Profiling the Privileges of Pyrrolidine-Based Catalysts in Asymmetric

Perspective Cite This: ACS Catal. 2019, 9, 6058−6072

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Profiling the Privileges of Pyrrolidine-Based Catalysts in Asymmetric Synthesis: From Polar to Light-Driven Radical Chemistry Alberto Vega-Peñaloza,‡ Suva Paria,‡ Marcella Bonchio, Luca Dell’Amico,* and Xavier Companyo*́

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Department of Chemical Sciences, University of Padova, Via Marzolo 1, 35131 Padova, Italy ABSTRACT: Asymmetric catalysis is a rapidly evolving field in synthetic chemistry. This is due to the growing needs of stereoselective synthetic routes to access enantiopure natural products and bioactive molecules. An efficient approach involves the use of readily available and robust catalysts, while ensuring high yields and stereocontrol. In this scenario, the pyrrolidine-based catalyst has played a dominant role over the past decades. Interestingly, simple scaffold modifications result in dramatic physicochemical and reactivity changes. These features have facilitated the generation of different catalyst variants for the development of highly diversified asymmetric transformations. In this Perspective, we analyze the structural evolution of the pyrrolidine-based catalyst, moving from polar to light-induced radical processes. We discuss the concepts underpinning the most relevant scaffold modifications while defining structure− reactivity relationships. The present work will encourage a rational scaffold design toward unprecedented reactivity pathways and improved catalytic performances. KEYWORDS: asymmetric organocatalysis, aminocatalysis, photocatalysis, photoredox catalysts, chiral scaffolds

1. INTRODUCTION Catalysis by chiral secondary amines is at the forefront of an intense research effort to discover new stereoselective transformations, unprecedented reactivities, and game-changing mechanistic pathways.1 In particular, the pyrrolidine-based catalyst I (Figure 1) is a privileged scaffold able to activate diverse types of aldehydes upon either enamine (En) or iminium ion (Im) formation (Figure 1b).2 Recently, two additional activation modes have arisen, evolving from the light irradiation of the corresponding enamine or iminium ion intermediates. Excited enamines (En*) and excited iminium ions (Im*) display unique reactivity patterns, able to channel radical reactions toward enantioselective paths (Figure 1b).3 Over the years, the original catalyst’s scaffold I has been extensively modified in order to adapt the catalyst features to the new reactivity challenges, giving rise to a number of structural variants. Moving from polar homogeneous reactivity to the recent lightdriven radical pathways, including in f low immobilized catalysis, scaffold I has shown high efficiency and high versatility with respect to a large variety of asymmetric transformations. However, a general classification, as well as the identification of structure−reactivity relationships, is still not completely defined, complicating their rational utilization. Herein we identify, across a puzzling scenario, the common structural features governing the reactivity of the pyrrolidinebased scaffold I. We describe four major points of modifications, which have a strong impact on the overall stereoelectronic properties of the catalytic systems. The © 2019 American Chemical Society

Figure 1. (a) Modification sites of the privileged pyrrolidine-based scaffold I and (b) activation modes displayed by catalyst I under polar and light-driven reactions.

substituents at the peripheral quaternary center (Figure 1a, red circles), have impact on the stereocontrol of different reactions, while being used also to promote catalyst Received: April 16, 2019 Revised: May 17, 2019 Published: May 23, 2019 6058

DOI: 10.1021/acscatal.9b01556 ACS Catal. 2019, 9, 6058−6072

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Figure 2. Profiling the privileges of pyrrolidine-based scaffold in asymmetric catalysis. Structural evolution of the pyrrolidine scaffolds; selected examples are shown. TBS = t-butyldimethylsilyl.

solubilization into water media (section 4) or as the anchor point for catalyst immobilization (section 5). A third substituent (Figure 1a, green circle) has a major influence on the 3-dimensional arrangement of the catalyst. Hence, modifications at this site highly influence the asymmetric induction. More recently, modifications at position four or five of the pyrrolidine ring (Figure 1a, gray circles) have been investigated to solve specific synthetic issues (section 4). Increasing the steric demand results in the enhanced discrimination of the substrate prochiral face, thus increasing the reaction enantioselectivity. Moreover, substitution at the four position of catalyst I is suited for catalyst immobilization and for proper tuning of the catalyst’s redox properties (see sections 5 and 6). 1.1. Pyrrolydine-Based Catalysis: The Evolution Timeline. In the following pages, we analyze the structural evolution of scaffold I, with a special focus on the concepts that have moved over time to the identification of novel structural variants. With a critical point of view, we evaluate the structural weaknesses of the diverse scaffolds together with their conceptual advancement. The first steps of the evolutionary time line, including the hydrogen bonding-type class of scaffolds and imidazolidinone-type catalysts, will not be discussed in this Perspective, being already extensively reviewed in previous papers.4 Our journey (Figure 2) starts by assessing the structural features of the pyrrolidine-based catalysts that have governed the classical polar reactivity. In this phase (1989−2005), the breakthrough concepts have been (i) the initial identification of the diarylprolinol motif and (ii) the protection of the prolinol alcohol delivering the general and efficient catalyst variant Ia (Figure 2). This relatively simple synthetic modification has reversed the activation mode from hydrogen-bonding to steric shielding, thus generating one of the most used purely organic chiral catalysts in the market. A further evolution milestone has involved the substitution of the terminal silyl ether with a smaller fluorine atom thus generating

the second structural variant Ib (2009, Figure 2). In this structure the fluorine gauche effect is exploited to introduce a conformational control strategy based on the combined stereoelectronic, electrostatic, and charge dipole interactions induced by the fluorinated quaternary center. In addition, immobilization strategies on solid supports for in flow applications have been explored for the structural variants Ia and Ib (2011−2015) leading to key synthetic applications. Reaching out to the state-of-the art modification (2017), the bis-fluorinated structural variant Ic has been revealed as an efficient catalyst in light-induced radical reactions. The presence of fluorine atoms deeply impacts the physicochemical properties of the pyrrolidine scaffold. We expect that this Perspective will assist the synthetic community toward a more rational catalyst selection for the development of new asymmetric transformations. It is also our hope that this critical analysis will serve as useful template for the design of the next successful generation of pyrrolidine-based catalysts.

