Chem Soc Rev View Article Online
Published on 22 October 2013. Downloaded by National University of Singapore on 13/06/2014 09:01:18.
TUTORIAL REVIEW
Cite this: Chem. Soc. Rev., 2014, 43, 577
View Journal | View Issue
Catalytic asymmetric aldol reactions in aqueous media – a 5 year update Jacek Mlynarski*ab and Sebastian Bas´b Asymmetric reactions in water and in aqueous solutions have become an area of fast growing interest recently. Although for a long time neglected as a medium for organic reactions, water has attracted attention as the most widely distributed solvent in the world. Indeed, water is the solvent used by nature for biological chemistry including aldol reactions being essential for glycolysis, gluconeogenesis and related processes. Consequently, artificial catalysts designed and used for aldol reactions in water can be
Received 15th June 2013
promising for the synthesis of enantiopure molecules and are also important for the under-
DOI: 10.1039/c3cs60202h
standing of complex chemistry of life. This tutorial review summarizes recent developments in the area of aqueous asymmetric aldol reactions highlighting two fundamental directions – development of water
www.rsc.org/csr
compatible chiral Lewis acids and amine-based organocatalysts.
Key learning points (1) (2) (3) (4) (5)
The latest developments in asymmetric aldol reactions in water. Water compatible Lewis acids and their synthetic application in Mukaiyama aldol reaction. Organocatalytic activation of carbonyl compounds by using the enamine mechanism in water. Synthesis of selected natural targets by using aqueous asymmetric aldol reactions. Stereochemistry of aldol addition based on models.
1. Introduction Water has been intensively explored as an important solvent for organic chemistry in recent years. Although this subject became more visible in the literature after 1980,1 organic reactions in water were occasionally reported previously, mostly as a curiosity or timid imitation of bio-processes. This inspiration is obvious, as life chemistry requires constant construction of chemical bonds in an aqueous environment. One of the most important organic reactions is the aldol reaction, being crucial for the biosynthesis of carbohydrates, keto acids, and some amino acids.2 Enzymes called aldolases catalyse reversible synthesis of b-hydroxy carbonyl compounds via aldol reaction in water with excellent efficiency and stereocontrol. Following nature’s lead, we started to consider water as a versatile solvent for organic reactions carried out with high efficiency and stereoselectivity and additionally as an environmentally benign alternative methodology.3
a
Faculty of Chemistry, Jagiellonian University, Ingardena 3, 30-060 Krakow, Poland. E-mail: [email protected]; Web: www.jacekmlynarski.pl; Tel: +48 12663 2035 b Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
This journal is © The Royal Society of Chemistry 2014
Promoted by aldolases in water, aldol reaction was one of the most inspiring lessons from nature. Interesting early examples of water chemistry come from the year 1909, and show that the aldol reaction can be catalysed by small-molecule aqueous catalysts.4 While initially the genesis of the reaction carried out in water was simply to imitate nature, now this argument is still important, but other features of water make it a desired solvent or reaction medium. Although organic chemists have become accustomed to the use of organic solvents, a benefit of using water is immediately evident from practical and synthetic standpoints. It is not necessary to dry solvents and substrates for the reactions in aqueous media, and aqueous solutions of substrates can be directly used without further drying, wherever possible. Also, from a green chemistry perspective, the use of water instead of organic solvent is preferred not only for possibly decreasing environmental contamination. The best example so far is the use of small organic molecules to catalyse sustainable reactions in water.5 Many authors described recently a number of asymmetric small-molecule amine catalysts that were proposed to utilize enamine intermediates in water. The following sections of this review will also discuss examples of enamine-based aldol reactions. However, referring to all reactions carried out in
Chem. Soc. Rev., 2014, 43, 577--587 | 577
View Article Online
Published on 22 October 2013. Downloaded by National University of Singapore on 13/06/2014 09:01:18.
Tutorial Review
water as environmentally friendly may be simply abusive. Indeed, small organic molecules, as compared to metal complexes, are generally more stable, mostly less expensive, readily available, and environmentally friendly. Assessment of green and economic merits of an aqueous-based organocatalytic process (and also all reactions carried out in water) is not easy and must be seen as including a complex set of parameters. The use of water in organocatalytic processes was discussed by Donna Blackmond in 20076 shortly after the first examples of highly asymmetric organocatalytic aldol reactions appeared in the literature. The authors considered two questions: how ‘‘green’’ and how efficient are aqueous-based organocatalytic reactions? It was pointed out that while conducting the reaction in water, we often forget how to get the organic products out of the water. Thus, not only the reaction step but also the economics and environmental impact of product workup and reagents preparation should be taken into account in the selection of the reaction medium. The choice, however, depends on whether we can replace organic solvents for water! So as to have a choice we need to explore deeply the subject and also to understand the mechanisms of the reactions carried out in water. Considering the advantages and disadvantages of the use of water as a solvent, it is undoubtedly important to expand its use to all areas where the application of the solvent of life is beneficial. Aqueous asymmetric aldol reaction is one such field where water quickly becomes an important alternative to organic solvents. Our previous ChemSocRev review on the subject described the pioneering use of water as a medium for the reaction catalysed by metal complexes and small organic molecules.7 This tutorial review describes the progress made over the past five years and tries to show the most important trends in the area of aqueous asymmetric aldol reaction based on selection of recently published research. To avoid repeating the basic issues further, we encourage readers to look into the initial review.7
Jacek Mlynarski studied chemistry at the Jagiellonian ´w. He University in Krako received his PhD (2000) from the Institute of Organic Chemistry of the Polish Academy of Sciences. In 2001 he obtained a research fellowship from the Alexander von Humboldt Foundation and ¨rstner worked with Prof. Alois Fu ¨r at the Max Planck Institut fu Kohlenforschung. Upon returning to Poland in 2002 he obtained an Jacek Mlynarski academic position at the Institute of Organic Chemistry in Warsaw. In 2008 he joined Faculty of Chemistry, Jagiellonian University in Krakow where he is a professor and group leader. His scientific interest includes enantioselective synthetic methodology that relies on metal-based and metal-free chiral catalysts.
578 | Chem. Soc. Rev., 2014, 43, 577--587
Chem Soc Rev
2. Indirect aldol reactions: water compatible chiral Lewis acids Lewis acid-catalysed aldol-type reactions of silyl enol ethers with aldehydes referred to as Mukaiyama reactions are very popular due to their high regio- and stereoselectivities. However, silyl enol ethers decompose relatively quickly in protic solvents, as do traditional Lewis acid catalysts, so the application of water as a reaction medium might seem to be limited. In addition, designing and application of chiral Lewis acids is difficult to achieve because of huge competition between chiral ligands and water molecules surrounding metal ions. In spite of or because of these problems, discovering new water compatible chiral Lewis acids seems to be a highly exciting challenge. While most Lewis acids decompose in water, it was found that rare earth triflates can be used as Lewis acid catalysts in water or water-containing solvents (water-compatible Lewis acids).8 Few examples of enantioselective, lanthanide-catalysed Mukaiyama aldol reaction in aqueous media exist and the most interesting utilise multicoordinating chiral ligands. This concept was elaborated by Kobayashi who showed that rare earth triflates in combination with chiral bis(pyridine-10-crown-6) ligand 4 promote the syn-selective reaction between the enolsilane 1 and several aldehydes enantioselectively (Table 1).9 Aromatic aldehydes are best suited for these reactions and the optimal fit between the ionic diameter of the cation and ligand cavity ensures best diastereo- and enantioselectivity. Organic co-solvent and high catalyst loading (20 mol%) have been crucial for both yield and enantioselectivity. This concept was further developed by Allen presenting a detailed study of C2-symmetric ligands 5 for lanthanide promoted Mukaiyama aldol reaction.10 The best conversion and stereoselectivity were observed for 20 mol% of Eu3+ and Nd3+ catalysts with as much as 42–48 mol% of the chiral ligand.
Sebastian Bas´
Sebastian Bas´ was born in Krakow. He studied chemistry at the Jagiellonian University where he joined the Jacek Mlynarski group in 2009. A year later he received MSc degree in chemistry and in 2011 he graduated in engineering studies at the University of Science and Technology in Krakow. His primary research interests include asymmetric aldol reactions and general synthesis of natural products in an asymmetric manner.
This journal is © The Royal Society of Chemistry 2014
View Article Online
Chem Soc Rev
Tutorial Review
Published on 22 October 2013. Downloaded by National University of Singapore on 13/06/2014 09:01:18.
Table 1 Mukaiyama aldol reaction of silyl enol ethers with aldehydes promoted by water compatible chiral Lewis acids
Scheme 1 Asymmetric Mukaiyama aldol reaction of silyloxyfuran 8 with benzaldehyde.
It was found that the loading of ligand 5 can be decreased when a neodymium salt was used instead of europium triflate. Most importantly, however, it was observed that broad substrate scope is compatible with the catalytic system described in the paper that includes more challenging substrates like aliphatic aldehydes (with up to 94% ee) and silyl enol ethers derived from aliphatic ketones. In addition, modular and low-cost synthesis of multidentate ligands presented by Allen opens new applications of lanthanide-based chiral catalysts for aqueous carbon– carbon bond formation. An interesting direction of research in the aqueous Mukaiyama aldol reaction is undoubtedly the use of cheap and environmentally friendly metals. Application of iron-based chiral Lewis acids to asymmetric synthesis seems to be particularly exciting as iron is one of the most abundant metals on earth and consequently one of the cheapest and most environmentally acceptable. In 2007, Mlynarski demonstrated application of the iron chloride with the pybox 6 ligand as a reliable chiral Lewis acid for Mukaiyama reaction of aromatic aldehydes with high diastereoselectivity and moderate enantioselectivity of up to 84% ee.11 An easy to prepare from threonine, hydrophobic hindered pybox 6 showed high selectivity in the reaction catalysed by both most abundant sustainable terrestrial metals – Fe2+ and Zn2+ (Table 1). Recently, Ollevier demonstrated a highly diastereo- and enantioselective Mukaiyama aldol reaction promoted by iron perchlorate and a chiral bipyridine ligand 7.12 A wide range of aromatic, heteroaromatic, and even aliphatic aldehydes proved to be excellent substrates for the aldol reaction by using benzoic acid-assisted iron perchlorate complex. The best solvent for the reaction was DME– H2O (7 : 3) allowing for only 5 mol% catalyst loading. Study of reactions performed under aqueous conditions also reveals that water may offer new reactivity or stereoselectivity.
This journal is © The Royal Society of Chemistry 2014
For example, regioselectivity of vinylogous Mukaiyama aldol reactions (VMARs) can be controlled by simple solvent tuning and application of water medium offers access to unexpected products (Scheme 1). Thus, cyclic dienoxy silane, including the widely exploited furan-based substrate 8, has been largely explored in vinylogous Mukaiyama aldol reactions (VMARs) to access a variety of highly functionalized g-substituted chiral butenolide type frameworks 9 (Scheme 1). Recently, Mlynarski showed that addition of water to a reaction mixture surprisingly reversed reactivity and resulted in the clean formation of Mukaiyama reaction-type alcohol 10.13 In addition, this product, formed with one stereogenic center, can be accessed, in an asymmetric manner (up to 70% ee) by using zinc-based chiral Lewis acid with chiral pybox ligand 6 (Scheme 1). This interesting observation can be seen as a general switch in regioselectivity of Mukaiyama aldol reactions in a conjugated butenolide system under aqueous conditions. All previously presented studies although demonstrating the elegant application of water compatible Lewis acids to asymmetric synthesis suffer from the same problem – the use of aqueous organic solvents instead of pure water. The presented catalytic systems are not selective in pure water while reactivity of unsoluble carbonyl compounds needs further attention. To address this issue Kobayashi developed a scandium-catalysed hydroxymethylation of silicon enolates with aqueous formaldehyde in water that does not require organic solvents (Table 2).14 After careful optimization of the reaction conditions with respect to various additives, catalytic asymmetric hydroxymethylation was successfully carried out with 10 mol% of the Sc3+ salt and 12 mol% of chiral ligands 7 or 14 to afford the desired products in good to high yields and with high selectivities. Further, Kobayashi developed this methodology for direct reaction of ketones in place of silicon enolates.15 Addition of base resulted in direct enolisation of ketone prior to the reaction with formaldehyde in pure water. Among organic bases tested, pyridine was found to be the best additive for the desired asymmetric hydroxylation by using scandium triflate and chiral N-oxide ligand 14. In spite of average enantioselectivity observed for the reaction of ketones (67–88% ee), this catalytic system and the abovepresented concept seem to be highly prospective for further development and application.
