Chapter 14: Nonquaternised Cinchona Alkaloid Derivatives as Asymmetric Organocatalysts for Carbon–Carbon Bond-forming Reactions

Cinchona alkaloids, isolated from the bark of Cinchona trees, are amongst the most well-known natural products. Quinine, the prominent member of this family, was isolated from Cinchona tree bark by Pelletier and Caventou in 1820.¹  Early on it was recognised as an important antimalarial drug and afterwards it was employed for countless applications, ranging from a bitter additive in the food and beverage industries to use as resolving agent for racemates, disclosed by Pasteur in 1853.²  Nevertheless, the most interesting applications of Cinchona alkaloids in chemistry dwell in asymmetric catalytic synthesis,³  the first example having been the addition of hydrogen cyanide to benzaldehyde with low enantioselectivity (10% optical purity) published by Bredig and Fiske as early as 1912.⁴  In the 1960s, Pracejus⁵  achieved, for the first time, moderate levels of enantioselectivity by applying a quinine-derived catalyst to the addition of methanol to phenylmethyketene. A new age in asymmetric catalysis driven by Cinchona alkaloids was definitively unlocked in the late 1970s by Wynberg and coworkers⁶  through their extensive studies elucidating how the basic bridgehead nitrogen atom in the quinuclidine core can be used in Brønsted and Lewis-base catalysis. Since then, many examples of the catalytic activity and enantioselectivity of Cinchona alkaloids have been reported. The Cinchona alkaloids may also act as metal-ion ligands. Sharpless⁷  developed in the 1980s, the osmium(iv)-catalysed asymmetric dihydroxylation of olefins and for his research findings was awarded the Nobel Prize in Chemistry in 2001. The vigorous rise of organocatalysis in the 2000s has caused a second renaissance of Cinchona alkaloids as general catalysts, transforming them into a privileged organic scaffold for chirality induction in most major chemical reactions.

The four principal members of the Cinchona alkaloid family namely quinine (QN), quinidine (QD), cinchonine (CN) and cinchonidine (CD) are small but multifunctional molecules containing five stereogenic centres (N1, C3, C4, C8 and C9), a basic and nucleophilic quinuclidine bridgehead nitrogen atom, a quinoline unit, a secondary alcohol, an aryl methyl ether (in the case of QN and QD) and a terminal olefin (Figure 14.1). Cinchona alkaloids with a saturated ethyl appendage instead of the olefin are usually referred to as the dihydro or hydro versions (e.g. dihydroquinine, DHQN), and are sometimes contained in non-negligible amounts in commercial samples of Cinchona alkaloids (especially in QD and CN). The absolute configurations at N1, C3 and C4 are identical in all Cinchona alkaloids. The other stereocentres (C8 and C9) have opposite absolute configurations in QD and QN (and in CN and CD). Since these two stereocentres are usually responsible for the asymmetric induction, diastereomeric Cinchona alkaloids are defined as pairs of “pseudoenantiomers” (or “quasienantiomers”). Both pseudoenantiomeric couples of alkaloids are commercially available in bulk amounts at relatively low prices.

The presence of the 1,2-aminoalcohol structural motif (the highly basic bridgehead nitrogen atom and the secondary alcohol) is in fact primarily responsible for the metal complexation and for the catalytic activity involving hydrogen bonding/base bifunctional catalysis or nucleophilic catalysis. However, the multifunctional character of Cinchona alkaloids allows several strategies for catalyst design capable of providing tailored structures capable of activating more substrate classes (Figure 14.1). The ability to synthesise quaternary ammonium salts allows the accomplishment of asymmetric phase-transfer catalysis (PTC) (see Chapter 16).⁸  The derivatisation of the 9-hydroxy group enables the formation of C9-ethers and esters, or the introduction of a primary amino moiety with inversion of configuration at C9 through a Mitsunobu-type reaction. This latter modification not only makes possible enantioselective aminocatalysis with Cinchona alkaloids,⁹  but also enables the synthesis of (thio)ureas, amides, sulfonamides and squaramides.¹⁰  Manipulations at the heteroaromatic quinoline ring can also be exploited leading to catalytically useful structures. The 6′-O-demethylated form of QN and QD, cupreine (CPN) and cupreidine (CPD), that feature a phenolic OH group,¹¹  allow a diverse set of asymmetric transformations, utilising again two separated sites for simultaneous activation of both nucleophile and electrophile, but involving drastically different geometrical features compared to the parent alkaloid structures. Finally, the terminal olefin of the alkaloids has been broadly used as a handle for anchoring to heterogeneous supports.¹² 

Cinchona alkaloids are flexible molecules, and in solution exist as a mixture of several conformations:^3a,b  the four low-energy conformers of quinidine QD, identified already by Wynberg¹³  and interconvertible via rotation along both the C8–C9 and C9–C4′ bonds, are depicted in Figure 14.2. The ratio between the conformers depends on the polarity of the medium, on the protonation of the quinuclidinic nitrogen (which might occur during the reactions), and on the overall structure of the molecule in the case of synthetically modified Cinchona alkaloids. This flexibility can raise doubts about the conformation actually relevant to the catalytic process. Furthermore, the interactions between the alkaloid catalyst and the substrates are often of a noncovalent nature and thus geometrically poorly defined. As a result, the rationalisation of the stereochemical outcomes of Cinchona alkaloid-catalysed reactions is far from trivial in most cases.

