Asymmetric Synthesis with Silicon-Based Bulky Amino Organocatalysts

Abstract

Recent years have witnessed an explosive growth in the field of amino organocatalysis, especially in asymmetric enamine and iminium catalysis. Except for the obvious interaction between organocatalyst and substrate, the impact of bulky side group ons stereoselectivity is not as simple as one could imagine. Within the development of bulky site-stereoselective organocatalysts, functional silyl organocatalysts with a bulky silicon group are promising and meet the high standards of modern synthetic methods. This review focuses on the recent advances in the synthetic applications of silicon-based, bulky amino organocatalysts in which catalysts containing an organosilicon moiety or group play a formative role in controlling both the course of the reaction as well as the stereoselectivity.

1 Introduction

One of the ultimate goals and challenges in asymmetric synthesis is to develop environmentally benign and perfectly stereoselective transformations for the creation of functionalized optically active molecules with structural diversity from simple and easily available starting materials. One promising strategy for this aim, the organocatalysis, very much like enzyme and transition metal catalysis, plays a determining role in the formation of prebiotic key building blocks with chirality.1 In addition, organocatalysts are generally non-toxic, readily available, and air-stable, which results in better reproducibility and operational simplicity than with metal metal-catalyzed procedures.2 Reported examples of organocatalysis have increased rapidly in the last decade, which shows that it has become a crucial method with general superiority in asymmetric synthesis.3 Various types of organocatalysts, such as amino acids, peptides, Cinchona alkaloids, chiral thioureas, chiral Bønsted acids, chiral ketones, etc. express privileged and intriguing characteristics.4 Their excellent ability to mediate corresponding enantioselective transformations makes the boundaries between enzyme- and organocatalyst-mediated reactions blurred.

In the past years, most of the organocatalysts used in site-selective reactions were generally focused on the interaction of a base or acid with a substrate via enamine, iminium, hydrogen bond, SOMO, counterion catalysis, or their combinations. However, the development of a perfect organocatalyst based on the above functionality is not easy and, unexpected in the some cases, because many participating factors exist in enantioselective reactions. Except for the obvious interaction between the organocatalyst and substrate, the impact of a side bulky group on the stereoselectivity is not as simple as one could imagine.

Recently, chemists have begun to appreciate the potential offered by silicon as a special bulky group in organocatalysis.5 Within the development of site-bulky stereoselective organocatalysts, functional silyl organocatalysts with a bulky silicon group are promising and meet the high standards of modern synthetic methods. Why does silicon play such an important role in many organocatalysts? Since the 1970s organosilicon chemistry has played an important role in organic synthesis, especially as a protecting group, which may allow the use of silicon in the development of new functional organocatalysts. Both carbon and silicon are members of group 14 of the periodic table, this proximity suggests that their chemistries should be very similar. In fact, there are not only many similarities but also striking differences between these two elements. Silicon and carbon differ in atomic size (covalent radii: r_Si=117 pm, r_C=77 pm) and electronegativity (χ_Si=1.74, χ_C=2.50).6a The SiC bond length is much longer than the analogous CC bond length (1.89 versus 1.54 Å).6 The apparent size of a silyl group is thus larger than the corresponding alkyl group. As the bulk of the alkyl groups on silicon increases, the silyl group becomes increasing inert to the conditions normally used in organic synthesis. Moreover, a trialkylsilyl compound is relatively easier to prepare than the corresponding trialkylcarbon compound. As a result of these properties, silyl protecting groups in general use simple, bulky, hydrophobic, spectator groups on silicon for steric protection.6b However, since 2004/2005, functional and sophisticated amino silyl ethers have been found application in asymmetric organocatalysis, as they allow one to “fine-tune” the stereoselectivity and reactivity of different organic transformations.

In this review, we have chosen to limit the discussion to asymmetric synthesis with amino organocatalysts in which a silicon-based bulky moiety or group plays a non-negligible role in the stereoselectivity and reactivity of different organic transformations.

2 Silyl Amino Acids

Among the numerous reports on amino acid organocatalysts, L-proline is arguably the most famous organocatalyst in a wide range of organic reactions. Since the milestone work of List and Barbas in 2000,7 the development of amino acids, including primary amino acids, as catalysts for asymmetric organic reactions has been an interesting subject of intense research. Several simple modifications of the proline catalyst such as the substitution of the carboxylic acid moiety of proline with an amide or tetrazole function have been performed to improve the enantioselectivity and reactivity. In 2004, Hayashi et al.8 found that the reproducibility of proline-catalyzed α-aminoxylations of aldehydes was poor owing to the poor solubility of proline in the organic solvent. The problem led them to find a better organocatalyst, trans-4-tert-butyldimethylsiloxy-L-proline (1a), which is easily prepared from commercially available trans-4-hydroxy-L-proline (Scheme 1). The silicon-modified proline derivative (1a) not only provided reproducible results, but also accelerated the reaction dramatically with a reduced amount of the catalyst. This is the first example of a silyl organocatalyst that possesses a higher reactivity than the parent catalyst. As shown in Scheme 2, the higher reactivity of 1a was found not only in the α-aminoxylation of ketones but also in that of aldehydes: the reaction of phenylacetaldehyde with nitrosobenzene was completed within 2 h using 10 mol% of 1a, while the product 4 or 5 was isolated in less than 5% yield in the presence of proline, although the reaction time was much longer (24 h). Two hours are enough for the reaction of 3-phenylpropanal catalyzed by 1, which is in marked contrast to 24 h for the same reaction catalyzed by proline.

Scheme 1. Silyl amino acids.

Catalyst 1a is effective not only in the α-aminoxylation of carbonyl compounds, but also in the Mannich reaction. For the Mannich reaction of electron-rich aldehydes, proline scarcely promotes this reaction, while catalysts 1a displayed a greater catalytic activity than proline also with excellent enantioselectivity (Scheme 3).8 Although the authors did not gave a direct mechanistic discussion of silyl amino acids in these reactions, the introduction of the silicon group resulted in a successful modification of parent catalyst.

In 2007, Lu et al.9 prepared bulky siloxy derivatives of serine and threonine (2), and found that the incorporation of hydrophobic siloxy groups into serine and threonine resulted in a series of effective organocatalysts (for example, 2c) capable of catalyzing the direct aldol reaction between cyclohexanone and various aromatic aldehydes with excellent yields (up to 99 %) and nearly perfect ee in water (up to 99% ee).

Teo was also independently found that the siloxy-L-serine (2b) was an effective organocatalyst in the direct asymmetric aldol reactions of various substrates in the presence of water and ionic liquids (Scheme 4). 5 mol% of catalyst was sufficient to furnish the aldol products in excellent yields and enantioselectivities.10

In the aldol reaction of dihydroxyacetone with 4-nitrobenzaldehyde using N-methylpyrrolidone (NMP) with added water as the solvent (Scheme 5), O-TBDPS-L-threonine (2d) affords a higher activity and enantioselectivity than O-t-Bu-L-threonine (10).11 Although the authors did not gave any proposed explanation for this hydrophobic group, the data presented in this report provide further support for the notion that the bulky silicon group plays an advantageous role in this threonine catalyst.

Realizing that silyl-L-threonine or its derivative are effective catalysts in the aldol reaction, Lu and co-workers12 extended its use to the direct Mannich reactions of aldehydes, ketones, and amines, which resulted in the finding that the direct three-component Mannich reactions of O-benzylhydroxyacetone with p-anisidine and aromatic or aliphatic aldehydes in the presence of an silyl L-threonine catalyst afforded anti-1,2-amino alcohols in good-to-excellent yields and with enantioselectivities of up to 97% (Scheme 6). In the absence of water, the enantiomeric excess was lower. This study is the first demonstration that direct, anti-selective, three-component Mannich reactions can be promoted by a silyl amino acid in water.

In 2007, Lu and co-workers13 developed the direct anti-selective Mannich reactions of O-TBS-hydroxyacetone with various N-tosylimines derived from aromatic aldehydes in the presence of L-threonine-derived catalyst (2c) that afforded 1,2-amino alcohol derivatives (12) in good yields and with enantioselectivities of 99% in almost all cases (Scheme 7).

3 Amino Alcohol-Derived Silyl Ethers

The first examples on the use of amino alcohol-derived silyl ethers (diarylprolinol silyl ethers) in asymmetric synthesis were independently developed by Jørgensen’s14 and Hayashi’s25 group in 2005. This novel class of silyl organocatalyst in the form of sterically encumbered chiral pyrrolidine derivatives expanded the potential of enamine catalysis for secondary amine catalysts. Since then, many amino alcohol-derived silyl ethers have been designed and prepared, this class of silyl organocatalysts has emerged as a privileged enamine organocatalyst in many organic transformations, except for classic aldol and Mannich reactions, such as Michael reactions, cycloaddition, domino reactions, and total syntheses (Scheme 8).

3.1 Aldol Reactions

The aldol reaction is the most classic and commonly applied CC bond forming reaction in the construction of chiral building blocks.4g In the past years, numerous reports on asymmetric aldol reactions have appeared, now it is one of the most well-developed asymmetric transformations. Very recently, Boeckman et al.15 described the direct enantioselective aldol-type hydroxymethylation of aldehydes utilizing α,α-diphenyl trimethylsilyl ether 13a as an organocatalyst. Since the corresponding direct adducts of the aldol reaction and desired β-hydroxyaldehydes were difficult to handle and purify owing to their proclivity for oligomerization, the authors carried out a Pinnick oxidation (NaClO₂, NaH₂PO₄, 2-methyl-2-butene) of the aldol adducts to obtain stable β-hydroxy acids (Scheme 9). Most of aldehydes bearing substitutents and branched side chains are tolerated under the optimized condition and give the desired hydroxy acids in excellent enantioslectivities (90–99% ee) and good yields.

3.2 Mannich Reactions

The asymmetric Mannich reaction is a highly useful transformation for the construction of nitrogen-cotaining molecules.16 Since the discovery of the proline-mediated, three-component, direct Mannich reaction by List in 2000,17 many asymmetric Mannich reactions involving organocatalysts have been developed. In 2008, Hayashi et al.18 reported that the silyl ether of diarylprolinol (13c) catalyzed Mannich reactions of acetaldehyde and N-benzoyl-, N-Boc-, and N-Ts-imines with several useful features, such as low catalyst loading, suppression of imine decomposition and the double Mannich reaction (side reaction products), excellent enantioselectivities, and good yields (Scheme 10). In contrast, scarcely any reaction occurred in the presence of trifluoromethyl-substituted diarylprolinol without the siloxy-protecting group.

Córdova et al.19a have investigated the diphenyl trimethylsilyl ethers-catalyzed Mannich-type reaction between ethyl N-p-methoxyphenyl (PMP)-protected α-iminoglyoxylate and aliphatic aldehydes. The diphenylprolinol silyl ether 13a-catalyzed direct Mannich-type reactions were highly enantioselective and amino acid derivatives (31) were isolated in moderate to high yields with 97–99%ee. The reactions were highly anti-selective (14:1–>19:1). The authors also investigated the organocatalytic asymmetric Mannich-type reactions in water, which gave the corresponding products with high enantioselectivity (90–98% ee) but low conversion (<40%). The Mannich reaction is one of the most general methods for the synthesis of β-amino acid derivatives, and the chemistry of fluorinated analogues of β-amino acid derivatives is an expanding field of activity. Very recently, Fustero et al.19c extended the ethyl N-p-methoxyphenyl (PMP)-protected α-iminoglyoxylate to fluoroimines in the diphenylprolinol silyl ethers-catalyzed Mannich-type reaction. The Mannich reaction of fluoroaldimines and aldehydes in NMP in the presence of 20 mol% of catalyst 13a or 13c gave highly enantioenriched anti-γ-amino alcohols (32). However, the L-proline-catalyzed Mannich reaction between fluoroimines and aldehydes after reduction gave syn-β-alkyl-γ-amino alcohols (33) in moderate yield and excellent diastereo- and enantioselectivities (Scheme 11). The asymmetric induction caused by the bulky pyrrolidine substituent is the opposite of that induced by hydrogen-bonding when proline is used as catalyst.