Chem. Soc. Rev., 2014, 43, 577--587 | 579
View Article Online
Tutorial Review
Published on 22 October 2013. Downloaded by National University of Singapore on 13/06/2014 09:01:18.
Table 2
Asymmetric hydroxymethylation in water elaborated by Kobayashi
3. Direct aldol reaction In nature, type I or type II aldolases catalyse the direct aldol reaction in water. These aldolases affect the coupling of unmodified substrates in aqueous media for achieving absolute stereocontrol via (i) an enamine mechanism or (ii) metal enolate formation, respectively.2 These biological processes always inspired chemists but only recently provided a template for successful development of small molecule artificial catalysts for direct asymmetric aldol reactions.16 The focus of this chapter will be on water compatible small organic molecules and metal complexes, with special emphasis on substrate scope and important current limitations. 3.1.
Enamine organocatalysis
The fast developing area of organocatalysis comprises the vast majority of reported methods for carrying out direct catalytic aldol reactions. Small organic molecules utilising the enamine mechanism analogously to type I aldolases are well known to promote asymmetric processes also in water.17 Reports of small-molecule enamine-based aldol reactions in water have been presented throughout the literature over the last several years.7 Some reactions have been performed under aqueous conditions, with the presence of water being reported to increase the reactivity and stereoselectivity. Although conceptually important, initially presented examples of small-moleculeorganocatalyzed aldol reactions in water with sufficient asymmetric induction would have immense synthetic utility because of low enantioselectivity and application of organic co-solvents.18 In 2006, two groups independently reported the asymmetric aldol reaction ‘‘in the presence of water’’ without using any organic solvent. Studies presented by Hayashi19 and Barbas20 have shown that highly enantioselective direct aldol reactions in water can be promoted by proline-based catalysts via an enamine mechanism. In the former studies, trans-L-siloxyproline (18, Table 3) was presented as a catalyst for high diastereo- and enantioselective aldol reactions of cyclohexanone (15, 5 equiv.) with 4-nitrobenzaldehyde (16) in the presence of water (18 equiv.). Although the role of water is not clear, it was shown that water is essential for high stereoselectivity. An elaborate aldol
580 | Chem. Soc. Rev., 2014, 43, 577--587
Chem Soc Rev
reaction proceeds with lower diastereo- and enantioselectivity in an organic solvent (DMSO). The reaction proceeds obviously in a two-phase system with small amounts of water (3–18 equiv.). In this case hydrophobic siloxyproline 18 acts as a catalyst in the organic phase formed by the aldehyde and ketone substrates. Aggregation of the organic molecules excludes water from the organic phase and drives the equilibrium toward enamine formation. Since the protocol uses only a small amount of water in a heterogeneous reaction mixture, these reactions are generally called ‘‘direct aldol reactions in the presence of water’’. Hayashi also described ‘‘a reaction in water’’ as one in which the reactants are dissolved homogeneously in water, whereas ‘‘a reaction in the presence of water’’ term should be used for a reaction that proceeds in a concentrated organic phase with water being present as a second phase. In this case, however, water is not only the inert second phase but influences the reaction yield and stereoselectivity, as was presented for aldol reaction promoted by catalyst 18. At around the same time Barbas designed a small hydrophobic diamine catalyst (19) which smoothly promoted the direct cross-aldol reaction of cyclohexanone (2 equiv.) with 4-nitrobenzaldehyde in pure water, giving the anti-aldol product 17 in quantitative yield with 94% ee (Table 3).20 Importantly, a stoichiometric amount of donor was enough to achieve the reaction, further increasing the economy of the reaction. Catalyst loading could also be decreased to 1 mol%. It is worth noting that both catalysts 18 and 19 were less efficient for non-activated aldehydes resulting in lower yield, and less selective for water soluble substrates (reactions of acetone with 4-trifluoromethyl benzaldehyde promoted by 18 – 65% ee, reactions of acetone with 4-nitrobenzaldehyde promoted by 19 – 55% ee). Both aldolase-type organocatalysts 18 and 19 are equipped with hydrophobic parts and conspicuously form an emulsion composed of water and organic substrates. Diamine 19 acts as a water soluble quaternary ammonium salt with long hydrophobic chains thus recalling surfactants operating at the water–organic interface. These two examples showed the direction for a number of scientists designing catalysts for the aqueous aldol reaction between cyclohexanone and activated aromatic aldehydes. A number of interesting contributions are collected in Table 3. Selected examples have been carried out only without organic co-solvents and with a nearly stoichiometric amount of ketone donors. The presented substrate set may not be promising for further applications but these examples offer an interesting overview of evolution of the concept of carrying out reaction of unsoluble substrates ‘‘in the presence of water’’. Gong21 and Singh22 demonstrated an efficient aldol reaction with very low catalyst loading (1 and 0.5 mol%, respectively). Particularly excellent stereoselectivities were observed using the prolinamide catalyst 21 in brine (Table 3).22 High reactivity and stereoselectivity are due to the salting-out effect as well as double activation of the aldehyde acceptor via a hydrogen bonding network with both NH and OH of the catalyst. These principles along with E-enamine formed from the cyclohexanone molecule resulted in the observed sense of stereochemistry induction (Table 3, TS-I).
This journal is © The Royal Society of Chemistry 2014
View Article Online
Chem Soc Rev
Structures of amine catalysts used in organocatalytic aldol reactions between cyclohexanone and 4-nitrobenzaldehyde in the presence of
Published on 22 October 2013. Downloaded by National University of Singapore on 13/06/2014 09:01:18.
Table 3 water
Tutorial Review
The role of hydrophobic catalysts also diminishes contacts between bulk water and the reaction transition states in an emulsion in the reaction solution of water and organic substrates. Such an excellent catalyst system was reported by the Armstrong group in 2007.23 Quantitative yields were obtained for stoichiometric direct aldol reactions by addition of sulfated b-CD (10 mol%), which binds tert-butylphenoxyproline (22, 2 mol%) and associated hydrophobic reactants (Table 3). Simple filtration or phase separation affords an anti-aldol (17) product in high optical purity. In 2007, Gryko showed that direct aldol reaction of cyclic ketones with aromatic aldehydes in the presence of water can be efficiently promoted by prolinethioamide salt 23.24 It was proved that the use of water effectively enhanced the activity of the catalyst. Thus, as little as 1.2 equivalents of cyclohexanone in the presence of the protonated thioamide catalyst (only 2.5 mol%) resulted in the formation of aldol 17 in high yield and high enantioselectivity. The authors speculated that a strong hydrophobic effect plays a crucial role in this aldol
This journal is © The Royal Society of Chemistry 2014
reaction performed in the presence of a large amount of water (2 mL). Both, the rate of acceleration and high stereoselectivity are supported by hydrophobic aggregation of the reactant and catalyst. Further, the Najera group observed that prolinethioamides exhibited higher enantioselectivity than the corresponding prolinamides in the model aldol reaction between cyclohexanone and 4-nitrobenzaldehyde in the presence of 4-nitrobenzoic acid as a co-catalyst.25 In particular, (S)-prolinethioamide 24, derived from proline and (R)-1-aminoindane, was shown to be the most efficient organocatalyst (5 mol%) promoting aldol reactions in the presence of water (1.2 mL) and under solvent free conditions employing only 4 equivalents of ketone. In this case, solvent-free conditions gave a slightly higher diastereo- and enantioselectivity than when using water as a solvent. 4-Substituted acyloxyprolines with different hydrophobic substituents have been also synthesized and used as catalysts in the direct asymmetric aldol reaction between cyclic ketones and substituted benzaldehydes. Tao presented isosteviol-proline
Chem. Soc. Rev., 2014, 43, 577--587 | 581
View Article Online
Published on 22 October 2013. Downloaded by National University of Singapore on 13/06/2014 09:01:18.
Tutorial Review
conjugated organocatalyst 25.26 With only 1 mol% of catalyst loading, the desired anti-aldols were obtained with good to excellent yields and the enantioselectivities were excellent in most cases. Only 5 equivalents of water were used as a solvent, or a better reaction additive to enhance stereoselectivity. Gruttadauria showed that catalyst 26 bearing hydrophobic acyl chains provided aldol products in excellent yields and stereoselectivities.27 The catalyst was successfully used in only 2 mol% loading at room temperature with a small amount of water as an additive. Interestingly, most presented examples have been based on a portion of proline equipped with hydrophobic groups. These may be attached to the pyrrolidine ring of natural hydroxyproline, or attached as an ester or amide linkage to the proline carboxyl group. All proline-based catalysts are very hydrophobic and the reactions are believed to take place in an organic phase, mimicking an enzymes’ separation of carbonyl substrates away from bulk water. Whereas in the natural enzyme the enamine is formed at the lysine residue in the active site, most presented catalysts contain a cyclic pyrrolidine motive for this purpose. Studies of aqua organocatalytic reactions promoted by primary amino acids and their derivatives provided interesting and competitive results. A siloxyserine organocatalyst 27 has been developed by Teo to catalyse direct aldol reaction in the presence of water (ca. 7 equivalents).28 Further, Lu presented application of tryptophan (28) to the aldol reaction performed in the presence of ca. 15–100 equivalents of water.29 For both primary amines high enantioselectivity was observed for the reaction of cyclohexanone and 4-nitrobenzaldehyde at room temperature but the catalyst activities were limited to cyclic ketones only. In 2010, Nugent used 2-picolylamine template as a new and promising organocatalyst.30 A chiral version of the catalyst containing a single stereogenic center (29) has been identified as allowing highly stereoselective anti-aldol product formation at a low catalyst loading (5 mol%). Reactions have been performed in water or brine (1 mL) with high yields and stereoselectivities for cyclohexanone and substituted benzaldehydes. The same amount of water (1 mL) allowed for highly enantioselective aldol reaction of cyclohexanone and 4-nitrobenzaldehyde in the presence of a valine-based organocatalyst (30).31 Interestingly, protonated valinamide 30 was active enough to promote aldol reaction of usually unreactive benzaldehyde (76%, 94% ee), although a 9 : 1 ketone–water mixture was necessary for high substrate conversion. A similar, yet more problematic and less studied reaction of cyclopentanone can also be promoted by water tolerant organocatalysts (Table 4). Reaction of a donor with a fivemembered ring is usually less diastereoselective but few catalysts provided access to the anti-aldol product with high optical purity. For example, highly efficient and enantioselective catalyst 26 developed by Gruttadauria27 has been used to control the reaction of cyclopentanone with aromatic aldehydes. For a number of tested aromatic aldehydes enantioselectivities ranged from 96 to 99%, only the 3-methoxy derivative showed a slightly lower enantioselectivity (93%). Only 2 mol% of organocatalyst 26 was enough to promote the reaction at room temperature in the
582 | Chem. Soc. Rev., 2014, 43, 577--587
Chem Soc Rev Table 4 Structures of amine catalysts used in organocatalytic aldol reactions between cyclopentanone and 4-nitrobenzaldehyde
presence of a small amount of water (175 mL) without organic co-solvent. In 2009, Li described prolinethioamide 33 prepared from readily available natural amino acid proline and amino alcohol valinol.32 This organocatalyst has been found to be active for the direct aldol reaction of various aldehydes with acetone, cyclohexanone and cyclopentanone at 0 1C under anhydrous conditions. The same catalyst promoted the direct aldol reaction of 4-nitrobenzaldehyde and cyclopentanone and cyclohexanone in water with 97 and 99% ee of anti-aldols, respectively (Table 4). Most of the above-mentioned catalysts have the limitation of giving moderate enantioselectivity with a water-miscible ketone such as acetone or hydroxyacetone (HA), a highly desirable substrate from a conceptual and synthetic point of view. Therefore, there was a great need for a chiral organocatalysts that could overcome these drawbacks and work in homogeneous solution without biphasic interactions described above. Two interesting examples of proline-based catalysts have been presented by Gong21 and Singh.22 Both catalysts (20 and 21, Table 5) afforded aldol products from cyclic and acyclic ketones and various aldehydes in an excess of water or brine. Catalysts 20 although still highly efficient (1 mol%) lost some selectivity for acyclic ketones (71% ee for acetone) when compared to cyclohexanone. More efficient, versatile and enantioselective catalysts have been developed by Singh.22 Prolinamide catalyst 21 bearing a nonpolar gemdiphenyl group works very efficiently for acetone in brine. In most cases, authors reported more than 99% ee by using 0.5 mol% of the catalyst 21 in brine. Based on the proposed transition state model for this catalyst (TS-II, Table 5) the stereochemistry of the aldol products was easy to be explained. Proline amide bears two hydrogen bond donors additionally stabilizing aldehyde molecule with the biggest substituent placed far from catalysts bulky groups. This excellent catalyst has been demonstrated to be efficient for activated- and non-activated aromatic aldehydes and worked also for aliphatic donors (3-propanal: 70%, 99% ee). Further, various catalysts for the asymmetric aldol reaction of water soluble acetone with aromatic aldehydes have been presented. The most active were: the prolinamide-based
This journal is © The Royal Society of Chemistry 2014
View Article Online
Chem Soc Rev
Published on 22 October 2013. Downloaded by National University of Singapore on 13/06/2014 09:01:18.