This chapter highlights significant examples of enantioselective C–C bond-forming reactions catalysed by Cinchona alkaloids and their derivatives, excluding (thio)ureas and other double hydrogen-bond donors, and quaternary ammonium salts, which are treated in Chapters 16 and 19. Our selection, which is far from being exhaustive, is mostly restricted to classic named reactions. We considered that simple transformations with commodity chemicals would illustrate the tremendous potential of Cinchona alkaloid derivatives as catalysts, as well as the principles behind their catalytic activity and stereoselectivity. These principles have built the foundations for subsequent applications with more complex substrates and reaction settings. We have tried to represent in our collection all the different catalytic modes expressed by Cinchona alkaloid catalysts (i.e. general Brønsted base, bifunctional Brønsted base/Brønsted acid, nucleophilic Lewis base and enamine/iminium-ion catalysis). Furthermore, we have also selected some disclosures that are relevant to the present monograph for their sustainable features (low catalyst loadings, benign reaction media, etc.), and that demonstrate prospective applications. In this context, it must be stressed that Cinchona alkaloids are readily available natural (i.e. renewable) products, and thus are intrinsically very appealing for the realisation of truly sustainable catalytic processes.

Asymmetric conjugate addition reactions of nucleophiles to electron-deficient alkenes represent some of the most significant C–C bond-forming reactions and are a fundamental approach to the construction of densely functionalised products. Since the initial studies by Wynberg^6,14  in the late 1970s and early 1980s on Cinchona-catalysed conjugate addition reactions, numerous examples of these reactions in which these alkaloids induce asymmetry have been reported. Thanks to the rapid development of asymmetric organocatalysis, significant progress has been made in recent years in achieving organocatalytic asymmetric Michael reactions with a diverse combination of Michael donors and acceptors. As shown in the following selected examples, the synthetic elaboration of the Cinchona scaffold has often been the key to achieve optimal results.

In 2004, Deng and coworkers¹⁵  reported the first preparatively useful results for the organocatalytic asymmetric Michael additions of malonates to nitro-olefins, a synthetically important C–C bond-forming reaction employing readily available starting materials (Scheme 14.1). Readily accessible 6′-demethylated quinine/quinidine (CPN and CPD), served as effective promoters (10 mol%) for the asymmetric Michael addition of dimethyl malonate to a wide range of nitroalkenes bearing aryl, heteroaryl, and alkyl groups with varying electronic and steric properties, affording the corresponding adducts in good to excellent yields and with excellent enantioselectivities.

Shortly after, the same laboratory¹⁶  developed a highly enantioselective and diastereoselective catalytic conjugate addition of an exceptionally wide range of trisubstituted carbon nucleophiles (cyclic and acyclic β-ketoesters, 2-substituted 1,3-diketones, α-nitroesters and α-cyanoesters) to nitroalkenes mediated by related CPN and CPD derivatives (Scheme 14.2). This simple methodology allowed the efficient synthesis of important building blocks containing adjacent quaternary and tertiary stereocentres.

Importantly, in both protocols the employment of the two pseudoenantiomeric catalysts CPN and CPD provided access to both enantiomers of the products with similar results. Notably, the corresponding natural alkaloids, quinine QN and quinidine QD provided much lower reaction rates and enantioselectivities. The obtained results are consistent with the bifunctional nature of the catalyst since the phenolic OH group together with the quinuclidine nitrogen are responsible for the stabilisation and organisation of the transition state of these reactions. The authors discovered that β-isocupreidine (β-ICPD), a conformationally rigid analogue of CPD, furnished remarkably similar stereoselectivity profiles to those obtained using CPD, providing powerful evidence to support an anti-open active conformer for CPD in the transition state (Figure 14.3 left). The obtained stereochemical outcome can be rationalised with a transition-state model where the catalyst simultaneously activates and orients the Michael donor and the Michael acceptor through a network of hydrogen-bonding interactions (Figure 14.3 right).

Subsequent studies demonstrated that the asymmetric Michael addition of trisubstituted carbon nucleophiles promoted by 6′-demethylated Cinchona alkaloids (CPD, CPN, RO-CPD and RO-CPN) could be efficiently achieved using α,β-unsaturated sulfones,¹⁷  enones¹⁸  and enals¹⁹  as Michael acceptors in a highly enantioselective and diastereoselective fashion.

More recently, Wang and coworkers²⁰  reinvestigated the enantioselective Michael addition of malonates to nitroalkenes from a sustainable point of view, developing an attractive protocol in water at room temperature with only 1 mol% loading of sodium CPN salt (NaCPN) (Scheme 14.3). Moderate to good yields and enantioselectivities were obtained, and, most importantly, the catalyst could be easily recovered and reused: in the case of 5 mol% of catalyst loading this recycling could be repeated seven times without loss in enantioselectivity, while the yield slightly decreased. However, the protocol was only applied to aromatic nitroalkenes.

Two years later, the same authors²¹  studied the reactions previously developed by Deng and coworkers (Scheme 14.2) for the synthesis of quaternary and tertiary carbon centres through the Michael addition of trisubstituted carbon nucleophiles to nitroalkenes, performed under this new protocol (low loading NaCPN (1 mol%), in water, at room temperature). Yields and selectivities were moderate to excellent (41–92%, dr 2.5:1-12.9:1, ee 21–88%) and the protocol could be applied even on a large scale (0.8 mol).