Thiourea-based silyl ether 14f was also found to be an efficient catalyst in the Mannich reaction of PMP-protected α-iminoglyoxylate and aldehydes (96–99% ee). When ketones were used as substrates, moderate to good yields were obtained but the enantioselectivities are excellent (up to 99% ee).20

With realization of the importance of the Mannich reaction in the synthesis of β-amino acid derivatives, Gellman21a and Córdova21b successfully exploited the enantioselective organocatalytic method for the Mannich reaction between formaldehyde-derived N-benzyl-N-(methoxymethyl)(phenyl)methanamine (35) and aldehydes. Formaldehyde does not form stable imines, so the use of N-benzyl-N-(methoxymethyl)(phenyl)methanamine (35) as a precursor of the methylene iminium species is practical. It was found that 3a rather than L-proline and 2-(methoxydiphenylmethyl)pyrrolidine (34)22 led to improved enantioselectivity (90–92%ee) and yields in the presence of HOAc (Scheme 12). A mechanistic analysis of the proline-catalyzed versions suggested that non-H-bonded ionic interactions can be used as a stereochemistry-determining feature in organocatalytic reactions and the steric repulsion strategy proved to be more effective for achieving the desired goal. Analogously, Córdova et al.21b independently employed the same substrates in Mannich reactions under almost the same conditions. The difference was in the addition of lithium halide salts. The authors found that lithium halide salts significantly increased the enantioselectivity in the following order: LiBr>LiCl>LiI.

3.3 Michael Reactions

The Michael reaction, a synthetically important carbon-carbon bond-forming reaction, represents a direct and most appealing approach to versatile β-functionalized intermediates in organic synthesis.4b Much effort has been made to develop efficient catalytic stereoselective methods, and now the asymmetric Michael addition is one of the most thoroughly studied chiral bond-forming processes.

3.3.1 Aldehydes and Ketones as Donor

The organocatalytic Michael addition of ketones and aldehydes to nitroalkenes is a useful synthetic method for the preparation of γ-nitro carbonyl compounds.23 The direct Michael additions of cyclohexanone to nitroolefins catalyzed by prolinol tert-butyldiphenylsilyl ether (14e, Scheme 13) via enamine catalysis were conducted successfully in good yields (up to 99%) and high stereoselectivities (up to 98:2 diastereomeric ratio and 95% enantiomeric excess).24 Later, the authors found that the 4-trifluoromethanesulfonamidylprolinol tert-butyldiphenylsilyl ether bifunctional organocatalyst 14a is a highly efficient catalyst for the asymmetric Michael addition reactions of ketones and aldehydes to nitrostyrenes, leading to excellent yields (>99%), high diastereoselectivities (up to 99:1 dr) and excellent enantioselectivities in the most cases (up to 99% ee). Control experiments suggested that the trans-configuration relationship between the silyl bulky group (CH₂OTBDPS) and the sulfonamido group at the 4-position of the pyrrolidine ring was important to achieve high yield and stereoselectivity. The support of silyl ether catalyst 14 on polymer was also reported by Peng et al.24c Very recently, they designed and introduced a trans-4-amino substituent on the pyrrolidine ring of the prolinol tert-butyldiphenylsilyl ether, and immobilized it on MPS resin. A 10 mol% catalyst loading was needed in the Michael reaction of ketones to nitroolefins for good yields (up to 100%) and high stereoselectivities (up to 97/3 dr and 93% ee). The resin-bound catalyst 25 was simply separated and recovered by filtration, and reused for six consecutive trials without significant loss of activity and enantioselectivity.

In the first report on the use of diarylprolinol silyl ether, Hayashi and co-workers25 observed that diphenylprolinol could catalyzed the Michael addition of aldehydes to nitroolefins with high enantioselectivity (95%ee), however, the progress of the reaction was slow and the yield was unsatisfactory (29%) even after 24 h. The reactivity and enantioselectivity of the catalyst were increased dramatically when the hydroxy group in the parent diphenylprolinol was exchanged for a siloxy group. The silylated diphenylprolinol promoted the Michael reaction rapidly in 1 h, and the adduct was obtained in good yield (82%), high diastereoselectivity (syn/anti 94:6), and excellent enantioselectvity (99% ee). Not only the TMS-substituted compound (13a), but also the TES and TBS derivatives 13e and 13l are excellent catalysts. Gan et al. investigated the reaction mechanism for the Michael reaction of aldehydes and nitroalkenes in the presence of TMS-protected diphenylprolinol (13a). As a result of the stereospecific blockade of the bulky diphenylsiloxymethyl group on the pyrrolidine ring, the Re face of the enamine double bond is effectively shielded. A DFT study was performed on the Michael reactions of nitroalkenes with acetaldehyde, there are four different transition states: the energy difference between the two lowest-energy transition states is 2.4 kcal mol⁻¹, and the calculated enantiomeric excess value of 96% is in good agreement with the experimental result. The calculations reveal that the intermediates and solvent play an important role in the reactions.26

The power of chiral diphenylprolinol silyl ethers in Michael reaction of nitroolefins and aldehydes has been demonstrated for promoting other types of substrates for the preparation of synthetically useful α,β-disubstituted γ-nitrobutanals and derivatives (Scheme 14). List, Gellman, Hayashi, and Badía, independently employed different aldehydes (R²=H, aliphatic group) and nitroolefins [R¹=H, CH(OMe)₂, aromatic or aliphatic group] in the asymmetric diphenylprolinol silyl ether-catalyzed Michael reactions.27 The use of TMS-protected diphenylprolinol (13a) for catalyzing these Michael reactions proved successful with excellent enantioselectivities. Very recently, Headley and co-workers28 designed a water-soluble di(methylimidazole)prolinol silyl ether (17) for Michael addition of aldehydes to nitroolefins. This catalyst was conceived based on the notions that the bimethylimidazole group would enhance the hydrophilic interaction when the reaction is done in water, and that the bulky silyl ether and bimethylimidazole group should also act as an effective steric controller near the catalytic site of the catalyst. In substantial experiments, di(methylimidazole)prolinol silyl ether (17) effectively catalyzed the Michael addition of aldehydes to nitroolefins using water as only solvent in high yields and excellent enantioselectivities. In a similar study, diphenylperhydroindolinol silyl ether (18) facilitated the reaction of aldehydes and nitroalkenes and provided Michael adducts in nearly optically pure form (99% ee), good yields and high diastereoselectivities (syn/anti up to 99:1). Similar to previous findings in the development of catalyst 3, the absence of a TMS-protected group on the diphenylperhydroindolinol resulted in poor yields and lower enantioselectivity.29

Lombardo et al. recently developed a new and efficient ion-tagged diphenylprolinol silyl ether for the asymmetric Michael addition of aldehydes to nitroalkenes, which displays remarkable features, such as high ee of >99% in most cases, low catalyst loading (0.25–5 mol%), slight excess of aldehydes (1.2–2.0 equiv.).30

In a related study, Zhao and co-workers31 reported the synthesis of polyether dendritic diarylprolinol silyl ether (22). The dendritic catalyst (22) was studied in the Michael addition of aldehydes to nitroolefins, giving the adducts with 97–99% ee. The recoverable catalyst could be reused at least five times with only a slight loss of activity. With a similar strategy, a recyclable diphenylpyrrolinol silyl ether organocatalyst bearing an n-C₈F₁₇ fluorous tag has been demonstrated for promoting the asymmetric Michael addition reactions of aldehydes with nitroolefins and excellent levels of enantio- and diastereoselectivities are achieved. The catalyst 23 can be conveniently recovered by fluorous solid-phase extraction and subsequently reused without significant loss of its catalytic activity and stereoselectivity for the process. In each reuse cycle, excellent levels of enantioselectivity (99% ee), diastereoselectivity(≥20:1 dr), high yields were observed.32 In considering the solid-state conditions that might permit recycling and reuse of reaction catalysts, Schore and Pericàs33 examined these processes using polymer-supported crosslink- and pendant-bound TMS-protected diarylprolinols 24 and 26 (the shaded circles in Scheme 8 represent linkages to a polystyrene backbone). The catalyst 24 or 26 was found to be effective with high enantioselectivity (up to 99% ee, >98:2 dr, 80–89% yield) at 5 °C in a hexane/benzene mixtures as solvent.

To facilitate recovery and reuse of the expensive diarylprolinol silyl ethers, Ni and co-workers34 provided a simple example of a modified organocatalyst using diarylprolinol silyl ether salts as efficient, water-soluble, and recyclable organocatalysts for the asymmetric Michael addition on pure water. The hypothesis is based on the fact that the dimethylamine of the catalyst 19 and the Brønsted acid can form ammonium salts. The strategy was proved to be efficient in the catalytic asymmetric Michael addition of aliphatic aldehydes to nitroolefins on water, which provided the Michael adducts with excellent diastereo- and enantioselectivities (>98% ee, >95/5 dr). And the catalytic system can be easily recovered and reused for at least six times without significant loss of catalytic activity.

The β-nitroacrylate compounds are useful intermediates and precursors of biologically important β-amino acids and other related derivatives (Scheme 15). Ma and co-workers35 reported an excellent asymmetric induction ability of the o-TMS-protected diphenylprolinol compounds in the Michael reaction of aldehydes to β-nitroacrylate. Very recently, Hayashi et al.36 applied this key reaction in the total synthesis of (−)-oseltamivir using alkoxyaldehyde, nitroalkene, and subsequent treatment with diethyl vinylphosphonate (Scheme 16). It is one of the most efficient total sytheses of (−)-oseltamivir (44) so far, thus providing direct evidence of the excellent asymmetric induction ability of o-TMS-protected diphenylprolinol and its similarities (13).

Despite the great interest in bi-activated Michael acceptors, such as vinylphosphonates, few reports have mentioned the highly diastereoselective conjugate addition of carbonyl compounds to these acceptors. In 2006, Alexakis et al.37 reported the first enantioselective organocatalytic Michael addition of aldehydes to vinylphosphonate (45) using diphenylprolinol silyl ether 13a, providing optically active γ-gem-phosphonate aldehydes in good yields (65–85% yield) and with high stereoselectivities (46–97% ee). It is notably that neither L-proline nor diphenylprolinol could generated the Michael adduct.