2. STRUCTURAL VARIANT Ia: A STAR IS BORN In 2005, the research groups of Jørgensen and Hayashi independently reported the use of the diarylprolinol silyl ether as catalyst Ia for the activation of aldehydes via chiral enamine intermediates (En, Figure 1). Jørgensen applied it to the αsulfenylation of aldehydes for the stereoselective generation of C−S bonds.5 Hayashi implemented it in the Michael addition of aldehydes to nitroalkenes, representing the first use of the catalyst Ia in C−C bond-forming reactions.6 In 2006, Jørgensen also demonstrated that the catalyst is competent to activate enals through iminium-ion intermediates (Im, Figure 1).7 Specifically, the authors reported the asymmetric conjugate addition of malonates to cinnamaldehyde derivatives. Soon after, the group of Enders reported a threecomponent reaction between aldehydes, nitroalkenes, and enals through an enamine−iminium−enamine activation sequence.8 Hence, they established the ability of scaffold Ia 6059


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electrophile to approach from the least hindered side (Scheme 2a).10 In the case of iminium ion activation, the most stable conformation 7 (Scheme 2b) presents an sc-exo relationship between the nitrogen and the OTMS group. The nucleophile addition occurs preferentially through the E,E isomer, since the Z,E isomer is associated with increased steric repulsion. The silyl group shields the Re face, thus forcing the nucleophile approach through the Si face.10,11 The pioneering works already established that the catalyst performance can be tuned by the introduction of substituents on the 3- and 5-positions of the aryl rings.1,12 In concordance with Taft’s Es values,13 increasing the size of the substituents from methyl in 12 to trifluoromethyl in 13 improved the enantiocontrol in α-sulfenylation of aldehydes (Scheme 3).12 It is important to note that the bulkiness of the aryl substituents also impacts the rate of enamine formation.

to activate cascade organocatalytic transformations by combining different activation modes. 2.1. Stereoelectronic Properties Define Your Catalyst. The introduction of a silyl protecting group at the oxygen of diphenylprolinol 1 (Scheme 1a), previously used by Corey, Scheme 1. (a) Introduction of a Silyl-Protecting Group on Prolinol Scaffold 1 and (b) Formation of Parasitic Oxazolidine Intermediate 3

Scheme 3. Enantioselective α-Sulfenylation of Aldehydesa

Enders, and Kagan in asymmetric synthesis,9 was crucial to obtain highly efficient catalysis, in terms of both chemical yields and asymmetric induction. The protecting group avoids the formation of the parasitic oxazolidine species 3a,b (Scheme 1b), increasing the turnover number (TON) of the process and therefore the reaction yield. Regarding the asymmetric induction in enamine activation, the silyl group promotes the selective formation of the antienamine (E-s-trans intermediate 6, Scheme 2), effectively shielding one face of the double bond, and thus forcing the

a

A linear correlation of the Taft’s Es values with the optical activity of the products.

In order to design new catalyst derivatives with enhanced performance, it is important to discern the trends in reactivity as well as in the stereoelectronic properties. Mayr and coworkers determined the nucleophilicity (N) of different enamines,14a measuring their reaction kinetics with benzhydrylium ions. The study shows that the enamine 6, derived from 2, is 100 times more nucleophilic than the enamine 14 (Figure 3).14a,10 The relative nucleophilicity of the catalyst with respect to the corresponding enamine is a relevant parameter in enamine chemistry. For instance, in the αamination of aldehydes with azodicarboxylates, the unselective reaction of the catalyst with the azo compound led to catalyst deactivation.15a,b Similarly, owing to the irreversible catalyst N-

Scheme 2. Catalytic Intermediates (a) Enamine and (b) Iminium Ion

Figure 3. Nucleophilicities (N) of enamines derived from phenylacetaldehyde with diverse secondary amines. 6060


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ACS Catalysis alkylation, the asymmetric α-alkylation of aldehydes with alkyl halides has been a historical challenge in aminocatalysis.15c Structural modifications of the catalyst scaffold Ia allow tuning of its stereoelectronic properties in order to overcome these reactivity issues (see section 6.1). The same group measured the electrophilicity (E) of various iminium ions using silyl ketene acetals (Figure 4).14b In this

Scheme 4. Effect of the Silyl Substituents in the Michael Addition of Bis(phenylsulfonyl)methane to α,β-Unsaturated Aldehydes

Figure 4. Electrophilicities (E) of iminium ions derived from diverse secondary amines.

case, the iminium ion 20 proved to be the most electrophilic, which is in agreement with the fact that imidazolidinone-based catalysts are particularly suitable for iminium ion catalyzed reactions with weak nucleophiles. Modifications of scaffold Ia increases its reactivity toward nucleophilic attack (see e.g. Scheme 5 and 19). However, the overall reaction rate is determined not only by the electrophilicity of the iminium ion intermediate but also by its rate of formation and concentration. In 2014, Mayr and co-workers also established that the electronegativity of the oxygen in scaffold Ia has a minor effect on the electronic properties of the catalyst.14c Thus, the stereoselectivities observed under both enamine or iminium activations are purely due to steric reasons. Seebach and Hayashi performed a systematic study on the effect of the silyl substituents in different reactions catalyzed by scaffold Ia.16 It was demonstrated that increasing the size of the silyl group gives better enantioselectivity in 1,4-additions via iminium ion activation. For instance, the enantiomeric excess of the Michael addition of bis(phenylsulfonyl)methane 2217a−c to enal 21 increases moving from the trimethylsilyl (TMS) ether 2 to the diphenylmethylsilyl (DPMS) derivative 24 (Scheme 4). The trifluoromethylated catalyst 13 provides comparable stereoselectivity although with poor yield. The same trend is observed in other reactions based on the iminium-ion intermediate.17d,e After X-ray and computational conformational analyses of the diverse iminium ion intermediates, the authors concluded that with catalyst 24, the β-carbon is completely shielded by the DPMS silyl group. This is in agreement with the resulting superior enantiocontrol (Figure 5a). Notably, this observation is no longer valid for other types of reactivity, including (i) cycloaddition reactions where both the α- and β-positions of the unsaturated system participate in the transition state, such as the [4 + 2]-cycloaddition between cyclopentene and cinnamaldehyde (Figure 5b),16 (ii) transformations that proceed via electrostatic interaction in the transition state, such as the cationic iminium ion and the nitronate anion in the Michael addition of nitromethane to enals (Figure 5c), and (iii) α-functionalization of aldehydes via enamine activation (Figure 5d). In these cases, the smaller TMS protecting group