Alternatively, to realise an easy recovery and reuse of the organocatalyst, Livingston and coworkers have recently proposed a polyalkylation of CPD to enlarge the catalyst, allowing its separation from lower molecular weight substrates and products through organic solvent nanofiltration (OSN) membranes.²²  The commercial availability of 1,3,5-tris(bromomethyl)benzene made it an attractive choice as an anchor for CPD (Scheme 14.4). This trimeric CPD catalyst was able to promote the addition of dimethyl malonate to various nitroalkenes in THF at −20 °C in good to excellent yields and enantioselectivities, and was highly retained by the OSN membrane (DuraMem^® 500). The authors reported that it was possible to recover the catalyst by diafiltration and to reuse it, confirming that the catalytic activity was preserved after the nanofiltration. As a result of the robustness and suitability for multiple reuses, the possibility of employment in a continuous process, was suggested. Thus, the use of membranes to retain the catalyst might render the high catalytic loadings typical of organocatalytic processes (10 mol%) economically feasible.

Ball-milling and pestle and mortar grinding have emerged as powerful methods for the development of environmentally benign chemical transformations. Recently, the use of these mechanochemical techniques in asymmetric organocatalysis has increased.²³  Chimni and coworkers²⁴  have reported an interesting application of grinding with pestle and mortar for highly stereoselective Michael addition of trisubstituted β-ketoesters to nitroalkenes. Grinding an equimolar quantity of cyclic β-ketoesters and various nitroalkenes, including nitrodienes, in the presence of 5 mol% of O-benzyl cupreine (BnO-CPN) provided the corresponding Michael adducts in good to high yields and stereoselectivities (Scheme 14.5). It was observed that the reaction proceeded much faster under grinding conditions, when compared with the reaction carried out under traditional stirring in toluene as solvent or under neat conditions. This was attributed to the fact that grinding facilitates the proper mixing of the catalyst and substrates and also provides additional mechanical pressure.

The conceptually different activation of carbonyl substrates through the formation of a nucleophilic enamine or an electrophilic iminium ion is achieved by use of 9-deoxy-epi-9-amino Cinchona catalysts. In contrast to typical secondary amine-based catalysts (i.e. derived from proline), the primary amine of these modified Cinchona alkaloids can combine also with sterically biased substrates, such as ketones and hindered aldehydes. This class of catalyst has thus allowed the scope of aminocatalysis to be extended beyond unhindered aldehydes/enals, and has proved to be remarkably powerful and general.

In the realm of enamine catalysis, the potential of these catalysts was disclosed by McCooey and Connon in 2007.²⁵  A combination of DHQDA and benzoic acid had a remarkable scope for the addition of carbonyl compounds to nitroalkenes, which could encompass for the first time a broad range of aldehydes, including α,α-disubstituted ones, and ketones (Scheme 14.6). Curiously, the facial selectivity at the nitroalkene prochiral face is opposite in the reactions with aldehydes and ketones, even if the same catalyst is used, indicating two drastically different enamine conformations are involved in the reactions.

At the same time, Chen and coworkers demonstrated that Cinchona-derived primary amines are efficient for iminium ion-type activation of enones, which were engaged in a vinylogous Michael reaction,²⁶  and a Friedel–Crafts-type addition of indoles (Scheme 14.7).²⁷  The latter reaction was also simultaneously reported by Melchiorre and coworkers (Scheme 14.7).²⁸  These two protocols for the conjugate Friedel–Crafts reaction differ not only in the catalyst and the solvent employed, but also in the acidic cocatalyst, wherein the chiral N-Boc protected α-phenylglycine with matching d-absolute configuration proposed by Melchiorre seems to provide better stereoselectivities. More recently, the stereochemical outcome and the key role exerted by acidic cocatalysts in these Friedel–Crafts-type reactions were rationalised with a combined experimental and computational approach.²⁹  Two molecules of acidic cocatalyst (TFA) are present in the proposed transition state, sketched in Scheme 14.7, wherein they play multiple roles: a first molecule of acid protonates the quinuclidinic nitrogen providing steric hindrance; the second molecule protonates the imine, giving the reactive iminium ion, and at the same time coordinates the indole N–H, stabilising the positive charge of the indole core. Overall, a highly ordered supramolecular complex, assembled by a combination of covalent and noncovalent interactions, is formed, accounting for the observed stereoselectivity. It is worth mentioning that a distinct transition state model, involving a single molecule of acidic cocatalyst, has been determined by List and coworkers for the peroxidation and epoxidation of enones catalysed by the same Cinchona-derived amine catalysts.³⁰ 

These reports triggered a considerable exploration and exploitation of Cinchona amine catalysts for a variety of enamine and iminium ion mediated reactions.⁹  Regarding C–C bond formation through a conjugate addition reaction, it is worth mentioning two examples of 1,4-additions to enones: the addition of coumarins and related derivatives, developed by Chen and coworkers,³¹  which leads to pharmaceutically relevant compounds such as warfarin, and the synthetically important addition of nitroalkanes to the same Michael acceptors, reported more recently by Wang, Duan and coworkers (Scheme 14.8).³² 