Similarly to the Michael addition of vinylphosphonates, the highly enantioselective catalytic Michael addition of aldeydes to vinyl sulfones (47) remains a challenging task. In 2008, Lu38 disclosed that silylated diarylprolinols promote the addition of modified aldehydes to vinyl sulfones with exceptional enantioselectivity. In the model Michael reaction of isovaleraldehyde to vinyl sulfone, the authors found that diphenylprolinol without a silyl group affording the desired adducts (48) with poor enantioselectivities whereas the silyl ether derivative (13c) increased the activity and enantioselectivity dramatically. For the target synthesis of α-methylene-δ-lactones and δ-lactams, Jørgensen39a and Palomo39b ultilized the silylated organocatalyst catalyzed Michael addition of unmodified aldehydes to ethyl 2-(diethoxyphosphoryl)acrylate (49), vinyl sulfone, and E-α-ethoxycarbonyl vinyl sulfones (51), as the key step (Scheme 17). With (S)-13c as catalyst, the adduct was formed as a mixture of two epimers in a ratio of 4:1 with the same absolute stereochemistry at the C-4 stereocenter and with different configurations at the C-2 stereocenter. Interestingly, the opposite enantiomer of the product was afforded with a lower dr of 1.7:1 by application of the catalyst (R)-13c.

Córdova and co-workers40 successfully expanded the scope of the diarylprolinol silyl ether-catalyzed Michael reactions of aldehydes to maleimides. The organocatalytic asymmetric conjugate additions of unmodified aldehydes to maleimides were highly chemo- and enantioselective, and the corresponding α-substituted succinimides were isolated in good-to-high yields with 97–99% ee for most of cases (Scheme 18).

Inspired by the success in employing α-keto-α,β-unsaturated esters as the Michael acceptors, Ma and co-workers41 explored the diarylprolinol silyl ether-catalyzed Michael reaction of aldehydes to α,β-unsaturated thiol esters (54) with a γ-ester or amide moiety. The experimental results revealed that diarylprolinol silyl ether 13a provided the corresponding products (55) with perfect enantioselectivities (Scheme 19).

3.3.2 Nitroalkanes as Donor

The conjugate additions of nitroalkanes to α,β-unsaturated carbonyl compounds are synthetically important and useful, as they can provide versatile synthetic intermediates such as amino carbonyl compounds and aminoalkanes. In spite of considerable effort, the protocol for achieving the Michael addition of nitroalkanes to α,β-unsaturated aldehydes is still somewhat cumbersome and difficult because the competive 1,2-addition reaction occurs readily due to the highly reactive aldehyde. In 2007/2008, three reports42 on this kind of Michael reaction using the same o-TMS-protected diphenylprolinol compound (13a) appeared independently. Ther silyl ether of diarylprolinol (o-TMS-protected diphenylprolinol) was employed in the Michael reaction of nitroalkanes to α,β-unsaturated aldehydes, the desired product was obtained with excellent enantioselectivity (up to 99% ee). It was found that both additive and solvent used in the reaction are important (Scheme 20). It should be noted that diphenylprolinol without the silyl group was ineffective in this reaction as lower conversion and enantioselectivity were obtained (52% yield, 77% ee).

3.3.3 Active Methylene Compounds as Donor

The silylated diarylprolinols-catalyzed Michael addition of malonates to a series of α,β-unsaturated aldehydes was reported by Jørgensen in 2006.43 In light of the high efficiency of diarylprolinol silyl ethers in previous organic transformations of aldehydes, the authors initially selected the silylated diarylprolinol (13c) as catalyst for the Michael addition of malonates to aromatic α,β-unsaturated aldehydes. A screening of the reaction conditions revealed the best enantioselectivity (94%) in EtOH at 0 °C. Furthermore, they developed new procedures for the formation of chiral lactones, lactams, (−)-paroxetine, and (+)-femoxetine (Scheme 21).

Liang and Ye44 also described that the model addition of diethyl malonate to cinnamaldehyde was influenced by both the α-subtituent group and the O-substituent group (SiR′₃) of the amine catalyst (Scheme 21). A protecting group of an appropriate size in the O-position was essential for the reaction. Very low conversion was observed when using an unsilylated catalyst (diphenylprolinol) or silylated biarylprolinols with a larger size of the O-substituent group under the same conditions.

Recently in 2008, Jørgensen and co-workers45 utilized the 13c-catalyzed Michael reaction of activated methylene compounds to prepare 1,4-dihydropyridines (DHPs). The synthetic strategy for the formation of the DHPs is based on the initial key Michael reaction of an α,β-unsaturated aldehyde and a dicarbonyl compound or β-keto ester in the presence of diarylprolinol silyl ether 13c as previously reported, followed by the addition of a primary amine under one-pot reaction conditions. The results proved that 13c is an efficient promoter in this reaction to give a broad range of DHPs with very good enantiomeric excesses.

To develop an efficient strategy for immobilized versions of α,α-diarylprolinol ethers in the Michael reaction of activated methylene compounds^[46], Zoltin and co-workers47 designed and prepared a new family of recoverable diarylprolinol silyl ether-type organocatalysts modified with ionic liquid (IL) moieties. The catalyst 29 proved to be an efficient catalyst in the Michael reaction of dialkyl malonates with trans-cinnamaldehyde and its derivatives (Scheme 21), which proceeded under mild conditions to afford the respective adducts in high yields (up to 98%) and high enantioselectivities (up to 98% ee). Unlike the known diarylprolinol silyl ethers-type catalysts 13, the IL-supported catalyst 29 could be reused four times without any decrease in its activity or decrease in the enantioselectivity of the reaction.47

The Michael reaction of bis(arylsulfonyl)methanes and derivatives as nucleophiles was investigated by several groups very recently due to the advantage of the variational ability of sulfones to be transformed into different functionalities (Scheme 22). The first organocatalytic additions of a bis(arylsulfonyl)methane to a wide-range of α,β-unsaturated aldehydes was reported by Alemán.48a The reactions take place with excellent yields and high enantioselectivities (up to 96% ee) in the presence of silylated diarylprolinols (13a and 13c). Independently, the Wang, Córdova, and Rios groups48 studied the Michael addition of FBSM [fluorobis(phenylsulfonyl)methane] to α,β-unsaturated aldehydes under almost the same conditions. The process is efficiently catalyzed by the O-TMS ether of diphenylprolinol with high levels of enantioselectivity (up to 99% ee). Similar to the foregoing reactions, use of diphenylprolinol without a silyl group resulted in poor conversion for this Michael addition. The bulky TBS catalyst (13l), significantly enhanced the enantioselectivity of the reaction, but with a low yield.

Another class of sulfonyl active methyl compounds, β-keto heterocyclic sulfones, as donors for the Michael addition, was reported by Jørgensen very recently.48d The advantage of these intermediates lies in their ability to be readily converted into important products, for example, in the presence of a weak base the β-keto heterocyclic sulfone moiety is transformed into a triple bond (alkynylation), while the treatment with mild reducing reagents leads to the formation of the corresponding double bond (alkenylation). Jørgensen and co-workers48d screened several organocatalysts and further confirmed the high efficiency of o-TMS-protected diphenylprolinol compound (13a) in the Michael addition of β-keto sulfones to (E)-pent-2-enal. Other catalysts were found to be less effective for the addition reaction.

The sulfone was used as an activated methylene compound in the Michael reaction of α,β-unsaturated aldehydes reported by Palomo and co-workers in 200949 The screening of iminium catalysts revealed that silyl ether 13a was effective in the reaction of sulfone and cinnamaldehyde with good yield and excellent enantioselectivity (Scheme 23).

Very recently, Hansen and co-workers50 found that diphenylphenylglycinol (77) was an effective catalyst in the Michael addition of 4-hydroxycoumarin (75) to benzylideneacetone albeit with only moderate enantioselectivity and yield. Further exploration showed that the TMS-protected diphenylphenylglycinol (21b) gave a promising higher enantioselectivity (Scheme 24). This seems to fit nicely into a pattern where the introduction of increasingly bulky groups increases the selectivity, but at the cost of a slight reduction in catalytic efficiency.

3.3.4 Hetero-Michael Reaction

The asymmetric hetero-Michael reaction, including thiol-, oxo-, and aza-Michael reactions, is one of the most convenient procedures for the creation of stereogenic carbon-heteroatom bonds.51 This approach provides an attractive route to optically active β-functionalized carbonyl compounds. The silyl ether of amino alcohols-catalyzed hetero-Michael reaction in combination with a multicomponent reaction was reported by Jørgensen in 2005.52 The thiol-Michael addition to α,β-unsaturated aldehydes is an equilibrium reaction, and the products quickly racemize at 20 °C. However, when the transformation takes place at −24 °C, the bulky silylated diarylprolinol catalyst (13c) guaranteed the minimization of the background reaction and the enantiomeric excess of the product is stable for days in the reaction mixture (Scheme 25).

Alongside enantioselective additions to achiral imines, catalytic asymmetric aza-Michael reactions provide another fundamentally important approach towards optically active chiral amines.53 Although much progress has been made recently in the development of asymmetric aza-Michael reactions with both chiral metallic and organocatalysts, highly enantioselective catalytic aza-Michael additions to simple α,β-unsaturated aldehydes remain rare. Córdova and co-workers54a found, after an initial catalyst screen, that the chiral O-TMS-protected diphenylprolinol 13a was the most efficient iminium catalyst in the aza-Michael reaction which mediates the formation of the Cbz- or Boc-protected β-amino aldehyde with the highest ee (92–99%). The aza-Michael addition of N-heterocyclic compounds (for example, 83) to α,β-unsaturated aldehydes is an key procedure for the preparation of biological active drug such as Voriconazole (antifungal), Fluconazole (antifungal), and Losartan (high blood pressure). Based on this importance, Jørgensen et al.54b studied the aza-Michael reaction of 1,2,4-triazole with 2-pentenal in the presence of 13c. With the optimized conditions as established by the screening of solvents, concentration, and additives, different aliphatic α,β-unsaturated aldehydes were found to be acceptors in this aza-Michael reaction, which resulted in high yields (76–87%) and good enantioselectivities (92–94% ee). Other aromatic N-heterocycles, such as 5-phenyltetrazole, were also suitable N-nucleophiles. Although the authors performed computational studies to understand the enantioselectivity of the aza-Michael addition of 1,2,4-triazole, the full function of the silyl group is not clear except for steric hindrance. Very recently, Lin and co-workers applied the silylated diarylprolinols (13d or 13f) catalyzed aza-Michael of pyrazoles to (E)-3-cyclopentylacrylaldehyde in the enantioselective synthesis of INCB018424 (85), an inhibitor of Janus kinases (JAKs) (Scheme 26).54c

An intramolecular aza-Michael reaction was reported by Fustero and co-workers in 2008,55 their optimized approach was carried out at −30 °C with silyl ethers of diarylprolinol (13a or 13c) in CHCl₃ (Scheme 27), which gave the product 87 with good yields (up to 72%) and excellent enantioselectivities (up to 99% ee).

An asymmetric oxa-Michael reaction, a direct and convenient procedure for the synthesis of chiral β-hydroxy carbonyl compounds and 1,3-diols, is a challenging topic for synthetic chemists. The difficulties encountered in the addition of hard oxygen nucleophiles are due to the reversibility of the reaction and affinity for acetal formation, which competes with selective β-addition to α,β-unsaturated aldehydes. Jørgensen et al.56 recently developed a clever oxa-Michael reaction by using oximes as oxo-nucleophiles (Scheme 28). In this reaction, the silyl ether of diarylprolinol 13c is an effective catalyst, superior to other iminium-based amine catalysts. For most of linear aliphatic α,β-unsaturated aldehydes, high yields (up to 75%) and high enantioselectivities (up to 95%) of adducts were obtained.