Table 5
Tutorial Review
Structures of amine catalysts used in organocatalytic aldol reactions between acetone and 4-nitrobenzaldehyde in water
catalyst developed by Da (36),33 and prolinethioamide 37 used by Li.34 Both catalysts promoted the aldol reaction of acetone (5–10 equivalents) in homogeneous water or brine solution (ca. 1 mL). It is worth noting that the asymmetric reaction of aliphatic aldehydes still remained problematic for the above mentioned catalysts. In 2008, Gruttadauria employed a new prolinamide derivative 38 attached to a polystyrene support (Table 5).35 This heterogeneous catalyst has been employed in the direct asymmetric aldol reaction of cyclohexanone and acetone with good results in terms of yield and stereoselectivity. The reaction was performed in a biphasic water–chloroform system, being a compromise between the good swelling properties of chloroform and the formation of a concentrated organic phase due to the presence of water. This catalyst can be easily recovered, regenerated and recycled, without loss of activity. Hydroxy- and dihydroxyacetone (DHA) are versatile C3 building blocks in the chemical and enzymatic syntheses of carbohydrates36 and thus an extremely important synthetic challenge. In addition, aldol reaction of hydroxyl- and dihydroxyacetone seems to be closely related to aldolase action in a natural water environment making designing of enamine-based organocatalysts for the reaction of hydroxyketones even more exciting. Although some organocatalysts are able to activate a hydroxyacetone donor in dry organic solvents, their application in aqueous solutions is limited to protected donors and failed to give promising results in the presence of water with unprotected hydroxyacetone. Primary amine-based amino acids i.e. siloxy-Lthreonine (41)37 have been demonstrated to be efficient organocatalysts for syn-selective aldol reaction between a variety of
This journal is © The Royal Society of Chemistry 2014
aromatic aldehydes and tert-butyldimethylsilyloxy hydroxyacetone as a donor in the presence of water (Table 6). Later, Chimni demonstrated application of a series of water compatible primary–tertiary diamine organocatalysts derived from natural primary amino acids bearing a hydrophobic side chain.38 The catalyst 42 having a morphinyl group gave the best results for the reaction of protected hydroxyacetone with aromatic aldehydes (Table 6). It is important to notice that the aldol reaction of hydroxyacetone with 4-nitrobenzaldehyde using catalyst 42 in aqueous medium produced an aldol adduct in very low yield (20%) and enantioselectivity (31% ee).38 More promising results have been observed for the reaction of this demanding donor in aqueous organic solvents by using other organocatalysts.
Table 6 Organocatalytic aldol reactions between TBS-protected hydroxyacetone and 4-nitrobenzaldehyde in water (TBS: tert-butyldimethylsilyl, TBDPS: tert-butyldiphenylsilyl)
Chem. Soc. Rev., 2014, 43, 577--587 | 583
View Article Online
Tutorial Review
Published on 22 October 2013. Downloaded by National University of Singapore on 13/06/2014 09:01:18.
Table 7 Organocatalytic aldol reactions between hydroxyacetone and 4-nitrobenzaldehyde in aqueous solvents
In 2009, Singh presented the chiral cyclohexyldiamine-based catalyst 45 that efficiently catalyses the syn-selective addition to hydroxyacetone donor in DMF–water (9 : 1) solution with high enantioselectivity (Table 7).39 The presented catalyst contained aromatic substituents forming a hydrophobic cavity with the reactants in aqueous medium. Thus, the catalyst successfully mimics the enzymes’ mode of action, and the reaction takes place in this cavity, resulting in high stereoselectivity. The idea behind this design is that a water-soluble substrate (i.e., natural dihydroxyacetone phosphate) can be efficiently activated in hydrophobic pockets of water-unsoluble catalysts. Taking advantage of this concept, catalysts 4640 equipped with hydrophobic alkyl chains and siloxyserine 4731 have been successfully applied for the synthesis of syn-aldols from hydroxyacetone (Table 7). In addition, the latter catalyst was also active and selective for aliphatic aldehydes making elaborated methodology acceptable for further synthesis of natural products. Additionally, authors confirmed formation of the enamine intermediate from hydroxyacetone and catalysts 47 by using the MS technique.31 In spite of the presented successful application of organocatalysts to the activation of hydroxyacetone, the dihydroxyacetone variant is still at its infancy. For example, reaction of dihydroxyacetone (DHA) with (R)-glyceraldehyde (49) should result in direct formation of four natural ketohexoses.36 Initial attempts at this strategy in aqueous organic solvent by using small organic molecules resulted in unselective formation of monosaccharides. In contrast, protected dihydroxyacetone as TBS-ether served as an excellent substrate in the reaction promoted by amide 51 in brine.41 A variety of aliphatic aldehydes provided syn-aldol products with good yields and ees up to 98% in brine allowing for the direct synthesis of a range of carbohydrates and their derivatives. Reaction of the acetonide of D-glyceraldehyde (49) provided the protected sorbose derivative in 86% yield, (3 : 1) syn-favored dr, and 98% ee. cis-Configured enamine formed in the presence of threonine-based catalyst 51 can be additionally stabilised by the hydrogen bond between OH (OR) and the amino acid nitrogen atom, even for reactions proceeding in the presence of water (Table 8, TS-IV).
584 | Chem. Soc. Rev., 2014, 43, 577--587
Chem Soc Rev Table 8 Aqueous organocatalytic aldol reactions between dihydroxyacetone and (R)-glyceraldehyde
Also catalysts 42, previously demonstrated for the reaction of protected hydroxyacetone (Table 6), have been useful for the reaction of TBS-dihydroxyacetone with aromatic 4-nitrobenzaldehyde, producing the aldol adduct in high yield (93%) and with excellent enantioselectivity (95% ee).38 Following previously published cross-aldol reactions promoted by siloxyserine, Hayashi developed a catalytic, direct asymmetric cross-aldol reaction of two different aldehydes in the presence of water, catalysed by a combined proline–surfactant organocatalyst 55.42 The reaction of 2-chlorobenzaldehyde (52) and propanal (53, 5 equiv.) was selected as a model and performed in the presence of water and several putative organocatalysts. The best results in terms of yield and anti-selectivity were observed for the proline catalyst with a decanoate side chain (Table 9). In contrast, the highly syn-selective cross-aldol reaction of aldehydes has remained a challenging subject in the field of aminocatalysis. To achieve this end, Cheng explored chiral L-phenylalanine derived primary–tertiary diamine 56. This catalyst was found to promote the cross-aldol reactions of aldehydes with high activity and synselectivity (Table 9, syn–anti up to 24 : 1, 87% ee).43 While discussing cross-aldol reactions of aldehydes it is important to also notice the dimerization of glycolaldehyde leading directly to formation of tetroses. This concept, however, has been studied previously and is the subject of another review.36
Table 9
Cross-aldol reaction of two aldehydes in water
This journal is © The Royal Society of Chemistry 2014
View Article Online
Chem Soc Rev
Published on 22 October 2013. Downloaded by National University of Singapore on 13/06/2014 09:01:18.
Table 10
Cross-aldol reactions of ketones in water
Tutorial Review Table 11
Synthesis of isotetronic acid in water
Various functionalized isotetronic acids were obtained with high yields (up to 94%) and excellent ees (99%). Examples of cross-aldol reactions of ketones in the presence of water are relatively rare. In 2009, Tomasini noticed that the addition of small quantities of water (ca. 20 equiv.) to the proline or prolinamide (59) promoted aldol reaction of acetone to isatin (57) resulting in an increased level of observed enantioselectivity (Table 10).44 The authors explained this phenomenon by using a transition state model incorporating water molecules into isatin carbonyl groups by hydrogen bonds. Interestingly, the addition of larger quantities of water was found to have a negative impact on the reaction selectivity. Later, Singh presented the highly enantioselective reaction of isatin (57) and cyclohexanone promoted by a primary–tertiary diamine in both aqueous and organic solvents (Table 10).45 A cyclic ketone was allowed to react with isatin in the presence catalyst 45/TFA salt (10 mol%) using water as a reaction medium. An organocatalyst bearing an aromatic group can form a hydrophobic cavity for the reaction active site diminishing contact between water molecules and thus forming the enamine intermediate (Table 10, TS-V). Another interesting field where application of water allowed for better reactivity and selectivity is the organocatalytic activation of keto acid molecules. Particularly interesting asymmetric synthesis of isotetronic acid 62 from oxobutyric acid (60) and isobutyraldehyde (61) has been explored by Landais (Table 11).46 Proline proved to be a poor catalyst for this reaction but application of benzoimidazolepyrrolidine (63) resulted in the formation of the desired 62 in 87% ee in water. Better yields and enantioselectivities were observed with aromatic aldehydes, particularly those having electron withdrawing groups. Postulated protonation of the benzoimidazole ring by keto acid provides a zwitterionic chair-like transition state TS-VI with bulky substituents in the equatorial positions. More recently, Liu and Li tested a series of catalysts having an imidazole motif, for the same cascade reaction leading to isotetronic acids.47 The best results in terms of yield and enantioselectivity were observed for the catalyst 64 having a long alkyl chain. This amphiphilic organocatalyst promoted reaction of aromatic and aliphatic aldehydes with ketoacids using water as a solvent. Both water and organic–water emulsions were found to be crucial for achieving the high reactivity and stereoselectivity.
This journal is © The Royal Society of Chemistry 2014
3.2.