As exemplified by the reactions highlighted in this subsection, one of the drawbacks of 9-deoxy-epi-9-amino Cinchona catalysts is their generally low catalytic proficiency. These structures are in general even less active than secondary amines, such as proline derivatives, for a number of reasons such as lower nucleophilicity, less effective iminium-ion stabilisation, and unfavourable imine–enamine equilibrium. As a consequence, these catalysts usually display low turnover numbers and frequencies (requiring high catalyst loadings, typically 10–30 mol%, and reaction times of several days are needed), and poor performance with substrates featuring low reactivity, such as β,β-disubstituted enones. However, the formation of a well-defined covalent assembly between catalyst and substrate (enamine or iminium ion) gives the possibility of preserving good stereochemical fidelity even when drastic reaction conditions are applied. In this context, an interesting and unconventional approach to the improvement of 9-amino Cinchona catalyst performance has been reported by Kwiatkowski and coworkers.³³  Exploiting the notion that high pressure can assist reactions occurring with a negative volume of activation, these workers demonstrated that the catalytic activity of 9-deoxy-epi-9-amino cinchonine CNA in two distinct reactions can be dramatically improved, if a sufficiently high pressure (ca. 10 kbar) is applied. Thus, they were able to develop a nitro-Michael and a Friedel–Crafts-type 1,4-addition to enones, both achieved with unusually low catalyst loadings and occurring efficiently even with until then unreactive β,β-disubstituted enone substrates (Scheme 14.9).

An alternative solution to overcome the economical unfeasibility of high catalyst loadings would in principle be provided by an efficient recovery and reuse of the catalyst species through its immobilisation via anchoring to solid supports. Furthermore, such a strategy seems well suited for an intensification of the catalytic process by shifting from batch (discontinuous) to flow (continuous) production modes, with relevant advantages in terms of safety, ease of scale up, catalyst productivity, equipment compactness and general savings in chemical waste and energy consumption.³⁴  Very recently, Benaglia, Puglisi and coworkers have reported a potential breakthrough in this area.³⁵  These authors demonstrated that a 9-deoxy-epi-9-amino quinine derivative featuring a styrene function (obtained by means of the Huisgen [3+2] cycloaddition) can be copolymerised with styrene, delivering a polystyrene resin containing 0.3–0.7 mmol g⁻¹ of 9-deoxy-epi-9-amino quinine units. This polymer was found to be active in both enamine and iminium ion-catalysed reactions (addition of aldehydes and ketones to nitroalkenes, addition of nitromethane to enones), and could be recovered and reused four times, although a drop in activity was observed. Nevertheless, a packed-bed reactor was prepared using this polymer, and applied to the catalytic asymmetric addition of isobutyric aldehyde to nitrostyrene (Scheme 14.10). The reactor, fed with a toluene solution of reactants and additive (BzOH), could operate continuously for almost 200 h, producing the expected product with constantly high enantioselectivity. Intercycle treatments (flushing with benzoic acid) were applied after 157 and 170 h to partially restore the catalytic activity of the reactor.

Additions of soft carbon nucleophiles to the carbonyl group of aldehydes, ketones and imines are reactions of obvious synthetic significance. For historical reasons, it is appropriate to start this short overview with the hydrocyanation reaction, as the addition of hydrogen cyanide to benzaldehyde was reported to proceed in an enantioselective fashion in the presence of natural Cinchona alkaloids as early as 1912.⁴  Also in recent times, the hydrocyanation reaction has furnished a very important breakthrough in the chemistry of Cinchona alkaloids. Tian and Deng demonstrated in 2001 that modified Cinchona alkaloids usually employed as ligands for osmium catalysed reactions are also useful in a highly stereoselective C–C bond-forming transformation, the cyanation of ketones.³⁶  Thus, dimeric AQN and PHAL or simpler O-PHN derived Cinchona (DHQN and DHQD) structures (Scheme 14.11) catalysed the highly enantioselective reaction of ketones with ethyl cyanoformate. The reaction, which was thought to proceed through the dynamic kinetic resolution of the intermediate cyanohydrins, was limited to dialkylketones. This limitation was overcome a few years later, by applying similar catalysts but with trimethylsilylcyanide as a cyanide source (Scheme 14.11).³⁷  In both cases, the reactions could be readily scaled up to ca. 0.1 mol, and the catalysts fully recovered by a simple extraction process.

The corresponding addition to imines (Strecker reaction) has also been a subject of study in the frame of Cinchona alkaloid catalysis. In addition to a pioneering contribution by Huang and Corey with a protonated Cinchona derivative,³⁸  it is worth mentioning a particularly interesting approach from a practical point of view, reported by Dahmen, Bräse and coworkers in 2009.³⁹  Salient features of this latter protocol are the usage of a cheap and industrially viable cyanide source (KCN), a natural Cinchona alkaloid (QN) as catalyst, and α-amido sulfones as imine surrogates allowing the preparation of N-Boc protected α-amino nitriles without requiring the isolation of intermediate N-Boc imines (Scheme 14.12). Unfortunately, enantioselectivities were moderate at best, and the reaction appears limited to aromatic substrates.

