Catalytic Enantioselective Deprotonation

Here both enantiomers of t-Bu-BisP (BH3)2 are prepared in almost enan-tiopure form with substoichiometric amounts of chiral inductor. A severe 

Entry Diamine, equiv. Yield (1) (%) Yield meso (%) ee (1) References 

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Since most chiral lithium amides are expensive to produce, an effective, readily available and cost-efficient catalytic system using a catalytic amount of chiral lithium amide is currently a significant challenge. The chiral lithium amide should also be available in both enantiomeric forms. Asami and coworkers reported in 1994110 the first catalytic enantioselective deprotonation using chiral lithium amides. 

Asami and coworkers synthesized and applied the chiral lithium amide 14, which appeared to be more reactive than 4. It was successfully used in catalytic enantioselective deprotonation of both cyclic and acyclic epoxides (Scheme 69). Interestingly, the addition of DBU lowered the enantioselectivity ... 

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. 

In the first experiments the two-ligand catalysis approach was followed /-butyldimethylphosphine borane, bispidine 137 and substoichiometric amounts (0.2 equiv.) of ( )-sp or Me-134. Later it has been found that the absence of the stoichiometric ligand (one-ligand catalysis) also lead to satisfactory results. " For example, an application of the catalytic enantioselective deprotonation can be seen in Scheme 5.55 (Table 5.21). 

A broad comparison between one- and two-ligand catalysis for the catalytic enantioselective deprotonation of phosphine borane 29 with either -BuLi or i-BuLi has been recently carried out by O Brien and co-workers (Scheme 5.56). In the two-ligand catalysis they employed bispidine 137, LiDMAE or A-methylmorpholine. 

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... 

Snapper and Hoveyda reported a catalytic enantioselective Strecker reaction of aldimines using peptide-based chiral titanium complex [Eq. (13.11)]. Rapid and combinatorial tuning of the catalyst structure is possible in their approach. Based on kinetic studies, bifunctional transition state model 24 was proposed, in which titanium acts as a Lewis acid to activate an imine and an amide carbonyl oxygen acts as a Bronsted base to deprotonate HCN. Related catalyst is also effective in an enantioselective epoxide opening by cyanide "... 

By contrast with the enantioselective deprotonation of meso oxiranes, there is only a limited number of reports on the kinetic resolution of unsymmetrically substituted oxiranes. This reaction involves the preferential recognition of one of the two enantiomers of a racemic mixture by a chiral reagent to provide both the starting material and the product in enantioenriched form . Several HCLA bases developed for enantioselective deprotonation have been tested as chiral reagent in stoichiometric or catalytic amount for the kinetic resolution of cyclic and linear oxiranes. 

Eaton s base also has stimulated use of an enantiopure alkylmagnesium amide for enantioselective deprotonation of a set of 4-substituted cyclohexanones (equation 36) further work in this area can be expected. Einally, efficient ortho-magnesiation of A-phenylsulfonylpyrrole has been achieved with an excess of (PrMgCl and a catalytic amount (5mol%) of (Pr2NH to serve as a proton transfer agent subsequent reaction with a range of electrophiles afforded decent yields of products (equation 37). ... 

The catalytic, enantioselective, vinylogous Mannich reaction has recently emerged as a very powerful tool in organic synthesis for the assembly of highly functionalized and optically enriched 6 amino carbonyl compounds. Two distinctly different strategies have been developed. The first approach calls for the reaction of preformed silyl dienolates as latent metal dienolates that react in a chiral Lewis acid or Bronsted acid catalyzed Mukaiyama type reaction with imines. Alternatively, unmodified CH acidic substrates such as a,a dicyanoalkenes or 7 butenolides were used in vinylo gous Mannich reactions that upon deprotonation with a basic residue in the catalytic system generate chiral dienolates in situ. 

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. 

While several stoichiometric chiral lithium amide bases effect the rearrangement of raeso-epoxides to allylic alcohols [1], few examples using catalytic amounts of base have been reported. Asami applied a pro line-derived ligand to the enantioselective deprotonation of cyclohexene oxide to afford 2-cyclohexen-... 

Using this concept, the Koga group have developed [14] catalytic asymmetric deprotonation of 4-alkylcyclohexanones (Scheme 3). For example, deprotonation of 12 gives silyl enol ether 13 in good enantioselectivity. The reaction is accomplished by combining 30 mol% of chiral lithium amide 15 along... 

Asami, M., Ishizuka, T. and Inoue, S. (1994) Catal3ftic enantioselective deprotonation of mejo-epoxides by the use of chiral lithium amide. Tetrahedron.Asymmetry, 5, 793-796 Seki, A. and Asami, M. (2002) Catalytic enantioselective rearrangement of mejo-epoxides mediated by chiral lithium amides in the presence of excess cross-linked polymer-bound hthium amides. Tetrahedron, 58, 4655 663. 