Direct aldol reaction promoted by metal complexes
In parallel to the fast-growing field of organocatalysis, application of metal-complexes for direct aldol reaction in water is also seen in the literature. Conceptually, this is often compared mechanistically to the type II aldolases, which employ a zinc ion to form more reactive metal enolate. Such a catalytic system mimicking aldolases’ mode of action although highly desired may be difficult to design in a water environment. In this case, the ketone donor can also be activated through enamine formation, while Lewis acid can activate the aldehyde carbonyl group instead of enolate formation from the ketone substrate. Nevertheless, such a scenario seems also highly attractive as the combination of organocatalysis with transition metal catalysis has emerged as a promising area in organic chemistry. In 2007, Mlynarski presented studies on application of bisprolinamide (65) zinc complexes for direct asymmetric aldol reactions in aqueous media.48 Both acetone and cyclohexanone served as convenient substrates in the reaction promoted by 10 mol% of a zinc complex, resulting in the formation of aldols with high yields and enantioselectivities (Table 12). Elaborate catalytic systems, although requiring a large excess of ketones, have been selective for both water soluble and unsoluble substrates. Later, the catalysts have been demonstrated to promote highly enantioselective reactions of formaldehyde with cyclic ketones in ethanol–water homogeneous mixtures.31 The presented catalyst Zn65 incorporates a metal center and two proline units, and the authors postulated a mechanism involving organocatalytic enamine formation (Table 12, TS-VII, VIII), where zinc complexation only stabilizes the formation of an enamine intermediate in water.31 Formation of the anti-product observed in the reaction of cyclic substrates resulted from the E enolate of cyclohexanone (TS-VII). By the same rules, aldol reaction of enamine with acetone or formaldehyde (TS-VIII) resulted in formation of (S)-aldol. In fact, the presented TS models VII and VIII use the same principle as for direct aldol reactions promoted by proline organocatalysts. Later, the same concept of application of zinc-based catalyst incorporating prolinamide units have been presented by a few other authors but reported results have not been progressive. Interestingly, Penhoat demonstrated that direct combination of various Lewis acids and L-proline 66 can promote direct aldol
Chem. Soc. Rev., 2014, 43, 577--587 | 585
View Article Online
Tutorial Review
Published on 22 October 2013. Downloaded by National University of Singapore on 13/06/2014 09:01:18.
Table 12
Direct aldol reaction in water promoted by chiral Lewis acids
reactions of cyclohexanone with aromatic aldehydes in a DMSO– water mixture.49 The chloride salts of the group 12 elements (ZnCl2, CdCl2 and HgCl2) led to the highest stereoselectivities and conversions. Although the authors declare that the procedure appears to be an excellent and readily available biomimetic model analogous to type II aldolases, no evidence for the metalenolate formation has been presented to prove this concept. In 2011, Wang developed a new class of primary aminebased ligand 67 for copper-supported direct aldol reactions of cyclohexanone and aromatic aldehydes in water (Table 12).50 In spite of high catalyst loading, this bifunctional catalyst displayed high activity in the direct aldol reactions of electron-rich and electron-poor aldehydes. According to the authors, the metal coordinates with the chelating ligand to form a rigid chiral Lewis acid which activates the aldehyde while the primary amine reacts with cyclohexanone to form an enamine as depicted in Table 12, structure TS-IX. To conclude the discussion on two possible mechanisms for direct aldol reaction promoted by a bifunctional catalyst composed of amine and Lewis acids, readers may consult the Aoki mechanistic studies of catalysts consisting of chiral amino acids and Zn–cyclene complexes.51 Aldol reactions of acetone and aromatic aldehydes were promoted by asymmetric catalysts to give aldol adducts with moderate to good ee values (up to 89%). The authors suggest that the formation of enamine from acetone and L-proline although possible is less efficient in the formation of C–C bond, while the Zn-enolate of acetone provides an efficient and enantioselective aldol reaction.
4. Conclusions Water as a solvent is not only inexpensive and environmentally benign, but may also offer completely new reactivity or
586 | Chem. Soc. Rev., 2014, 43, 577--587
Chem Soc Rev
stereoselectivity when compared to classical organic solvents. These features constitute the most important motivation for the use of water as everyday solvent for chemists. In addition, the role of water in organic reactions, and also in life processes, is often complex and not well understood. This makes water an even more important solvent and its application not only interesting from an environmental concern perspective but also crucial for revealing reaction mechanisms. Although the direct catalytic aldol systems which were assumed to proceed through an enamine mechanism by mimicking type I aldolases have been well established and explored, the direct activation of carbonyl partners by using the methods analogous to the action of type II aldolases containing a zinc cofactor has still remained challenging. Nevertheless, development of water compatible organocatalysts and metal complexes highly influences organic synthesis and designing of chiral catalysts and finally greatly contributes to our understanding of life chemistry. Our projects related to the presented subject operate within the Foundation for Polish Science TEAM Programme co-financed by the EU European Regional Development Fund.
Notes and references 1 The use of water to accelerate the Diels–Alder is often cited as an important turning point in the field: D. C. Rideout and R. Breslow, J. Am. Chem. Soc., 1980, 102, 7816. 2 S. M. Dean, W. A. Greenberg and C.-H. Wong, Adv. Synth. Catal., 2007, 349, 1308. 3 R. N. Butler and A. G. Coyne, Chem. Rev., 2010, 110, 6302. 4 H. D. Dakin, J. Biol. Chem., 1909, 7, 49. 5 J. G. Hernandez and E. Juaristi, Chem. Soc. Rev., 2012, 48, 5396. 6 D. G. Blackmond, A. Armstrong, V. Coombe and A. Wells, Angew. Chem., Int. Ed., 2007, 46, 3798. 7 J. Mlynarski and J. Paradowska, Chem. Soc. Rev., 2008, 37, 1502. 8 S. Kobayashi and C. Ogawa, Chem.–Eur. J., 2006, 12, 5954. 9 T. Hamada, K. Manabe, S. Ishikawa, S. Nagayama, M. Shiro and S. Kobayashi, J. Am. Chem. Soc., 2003, 125, 2989. 10 Y. Mei, D. J. Averill and M. J. Allen, J. Org. Chem., 2012, 77, 5624. 11 J. Jankowska, J. Paradowska, B. Rakiel and J. Mlynarski, J. Org. Chem., 2007, 72, 2228. 12 T. Ollevier and B. Plancq, Chem. Commun., 2012, 48, 2289. 13 M. Woyciechowska, G. Forcher, S. Buda and J. Mlynarski, Chem. Commun., 2012, 48, 11029. 14 M. Koubo, C. Ogawa and S. Kobayashi, Angew. Chem., Int. Ed., 2008, 47, 6909. 15 M. Kobuko, K. Kawasami, T. Nagano and S. Kobayashi, Chem.–Asian J., 2010, 5, 490. 16 B. M. Trost and Ch. S. Brindle, Chem. Soc. Rev., 2010, 39, 1600. 17 M. Gruttadauria, F. Giacalone and R. Notoa, Adv. Synth. Catal., 2009, 351, 33.
This journal is © The Royal Society of Chemistry 2014
View Article Online
Published on 22 October 2013. Downloaded by National University of Singapore on 13/06/2014 09:01:18.
Chem Soc Rev
18 A. P. Brogan, T. J. Dickerson and K. D. Janda, Angew. Chem., Int. Ed., 2006, 45, 8100. 19 Y. Hayashi, T. Sumiya, J. Takahashi, H. Gotoh, T. Urushima and M. Shoji, Angew. Chem., Int. Ed., 2006, 45, 958. 20 N. Mase, Y. Nakai, N. Ohara, H. Yoda, K. Takabe, F. Tanaka and C. F. Barbas III, J. Am. Chem. Soc., 2006, 128, 734. 21 J.-F. Zhao, L. He, J. Jiang, Z. Tang, L.-F. Cun and L.-Z. Gong, Tetrahedron Lett., 2008, 49, 3372. 22 V. Maya, M. Raj and V. K. Singh, Org. Lett., 2007, 9, 2593. 23 J. Huang, X. Hang and D. W. Armstrong, Angew. Chem., Int. Ed., 2007, 46, 9073. 24 W. J. Saletra and D. Gryko, Org. Biomol. Chem., 2007, 5, 2148. 25 D. Almasi, D. A. Alonso, A.-N. Balaguer and C. Najera, Adv. Synth. Catal., 2009, 351, 1123. 26 Y.-J. An, Y.-X. Zhang, Y. Wua, Z.-M. Liu, C. Pi and J.-C. Tao, Tetrahedron: Asymmetry, 2010, 21, 688. 27 F. Giacalone, M. Gruttadauria, P. L. Meo, S. Riela and R. Notoa, Adv. Synth. Catal., 2008, 350, 2747. 28 Y.-C. Teo, Tetrahedron: Asymmetry, 2007, 18, 1155. 29 Z. Jiang, H. Yang, X. Han, J. Luo, M. W. Wong and Y. Lu, Org. Biomol. Chem., 2010, 8, 1368. 30 T. C. Nugent, M. N. Umar and A. Bibi, Org. Biomol. Chem., 2010, 8, 4085. 31 J. Paradowska, M. Pasternak, B. Gut, B. Gryzlo and J. Mlynarski, J. Org. Chem., 2012, 77, 173. 32 B. Wang, G.-H. Chen, L.-Y. Liu, W.-X. Chang and J. Li, Adv. Synth. Catal., 2009, 351, 2441. 33 Y. N. Jia, F. C. Wu, X. Ma, G.-J. Zhu and C.-S. Da, Tetrahedron Lett., 2009, 50, 3059. 34 B. Wang, X.-W. Liu, L.-Y. Liu, W.-X. Chang and J. Li, Eur. J. Org. Chem., 2010, 5951. 35 F. Giacalone, M. Gruttadauria, P. L. Meo, S. Riela and R. Notoa, Adv. Synth. Catal., 2008, 350, 1397.
This journal is © The Royal Society of Chemistry 2014
Tutorial Review
36 J. Mlynarski and B. Gut, Chem. Soc. Rev., 2012, 41, 587. 37 X. Wu, Z. Jiang, H.-M. Shen and Y. Lu, Adv. Synth. Catal., 2007, 349, 812. 38 A. Kumar, S. Singh, V. Kumar and S. S. Chimni, Org. Biomol. Chem., 2011, 9, 2731. 39 M. Raj, G. S. Parashari and V. K. Singh, Adv. Synth. Catal., 2009, 351, 1284. 40 C. Wu, X. Fu and S. Li, Tetrahedron: Asymmetry, 2011, 22, 1063. 41 S. S. V. Ramasastry, K. Albertshofer, N. Utsumi and C. F. Barbas III, Org. Lett., 2008, 10, 1621. 42 Y. Hayashi, S. Aratake, T. Okano, J. Takahashi, T. Sumiya and M. Shoji, Angew. Chem., Int. Ed., 2006, 45, 5527. 43 J. Li, N. Fu, X. Li, S. Luo and J.-P. Cheng, J. Org. Chem., 2010, 75, 4501. 44 G. Angelici, R. J. Correa, S. J. Garden and C. Tomasini, Tetrahedron Lett., 2009, 50, 814. 45 M. Raj, N. Veerasamy and V. K. Singh, Tetrahedron Lett., 2010, 51, 2157. 46 J.-M. Vinvent, C. Margottin, M. Berlande, D. Cavagnat, T. Buffeteau and Y. Landais, Chem. Commun., 2007, 4782. 47 B. Zhang, Z. Jiang, X. Zhou, S. Lu, J. Li, Y. Liu and C. Li, Angew. Chem., Int. Ed., 2012, 51, 13159. 48 J. Paradowska, M. Stodulski and J. Mlynarski, Adv. Synth. Catal., 2007, 349, 1041. 49 M. Penhoat, D. Barbry and C. Rolando, Tetrahedron Lett., 2011, 52, 159. 50 P. Daka, Z. Xu, A. Alexa and H. Wang, Chem. Commun., 2011, 47, 224. 51 S. Itoh, M. Kitamura, Y. Yamada and S. Aoki, Chem.–Eur. J., 2009, 15, 10570.
