Asymmetric catalytic deprotonation

Liu and Kozmin used the asymmetric deprotonation of hetero-epoxides such as 106 as key step in the synthesis of chiral polyols120. The deprotonation was carried out using the chiral lithium amide pool published in the literature and both stoichiometric and catalytic deprotonations gave satisfactory results (Scheme 78). 

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. 

In 2004, Trauner and co-workers published a follow-up communication on their asymmetric catalytic system. Under optimized conditions, they were able to achieve good to excellent levels of enantioselectivity for a variety of substrates using complex 78 with lower catalyst loadings (10 mol %). It is important to note however, that the specific use of an alkoxy dienone substrate lacking a i-substituent on one of the alkenes (such as 76) was required for high yields and good enantioselectivities. Since the stereocenter formed during electrocyclization is subsequent destroyed on deprotonation of the allylic cation (see Section 3.4.3), the control of absolute stereochemistry in this case is solely due to facially selective reprotonation of the enolate. 

The first attempt at a catalytic asymmetric sulfur ylide epoxidation was by Fur-ukawa s group [5]. The catalytic cycle was formed by initial alkylation of a sulfide (14), followed by deprotonation of the sulfonium salt 15 to form an ylide 16 and... 

Enantioselective deprotonations of meso substrates such as ketones or epoxides are firmly entrenched as a method in asymmetric synthesis, although the bulk of this work involves stoichiometric amounts of the chiral reagent. Nevertheless, a handful of reports have appeared detailing a catalytic approach to enantioselective deprotonation. The issue that ultimately determines whether an asymmetric deprotonation may be rendered catalytic is a balance of the stoichiometric base s ability... 

In the presence of thiourea catalyst 122, the authors converted various (hetero) aromatic and aliphatic trons-P-nitroalkenes with dimethyl malonate to the desired (S)-configured Michael adducts 1-8. The reaction occurred at low 122-loading (2-5 mol%) in toluene at -20 to 20 °C and furnished very good yields (88-95%) and ee values (75-99%) for the respective products (Scheme 6.120). The dependency of the catalytic efficiency and selectivity on both the presence of the (thio) urea functionality and the relative stereochemistry at the key stereogenic centers C8/C9 suggested bifunctional catalysis, that is, a quinuclidine-moiety-assisted generation of the deprotonated malonate nucleophile and its asymmetric addition to the (thio)urea-bound nitroalkene Michael acceptor [279]. 

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. 

Deracemization. Results from Michael additions described earlier (Scheme 10.8) led Toke and co-workers to an interesting deracemization study. When racemic Michael adduct 106 was reacted with a catalytic amount of base in the presence of the chiral crown 12 for 8 min, the resulting product was optically active (40% ee). The authors propose that a deprotonation followed by reprotonation of the resulting chiral ion-pair accounts for the asymmetric induction [39]. 

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). 

Fig. 10.1 Selected chiral sulfides and results obtained using alkylation/ deprotonation catalytic methodology for the asymmetric synthesis of trans-stilbene oxide, dr = trans cis solvents and additives vary.

As in catalytic ylide epoxidation (see Section 10.2.1.1), an alternative catalytic cycle can be based on generation of the ylide in situ by reaction of a sulfide with an alkyl halide to form a salt, which can then be deprotonated [76]. In 2001, Saito et al. reported the asymmetric version of this cycle using a 3 1 ratio of alkyl halide to sulfonyl imine (see Scheme 10.18) [81]. Good yields and ee-values were reported for aryl- and styryl-substituted aziridines using stoichiometric amounts of sulfide 24, and the diastereoselectivities ranged from 1 1 to 4 1. Unfortunately, when loadings were reduced the reaction times became longer and lower yields were reported (see Table 10.2). 

Scheme 10.18 Catalytic asymmetric aziridination via alkylation of sulfide 24 and deprotonation.

Scheme 10.22 Catalytic asymmetric cyclopropanation using sulfur ylides via an alkylation/deprotonation route.

Table 10.4 Catalytic asymmetric cyclopropanation with 41a using sulfide alkylation/deprotonation route (according to Scheme 10.22).

Catalytic versions of the asymmetric deprotonations have been conceived remarkably early107. High e.e. values (up to 82%) were obtained in the test reaction of t-butylcyclohexanone provided 2 equivalents HMPA and TMSC1 were added to the medium at — 78 °C. A catalytic cycle has been proposed on the basis of NMR observations (Scheme 24). 

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