Nitromethane is an alternative to cyanide as a C1 α-amino anion synthetic equivalent. Regarding the addition of this pro-nucleophile to carbonyl compounds, cupreine CPN and cupreidine CPD derivatives have largely dominated the scene, since the first report in 2006 by Deng and coworkers⁴⁰  that proved the efficiency of CPN and CPD benzoylated at their C9 hydroxyl group (BzO-CPN and BzO-CPD) in the promotion of the addition of nitromethane to α-ketoesters (Scheme 14.13a). By applying catalysts with different ether or ester moieties at C9, the scope of this reaction was then enlarged to α-ketophosphonates (Scheme 14.13b),⁴¹  polyfluoromethyl ketones (Scheme 14.13c),⁴²  and finally to isatins (Scheme 14.13d).⁴³  A bifunctional activation involving a soft-enolisation type process of nitromethane and a multiple coordination of both substrates through a hydrogen-bond network in the ensuing C–C bond-forming transition state, along the lines of the reaction model described in the Michael addition of dicarbonyl compounds to nitroalkenes (Figure 14.3), can be hypothesised to be operative in these reactions. However, the same catalysts afforded only low stereoselectivities in the Henry reaction with simple aldehydes.⁴⁴ 

Examples of 1,2-additions to aldehydes and ketones of other pro-nucleophiles prone to an easy soft-enolisation process (i.e. acidic enough, such as 1,3-dicarbonyl compounds) are extremely scarce, presumably due to the pronounced reversibility of such aldol-type processes. A strategy to avoid the retro-aldol process that has proven remarkably successful in the frame of Cinchona alkaloid-promoted reactions is given by the decarboxylative addition of malonate half-thioesters and related derivatives to carbonyl compounds. These decarboxylative additions, inspired by the biochemical pathway operative in Claisen reactions catalysed by polyketide synthase enzymes, were disclosed by our and Wennemer's laboratories some years ago,⁴⁵  and have been successfully applied to various electrophilic reaction partners, such as imines, isatins and Michael acceptors, as recently reviewed.⁴⁶  Considering the challenging aldol reaction with simple (i.e. inactivated and more prone to retro-aldol) benzaldehydes, List, Song and coworkers have recently reported that the sulfonamide SA–QNA readily derived from 9-deoxy-9-amino-epi-quinine is able to promote the reaction between malonic acid half-thioesters and benzaldehydes with good results, although a high catalyst loading (30 mol%) is required (Scheme 14.14).⁴⁷  In this and related transformations, two reaction pathways can be envisioned, one involving the generation of an active enolate by decarboxylation (pathway (a), as in the enzymatic Claisen reactions), and one involving decarboxylation following C–C bond formation (pathway (b)). Compelling evidence collected in several of the reports describing these reactions strongly suggest that pathway (b) is favoured, i.e. that decarboxylation follows C–C bond formation.

The reversibility problem in 1,2-additions is alleviated when imines bearing an electron-poor protecting group at nitrogen (sulfonyl, acyl, carbamoyl) are employed as acceptor partners, rendering possible even the use of 1,3-dicarbonyl compounds as donors. For example, Schaus and coworkers reported the highly enantioselective Mannich reaction of acetoacetates⁴⁸  and cyclic 1,3-dicarbonyl compounds⁴⁹  with N-carbamoyl imines derived from benzaldehydes and cinnamaldehydes catalysed by the natural Cinchona alkaloid cinchonine (CN) (Scheme 14.15). On the basis of the obtained results they developed a model that accounts for the observed diastereo- and enantioselectivity based on the bifunctional nature of the catalyst, which acts simultaneously as a hydrogen-bond donor and acceptor.

Shortly after, the same authors proposed a more convenient protocol for this CN promoted Mannich reaction.⁵⁰  Employing α-amido sulfones as imine precursors, isolation if the N-acyl imines that were formed in situ under basic conditions was no longer required, which allowed the scope of the reaction to be extended to unstable imines derived from aliphatic aldehydes. The authors reported good yields and high enantioselectivities even when less-acidic malonates were employed, giving access to highly functionalised and synthetically useful building blocks (Scheme 14.16). It was also found that CN is responsible for imine formation through sulfinic acid elimination from the α-amido sulfone. The inorganic base thus serves only to regenerate the CN catalyst by neutralising the sulfinic acid formed.

In many of the transformations highlighted so far, the role of the Cinchona-derived catalysts is to promote a soft-enolisation process, thanks to their basic bridgehead nitrogen assisted in many instances by hydrogen-bond donor functionalities. Enantioselective C–C bond formation through an aldol, Mannich or conjugate addition follows (for examples see Figure 14.3 and Scheme 14.15). Such reaction pathways are possible only when donors featuring sufficient acidity (e.g. nitromethane, malonates) are employed in the reactions. However, it has been clearly demonstrated that the bifunctional nature of Cinchona alkaloids might serve as an exceedingly useful platform also for additions of “neutral” electron-rich nucleophiles, such as indoles. The catalytic activity of the Cinchona alkaloid derivatives is more reasonably defined in these cases as a transition-state coordination, wherein the acidic portion of the catalyst coordinates the acceptor, and the basic quinuclidinic nitrogen binds the indole N–H, stabilising its positive charge. In this context, naturally occurring cinchonidine (CD) and cinchonine (CN) have been exploited in highly efficient stereoselective Friedel–Crafts hydroxyalkylations of indoles with 3,3,3-trifluoropyruvate by Török, Prakash and coworkers.⁵¹  High yields and enantiomeric excesses of both enantiomers of the products, depending on the catalyst used, indicated the usefulness of the developed methodology (Scheme 14.17).