Chem. Soc. Rev., 2014, 43, 577--587 | 587
Published on 22 October 2013. Downloaded by National University of Singapore on 13/06/2014 09:01:18.
TUTORIAL REVIEW
Cite this: Chem. Soc. Rev., 2014, 43, 577
View Journal | View Issue
Catalytic asymmetric aldol reactions in aqueous media – a 5 year update Jacek Mlynarski*ab and Sebastian Bas´b Asymmetric reactions in water and in aqueous solutions have become an area of fast growing interest recently. Although for a long time neglected as a medium for organic reactions, water has attracted attention as the most widely distributed solvent in the world. Indeed, water is the solvent used by nature for biological chemistry including aldol reactions being essential for glycolysis, gluconeogenesis and related processes. Consequently, artificial catalysts designed and used for aldol reactions in water can be
Received 15th June 2013
promising for the synthesis of enantiopure molecules and are also important for the under-
DOI: 10.1039/c3cs60202h
standing of complex chemistry of life. This tutorial review summarizes recent developments in the area of aqueous asymmetric aldol reactions highlighting two fundamental directions – development of water
www.rsc.org/csr
compatible chiral Lewis acids and amine-based organocatalysts.
Key learning points (1) (2) (3) (4) (5)
The latest developments in asymmetric aldol reactions in water. Water compatible Lewis acids and their synthetic application in Mukaiyama aldol reaction. Organocatalytic activation of carbonyl compounds by using the enamine mechanism in water. Synthesis of selected natural targets by using aqueous asymmetric aldol reactions. Stereochemistry of aldol addition based on models.
1. Introduction Water has been intensively explored as an important solvent for organic chemistry in recent years. Although this subject became more visible in the literature after 1980,1 organic reactions in water were occasionally reported previously, mostly as a curiosity or timid imitation of bio-processes. This inspiration is obvious, as life chemistry requires constant construction of chemical bonds in an aqueous environment. One of the most important organic reactions is the aldol reaction, being crucial for the biosynthesis of carbohydrates, keto acids, and some amino acids.2 Enzymes called aldolases catalyse reversible synthesis of b-hydroxy carbonyl compounds via aldol reaction in water with excellent efficiency and stereocontrol. Following nature’s lead, we started to consider water as a versatile solvent for organic reactions carried out with high efficiency and stereoselectivity and additionally as an environmentally benign alternative methodology.3
a
Faculty of Chemistry, Jagiellonian University, Ingardena 3, 30-060 Krakow, Poland. E-mail: [email protected]; Web: www.jacekmlynarski.pl; Tel: +48 12663 2035 b Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
This journal is © The Royal Society of Chemistry 2014
Promoted by aldolases in water, aldol reaction was one of the most inspiring lessons from nature. Interesting early examples of water chemistry come from the year 1909, and show that the aldol reaction can be catalysed by small-molecule aqueous catalysts.4 While initially the genesis of the reaction carried out in water was simply to imitate nature, now this argument is still important, but other features of water make it a desired solvent or reaction medium. Although organic chemists have become accustomed to the use of organic solvents, a benefit of using water is immediately evident from practical and synthetic standpoints. It is not necessary to dry solvents and substrates for the reactions in aqueous media, and aqueous solutions of substrates can be directly used without further drying, wherever possible. Also, from a green chemistry perspective, the use of water instead of organic solvent is preferred not only for possibly decreasing environmental contamination. The best example so far is the use of small organic molecules to catalyse sustainable reactions in water.5 Many authors described recently a number of asymmetric small-molecule amine catalysts that were proposed to utilize enamine intermediates in water. The following sections of this review will also discuss examples of enamine-based aldol reactions. However, referring to all reactions carried out in
Chem. Soc. Rev., 2014, 43, 577--587 | 577
View Article Online
Published on 22 October 2013. Downloaded by National University of Singapore on 13/06/2014 09:01:18.
Tutorial Review
water as environmentally friendly may be simply abusive. Indeed, small organic molecules, as compared to metal complexes, are generally more stable, mostly less expensive, readily available, and environmentally friendly. Assessment of green and economic merits of an aqueous-based organocatalytic process (and also all reactions carried out in water) is not easy and must be seen as including a complex set of parameters. The use of water in organocatalytic processes was discussed by Donna Blackmond in 20076 shortly after the first examples of highly asymmetric organocatalytic aldol reactions appeared in the literature. The authors considered two questions: how ‘‘green’’ and how efficient are aqueous-based organocatalytic reactions? It was pointed out that while conducting the reaction in water, we often forget how to get the organic products out of the water. Thus, not only the reaction step but also the economics and environmental impact of product workup and reagents preparation should be taken into account in the selection of the reaction medium. The choice, however, depends on whether we can replace organic solvents for water! So as to have a choice we need to explore deeply the subject and also to understand the mechanisms of the reactions carried out in water. Considering the advantages and disadvantages of the use of water as a solvent, it is undoubtedly important to expand its use to all areas where the application of the solvent of life is beneficial. Aqueous asymmetric aldol reaction is one such field where water quickly becomes an important alternative to organic solvents. Our previous ChemSocRev review on the subject described the pioneering use of water as a medium for the reaction catalysed by metal complexes and small organic molecules.7 This tutorial review describes the progress made over the past five years and tries to show the most important trends in the area of aqueous asymmetric aldol reaction based on selection of recently published research. To avoid repeating the basic issues further, we encourage readers to look into the initial review.7
Jacek Mlynarski studied chemistry at the Jagiellonian ´w. He University in Krako received his PhD (2000) from the Institute of Organic Chemistry of the Polish Academy of Sciences. In 2001 he obtained a research fellowship from the Alexander von Humboldt Foundation and ¨rstner worked with Prof. Alois Fu ¨r at the Max Planck Institut fu Kohlenforschung. Upon returning to Poland in 2002 he obtained an Jacek Mlynarski academic position at the Institute of Organic Chemistry in Warsaw. In 2008 he joined Faculty of Chemistry, Jagiellonian University in Krakow where he is a professor and group leader. His scientific interest includes enantioselective synthetic methodology that relies on metal-based and metal-free chiral catalysts.
578 | Chem. Soc. Rev., 2014, 43, 577--587
Chem Soc Rev
2. Indirect aldol reactions: water compatible chiral Lewis acids Lewis acid-catalysed aldol-type reactions of silyl enol ethers with aldehydes referred to as Mukaiyama reactions are very popular due to their high regio- and stereoselectivities. However, silyl enol ethers decompose relatively quickly in protic solvents, as do traditional Lewis acid catalysts, so the application of water as a reaction medium might seem to be limited. In addition, designing and application of chiral Lewis acids is difficult to achieve because of huge competition between chiral ligands and water molecules surrounding metal ions. In spite of or because of these problems, discovering new water compatible chiral Lewis acids seems to be a highly exciting challenge. While most Lewis acids decompose in water, it was found that rare earth triflates can be used as Lewis acid catalysts in water or water-containing solvents (water-compatible Lewis acids).8 Few examples of enantioselective, lanthanide-catalysed Mukaiyama aldol reaction in aqueous media exist and the most interesting utilise multicoordinating chiral ligands. This concept was elaborated by Kobayashi who showed that rare earth triflates in combination with chiral bis(pyridine-10-crown-6) ligand 4 promote the syn-selective reaction between the enolsilane 1 and several aldehydes enantioselectively (Table 1).9 Aromatic aldehydes are best suited for these reactions and the optimal fit between the ionic diameter of the cation and ligand cavity ensures best diastereo- and enantioselectivity. Organic co-solvent and high catalyst loading (20 mol%) have been crucial for both yield and enantioselectivity. This concept was further developed by Allen presenting a detailed study of C2-symmetric ligands 5 for lanthanide promoted Mukaiyama aldol reaction.10 The best conversion and stereoselectivity were observed for 20 mol% of Eu3+ and Nd3+ catalysts with as much as 42–48 mol% of the chiral ligand.
Sebastian Bas´
Sebastian Bas´ was born in Krakow. He studied chemistry at the Jagiellonian University where he joined the Jacek Mlynarski group in 2009. A year later he received MSc degree in chemistry and in 2011 he graduated in engineering studies at the University of Science and Technology in Krakow. His primary research interests include asymmetric aldol reactions and general synthesis of natural products in an asymmetric manner.
This journal is © The Royal Society of Chemistry 2014
View Article Online
Chem Soc Rev
Tutorial Review
Published on 22 October 2013. Downloaded by National University of Singapore on 13/06/2014 09:01:18.
Table 1 Mukaiyama aldol reaction of silyl enol ethers with aldehydes promoted by water compatible chiral Lewis acids
Scheme 1 Asymmetric Mukaiyama aldol reaction of silyloxyfuran 8 with benzaldehyde.
It was found that the loading of ligand 5 can be decreased when a neodymium salt was used instead of europium triflate. Most importantly, however, it was observed that broad substrate scope is compatible with the catalytic system described in the paper that includes more challenging substrates like aliphatic aldehydes (with up to 94% ee) and silyl enol ethers derived from aliphatic ketones. In addition, modular and low-cost synthesis of multidentate ligands presented by Allen opens new applications of lanthanide-based chiral catalysts for aqueous carbon– carbon bond formation. An interesting direction of research in the aqueous Mukaiyama aldol reaction is undoubtedly the use of cheap and environmentally friendly metals. Application of iron-based chiral Lewis acids to asymmetric synthesis seems to be particularly exciting as iron is one of the most abundant metals on earth and consequently one of the cheapest and most environmentally acceptable. In 2007, Mlynarski demonstrated application of the iron chloride with the pybox 6 ligand as a reliable chiral Lewis acid for Mukaiyama reaction of aromatic aldehydes with high diastereoselectivity and moderate enantioselectivity of up to 84% ee.11 An easy to prepare from threonine, hydrophobic hindered pybox 6 showed high selectivity in the reaction catalysed by both most abundant sustainable terrestrial metals – Fe2+ and Zn2+ (Table 1). Recently, Ollevier demonstrated a highly diastereo- and enantioselective Mukaiyama aldol reaction promoted by iron perchlorate and a chiral bipyridine ligand 7.12 A wide range of aromatic, heteroaromatic, and even aliphatic aldehydes proved to be excellent substrates for the aldol reaction by using benzoic acid-assisted iron perchlorate complex. The best solvent for the reaction was DME– H2O (7 : 3) allowing for only 5 mol% catalyst loading. Study of reactions performed under aqueous conditions also reveals that water may offer new reactivity or stereoselectivity.
This journal is © The Royal Society of Chemistry 2014
For example, regioselectivity of vinylogous Mukaiyama aldol reactions (VMARs) can be controlled by simple solvent tuning and application of water medium offers access to unexpected products (Scheme 1). Thus, cyclic dienoxy silane, including the widely exploited furan-based substrate 8, has been largely explored in vinylogous Mukaiyama aldol reactions (VMARs) to access a variety of highly functionalized g-substituted chiral butenolide type frameworks 9 (Scheme 1). Recently, Mlynarski showed that addition of water to a reaction mixture surprisingly reversed reactivity and resulted in the clean formation of Mukaiyama reaction-type alcohol 10.13 In addition, this product, formed with one stereogenic center, can be accessed, in an asymmetric manner (up to 70% ee) by using zinc-based chiral Lewis acid with chiral pybox ligand 6 (Scheme 1). This interesting observation can be seen as a general switch in regioselectivity of Mukaiyama aldol reactions in a conjugated butenolide system under aqueous conditions. All previously presented studies although demonstrating the elegant application of water compatible Lewis acids to asymmetric synthesis suffer from the same problem – the use of aqueous organic solvents instead of pure water. The presented catalytic systems are not selective in pure water while reactivity of unsoluble carbonyl compounds needs further attention. To address this issue Kobayashi developed a scandium-catalysed hydroxymethylation of silicon enolates with aqueous formaldehyde in water that does not require organic solvents (Table 2).14 After careful optimization of the reaction conditions with respect to various additives, catalytic asymmetric hydroxymethylation was successfully carried out with 10 mol% of the Sc3+ salt and 12 mol% of chiral ligands 7 or 14 to afford the desired products in good to high yields and with high selectivities. Further, Kobayashi developed this methodology for direct reaction of ketones in place of silicon enolates.15 Addition of base resulted in direct enolisation of ketone prior to the reaction with formaldehyde in pure water. Among organic bases tested, pyridine was found to be the best additive for the desired asymmetric hydroxylation by using scandium triflate and chiral N-oxide ligand 14. In spite of average enantioselectivity observed for the reaction of ketones (67–88% ee), this catalytic system and the abovepresented concept seem to be highly prospective for further development and application.
