Aromatic hydroxyl group—a hydrogen bonding activator in bifunctional asymmetric organocatalysis

Pankaj Chauhan and Swapandeep Singh Chimni *
Department of Chemistry, U.G.C. Centre of Advance Studies in Chemistry, Guru Nanak Dev University, Amritsar, 143005, India. E-mail: sschimni@yahoo.com; Fax: (+)91-183-2258820

Received 11th October 2011 , Accepted 2nd November 2011

First published on 2nd December 2011


Recent progress in asymmetric catalysis has contributed to the development of a diverse range of chiral organocatalysts that differ in their origin, structure and mode of activation. The bifunctional organocatalysts bearing aromatic hydroxyl (or phenolic) groups have emerged as a privileged class of organocatalyst. In these bifunctional organocatalysts, the aromatic hydroxyl group functions as a weak Brønsted acid or hydrogen bonding site and a nucleophilic or basic moiety such as amine and phosphine serve as a base or hydrogen bond acceptor. The bifunctional organocatalysts having these moieties have not been reviewed. In this review we are presenting the asymmetric transformations catalyzed by the bifunctional organocatalyst bearing an aromatic hydroxyl group.


Pankaj Chauhan

Pankaj Chauhan

Pankaj Chauhan was born in 1984 at Bindal, a small village in Shimla District of Himachal Pradesh in India. He obtained his B.Sc. from Himachal Pradesh University in 2004. After completing his M.Sc. from Guru Nanak Dev University, Amritsar in 2007, he commenced his Ph.D. under the supervision of Dr Swapandeep Singh Chimni in the same University. His research interests include synthesis and application of chiral bifunctional organocatalysts for the development of new asymmetric transformation and green chemistry.

Swapandeep Singh Chimni

Swapandeep Singh Chimni

Swapandeep Singh Chimni was born in 1962 at Amritsar, India. He received his M.Sc.(Hons. Sch.) in Chemistry in 1985 and Ph.D. in 1991 from the Guru Nanak Dev University, Amritsar. After two years as Lecturer in Regional Engineering College (now NIT) Jalandhar, he joined the Department of Chemistry, Guru Nanak Dev University as Lecturer in 1992. He is presently working as Professor in the same department. He has 21 years of research experience and published over 80 publications. He works in the area of synthetic organic chemistry with emphasis on asymmetric organocatalysis, biocatalysis and phase transfer catalysis as well as green chemistry.


1. Introduction

Organocatalysis has emerged as a dynamic area of research in the domain of catalytic asymmetric synthesis.1,2 Over the years, many chiral organocatalysts have been developed and explored for a wide array of organic transformations. Among these diverse organocatalysts, bifunctional organocatalysts have been found to be highly efficient for bringing out a variety of useful asymmetric transformations. The bifunctional organocatalysts provide synergic activation to nucleophile and electrophile with two activating sites, either through hydrogen bonding or Brønsted acid-Lewis/Brønsted base activation.3 Several natural catalytic processes also proceed through hydrogen bonding of the active site of the enzyme with the substrate, but it is only recently that chemists have shown keen interest in exploiting the hydrogen bonding tendency of small organic molecules for catalyzing a variety of asymmetric transformations. Asymmetric organocatalysis with hydrogen bonding activation have been carried out using chiral urea/thiourea derivatives, chiral phosphoric acids, amides including phosphoramides and sulphonamides and phenol based chiral catalysts. Recent reviews on this mode of activation have illustrated the importance of proline and its analogues,4 urea/thiourea5 and phosphoric acid based organocatalysts.6 Beside these useful chiral organocatalysts there exist another class of valuable bifunctional catalysts bearing aromatic hydroxyl group in combination with a basic nitrogen or phosphorous moiety. The hydrogen bonding capability or Brønsted acid character of phenolic OH is more than that of aliphatic hydroxyl group. Enzymes such as class II aldolase, epoxide hydrolase (Fig. 1) and Δ5-3-ketosteroid isomerase (KSI) also activate the substrate through hydrogen bonding with an aromatic hydroxyl group.7
Mode of activation in enzymes (A) class II aldolase and (B) epoxide hydrolyse.
Fig. 1 Mode of activation in enzymes (A) class II aldolase and (B) epoxide hydrolyse.

Most hydrogen bonding chiral catalysts have a basic or nucleophilic moiety along with hydrogen bonding group. Tertiary ‘Group V elements’ mainly nitrogen and phosphorous are basic in nature viz tertiary amines and phosphines. These tertiary amines and phosphines serve as a Lewis base for hydrogen bonding or a Brønsted base for proton abstraction from nucleophile (Fig. 2). These moieties have been successfully exploited in bifunctional asymmetric catalysis in cooperation with hydrogen bonding moiety such as urea/thiourea, hydroxyl and aromatic hydroxyl for the synergic activation of substrates.


Synergic mode of activation.
Fig. 2 Synergic mode of activation.

In the last decade, bifunctional organocatalysts bearing aromatic hydroxyl groups have emerged as a powerful tool for bringing out a wide range of organic transformations. The aromatic hydroxyl group as a hydrogen bonding unit has not been reviewed, there is only one review on 6′–OH Cinchona alkaloids and their modified thiourea derivatives published in 2006.8c Since then, significant progress has been made in the application of 6′–OH Cinchona alkaloids as bifunctional organocatalysts. Other than 6′–OH Cinchona alkaloids, the BINOL derived organocatalysts bearing aromatic hydroxyl groups and amine/phosphine moieties, have emerged as efficient chiral catalysts in asymmetric synthesis. In this review we are presenting the catalytic potential of chiral bifunctional organocatalysts bearing aromatic hydroxyl groups as hydrogen bond donors and nitrogen or phosphorous moiety as basic units or hydrogen bond acceptors. For simplicity in presentation as well as understanding, this review has been classified into three major classes, based on the chiral scaffold of the catalysts: 1) Cinchona alkaloid derivatives 2) BINOL derivatives and 3) miscellaneous organocatalysts.

2. Cinchona alkaloid derivatives (Cinchona derived organocatalysts bearing aromatic hydroxyl and tertiary amino groups)

The multifunctional Cinchona alkaloids have unique molecular recognition abilities that render them and their derivatives as invaluable molecules in nearly every field of chemistry dealing with chirality: they are used as asymmetric catalysts, surface modifiers and selectors for chromatographic separations, bases for the resolution of racemates, ligands for transition-metal complexes and building blocks for supramolecular architectures. These alkaloids also find applications in asymmetric metal catalysis as well as organocatalysis. The Cinchona alkaloids are valuable motif in asymmetric organocatalysis both in their native form and modified form. They find applications in enamine catalysis, iminium catalysis, Lewis base catalysis, phase transfer catalysis as well as in bifunctional Lewis base-Brønsted acid catalysis.8 The latter property of these molecules arises from their structure as they possess a secondary alcohol and tertiary nitrogen. These features render them to be used as bifunctional organocatalysts.

Selective demethylation of quinine and quinidine generate C6′–OH species, that are known as cupreines and cupreidines, respectively. The demethylated form of the Cinchona derivatives or 6′–OH Cinchona alkaloids such as cupreines, cupreidines and β-isocupreidine (β-ICPD) and other simpler congeners containing a free hydroxyl group at C6 positions were recently shown to be powerful chiral organocatalysts for a wide array of asymmetric reactions (Fig. 3). Like parent alkaloids these catalysts feature two different sites for simultaneous activation of both nucleophiles and electrophiles. The cupreines and cupreidines also have increased acidity of the Brønsted acid site due to the presence of phenolic OH and a free site for further functionalization (C9–OH) that can be exploited to fine-tune properties such as basicity and conformation, therefore affecting the catalytic performance. In the following sections, the catalytic applications of 6′–OH Cinchona alkaloids for asymmetric transformations are being discussed.


Structures and abbreviations of some 6′–OH Cinchona alkaloids.
Fig. 3 Structures and abbreviations of some 6′–OH Cinchona alkaloids.

2.1 Carboncarbon bond formations

2.1.1 Morita–Baylis–Hillman (MBH) reaction. The Morita–Baylis–Hillman (MBH) reaction, is one of the most useful and interesting carboncarbon bond-forming reactions to synthesize β-hydroxy carbonyl compound with an α-alkylidene group.9 Hatakeyama and co-workers were the first to explore the application of 6′–OH Cinchona alkaloid for asymmetric transformation. They developed a β-isocupreidine (β-ICPD) catalyzed asymmetric MBH reaction between hexatrifluoroisopropyl acrylate (HFiPA) (4) and aldehydes (5) (Scheme 1).10aβ-ICPD catalyzes the MBH reaction of various aromatic and aliphatic aldehydes with highly reactive HFiPA in a highly stereoselective manner (91–99% ee). Due to the formation of dioxanone (7) as a side product, the product (6) was obtained in low yield (31–58%). This report was considered as a significant breakthrough in asymmetric synthesis, due to two main reasons: (1) it was the first example of a highly enantioselective MBH reaction, and (2) as well as the first application of 6′–OH Cinchona alkaloids in asymmetric organocatalysis.

              β-ICPD catalyzed MBH reaction of hexatrifluoroisopropyl acrylate (4) and aldehydes (5).
Scheme 1 β-ICPD catalyzed MBH reaction of hexatrifluoroisopropyl acrylate (4) and aldehydes (5).

In the mechanistic studies, they highlighted the prerequisite of the aromatic hydroxyl group for the observed stereochemistry. The reaction proceeds through initial nucleophilic addition of tertiary amine of the catalyst to acrylate, resulting in an enolate (8), which undergoes aldol type addition on the aldehyde to provide an equilibirium mixture of several diastereomers. The intramolecular hydrogen bonding between oxy-anion and aromatic OH, stabilizes the betaine intermediates, (9) and (10). The intermediate (9) can easily adopt the anti-periplanar arrangement (11) of the quaternary nitrogen and the α-hydrogen atom, required for the elimination to take place, leading to the preferential formation of one single enantiomer of the MBH adduct. The other structure (10), experiences severe steric repulsions in doing this and therefore reacts with another molecule of aldehyde, yielding dioxanone (7).

Later in 2006, they established, that water bound β-ICPD leads to the partial hydrolysis of HFiPA and found that azotropically dried β-ICPD showed remarkable catalytic activity, in particular, for aromatic aldehydes resulting in MBH adduct in excellent enantioselectivity (94–100% ee) and improved yield (27–82%).10b

The application of this methodology was extended for the total synthesis of (−)-mycestericin E (14),11 a potent immunosuppressant and the formal synthesis of epopromycin B (17) (Scheme 2).12 In the latter case chiral aldehyde (15) was used and the role of the catalyst was envisioned to achieve high levels of diastereoselectivity.


Synthesis of (–)-mycestericin E (14) and epopromycin B (17).
Scheme 2 Synthesis of (–)-mycestericin E (14) and epopromycin B (17).