Since the scope of the reaction with respect to the electrophile was limited to trifluoropyruvate, in 2006 Deng and coworkers searched for a more efficient catalyst for the Friedel–Crafts hydroxyalkylation of indoles. O-Phenanthryl cupreidine and cupreine derivatives PHNO-CPD and PHNO-CPN were identified as optimal structures, allowing the use of aryl and alkynyl pyruvates, glyoxalate and (electron-poor) benzaldehydes in this reaction (Scheme 14.18).⁵² 

Whereas closely related catalysts allowed the Friedel–Crafts-type additions to be expanded to other carbonyl acceptors, such as isatins,⁵³  the same reactions depicted in Schemes 14.17 and 14.18 have also been achieved in an environmentally more benign solvent, namely Solkane^® 365 mfc, a liquid hydrofluorocarbon (CF₃CH₂CF₂CH₃) that is nontoxic with no impact on the ozone layer, and is used as an insulating and blowing agent for polyurethane foams. To achieve useful yields and enantioselectivities in this fluorinated reaction medium, perfluorinated CPN and CPD Cinchona alkaloid derivatives, able to dissolve in it, were designed and synthesised by Shibata and coworkers (Figure 14.4).⁵⁴ 

Cinchona alkaloid derivatives can also serve as useful Lewis basic catalysts, as very well exemplified by their successful employment in the Morita–Baylis–Hillman (MBH) reaction and its aza variant (aza-MBH), which provide a convenient access to functionalised allylic alcohols and amines. As early as 1999 Hatakeyama and coworkers⁵⁵  reported the use of β-isocupreidine (β-ICPD) as a catalyst for the reaction of aliphatic and aromatic aldehydes with 1,1,1,3,3,3-hexafluoroisopropyl acrylate, affording the desired adducts with very high enantioselectivities (Scheme 14.19). The concomitant formation of the dioxanone derivatives lowered the yield in the MBH adducts and caused difficulties in the experimental procedure. Interestingly, the dioxanone derivatives had the opposite configuration at the alcoholic stereocentre compared to the MBH product, highlighting an intriguing mechanistic feature of this Lewis-base catalysed reaction.⁵⁶ 

Whereas an activated hexafluoropropyl ester is essential for reactivity and enantioselectivity with simple aldehydes, the engagement of acrolein⁵⁷  and other acrylates⁵⁸  as olefin partners is possible when isatins are used as MBH acceptors (Scheme 14.20). Catalyst β-ICPD was found to be optimal also for these reactions.

Interestingly, even in the aza-version of this reaction, applicable to imines bearing electron-withdrawing protecting groups at nitrogen (e.g. sulfonyl, phosphinoyl) the same β-ICPD catalyst was found to be the most efficient, allowing the development of various useful protocols encompassing different MBH donors (vinyl ketones,⁵⁹  acrylates⁶⁰ ). However, amide variations (RCO-β-ICPDA) proposed by Masson, Zhu and coworkers, obtained by swapping the phenolic OH for an amide moiety, provided some advantages in some aza-MBH processes (Scheme 14.21).⁶¹  The major enantiomer obtained in these reactions inverted in the presence of 2-naphthol as additive, suggesting a dramatic structural change in the stereodetermining step driven by this H-bond donor and opening the important possibility of obtaining both enantiomers of the products with the same Cinchona alkaloid catalyst. More recently, the employment of α-amido sulfones as imine surrogates, disclosed nearly simultaneously by the same authors and Wei, Shi and coworkers gave a more practical dimension to this transformation.⁶² 

Both the phenolic OH (or the related amide donor) and the rigid tricyclic structures encompassing the Lewis basic nitrogen are considered to be essential for achieving useful enantioselectivities in MBH and aza-MBH reactions, making β-ICPD an ideal catalyst for these transformations. However, obtaining both enantiomers of (aza-)MBH products with these methodologies is not an easy task, as the pseudoenantiomeric form of β-ICPD is not readily available. β-ICPD is in fact prepared from quinidine by cyclisation of its O9 onto a tertiary carbocation derived from the pendant olefin by acidic treatment – hydride shift.⁶³  The O9 of quinine cannot cyclise onto a related carbocation (see Figure 14.1). A (partial) solution to this issue has been recently proposed by Hatakeyama and coworkers,⁶⁴  by exploiting a different skeletal rearrangement in the quinuclidinic portion of quinine rendering α-isocupreine (α-ICPN). This structure, and the corresponding amide RCO-α-ICPNA, were in fact able to afford the MBH and aza-MBH adducts with enantioselectivity opposite than β-ICPD and with good results (Scheme 14.22).

Moving to the use of 9-deoxy-9-amino-epi Cinchona; in 2007, shortly after the disclosure of their usefulness in conjugate additions, summarised in Section 14.2, Liu and coworkers demonstrated that these primary amines are also efficient in catalytic asymmetric 1,2-additions proceeding through enamine intermediates.⁶⁵  The authors reported a highly enantioselective aldol addition of cyclic ketones to aromatic aldehydes catalysed by a primary amine derived from cinchonine (CNA) and proceeding in the absence of solvent (Scheme 14.23). Acyclic aldol donors, such as acetone, were found to be less suitable in this reaction protocol, affording the product with unsatisfactory results (25% yield and 56% ee).

