Direct catalysis asymmetric aldol reactions

Shibasaki, M., Yoshikawa, N., Matsunaga, S. Direct catalytic asymmetric aldol reaction. Comprehensive Asymmetric Catalysis, Supplement 2004, 1, 135-141. 

Keywords Aldol, Direct, Ketone, Asymmetric catalysis, Enantioselective reaction, Diastereo-selectivity, 1,2-Diol, Aldehyde, Enamine, Lewis acid, Bronsted base, Organocatalysis, Bimetal-... 

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). 

Aminocatalysis is a biomimetic strategy used by enzymes such as class I aldolases. Application of aminocatalysis in an asymmetric aldol reaction was reported in the early 1970s. Proline (19) efficiently promoted an intramolecular direct aldol reaction to afford Wieland-Miescher ketone in 93% ee [17,18]. More than 25 years later, in 2000, List, Barbas, and co-workers reported that proline (19) is also effective for intermolecular direct aldol reactions of acetone (le) and various aldehydes 3. Notably, the reaction proceeded smoothly in anhydrous DMSO at an ambient temperature to afford aldol adducts in good yield and in modest to excellent enantioselectivity (up to >99% ee, Scheme 9) [19-22]. The chemical yields and selectivity of proline catalysis are comparable to the best metallic catalysts, although high catalyst loading (30 mol %) is required. Proline (19)... 

Important extensions of proline catalysis in direct aldol reactions were also reported. Pioneering work by List and co-workers demonstrated that hydroxy-acetone (24) effectively serves as a donor substrate to afford anfi-l,2-diol 25 with excellent enantioselectivity (Scheme 11) [24]. The method represents the first catalytic asymmetric synthesis of anf/-l,2-diols and complements the asymmetric dihydroxylation developed by Sharpless and other researchers (described in Chap. 20). Barbas utilized proline to catalyze asymmetric self-aldoli-zation of acetaldehyde [25]. Jorgensen reported the cross aldol reaction of aldehydes and activated ketones like diethyl ketomalonate, in which the aldehyde... 

Saito S, Yamamoto H. Design of acid-base catalysis for the asymmetric direct aldol reaction. Acc. Chem. Res. 2004 37 570-579. 

Catalytic aldol reactions are among the most useful synthetic methods for highly stereo-controlled asymmetric synthesis. In this account we discuss the recent development of a novel synthetic technique which uses tandem enzyme catalysis for the bi-directional chain elongation of simple dialdehydes and related multi-step procedures. The scope and the limitations of multiple one-pot enzymatic C-C bond formations is evaluated for the synthesis of unique and structurally complex carbohydrate-related compounds that may be regarded as metabolically stable mimetics of oligosaccharides and that are thus of interest because of their potential bioactivity. 

Design of Acid-Base Catalysis for the Asymmetric Direct Aldol Reaction ... 

Type I aldolases activate the aldol donor by the formation of enamines with active site amino acids and an alternate approach to the direct catalytic asymmetric aldol reaction centres on mimicking this process using proline-based organocatalysts. In fact, one of the earliest examples of asymmetric catalysis uses (S)-profine (7.66) as a catalyst for the intramolecular aldol reaction (the Hajos-Eder-Saeur-Wiechert reaction).As an example the achiral triketone (7.67) cyclises to give the aldol product (7.68) with good enantioselectivity. 

With respect to the covalent activation in conjugate additions, the catalyst, usually a primary or a secondary amine, can reversibly form a chiral enamine [ 11 ] to activate the nucleophile (D, Fig. 2.2) or a chiral iminium ion [12] to activate the acceptor (E, Fig. 2.2). The detection of enamine intermediates in asymmetric oiganocatalysis has been for a long time the missing piece of evidence for the commonly accepted mechanism of enamine catalysis. This gap has been recently solved with the first detection and structnral characterization of enamine intermediates in proUne-cata-lyzed aldol reactions by real-time NMR spectroscopy [13] and the direct observation of an enamine intermediate in the crystal strnctnre of an aldolase antibody [14]. 

The direct asymmetric aldol reaction is a powerful tool for C-C bond formation. Enamine-iminium catalysis is the most developed, and it is nicely complimented by other modes of activation that rely on hydrogen bond formation. Mechanistically, all proline-based catalysts activate donors through the formation of an enamine intermediate. Other activation modes rely on enolate formation, ionic interactions, or hydrogen bond formation, though the mechanism is not always known. 

As depicted in Scheme 7, the synthesis of the mosquito oviposition pheromone (-)-6-acetoxy-5-hexadecanolide (28) via an intermolecular aldol reaction represents a powerful demonstration of the high potential of asymmetric enamine catalysis (45, 46). It is noteworthy that a methodologically different successful organocatalytic approach towards 28, based on an asymmetric a-oxygenation, was reported recently (727). Reaction of aldehyde 136 with dibenzoyl peroxide (BzOOBz) and hydroqui-none (HQ) (722) in the presence of the TMS-protected prolinol catalyst (S)-138 followed by a direct allyation gave the benzoyl-protected 139 in moderate yield and good selectivity. Intermediate 139 could then be further transformed to give (—)-(57 ,65)-6-acetoxy-5-hexadecanolide (28) (Scheme 33). 

General reviews include the direct aldol/" aldoi and related processes,the Zimmerman-Traxler TS model used to explain the stereochemistry of the aldoi condensation,catalysis of direct asymmetric aldols by prolinamides versus prolinef/zioamides, " " the catalytic asymmetric aldoi reaction in aqueous media (considering both organometallic and organocatalytic approaches), " the use of BINAP oxide in enantioselective direct aldols,and the use of metal enolates as synthons. " ... 

Direct asymmetric aldol reactions in aqueous media catalysed by phenolic proli-namides show enhanced de and ee when the catalysis is augmented by LiCl, ZnClj or 0... 

The aldol reaction is an important carbon-carbon bond-forming method for constructing p-hydroxy carbonyl compounds in which new stereogenic centers are created. Especially, regio- and stereoselective aldol reactions are the most useful for organic synthesis of complex molecular skeletons [11-15]. From a viewpoint of atom economy, an aldol reaction via direct formation of an enolate with a catalytic amoimt of base is highly desired, and high Brpnsted basicity of the alkaline-earth metal compounds is suitable for this purpose. In recent researches on chiral alkaline-earth metal catalysis, direct-type asymmetric aldol and related reactions have been developed. 

In 1999, Shibasaki et al. reported on the direct catalytic asymmetric aldol reaction (Scheme 8.36), which was not necessary to preconvert the ketone moiety into the more reactive species such as an enolate ion and enol ether." The addition of bulky aldehyde 248 into the mixture of ethyl methyl ketone 249 and LaLi3tris(/ -binaphthoxide) [(/ )-LLB)] afforded aldol adduct 250 in excellent stereoselectivity. However, this reaction required a large amount of ketones (50 equiv), and catalyst (20 mol%) were required. They improved the conditions to reduce the amount of ketone (5 equiv) and catalyst (8 equiv) by using the hetero-polymetallic asymmetric catalyst (Scheme 8.37). The addition of the catalytic amount of potassium bis(trimethylsilyl) amide (KHMDS) and H2O was found to be effective to the catalysis. Adduct 253 was converted into ester 254 by the... 

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