Chiral Bronsted acids

Hall and coworkers developed the novel enantioselective allylboration of aldehydes catalyzed by chiral Bronsted acid in 2006 (Scheme 1.10) [12]. Moderate to good enantioselectivities (up to 80% ee) were observed in the reactions of allylboronate and both aromatic and aliphatic aldehydes with 10mol% of chiral Bronsted acid (7) [13], a Lewis acid-assisted chiral Bronsted acid (chiral LBA) developed by Yamamoto group. On the basis of their previous studies on allylboration reactions, the authors proposed that the use of the strong chiral Bronsted acid provides the chiral recognition event through B LA-type cyclic transition state with coordination to the oxygen atom of the allylboronate. 

A new type of Bronsted acid-assisted chiral Bronsted acid (chiral BBA) catalyst (30) possessing a bis(triflyl)methyl group was developed for enantioselective Mannich-type reaction by Yamamoto, Ishihara and coworkers [35]. The authors proposed the two possible chiral BBA form generated through intramolecular hydrogen bonding as shown in Scheme 1.34. 

Hodous BL, Fu GC (2002) Enantioselective addition of amines to ketenes catalyzed by a planar-chiral derivative of PPY possible intervention of chiral Bronsted-acid catalysis. J Am Chem Soc 124 10006-10007... 

Recently, catalytic asymmetric Diels-Alder reactions have been investigated. Yamamoto reported a Bronsted-acid-assistcd chiral (BLA) Lewis acid, prepared from (R)-3-(2-hydroxy-3-phcnylphenyl)-2,2 -dihydroxy-1,1 -binaphthyl and 3,5A(trifluoromethy I) - be nzeneboronic acid, that is effective in catalyzing the enantioselective Diels-Alder reaction between a,(3-enals and various dienes.62 The interesting aspect is the role of water, THF, and MS 4A in the preparation of the catalyst (Eq. 12.19). To prevent the trimerization of the boronic acid during the preparation of the catalyst, the chiral triol and the boronic acid were mixed under aqueous conditions and then dried. Using the catalyst prepared in this manner, a 99% ee was obtained in the Diels-Alder reaction... 

Chiral Bronsted acid co-catalysts do not promote formation of optically enriched products in analogous couplings to pyruvates, although increased rate and conversion in response to the Bronsted acid co-catalyst is unmistakably apparent. For pyruvates, protonation likely occurs subsequent to the C-C... 

Scheme 10 Plausible catalytic mechanism for alkyne-carbonyl coupling as supported by the effect of chiral Bronsted acid catalyst and deuterium-labeling...

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... 

Bronsted Acid-Assisted Chiral Lewis Acid Catalysts 285... 

Bronsted acid-assisted chiral Lewis acid... 

CHIRAL BRONSTED BASE-BRONSTED ACID BIFUNCTIONAL CATALYSIS... 

Inspired by the reaction mechanism of Noyori s catalytic enantioslective transfer hydrogenation of ketones (32) using a chiral Ru-amido complex 31, Dcariya et al. reported that 31 can also function as a unique Bronsted base-Bronsted acid catalyst... 

Finally in Chapters 11-13, some of the more recent discoveries that have led to a renaissance in the field of organocatalysis are described. Included in this section are the development of chiral Brdnsted acids and Lewis acidic metals bearing the conjugate base of the Bronsted acids as the ligands and the chiral bifunctional acid-base catalysts. 

Recent progress in chiral Bronsted-acid catalysis. (T. Akiyama, 2006) [Igj. 

Examples of the Bronsted-acid catalysts and hydrogen-bond catalysts are shown in Figure 2.1. We have recently reported the Mannich-type reaction of ketene silyl acetals with aldimines derived from aromatic aldehyde catalyzed by chiral phosphoric acid 7 (Figure 2.2, Scheme 2.6) [12]. The corresponding [5-amino esters were obtained with high syn-diastereoselectivities and excellent enantioselectivities. 

A well-defined chiral pocket produced by the binaphthyl skeleton and the appended bulky 3,3 substituents, (iii) A ring structure attached to the phosphoric acid moiety to prevent free rotation at the a-position of the phosphorus center. This feature is not found in other Bronsted acids such as carboxylic and sulfonic acids (Figure 5.2). 

This novel Bronsted acid catalyzes the Diels-Alder reaction between ethyl vinyl ketone and various acycUc siloxy dienes to furnish adducts in uniformly high yields and ee s. Further, the corresponding chiral phosphoric acid was unable to catalyze this reaction. 

