enriched (2S, 4i )-y-methyl glutamic add 15. 

SAMs of a molecular rectifier candidate - donor-jr-acceptor molecule 88 - were investigated with an alkanethiolate-covered STM probe by Ashwell et al. [25]. The molecular junction shown in Fig. 10.3 demonstrated highly asymmetric I(V) characteristics, which was taken as evidence for rectification of the monolayer. Depending on the experimental details, rectification ratios up to around 18 was observed. Reversible protonation and deprotonation of the donor moiety, C6H4N(CH3)2, in acidic or basic media, respectively, switched the rectification capability of the monolayer OFF and ON. This observation strongly indicates that the rectification behavior is an inherent property of the molecule. 

The proposed mechanism for this catalytic asymmetric hydrophosphonylation is shown in Figure 35. The first step of this reaction is the deprotonation of dimethyl phosphite by LPB to generate potassium dimethyl phosphite. This potassium phosphite immediately coordinates to a lanthanoid to give I due to the strong oxophilicity of lanthanoid metals. The complex I then reacts (in the stereochemistry-determining step) with an imine to give the potassium salt of the a-aminophosphonate. A proton-exchange reaction affords the product... 

The design for a direct catalytic asymmetric aldol reaction of aldehydes and unmodified ketones with bifunctional catalysts is shown in Figure 36. A Brpnsted basic functionality (OM) in the heterobimetallic asymmetric catalyst (I) could deprotonate the a-proton of a ketone to generate the metal enolate (II), while at the same time a Lewis acidic functionality (LA) could activate an aldehyde to give (III), which would then react with the metal enolate (in a chelation-controlled fashion) in an asymmetric environment to afford a P-keto metal alkoxide (IV). 

The deprotonation of the polyprotic amino acid mentioned above occurs in a series. However, polyprotic amino acids may either give up or take up protons in a combination of parallel and series ways. For example, an asymmetrical dibasic amino acid may undergo ionization in parallel followed by further ionization in series. The same basic approach for polyprotic amino acids is applied to the asymmetrical ionization process, then ... 

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