The same reaction was taken as a benchmark by Ma and coworkers to test the performance of a supported Cinchona catalyst prepared by copolymerisation of 9-deoxy-9-amino-epi-cinchonidine (CDA) with acrylonitrile for enamine/iminium ion catalysis.⁶⁶  This supported catalyst could promote the aldol reaction under heterogeneous conditions using water as the reaction medium (Scheme 14.24), delivering results in line with its homogeneous version. The polymeric material could be recovered by filtration through an organic membrane, and reused after washing with aqueous ammonia and drying. The activity displayed by the polymeric catalyst was nearly unchanged for the first five cycles, a small drop being observed only after seven reaction batches. Interestingly, this drop was not attributed to leaching of the amine from the polymer, or to its decomposition/degradation, but rather to the physical phenomenon of porous occlusion by adsorbed reactants, products or impurities.

Recently, an organocatalytic procedure for the direct aldol reaction of unprotected acetol and activated aromatic aldehydes catalysed by CNA ditartrates has been presented by Kacprzak and coworkers.⁶⁷  This enamine-based protocol, which complements related work by Mlynarski and other authors with natural Cinchona alkaloids acting as chiral bases,⁶⁸  avoids the use of problematic solvents and toxic reagents as well as chromatographic purification of the products, and provides exclusively linear aldols with high yields, syn-diastereoselectivities ranging between 1 : 1 to 8.7 : 1 and good enantioselectivities (72–90%). However, the scope of the reaction is limited to electron-poor benzaldehydes. Nevertheless, the operationally convenient and scalable organocatalytic procedure using cheap and renewable chemicals – both acetol and the catalysts, offers a sustainable way for the synthesis of some α-keto-syn-diols (Scheme 14.25).

An important contribution elucidating the potential of primary amines derived from Cinchona alkaloids has been the aldol cyclodehydration of achiral 4-substituted-2,6-heptanediones to enantiomerically enriched 5-substituted-3-methyl-2-cyclohexene-1-ones, presented by List and coworkers in 2008 (Scheme 14.26).⁶⁹  Both 9-deoxy-9-amino-epi-quinine (QNA) and its pseudoenantiomeric, quinidine-derived amine QDA, in combination with acetic acid as cocatalyst, proved to be efficient and highly enantioselective catalysts for this transformation, giving both enantiomers of 5-substituted-3-methyl-2-cyclohexene-1-ones with very good results. The authors observed that proline and the catalytic antibody 38C2 delivered poor enantioselectivity in this reaction. Furthermore, the synthetic utility of the reaction was exemplified by the first asymmetric synthesis of both enantiomers of celery ketone, a synthetic fragrance used in perfumery. The origin of the enantioselectivity in the reaction with QNA was very recently elucidated computationally by Lam and Houk.⁷⁰  The proposed transition state, depicted in Scheme 14.26, involves two medium rings, a six-membered and an eight-membered one. In the most favourable conformations of these two rings (approximately a chair–boat–chair), the major enantiomer of the product is obtained by placing both the quinoline moiety of the Cinchona catalyst and the R₁ substituent of the substrate in equatorial positions.

Cinchona alkaloid-derived catalysts have also been very useful for the promotion of various types of (formal) cycloaddition reactions, ranging from [2+2] to more classic [4+2] Diels–Alder-type transformations. Following the successful experiences with the use of Cinchona alkaloids in base-catalysed 1,4-addition reactions, Wynberg and coworkers already in 1982 revisited the [2+2]-cycloaddition reaction between ketene and chloral to form β-(trichloromethy1)-β-propiolactone in excellent yield and stereoselectivity by using 1–2 mol% of quinidine (QD) (Scheme 14.27).⁷¹  The obtained lactone is a precursor for the asymmetric synthesis of (S)-malic acid. The authors proposed the formation of a chiral, zwitterionic, ammonium-enolate arising from the nucleophilic attack of the quinuclidine ring of the catalyst to the ketene. The subsequent highly enantioselective aldol reaction between the enolate and chloral leads to the formation of the chiral lactone. The proposed mechanism suggests that the stereocentre adjacent to the tertiary nitrogen determines the stereochemistry of the product.

The same class of [2+2] cycloaddition reactions between ketenes and aldehydes has been the subject of subsequent studies, which have enlarged its scope to different substrates.⁷²  Thus, key contributions by Lectka and coworkers have demonstrated the applicability of zwitterionic enolates from acyl chlorides and O-benzoyl Cinchona alkaloids to the Staudinger reaction, that is the [2+2] cycloaddition with imines giving β-lactams (see also Chapter 15).⁷³  In this context, already in 2000, the authors studied the possibility of obtaining β-lactams under continuous-flow conditions. In the first attempt, the device was formed of three columns, the first one containing a heterogeneous base (PS-BEMP, a supported phosphazene base), the next the Cinchona catalyst anchored to a polystyrene resin, and, at the end, a scavenger to prevent unreacted material from contaminating the outstream (Scheme 14.28).⁷⁴  In the first column, the ketene was generated from the corresponding acyl chloride. Then, it was treated with a sulfonylimine in the second column packed with the catalyst. Later, the same authors described an alternative methodology that allowed generation of the ketene and of the imine in parallel (Scheme 14.28). The apparatus was formed with two columns working in parallel, one for the generation of the ketene and the other, packed with a 6 : 1 (w/w) mixture of NaH and Celite, which allowed the transformation of a chloroglycine derivative into the corresponding imine. The effluents from these two columns were combined and then the catalytic reaction was performed in the third column packed with the supported Cinchona alkaloid catalyst.⁷⁵  A third and simpler setup for β-lactam synthesis was also proposed by the same laboratory, based on the idea that the supported quinine derivative could play a catalytic role both in the ketene formation and in the β-lactam generation. Thus, a single column was packed with a mixture of finely powdered potassium carbonate and the Cinchona alkaloid derivative supported on a polystyrene resin (Scheme 14.28). Remarkably, the reaction took place smoothly under these conditions, albeit the results were not as good as in the previous cases.