Chem. Soc. Rev., 2014, 43, 577--587 | 579
View Article Online
Tutorial Review
Published on 22 October 2013. Downloaded by National University of Singapore on 13/06/2014 09:01:18.
Table 2
Asymmetric hydroxymethylation in water elaborated by Kobayashi
3. Direct aldol reaction In nature, type I or type II aldolases catalyse the direct aldol reaction in water. These aldolases affect the coupling of unmodified substrates in aqueous media for achieving absolute stereocontrol via (i) an enamine mechanism or (ii) metal enolate formation, respectively.2 These biological processes always inspired chemists but only recently provided a template for successful development of small molecule artificial catalysts for direct asymmetric aldol reactions.16 The focus of this chapter will be on water compatible small organic molecules and metal complexes, with special emphasis on substrate scope and important current limitations. 3.1.
Enamine organocatalysis
The fast developing area of organocatalysis comprises the vast majority of reported methods for carrying out direct catalytic aldol reactions. Small organic molecules utilising the enamine mechanism analogously to type I aldolases are well known to promote asymmetric processes also in water.17 Reports of small-molecule enamine-based aldol reactions in water have been presented throughout the literature over the last several years.7 Some reactions have been performed under aqueous conditions, with the presence of water being reported to increase the reactivity and stereoselectivity. Although conceptually important, initially presented examples of small-moleculeorganocatalyzed aldol reactions in water with sufficient asymmetric induction would have immense synthetic utility because of low enantioselectivity and application of organic co-solvents.18 In 2006, two groups independently reported the asymmetric aldol reaction ‘‘in the presence of water’’ without using any organic solvent. Studies presented by Hayashi19 and Barbas20 have shown that highly enantioselective direct aldol reactions in water can be promoted by proline-based catalysts via an enamine mechanism. In the former studies, trans-L-siloxyproline (18, Table 3) was presented as a catalyst for high diastereo- and enantioselective aldol reactions of cyclohexanone (15, 5 equiv.) with 4-nitrobenzaldehyde (16) in the presence of water (18 equiv.). Although the role of water is not clear, it was shown that water is essential for high stereoselectivity. An elaborate aldol
580 | Chem. Soc. Rev., 2014, 43, 577--587
Chem Soc Rev
reaction proceeds with lower diastereo- and enantioselectivity in an organic solvent (DMSO). The reaction proceeds obviously in a two-phase system with small amounts of water (3–18 equiv.). In this case hydrophobic siloxyproline 18 acts as a catalyst in the organic phase formed by the aldehyde and ketone substrates. Aggregation of the organic molecules excludes water from the organic phase and drives the equilibrium toward enamine formation. Since the protocol uses only a small amount of water in a heterogeneous reaction mixture, these reactions are generally called ‘‘direct aldol reactions in the presence of water’’. Hayashi also described ‘‘a reaction in water’’ as one in which the reactants are dissolved homogeneously in water, whereas ‘‘a reaction in the presence of water’’ term should be used for a reaction that proceeds in a concentrated organic phase with water being present as a second phase. In this case, however, water is not only the inert second phase but influences the reaction yield and stereoselectivity, as was presented for aldol reaction promoted by catalyst 18. At around the same time Barbas designed a small hydrophobic diamine catalyst (19) which smoothly promoted the direct cross-aldol reaction of cyclohexanone (2 equiv.) with 4-nitrobenzaldehyde in pure water, giving the anti-aldol product 17 in quantitative yield with 94% ee (Table 3).20 Importantly, a stoichiometric amount of donor was enough to achieve the reaction, further increasing the economy of the reaction. Catalyst loading could also be decreased to 1 mol%. It is worth noting that both catalysts 18 and 19 were less efficient for non-activated aldehydes resulting in lower yield, and less selective for water soluble substrates (reactions of acetone with 4-trifluoromethyl benzaldehyde promoted by 18 – 65% ee, reactions of acetone with 4-nitrobenzaldehyde promoted by 19 – 55% ee). Both aldolase-type organocatalysts 18 and 19 are equipped with hydrophobic parts and conspicuously form an emulsion composed of water and organic substrates. Diamine 19 acts as a water soluble quaternary ammonium salt with long hydrophobic chains thus recalling surfactants operating at the water–organic interface. These two examples showed the direction for a number of scientists designing catalysts for the aqueous aldol reaction between cyclohexanone and activated aromatic aldehydes. A number of interesting contributions are collected in Table 3. Selected examples have been carried out only without organic co-solvents and with a nearly stoichiometric amount of ketone donors. The presented substrate set may not be promising for further applications but these examples offer an interesting overview of evolution of the concept of carrying out reaction of unsoluble substrates ‘‘in the presence of water’’. Gong21 and Singh22 demonstrated an efficient aldol reaction with very low catalyst loading (1 and 0.5 mol%, respectively). Particularly excellent stereoselectivities were observed using the prolinamide catalyst 21 in brine (Table 3).22 High reactivity and stereoselectivity are due to the salting-out effect as well as double activation of the aldehyde acceptor via a hydrogen bonding network with both NH and OH of the catalyst. These principles along with E-enamine formed from the cyclohexanone molecule resulted in the observed sense of stereochemistry induction (Table 3, TS-I).
This journal is © The Royal Society of Chemistry 2014
View Article Online
Chem Soc Rev
Structures of amine catalysts used in organocatalytic aldol reactions between cyclohexanone and 4-nitrobenzaldehyde in the presence of
Published on 22 October 2013. Downloaded by National University of Singapore on 13/06/2014 09:01:18.
Table 3 water
Tutorial Review
The role of hydrophobic catalysts also diminishes contacts between bulk water and the reaction transition states in an emulsion in the reaction solution of water and organic substrates. Such an excellent catalyst system was reported by the Armstrong group in 2007.23 Quantitative yields were obtained for stoichiometric direct aldol reactions by addition of sulfated b-CD (10 mol%), which binds tert-butylphenoxyproline (22, 2 mol%) and associated hydrophobic reactants (Table 3). Simple filtration or phase separation affords an anti-aldol (17) product in high optical purity. In 2007, Gryko showed that direct aldol reaction of cyclic ketones with aromatic aldehydes in the presence of water can be efficiently promoted by prolinethioamide salt 23.24 It was proved that the use of water effectively enhanced the activity of the catalyst. Thus, as little as 1.2 equivalents of cyclohexanone in the presence of the protonated thioamide catalyst (only 2.5 mol%) resulted in the formation of aldol 17 in high yield and high enantioselectivity. The authors speculated that a strong hydrophobic effect plays a crucial role in this aldol
This journal is © The Royal Society of Chemistry 2014
reaction performed in the presence of a large amount of water (2 mL). Both, the rate of acceleration and high stereoselectivity are supported by hydrophobic aggregation of the reactant and catalyst. Further, the Najera group observed that prolinethioamides exhibited higher enantioselectivity than the corresponding prolinamides in the model aldol reaction between cyclohexanone and 4-nitrobenzaldehyde in the presence of 4-nitrobenzoic acid as a co-catalyst.25 In particular, (S)-prolinethioamide 24, derived from proline and (R)-1-aminoindane, was shown to be the most efficient organocatalyst (5 mol%) promoting aldol reactions in the presence of water (1.2 mL) and under solvent free conditions employing only 4 equivalents of ketone. In this case, solvent-free conditions gave a slightly higher diastereo- and enantioselectivity than when using water as a solvent. 4-Substituted acyloxyprolines with different hydrophobic substituents have been also synthesized and used as catalysts in the direct asymmetric aldol reaction between cyclic ketones and substituted benzaldehydes. Tao presented isosteviol-proline
Chem. Soc. Rev., 2014, 43, 577--587 | 581
View Article Online
Published on 22 October 2013. Downloaded by National University of Singapore on 13/06/2014 09:01:18.
Tutorial Review
conjugated organocatalyst 25.26 With only 1 mol% of catalyst loading, the desired anti-aldols were obtained with good to excellent yields and the enantioselectivities were excellent in most cases. Only 5 equivalents of water were used as a solvent, or a better reaction additive to enhance stereoselectivity. Gruttadauria showed that catalyst 26 bearing hydrophobic acyl chains provided aldol products in excellent yields and stereoselectivities.27 The catalyst was successfully used in only 2 mol% loading at room temperature with a small amount of water as an additive. Interestingly, most presented examples have been based on a portion of proline equipped with hydrophobic groups. These may be attached to the pyrrolidine ring of natural hydroxyproline, or attached as an ester or amide linkage to the proline carboxyl group. All proline-based catalysts are very hydrophobic and the reactions are believed to take place in an organic phase, mimicking an enzymes’ separation of carbonyl substrates away from bulk water. Whereas in the natural enzyme the enamine is formed at the lysine residue in the active site, most presented catalysts contain a cyclic pyrrolidine motive for this purpose. Studies of aqua organocatalytic reactions promoted by primary amino acids and their derivatives provided interesting and competitive results. A siloxyserine organocatalyst 27 has been developed by Teo to catalyse direct aldol reaction in the presence of water (ca. 7 equivalents).28 Further, Lu presented application of tryptophan (28) to the aldol reaction performed in the presence of ca. 15–100 equivalents of water.29 For both primary amines high enantioselectivity was observed for the reaction of cyclohexanone and 4-nitrobenzaldehyde at room temperature but the catalyst activities were limited to cyclic ketones only. In 2010, Nugent used 2-picolylamine template as a new and promising organocatalyst.30 A chiral version of the catalyst containing a single stereogenic center (29) has been identified as allowing highly stereoselective anti-aldol product formation at a low catalyst loading (5 mol%). Reactions have been performed in water or brine (1 mL) with high yields and stereoselectivities for cyclohexanone and substituted benzaldehydes. The same amount of water (1 mL) allowed for highly enantioselective aldol reaction of cyclohexanone and 4-nitrobenzaldehyde in the presence of a valine-based organocatalyst (30).31 Interestingly, protonated valinamide 30 was active enough to promote aldol reaction of usually unreactive benzaldehyde (76%, 94% ee), although a 9 : 1 ketone–water mixture was necessary for high substrate conversion. A similar, yet more problematic and less studied reaction of cyclopentanone can also be promoted by water tolerant organocatalysts (Table 4). Reaction of a donor with a fivemembered ring is usually less diastereoselective but few catalysts provided access to the anti-aldol product with high optical purity. For example, highly efficient and enantioselective catalyst 26 developed by Gruttadauria27 has been used to control the reaction of cyclopentanone with aromatic aldehydes. For a number of tested aromatic aldehydes enantioselectivities ranged from 96 to 99%, only the 3-methoxy derivative showed a slightly lower enantioselectivity (93%). Only 2 mol% of organocatalyst 26 was enough to promote the reaction at room temperature in the
582 | Chem. Soc. Rev., 2014, 43, 577--587
Chem Soc Rev Table 4 Structures of amine catalysts used in organocatalytic aldol reactions between cyclopentanone and 4-nitrobenzaldehyde
presence of a small amount of water (175 mL) without organic co-solvent. In 2009, Li described prolinethioamide 33 prepared from readily available natural amino acid proline and amino alcohol valinol.32 This organocatalyst has been found to be active for the direct aldol reaction of various aldehydes with acetone, cyclohexanone and cyclopentanone at 0 1C under anhydrous conditions. The same catalyst promoted the direct aldol reaction of 4-nitrobenzaldehyde and cyclopentanone and cyclohexanone in water with 97 and 99% ee of anti-aldols, respectively (Table 4). Most of the above-mentioned catalysts have the limitation of giving moderate enantioselectivity with a water-miscible ketone such as acetone or hydroxyacetone (HA), a highly desirable substrate from a conceptual and synthetic point of view. Therefore, there was a great need for a chiral organocatalysts that could overcome these drawbacks and work in homogeneous solution without biphasic interactions described above. Two interesting examples of proline-based catalysts have been presented by Gong21 and Singh.22 Both catalysts (20 and 21, Table 5) afforded aldol products from cyclic and acyclic ketones and various aldehydes in an excess of water or brine. Catalysts 20 although still highly efficient (1 mol%) lost some selectivity for acyclic ketones (71% ee for acetone) when compared to cyclohexanone. More efficient, versatile and enantioselective catalysts have been developed by Singh.22 Prolinamide catalyst 21 bearing a nonpolar gemdiphenyl group works very efficiently for acetone in brine. In most cases, authors reported more than 99% ee by using 0.5 mol% of the catalyst 21 in brine. Based on the proposed transition state model for this catalyst (TS-II, Table 5) the stereochemistry of the aldol products was easy to be explained. Proline amide bears two hydrogen bond donors additionally stabilizing aldehyde molecule with the biggest substituent placed far from catalysts bulky groups. This excellent catalyst has been demonstrated to be efficient for activated- and non-activated aromatic aldehydes and worked also for aliphatic donors (3-propanal: 70%, 99% ee). Further, various catalysts for the asymmetric aldol reaction of water soluble acetone with aromatic aldehydes have been presented. The most active were: the prolinamide-based
This journal is © The Royal Society of Chemistry 2014
View Article Online
Chem Soc Rev
Published on 22 October 2013. Downloaded by National University of Singapore on 13/06/2014 09:01:18.