Among the hetero-Michael reactions, the phos-Michael addition, also named hydrophosphination, provides a direct route to useful chiral phosphine compounds, which would be important for the preparation of chiral phosphine ligands containing different chemical functionalities. Almost at the same time, Córdova’s and Melchiorre’s groups57 independently used the same silyl ether of diarylprolinol as catalysts (13a or 13c) in the phos-Michael addition of diphenylphosphine to α,β-unsaturated aldehydes via iminium catalysis (Scheme 29). Apart from the catalysts, the nature of the acidic additive and the reagent concentration were the crucial factors for obtaining a highly efficient and general catalytic system, so their slight difference is the additive of the aromatic acid and temperature. Both gave excellent results with the corresponding phosphine derivatives (91) in high yields and enantioselectivities under optimized conditions (Scheme 29). To shed more light on the origin of the enantioselectivity, Córdova et al. performed density functional theory (DFT) calculations on the PC bond-forming step. The calculation supported the prediction that the bulky silyl group of 13a shielded the Re face (R=Ar) of the E-iminium ion, which led to Si facial attack. It is a pity that the role of silicon is not clear from the performed calculations.

The organocatalytic enantioselective phos-Michael reaction of α,β-unsaturated aldehydes with phosphite was one of the most challenging reactions and first studied by Jørgensen.57d Although the enantioselectivities of chiral phosphites derivatives were not perfect in their report, the mechanistic investigations are useful to understand the enantioselective phos-Michael reaction, which revealed that the rate-determining step, the transformation of P(III) to P(V), made control of the competing 1,4- and 1,2-additions difficult. Further screening experiments showed that diarylprolinol silyl ethers as catalysts could gave good enantioselectivities (92, up to 88% ee) in the presence of additives (both PhCOOH and NaI) in dichloromethane (DCM). The existence of a bulky silyl group in the imnium-based catalyst affected the equilibrium between possible diastereomeric intermediates, leading to the high enantiomeric excess when additive is used.

3.3.5 Other Donors

The use of indoles as donors in the Michael addition of α,β-unsaturated aldehydes has been less studied and represents a considerable synthetic challenge.58 MacMillan was the first to report the asymmetric Michael addition of indoles to α,β-unsaturated aldehydes by use of imidazolidinone via a LUMO-lowering activation (Scheme 30).59 Very recently, Wang et al.60 reported the diphenylprolinol silyl ether-catalyzed Michael addition of α,β-unsaturated aldehydes with indoles in the presence of Lewis base. In their catalyst screen, the outcomes of silylated diarylprolinol catalysts varied dramatically when changing the trimethylsilyl group into either a tert-butyldimethylsilyl group (13l) or a triethylsilyl group (13e). The TBS derivative 13l catalyzed the reaction to afford a product with similar enantioselectivity to that obtained with 13a, but in lower yield. However, the TES derivative 13e was not active in the Michael reaction with racemic products, which is diffcult to explain convincingly in terms of the bulky silyl group.

Racemic oxazolones (94) were used as donors in catalytic asymmetric Michael reaction in a new and attractive procedure for the synthesis of chiral α,α-disubstituted α-amino acid derivatives (Scheme 31). Jørgensen et al.61 first described that racemic oxazolones are excellent reagents for the synthesis of chiral quaternary amino acids and their derivatives by the diastereo- and enantioselective nucleophilic addition to α,β-unsaturated aldehydes catalyzed by diarylprolinol silyl ethers (13). (S)-2-[Bis(3,5-bis-trifluoromethylphenyl)trimethylsilyloxymethyl]pyrrolidine (13c) as the catalyst gave good enantioselective control in the range of 88–96% ee under optimized conditions for different α,β-unsaturated aldehydes and oxazolones. Later, Hayashi et al.62 also found the silylated organocatalyst 13l was an excellent promoter in the Michael reaction of α,β-unsaturated aldehydes with 4-substituted oxazolinones. Higher yields and enantioselectivities (up to 99% ee) of adducts were obtained under Hayashi’s conditions.

In 2006, Hayashi et al.63 developed a novel Michael reaction with alkenes and aromatic α,β-unsaturated aldehydes, also named ene reaction, when they focused on the diarylprolinol silyl ether as catalyst in the reaction of cyclopentadiene and cinnamaldehyde (Scheme 32). The silyl moiety affected the enantioselectivity, among the silyl ethers of diarylprolinol catalysts, the bulkier TBS-protected catalyst 13l led to higher enantioselectivity with a decrease in reactivity. The additive and solvent are also important: p-nitrophenol promotes the ene reaction efficiently in MeOH. When the CF₃COOH was employed with catalyst 13 in toluene, the Diels–Alder adduct (96) was obtained in good optical purity in spite of low yield [10 mol% yield, exo/endo=79:21, 79% ee (exo)].

Later in 2007,63b the author reported that the bistrifluoro-substituted catalyst 13f proved to be the most effective silyl organocatalyst in the Diels–Alder reaction of cyclopentadiene and α,β-unsaturated aldehydes with exo-selectivity. The results showed that after appropriate modification the same small molecule, silyl ethers of diarylprolinols, can act both as a Lewis acid catalyst and as an organocatalyst in the asymmetric Diels–Alder reaction. On the basis of their early findings on organocatalytic reaction of alkenes and aromatic α,β-unsaturated aldehydes, Hayashi et al.63c further elaborated the bistrifluoro-substituted catalyst 13c for the Diels–Alder reaction of various dienes and α,β-unsaturated aldehydes. The combination of catalyst 13c and HClO₄ was found be highly efficient to provide the Diels–Alder adducts (97) with excellent enantioselectivities and high exo selectivities in the presence of water (Scheme 32).

1n 2008, Kim et al.64 reported arylvinylboronic acids were able to perform 1,4-conjugate addition (Michael addition) on γ-hydroxy-α,β-unsaturated aldehydes to give chiral γ-hydroxy-β-substituted aldehydes, which are equilibrated or shifted to chiral β-substituted γ-lactols. In this reaction, trifluoromethyl-substituted diarylprolinol silyl ether 13c afforded excellent reactivity and promising enantioselectivity with up to 91% ee (Scheme 33). Other secondary amines only resulted in moderate enantioselectivities for the addition of styrylboronic acid (98) to 4-hydroxybut-2-enal (99). The authors have also found that this process works well with heteroarylboronic acids including furan, benzofuran, thiophen, benzothiophen and N-Boc-pyrrole. However, unfortunately in all cases, poor levels of enantioselection were observed (3–22% ee).

In contrast with the intermolecular additions of carbon nucleophiles to α,β-unsaturated aldehyde, there are only few examples on intramolecular Michael additions. Traditionally, an α,β-unsaturated aldehyde was used as a 1,3-acceptor (a¹/a³)-synthon, however, Christmann et al.65 reported a functional α,β-unsaturated aldehyde as a d²-synthon in a mechanistically distinct Rauhut–Currier-type Michael reaction (Scheme 34). The authors successfully exploited the activation mode of iminium/enamine for an abnormal intramolecular Michael reaction. The screening of L-proline-derived secondary amine catalysts in the absence of any additives revealed catalyst 13a to be best in terms of both reactivity and enantioselectivity. In addition, the use of acetic acid as an additive led to a considerable increase in the reaction rate without imparing the enantioselectivity. It is conceivable that acetic acid assists in the formation of the carbon-carbon bond by activating the acceptor via iminium catalysis.

3.4 Oxidation and Reduction

Organocatalytic oxidation with molecular oxygen is a challenging topic. Córdova et al.66 reported a simple enantioselective α-oxidation of aldehyde with molecular oxygen, which after in situ reduction provides chiral 1,2-diols (105) with up to 98%ee (Scheme 35). The key catalyst is diarylprolinol silyl ether. Obviously, the TMS protection of diphenylprolinol had a remarkable effect on the reactivity and enantioselectivity. The bulk of the aryl groups going from phenyl (13a) to 2-naphthyl (13b) slightly increased the enantioselectivity of the reaction.

Inspired by the seminal work of Córdova and co-workers on the direct oxidation of aldehydes with oxygen, Hayashi et al.67 developed the novel enantioselective α-benzoyloylation of aldehydes with benzoyl peroxide to afford the oxidized products (106) in good yields and excellent enantioselectivities (Scheme 36). The screening of catalysts indicated that diphenylprolinol with a bulkier tert-butyldimethyl silyl ether (13l) gave better enantioselectivity than the diphenylprolinol trimethylsilyl ether 13a, and trifluoromethyl-substituted diarylprolinol silyl ethers 13c and 13f are not effective in the present reaction (Scheme 36).

Catalytic asymmetric epoxidation holds a prominent place in asymmetric catalysis due to the fundamental importance of epoxides in organic chemistry. Although a variety of efficient synthetic methods in epoxidation have been developed in the past thirty years, the asymmetric epoxidation of α,β-unsaturated aldehydes remains a challenge to chemists. In this context, Jørgensen et al.68 first reported the iminium catalysis-based the direct enantioselective epoxidation of α,β-unsaturated aldehydes by using of silyl-protected 2-[bis(3,5-bis-trifluoromethylphenyl)trimethylsilyloxymethyl]pyrrolidine (13c) (Scheme 37). The diarylprolinol silyl ether-catalyzed epoxidation can take place under environmentally friendly conditions, it even proceeds in different solvents and water, and is suitable for a series of different substituted α,β-unsaturated aldehydes. In the similar studies of Córdova’s group,69 the author expanded it to the more broad substrate scope of epoxidation of α,β-unsaturated aldehydes. In their catalysts screen for the epoxidation, it was shown that the protection of the hydroxy group of diarylprolinols or hydroxyproline is an excellent strategy to improve the efficiency and enantioselectivity. Even with simple TBDPS-protected prolinol 14e, the asymmetric epoxidation of α,β-unsaturated aldehydes could result in promising enantioselectivity (68% ee).

The employment of Hantzsch esters (109) as the nucleophile for asymmetric hydrogenation, which originates from biological systems, was first developed independently by List and MacMillan with chiral secondary ammonium salts.70 With realization of the strong activation of diarylprolinol silyl ethers with branched aromatic α,β-unsaturated aldehydes, Córdova et al.71 found the reduction reaction of branched α,β-unsaturated aldehydes (108) proceed smoothly and gave corresponding chiral aldehydes (110) in good yields with 92-97% ee (Scheme 38).

3.5 α- and γ-Heterofunctionalization

The organocatalytic control of the transformation of a CH bond into a stereogenic CX (X=O, N, F, Cl, Br, S) bond adjacent to a carbonyl group via enamine catalysis has been thoroughly investigated in the past eight years.72 Among these studies, silyl ethers of diarylprolinols have provided useful entries to the efficient formation of stereogenic CX bonds of α-amino, α-hydroxy, α-halo, α-thiol, and α-seleno aldehydes; in addition, optically active propargylic fluorides could be prepared based on the organocatalytic α-fluorination of aldehydes.

In 2005, diarylprolinol silyl ethers (13a–g) were applied successfully to the α-sulfenylation of aldehydes by Jørgensen (Scheme 39).14 In the creative example of amino alcohol-derived silyl ether-catalyzed α-sulfenylation of aldehydes, no reaction occurred with α,α-diphenyl-L-prolinol, the author supposed probably the formation of the relatively stable and unreactive hemiaminal species. Interestingly, trimethysilyl protection of the free hydroxy moiety of α,α-diphenyl-L-prolinol restored reactivity and enhanced selectivity due to the prevention of the proposed hemiaminal formation. Further improvements led to the idenfication of 13c as the best catalyst in this reaction.