Moving to a related type of [2+2] cycloaddition, not involving aldehydes or imines as partners, Calter and coworkers⁷⁶  reported Cinchona alkaloid (TMSO-QN) catalysed asymmetric dimerisation of ketenes, generated in situ from the corresponding acid chlorides, yielding β-lactones via a formal Claisen condensation (Scheme 14.29). The unstable ketene dimers were trapped with an alkoxyamine to afford β-keto amides (i.e. Weinreb amides) with variable yields and excellent enantioselectivities.

Regarding [4+2] cycloaddition reactions, it was recognised early on that basic Cinchona alkaloids can promote, with moderate enantioselectivities, some specific Diels–Alder transformations involving dienes such as 9-anthrones⁷⁷  and 2-pyrones⁷⁸  amenable to activation (i.e. HOMO raising) through partial deprotonation. However, it was only recently that some of these reactions were taken to a highly stereoselective level. Exploiting cupreine-CPN and cupreidine-CPD type catalysts, the highly enantioselective [4+2] cycloaddition of 2-pyrones with enones was reported in 2007 by Deng and coworkers,⁷⁹  soon followed by the reaction of the same dienes with nitroalkenes (Scheme 14.30).⁸⁰  By analogy with the other reactions highlighted in this chapter, the cupreine and cupreidine derivatives involved in these transformations act as bifunctional catalysts. While their quinuclidinic nitrogen coordinates the 2-pyrone diene, the phenolic OH binds the dienophile, resulting in a highly ordered transition state accounting for the observed high enantioselectivity.

Since this asymmetric Diels–Alder reaction of 2-pyrones with enones appeared limited in scope, the same group investigated the potential of a different type of substrate activation, still based on Cinchona alkaloid catalysts. The primary amine QDA, able to combine with enone substrates forming activated iminium-ion intermediates, was applied to the reaction. This resulted in a new and improved protocol (Scheme 14.31),⁸¹  which allowed a broader range of enones, featuring aryl and alkyl groups as β-substituents (or no β-substituents) to engage as dienophiles in the Diels–Alder reaction with 2-pyrones, and afforded the corresponding adducts with excellent enantioselectivities.

In the area of Cinchona alkaloid catalysis, a distinct approach to [4+2] cycloaddition reactions that has been found to be very powerful is the formal cycloaddition between enones and electron-poor dienophiles. The viability of this strategy, wherein enones are activated through the formation of a dienamine intermediate, was disclosed by Melchiorre and coworkers in 2009,⁸²  by demonstrating that the primary amine DHQNA in combination with 2-fluorobenzoic acid as cocatalyst could promote formal [4+2] cycloaddition reactions between enones and nitroalkenes, α-cyanocinnamates and maleimides, delivering the corresponding products with excellent enantioselectivities (Scheme 14.32). Experimental evidence discarded a concerted Diels–Alder pathway, leading the authors to propose a sequential C–C bond-forming reaction. Thus, the dienamine formed by combining the enone with the catalyst undergoes first a nucleophilic addition, followed by a ring closure on the thus formed iminium ion. By applying the same catalyst system, but using 3-alkylideneoxindoles as electron-poor dienophilic reaction partners, the same authors demonstrated the usefulness of this methodology for the preparation of highly enantioenriched spirocyclic oxindoles.⁸³ 

Hiemstra and Wynberg, in their seminal 1981 paper describing the conjugate addition of thiophenols to cyclohexanone, when facing with the frustration of going beyond moderate levels of enantioselectivity using natural Cinchona alkaloids,^6a  stated that “the inescapable conclusion is that still higher ees in this particular reaction can only be achieved by modification of the structure of the catalyst”. After 35 years, we can say that when natural Cinchona alkaloids failed in providing satisfactory results, it has often been the synthetic modification of their structure that has allowed satisfactory results to be reached, rather than the employment of distinct catalysts derived from other chiral sources. From a time perspective, however, only the dramatic upsurge of organocatalytic technology that has occurred in the last 10–15 years has provided a fertile framework for the disclosure of the full potential of this remarkable class of natural compounds in asymmetric catalytic settings. It is also surprising to observe that even very simple one-step manipulations, such as alcohol substitution with an amine or 6′-demethylation, have provided dramatic breakthroughs rendering catalysts useful in a broad range of unrelated transformations. It can be safely concluded that Cinchona alkaloids well deserve being included into the “privileged” chiral sources of asymmetric catalysis.

This chapter has attempted to give an overview of some of the most representative Cinchona catalyst structures, their substrate activation modes and reaction types, complementing other chapters of this book in giving the reader an idea of the synthetic potential expressed by these natural compounds. Unfortunately, studies specifically directed at a more sustainable utilisation of this catalyst class are somewhat lacking, as researchers have been mostly involved in the application of known structures to new reactions, or in the study of new catalyst structures, disregarding aspects such as solvent type, catalyst productivity, catalyst recovery and reuse, energy consumption, etc. However, as more and more workers are being involved in the broad field of green chemistry, studies paying particular attention at the sustainable nature of the catalytic process can be expected to increase, especially considering that these natural, and thus renewable, compounds are intrinsically extremely appealing from a sustainable point of view.