Shi and co-workers have extended the substrate scope for β-ICPD catalyzed MBH reaction for methyl vinyl ketone (MVK) and α-naphthyl acrylate (18) with aldehydes (5) (Scheme 3).13 The β-ICPD provides a poor to moderate level of enantioselectivity (7–49% ee) when MVK was used. Although, α-naphthyl acrylate reacts with aromatic and aliphatic aldehydes to provide MBH product (19) with moderate to good level of enantioselectivity (33–92% ee) but, the reaction rate was very slow in the reaction conditions affording high enantioselectivity.



              β-ICPD catalyzed MBH reaction of (18) with aldehydes (5).
Scheme 3 β-ICPD catalyzed MBH reaction of (18) with aldehydes (5).

Very recently, three reports have been published that describe the catalytic application of β-ICPD for the synthesis of enantiomerically enriched 3-substituted-3-hydroxyoxindole derivatives via Morita–Baylis–Hillman reaction of unsaturated nucleophile (20) with isatin (21) (Scheme 4).14 Zhou and co-workers have developed a β-ICPD catalyzed asymmetric MBH reaction of acrolein with isatin derivatives to procure chiral quaternary hydroxylated carbon at C3-position of oxindole (22) in good to excellent yield (65–97%) and high enantioselectivity (90–98% ee) at −20 °C in dichloromethane as solvent.14a The product of this transformation has been utilized for the synthesis of chiral lactone and (+)-madindoline analogue precursor. Shi and co-workers have reported the β-ICPD catalyzed asymmetric MBH reaction of acrylate with isatin derivatives to generate quaternary hydroxylated stereocenter on oxindole with moderate to excellent yield (17–99%) and good enantioselectivity (46–94% ee) in dichloromethane at room temperature.14b Lu et al. have also reported a similar transformation in good yield (61–96% yield) and high enantioselectivity (86–96% ee) catalyzed by 10 mol% of β-ICPD in chloroform with 4 Å molecular sieves (MS) as additives at room temperature.14c All these reactions seem to proceed with a mechanism similar to that of the β-ICPD catalyzed MBH reaction of aldehydes with HFiPA. The synergic activation of unsaturated compound with tertiary amine and the activation of isatin carbonyl group with aromatic hydroxyl group of the catalyst via hydrogen bonding leads to the formation of MBH adduct with quaternary stereocenters with high ee.



              β-ICPD catalyzed asymmetric MBH reaction of isatin (21).
Scheme 4 β-ICPD catalyzed asymmetric MBH reaction of isatin (21).
2.1.2 aza-Morita–Baylis–Hillman (aza-MBH) reaction. The aza-Morita–Baylis–Hillman (aza-MBH) reaction, is one of the most useful carboncarbon bond forming reactions that provides β-amino carbonyl compounds bearing an α-alkylidene group.15 The first organocatalytic asymmetric aza-MBH reaction of methyl vinyl ketone with N-tosyl imines (23) was developed by Shi et al.16 The β-ICPD catalyzes the reaction between MVK and N-tosyl imine derivatives to provide an access to aza-MBH adduct (24) in moderate to good yield (54–80%) and in moderate to excellent enantioselectivity (46–99% ee). β-ICPD also efficiently catalyzes the reaction when methyl acrylate was used instead of MVK, which provides aza-MBH adducts (25) in 58–87% yield and 70–83% ee. With acrylonitrile the product was isolated only in 35% yield and 55% ee.

Balana and Adolfsson later modified this protocol with in situ generation of N-tosyl imine with titanium isopropoxide and molecular sieves from aldehydes and p-toluenesulfonamide. β-ICPD catalyzes the three component aza-MBH reaction with low to good yield (12–95%) and moderate level of enantioselectivity (49–74% ee).17

Zhu and co-workers have demonstrated the reversal of enantioselectivity of aza-MBH product of MVK and N-sulfonyl imines on using β-naphthol as an additive in the β-ICPD catalyzed asymmetric aza-MBH reaction.18

Hatakeyama and co-worker have developed β-ICPD catalyzed asymmetric aza-MBH reaction of HFiPA (4) and aromatic phosphonyl imines (26) (Scheme 5).19 The S isomer of N-protected-α-methylene-β-amino acid esters (27) were obtained in moderate to high yield (42–90%) and moderate enantioselectivity (54–73% ee). The enantioselectivity was enriched to 99% after single crystallization with quite a satisfactory yield. On the basis of observed stereochemistry of the product, the proposed transition state has been illustrated to involve two hydrogen bonded stable betaine intermediates (28) and (29). The ammonium cation and α-hydrogen of ester group, adopt anti-periplanar geometry in both the intermediates, since (28) is free from the steric interaction, so it affords the major (S) enantiomer. The chiral aza-MBH product of this transformation was used as a precursor for the synthesis of β-lactam.



              β-ICPD catalyzed aza-MBH reaction.
Scheme 5 β-ICPD catalyzed aza-MBH reaction.
2.1.3 Mannich reaction. Asymmetric Mannich reactions provide a powerful method for synthesizing optically active β-amino carbonyl units, which are useful chiral building blocks for a number of biologically active and pharmaceutically important compounds.20 Inspired by naturally occurring enzymatic polyketide biosynthesis that involves generation of thioester enolate through decarboxylation, Ricci and co-workers have developed organocatalytic enantioselective decarboxylative Mannich reaction of malonic half thioesters (30) with N-tosyl imines (23) (Scheme 6).21 The resulting N-tosyl-β-amino thioesters (31) were obtained in moderate to good yield (41–84%) and enantioselectivity (38–79% ee) in the presence of β-ICPD catalyst. The mechanism of this reaction involves the deprotonation of (30) with tertiary amine of β-ICPD catalyst, followed by decarboxylation to form thioacetate enolate. The enolate thus formed acts as an active nucleophile which is directed by the quinuclidine nitrogen of the catalyst to add on the imine carbon, which is activated and oriented through hydrogen bonding to the aromatic OH group of the catalyst (32).

              β-ICPD catalyzed decarboxylative Mannich reaction of malonic half thioestsers (30) with N-tosyl imines (23).
Scheme 6 β-ICPD catalyzed decarboxylative Mannich reaction of malonic half thioestsers (30) with N-tosyl imines (23).

On achieving remarkable success employing α-isothiocyano imides in catalytic asymmetric aldol reaction with thiourea tertiary amine catalyst, Seidel and co-workers employed the α-isothiocyanato imides (33) as a nucleophile for Mannich reactions with sulfonyl imines (23) (Scheme 7).22 The qunidine derived catalyst AcCPD catalyzes the formation of Mannich product (34) in good to high yield (53–99%), with good to excellent syn-diastereoselectivity (72[thin space (1/6-em)]:[thin space (1/6-em)]28–95[thin space (1/6-em)]:[thin space (1/6-em)]5 dr) and high enantioselectivity (89–99% ee) using a diverse range of imines (Ts, Bs and Ns) with substituted aromatic, heteroaromatic and α,β-unsaturated groups. The reactions with Bs- and Ns-imines were much faster than Ts-imine and the reaction of Bs- and Ns-imines proceeds at a remarkably low catalyst loading (0.25–1.0 mol%) with a reasonable reaction rate.



              AcCPD catalyzed asymmetric Mannich reaction α-isothiocyanato imides (33) with sulfonyl imines (23).
Scheme 7 AcCPD catalyzed asymmetric Mannich reaction α-isothiocyanato imides (33) with sulfonyl imines (23).

The similiar transformation catalyzed by BzCPN, has been developed by Zhong and co-workers, where 2.5 mol% BzCPN catalyzes the Mannich reaction of α-isothiocyanato imides (33) with N-tosyl imines (23) to provide (34) in 80–99% yield, 86–99% ee and 67[thin space (1/6-em)]:[thin space (1/6-em)]33–97[thin space (1/6-em)]:[thin space (1/6-em)]3 dr.23

Chen and co-workers have reported the 6′–OH Cinchona alkaloid catalyzed direct anti-selective Mannich reaction of 2-oxindoles (35) with N-tosyl imines (23) (Scheme 8).24 The 10 mol% of quinine derived catalyst PHNCPN efficiently catalyzes the addition of (35) to (23) leading to the formation of anti-3,3-disubstituted 2-oxindoles (36) with vicinal quaternary and tertiary stereogenic centers in good to excellent diastereoselectivity (79[thin space (1/6-em)]:[thin space (1/6-em)]21–95[thin space (1/6-em)]:[thin space (1/6-em)]5) and good enantioselectivity (70–89% ee). The transition state (37) involves the initial formation of enolate that is stabilized by the tertiary amine, which directs the re-face attack of the enolate to the re-face of the imine, which is oriented by the hydrogen bonding with 6′–OH of the catalyst.



              BnCPN catalyzed anti-Mannich reaction of 2-oxindoles (35) with N–tosyl imines (23).
Scheme 8 BnCPN catalyzed anti-Mannich reaction of 2-oxindoles (35) with N–tosyl imines (23).
2.1.4 Michael addition. The organocatalytic asymmeric Michael reaction has emerged as a very important carboncarbon bond forming reaction in organic synthesis.25 The pioneering report from Deng and co-workers on organocatalytic asymmetric Michael addition demonstrates the successful application of 6′–OH Cinchona alkaloids for the asymmetric 1,4-addition of malonic ester (38) to nitro-olefins (39) (Scheme 9).26 The catalysts derived from quinine and quinidine i.e.CPN or CPD efficiently catalyzes the Michael addition of (38) to aromatic, heteroaromatic, aliphatic as well as alicyclic nitroalkenes yielding both the enantiomers of (40) in good to excellent yield (71–99%) and high enantioselectivity (91–99% ee). The CPN also catalyze the Michael addition of ethyl acetoacetate to nitrostyrene to provide the two diastereomers in 1[thin space (1/6-em)]:[thin space (1/6-em)]1 ratio, 91% yield and 91% ee.
6′–OH Cinchona alkaloids catalyzed Michael addition of malonic ester (38) to nitro-olefins (39).
Scheme 9 6′–OH Cinchona alkaloids catalyzed Michael addition of malonic ester (38) to nitro-olefins (39).

Very recently, Lin and co-workers have developed a new bifunctional bis 6′–OH Cinchona alkaloid catalyst (41) for asymmetric conjugate addition of malonate (38) to nitroalkenes (39) (Scheme 9).27 With 1 mol% of catalyst (41) and its pseudoenantiomeric form, the Michael adducts (40) with opposite configuration were obtained in high yield (79–99%) and very good enantioselectivity (86–97% ee).