Figure 5. Schematic approaches of the reactants.

of 2 provides enough steric shielding to confer high enantiocontrol. Based on these observations, Hayashi and co-workers demonstrated that, by the judicious selection of the catalytic system, the same substrates can afford diverse products.18 Specifically, the reaction between 26 and 27 catalyzed by two different catalytic systems proceeds through diverse reaction pathways, furnishing either the [4 + 2]-cycloadduct 28 or the Michael product 29 (Scheme 5). The reaction catalyzed by 13 under strongly acidic conditions in toluene affords the [4 + 2]adduct 28. The reactivity is rationalized according to the higher electrophilicity of iminium ion 31, owing to the electron-withdrawing effect of the aryl groups (see also Figure 4). On the other hand, when catalyst 30 is used along with weak acids in MeOH, the conjugated addition is promoted. In this case, the generation of the reactive iminium species 32 is faster under the influence of the more electron-rich catalyst 30 (Scheme 5b). In both cases, the suitable acidic additive is key to promoting the intended reactivity. In fact, the strong trifluoroacetic acid (TFA) increases the iminium ion 6061


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ACS Catalysis Scheme 5. Divergent Reaction Pathways via Iminium Ion Intermediates Depending on the Catalyst Structure and Reaction Conditions

Figure 6. TMS cleavage rates of diphenylprolinolsilyl ether 2 in (a) different solvents and (b) different additives in DMSO-d6.

concentration in the reaction medium (Scheme 5a), while the weaker acid p-nitrophenol enables the formation of the anionic nucleophilic species in sufficient reactive concentration (Scheme 5b). This is a fine example of how the appropriate catalyst structure, together with the suitable reaction conditions, determines divergent reaction pathways. The same concept was exploited using remotely enolizable dicyanodienes as pro-vinylogous nucleophiles.19 2.2. Catalyst Performances: TON vs TOF. One of the weak points of organocatalytic transformations is the need for relatively large catalyst loadings to achieve satisfactory reactivity.20 This fact hampers their general implementation in large-scale industrial processes.1c,21 The common catalyst loadings employed in diarylprolinol catalyzed transformations is 10−20 mol %.1d,2b The relatively low efficiency of these catalysts is generally attributed to the fact that the reaction proceeds with low TON, owing to catalyst deactivation. The main deactivation pathway is the cleavage of the silyl protecting group to furnish the corresponding aminoalcohol 1 (Figure 6). In 2012, Zeitler, Gschwind and co-workers published an in situ NMR study on the rate of degradation of the diarylprolinol silyl ether catalysts under different reactions conditions (Figure 6).22 The study revealed that the cleavage rates are significant in highly polar solvents with strong H-bond acceptor properties, reaching 0.84%·h−1 for DMF (Figure 6a). The authors also investigated the catalyst degradation under the effect of different additives in DMSO. Very weak acids strongly accelerate the deactivation pathway (Figure 6b). For example, benzoic acid, a common additive in aminocatalysis, decreases the amount of available catalyst 2 from 84% to 10% in only 6 h. Taking into account that common reaction times span from several hours to days, catalyst degradation should be considered in order to enable the development of robust and more efficient catalytic processes. Conversely, if deactivation is not significantly operative under certain reaction conditions, the low catalyst efficiency can be ascribed to low turnover frequency (TOF). In 2017, the group of Burés presented the distribution of catalytic species as an indicator to evaluate and optimize the performance of

catalyst 2 in the conjugate addition of C-nucleophiles to enals under iminium activation.23 The indicator graphically correlates the percentage of the different catalytic species present during the reaction (free catalyst, iminium ion, and product enamine) with its associated TOF (Figure 7a). Therefore, the TOF of a specific reaction can be directly measured by a single NMR analysis and in situ optimized in order to maximize the catalyst performance. The authors realized that at very low catalyst loadings, even if the catalyst is properly optimized at its maximum performance (point 1, Figure 7a), the acid impurities formed by aldehyde oxidation drastically reduce the efficiency of the catalyst, and the reaction virtually stops (point 1′, Figure 7a). The use of the distribution of catalytic species enables the in situ correction of this detrimental perturbation by subsequent addition of the suitable additive (Figure 7c), maintaining the catalyst performance at maximum TOF (points 2−5, Figure 7a). Hence, the conjugated addition of dimethyl malonate 33 to cinnamaldehyde 26 catalyzed by as little as 0.1 mol % of 2 was completed within 60 h, affording the final product in 91% ee (Figure 7b). In addition, the authors demonstrated that the indicator is not only restricted to NMR scale but is also amenable to gram-scale reactions by using non-D NMR. This work demonstrates that the suitable control and maximization of the TOF enables reduction of the catalyst loading of catalyst 2 to 0.1 mol % while maintaining the synthetic utility of the transformation.