Since 2005, Jørgensen and co-workers73 have described a series of α-heterofunctionalizations of aldehydes by using silyl ethers of diarylprolinols (13) as catalyst. The silyl modification of diarylprolinol drastically increased the catalytic turnover of the parent catalyst in α-heterofunctionalization reactions, such as α-aminination, α-fluorination, α-bromination, and α-thiolation (α-sulfenylation) of aldehydes. In the α-amination of aldehydes with azodicarboxylates, it is interesting to note that the absolute configuration of the aminated product obtained with (S)-13c is opposite to the configuration obtained with L-proline, although the absolute configurations of the catalysts are the same. As shown in Scheme 40, the result is in agreement with the different natures of the transition state. In subsequent density functional theory calculations, eight different reaction paths have been considered which are based on four different conformers of the TMS-protected prolinol-enamine intermediate. Optimization of the enamine structures gave two intermediates with nearly the same energy. These intermediates both have an E-configuration at the CC bond and the double bond is positioned anti or syn, relative to the 2-substituent in the pyrrolidine ring (Scheme 41). For the four intermediates, the chiral TMS-protected diarylsubstituent effectively shields one of the faces of the reacting CC bond in the enamine intermediate.74

Similarly to previous α-aminations, Jørgensen and co-workers75 later disclosed that the catalyst 13c catalyzed the direct γ-heterofunctionalization of α,β-unsaturated aldehydes with azodicarboxylates efficiently via dienamine catalysis (Scheme 42). It should be noted that other secondary amines without a bulky silyl group were poor catalysts in the direct γ-heterofunctionalization.

In 2007, Marini and Melchiorre76 applied the air-stable and commercially available N-(phenylseleno)phthalimide as the electrophilic selenium source in the α-selenenylation of aldehydes (Scheme 43). As expected, the silyl ethers of diarylprolinol exhibited superior selectivity and much higher catalytic activity during the extensive evaluation of a variety of catalysts. The silyl catalyst 13c proved successful for the α-selenenylation of a wide range of aldehyde substituents, including alkyl, alkenyl, and hetero-substituted groups.

Nitrosobenzene has been proven to be another promising reagent for the α-amination or α-oxygenation (α-aminoxylation) of carbonyl compounds. In contrast to the L-proline-catalyzed α-oxygenation reaction of nitrosobenzene and carbonyl compounds, use of silylated organocatalyst 13a resulted in the direct α-amination reaction of aldehydes with nitrosobenzene. In agreement with the calculations by density functional theory (DFT), the differences for the formation of the CN and CO bonds in the presence of different enamine catalysts are due to the existence of hydrogen-bonding scources (Scheme 44). Very recently, a theoretical investigation on the reaction mechanism of a chiral prolinol silyl ether-catalyzed α-amination reaction of nitrosobenzene strongly suggested that the reaction proceeds via an enol intermediate and not via an enamine intermediate.77

3.6 Cycloaddition Reactions

The stereocontrolled construction of three-membered rings via cycloaddition, such as cyclopropane derivatives, aziridines, is a challenging topic for synthetic chemists. The cyclopropane and aziridine rings are constitutents in more than 4000 natural isolated and 100 biologically active agents.78 In addition, they are useful synthetic intermediates or building blocks for the synthesis of natural products and pharmaceuticals, and as templates for the construction of conformationally restricted amino acids and peptides.79 Since Aggarwal et al.80 pioneered the use of organocatalyst in the enantioselective cyclopropanation reaction in 2001, significant advances have been made in the development of organocatalytic methods.81 Very recently, the employment of readily available alkyl halides for a catalytic cyclopropanation reaction with α,β-unsaturated aldehydes to produce cyclopropanes has been developed by several groups independently.82 The key issue is the use of active alkyl halides that serve as nucleophiles for the initial Michael addition reaction with α,β-unsaturated aldehydes and then as the electrophiles for the subsequent alkylation process. As shown in Scheme 45, Wang82b and Córdova82a found that the chiral silylamines 13a or 13d are better promoters than MacMillan’s chiral imidazolidinone in the asymmetric formation of the corresponding cyclopropanes with up to >30:1 dr (trans/cis) and ee values ranging from 92–99%. The authors deduced that (i) the catalyst activities vary significantly and (ii) the steric effect imposed by these catalysts plays a key role in catalytic activity and stereoselectivity, which is why catalysts 13a and 13d are identified as the best promoters for the domino reactions of α,β-unsaturated aldehydes and 2-bromomalonates (129). Later, Córdova et al.82c extended the reaction to the synthesis of nitrocyclopropanes with 2-bromonitromethane (132) as the active alkyl halide. The silyl catalyst 13a-catalyzed cyclopropanation reactions were highly chemo- and enantioselective (91–99% ee) and gave the corresponding 1-nitro-2-formylcyclopropanes in moderate to high yields. Similarly, Rios et al.82d described the organocatalytic domino Michael–alkylation reaction with the same silyl catalyst 13a by using 2-bromo-3-keto esters (127) instead of 2-bromomalonates, which resulted in the chiral cyclopropanes bearing three stereogenic centers (Scheme 45).

Scheme 45. Cyclopropanation reactions.

Aziridines also are important chiral building blocks in organic synthesis and are found in natural products, such as mitomycin and porfiromycin. The first example of the asymmetric catalytic aziridination of α,β-unsaturated aldehydes was reported by Córdova’s group^[83], in which the nitrogen atom source first acted as a nucleophile and at a later stage became the electrophilic. The authors found the diarylprolinol silyl ethers-catalyzed stereoselective aziridination reaction of α,β-unsaturated aldehydes with acylated hydroxycarbamates (134) with good yields and excellent setereoselectivities (87–99% ee). The catalytic power of 13a was realized in the extensive screening of versatile catalysts, whereas other substituted diarylprolinol silyl ethers gave poor in yields (13c) or setereoselectivies (13b). Very recently, Hamada et al.84 also described an enantioselective aziridination reaction of α,β-unsaturated aldehydes with N-arenesulfonyloxycarbamates (136) via a domino procedure (Scheme 46). The enantioselective aziridination via aza-Michael addition/N-alkylation cycloaddition of α,β-unsaturated aldehydes proceeded with a high enantioselectivity and diastereoselectivity in the presence of diphenylprolinol triethylsilyl ether (13e).

In 2007, the bistrifluoro-substituted catalyst 13f was proven to be an excellent class of organocatalyst in the [4+2] cycloaddition (Diels–Alder) reaction of cyclopentadiene and α,β-unsaturated aldehydes with exo-selectivity.63 Very recently, inspired by Jørgensen’s seminal work on the [4+2] cycloaddition of electron-rich dieneamines and maleimide,75 Christmann and co-workers85 investigated the enantioselective intramolecular addition of in situ formed dienolate equivalents to Michael acceptors [Scheme 47, Eq. (2)]. Their results complement previous organocatalytic approaches by installing the transient chiral directing group at diene moiety. As shown in Scheme 47 [Eq. (3)], a rapid intramolecular Diels–Alder reaction occurs after the vinylogous enamine activation is operative, and subsequent elimination of enamine catalyst leads to the cycloadduct. Silyl diphenylprolinol 13a proved sufficient to convert the diconjugated aldehyde into the bicyclic product, and increasing bulk in the diarylsiloxy moiety in the diarylprolinol backbone lowers the reaction rate.

3.7 Domino Reactions

The use of domino or domino multicomponent reactions in asymmetric synthesis is increasing constantly and has gained wide acceptance, because they increase synthetic efficiency by decreasing the number of laboratory operations required and quantities of chemicals and solvents used. Although the proliferation of domino reactions is evidenced by the number of recent reviews covering the literature in the past 30 years,86 the design and development of new asymmetric domino reactions is regarded as a great intellectural challenge for organic chemists. Correspondingly, organocatalysis has shown to be a powerful tool for multiple stereocenters in a domino protocol by employing either a single catalyst or a combination of catalysts. In the past years, the abilities of silylated diarylprolinols in asymmetric domino reactions have been realized fully. To facilitate the understanding, the classification of domino reactions is based on the substrate of the key step.

3.7.1 Aldehydes

In this context, Jørgensen and co-workers87 reported a new enantio- and diastereoselective domino α-bromination/Henry/O-alkylation cyclization sequence to access 4,5-disubstituted isoxazoline N-oxides, as well as demonstrate the use of this domino protocol for the de novo synthesis of β,γ-dihydroxylated and β,γ,δ-trihydroxylated α-amino acid derivatives, phytosphingosines, and amino sugars. In this domino reaction, the chirality stored within this α-carbonyl sp³-carbon center, formed by the direct α-bromination of aldehydes by the electrophilic bromination reagent (142) catalyzed by the TMS-protected diarylprolinol 13c, is fully exploited by a base-promoted face-selective Henry addition of nitroacetates and subsequent stereospecific O-alkylation, furnishing the enantio- and diastereoselective synthesis of 4,5-disubstituted isoxazoline N-oxides in one pot (Scheme 48).

Scheme 48. α-Bromination/Henry/O-alkylation cyclization

3.7.2 α,β-Unsaturated Aldehydes

For the organic functional transformation of α,β-unsaturated aldehydes, diarylprolinol silyl ethers have proved to be powerful catalysts in the Michael reactions and epoxidations. In combination of the Michael addition or epoxidation of α,β-unsaturated aldehydes with other reactions, it would be possible to construct complex chiral molecules. In addition, the domino reaction of α,β-unsaturated aldehydes with other substrates has proved to be a convenient procedure for the preparation of cyclic compounds (from 5–6 rings) very recently.

3.7.2.1 The Construction of Five-Membered Rings

The invention and development of efficient and stereospecific domino reactions of α,β-unsaturated aldehydes has proved to be efficient and easy procedure for the preparation of complex molecules with five-membered rings. In this context, the choice of synthons with 1-donor-3-acceptor (d¹/a³) functional groups is a basic strategy for the contruction of five-membered rings. The silyl ethers of amino alcohols, especially silyl ethers of diphenylprolinols, have been introduced in domino reactions of α,β-unsaturated aldehydes and other versatile compounds.

The first example of the construction of five-membered rings via a silyl organocatalyst-promoted domino reaction was reported by Jørgensen et al. in 2006.88 They reported a diphenylprolinol silyl ether-catalyzed one-step thiol-Michael-aldol domino reaction for the synthesis of diastereo- and enantiomerically pure tetrahydrothiophenes with three stereocenters (Scheme 49). For the key Michael addition step of thiol (2-mercapto-1-phenylethanone) to α,β-unsaturated aldehydes, the organocatalyst 13c could highlight the fact that this catalyst is effective in iminium-ion activation of α,β-unsaturated aldehydes and, through a steric shielding of one side of α,β-unsaturated aldehyde, resulted in a high asymmetric induction. The course of the organocatalytic domino reaction is dependent on variations in the cyclization reaction step. Temperature and solvent have an influence on yield and enantioselectivity, and the additive benzoic acid increases the rate of the domino reaction path to the tetrahydrothiophene-carbaldehydes 146. On changing the additive benzoic acid to a base, the authors observed in several cases a competing reaction path and formation of tetrahydrothiophene 146. With NaHCO₃ as additive, the tetrahydrothiophen-3-ols 148 are formed as a single diastereomer in good yields of 43–66% over two steps and with 64–82% ee. The role of NaHCO₃ as additive is to promote the hydrolysis of the iminium intermediate of the TMS-protected diphenylprolinol with Michael adduct and enolization. Therefore no asymmetric induction through the catalyst 13c is observed for the second catalytic step in the formation of (tetrahydrothiophen-2-yl)phenylmethanones 148. To explore the domino reaction with other functional thiols, Wang et al.89 carried out the model domino reaction of 3-phenylpropenal and ethyl 3-mercapto-2-oxopropanonate (144). Screening of organocatalysts revealed that (S)-diarylprolinol silyl ethers afforded promising results in terms of reaction yields (yield 46–71%, 13a:83% ee; 13c: 82% ee; 13e: 87%ee).