The extension of application of 6′–OH Cinchona alkaloids for the asymmetric conjugate addition reaction to generate vicinal stereocenters was reported by the Deng et al. in 2005. The C9 protected 6′–OH Cinchona alkaloids catalyze the enantioselective Michael addition of racemic tri-substituted carbon nucleophiles (42) to nitro-olefins (39) to generate adjacent quaternary and tertiary chiral carbon in the addition products (43) (Scheme 10).28 Various cyclic and acyclic β-ketoester, diketones, nitroester and cyanoester react with substituted aromatic, heteroaromatic and aliphatic nitroolefins in the presence of BnCPN or BnCPD to provide Michael adduct (43) in excellent diastereoselectivity (82[thin space (1/6-em)]:[thin space (1/6-em)]18–98[thin space (1/6-em)]:[thin space (1/6-em)]2 dr) and enantioselectivity (89–99% ee). The catalyst β-ICPD provides Michael adduct with yield and stereoselectivity comparable to BnCPD. This result led them to propose that in the transition state BnCPD being a flexible molecule, adopts a gauche-open conformation, like more rigid β-ICPD and simultaneously activate and orient the Michael donor with tertiary amine moiety and the acceptor via a network of hydrogen-bonding interactions with aromatic hydroxyl group (44). In the transition state the substituents of the two bond-forming carbons remained in a staggered rather than eclipsed arrangement.


6′–OH Cinchona alkaloids catalyzed Michael addition of racemic tri-substituted carbon nucleophiles (42) to nitro-olefins (39).
Scheme 10 6′–OH Cinchona alkaloids catalyzed Michael addition of racemic tri-substituted carbon nucleophiles (42) to nitro-olefins (39).

Young and White have synthesized many racemic trisubstituted nitroacetates with Pd(II) catalyzed allylic C–H alkylation reaction.29 The synthetic utility of nitroacetate (45) was demonstrated by BnCPN catalyzed Michael addition of (45) to the nitrostyrene (39) to obtain 1,4-adduct (46) in 88% yield, and 95% ee and 12[thin space (1/6-em)]:[thin space (1/6-em)]1 dr (Scheme 11).



              BnCPN catalyzed asymmetric Michael addition of nitroacetate (45) to the nitrostyrene (39).
Scheme 11 BnCPN catalyzed asymmetric Michael addition of nitroacetate (45) to the nitrostyrene (39).

Wang and co-workers developed the organocatalytic asymmetric 1,4-conjugate addition of α-fluoroketoester to nitro-olefins catalyzed by 9–OH protected cupreine (Scheme 12).30 1 mol% of PHNCPN catalyzes the formation of non-enolizable ketoesters (48) with vicinal fluorinated quaternary and tertiary stereocenters from α-fluoroethyl acetoacetate (47) and nitro-olefins (39) in high yield (75–98%) and excellent enantioselectivity (94–99% ee) with acceptable diastereoselectivity (1.7[thin space (1/6-em)]:[thin space (1/6-em)]1–4[thin space (1/6-em)]:[thin space (1/6-em)]1 dr).



              PHNCPN catalyzed asymmetric synthesis of non-enolizable ketoesters (48) with fluorinated quaternary stereocenter.
Scheme 12 PHNCPN catalyzed asymmetric synthesis of non-enolizable ketoesters (48) with fluorinated quaternary stereocenter.

They have also developed PHNCPN catalyzed asymmetric Michael addition of 2-fluoromalonate with nitro-olefin derivatives to provide corresponding 1,4-adduct in good to high yield (65–98%) and high enantioselectivity (86–99% ee).31

Yan and co-workers utilized the catalytic potential of 6′–OH Cinchona alkaloids for the synthesis of enantioenriched nitrocyclopropane (50) viaCPN catalyzed initial asymmetric conjugate addition of bromomalonate (49) to aromatic and heteroaromatic nitro-olefins (39) followed by DABCO mediated intramolecular cyclopropanation (Scheme 13).32 The substituted nitrocyclopropane products (50) were obtained in moderate to good yield (47–78%) and excellent stereoselectivity (75–99% ee and >99[thin space (1/6-em)]:[thin space (1/6-em)]1 dr).


Asymmetric cyclopropanation reaction catalyzed with CPN.
Scheme 13 Asymmetric cyclopropanation reaction catalyzed with CPN.

The application of asymmetric 1,4-addition to nitroalkenes for the synthesis of functionalized cyclopentanes (52), with oxime unit have been reported by Rodriguez et al. in a one-pot three step procedure.33 The one pot sequence involves Takemoto's catalyst (53) or CPN catalyzed initial asymmetric Michael reaction of substituted malonates (51) with nitro-olefins (39) followed by carbohydroxylation via an intramolecular [3 + 2]-silylnitronate olefin cyclization (ISOC)-fragmentation sequence with Me3SiCl and triethyl amine, followed by fragmentation with tetrabutylammonium fluoride (TBAF) (Scheme 14). Many aryl and heteroaryl substituted cyclopentanes (52) have been synthesized in good to high yield (60–99%) and high enantioselectivity (88–97% ee).


Asymmetric synthesis of functionalized cyclopentanes (52).
Scheme 14 Asymmetric synthesis of functionalized cyclopentanes (52).

Recently, Feng and co-workers have developed the asymmetric synthesis of multifunctionalized tetrahydroindan (55) with four contiguous stereocenters via two sequential conjugate addition reaction, involving initial BnCPN catalyzed stereoselective addition of cyclic γ,δ-unsaturated-β-ketoester (54) to substituted nitroalkenes (39), followed by 1,1,3,3-tetramethylguanidine (TMG) catalyzed intramolecular Michael reaction (Scheme 15).34 The aromatic, heteroaromatic, cinnamic as well as aliphatic nitro-olefins provide chiral indan (55) in good to high yield (50–99%) with excellent enantioselectivity (95–99% ee) and diastereoselectivity (>99[thin space (1/6-em)]:[thin space (1/6-em)]1) with low catalyst loading of BnCPN (0.5–2 mol%).


Asymmetric synthesis of multifunctionalized tetrahydroindans (55).
Scheme 15 Asymmetric synthesis of multifunctionalized tetrahydroindans (55).

Wang et al. reported the asymmetric conjugate addition of nitroalkanes (56) to nitro-olefins (39) using cupreine as catalysts (Scheme 16).35 The 10 mol% of CPN catalyzes the Michael addition of nitroalkanes such as nitropropane, nitroethane and cyclic nitroalkanes to aromatic and heteroaromatic nitro-olefins to yield 1,3-dinitro compounds (57) in good yield (73–82%) and enantioselectivity (64–88% ee) under neat condition.



              CPN catalyzed Michael addition of nitroalkanes (56) to nitroalkenes (39).
Scheme 16 CPN catalyzed Michael addition of nitroalkanes (56) to nitroalkenes (39).

Shi and co-workers reported the Michael addition of anthrone (58) to nitro-olefins (39) catalyzed by BzCPN to provide (59) in excellent yield (91–99%) and high enantioselectivity (80–99% ee) (Scheme 17).36 It is noteworthy that the anthrone acts as an active nucleophile rather than as an active diene.



              BzCPN catalyzed asymmetric Michael reaction of anthrone (58) with nitroalkenes (39).
Scheme 17 BzCPN catalyzed asymmetric Michael reaction of anthrone (58) with nitroalkenes (39).

Very recently, Chauhan and Chimni have developed a highly regio- and stereoselective route for the synthesis of vicinal quaternary and tertiary stereocenters via 6′–OH Cinchona alkaloid catalyzed Michael addition of tri-substituted racemic nucleophiles (42) to nitrodienes (60) (Scheme 18).37 At low catalyst loading (0.5–5 mol%) of BnCPN or BnCPD, the nucleophiles such as cyclic and acyclic β-ketoesters as well as cyclic diketone were successfully added to aromatic and aliphatic nitrodienes to provide adduct (61) with adjacent quaternary and tertiary stereocenters in good to excellent yield (57–99%), high enantioselectivity (88–99% ee) and good to high diastereoselectivity (56[thin space (1/6-em)]:[thin space (1/6-em)]44–99[thin space (1/6-em)]:[thin space (1/6-em)]1 dr).


6′–OH Cinchona alkaloids catalyzed Michael addition of tri-substituted carbon nucleophiles (42) to nitrodienes (60).
Scheme 18 6′–OH Cinchona alkaloids catalyzed Michael addition of tri-substituted carbon nucleophiles (42) to nitrodienes (60).

Deng and co-workers demonstrated the practical as well as preparative utility of PHNCPD and PHNCPN catalysts for asymmetric 1,4-conjgate addition of a diverse range of cyclic and acyclic α-substitued β-ketoesters to various α,β-unsaturated ketones and various α,β-unsaturated aldehydes to yield Michael adducts (62) and (63) bearing quaternary stereocenters in excellent yield (82–99%) and enantioselectivity (85–99% ee) (Scheme 19).38 In case of β-substituted α,β-unsaturated aldehydes a very good diastereoselectivity ranging from 18[thin space (1/6-em)]:[thin space (1/6-em)]1 to 25[thin space (1/6-em)]:[thin space (1/6-em)]1 has been observed. This approach was utilized for the concise total synthesis of (+)-tanikolide. The new cupreidine derived catalyst (66) catalyzes the Michael addition of α-aryl/heteroaryl α-cyanoacetate (64) to acrolein to provide (65) in quantitative yield and up to 95% ee (Scheme 19).


6′–OH Cinchona alkaloids catalyzed Michael addition of tri-substituted carbon nucleophiles to enones and enals.
Scheme 19 6′–OH Cinchona alkaloids catalyzed Michael addition of tri-substituted carbon nucleophiles to enones and enals.

Rigby and Dixon reported the PHNCPD catalyzed 1,4-addition of various β-keto ester pro-nucleophiles to acrylic esters, thioesters and N-acryloyl pyrrole (Scheme 20).39 The 10 mol% of catalyst provides an access to all-carbon quaternary chiral carbon containing 1,4-adducts (68) from a diverse range of tri-substituted racemic nucleophiles (42) and unsaturated acceptor (67) in moderate to high yield (52–96%) and good to excellent enantioselectivity (67–98% ee).


6′–OH Cinchona alkaloids catalyzed Michael addition to acrylic esters, thioesters and N-acryloyl pyrrole (67).
Scheme 20 6′–OH Cinchona alkaloids catalyzed Michael addition to acrylic esters, thioesters and N-acryloyl pyrrole (67).

Deng and co-workers developed the first enantioselective 1,4-addition of α-substituted α-cyanoacetates (64) to arylvinyl sulfones (69) (Scheme 21). The catalysts PHNCPN or PHNCPN provide conjugate adduct (70) with all-carbon quaternary stereogenic centre from α-aryl or heteroaryl α-cyanoacetate and phenyl vinyl sulfone in high yield (80–96%) and excellent enantioselectivity (88–97% ee).40 The reaction of α-alkyl α-cyanoacetate with phenylvinyl sulfone proceeded with slow rate but in case of 3,5-bis-(triflouromethyl)phenyl vinyl sulfone, a higher yield was obtained, which is attributed to the enhanced electrophilicity of sulfone. The corresponding 1,4-adduct was obtained in up to 94% ee. Later in 2009, they extended the scope of this reaction to α-cyanoketone and β-ketoesters. These nucleophiles add to the unsubstituted and β-substituted sulfones to yield 1,4-adduct in high stereoselectivity.41


6′–OH Cinchona alkaloids catalyzed Michael addition of α-cyanoacetates (64) and vinyl sulfones (69).
Scheme 21 6′–OH Cinchona alkaloids catalyzed Michael addition of α-cyanoacetates (64) and vinyl sulfones (69).