3. STRUCTURAL VARIANT Ib: EXPLOITING THE GAUCHE EFFECT Inspired by nature, where noncovalent stabilizing interactions determine structural preorganization, Gilmour and co-workers introduced a novel concept, replacing the oxygen atom by a fluorine in scaffold 2, leading to variant Ib.24 The presence of a C−F bond in catalyst 36 exploits the gauche effect as a conformational tool in asymmetric catalysis. Upon condensation with cinnamaldehyde 26, a highly organized iminium ion 6062


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Scheme 6. Exploiting the Gauche Effect as Conformational Tool in the Enantioselective Epoxidation of Cinnamaldehyde

hyde 39 with electron-deficient dienes 40 and nitroalkenes 41 (Scheme 7).27 In the hetero-[6 + 4]-cycloaddition between 39 and 40 (Scheme 7a), catalyst 36 showed the best performance, balancing yield, and enantioselectivity. Experimental and computational studies indicated a stepwise reaction mechanism where the second C−C bond-forming step controls the overall stereoselectivity. A disfavored F···O interaction is sufficient to destabilize the minor diastereomeric transition states, and thus provides the excellent enantioselectivity. Conversely, in the hetero-[6 + 2]-cycloaddition between 39 and 41 (Scheme 7b), the difference in energy of the two transition states with catalyst 36 is not so pronounced and therefore the asymmetric induction is modest. Based on this information, the authors redesigned catalyst 36, introducing methyl groups at the 3- and 5-positions of the phenyl rings, in order to destabilize the minor transition state by steric hindrance. Indeed, the structurally optimized catalyst 45 affords the product 43 with better yield and enantioselectivity.

Figure 7. Distribution of catalytic species allows evaluation and in situ optimization of the performance of catalyst 2. (a) Confinement of the catalytic species distribution to maximum TOF area; (b) kinetic profiles of the optimized (green) and the blank (yellow) reactions with 0.1 mol % of 2; (c) additive addition profile.

38 is produced due to (i) the electrostatic N+···F(δ−) interaction, (ii) the π-stacking interactions between a phenyl ring and the conjugated iminium moiety, and (iii) the hyperconjugative electron-donation σC−H → *σC−F (Scheme 6). In order to maximize the overlap, the best σdonor bond at the stereocenter (C−H) is placed anti to the best σ-acceptor bond (C−F). In this conformation, one phenyl group shields one of the diastereotopic faces. The catalyst 36 was successfully tested in the asymmetric epoxidation of 26. The effective implementation of the Gauche effect was corroborated by comparison with catalyst 37 and 11 (Scheme 6).25 Although in this case 37 affords the product in lower diastereoselectivities than 2, the yields are higher, maintaining the excellent enantiocontrol. This catalytic system has also been applied in the aziridination of enals26a and in the 1,3dipolar cycloaddition of nitrones to alkynals26b becoming a common tool in asymmetric synthesis. Very recently, Jørgensen, Houk, and co-workers further evolved the catalyst scaffold Ib for higher order cycloadditions. Specifically, they investigated the enantioselective hetero-[6 + 4]- and hetero-[6 + 2]-cycloadditions of pyrrolecarboxyalde-

4. CATALYSIS À LA CARTE: STRUCTURAL MODIFICATIONS TO SOLVE SPECIFIC SYNTHETIC CHALLENGES In 2016, Pihko and co-workers reported an example of how the privileged scaffold Ia can be modified to improve the enantiocontrol in Mukaiyama−Michael reactions between silyl ketene thioacetals 47 and acrolein 46.28 This is a challenging transformation because the only chiral center is generated at the α-position of 47. Thus, the catalyst has to efficiently transfer its chiral information to the incoming nucleophile through noncovalent interactions. In the catalyst design, the three main structural points (Figure 1) were systematically tuned. Remarkably, the use of 49, bearing a trans-phenyl group at position five, increased the enantioselectivity from −4% to 72% (Scheme 8). After the evaluation of different scaffolds, catalyst 50 provided the best enantiocontrol (90% ee) and highest yield (94%). The results were rationalized through DFT calculations. In fact, the energetic difference between the diastereomeric transition states (TS16063


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ACS Catalysis Scheme 7. Catalytic Enantioselective Hetero-[6 + 4]- and Hetero-[6 + 2]-Cycloadditions

Scheme 8. Catalyst Design for the Mukaiyama−Michael Reaction of Alkylated Silyl Ketene Thioacetals with Acrolein

Scheme 9. Catalyst Design for the Asymmetric α-Alkylation of Aldehydes by 1,6-Conjugated Addition of Enamines to pQuinone Methides

51 and TS2-52, Scheme 8) is due to a combination of repulsive steric effects and attractive interactions. The most favored transition state (TS1-51) leading to the major product (R)-48 presents two favorable attractive interactions, while the minor TS2-52 presents a highly repulsive steric interaction between the aryl group at position five of 50 and the TMS group of 47. In 2014, Jørgensen and co-workers reported the asymmetric α-alkylation of aldehydes 53 by 1,6-conjugated addition of enamines to p-quinone methides 54 (Scheme 9).29a The reaction with catalyst 2 and urea 55 as additive delivered the product 56 in high conversion and enantioselectivity albeit with poor diastereocontrol. Again, the catalyst needs to control the chiral center generated at the incoming electrophile.