Scheme 49. Domino reaction via thiol-Michael addition/aldol reaction.

The domino Michael–Michael (also called “double Michael”) reaction of functional thiols is also a rapid and efficient approach for the construction of complex and synthetically useful chiral tetrahydrothiophenes (Scheme 50). In 2007, Wang and co-workers90 reported a process catalyzed by (S)-diphenylprolinol TMS ether (13a) under mild reaction conditions to furnish chiral tetrahydrothiophenes from achiral substances in excellent enantioselectivities (94–99% ee) and good dr (6:1 to 18:1). In this reaction, the authors have probed other diarylprolinol silyl ethers (13c, 13e, 13l) as well. Catalysts 13e and 13l with TES and TBS groups afforded similar results to that of catalyst 13a. However, no reaction occurred when catalyst 13c, with a more bulky and strong electron-withdrawing (CF₃)₂C₆H₃ moiety, was employed. The reaction scope proved to be quite broad with respect to α,β-unsaturated aldehydes. It is realized that the steric hindrance in substrates has a very limited effect on the domino reactions.

Scheme 50. Domino reaction via double Michael reaction.

As described in silyl organocatalyst-promoted hetero-Michael reactions, it has to be pointed out that oxa-Michael initiated domino reactions have received little attention, just as the organocatalytic oxa-Michael reaction, which still remains a rather unexplored transformation. In fact, literature examples are exclusively limited to the use of functionalized phenols as nucleophiles91 and also a couple of elegant procedures have been reported by Jørgensen and co-workers92 for the β-hydroxylation of α,β-unsaturated aldehydes using oximes as O-nucleophiles.

In 2009, Pihko and co-workers93 used a modification of the Jørgensen’s oxo-Michael protocol in a domino oxa-Michael/oxime-tranfer process, and found the treatment of α,β-unsaturated aldehydes with acetone oxime, together with catalytic amounts of silyl catalyst 13c and PhCOOH in toluene at 0 °C for 3.5 h, and subsequent brief treatment of the reaction mixture with either 2.3 M H₂SO₄ in MeOH or a mixture of aqueous HCl in THF at 0 °C afforded the desired isoxazolines in moderate yields and high enantioselectivies (Scheme 51). The isolated yields of this process appear to be limited by the competing decomposition of the starting materials in the process, as well as the K_eq value of the initial addition step. In general, the most popular method by far for the construction of chiral 2-isoxazolines is the 1,3-dipolar cycloaddition between nitrile oxides and alkenes. Nevalainen and co-workers94 have revealed (S)-diarylprolinol silyl ether 13a performed best in the [3+2] 1,3-dipolar cycloaddition of α,β-unsaturated aldehydes to nitrones in terms of rate, diastereoselectivity and enantioselectivity in comparison with other proline-derived secondary amine amine catalysts. The scope of the organocatalytic 1,3-dipolar cycloaddition between α,β-unsaturated aldehydes to nitrones catalyzed by 13a was achieved with excellent enantioselectivity in the most cases (Scheme 52).

Scheme 51. Domino reaction via double Michael reaction.

Related to the above synthesis of oxygen-containing five-membered rings with an oxa-Michael initiated domino reaction, a triple domino reaction was developed for the preparation of the bicyclic polysubstituted furofurans with four stereocenters in a single step starting from α,β-unsaturated aldehydes and dihydroxyacetone dimer via silyl iminium/enamine catalysis.95 This transformation consists of an initial oxa-Michael reaction of dihydroxyacetone dimer (154), a subsequent intramolecular aldol reaction, and lastly a hemiacetalization step, and it proceeds with the generation of four new stereocenters (Scheme 53). The identification of the best catalyst and reaction conditions for this domino reaction required the combination of 13a and PhCOOH in CHCl₃. Under these conditions, a wide variety of differently substituted hexahydrofuro[3,4-c]furans were obtained with excellent yields (67–98%) and remarkably, as single diastereoisomers in almost all cases (>10:1 dr, 90–99% ee).

Scheme 53. Domino reaction via Michael/aldol/hemiacetalization reaction.

The use of indoles in the direct catalytic asymmetric aza-Michael reaction is a very difficult and challenging task. Very recently, Wang and co-workers established optimal reaction conditions to complete the aza-Michael addition of the NH unit of indole to α,β-unsaturated aldehydes using a strategy of domino process to limit the retro-Michael reaction. In addition, the results showed that the catalysts probed exhibited significantly different catalytic activities towards the process. Poor catalytic activities were observed for L-proline and the MacMillan catalyst. The diphenylprolinol silyl ether gave moderate to good yields (57–84%) and good to excellent enantioselectvitites (71–96%ee).96 It is a highly useful method for the construction of pyrrolo[1,2-a]indole-2-carbaldehydes with new five-membered ring through a diphenylprolinol silyl ether-catalyzed domino aza-Michael/aldol reaction (Scheme 54).

The first example of the direct α-arylation of aldehydes using quinones as the aromatic partner, leading to optically active α-arylated aldehydes and their hemiacetal derivatives, was reported by Jørgensen (Scheme 55).97 In the course of their continous studies of diarylprolinol silyl ethers-catalyzed organic transformations, they found that 13a was an effective catalyst and provided full conversion with excellent enantioselectivities (92–99% ee), however, 13c was not active in the present reaction. The proposed mechanism for the direct α-arylation involves enamine catalysis and proton-transfer, in which the stereogenic center is formed when the reaction of the enamine intermediate with the quinine occurred. The proton-transfer reaction leadis to the optically active α-arylated aldehyde that has a dihydroquinone functionality (157). The proton-transfer reactions might involve H₂O, as no reaction occurs in its absence.

The construction of highly multifunctionalized chiral carbocycles with five-membered ring (cyclopentanes) and different groups, such as NO₂ and carbonyl, has recently been achieved by the employment of an enantioselective domino reaction. In 2008, Córdova et al.98 reported that (S)-diphenylprolinol TMS ether (13a) catalyzed the asymmetric domino double Michael (nitro-Michael/Michael reaction) reaction between α,β-unsaturated aldehydes and methyl 5-nitropentenoate (Scheme 56), which gave the corresponding nitrogen-, formyl-, and ester-functionalized cyclopentene derivatives with four stereocenters (97–99% ee).

Scheme 56. Domino reaction via double Michael reaction.

With the exploration of the diarylprolinol silyl ethers in the catalytic domino reaction of α,β-unsaturated aldehydes, Wang and co-workers99 reported two novel strategies for the preparation of chiral cyclopentenes through an enantioselective cascade double Michael or Michael-aldol condensation reaction. In the double Michael procedure, the authors designed a d¹/a³-synthon with activated methylene and α,β-unsaturated ester moieties (Scheme 57). The efforts were focused on the establishment of the optimal conditions for the catalytic asymmetric double Michael addition which is successful with diphenylprolinol silyl ether 13a. The new methodology provided a facile approach to a range of tetrasubstituted, highly functionalized chiral cyclopentanes with the generation of new stereogenic centers in high enantiomeric excess (84 to 99% ee) and high diastereoselectivity (9:1 to >20:1 dr.).

Scheme 57. Domino reaction via double Michael reaction.

In another strategy of the Michael-aldol addition, the authors designed a novel d¹/a³-synthon with activated methylene and aldehyde units.100 The domino Michael-aldol reaction was found to be a practical procedure for the preparation of highly functionalized cyclopentanes. The authors surveyed different catalysts and found that the silyl-protected diphenylprolinol 13e afforded excellent results with the cascade sequence, which enabled the quick construction of heavily functionalized cyclopentenes with the generation of two new CC bonds with high enantioselectively (91–97% ee) from readily available starting materials under mild reaction conditions (Scheme 58).

Scheme 58. Domino reaction via Michael-aldol reaction.

In the Michael/aldol reaction of 1,2-cyclohexadione and cinnamylaldehyde, the unprotected diphenylprolinol gave good selectivity and moderate yield (53% yield, 81% ee), however, the introduction of the bulky silyl ether in this parent catalyst resulted in increased reactivity and excellent stereoselectivity (77% yield, 96% ee). Remarkably, the bicyclo[3.2.1]octane-6-carbaldehyde derivative was obtained exclusively as a single diastereomer with four stereogenic centers. Several α,β-unsaturated aldehydes can be used to provide access to chiral bicyclo[3.2.1]octane-6-carbaldehydes in good yields and with excellent enantioselectivities (90–98% ee) (Scheme 59).101

Scheme 59. Domino reaction via Michael-aldol reaction.

It is a challenge that each catalyst should be compatible with all reagents, intermediates, and other catalysts present from the onset of the multiple catalyst system for domino reactions. However, Rovis and co-workers102 have successfully developed a novel one-pot, asymmetric multicatalytic Michael/crossed benzoin reaction (formal [3+2] reaction) between 1,3-dicarbonyl compounds and α,β-unsaturated aldehydes based on the combination of diarylprolinol silyl ether and N-heterocyclic carbene catalysts just recently. The multicatalytic process involves a secondary amine-catalyzed Michael addition followed by a N-heterocyclic carbene (165)-catalyzed intramolecular crossed benzoin reaction to afford densely functionalized cyclopentanones with high enantioselectivities (Scheme 60). The reaction proceeds with a variety of alkyl- and arylenals as well as a range of 1,3-dicarbonyl compounds (diketones and β-keto esters).

3.7.2.2 The Construction of Six-Membered Rings

Similarly to the construction of five-membered rings, the use of synthons with a 1-donor-4-acceptor (d¹/a⁴) functional group will be the key factor for the construction of six-membered rings. Many examples on chiral silyl ether-catalyzed asymmetric domino reactions of α,β-unsaturated aldehydes and versatile synthons with 1-donor-4-acceptor functional groups are known.

In 2006, Wang et al.103 and Córdova et al.104 reported the one-pot synthesis of chiral thiochromenes independently (Scheme 61). The results showed that the catalysts probed exhibited significantly different catalytic activities and enantioselectivities towards the process. Among the chiral pyrrolidine organocatalysts surveyed, (S)-pyrrolidine silyl ethers showed promising results. It was realized that the catalyst 13c was the best one for catalyzing the domino thia-Michael/aldol process. The analogue 13f with a TES group displayed similar results under the same reaction conditions, but with long reacton times. Subsequently, Córdova et al.104b included the 2-mercaptobenzaldehyde (167) and 2-mercaptoacetophenone (169) in this pyrrolidine silyl ether-catalyzed thia-Michael/aldol domino reaction. The reactions proceed with excellent chemo-, diastereo- and enantioselectivities to give the corresponding benzothiopyran derivatives with three contiguous stereocenters in high yields with up to >15:1 dr and >99% ee.