Very recently, Marini and co-workers have described an elegant organocatalytic protocol for the synthesis of chiral spirolactones (73) from cyclic β-ketoesters (71) and vinyl selenone (72) by a one-pot Michael addition-cyclization reaction (Scheme 22).42PHNCPN catalyzes the initial Michael reaction of β-ketoesters (71) with (72) in a highly enantioselective manner. The corresponding Michael adduct undergoes lactonization in the presence of silica gel to provide (73) in good to excellent yield (71–99%).


One-pot Michael addition-cyclization reaction catalyzed by PHNCPN.
Scheme 22 One-pot Michael addition-cyclization reaction catalyzed by PHNCPN.

Loh et al. reported the highly efficient vinylogous Michael addition of α,α-dicyanoolefins (74) to the maleimides (75) using 6′–OH Cinchona alkaloids (Scheme 23).43 The BnCPD or 2-naphthyl cupreidine (NpCPD) catalysts have shown to be equally efficient for the addition from the γ-carbon of the various nucleophiles (74) to the N-protected maleimides (75) to provide the desired product (76) with anti-conformation in moderate to good yield (35–90%) and high enantioselectivity (80–99% ee).


Asymmetric vinylogous Michael addition of α,α-dicyanoolefins (74) to maleimides (75).
Scheme 23 Asymmetric vinylogous Michael addition of α,α-dicyanoolefins (74) to maleimides (75).

Deng and co-workers developed 6′–OH Cinchona alkaloid catalyzed organocatalytic asymmetric tandem Michael addition-protonation for the direct synthesis of two non adjacent quaternary and tertiary stereogenic centers (Scheme 24).44 The PHNCPN or PHNCPD (for cyclic nucleophile) or AcCPD (for acyclic nucleophile) catalyzes the asymmetric tandem reaction between carbon nucleophiles (77) and (78) with α-chloroacrylonitrile (79) in very good yield (60–95%) and good to excellent stereoselectivity (85–99% ee and 2[thin space (1/6-em)]:[thin space (1/6-em)]1–25[thin space (1/6-em)]:[thin space (1/6-em)]1 dr). This strategy was further extended for the asymmetric synthesis of (−)-manzacidin.


6′–OH Cinchona alkaloids catalyzed organocatalytic asymmetric tandem Michael addition-protonation reaction.
Scheme 24 6′–OH Cinchona alkaloids catalyzed organocatalytic asymmetric tandem Michael addition-protonation reaction.

Yuan and co-workers have developed cupreine catalyzed enantioselective construction of spiro[4H-pyran-3,3′-oxindoles] (84) via two or three component domino Knoevenagel–Michael-cyclization sequence (Scheme 25).45 A wide range of optically active (84) were obtained in excellent yield (up to 99%) with good to excellent enantioselectivity (up to 97%) from simple and readily available starting materials under mild reaction conditions. The two component reaction involves α,α-dicyano olefin derived from isatin (21) and malononitrile (83), and active methylene compounds (82) as reactant that tune into a CPN catalyzed domino sequence providing high yield and enantioselectivity. The three component reaction involves the in situ formation of α,α-dicyano olefin followed by Knoevenagel–Michael-cyclization reaction providing an access to spiro compound in good to high enantioselectivity.


Cupreine catalyzed enantioselective synthesis of spiro[4H-pyran-3,3′-oxindoles] (84).
Scheme 25 Cupreine catalyzed enantioselective synthesis of spiro[4H-pyran-3,3′-oxindoles] (84).
2.1.5 Rauhut–Currier reaction. The Rauhut–Currier (RC) reaction is the phosphine-catalyzed dimerization of activated alkenes, that creates a new C–C bond between the α-position of an activated alkene and the β-position of the second alkene.46 Very recently, Shi and co-workers have developed the first example of a β-isocupreidine (β-ICPD) catalyzed highly enantioselective intermolecular Rauhut–Currier reaction of maleimides (75) with allenoates (85) and penta-3,4-dien-2-one (Scheme 26).47β-ICPD catalyzes the synthesis of optically active functionalized allene derivatives (86) in good to high yield (68–99%) along with good to excellent enantioselectivity (67–98% ee).
Enantioselective Rauhut–Currier reaction catalyzed by β-ICPD.
Scheme 26 Enantioselective Rauhut–Currier reaction catalyzed by β-ICPD.
2.1.6 Allylic alkylation. Lu and co-workers have reported the first allylic alkylation of Morita–Baylis–Hilmann carbonates (87) with different nitrogen, oxygen and carbon nucleophiles (88) catalyzed by β-ICPD (Scheme 27).48 The alkylated products (89) with an allylic stereocenter were obtained in good to high yield (84–96%) and moderate enantioselectivity (51–72% ee).

              β-ICPD catalyzed asymmetric allylic alkylation of Morita–Baylis–Hilmann carbonates (87).
Scheme 27 β-ICPD catalyzed asymmetric allylic alkylation of Morita–Baylis–Hilmann carbonates (87).

Later in 2007, Hiemstra et al. extended this approach to generate adjacent quaternary and tertiary stereocenters. The β-ICPD catalyzed the allylic alkylation of (87) with α-phenyl or methyl cyano esters (64) to generate vicinal quaternary and tertiary stereocenters in high yield (up to 94%) and moderate to good stereoselectivity (16–85% ee and 1.1[thin space (1/6-em)]:[thin space (1/6-em)]1–4[thin space (1/6-em)]:[thin space (1/6-em)]1 dr).49 The kinetic resolution of carbonate (87) has also been observed with 90% ee, when used in excess.

Chen and co-workers have reported allylic alkylation of 87 with N-protected oxindoles (35) catalyzed by β-ICPD.50 The various aromatic and heteroaromatic carbonates react with N-protected oxindole derivatives providing access to vicinal quaternary and tertiary stereocenters (91) with good to high yield (50–98% yield) and stereoselectivity (88–97% ee and 63[thin space (1/6-em)]:[thin space (1/6-em)]37–92[thin space (1/6-em)]:[thin space (1/6-em)]8 dr).

Very recently, the same research group has utilized the MBH carbonate of the isatin (92) for β-ICPD catalyzed asymmetric allylic alkylation with α,α-dicyanoolefins (74) to obtain 3-substituted oxindole derivatives (93) bearing vinical quaternary and tertiary stereocenter in good to high yield (50–98%) with good to excellent enantioselectivity (86–97% ee) and excellent diastereoselectivity (>99[thin space (1/6-em)]:[thin space (1/6-em)]1 dr).51

2.1.7 Friedel–Crafts reaction. The asymmetric Friedel–Crafts reaction emerged as a powerful carboncarbon bond formation reaction for the synthesis of chiral arene derivatives.52 Deng and coworkers have reported the first 6′–OH Cinchona alkaloids catalyzed asymmetric Friedel–Crafts reaction of indole (94) with α-ketoesters (95) or aromatic aldehydes (5) (Scheme 28).53 The 9–OH Cinchona alkaloids proved inefficient in terms of product formation and enantio-induction. The PHNCPD or PHNCPN resulted in the formation of chiral Friedel–Crafts products (96) and (97) in very good yield (60–97%) and in excellent enantioselectivity (81–99% ee) for a wide range of indole derivatives and carbonyl compounds.
6′–OH Cinchona catalyzed asymmetric Friedel–Crafts reaction of indole (94) with carbonyl compounds (95) and (5).
Scheme 28 6′–OH Cinchona catalyzed asymmetric Friedel–Crafts reaction of indole (94) with carbonyl compounds (95) and (5).

Chen and co-workers have reported an elegant protocol for the synthesis of chiral trifluoromethyl-substituted tertiary alcohols via asymmetric organocatalytic Friedel–Crafts reaction of various 2-substituted and 2,6-disubstituted phenols (98) with trifluoropyruvates (99) (Scheme 29).54 With 10 mol% PHNCPD, alkylation of substituted phenols have been performed regioselectively at the 4-position of phenol to afford the Friedel–Crafts adducts (100) in moderate to good yield (58–96%) and good enantioselectivity (71–94% ee).


Asymmetric synthesis trifluoromethyl-substituted tertiary alcohols via Friedel–Crafts reaction (100).
Scheme 29 Asymmetric synthesis trifluoromethyl-substituted tertiary alcohols via Friedel–Crafts reaction (100).

Wang and co-workers have reported a highly efficient CPN catalyzed Friedel–Crafts reaction of indole and isatin derivatives to provide 3-indolyl-3-hydroxyoxindoles (101) (Scheme 30).55 20 mol% of CPN and benzoic acid catalyzes the Friedel–Crafts reaction of indole derivatives with different isatins in dioxane yielding chiral (101) in high yield (68–97%) and good enantioselectivity (76–91% ee).


6′–OH Cinchona alkaloids catalyzed asymmetric synthesis of 3-indolyl-3-hydroxyoxindole derivatives (101).
Scheme 30 6′–OH Cinchona alkaloids catalyzed asymmetric synthesis of 3-indolyl-3-hydroxyoxindole derivatives (101).

Concurrently, Chauhan and Chimni have developed a highly enantioselective Friedel–Crafts reaction of indole and isatin derivatives catalyzed by BnCPN (Scheme 30).56 The 3-indolyl-3-hydroxyoxindole derivatives (100) were synthesized in high yield (88–99%) and good to excellent enantioselectivity (80–99% ee) under mild reaction conditions. The methodology was free from competing double addition of indole to isatin. On the basis of several experiments the bifunctional mode of activation of the catalyst was demonstrated. The protection of either 6′–OH or quinuclidine N results in the failure of the reaction. This was further proven by the lack of product formation when N-methyl indole was used. The proposed transition state (102) involves a ternary complex between the catalyst, isatin and indole, in which tertiary amine activate and orient the indole by forming hydrogen bond with NH of indole and aromatic OH group activate the isatin with hydrogen bonding.

Very recently, Wang et al. have reported the organocatalytic asymmetric aza-Friedel–Crafts reaction of 1-naphthols (103) with N-sulfonyl aldimines (23) catalyzed by PHNCPD to provide chiral aminonaphthol derivatives (104) (Scheme 31).57PHNCPD catalyzes the Friedel–Crafts reaction of 1-naphthol derivatives with aryl, heteroaryl and alkyl sulfonyl imines to provide (104) with good to quantitative yield (62–100%) and high enantioselectivity (80–96% ee). Only a moderate level of enantioselectivity was achieved in the case of 2-naphthol (105).


6′–OH Cinchona alkaloids catalyzed asymmetric aza-Friedel–Crafts reaction of naphthols.
Scheme 31 6′–OH Cinchona alkaloids catalyzed asymmetric aza-Friedel–Crafts reaction of naphthols.