Although the silyl group of 2 effectively shields the enamine Re face, the electrophile approach is not controlled, which results in low diastereoselectivity. To solve this issue, the authors envisaged that the introduction of a trans-silyloxy group at position four of the pyrrolidine ring could sterically determine the approach of 54 to the enamine intermediate 60, ensuring enhanced diastereocontrol (Scheme 9). Indeed, increasing the size of the silyl group from TMS in catalyst 57 to TIPS in catalyst 59 leads to the product 56 formation in higher diastereocontrol (6.8:1 dr), while maintaining excellent yields and enantiomeric excesses. In recent examples, this strategy was exploited for the construction of bioactive molecules.29b,c Water offers interesting features as solvent in organic synthesis due to its abundance, environmental compatibility, and nonflammability. However, from a technical point of view, 6064


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and the enantioselectivity of the transformation. However, longer alkyl chains such as nonyl and dodecyl had a detrimental effect on both parameters (not shown). Regarding the silyl protecting group, catalyst 70 bearing a triphenylsilyl group afforded product 66 with the highest enantioselectivity (96% ee) and 70% yield. Interestingly, the amino alcohol 67 furnished the product with opposite asymmetric induction, presumably due to hydrogen-bond formation between the catalyst and the nitro group. The authors also applied this catalytic system to the asymmetric conjugated addition of malonates and α-enolizable aldehydes to enals.31

water possesses some practical limitations such as low solubility of organic reagents, inhibition of the catalytic activity, or disruption of key noncovalent interactions in transition state stabilization. In this sense, Ni and co-workers designed a water-soluble pyrrolidine-based catalyst by the introduction of trimethylamino groups in the aryl rings 63 (Scheme 10).30a Protonation of 63 forms the corresponding Scheme 10. Design of Diarylprolinol Silyl Ether Salts as Water-Soluble and Recyclable Catalyst in the Enantioselective Michael Addition

5. CATALYST HETEROGENIZATION FOR IN FLOW APPLICATIONS Catalyst heterogenization has become an important approach toward green and sustainable organic synthesis, since it allows easy catalyst recovery and recycling, as well as the implementation in continuous-flow processes for large-scale reactions.32a The suitable selection of the support material and the linker between the support and the catalyst are essential in order to obtain competent catalytic systems. The diaryl prolinol scaffold possesses different anchoring points. Pericàs and co-workers illustrated this concept by synthesizing a set of six solid-supported catalysts based on the scaffold Ia. As support, microporous polystyrene resins (low cross-linking) and macroporous monoliths (high cross-linking) were tested (Scheme 12).32b The catalyst was anchored to the support

ammonium salt 64 creating hydrophilic groups, which enhance the catalyst solubility in water. The authors applied this catalytic system to the Michael addition of aldehyde 61 to nitroalkene 41 in water with excellent results, using a catalyst loading of only 3 mol %. Remarkably, 63 can be recovered and used at least 6 times without significant loss of performance.30b The group of Palomo designed a new family of catalyst Ia that enabled the iminium activation in aqueous media for the asymmetric conjugate addition of nitromethane 65 to enals 26.31 The key structural characteristic of the novel catalyst 70 is the hydrophobic long alkyl chains that promote the assembly of the catalyst and the reactants within emulsions. Also, the bulky silyl group offers effective control over the iminium ion geometry as well as efficient face shielding (Scheme 11). Increasing the length of aliphatic chains from propyl in 68 to hexyl in 69 led to substantial improvement in both the yield

Scheme 12. Design of Anchored Catalyst for Enantioselective Continuous-Flow Cyclopropanation

Scheme 11. Catalyst Design for Water-Compatible Iminium Ion Activation

through the pyrrolidine ring with a benzylic linker 73a,b and a triazole linker 74a,b, starting from 4-trans-hydroxyproline. Also, the phenyl rings of the catalyst can serve as anchoring point via copolymerization reaction with the resin to obtain 75a,b. The authors tested the different heterogeneous catalysts in the cyclopropanation on enals 26 with bromomalonates 71 in continuous flow. The catalyst 73a proved the most efficient, affording product 72 in excellent ee’s and diastereoselectivities. Moreover, the flow process can be run for up to 48 h without significant changes in the reaction performance, with a productivity of 2.1 mmol·h−1·gresin−1 and an overall TON of 94. 6065


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light absorbing properties of enamines.36 Upon light irradiation, chiral enamine can reach an electronically excited state 83 that can serve as photoinitiator for bromomalonate 80. The generated alkyl radical then participates in a stereodetermining C−C bond forming process with the ground state enamine (Scheme 14). Among all the catalysts screened,

In 2015, Gilmour, Pericàs, and co-workers successfully immobilized catalyst 36, implementing the advantages of the gauche effect conformational tool as well as the absence of the labile silyl group into a continuous flow system.33 The heterogeneous catalyst 78, prepared via copolymerization at the phenyl rings, was tested in the asymmetric Michael addition of aldehyde 76 to nitroalkene 41 through enamine activation (Scheme 13). The effective catalyst loading for the

Scheme 14. Enantioselective α-Alkylation of Aldehydes and Enals by Photoexcited Enamine

Scheme 13. Exploiting the Gauche Effect in the Enantioselective Continuous-Flow Michael Reaction

whole operation period was determined to be 1.6 mol %, which corresponds to an overall TON around 60 and a constant TOF of 4.6 h−1. Subsequently, a library of product derivatives 77 was synthesized in high yields and stereoselectivities in 16 consecutive runs and 18.5 h operation. It is worth mentioning that this is the first example of the use of catalyst Ib in enamine activation. Immobilized diarylprolinols under continuous flow conditions have also been employed in other asymmetric transformations, such as the α-amination of aldehydes15b and the Michael−Knoevenagel cascade between enals and oxodiesters.34a Moreover, other types of materials have been successfully employed as supports such as methoxy poly(ethylene glycol) polymers (MeOPEG5000),34b polystyrene resins,34c superparamagnetic nanoparticles,34d and embedded into a nanoporous polymer.34e