Scheme 61. Domino thia-Michael/aldol reactions.

The slight difference between salicylaldehyde and 3-phenylpropenal made the understanding of oxa-Michael/aldol domino reaction easily. Asymmetric domino oxa-Michael/aldol sequences constitute a very effective and straightforward entry to enantioenriched benzopyrans, also known as chromenes, widespread elements in natural products with proven pharmacological activities. Almost at the same time in comparison to the studies of domino thia-Michael/aldol reaction, three groups, including those of Arvidsson, Wang, and Córdova, reported their findings on the pyrrolidine silyl ether 13a or 13e catalyzed oxa-Michael-initiated domino reaction independently.105 A series of secondary amine organocatalysts has been tested for the conjugate addition of salicylaldehyde to trans-cinnamaldehyde, which showed that the TMS and TES ethers of diphenylprolinol gave considerable turnover numbers and promising levels of enantioselectivity. However, the MacMillan catalyst (172) and diphenylprolinol (171) resulted in low conversion or even no reaction (Scheme 62).

Scheme 62. Domino oxa-Michael/aldol reactions.

In 2008, Woggon and co-workers106 prepared the biologically most significant member of the vitamin E family, named α-tocopherol 177, by using pyrrolidine silyl ether 13f as catalyst in the domino reaction of phytenal and ortho-hydroxyaldehyde (Scheme 63). Different from previous reports, this is an aldol-initiated domino reaction, also aldol/oxa-Michael reaction, via dienamine/iminium catalysis.

Very recently, Wang et al.107 modified this reaction by using an unprecedented asymmetric cascade oxa-Michael–Michael reaction, which afforded chiral highly functionalized chromans with the creation of three new stereogenic centers. The domino process is efficiently catalyzed by commercially available diphenylprolinol silyl ether, starts from simple achiral substances and provides a one-pot access to enantioenriched chromans. It was found that the class of chiral diarylprolinol silyl ethers was promising for this domino process (Scheme 64). No reaction occurred when diphenylprolinol was employed. Under the same conditions, excellent results were obtained for the analogue catalysts 13a and 13e, while 13c catalyzed process proceeded very sluggishly.

Very recently, Hong et al.108 reported a complicated quadruple-cascade reaction, oxa-Michael/Michael/Michael/aldol condensation of 2-[(E)-2-nitrovinyl]phenol and 2 equivalents of α,β-unsaturated aldehydes. The reaction is applicable to the synthesis of a tetrahydro-6H-benzo[c]chromene 183 with five contiguous centers (Scheme 65). In an initial screening of catalysts, the authors found the L-proline and its derivatives without silyl groups gave amost no reaction or afforded a complex mixture under different conditions, however, the application of diphenylprolinol silyl ether 13a in the presence of HOAc afforded the best yields and enantioselectivities (>99% ee) for different α,β-unsaturated aldehydes.

Starting from 2-aminobenzaldehydes and α,β-unsaturated aldehydes the aza version of the above thia-Michael- or oxa-Michael-initiated intramolecular cascade aldol-dehyration sequence leads to 1,2-dihydroquinolines with excellent chemo- and enantioselectivities. Almost at the same time, Córdova et al.109 and Wang et al.110 reported similar domino reactions with N-protected or unprotected 2-aminobenzaldehydes in the presence of diarylprolinol silyl ether catalysts. It was shown in Córdova’s work that diphenylprolinol silyl ether 13a catalyzed the asymmetric formation of 1,2-dihydroquinoline derivatives in high yields with excellent enantioslectivities for most of β-aryl- and β-alkoxycarbonyl α,β-unsaturated aldehydes. The addition of benzoic acid gave superior results with respect to conversion.

In the domino aza-Michael/aldol reaction of 2-N-protected benzaldehydes and α,β-unsaturated aldehydes, it was found that (S)-diarylprolinol silyl ethers were the most promising promoters amongst the amine catalysts probed, and 13e with a TES group is the best catalyst for the domino reaction of a wide range of readily available α,β-unsaturated aldehydes with 2-N-protected aminobenzaldehyde. And in the presence of NaOAc and 4 Å MS, the reaction yield was dramatically improved without sacrificing enantioselectivity (Scheme 66). Subsequently in 2008, Hamada et al.111 prepared the martinelline chiral core 187 and its diastereomer by using an asymmetric domino aza-Michael/aldol reaction as the key step from 4-methoxycarbonylanthranaldehyde and an α,β-unsaturated aldehyde. The reaction conditions, in contrast to those of Wang’s work, revealed that the presence of 4 Å MS indicated a negative effect on the chemical yield, while NaOAc had no effect on the yield and enantioselectivity. However, the addition of HOAc was found to improve the catalytic ability of 13a in yield without loss of enantioselectivity.

As seen in Scheme 67, when 1,4-naphthoquinones (191) are used as donors in the Michael reaction of α,β-unsaturated aldehydes, 1,4-pyranonaphthoquinones are obtained via a domino Michael/acetalization reaction. In this reaction, Rueping and co-workers112a investigated the scope of the diarylprolinol ethers 13 catalyzed enantioselective Michael addition-cyclization reaction cascade using various α,β-unsaturated aldehydes. In general, aliphatic as well as aromatic α,β-unsaturated aldehydes could be employed successfully in this new transformation, and a diverse set of 1,4-pyranonphthoquinones was isolated in good yields and with excellent enantioselectivities (90–99% ee). Additionally, the authors extended this procedure to the catalytic enantioselective synthesis of pyranocoumarins or pyranones by employing 4-hydroxycoumarin or 4-hydroxy-6-methyl-2-pyrone (195).112b The reactions proceeded smoothly in various solvents in the presence of diarylprolinol ether 13. Further evaluation of the reaction parameters revealed that the best results with regard to both selectivity and reactivity were achieved when the reaction was conducted with catalyst 13c in dichloromethane.

In a related work, replacement of the 4-hydroxycoumarin (189) by naphthols in a Friedel–Crafts-type Michael/acetalization reaction resulted in the synthesis of optically active chromanes and dihydrobenzopyrans. Wang and co-worker113 successfully applied the diarylprolinol silyl ether 13a after screening different amine catalysts in the asymmetric Friedel–Crafts-type Michael/acetalization reaction in the presence of 2-nitrobenzoic acid.

Similar to this strategy in the domino Michael/acetalization reaction, Rueping114 and Jørgensen115 described the addition of 1,3-dicarbonyl compounds (197) to α,β-unsaturated aldehydes which, after cyclization, resulted in the formation of 3,4-dihydropyrans, the reactions proceeded smoothly with excellent enantioselectivies and good diastereoselectivities in the presence of the same silylamine catalyst 13c. Surprisingly, when 13a was used as the catalyst, no formation of the corresponding product was detected. Other secondary amine catalysts, such as proline and proline amide, were unable to catalyze the reaction. The use of (S)-diphenyl(pyrrolidin-2-yl)methanol without a silyl protecting group resulted in an only 38% yield and −40% ee with opposite enantiomers. The bulk of the C-substituted TMS group in the catalyst shields the Si face of the β-carbon atom in the iminium-ion intermediate of the α,β-unsaturated aldehyde, which favors the Re-face attack of the nucleophile on the planar iminium ion.

Hayashi and co-worker116 applied nitroethanol to the diarylprolinol silyl ethers-catalyzed Michael addition of α,β-unsaturated aldehydes. The catalyst 13a-catalyzed Michael reactions generated the γ-nitroaldehydes which then cyclized to afford substituted tetrahydropyrans by acetalization. Good enantioselectivities and yields have been obtained for a broad range of α,β-unsaturated aldehydes (Scheme 68).

Enecarbamates and enamides have been successfully utilized as reactive nucleophiles in asymmetric catalysis. Recently, Hayashi et al.117 employed enamides and α,β-unsaturated aldehydes to construct the piperidine ring system. The reaction occurred as a domino Michael/acetalization sequence, also named a formal aza [3+3] cycloaddition or cascade aza-ene-type cyclization, which afforded the piperidine derivatives as α (minor) and β (major) isomers. In the reaction catalyzed by a catalyst with bulkier silyl substituent, such as the tert-butyldimethylsilyl (TBS) group, the enantioselectivity increased to 95% ee, superior over the other silyl ethers of diarylprolinol. Bis(trifluoromethyl)-substituted arylprolinol silyl ether 13c was not effective in the present reaction. The TBS-protected diphenylprolinol 13l was a suitable catalyst for versatile substituted acroleins in the domino Michael/acetalization reaction with excellent enantioselectivity and good yield. In a related study, Wang and co-workers118 ultilized Ac-enamide 201 instead of Boc-enamide 203, for example, N-(1-phenylvinyl)acetamide, as nucleophiles for the diarylprolinol silyl ether-catalyzed cascade aza-ene-type cyclization (Scheme 69). Notably, reactions did not take place with unprotected diphenylprolinol and MacMillan’s catalyst. In addition, the authors observed that the cascade process involves an unprecedented multistep imminium/enamine transformation.

In an investigation of the organoctalytic conjugate addition of activated amides to α,β-unsaturated aldehydes, Franzén et al.119 developed a short enantioselective one-pot, two-step synthesis of the indolo[2,3-a]quinolizidine and the benzo[a]quinolizidine skeletons using secondary amines as the catalyst. A series of catalysts was screened and evaluated with respect to the ee value and the conversion. The diphenylprolinol silyl ether 13a was proven to be best catalyst in this reaction, however, both the analogue 13c and L-proline or its derivatives without silyl groups were less active and less selective for this reaction. As shown in Scheme 70, the sequence, that involves an organocatalytic conjugate addition and subsequent acid-catalyzed cyclization of the acyliminium ion, also known as Michael/intramolecular Pictet–Spengler condensation, and gives direct access to the quinolization skeleton 206. Good to excellent enantioselectivities were obtained for all the annulation products from a series of aromatic α,β-unsaturated aldehydes, ranging from 87% to 95% ee.

Different functionally active carbonyl compounds have been used in the domino reaction of α,β-unsaturated aldehydes for the construction of six-membered ring systems with different functional groups. As shown in Scheme 71, Jørgensen and co-workers120a achieved a highly enantioselective synthesis of 2,5-disubstituted-cyclohexene-2-one derivatives through a diarylprolinol silyl ether 13c-catalyzed domino Michael/cyclization of β-keto esters to α,β-unsaturated aldehydes. Later, as a simple alternative, Jørgensen et al.120b extended the utility of silicon-substituted α,β-unsaturated aldehydes to the asymmetric one-pot domino reaction, which afforded the desired 5-(trialkylsilyl)cyclohex-2-enones 208 in excellent enantioselectivies (99% ee for most cases).

Using a similar strategy, Jørgensen and co-workers121 applied different d¹/d³-synthons with functional active methylene compounds to the diarylprolinol silyl ether-catalyzed domino cyclization of α,β-unsaturated aldehydes. As shown in Scheme 72, Jørgensen122 and Hayashi123 employed dinitroalkanes, Nazarov reagent, 4-diethoxyphosphoryl-3-oxobutanoate, and dimethyl 3-oxopentanedioate, as d¹/d³-synthons for the preparation of highly substituted adducts through nitro-Michael/Henry reactions, Michael/Morita–Baylis–Hillman reactions, and Michael/Knoevenagel condensations, respectively. It was believed that diarylprolinol silyl ethers play a key role with high catalytic activity in the stereoselectivity of the first step of the Michael reaction of nucleophiles to α,β-unsaturated aldehydes.