Chauhan and Chimni have applied the catalytic potential of 6′–OH Cinchona alkaloids for the aza-Friedel–Crafts reaction of 2-naphthols (105) with N-sulfonyl imines (23) (Scheme 31).58BzCPN catalyzes the formation of aza-Friedel–Crafts products (106) from 2-naphthol derivatives and N-tosyl imines in good to high yield (58–99%) and moderate to excellent enantioselectivity (48–99%). This methodology was successfully extended for aza-Friedel–Crafts reaction of 1-naphthols (103) with N-tosyl imines as well, the aminonaphthol adducts (104) were obtained in very good yield (68–76%) and enantioselectivity (80–98% ee). The bifunctional mode of catalysis has been established on the basis of designed experiments and the transition state (107) was proposed to involve the ternary complex of catalyst, naphthol and imine in which the phenolic group of the catalyst activates the imine through hydrogen bonding and the tertiary amine moiety activate and orient the naphthol for the re-face attack to provide S-enantiomer of the product.

2.1.8 Henry reaction. The asymmetric Henry reaction emerged as a powerful transformation to procure chiral β-nitro alcohol.59 In 2005, Hiemstra and co-workers were able to gain only limited success in BnCPD catalyzed Henry reaction of activated aromatic aldehydes (5) substituted with electron withdrawing group and nitromethane (Scheme 32).60 Although the product (108) was formed in very good yield (84–92%) but the enantioselectivity (24–35% ee) observed was rather low.

              BnCPD catalyzed asymmetric Henry reaction of aldehydes.
Scheme 32 BnCPD catalyzed asymmetric Henry reaction of aldehydes.

Deng and co-workers have developed the first organocatalytic asymmetric Henry reaction of nitromethane with α-ketoesters (95) (Scheme 33).61 With BzCPN or BzCPD, the chiral β-nitro alcohols (109) were obtained in high yield (84–99%) and excellent enantioselectivity (93–97% ee). The remarkable finding of this study was that, the β,γ-unsaturated α-ketoesters undergo 1,2-addition of nitromethane, instead of 1,4-addition with high chemoselectivity. The high enantioselectivity was not only obtained for alkenyl α-ketoesters, but a wide variety of aryl and alkyl α-ketoesters also provide access to chiral tertiary alcohols. The chiral nitroaldol product so formed was utilized for the new and concise asymmetric synthesis of aziridines (110), β-lactams (111) and α-methylcysteine derivatives (112).


6′–OH Cinchona alkaloids catalyzed asymmetric Henry reaction of α-ketoesters (95) and α-ketophosphonates (114).
Scheme 33 6′–OH Cinchona alkaloids catalyzed asymmetric Henry reaction of α-ketoesters (95) and α-ketophosphonates (114).

Cossy and co-worker have extended the application of BzCPN catalyzed Henry reaction of α-ketoester with nitromethane for enantioselective synthesis of SSR 241586 (113) a 2,2-disubstituted morpholine active in the treatment of schizophrenia and irritable bowel syndrome (IBS) (Scheme 33).62

Zhao and co-workers have reported CPN or BnCPN catalyzed organocatalytic asymmetric nitroaldol reaction of α-ketophosphonates (114) and nitromethane.63 Both catalysts proved to be equally efficient, providing α-hydroxy-β-nitrophosphonates (115) in good yield (60–93%) and excellent enantioselectivity (90–99% ee) using aromatic as well as aliphatic α-ketophosphonates. The chiral nitro-alcohol (115) was transformed into enantioenriched β-amino-α-hydroxyphosphonate (116) by reduction and subsequent benzylation (Scheme 33).

Bandini and co-workers developed the asymmetric organocatalytic nitroaldol reaction of fluoromethyl ketones (117) utilizing the catalytic applications of 6′–OH Cinchona alkaloids (Scheme 34).64 They found remarkable enantioenrichment by introduction of an electron withdrawing group on the benzoyl group at C9 of cupreine. A newly developed catalyst (119), catalyzes the Henry reaction of nitromethane with tri- and di-fluoromethyl ketone (117), resulting in the formation nitroaldol product (118) in moderate to high yield (67–99%) and excellent enantioselectivity (76–99% ee).


Asymmetric organocatalytic nitroaldol reaction of fluoromethyl ketones (117).
Scheme 34 Asymmetric organocatalytic nitroaldol reaction of fluoromethyl ketones (117).

Very recently, Wei Wang and co-workers of the University of New Mexico have reported the first asymmetric Henry reaction of isatin derivatives catalyzed by cupreine (Scheme 35).65CPN catalyzes the nitro-aldol reaction of nitroalkanes such as nitromethane, nitroethane and nitropropane (56) with various isatin derivatives (21) to provide an easy access to chiral 3-substituted 3-hydroxyoxindole derivatives (120) in excellent yield and good to high stereoselectivity.65a The chiral adduct of this reaction was successfully transformed to oxindole alkaloids such as (+)-dioxibrassinin and (S)-(−)-spirobrassinin.



              CPN catalyzed Henry reaction of isatin derivatives (21).
Scheme 35 CPN catalyzed Henry reaction of isatin derivatives (21).

Simultaneously with this, two independent reports have been published on similar transformations catalyzed by 6′–OH Cinchona alkaloids. Xing-Wang Wang and co-workers have reported the synthesis of hydroxylated quaternary chiral carbon on oxindole viaBnCPN catalyzed asymmetric Henry reaction of nitromethane with isatin derivatives.65b The corresponding nitro-aldol product was isolated in good to high yield (90–98%) and moderate to good enantioselectivity (72–95% ee). Wei Wang et al. at Lanzhou University have reported the 6′–OH Cinchona alkaloid (119) catalyzed asymmetric Henry reaction of nitromethane with isatin derivatives in very high yield (95–97%) and moderate to good enantioselectivity (71–92% ee).65c

2.1.9 Hydroxymethylation. Very recently, Zhou and co-workers have reported cupreidine catalyzed hydroxymethylation of α-substituted nitroacetates (121) (Scheme 36).66 The corresponding products (123) were isolated in good yield (72–89%) and low to moderate enantioselectivity (25–64% ee) form hydroxymethylation of aryl and alkyl nitroesters with paraformaldehyde (122).
Hydroxymethylation of α-substituted nitroacetates (121).
Scheme 36 Hydroxymethylation of α-substituted nitroacetates (121).

2.2 Carbon-hetero-atom bond formation

2.2.1 Carbon-nitrogen bond formation.
2.2.1.1 Aminaton reaction. Jørgensen and co-workers have reported highly enantioselective organocatalytic amination of α-substituted α-cyanoacetate (64) with di-tert-butyl azodicarboxylate (124) catalyzed by β-ICPD to yield aminated product (125) with quaternary stereocenter (Scheme 37).67 The diverse range of variation in the nucleophile provided (125) in excellent yield (84–99%) and enantioselectivity (91–98% ee) with remarkably low catalyst loading (0.1–5 mol%). β-ICPD also catalyzes the amination of open chain as well as cyclic β-ketoesters and β-diketones with di-tert-butyl azodicarboxylate (DTAD) to provide the aminated adducts (126) and (127) with high yield (90–99%) and enantioselectivity (83–90% ee).
6′–OH Cinchona alkaloids catalyzed asymmetric amination reaction.
Scheme 37 6′–OH Cinchona alkaloids catalyzed asymmetric amination reaction.

In 2005, Deng et al. have used BnCPD or BnCPN to obtain both enantiomers of the aminated product (128) in high yield (72–99%) and moderate to high enantioselectivity (23–99% ee) by asymmetric amination of α-aromatic substituted α-cyanoacetate (64) with tert-butyl/benzyl azodicarboxylate (124) (Scheme 37).68a The aliphatic α-cyanoacetate resulted in low enantiomeric excess. Later in 2009, Deng's group established a highly enantioselective amination of acyclic α-alkyl β-keto thioesters and trifluoroethyl α-methyl α-cyanoacetate with as low as 0.05 mol% of BnCPN or BnCPD.68b The corresponding aminated products were isolated in 91–99% yield and 81–90% ee.

Jørgensen and co-workers have reported an elegant protocol for the asymmetric catalytic Friedel–Crafts amination of 8-amino 2-naphthol (129) with azodicarboxylate (124) using 20 mol% demethylated quinine (131) catalyst in excellent yield (87–98%) and enantioselectivity (94–98% ee) (Scheme 38).69a The authors have envisioned that cupreidine and cupreine might themselves be substrates for this reaction.69b Although cupreidines do not undergo reaction with DTAD (124) under the optimized conditions, but they could be efficiently aminated at the C′–5 position simply by changing solvent and temperature. Remarkably, the resulting compounds (132) and (133) were shown to be even better catalysts for the amination of aminonaphthols. C5–Aminated cupreidines were also shown to promote enantioselective Michael addition of cyclic β-ketoesters to acrolein and methyl vinyl ketones with good enantiomeric excess, although with no real advantage over the parent catalysts.


Asymmetric amination of amino-naphthol catalyzed by 6′–OH Cinchona alkaloids.
Scheme 38 Asymmetric amination of amino-naphthol catalyzed by 6′–OH Cinchona alkaloids.

Very recently, Shi and co-workers have disclosed 6′–OH Cinchona alkaloid catalyzed biomimetic transamination of α-ketoesters (95) using benzylamines derivatives (Scheme 39).70 With 10 mol% of catalyst (135) a wide variety of α-amino esters (134) containing various functional groups have been synthesized in high enantioselectivity (88–92% ee) and reasonable yield (47–71%).


Enantioselective transamination of α-ketoesters (95).
Scheme 39 Enantioselective transamination of α-ketoesters (95).

2.2.1.2 aza-Michael reaction. The asymmetric organocatalytic addition of amine to unsaturated acceptors i.e. the aza-Michael reaction is a convenient method for the synthesis of chiral amine derivatives.71 The application of cupreine for the asymmetric aza-Michael reaction of nitrogen heterocycles to nitro-olefins (39) was explored by Wang and co-workers (Scheme 40).72CPN catalyzes the conjugate addition of benzotriazole (136) from N1 to aromatic, heteroaromatic and aliphatic nitro-olefins (39) in moderate to good yield (64–90%) and moderate to high enantioselectivity (57–94% ee). The conjugate addition of other N–heterocycles such as 1H–[1,2,3]triazole and 5-phenyl-1H-tetrazole to the nitro-olefin took place with moderate yield (65% and 76%, respectively) and with good enantioselectivity (84% and 85%, respectively).

                CPN catalyzed enantioselective aza-Michael reaction of benzotriazole with nitroalkenes.
Scheme 40 CPN catalyzed enantioselective aza-Michael reaction of benzotriazole with nitroalkenes.