Table 5
Tutorial Review
Structures of amine catalysts used in organocatalytic aldol reactions between acetone and 4-nitrobenzaldehyde in water
catalyst developed by Da (36),33 and prolinethioamide 37 used by Li.34 Both catalysts promoted the aldol reaction of acetone (5–10 equivalents) in homogeneous water or brine solution (ca. 1 mL). It is worth noting that the asymmetric reaction of aliphatic aldehydes still remained problematic for the above mentioned catalysts. In 2008, Gruttadauria employed a new prolinamide derivative 38 attached to a polystyrene support (Table 5).35 This heterogeneous catalyst has been employed in the direct asymmetric aldol reaction of cyclohexanone and acetone with good results in terms of yield and stereoselectivity. The reaction was performed in a biphasic water–chloroform system, being a compromise between the good swelling properties of chloroform and the formation of a concentrated organic phase due to the presence of water. This catalyst can be easily recovered, regenerated and recycled, without loss of activity. Hydroxy- and dihydroxyacetone (DHA) are versatile C3 building blocks in the chemical and enzymatic syntheses of carbohydrates36 and thus an extremely important synthetic challenge. In addition, aldol reaction of hydroxyl- and dihydroxyacetone seems to be closely related to aldolase action in a natural water environment making designing of enamine-based organocatalysts for the reaction of hydroxyketones even more exciting. Although some organocatalysts are able to activate a hydroxyacetone donor in dry organic solvents, their application in aqueous solutions is limited to protected donors and failed to give promising results in the presence of water with unprotected hydroxyacetone. Primary amine-based amino acids i.e. siloxy-Lthreonine (41)37 have been demonstrated to be efficient organocatalysts for syn-selective aldol reaction between a variety of
This journal is © The Royal Society of Chemistry 2014
aromatic aldehydes and tert-butyldimethylsilyloxy hydroxyacetone as a donor in the presence of water (Table 6). Later, Chimni demonstrated application of a series of water compatible primary–tertiary diamine organocatalysts derived from natural primary amino acids bearing a hydrophobic side chain.38 The catalyst 42 having a morphinyl group gave the best results for the reaction of protected hydroxyacetone with aromatic aldehydes (Table 6). It is important to notice that the aldol reaction of hydroxyacetone with 4-nitrobenzaldehyde using catalyst 42 in aqueous medium produced an aldol adduct in very low yield (20%) and enantioselectivity (31% ee).38 More promising results have been observed for the reaction of this demanding donor in aqueous organic solvents by using other organocatalysts.
Table 6 Organocatalytic aldol reactions between TBS-protected hydroxyacetone and 4-nitrobenzaldehyde in water (TBS: tert-butyldimethylsilyl, TBDPS: tert-butyldiphenylsilyl)
Chem. Soc. Rev., 2014, 43, 577--587 | 583
View Article Online
Tutorial Review
Published on 22 October 2013. Downloaded by National University of Singapore on 13/06/2014 09:01:18.
Table 7 Organocatalytic aldol reactions between hydroxyacetone and 4-nitrobenzaldehyde in aqueous solvents
In 2009, Singh presented the chiral cyclohexyldiamine-based catalyst 45 that efficiently catalyses the syn-selective addition to hydroxyacetone donor in DMF–water (9 : 1) solution with high enantioselectivity (Table 7).39 The presented catalyst contained aromatic substituents forming a hydrophobic cavity with the reactants in aqueous medium. Thus, the catalyst successfully mimics the enzymes’ mode of action, and the reaction takes place in this cavity, resulting in high stereoselectivity. The idea behind this design is that a water-soluble substrate (i.e., natural dihydroxyacetone phosphate) can be efficiently activated in hydrophobic pockets of water-unsoluble catalysts. Taking advantage of this concept, catalysts 4640 equipped with hydrophobic alkyl chains and siloxyserine 4731 have been successfully applied for the synthesis of syn-aldols from hydroxyacetone (Table 7). In addition, the latter catalyst was also active and selective for aliphatic aldehydes making elaborated methodology acceptable for further synthesis of natural products. Additionally, authors confirmed formation of the enamine intermediate from hydroxyacetone and catalysts 47 by using the MS technique.31 In spite of the presented successful application of organocatalysts to the activation of hydroxyacetone, the dihydroxyacetone variant is still at its infancy. For example, reaction of dihydroxyacetone (DHA) with (R)-glyceraldehyde (49) should result in direct formation of four natural ketohexoses.36 Initial attempts at this strategy in aqueous organic solvent by using small organic molecules resulted in unselective formation of monosaccharides. In contrast, protected dihydroxyacetone as TBS-ether served as an excellent substrate in the reaction promoted by amide 51 in brine.41 A variety of aliphatic aldehydes provided syn-aldol products with good yields and ees up to 98% in brine allowing for the direct synthesis of a range of carbohydrates and their derivatives. Reaction of the acetonide of D-glyceraldehyde (49) provided the protected sorbose derivative in 86% yield, (3 : 1) syn-favored dr, and 98% ee. cis-Configured enamine formed in the presence of threonine-based catalyst 51 can be additionally stabilised by the hydrogen bond between OH (OR) and the amino acid nitrogen atom, even for reactions proceeding in the presence of water (Table 8, TS-IV).
584 | Chem. Soc. Rev., 2014, 43, 577--587
Chem Soc Rev Table 8 Aqueous organocatalytic aldol reactions between dihydroxyacetone and (R)-glyceraldehyde
Also catalysts 42, previously demonstrated for the reaction of protected hydroxyacetone (Table 6), have been useful for the reaction of TBS-dihydroxyacetone with aromatic 4-nitrobenzaldehyde, producing the aldol adduct in high yield (93%) and with excellent enantioselectivity (95% ee).38 Following previously published cross-aldol reactions promoted by siloxyserine, Hayashi developed a catalytic, direct asymmetric cross-aldol reaction of two different aldehydes in the presence of water, catalysed by a combined proline–surfactant organocatalyst 55.42 The reaction of 2-chlorobenzaldehyde (52) and propanal (53, 5 equiv.) was selected as a model and performed in the presence of water and several putative organocatalysts. The best results in terms of yield and anti-selectivity were observed for the proline catalyst with a decanoate side chain (Table 9). In contrast, the highly syn-selective cross-aldol reaction of aldehydes has remained a challenging subject in the field of aminocatalysis. To achieve this end, Cheng explored chiral L-phenylalanine derived primary–tertiary diamine 56. This catalyst was found to promote the cross-aldol reactions of aldehydes with high activity and synselectivity (Table 9, syn–anti up to 24 : 1, 87% ee).43 While discussing cross-aldol reactions of aldehydes it is important to also notice the dimerization of glycolaldehyde leading directly to formation of tetroses. This concept, however, has been studied previously and is the subject of another review.36
Table 9
Cross-aldol reaction of two aldehydes in water
This journal is © The Royal Society of Chemistry 2014
View Article Online
Chem Soc Rev
Published on 22 October 2013. Downloaded by National University of Singapore on 13/06/2014 09:01:18.
Table 10
Cross-aldol reactions of ketones in water
Tutorial Review Table 11
Synthesis of isotetronic acid in water
Various functionalized isotetronic acids were obtained with high yields (up to 94%) and excellent ees (99%). Examples of cross-aldol reactions of ketones in the presence of water are relatively rare. In 2009, Tomasini noticed that the addition of small quantities of water (ca. 20 equiv.) to the proline or prolinamide (59) promoted aldol reaction of acetone to isatin (57) resulting in an increased level of observed enantioselectivity (Table 10).44 The authors explained this phenomenon by using a transition state model incorporating water molecules into isatin carbonyl groups by hydrogen bonds. Interestingly, the addition of larger quantities of water was found to have a negative impact on the reaction selectivity. Later, Singh presented the highly enantioselective reaction of isatin (57) and cyclohexanone promoted by a primary–tertiary diamine in both aqueous and organic solvents (Table 10).45 A cyclic ketone was allowed to react with isatin in the presence catalyst 45/TFA salt (10 mol%) using water as a reaction medium. An organocatalyst bearing an aromatic group can form a hydrophobic cavity for the reaction active site diminishing contact between water molecules and thus forming the enamine intermediate (Table 10, TS-V). Another interesting field where application of water allowed for better reactivity and selectivity is the organocatalytic activation of keto acid molecules. Particularly interesting asymmetric synthesis of isotetronic acid 62 from oxobutyric acid (60) and isobutyraldehyde (61) has been explored by Landais (Table 11).46 Proline proved to be a poor catalyst for this reaction but application of benzoimidazolepyrrolidine (63) resulted in the formation of the desired 62 in 87% ee in water. Better yields and enantioselectivities were observed with aromatic aldehydes, particularly those having electron withdrawing groups. Postulated protonation of the benzoimidazole ring by keto acid provides a zwitterionic chair-like transition state TS-VI with bulky substituents in the equatorial positions. More recently, Liu and Li tested a series of catalysts having an imidazole motif, for the same cascade reaction leading to isotetronic acids.47 The best results in terms of yield and enantioselectivity were observed for the catalyst 64 having a long alkyl chain. This amphiphilic organocatalyst promoted reaction of aromatic and aliphatic aldehydes with ketoacids using water as a solvent. Both water and organic–water emulsions were found to be crucial for achieving the high reactivity and stereoselectivity.
This journal is © The Royal Society of Chemistry 2014
3.2.
