Mukaiyama Bronsted acids

In addition to Bronsted acid promoted Fischer-type glycosylations, Lewis acids have been investigated (Scheme 3.4). A variety of Lewis acids promote glycosylation under mild conditions, often in substoichiometric amounts. The earliest examples include ZnCl2 [18] and FeCl3 [19], although these readions were demonstrated only for preparation of trehalose-type disaccharides. Mukaiyama et al. have very recently developed metal triflate catalysts for the dehydrative glycosylation with... 

Sc(() l f) ( is an effective catalyst of the Mukaiyama aldol reaction in both aqueous and non-aqueous media (vide supra). Kobayashi et al. have reported that aqueous aldehydes as well as conventional aliphatic and aromatic aldehydes are directly and efficiently converted into aldols by the scandium catalyst [69]. In the presence of a surfactant, for example sodium dodecylsulfate (SDS) or Triton X-100, the Sc(OTf)3-catalyzed aldol reactions of SEE, KSA, and ketene silyl thioacetals can be performed successfully in water wifhout using any organic solvent (Sclieme 10.23) [72]. They also designed and prepared a new type of Lewis acid catalyst, scandium trisdodecylsulfate (STDS), for use instead of bofh Sc(OTf) and SDS [73]. The Lewis acid-surfactant combined catalyst (LASC) forms stable dispersion systems wifh organic substrates in water and accelerates fhe aldol reactions much more effectively in water fhan in organic solvents. Addition of a Bronsted acid such as HCl to fhe STDS-catalyzed system dramatically increases the reaction rate [74]. 

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. 

As a result of the preliminary examples described in Sect. 3.1 and the quest for automation techniques in solution-phase synthesis, various examples of continuous flow processes appeared in the literature lately which utilized solid-phase-bound chemical catalysts. In a simple example, Yamamoto and coworkers studied the use of super Bronsted acids loaded on polystyrene beads 5 for use in a single-pass column system (Fig. 4) [30]. It was shown that these columns are suited for the acetylation of alcohols, acetalization of carbonyl compounds, Sakurai-Hosomi allylation reactions, and Mukaiyama aldol reactions. 

Alternatively, the iminium-activation strategy has also been apphed to the Mukaiyama-Michael reaction, which involves the use of silyl enol ethers as nucleophiles. In this context, imidazolidinone 50a was identified as an excellent chiral catalyst for the enantioselective conjugate addition of silyloxyfuran to a,p-unsaturated aldehydes, providing a direct and efficient route to the y-butenolide architecture (Scheme 3.15). This is a clear example of the chemical complementarity between organocatalysis and transition-metal catalysis, with the latter usually furnishing the 1,2-addition product (Mukaiyama aldol) while the former proceeds via 1,4-addition when ambident electrophiles such as a,p-unsaturated aldehydes are employed. This reaction needed the incorporation of 2,4-dinitrobenzoic acid (DNBA) as a Bronsted acid co-catalyst assisting the formation of the intermediate iminium ion, and also two equivalents of water had to be included as additive for the reaction to proceed to completion, which... 

A. Scettri, V. De Sio, R. Villano, M.R. Acocella, Solvent-Free organocatalytic Mukaiyama-Michael addition of 2-trimethylsilyloxy furan to nitroalkenes catalyzed by bronsted acids, Synlett (2009) 2629-2632. 

Vinylogous Mukaiyama Aldol Reactions in Bronsted Acid Catalysis... 

The Mukaiyama aldol reaction is beyond doubt a brilliant triumph of modem synthetic organic chemistry however, the reaction products are contaminated with pre-activated silyl enol ethers derived from the carbonyl compounds with stoichiometric amounts of silylation agent and base. In addition, silylated wastes are inherently formed. Circumventing the pre-activation process improves atom efH-ciency in this case, the carbonyl nucleophiles react directly with the carbonyl electrophiles in the presence of catalyst. The first Bronsted acid-catalyzed direct aldol reactions have been achieved using chiral Hg-BINOL-derived phosphoric acid 96 (Scheme 28.12) [66], The aldol products (127) have syn-configurations and, thus, this reaction is complementary to (S)-proHne catalysis in Brpnsted acids, which in general yields the anti configuration [11]. 

Studies of catalytic asymmetric Mukaiyama aldol reactions were initiated in the early 1990s. Until recently, however, there have been few reports of direct catalytic asymmetric aldol reactions [1]. Several groups have reported metallic and non-metallic catalysts for direct aldol reactions. In general, a metallic catalysis involves a synergistic function of the Bronsted basic and the Lewis acidic moieties in the catalyst (Scheme 2). The Bronsted basic moiety abstracts an a-pro-ton of the ketone to generate an enolate (6), and the Lewis acidic moiety activates the aldehyde (3). 

In 2009, List introduced a binaphthyl-derived, chiral disuUbnimide (28) as a new structural motif of a powerful chiral Bronsted add that could activate simple aldehydes [80, 81]. Evaluation of the catalytic activity and stereocontrolling ability of 28 in the Mukaiyama aldol reaction of silyl ketene acetal with naphthaldehyde revealed that 28 was not only far more reactive than phosphoric acid 29 and phos-phoramide 30 but also capable of affording the aldol product with high enantiose-lectivity (Scheme 7.53). 

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