2.2.1.3 N-Nitroso-aldol reaction. Chen and co-workers have reported an organocatalytic asymmetric N-nitroso-aldol reaction of 2-oxindoles (35) with nitrosobenzene (139) catalyzed by CPN (Scheme 41).73 The corresponding products (140) having a quaternary stereocenter were obtained in good to excellent yield (71–100%) and moderate enantioselectivity (59–72% ee).
Asymmetric N-nitroso-aldol reaction catalyzed by CPN.
Scheme 41 Asymmetric N-nitroso-aldol reaction catalyzed by CPN.
2.2.2 Carbonoxygen bond formation. The oxa-Michael reaction, once seldom used in the organic synthesis laboratory, has turned into a useful synthetic tool over recent years.74 The first application of 6′–OH Cinchona alkaloids for the synthesis of chiral tertiary alcohols has been reported by Taylor.75 The hydroxylated quaternary stereocenters were obtained in moderate enantioselectivity by CPD catalyzed reaction of cyclic β-ketoesters with tert-butyl hydroperoxide.

Zhao et al. reported asymmetric synthesis of fluorinated flavanone (142) by an organocatalytic intramolecular oxa-Michael addition of phenol to chalcone followed by base mediated electrophilic fluorination with N-fluorobenzenesulfonimide (NFSI) (Scheme 41).76 The quinidine derived catalyst (143) catalyzes the intramolecular tandem reaction of substituted alkylidene β-ketoesters (141) in good to excellent yield (56–99%) and moderate to high enantioselectivity (17–96% ee) of single diastereomer. In the proposed transition state (144) bifunctional catalyst simultaneously activate the oxygen nucleophile with tertiary amine assisting its deprotonation, while 6′–OH activate the two carbonyl oxygen in unsaturated part of the substrate by hydrogen bonding, thus facilitating the re-face attack to generate the (R) enantiomer.

Recently, the same research group have reported an intramolecular oxa-Michael addition/decarboxylation reaction (Scheme 42).77 The alkylidene β-ketoesters (141) undergoes oxa-Michael addition in the presence of BnCPD, followed by an acid mediated decarboxylation reaction to provide an easy access to a series of chiral flavanone derivatives (145) with moderate to good enantioselectivity (60–90% ee) and good to high yield (85–97%). A simple extension of this work to synthesize flavanones (146) with varied functionalities, the base catalyzed electrophilic cascade reaction was successfully performed using electrophiles such as methyl vinyl ketone (MVK), Nbromosuccinimide (NBS) and Nchlorosuccinimide (NCS).


6′–OH Cinchona alkaloids catalyzed synthesis of chiral flavanone derivatives involving the oxa-Michael addition as key step.
Scheme 42 6′–OH Cinchona alkaloids catalyzed synthesis of chiral flavanone derivatives involving the oxa-Michael addition as key step.

Xiao and co-workers have developed asymmetric organocatalytic conjugate addition of oximes (147) to trisubstituted β-nitroacrylate (148) (Scheme 43).78 The 6′–OH Cinchona alkaloids derived from quinine (151) and quinidine (150) provide the adduct (149) in good to high yield (91–98%) and moderate to high enantioselectivity (61–93% ee). The formation of (S) enantiomer of the product from quinidine derived catalyst was elucidated by the formation of ternary complex in the transition state (152) involving oxime, β-nitroacrylate and the catalyst. The 6′–OH group of the catalyst act as hydrogen bond donor that activate the nitroalkene and the tertiary amine activates and orients the nucleophilic attack of oxime on the si-face of the β-nitroacrylate rather than re-face attack. The later attack seems to be disfavoured due to steric reasons.


Asymmetric synthesis of protected tertiary alcohol (149) via 6′–OH Cinchona alkaloids catalyzed oxa-Michael reaction.
Scheme 43 Asymmetric synthesis of protected tertiary alcohol (149) via 6′–OH Cinchona alkaloids catalyzed oxa-Michael reaction.
2.2.3 Carbonsulfur bond formation. Zhao and co-workers have reported the enantioselective synthesis of 2,3,4-trisubstituted thiochromones (154) via 6′–OH Cinchona alkaloids catalyzed asymmetric tandem sulfa-Michael–Henry reaction (Scheme 44).79CPN catalyzes the synthesis of 154 from substituted 2-mercaptobenzaldehydes (153) and various aromatic nitro-olefins (39) in high yield (84–97%), acceptable diastereoselectivity (65[thin space (1/6-em)]:[thin space (1/6-em)]35–77[thin space (1/6-em)]:[thin space (1/6-em)]23 dr) and good enantioselectivity (72–86% ee). The thiochromone derivatives with high diastereoselectivity (87[thin space (1/6-em)]:[thin space (1/6-em)]13–9[thin space (1/6-em)]:[thin space (1/6-em)]1 dr) and enantioselectivity (85–99% ee) were obtained, after single crystalization. In the proposed transition state (155), CPN acts as a bifunctional catalyst which activates the nitro-group of nitroalkene with 9–OH and 6′–OH group and the tertiary amine of the catalyst activates the sulfur nucleophile for the re-face attack.

              CPN catalyzed tamdem sulfa-Michael–Henry reaction.
Scheme 44 CPN catalyzed tamdem sulfa-Michael–Henry reaction.

Very recently, Melchiorre and co-workers have developed diastereodivergent asymmetric sulfa-Michael additions to α-branched enones using a single organocatalyst, by applying an external chemical stimulus (Scheme 45).80a The quinidine derived organocatalyst (159) bearing primary-tertiary amine and phenolic moiety and 2-flourobenzoic acid as additive catalyzes the Michael addition of various aliphatic sulfur nucleophiles (157) to the various α-branched enones (156) to provide the major syn diastereomer of Michael adducts (158) in moderate to good yield (40–79%), good to high enantioselectivity (61–90% ee) and good diastereoselectivity (syn:anti 2.8[thin space (1/6-em)]:[thin space (1/6-em)]1–9.3:1dr). The anti Michael adducts (158′) were obtained in moderate to good yield (43–80%), high enantioselectivity (83–99% ee) and good diastereoselectivity (anti:syn 2.0[thin space (1/6-em)]:[thin space (1/6-em)]1–7.2[thin space (1/6-em)]:[thin space (1/6-em)]1 dr) using phosphoric acid (160) or diphenyl phosphoric acid (DPP) as additive. The cooperative catalytic system of (159) and (160) has also been used for direct asymmetric γ-alkylation of α-branched enals.80b


Diastereodivergent asymmetric sulfa-Michael additions to α-branched enones.
Scheme 45 Diastereodivergent asymmetric sulfa-Michael additions to α-branched enones.

2.3 Cycloaddition reaction

Deng and co-workers developed the asymmetric Diels–Alder reaction of pyrones (156) with various unsaturated dienophiles catalyzed by bifunctional 6′–OH Cinchona alkaloids, The catalysts simultaneously raised the energy of the HOMO of the diene and lowered the energy of the LUMO of the dienophile (Scheme 46).81 The 6′–OH Cinchona alkaloid catalysts (164) or (165) catalyzes synthesis of [4 + 2] adduct (163) with adjacent quaternary chiral carbon in good to high yield (63–100%) and stereoselectivity (82–94% ee and 85[thin space (1/6-em)]:[thin space (1/6-em)]15–95[thin space (1/6-em)]:[thin space (1/6-em)]5 dr), by the reaction of pyrone derivatives (161) with unsaturated ester/ketones (162). The catalyst (164) and (165) catalyzes the reaction of pyrone with α-chloroacrylonitrile (79) to provide the cycloaddition product in high yield (85% and 90%, respectively) and good stereoselectivity (85% and 75% ee; 87[thin space (1/6-em)]:[thin space (1/6-em)]13 and 78[thin space (1/6-em)]:[thin space (1/6-em)]22 exo:endo, respectively).
Asymmetric organocatalytic Diels–Alder reaction catalyzed by 6′–OH Cinchona alkaloids.
Scheme 46 Asymmetric organocatalytic Diels–Alder reaction catalyzed by 6′–OH Cinchona alkaloids.

Very recently, Deng and co-workers have developed a new series of bifunctional 6′–OH Cinchona alkaloids bearing bulky silylated groups at C9, for the first asymmetric [4 + 2] cycloaddition reaction between 2-pyrones (161) and aliphatic nitroalkenes (39) (Scheme 47).82 The corresponding endo-[2.2.2] bicyclic adducts (166) were obtained in good yield (56–86%) with excellent diastereo- and enantioselectivity (95–98% ee) using 167 as the catalyst. On the basis of a carbon kinetic isotope effect study, it was proved that the reaction did not occur through a concerted pathway, but instead involves a stepwise pathway.


Asymmetric [4 + 2] cycloaddition reaction of 2-pyrones (156) with aliphatic nitroalkenes (39).
Scheme 47 Asymmetric [4 + 2] cycloaddition reaction of 2-pyrones (156) with aliphatic nitroalkenes (39).

Chen and co-workers have reported the first organocatalytic enantioselective 1,3-dipolar cycloaddition of cyclic enones (168) and azomethine imines (169), by using multi-functional primary amine catalysts (159) or (171) derived from Cinchona alkaloids (Scheme 48).83 A wide range of cycloaddition products (170) have been synthesized in good to excellent yield and with excellent stereoselectivity by using 10 mol% of catalyst and 2,4,6-triisopropylbenzenesulfonic acid as acid additive in THF. The phenolic OH at the C′–6 position provide an additional site for hydrogen bonding interaction of catalyst and 1,3-dipole to introduce high stereocontrol (85–95% ee, >99[thin space (1/6-em)]:[thin space (1/6-em)]1 dr). In plausible transition state (172), the ketiminium cation adopt trans conformation between catalyst and enone. The aromatic OH activates ketiminium cation with hydrogen bonding and the steric hindrance exerted by the ion pair of the tertiary amine moiety enforce endo- and re-face selectivity to give the desired cycloaddition product.


Organocatalytic enantioselective 1,3-dipolar cycloaddition reaction.
Scheme 48 Organocatalytic enantioselective 1,3-dipolar cycloaddition reaction.

Gong and co-workers have developed elegant asymmetric [3 + 2] cycloaddition reaction of isocyanoesters (173) to nitroolefins (39) and aldehydes (5) leading to the formation of highly substituted 2,3-dihydropyrrole (174) and 2-oxazoline (175) derivatives, respectively (Scheme 49).84–85 The C9 benzoyl ester of cupreine and cupreidine (BzCPN and BzCPD) efficiently catalyzes the cycloaddition of aryl or benzyl isocyanoacetate (169) with aryl, heteroaryl as well alkyl nitroalkenes (39) giving access to various dihydropyrrole derivatives (174) in moderate to high yield (52–99%) and excellent stereoselectivity (90–99% ee and 4[thin space (1/6-em)]:[thin space (1/6-em)]1–20[thin space (1/6-em)]:[thin space (1/6-em)]1 dr).84 The C9 α-naphthyl ester of cupreine (α-C7H10COCPN) catalyzes the asymmetric synthesis of oxazolines (175) via [3 + 2] cycloaddition of (173) with various aromatic, heteroaromatic and aliphatic aldehydes (5) in moderate to good yield (18–95%) and with moderate to high stereoselectivity (31–90% ee, 1[thin space (1/6-em)]:[thin space (1/6-em)]1–18[thin space (1/6-em)]:[thin space (1/6-em)]1 dr).85 The reaction mechanism seems to involve the initial tertiary amine catalyzed Michael addition of isocyanoester to nitro-olefin or aldol type addition to aldehyde, which is activated and positioned by the 6′–OH of the catalyst.