secondary amine ent-11 lacking the silyl ether moiety delivered the product in negligible yield, highlighting the importance of the silyloxy moiety for good reactivity. Commercially available ent-2 with a silyl ether group provided the product 81 in good yield and reasonable enantioselectivity, whereas catalyst ent-13 with sterically demanding aryl substitutions was found to be best in terms of selectivity due to the better stereocontrol in the radical trapping step. The same group further extended the application of the light-excited enamine as radical initiator for a formal enantioselective α-methylation and benzylation of aldehydes.37 I n t h i s c a s e , ( p h e n y l s u l f o n yl ) m et h y l i od i d e or (phenylsulfonyl)benzyl iodides (for methylation and benzylation, respectively) are reduced by excited enamine under visible light irradiation. In 2013, Melchiorre and co-workers established the first light-driven radical method based on the use of catalyst scaffold Ia.38 The chemistry is based on the formation of a chiral absorbing colored electron-donor−acceptor (EDA) complex 87, formed between the enamine 88 and the electron deficient alkyl halide 84 (Scheme 15). The benzyl radical, generated by the photoirradiation of the EDA complex, engages in a stereodetermining C−C bond forming event with the chiral enamine 88 (Scheme 15). It is interesting to note that, while the commercially available catalysts 2 and 13 delivered promising levels of enantiocontrol, the best catalyst was 86 with a peculiar octahydro-1H-indole structural motif. This is due to the comparatively more rigid conformation of the enamine 88 resulting from catalyst 86, which imparted the highest stereoselectivity in the enamine−benzyl radical coupling step. In 2017, MacMillan and co-workers developed

6. PYRROLIDINE-BASED CATALYSIS: A RISING SUN Recently the utilization of pyrrolidine-based scaffolds under light-mediated asymmetric catalysis has experienced tremendous growth. Similar to polar reactivity, both the enamine and iminium activation modes can be suited for the development of the selected reaction pathway.1e,35 More importantly, unprecedented reactivity pathways have been unlocked exploiting these complementary activation modes to deliver synthetically useful asymmetric transformations difficult or impossible to achieve under classical polar pathways. Specific structural modifications of the pyrrolidine-based scaffolds were key to the successful development of new light-driven synthetic methods. In this section, we will summarize how these modifications have shaped the original scaffold to meet the specific requirements of light-driven asymmetric transformations in terms of catalyst stability, redox properties, and stereocontrol. 6.1. Structural Variant Ia toward Light-Mediated Stereoselective Transformations. In 2015, Melchiorre and co-workers reported an innovative concept to exploit the 6066


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ACS Catalysis Scheme 15. Enantioselective α-Alkylation of Aldehydes by Chiral EDA Complex

found to be the optimal for the intramolecular approach (not shown), secondary amine catalyst 13 delivered the best result in the intermolecular process. As described before, the catalyst variant Ia can be efficiently used together with enals to generate the corresponding chiral iminium ion. The same principle can be applied to trap radicals or other transiently photogenerated species, leading to the formation of enantioenriched β-functionalized aldehydes. Maseras, Melchiorre and co-workers reported in 2017 the first example of light-driven β-benzylation of enals.40 Photoenol 97, photogenerated from the corresponding 2-alkyl benzophenones (95),41 is able to engage into a vinylogous Michael addition with the chiral iminium ion intermediate (Scheme 17). The uncatalyzed background addition of highly Scheme 17. Enantioselective β-Benzylation of Enals

an elegant multicatalytic procedure for the α-alkylation of aldehydes with styrenes.39 The triple catalytic process consists of the perfect combination of three distinct yet cooperative catalytic cycles: (i) the chiral secondary amine catalyst 13 for enamine formation, (ii) an iridium complex as photoredox catalyst, and (iii) a thiophenol as hydrogen atom transfer (HAT) catalyst (Scheme 16). The main difference in this approach from the former one is that the enamine intermediate 92 is oxidized by the excited iridium photoredox catalyst to deliver the crucial electrophilic enaminyl radical intermediate 93, which then engages in a stereocontrolled C−C bond formation with the styrene. While imidazolidinone catalyst was Scheme 16. Enantioselective α-Alkylation of Aldehydes Using Simple Olefins

reactive photoenol species was circumvented by the rate acceleration of the trapping event by the chiral iminium ion 32, providing enantioenriched β-benzylated aldehydes. While the use of biphenyl phosphoric acid as additive was essential to enhance the reactivity, possibly by helping the formation of iminium ion, catalyst 30 bearing a bulkier silyl protecting group provided the highest enantiocontrol while maintaining good reactivity (Scheme 17). 6.2. Structural Variant Ic: Tuning the Redox Properties. Apart from the asymmetric radical trapping by ground state iminium ions, the photoredox properties of light-excited iminium ions were also exploited toward the development of novel enantioselective transformations. Specifically, the high oxidation potential enables single electron transfer (SET) oxidation of electron rich substrates, delivering open shell radical species, which can then participate in stereoselective radical couplings. Photoexcited iminium ions are strong oxidants (e.g., Ered * (103*/103•−) = +2.32 V, Ered * (104*/104•−) = +2.45 V versus Ag/Ag+ in CH3CN); therefore they are able to oxidize a wide range of organic substrates. Following initial reports by Mariano and co-workers,42 the group of Melchiorre exploited the oxidizing property of chiral excited iminium ions for the 6067


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ACS Catalysis asymmetric β-benzylation of enals (Scheme 18).43 The oxidation of benzyl trimethylsilane 98 by 104 generates the

Expanding this concept, other innovative asymmetric synthetic methods have been developed, such as enantioselective β-alkylation of enals and cascade reactions.44 In 2019, the groups of Melchiorre45 and Yu46 independently reported the enantioselective Giese-type acyl radical addition to chiral iminium ions. Interestingly these methods allow the synthesis of chiral 1,4-dicarbonyls 108 (Scheme 19). The report by Melchiorre and co-workers relies on the direct excitation of 4-acyl-1,4-dihydropyridine 109 as acyl radical source, whereas the group of Yu employed α-ketoacids 110 as acyl radical source. In the latter case, a photoexcited ruthenium complex was responsible for acyl radical generation through a SET mediated decarboxylation mechanism. This highly nucleophilic species 107 is then trapped by the chiral iminium ion generated upon condensation of the enal 26 with the catalyst 101. The extensive screening of a wide library of catalysts established the critical features of the optimal catalyst in order to achieve high reactivity and stereoselectivity. Bulky substituents both in the aryl moieties and in the silyl protecting group were found to be requisite for high enantiocontrol. On the other hand, since the electrophilicity of the iminium ion positively correlated with the reaction yield (see Figure 4), the use of gem-difluorinated 101 enhanced the electrophilicity of the iminium ion intermediate 103, increasing the reaction yields.