Reactions catalyzed by phosphazenes have also been described. The catalytic enantioselective alkylation of the amino acid intermediate Ph2C = NCH2C02-t-Bu by alkyl halides was reported to occur efficiently in the presence of BEMP or BTTP [52], and such bases catalyze Michael additions in non-aqueous [53] and aqueous media [54]. Methyl [55] and butyl [56] methacrylates are anionically polymerized using a phosphazene base as an initiator in the presence of an ester that is apparently deprotonated in the process. Functioning as promoters in the... 

Shibasaki developed the first catalytic enantioselective hydropho-sphonylation of aldimines with the use of chiral heterobimetallic lantha-num(iii) potassium(i) tris(binaphtholate) 89, which provides optically active a-amino phosphonates with high enantioselectivities (Scheme 2.50). Similar to lithium catalyst 26 and sodium catalyst 67, potassium catalyst 89 acts as an acid-base bifunctional catalyst to activate both nucleophiles and electrophiles. In particular, in this reaction, deprotonation of dimethyl phosphite by more basic potassium catalyst 89 was essential for increasing the reactivity and enantioselectivity, while less basic lithium catalyst 26 and sodium catalyst 67 were not effective. 

In 2001, Lectka and co-workers [52] adapted their method for catalytic asymmetric a-halogenation of acid chlorides to include bromination reactions (Scheme 13.24). Through use of the same organocatalyst and shuttle-deprotonation strategy, and a polybromoquinone as the bromine source, the catalytic enantioselective... 

The diphosphines discussed in this section are of the same type as those seen in the beginning of Section 5.2.1.2, the only difference being that they do not bear any aromatic substituent, i.e. they are l,2- )w(alkylmethylphosphino)ethanes. They have been proved to be superb in hydrogenation reactions (Chapter 7) and other catalytic transformations (Chapter 8) and form one of the most important types of new generation R-stereogenic ligands. The name BisP was coined when their synthesis was first reported by Imamoto and co-workers. Their preparation consists of the enantioselective deprotonation protocol followed by Cu(II) oxidative coupling (Scheme 5.28 and Table 5.14). 

It is well known that certain diamines increase the reactivity of organolithium compounds by complexation to the Li atom. Consequently, with the appropriate chiral diamines it should be possible to perform catalytic asymmetric deprotonations. In the original report of Evans and co-workers it is mentioned that the enantioselection can be maintained with only 0.7 equivalents of ( )-sparteine, with no further details. These ideas have been recently exploited for t-butyldimethylphosphine borane and the analogous sulfide with sparteine and its surrogates. It can be understood with the catalytic cycle of Scheme 5.54, reported by O Brien and co-workers. 

In this chapter, catalytic methods for ligand synthesis are described in detail. In spite of that, the enantioselective deprotonation of tert-butyldimethylpho-sphine borane with a catalytic amount of (—)-sparteine or a (+)-sparteine surrogate, reported by O Brien and co-workers, is included for convenience in Chapter 5, Section 5.4.2, following the discussion on the general strategy of desymmetrisation by enantioselective deprotonation. The coverage of Section 6.2 is mainly limited to systems in which the chiral catalyst acts in the step where the... 

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). 

Hafez AM, Taggi AE, Wack H, Esterbrook J, Lectka T. Reactive ketenes through a carbonate/amine shuttle deprotonation strategy catalytic, enantioselective a-bromination of acid chlorides. Org. Lett. 2001 3(13) 2049-2051. 

Metzner and co-workers reported a one-pot epoxidation reaction in which a chiral sulfide, an allyl halide, and an aromatic aldehyde were allowed to react to give a trons-vinylepoxide (Scheme 9.16c) [77]. This is an efficient approach, as the sulfonium salt is formed in situ and deprotonated to afford the corresponding ylide, and then reacts with the aldehyde. The sulfide was still required in stoichiometric amounts, however, as the catalytic process was too slow for synthetic purposes. The yields were good and the transxis ratios were high when Ri H, but the enantioselectivities were lower than with the sulfur ylides discussed above. 

A number of workers have made progress on this front. Asami and coworkers have anchored the stoichiometric base on the solid phase to realize a catalytic desymmetrization using lithiated diamine 135. Andersson has shown that slow addition of LDA results in an improvement in enantioselectivity when using his bicyclic base 136, while Ahlberg has illustrated that a stoichiometric base such as lithiated 1,2-dimethylimidazole results in an efficient catalytic system using diamine 137. Alexakis has published a smdy involving a number of chiral ethane-and propane-diamines in the catalytic deprotonation of cyclohexene oxide. Enan-tioselectivities observed are moderate, with diamine 138 providing the desired product in 59% ee and 80% yield. ... 

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