[3 + 2] cycloaddition reaction of isocyanoesters catalyzed by 6′–OH Cinchona alkaloids.
Scheme 49 [3 + 2] cycloaddition reaction of isocyanoesters catalyzed by 6′–OH Cinchona alkaloids.

Recently, Cai and co-workers reported a highly enantioselective [4 + 2] cycloaddition reaction of β,γ-unsaturated α-keto esters (162) with oxazolones (176) catalyzed by 6′–OH Cinchona alkaloid (Scheme 50).86 Using 20 mol% of α-C7H10COCPN, a series of highly functionalized δ-lactones (177) with vicinal quaternary and tertiary stereocenters have been synthesized in high yield (44–96%) and moderate to excellent enantioselectivity (20–97% ee).


Enantioselective [4 + 2] cycloaddition reaction of β,γ-unsaturated α-keto esters (157) with oxazolones (174).
Scheme 50 Enantioselective [4 + 2] cycloaddition reaction of β,γ-unsaturated α-keto esters (157) with oxazolones (174).

In 2001, Romo and co-workers have developed an elegant procedure for an intramolecular ketene-aldehyde formal [2 + 2] cycloaddition for the synthesis of bicyclic cis-lactones (178) catalyzed by O–acetylquinidine (Scheme 51).87 With β-ICPD complete reversal of asymmetric induction with identical level of stereoinduction was observed.


Asymmetric intramolecular ketene-aldehyde formal [2 + 2] cycloaddition.
Scheme 51 Asymmetric intramolecular ketene-aldehyde formal [2 + 2] cycloaddition.

2.4 Rearrangement

Toste and co-workers utilized the catalytic potential 6′–OH Cinchona alkaloids for the synthesis of γ-hydroxyenones (180) via Kornblum DeLaMare rearrangement (Scheme 52).88AcCPN and AcCPD catalyzes the enantioselective desymmetrization of various substituted bicyclic endoperoxides (179) to γ-hydroxyenones (180) in good to excellent yield (76–99%) and moderate to excellent enantioselectivity (50–99% ee). On the basis of their experimental observation they proposed a transition state (181) in which quinuclidine N and 6′–OH group of the catalyst interact with the endoperoxide via hydrogen bonding, in such a manner that the alkene gets positioned in the sterically demanding pocket covered by the quinoline ring.
Asymmetric synthesis of γ-hydroxyenones (180) via Kornblum DeLaMare rearrangement.
Scheme 52 Asymmetric synthesis of γ-hydroxyenones (180) via Kornblum DeLaMare rearrangement.

Tu and co-workers developed catalytic enantioselective vinylogous α-ketol rearrangement of vinylogous α-hydroxy enones (182) by the application of iminium ion catalysis affording spirocyclic ketones (183) with an all-carbon stereogenic centre (Scheme 53).89 The N-Boc-L-phenylglycine salt of 6′–OH Cinchona alkaloid derived 9-amino (171) catalyzes semipinacol-type 1,2-carbon sigmatropic migration that converts cyclobutanol moiety into a cyclopentanone with good to high yield (57–95%) and moderate to high enantioselectivity (48–97% ee) and high diastereoselectivity (2.3[thin space (1/6-em)]:[thin space (1/6-em)]1–29[thin space (1/6-em)]:[thin space (1/6-em)]1% dr).


Asymmetric semipinacol-type 1,2-carbon sigmatropic migration catalyzed by 6′–OH Cinchona alkaloids.
Scheme 53 Asymmetric semipinacol-type 1,2-carbon sigmatropic migration catalyzed by 6′–OH Cinchona alkaloids.

2.5 Oxaziridination

Jørgensen and co-workers have developed the first catalytic enantioselective oxaziridination reaction of N-tosyl imines (23) catalyzed by 6′–OH Cinchona alkaloid (Scheme 54).90 The oxidation of aryl and alkyl aldimines with m-CPBA in the presence of cupreidine derivative (164), to provide the optically active oxaziridine (184) in good yield (50–97%) and moderated to high enantioselectivity (46–94% ee).
Asymmetric oxaziridination of N-tosyl imines.
Scheme 54 Asymmetric oxaziridination of N-tosyl imines.

2.6 Isomerization

Recently, Deng and co-workers have developed an unprecedented and general method for enantioselective olefin isomerization via biomimetic proton transfer catalysis with a new 6′–OH Cinchona alkaloid organocatalyst (187) (Scheme 55).91 A broad range of mono- and disubstituted β,γ-unsaturated butenolides (185) were transformed into the corresponding chiral α,β-unsaturated butenolides (186) in good to high yield (56–95%) and good enantioselectivity (81–94% ee) using as low as 0.1 mol% of catalyst.
Enantioselective isomerisation of disubstituted β,γ-unsaturated butenolides (185).
Scheme 55 Enantioselective isomerisation of disubstituted β,γ-unsaturated butenolides (185).

2.7 Dynamic kinetic resolution (DKR)

Very recently, Connon and co-workers have developed a new library of Cinchona alkaloids derived bifunctional organocatalyst bearing phenolic moiety at the C9 position (Scheme 56).92 The newly developed organocatalyst (189) catalyzes the DKR of azlactone (172) to provide (188) with good to excellent yield (91–96%) and high enantioselectivity (83–100% ee).
Asymmetric DKR of azlactone (172) catalyzed with (189).
Scheme 56 Asymmetric DKR of azlactone (172) catalyzed with (189).

3. BINOL derivatives

The enantiomeric atropisomers of 1,1′-binaphthyl-2,2′-diol (BINOL) are the best-known representatives of axially chiral molecules, that are widely used for both stoichiometric and catalytic asymmetric reactions.93 In recent years, BINOL and its derivatives have been shown to be a powerful organocatalyst for a wide variety of organic transformations.

3.1 BINOL derived organocatalysts bearing aromatic hydroxyl and tertiary phosphino groups

The catalytic potential of the bifunctional organocatalysts bearing tertiary phosphine in cooperation with aromatic OH groups derived BINOL are being discussed in this section.
3.1.1 aza-Morita Baylis–Hillman reaction. In 2003, Shi and Chen utilized the bifunctional chiral monodentate phosphine catalyst (192) derived from BINOL, for the asymmetric aza-MBH reaction of methyl vinyl ketone and phenyl acrylate with N-tosylimines (23) (Scheme 57).94 The corresponding aza-MBH product (191) was isolated in moderate to high yield (49–99%) and enantioselectivity (52–95% ee). It was shown that aromatic –OH group is important for achieving high yield and high enantiomeric excess, since the protection of –OH led to much lower yield and ee of the adduct. The bifunctional mode of catalysis by (192) for aza-MBH reaction was also demonstrated through the 1H and 31P NMR spectroscopic tracing experiments, which strongly suggested the involvement of intramolecular hydrogen bonding between the aromatic hydroxyl group and the oxygen atom of the carbonyl group. On the basis of these observations, a mechanism was proposed, involving the initiation of the reaction by a phosphorous center, acting as a Lewis base to generate (193). The phenolic –OH group acts as a Brønsted acid which stabilizes the key enolate intermediates (194) and (195) through hydrogen bonding. The enolate intermediate (194) being most favorable for subsequent proton transfer and β-elimination, leads to the desirable enantiopure adduct (191).
Asymmetric aza-MBH reaction catalyzed by (192).
Scheme 57 Asymmetric aza-MBH reaction catalyzed by (192).

Shi and co-workers have demonstrated the application of dimethyl phosphine catalyst (198) with enhanced nucleophilicity at a phosphorous centre for catalyzing aza-MBH reaction of less reactive substrate such as 2-cyclopenten-1-one (196) and 2-cyclohexene-1-one with N-tosyl imines (23) (Scheme 58).94b The aza-MBH adducts (197) in good to high yield and moderate enantioselectivity were obtained with 10 mol% of the catalyst (198).


Asymmetric aza-MBH reaction of cyclic enones (196).
Scheme 58 Asymmetric aza-MBH reaction of cyclic enones (196).

After the successful establishment of this nucleophilicity effect Shi and co-workers synthesized a new series of bifunctional catalysts (199) having aromatic hydroxyl group and alkylated phosphine moiety in order to effect the nucleophilicity and the steric hindrance at Lewis base site of the catalyst.95 The catalyst bearing butyl chain efficiently catalyzes the aza-MBH reaction of MVK with N-tosyl imines in short duration with high yield (80–96%) and moderate to high enantioselectivity (44–88% ee) (Fig. 4).


BINOL derived bifunctional organocatalysts for asymmetric aza-MBH reaction.
Fig. 4 BINOL derived bifunctional organocatalysts for asymmetric aza-MBH reaction.

The more efficient catalyst bearing long perfluoroalkane chains so called ‘pony tail’ at the naphthalene framework of the chiral phosphine catalysts (200) and (201) catalyzes aza-MBH reaction of N-tosyl imines with MVK giving aza-MBH adduct in good yield (53–98%) and moderate to high enantioselectivity (52–95% ee).96

Working on the hypothesis that the presence of multiple phenolic groups on the catalyst can stabilize the phosphonium enolate of aza-MBH reaction via hydrogen bonding, Shi and co-workers synthesized chiral phosphine catalyst (202) bearing three phenolic groups.97 This multiple phenolic catalyst, catalyzes aza-MBH reaction of MVK, ethyl vinyl ketone or acrolein with N-sulfonyl imines with good to high yield (67–97%) and enantio-induction (72–99% ee).

Sasai and co-workers have developed new organocatalysts by functionalizing the 3-position of BINOL with a series of aryl phosphines.98 10 mol% of catalyst (203) was found to catalyze the aza-MBH reaction of substituted aromatic and heteroaromatic N-tosyl imines with alkyl and phenyl vinyl ketone in good to quantitative yield (85–99%) and good to high enantioselectivity (82–95% ee).

In 2007, Ito et al. developed biphenol based bifunctional catalyst (204) for aza-MBH reaction of MVK with various N-tosyl imines.99 Remarkably, low catalyst loading of 1 mol% provides the aza-MBH adducts in good to excellent yield (84–100%) and high enantioselectivity (87–96% ee).

Shi and Liu developed a more efficient dendrimer immobilized bifunctional catalyst (205) for aza-MBH reaction of N-sulfonyl imine with vinyl ketone or acrolein.100 The catalyst could be easily separated by simple filtration and recycled without much loss in the catalytic activity.