In the double Michael process, the use of d¹/a⁴-synthons, namely conjugated β-keto esters, also enable the preparation of desired polysubstituted and fused cyclohexanes (218) (Scheme 73). Brenner et al.124 very recently developed a new efficient diphenylprolinol silyl ether 13a-catalyzed domino Michael–Michael reaction through rational modification of substrates and manipulation of the catalytic cycle. This transformation generated highly substituted, fused carbocycles withdr ≥91:9 and ee ≥96%.

Another special d¹/d³-synthon, γ-chloro-β-keto esters, in the construction of highly functional cyclohexanes was reported by Jørgensen et al. in 2006 (Scheme 74)^[125], which gave epoxycyclohexanone derivatives with four stereogenic centers. The one-pot domino reactions between γ-chloro-β-keto esters and α,β-unsaturated aldehydes occurred with very good enantiomeric excess and high diastereomeric ratio in the presence of diarylprolinol silyl ether 13c and AcONa as additive in DCM. The product is then converted into the optically active epoxycyclohexanone in the presence of K₂CO₃ and DMF as cosolvent. The Michael addition reaction is very important in this multistep Michael–Darzens reaction, since it determines the enantiomeric excess of the product formed at the end of the reaction sequence.

Scheme 74. Domino Michael/Darzens reactions.

Pentane-1,5-dial (221) acting as a d¹/a⁴-synthon was reported by Hayashi et al. in 2007.126 In this seminal report, the author found that the powerful diarylprolinol silyl ether was an excellent enamine catalyst in the domino reaction of pentane-1,5-dial (221) and nitroalkene through a Michael–Henry reaction process (Scheme 75). Besides the catalyst, the yield and the diastereomer ratio were also dependent on the solvent. It was found that the substituted nitrocyclohexane derivatives with four stereogenic centers were obtained in good yields and excellent enantioselectivities in THF in the presence of silyl organocatalyst 13a. Very recently, Córdova et al.127 expanded scope of the nitroolefins of the domino reaction to alkylidene malonates or analogues (222). This transformation also resulted in the formation of the highly functional cyclohexanes with four stereogenic centers in good yields (72–98% yield, 5:1–10:1 dr) and excellent enantioselectivities (83–98% ee).

The design of new catalytic, asymmetric, multi-component domino reactions is a continuing challenge at the forefront of synthetic chemistry. In this context, Enders and co-workers128 have reported a diarylprolinol silyl ether-catalyzed triple domino reaction for the synthesis of tetra-substituted cyclohexene-carbaldehydes successfully (Scheme 76). This three-component domino reaction comprising a linear aldehyde, nitroalkene, and α,β-unsaturated aldehyde proceeds by the way of Michael/Michael/aldol condensation sequence affording the products with moderate yields (25–58%). This domino reaction generates four stereogenic centres, and theoretically could give rise to 2⁴=16 different stereoisomers. Interestingly, during this sequence, four stereogenic centres are formed with high diastereoselectivity and complete enantioselectivity. The best results concerning yields and selectivity were obtained with 20 mol% of the OTMS-protected diphenylprolinol (13a).

To implement various reaction concepts in a multicomponent domino reaction, Jørgensen et al.129 disclosed a new approach for an enantioselective concurrent multicomponent domino organocatalytic reaction with combination of enamine-iminum-enamine catalysis (Scheme 77). The stereoselective multicomponent domino organocatalytic formation of cyclohex-1-ene-carbaldehyde derivatives can be obtained through a double Michael-aldol sequence. High selectivities were observed in the domino addition of malononitrile to crotonaldehyde in the presence of diarylprolinol silyl ether 13c. The reaction can be performed with only 5 mol% of catalyst 13c to provide the corresponding isolated product in 90% yield without affecting the enantioselectivity.

A three-component domino reaction of malonate esters, nitroalkenes, and α,β-unsaturated aldehydes was realized by Xu and Dixon130 very recently, in which the authors used a strategy involving the combination of two different organocatalysts (Scheme 78). The study revealed that quinine-based thiourea (QT, 227) and diphenylprolinol silyl ether 13e were the most promising catalyst pair for this domino reaction. The three-component domino process was also found to be broad in scope, with very good to excellent enantioselectivities (up to 99% ee) and moderate diastereoselectivities (2.1:1.5:1–9.3:1.8:1) obtained for the corresponding polysubstituted cyclohexanes.

With the realization of the strong activation capacity of diphenylprolinol silyl ethers with α,β-unsaturated aldehydes, the direct Michael addition of α,β-unsaturated aldehydes to nitroolefins should proceed via dienamine activation to give Baylis–Hillman-type Michael adducts. Along these lines, Chen and co-workers131 successfully developed the chiral diphenylprolinol silyl ether 13a as a catalyst for the asymmetric Michael addition of α,β-unsaturated aldehydes to nitroolefins (Scheme 79). The process afforded synthetically useful chiral functional nitro compounds with excellent enantioselectivities and yields. Furthermore, the authors then conducted a cascade reaction with the multifunctional Michael adducts and another molecul of α,β-unsaturated aldehyde by tandem a iminium-enamine catalysis of 13a, similar to that reported by Enders and co-workers. The presence of an additional basic catalyst, diisopropylethylamine (DIEPA), was crucial for the Michael/aldol domino reaction. As shown in Scheme 79, the densely functionalized 1-cyclohexene-1-carboxaldehyde 231 with multiple chiral centers could be directly isolated with almost complete enantiopurity in moderate to good yields.

4 Other Functional Silyl Ethers as Amino Organocatalysts

During the application of siloxyproline to the asymmetric Mannich reaction in the presence of water, and with organocatalysts that were screened, Hayashi and co-workers132 found that the siloxytetrazole hybrid catalyst 232 afforded syn-adducts with excellent enantioselectivity (Scheme 80). Low yield and enantioselectivity were obtained in the reactions with proline and 4-hydroxyproline. The proline-derived tetrazole catalyst gave only 50% ee. Siloxyproline (1b) gave moderate enantioselectivity (72% ee) with the anti-isomer predominating. It is interesting to note that the proline-derived tetrazole (237) is not a suitable catalyst, but the combination of a siloxy and a tetrazole moiety in a pyrrolidine scaffold created a highly efficient Mannich catalyst, 232. Cyclic ketones are suitable nucleophiles to afford the Mannich adduct with high diastereoselectivity (2.9:1–>20:1) and enantioselectivity (83–97% ee) (Scheme 81).

Similarly, a dramatic promotion in enantioselectivity by the silyl group was realized by Wu and Zhao133 recently (Scheme 82). In the aldol reaction of isobutyraldehyde and hydroxyacetone, silyl amino acids (1 and 2) are not suitable organocatalysts, however, the corresponding silyl ether derivatives of peptide analogues 233 provide excellent results for this reaction. The catalysts are derived from L-threonine and L-tryptophan. For various aliphatic aldehydes, excellent yields, diastereoselectivities, and enantioselectivities were achieved with loadings as low as 2 mol% of these catalysts.

Chiral thiourea-based bifunctional organocatalysts are an important class of hydrogen bonding-based catalyst and have produced outstanding efficiency in a wide variety of asymmetric transformations. Very recently, Chen et al.134 reported a novel silyl-protected thiourea and amine bifunctional organocatalyst. The silyl-protected amine-thiourea catalyst 234 was prepared from (1S,2S)-2-amino-1-(p-nitrophenyl)propane-1,3-diol easily and its application in the alcoholysis of meso-cyclic anhydrides is satisfactory (Scheme 83). In the presence of a catalytic amount of 234, asymmetric methanolysis of various meso-cyclic anhydrides proceeded smoothly to afford the corresponding hemiesters in high yields and with good to excellent enantioselectivities (up to 95% ee). The kinetic resolution of racemic alcohols catalyzed by silicon-based bulky catalyst 235 was also reported with good enantioselectivity.135

To reduce the catalyst loadings and short reaction time, Chen and coworkers136 developed a new organocatalysts (236) with a pyrrolidinyl motif linked with appropriate functionalities, such as sulfides, sulfones, sulfonamides. With different pyrrolidinylcamphor compounds in hand, the authors found significant improvement in the enantioselectivity was obtained by the introduction of silicon-based bulky group (OTBDPS) to the parent catalyst. And excellent enmantioselectivity was retained when the reaction proceed with only 2 mol% of catalysts 236 (84% yield, 95% ee) (Scheme 84).

5 Conclusions

Interest in organocatalysis has increased spectacularly in the last few years as a result of the nolvelty of the concept, the exclusion of any traces of harzardous metals, and several advantages from an economical and environmetal point of view. Although chiral bulky silyl organocatalyst as a special functional catalysts have been neglected by organic chemists to some extent, the modification of general amino catalysts with silanes is fascinating since it has enabled unprecedented or non-selective transformations to become highly reactive and has provided stereoselective catalysis for various reactions. As can be seen from the research results reported above, the introduction of silane groups to general enamine or iminium-based amino organocatlysts has proved to be an effective strategy for the improvement of efficiency and selectivity. In particular, impressive progress has been made in diarylprolinol silyl ethers-catalyzed organic transformations. Undoubtedly, future work will continue to expand the scope of organocatalysts with unique structural features through the investigation of the potential offered by silicon or silane groups. Therefore it is envisaged that future developments will include a greater emphasis on ‘silyl organocatalysts’ with excellent activity and stereoselectivity in new reactions or reactions that are superior to those performed with more-conventional catalytic methods.

Acknowledgements

Partial financial support by the National Natural Science Founder of China (No. 20973051) and Zhejiang Provincial Natural Science Foundation of China (Y4090139) is appreciated. XLW is greatly indebted to Prof. Masakatsu Shibasaki, Graduate School of Pharmaceutical Sciences, The University of Tokyo, and Prof. Guo-Qiao Lai, for their help.

Biographical Information

Li-Wen Xu received his PhD degree from the Graduate School of Chinese Academy of Sciences, and was awarded the Presidential Award of the Chinese Academy of Science in this year. From 2004 to 2006, he worked as an associate research professor at Lanzhou Institute of Chemical Physics (CAS). He spent one year (2005–2006) as a postdoctoral fellow at the Université du Maine and CNRS (Mortier’s group). From 2007 to 2009, He held a research fellow at the Department of Chemistry, National University of Singapore (Lu’s group), and a was a JSPS fellow at The University of Tokyo (Shibasaki’s group). Now he is professor at the Key Laboratory of Organosilicon Chemistry and Material Technology of MOE, Hangzhou Normal University. He has authored about 80 research publications. His current scientific interests are focused on organosilicon chemistry, heteroatom chemistry and asymmetric synthesis mediated by homogeneous organometallic and organic catalysts (organocatalysis).

Biographical Information

Li Li was born in Anhui in 1977. She received her PhD degree from the Graduate School of Chinese Academy of Sciences in 2005, and she subsequently moved to the College of Material, Chemistry and Chemical Engineering, Hangzhou Normal University as an associate professor in 2006. Her research is focused on the development of novel asymmetric synthetic methods and chiral separation.

Biographical Information

Zhi-Hui Shi was born in Anhui in 1983, China. She received her BS degree from Hefei University of Technology in 2005 and a masters degree from Chengde Medical University in 2009, and now she was a researcher in Hangzhou Normal University. Her research is focused on silicon-mediated asymmetric synthesis.