Scheme 18. Enantioselective β-Benzylation of Enals by Photoexcited Iminium Ion

7. SUMMARY AND PERSPECTIVES Pyrrolidine-based catalysts have been widely used by the synthetic community in asymmetric synthesis, representing nowadays the most employed catalysts for the functionalization of aldehydes under transition-metal-free conditions. This success can be ascribed to several exclusive features, such as (i) high compatibility with a myriad of reaction partners as well as reaction conditions, (ii) excellent combination with other catalytic systems for dual or synergistic catalytic activation, (iii) diverse and complementary activation modes, and (iii) exquisite asymmetric induction, connected to (iv) the welldefined reactive transition states that enable the understanding and prediction of the reactivity and selectivity. As highlighted in the present work, scaffold I is amenable to tailored structural modifications at diverse points in order to solve the encountered synthetic issues. This fact has enabled an evolution along 15 years, giving rise to different catalyst variants described herein. In addition, their successful heterogenization toward in f low methodologies has led to broader application for large scale synthesis of chiral molecules with the advantages of catalyst recovery and recycling. More recently, their implementation to the emerging field of photochemistry, further underscore the high versatility of this pyrrolidine based scaffold. Nevertheless, catalyst I also suffers from a series of drawbacks. The relatively low catalytic performance, when compared with metal-based catalysis, generally forces their utilization with catalyst loadings between 10 and 20 mol %. The impressive growth of organocatalysis, with the diarylprolinol catalysts playing a central role, led to a highly competitive rush, where the development of new methodologies has prevailed over a deep investigation of the catalytic systems. Hence, the diverse parameters that determine the catalyst performance, such as the catalyst decomposition, catalyst deactivation, unselective substrate activation, or low turnover frequencies, have been generally overlooked. Although the problem of catalyst Ia degradation due to

benzyl radical 105, which then participated in a stereocontrolled biradical coupling with the chiral β-enaminyl radical intermediate 106. The modifications of the catalyst scaffold were key for the development of effective asymmetric transformations. Specifically, the ideal catalyst structure should guarantee (i) the formation of an extremely electron-deficient and very easy to reduce iminium intermediate, (ii) high stability under the reaction conditions, and (iii) high level of asymmetric induction. The commonly encountered secondary amine catalysts 100 in thermal reactions, though they delivered reasonable enantioselectivity, showed poor reactivity due to extensive degradation under the reaction conditions. This was mainly due to the easily oxidizable (Eox(100•+/100) = +1.57 V) electron-rich catalyst scaffold, which was prone to reduce the excited iminium ion. To circumvent this issue, the authors introduced gem-difluoride atoms at position four of the pyrrolidine ring leading to structural variant Ic. This modification not only mitigated the undesired oxidative degradation due to enhanced oxidation potential (Eox(100•+/ 100) = +1.57 V to Eox(101•+/101) = +2.20 V) but also imparted a strong conformation bias over the pyrrolidine scaffold, which resulted in increased levels of asymmetric induction. Further improvements in the catalyst enantiocontrol were achieved by installing bulky perfluoro-isopropyl groups in the arene rings 102. 6068


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ACS Catalysis Scheme 19. Stereocontrolled Synthesis of 1,4-Dicarbonyls

desilylation can be addressed by replacing labile protecting groups with more robust ones, the development of efficient and general catalytic transformations in really low catalyst loadings is still a formidable goal that would boost the use of the catalyst I for industrialized large-scale applications. The implementation of the catalyst heterogenization for in flow methodologies also faces diverse challenges to be addressed. The choice of the solid support adds one more variable to take into account during the catalytic system design and optimization. Indeed, both resins and linkers should not interfere with the catalytic performance or with the asymmetric induction. In addition, the anchoring process itself adds extra synthetic steps that must be minimized. In this light, Cucatalyzed azide−alkyne cycloaddition has proven one of the more efficient approaches for catalyst installation. The issue of catalyst degradation is especially relevant in the light-driven transformation, due to the exposure of the chiral amine to light irradiation along with highly reactive excited species. The implementation of scaffold Ic is an excellent example of how the catalyst evolution enables it not only to meet key parameters that are essential for reactivity but also to circumvent undesired catalyst decomposition. In this line, the application of the structural variant Ib in light-induced transformations could unravel novel reactivity pathways.

Apart from taking advantage of the gauche effect for asymmetric induction, the fluorine substitution could provide robustness to oxidation thus providing better catalytic performance. The accurate study and understanding of the physicochemical properties of the catalyst and its behavior under illumination could also direct the development of other catalyst scaffolds for photoinduced transformations. The translation of photochemical transformations into photomicrofluidics setups is expected to boost the performance of the corresponding batch reaction.47 To the best of our knowledge, only a few homogeneous catalytic photoreactions have been reported under flow conditions,48 and none of them feature the use of catalyst I. An alternative approach could be to anchor the pyrrolidine scaffold into transparent supports for heterogeneous in flow photochemical reactions. This may open new synthetic horizons for the field of enantioselective photocatalysis. Also, emerging new porous materials with embedded chiral pyrrolidine scaffolds49 will represent a turning point toward organocatalytic materials with multiple activation and recognition effects mimicking natural enzymes’ perfection.50 6069