The application of asymmetric counterion directed organocatalysis for aza-MBH reactions was explored by Liu and co-workers using new trifunctional organocatalyst (206).101 The protonation of Brønsted base part of catalyst with benzoic acid switches the activity of the catalyst, thus catalyzing the aza-MBH reactions between electron-deficient or electron rich aromatic N-tosyl imines and MVK at ambient temperature in short duration in moderate to high yield (26–99%) and good to high enantioselectivity (76–97% ee).

Shi and Zhao found that catalyst (192) could not give good enantiomeric excess in the reaction of N-arylmethylidenediphenylphosphinamides (26) with activated alkenes such as MVK, acrylonitrile, or phenyl acrylate.102 However, later in 2007, they developed bifunctional chiral phosphine Lewis base catalyzed asymmetric aza-MBH reaction of ethyl (arylimino)acetates (207) with α,β-unsaturated ketones (Scheme 59).103 10 mol% bifunctional catalyst (192) in the presence of 4 Å molecular sieves (MS) additive, catalyzes the aza-MBH reaction of (207) with MVK or EVK providing corresponding adducts (208) in moderate to good yield (53–99%) and enantioselectivity (66–97% ee).


Asymmetric aza-MBH reaction ethyl (arylimino)acetates (207) with α,β-unsaturated ketones.
Scheme 59 Asymmetric aza-MBH reaction ethyl (arylimino)acetates (207) with α,β-unsaturated ketones.

Recently, Sasai and co-workers have reported first domnio process involving aza-MBH/intramolecular aza-Michael reaction of electron deficient alkenes and N-tosyl imines (209) catalyzed by (192) (Scheme 60).104 The corresponding cis 1,3-disubstituted isoindolin (210) were obtained in good to excellent yield (49–97%) with high diastereo- and enantioselectivity (63–93% ee).


Asymmetric organocatalytic aza-MBH/intramolecular aza-Michael reaction.
Scheme 60 Asymmetric organocatalytic aza-MBH/intramolecular aza-Michael reaction.
3.1.2 Morita–Baylis–Hillman reaction. Shi and co-workers have explored the application of multiphenolic phosphine organocatalyst (202) for asymmetric MBH reaction (Scheme 61).105 The MBH adducts (211) from MVK and aromatic aldehydes (5) were obtained in low to good yield (16–71%) and poor enantioselectivity (4–39% ee). The methyl protection of two phenolic groups at the second binaphthalene moiety resulted in failure of the reaction under optimum conditions, which led them to conclude that the phenolic group plays a very important role in acceleration of reaction rate. The catalyst (212) bearing phenyl and n-butyl group at phosphorous provide MBH adduct (211) in good yield (65–86%) and moderate enantioselectivity (29–55% ee) in relatively less time.106
Asymmetric MBH reaction of unsaturated ketones with aldehydes.
Scheme 61 Asymmetric MBH reaction of unsaturated ketones with aldehydes.

3.2 BINOL derived organocatalysts bearing aromatic hydroxyl and tertiary amino group

3.2.1 aza-Morita–Baylis–Hillman reaction. In 2005 Sasai and co-workers developed a novel bifunctional organocatalyst (S)-3-(N-isopropyl-N-3-pyridinylaminomethyl)BINOL (213) bearing aromatic hydroxyl group and a tertiary amine moiety, for the highly enantioselective aza-MBH reaction (Scheme 62).107 The catalyst (213), catalyzes the aza-MBH reaction of unsaturated ketones or unsaturated aldehydes with N-tosyl aldimine (23) to provide the aza-MBH product (191) in excellent yield (88–99%) and moderate to high enantioselectivity (58–95% ee). The catalytic role of two aromatic hydroxyl groups and the basic moiety of the catalysts was demonstrated on the basis of several experiments performed by designing some new chiral catalysts (214217). The failure of these catalysts for enantio-induction and product yield showed that one acid–base pair in the catalyst fixes the conformation of organocatalyst, the other acid–base unit appears to activate the substrate with high enantiocontrol.
(S)-3-(N-isopropyl-N-3-pyridinylaminomethyl)BINOL (213) catalyzed asymmetric aza-MBH reaction.
Scheme 62 (S)-3-(N-isopropyl-N-3-pyridinylaminomethyl)BINOL (213) catalyzed asymmetric aza-MBH reaction.

Later on, in 2010, they developed two new bifunctional catalysts (219) and (220) bearing phenolic hydroxyl groups and imidazole unit (Scheme 63).108 Both the catalyst catalyzes the aza-MBH reaction of nitroalkenes (39) with N-tosyl imines (23) to afford the MBH adduct (218) in low to good yield (14–98%) and low to moderate enantioselectivity (21–57% ee).


Asymmetric organocatalytic aza-MBH reaction of nitroalkenes (39) with N-tosyl imines (23).
Scheme 63 Asymmetric organocatalytic aza-MBH reaction of nitroalkenes (39) with N-tosyl imines (23).
3.2.2 Morita–Baylis–Hillman reaction. Sasai et al. have reported the asymmetric synthesis of tetrahydropyridine derivatives (221) domino process involving aza-MBH/aza-Michael/aldol/dehydration sequence between acrylaldehyde and N-tosyl imines (23) (Scheme 64).109 The corresponding cyclized products (221) were isolated in moderate yield (40–60%) and good to high enantioselectivity (75–88% ee) using 20 mol% of (192). With MVK the tetrahydropyridine adduct (222) have been synthesized in two step domino-sequence involving the initial aza-MBH reaction of MVK with (23) followed by DBU catalyzed reaction of acrylaldehyde with corresponding aza-MBH adduct that follows the aza-Michael/aldol/dehydration sequence.
Asymmetric organocatalytic aza-MBH/aza-Michael/aldol/dehydration reaction.
Scheme 64 Asymmetric organocatalytic aza-MBH/aza-Michael/aldol/dehydration reaction.

Very recently, Chen and co-workers have reported asymmetric variant of cross-Rauhut–Currier/Michael/aldol condensation triple domino reaction between acrylaldehyde and alkene (223) catalyzed by (192) (Scheme 65). The adduct (224) was obtained in 35% yield and 32% and 4% ee with cis-selectivity.110


Cross-Rauhut–Currier/Michael/aldol condensation triple domino reaction.
Scheme 65 Cross-Rauhut–Currier/Michael/aldol condensation triple domino reaction.

4. Miscellaneous organocatalysts

Sasai and coworkers have developed a unique spiro-type organocatalyst (225) bearing an aromatic hydroxyl group and phosphine as Brønsted acid and Lewis base unit (Scheme 66).111 This newly synthesized bifunctional organocatalyst catalyzes the aza-Morita–Baylis–Hillman reactions of unsaturated ketones with N-tosyl imines (23) in good to high yield (72–99%) and enantioselectivity (85–98% ee). Interestingly, spiro-type organocatalyst (225) provides aza-MBH adduct (191) with an enantioselectivity higher than those achieved using a BINOL derived catalyst (192). The spiro organocatalyst was assumed to provide a geometrically distinct and more rigid chiral pocket than its BINOL-derived counterpart. The rigid spiro catalyst backbone could reduce the conformational flexibility in the transition state for the catalyzed reaction resulting in the formation of the aza-MBH adducts with excellent enantioselectivity.
Asymmetric aza-MBH reaction catalyzed with (225).
Scheme 66 Asymmetric aza-MBH reaction catalyzed with (225).

A highly enantio- and diastereoselective direct vinylogous Mannich reaction of α,α-dicyanoolefins (74) and alkyl N-sulfonyl alkylimines (226) has been reported by Chen and co-workers (Scheme 67).112 A new family of bifunctional organocatalysts (228) have been developed by merging chiral BINOLs and 9-amino-9-deoxy-epi-Cinchona alkaloid skeletons for the asymmetric synthesis of chiral amino compounds (227) in good to high yield (58–98%) and moderate to high enantioselectivity (52–97% ee) and good diastereoselectivity (70[thin space (1/6-em)]:[thin space (1/6-em)]30–91[thin space (1/6-em)]:[thin space (1/6-em)]9 dr).


Vinylogous Mannich reaction catalyzed with (228).
Scheme 67 Vinylogous Mannich reaction catalyzed with (228).

Recently, Zhu, Cheng and co-workers have developed a new phenolic OH–primary amineimine organocatalyst (232), generated in situ from a chiral diamine (231) under acidic conditions (Scheme 68).113 This newly synthesized catalyst has been found to catalyze the direct asymmetric aldol reaction between ketones (229) and α-keto esters to afford aldol product (230) in high yield (65–88%) and with excellent enantioselectivity (87–97% ee).113a



          In situ generated aromatic OH–primary amine–imine catalyst (231) catalyzed asymmetric aldol and Michael reaction.
Scheme 68 In situ generated aromatic OH–primary amineimine catalyst (231) catalyzed asymmetric aldol and Michael reaction.

Further, in situ generated aromatic OH–primary amineimine catalyst (232) efficiently catalyze the enantioselective Michael addition reaction of substituted 4-hydroxycoumarin derivatives (233) with cyclic and acyclic enones (234) (Scheme 68).113b High yield (61–96%) and excellent enantioselectivity (88–97% ee) were achieved for a series of addition products (235) bearing a 4-hydroxycoumarin unit.

Irie and co-workers have developed an optically active tripodal amine (238), as a potent chiral catalyst for methanolytic asymmetric desymmetrization of cyclic meso-anhydrides (236) to hemiesters (237) (Scheme 69).114 Moderate to high yield (33–99%) and a good level of enantioselectivity (52–81% ee) were achieved for various cyclic anhydrides, some of which are considered as difficult substrates in the Cinchona alkaloid-mediated ring-opening.


Asymmetric desymmetrization of cyclic meso-anhydrides (236) catalyzed with (238).
Scheme 69 Asymmetric desymmetrization of cyclic meso-anhydrides (236) catalyzed with (238).

Conclusions

Since the origin of asymmetric organocatalysis, tremendous progress has been achieved in the development of new synthetic methodologies and new chiral organocatalysts. This review summarized the application of bifunctional organocatalysts bearing aromatic hydroxyl groups and tertiary amines/phosphines in asymmetric synthesis. The unique properties of these organocatalysts not only enable them to be broadly used in a wide spectrum of simple carboncarbon, carbon–hetero atom bond formations but also enable them as successful organocatalysts in more complex tandem, cascade and domino reactions as well as multicomponent asymmetric transformations. These chiral catalysts are mild and their pseudoenantiomeric catalysts can be easily obtained. The superior reactivity and stereoselectivity of these catalysts over other types of bifunctional organocatalysts have been observed in several cases. Considering the inherent structural advantages as well as increased interest in catalytic potential at the current stage, we believe that these bifunctional organocatalysts will give rise to more promising findings in the near future. Further, the mechanistic investigations could be beneficial for future development of new bifunctional organocatalysts having aromatic hydroxyl groups in cooperation with a basic unit.

Acknowledgements

Our research work was supported by the research project sanctioned to S. S. C. by the University Grant Commission (UGC), India. Financial support from the Department of Science and Technology (DST), India under FIST program and UGC, India, under CAS-I is gratefully acknowledged.

References

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