Thereafter, Yamamoto reported the first metal-free Bronsted add catalyzed asymmetric protonahon reachons of silyl enol ethers using chiral Bronsted acid 13c in the presence of achiral Bronsted add media (Scheme 5.34) [61]. Importantly, replacement of sulfur and selenium into the N-triflyl phosphoramide increases both reactivihes and enanhoselectivihes for the protonation reaction. 

Figure 5.3 General modes of electrophilic activation by a chiral Bronsted acid.

Figure 1.20 Chiral Bronsted acid induced reductions.

Asymmetric Mannich reactions provide useful routes for the synthesis of optically active p-amino ketones or esters, which are versatile chiral building blocks for the preparation of many nitrogen-containing biologically important compounds [1-6]. While several diastereoselective Mannich reactions with chiral auxiliaries have been reported, very little is known about enantioselective versions. In 1991, Corey et al. reported the first example of the enantioselective synthesis of p-amino acid esters using chiral boron enolates [7]. Yamamoto et al. disclosed enantioselective reactions of imines with ketene silyl acetals using a Bronsted acid-assisted chiral Lewis acid [8]. In all cases, however, stoichiometric amounts of chiral sources were needed. Asymmetric Mannich reactions using small amounts of chiral sources were not reported before 1997. This chapter presents an overview of catalytic asymmetric Mannich reactions. 

Considerable effort has been devoted to the development of enantiocatalytic MBH reactions, either with purely organic catalysts, or with metal complexes. Paradoxically, metal complex-mediated reactions were usually found to be more efficient in terms of enantioselectivity, reaction rates and scope of the substrates, than their organocatalytic counterparts [36, 56]. However, this picture is actually changing, and during the past few years the considerable advances made in organocatalytic MBH reactions have allowed the use of viable alternatives to the metal complex-mediated reactions. Today, most of the organocatalysts developed are bifunctional catalysts in which the chiral N- and P-based Lewis base is tethered with a Bronsted acid, such as (thio)urea and phenol derivatives. Alternatively, these acid co-catalysts can be used as additives with the nucleophile base. 

In contrast to chiral amines, phosphorus-based chiral catalysts were less developed for asymmetric MBH transformations. As with amine-based reactions, the selectivity of the addition in phosphine-mediated reactions depends clearly on the nature of the complementary Bronsted acid co-catalysts used. 

A similar system was studied a few years later by the S chaus group [89], who compared several binaphthol-derived chiral Bronsted acids such as 92a and 94a-d in the triethylphosphine-mediated MBH reaction between cyclohexenone and aldehydes. Optimized conditions were found with 2-20 mol% of chiral Bronsted acid and an excess of triethylphosphine (200 mol%) as the nucleophilic promoter at 0-10 °C in THF. Using PMe3 or P(n-Bu)3 in the reaction afforded 76 in yields similar to that of PEt3, but in lower enantioselectivity (50% and 64% ee, respectively). The use of only (R)-BINOL in the MBH reaction of dihydrocinnamaldehyde 74 and cyclohexenone 75 resulted in the formation of 76 in 16% ee. Partially saturated BINOL derivatives such as 94a-d offered high chemical yield and enantio selectivity (Scheme 5.19) [91]. Optimal results with the addition of aliphatic al-... 

Scheme 5.19 The achiral phosphine and chiral binaphthol-derived Bronsted acid-catalyzed MBH reaction of cyclohexenone and 3-phenyl propionaldehyde.

As discussed previously for the MBH reaction, the aza-MBH reaction involves rate-limiting proton transfer in the absence of added protic species (Scheme 5.22) [93]. In contrast to the MBH reaction, however, the aza-MBH exhibits no autocatalysis. Bronsted acidic additives lead to substantial rate enhancements through acceleration of the elimination step. It has been shown that phosphine catalysts - either alone or in combination with protic additives - may trigger epimerization of the aza-MBH product by proton exchange at the stereogenic center. This fact indicates that the spatial arrangement of a bifunctional chiral catalyst in this reaction is crucial not only for the stereodifferentiation within the catalytic cycle but also to prevent subsequent epimerization. 

Asymmetric organocatalytic Morita-Baylis-Hillman reactions offer synthetically viable alternatives to metal-complex-mediated reactions. The reaction is best mediated with a combination of nucleophilic tertiary amine/phosphine catalysts, and mild Bronsted acid co-catalysts usually, bifunctional chiral catalysts having both nucleophilic Lewis base and Bronsted acid site were seen to be the most efficient. Although many important factors governing the reactions were identified, our present understanding of the basic factors, and the control of reactivity and selectivity remains incomplete. Whilst substrate dependency is still considered to be an important issue, an increasing number of transformations are reaching the standards of current asymmetric reactions. 

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