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MacMillan, D. W. C. Enantioselective Organocatalysis Using SOMO Activation. Science 2007, 316, 582−585. (h) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C New Strategies for Organic Catalysis: The First Highly Enantioselective Organocatalytic DielsAlder Reaction. J. Am. Chem. Soc. 2000, 122, 4243−4244. (5) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen, K. A. Enantioselective Organocatalyzed α-Sulfenylation of Aldehydes. Angew. Chem., Int. Ed. 2005, 44, 794−797. (6) Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Diphenylprolinol Silyl Ethers as Efficient Organocatalysts for the Asymmetric Michael Reaction of Aldehydes and Nitroalkenes. Angew. Chem., Int. Ed. 2005, 44, 4212−4215. (7) Brandau, S.; Landa, A.; Franzén, J.; Marigo, M.; Jørgensen, K. A. Organocatalytic Conjugate Addition of Malonates to α,β Unsaturated Aldehydes: Asymmetric Formal Synthesis of (−) Paroxetine, Chiral Lactams, and Lactones. Angew. Chem., Int. Ed. 2006, 45, 4305−4309. (8) Enders, D.; Hüttl, M. R. M.; Grondal, C.; Raabe, G. Control of Four Stereocentres in a Triple Cascade Organocatalytic Reaction. Nature 2006, 441, 861−863. (9) (a) Enders, D.; Kipphardt, H.; Gerdes, P.; Breña-Valle, L. J.; Bhushan, V. Bull. Soc. Chim. Belg. 1988, 97, 691. (b) Corey, E. J.; Shibata, T.; Lee, T. W. Asymmetric Diels-Alder Reactions Catalyzed by a Triflic Acid Activated Chiral Oxazaborolidine. J. Am. Chem. Soc. 2002, 124, 3808−3809. (c) Riant, O.; Kagan, H. B. Asymmetric Diels-Alder reaction catalyzed by chiral bases. Tetrahedron Lett. 1989, 30, 7403−7406. (d) Vargas-Caporali, J.; Juaristi, E. The Diamino Analogues of Privileged Corey−Bakshi−Shibata and Jørgensen− Hayashi Catalysts: A Comparison of Their Performance. Synthesis 2016, 48, 3890−3906. (10) (a) Dinér, P.; Kjærsgaard, A.; Lie, M. A.; Jørgensen, K. A. On the Origin of the Stereoselectivity in Organocatalysed Reactions with Trimethylsilyl-Protected Diarylprolinol. Chem. - Eur. J. 2008, 14, 122−127. (b) Seebach, D.; Grošelj, U.; Badine, D. M.; Schweizer, W. B.; Beck, A. K. Isolation and X Ray Structures of Reactive Intermediates of Organocatalysis with Diphenylprolinol Ethers and with Imidazolidinones. Helv. Chim. Acta 2008, 91, 1999−2034. (c) Grošelj, U.; Seebach, D.; Badine, D. M.; Schweizer, W. B.; Beck, A. K.; Krossing, I.; Klose, P.; Hayashi, Y.; Uchimaru, T. Structures of the Reactive Intermediates in Organocatalysis with Diarylprolinol Ethers. Helv. Chim. Acta 2009, 92, 1225−1259. (d) Seebach, D.; Gilmour, R.; Grošelj, U.; Deniau, G.; Sparr, C.; Ebert, M. O.; et al. Stereochemical Models for Discussing Additions to α,β Unsaturated Aldehydes Organocatalyzed by Diarylprolinol or Imidazolidinone Derivatives − Is There an ‘(E)/(Z) Dilemma? Helv. Chim. Acta 2010, 93, 603−634. (11) (a) Ibrahem, I.; Hammar, P.; Vesely, J.; Rios, R.; Córdova, A.; Eriksson, L. Organocatalytic Asymmetric Hydrophosphination of α,βUnsaturated Aldehydes: Development, Mechanism and DFT Calculations. Adv. Synth. Catal. 2008, 350, 1875−1884. (b) Dinér, P.; Nielsen, M.; Marigo, M.; Jørgensen, K. A. Enantioselective Organocatalytic Conjugate Addition of N Heterocycles to α,βUnsaturated Aldehydes. Angew. Chem., Int. Ed. 2007, 46, 1983−1987. (12) Franzén, J.; Marigo, M.; Fielenbach, D.; Wabnitz, T. C.; Kjærsgaard, A.; Jørgensen, K. A. A General Organocatalyst for Direct n-Functionalization of Aldehydes: Stereoselective C-C, C-N, C-F, CBr, and C-S Bond-Forming Reactions. Scope and Mechanistic Insights. J. Am. Chem. Soc. 2005, 127, 18296−18304. (13) Taft’s Es values are steric substituent constants that correlate the linear free energy of the reaction with the size of the substituent; see, for example: (a) Taft, R. W., Jr. Linear Free Energy Relationships from Rates of Esterification and Hydrolysis of Aliphatic and Orthosubstituted Benzoate Esters. J. Am. Chem. Soc. 1952, 74, 2729−2732. (b) Taft, R. W., Jr. Polar and Steric Substituent Constants for Aliphatic and o-Benzoate Groups from Rates of Esterification and Hydrolysis of Esters. J. Am. Chem. Soc. 1952, 74, 3120−3128. (c) Taft, R. W., Jr. Linear Steric Energy Relationships. J. Am. Chem. Soc. 1953, 75, 4231−4238. (14) (a) Lakhdar, S.; Maji, B.; Mayr, H. Imidazolidinone-Derived Enamines: Nucleophiles with Low Reactivity. Angew. Chem., Int. Ed.

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Marcella Bonchio: 0000-0002-7445-0296 Luca Dell’Amico: 0000-0003-0423-9628 Xavier Companyó: 0000-0001-8969-7315 Author Contributions ‡

A.V-P. and S.P. contributed equally.

Funding

This work was supported by the CariParo Foundation AMYCORES starting grant 2015 (L.D.) and by the GREEN C−C STARS starting grant 2017 (X.C.). Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS A.V.-P. thanks the University of Padova for the Seal of Excellence @unipd PLACARD fellowship, and S. P. thanks the GREEN C−C STARS starting grant 2017 for a postdoctoral fellowship.

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REFERENCES

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Perspective

ACS Catalysis

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