Direct aldol reaction promoted by metal complexes
In parallel to the fast-growing field of organocatalysis, application of metal-complexes for direct aldol reaction in water is also seen in the literature. Conceptually, this is often compared mechanistically to the type II aldolases, which employ a zinc ion to form more reactive metal enolate. Such a catalytic system mimicking aldolases’ mode of action although highly desired may be difficult to design in a water environment. In this case, the ketone donor can also be activated through enamine formation, while Lewis acid can activate the aldehyde carbonyl group instead of enolate formation from the ketone substrate. Nevertheless, such a scenario seems also highly attractive as the combination of organocatalysis with transition metal catalysis has emerged as a promising area in organic chemistry. In 2007, Mlynarski presented studies on application of bisprolinamide (65) zinc complexes for direct asymmetric aldol reactions in aqueous media.48 Both acetone and cyclohexanone served as convenient substrates in the reaction promoted by 10 mol% of a zinc complex, resulting in the formation of aldols with high yields and enantioselectivities (Table 12). Elaborate catalytic systems, although requiring a large excess of ketones, have been selective for both water soluble and unsoluble substrates. Later, the catalysts have been demonstrated to promote highly enantioselective reactions of formaldehyde with cyclic ketones in ethanol–water homogeneous mixtures.31 The presented catalyst Zn65 incorporates a metal center and two proline units, and the authors postulated a mechanism involving organocatalytic enamine formation (Table 12, TS-VII, VIII), where zinc complexation only stabilizes the formation of an enamine intermediate in water.31 Formation of the anti-product observed in the reaction of cyclic substrates resulted from the E enolate of cyclohexanone (TS-VII). By the same rules, aldol reaction of enamine with acetone or formaldehyde (TS-VIII) resulted in formation of (S)-aldol. In fact, the presented TS models VII and VIII use the same principle as for direct aldol reactions promoted by proline organocatalysts. Later, the same concept of application of zinc-based catalyst incorporating prolinamide units have been presented by a few other authors but reported results have not been progressive. Interestingly, Penhoat demonstrated that direct combination of various Lewis acids and L-proline 66 can promote direct aldol
Chem. Soc. Rev., 2014, 43, 577--587 | 585
View Article Online
Tutorial Review
Published on 22 October 2013. Downloaded by National University of Singapore on 13/06/2014 09:01:18.
Table 12
Direct aldol reaction in water promoted by chiral Lewis acids
reactions of cyclohexanone with aromatic aldehydes in a DMSO– water mixture.49 The chloride salts of the group 12 elements (ZnCl2, CdCl2 and HgCl2) led to the highest stereoselectivities and conversions. Although the authors declare that the procedure appears to be an excellent and readily available biomimetic model analogous to type II aldolases, no evidence for the metalenolate formation has been presented to prove this concept. In 2011, Wang developed a new class of primary aminebased ligand 67 for copper-supported direct aldol reactions of cyclohexanone and aromatic aldehydes in water (Table 12).50 In spite of high catalyst loading, this bifunctional catalyst displayed high activity in the direct aldol reactions of electron-rich and electron-poor aldehydes. According to the authors, the metal coordinates with the chelating ligand to form a rigid chiral Lewis acid which activates the aldehyde while the primary amine reacts with cyclohexanone to form an enamine as depicted in Table 12, structure TS-IX. To conclude the discussion on two possible mechanisms for direct aldol reaction promoted by a bifunctional catalyst composed of amine and Lewis acids, readers may consult the Aoki mechanistic studies of catalysts consisting of chiral amino acids and Zn–cyclene complexes.51 Aldol reactions of acetone and aromatic aldehydes were promoted by asymmetric catalysts to give aldol adducts with moderate to good ee values (up to 89%). The authors suggest that the formation of enamine from acetone and L-proline although possible is less efficient in the formation of C–C bond, while the Zn-enolate of acetone provides an efficient and enantioselective aldol reaction.
4. Conclusions Water as a solvent is not only inexpensive and environmentally benign, but may also offer completely new reactivity or
586 | Chem. Soc. Rev., 2014, 43, 577--587
Chem Soc Rev
stereoselectivity when compared to classical organic solvents. These features constitute the most important motivation for the use of water as everyday solvent for chemists. In addition, the role of water in organic reactions, and also in life processes, is often complex and not well understood. This makes water an even more important solvent and its application not only interesting from an environmental concern perspective but also crucial for revealing reaction mechanisms. Although the direct catalytic aldol systems which were assumed to proceed through an enamine mechanism by mimicking type I aldolases have been well established and explored, the direct activation of carbonyl partners by using the methods analogous to the action of type II aldolases containing a zinc cofactor has still remained challenging. Nevertheless, development of water compatible organocatalysts and metal complexes highly influences organic synthesis and designing of chiral catalysts and finally greatly contributes to our understanding of life chemistry. Our projects related to the presented subject operate within the Foundation for Polish Science TEAM Programme co-financed by the EU European Regional Development Fund.
Notes and references 1 The use of water to accelerate the Diels–Alder is often cited as an important turning point in the field: D. C. Rideout and R. Breslow, J. Am. Chem. Soc., 1980, 102, 7816. 2 S. M. Dean, W. A. Greenberg and C.-H. Wong, Adv. Synth. Catal., 2007, 349, 1308. 3 R. N. Butler and A. G. Coyne, Chem. Rev., 2010, 110, 6302. 4 H. D. Dakin, J. Biol. Chem., 1909, 7, 49. 5 J. G. Hernandez and E. Juaristi, Chem. Soc. Rev., 2012, 48, 5396. 6 D. G. Blackmond, A. Armstrong, V. Coombe and A. Wells, Angew. Chem., Int. Ed., 2007, 46, 3798. 7 J. Mlynarski and J. Paradowska, Chem. Soc. Rev., 2008, 37, 1502. 8 S. Kobayashi and C. Ogawa, Chem.–Eur. J., 2006, 12, 5954. 9 T. Hamada, K. Manabe, S. Ishikawa, S. Nagayama, M. Shiro and S. Kobayashi, J. Am. Chem. Soc., 2003, 125, 2989. 10 Y. Mei, D. J. Averill and M. J. Allen, J. Org. Chem., 2012, 77, 5624. 11 J. Jankowska, J. Paradowska, B. Rakiel and J. Mlynarski, J. Org. Chem., 2007, 72, 2228. 12 T. Ollevier and B. Plancq, Chem. Commun., 2012, 48, 2289. 13 M. Woyciechowska, G. Forcher, S. Buda and J. Mlynarski, Chem. Commun., 2012, 48, 11029. 14 M. Koubo, C. Ogawa and S. Kobayashi, Angew. Chem., Int. Ed., 2008, 47, 6909. 15 M. Kobuko, K. Kawasami, T. Nagano and S. Kobayashi, Chem.–Asian J., 2010, 5, 490. 16 B. M. Trost and Ch. S. Brindle, Chem. Soc. Rev., 2010, 39, 1600. 17 M. Gruttadauria, F. Giacalone and R. Notoa, Adv. Synth. Catal., 2009, 351, 33.
This journal is © The Royal Society of Chemistry 2014
View Article Online
Published on 22 October 2013. Downloaded by National University of Singapore on 13/06/2014 09:01:18.
Chem Soc Rev
18 A. P. Brogan, T. J. Dickerson and K. D. Janda, Angew. Chem., Int. Ed., 2006, 45, 8100. 19 Y. Hayashi, T. Sumiya, J. Takahashi, H. Gotoh, T. Urushima and M. Shoji, Angew. Chem., Int. Ed., 2006, 45, 958. 20 N. Mase, Y. Nakai, N. Ohara, H. Yoda, K. Takabe, F. Tanaka and C. F. Barbas III, J. Am. Chem. Soc., 2006, 128, 734. 21 J.-F. Zhao, L. He, J. Jiang, Z. Tang, L.-F. Cun and L.-Z. Gong, Tetrahedron Lett., 2008, 49, 3372. 22 V. Maya, M. Raj and V. K. Singh, Org. Lett., 2007, 9, 2593. 23 J. Huang, X. Hang and D. W. Armstrong, Angew. Chem., Int. Ed., 2007, 46, 9073. 24 W. J. Saletra and D. Gryko, Org. Biomol. Chem., 2007, 5, 2148. 25 D. Almasi, D. A. Alonso, A.-N. Balaguer and C. Najera, Adv. Synth. Catal., 2009, 351, 1123. 26 Y.-J. An, Y.-X. Zhang, Y. Wua, Z.-M. Liu, C. Pi and J.-C. Tao, Tetrahedron: Asymmetry, 2010, 21, 688. 27 F. Giacalone, M. Gruttadauria, P. L. Meo, S. Riela and R. Notoa, Adv. Synth. Catal., 2008, 350, 2747. 28 Y.-C. Teo, Tetrahedron: Asymmetry, 2007, 18, 1155. 29 Z. Jiang, H. Yang, X. Han, J. Luo, M. W. Wong and Y. Lu, Org. Biomol. Chem., 2010, 8, 1368. 30 T. C. Nugent, M. N. Umar and A. Bibi, Org. Biomol. Chem., 2010, 8, 4085. 31 J. Paradowska, M. Pasternak, B. Gut, B. Gryzlo and J. Mlynarski, J. Org. Chem., 2012, 77, 173. 32 B. Wang, G.-H. Chen, L.-Y. Liu, W.-X. Chang and J. Li, Adv. Synth. Catal., 2009, 351, 2441. 33 Y. N. Jia, F. C. Wu, X. Ma, G.-J. Zhu and C.-S. Da, Tetrahedron Lett., 2009, 50, 3059. 34 B. Wang, X.-W. Liu, L.-Y. Liu, W.-X. Chang and J. Li, Eur. J. Org. Chem., 2010, 5951. 35 F. Giacalone, M. Gruttadauria, P. L. Meo, S. Riela and R. Notoa, Adv. Synth. Catal., 2008, 350, 1397.
This journal is © The Royal Society of Chemistry 2014
Tutorial Review
36 J. Mlynarski and B. Gut, Chem. Soc. Rev., 2012, 41, 587. 37 X. Wu, Z. Jiang, H.-M. Shen and Y. Lu, Adv. Synth. Catal., 2007, 349, 812. 38 A. Kumar, S. Singh, V. Kumar and S. S. Chimni, Org. Biomol. Chem., 2011, 9, 2731. 39 M. Raj, G. S. Parashari and V. K. Singh, Adv. Synth. Catal., 2009, 351, 1284. 40 C. Wu, X. Fu and S. Li, Tetrahedron: Asymmetry, 2011, 22, 1063. 41 S. S. V. Ramasastry, K. Albertshofer, N. Utsumi and C. F. Barbas III, Org. Lett., 2008, 10, 1621. 42 Y. Hayashi, S. Aratake, T. Okano, J. Takahashi, T. Sumiya and M. Shoji, Angew. Chem., Int. Ed., 2006, 45, 5527. 43 J. Li, N. Fu, X. Li, S. Luo and J.-P. Cheng, J. Org. Chem., 2010, 75, 4501. 44 G. Angelici, R. J. Correa, S. J. Garden and C. Tomasini, Tetrahedron Lett., 2009, 50, 814. 45 M. Raj, N. Veerasamy and V. K. Singh, Tetrahedron Lett., 2010, 51, 2157. 46 J.-M. Vinvent, C. Margottin, M. Berlande, D. Cavagnat, T. Buffeteau and Y. Landais, Chem. Commun., 2007, 4782. 47 B. Zhang, Z. Jiang, X. Zhou, S. Lu, J. Li, Y. Liu and C. Li, Angew. Chem., Int. Ed., 2012, 51, 13159. 48 J. Paradowska, M. Stodulski and J. Mlynarski, Adv. Synth. Catal., 2007, 349, 1041. 49 M. Penhoat, D. Barbry and C. Rolando, Tetrahedron Lett., 2011, 52, 159. 50 P. Daka, Z. Xu, A. Alexa and H. Wang, Chem. Commun., 2011, 47, 224. 51 S. Itoh, M. Kitamura, Y. Yamada and S. Aoki, Chem.–Eur. J., 2009, 15, 10570.
Chem. Soc. Rev., 2014, 43, 577--587 | 587
