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Profiling the Privileges of Pyrrolidine-Based Catalysts in Asymmetric Synthesis - from Polar to Light-Driven Radical Chemistry Alberto Vega Penaloza, Suva Paria, Marcella Bonchio, Luca Dell'Amico, and Xavier Companyó ACS Catal., Just Accepted Manuscript • Publication Date (Web): 23 May 2019 Downloaded from http://pubs.acs.org on May 23, 2019
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ACS Catalysis
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 Companyó* 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’s 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 underdipping the most relevant scaffold modifications while defining structure-reactivity relationships. The present work will encourage a rational scaffold design towards 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, unprecedent reactivities and game-changer 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 a)
one scaffold 4 tunable positions position 4 - H, OSiR3, F aryl, alkyl: - stereo-electronic modulator - stereo-electronic modulator - anchoring position for - anchoring position for ..heterogenization ..heterogenization 4 - redox modulator - solubilization position 5
position 5 - H, aryl - stereo-electronic modulator
N 2 H I
O b)
H, phenyl, OSiR3, F: - conformational control position - Gauche effect inducer O H
H one catalyst 4 activation modes R
R
* N
N
*
H R En
h
R
N H
En*
-functionalization
N H
R
Im
h
H * R Im
-functionalization
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.
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 towards 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 the polar homogenous reactivity to the recent light-driven radical pathways, including in-flow immobilized catalysis, scaffold I has shown high efficiency/high versatility with respect to a large variety of asymmetric transformations. However, a general classification as well as the identification of structural-reactivity relationships are still not completely defined, complicating their rational utilization. Herein we identify, across a puzzling scenario, the common structural features governing the reactivity of the pyrrolidine-based scaffold I. We describe four major points of modifications, which have a strong impact on the overall stereoelectronic properties of the catalytic systems. The 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 solubilization into water media (chapter 4) or as the anchor point for catalyst immobilization (chapter 5). A third different 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, grey circles) have been investigated to solve specific synthetic issues (chapter 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 the catalyst I, are suited for catalyst immobilization and for proper tuning of the catalyst’s redox properties (see chapter 5 and 6).
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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
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over the time to the identification of novel structural variants. With a critical
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. critical analysis will serve as useful template for the design of point of view, we evaluate the structural weaknesses of the the next successful generation of pyrrolidine-based catalysts. diverse scaffolds together with their conceptual advancement. The first steps of the evolutionary time-line, including the 2. STRUCTURAL VARIANT Ia – A STAR IS BORN hydrogen bonding-type class of scaffolds and imidazolidinoneIn 2005 the research groups of Jørgensen and Hayashi type catalysts, will not be discussed in this perspective, being independently reported the use of the diarylprolinol silyl ether 4 already extensively reviewed in previous papers. as catalyst Ia for the activation of aldehydes via chiral enamine Our journey (Figure 2) starts by assessing the structural features intermediates (En, Figure 1). Jørgensen applied it to the of the pyrrolidine-based catalysts which have governed the sulfenylation of aldehydes for the stereoselective generation of classical polar reactivity. In this phase (1989-2005), the C-S bonds.5 Hayashi implemented it to the Michael addition of breakthrough concepts have been: (i) the initial identification of aldehydes to nitroalkenes, representing the first use of the the diarylprolinol motif and (ii) the protection of the prolinol catalyst Ia in C-C bond-forming reactions.6 In 2006, Jørgensen alcohol delivering the general and efficient catalyst variant Ia also demonstrated that the catalyst is competent to activate enals (Figure 2). This relatively simple synthetic modification has through iminium-ion intermediates (Im, Figure 1).7 reversed the activation mode from hydrogen-bonding to steric Specifically, the authors reported the asymmetric conjugate shielding, thus generating one of the most used purely-organic addition of malonates to cinnamaldehyde derivatives. Soon chiral catalyst in the market. A further evolution milestone has after, the group of Enders reported a three-component reaction involved the substitution of the terminal silyl ether with a between aldehydes, nitroalkenes and enals through an enaminesmaller fluorine atom thus generating the second structural iminium-enamine activation sequence.8 Hence, they established variant Ib (2009, Figure 2). In this structure the Fluorine the ability of scaffold Ia to activate cascade organo-catalytic Gauche effect is exploited to introduce a conformational control transformations by combining different activation modes. strategy based on the combined stereoelectronic, electrostatic 2.1. Stereo-Electronic Properties Define your Catalyst. The and charge‐dipole interactions induced by the fluorinated introduction of a silyl protecting group at the oxygen of quaternary center. In addition, immobilization strategies on diphenylprolinol 1 (Scheme 1a), previously used by Corey, solid supports for in flow applications have been explored for Enders and Kagan in asymmetric synthesis,9 was crucial to the structural variants Ia and Ib (2011-2015) leading to key obtain highly efficient catalysis, both in terms of chemical synthetic application. Reaching out to the state-of-the art yields and asymmetric induction. The protecting group avoids modification (2017), the bis-fluorinated structural variant Ic has the formation of the parasitic oxazolidine species 3a-b (Scheme been revealed as an efficient catalyst in light-induced radical 1b), increasing the turnover number (TON) of the process and reactions. The presence of fluorine atoms is deeply impacting therefore the reaction yield. the physicochemical properties of the pyrrolidine scaffold. We Scheme 1. (a) Introduction of a silyl-protecting group on expect that this perspective will assist the synthetic community prolinol scaffold 1 and (b) formation of parasitic oxazolidine towards a more rational catalyst selection for the development intermediate 3 of new asymmetric transformations. It is also our hope that this
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ACS Catalysis Scheme 3. Enantioselective -Sulfenylation of Aldehydes. A linear correlation of the Taft’s Es values with the optical activity of the products
a)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
OH-protection N H
N H
OH 1
O
Si
2
b)
catalyst (10 mol%)
O
a versatile and robust catalyst
N
H
N
8
Ph
N
N
OH H 4
H
Ph
Ph
Ph
3a
Ph
Ph Ph
N H
H
11
N
OH H 5
O 3b
En
enamine intermediate
N
Si
H Re-face Ph blocked 6 E-trans-intermediate
nd yield 90% ee
0
-1.24
E
O H
Si
sc-exo conformation
O H
N
Ph Ph
Im
Nu Ph
N
Si
-Re-face 7 blocked
E,E intermediate
N H
CH3
O 13
Si
CF3
90% yield 96% ee -2.40 higher enantiocontrol
N N
N
H Ph
14
7
N
Si
O
Ph
iminium ion intermediate
CF3
tuning the electronic propierties
H b)
CF3
F3C
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 azocompound led to catalyst deactivation. 15a,b Similarly, owing to the irreversible catalyst Nalkylation, the asymmetric -alkylation of aldehydes with alkyl halides has been an historical challenge in aminocatalysis.15c Structural modifications of the catalyst scaffold Ia allow to tune its stereoelectronic properties in order to overcome these reactivity issues (see chapter 6.1). En
O
N
O 12
increasing steric demand
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 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 a 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 an increased steric repulsion. The silyl group shields the Re face, thus forcing the nucleophile approach through the Si face.10, 11 Scheme 2. Catalytic intermediates (a) enamine and (b) iminium ion a)
N H
90% yield 77% ee
Taft´s Es values
Ph
Ph
Si
2
56% yield 52% ee
N
O
H
CH3
Ph
N H
S 10
CH3
H 3C
O
OH
toluene, rt
9
H N
O Ph
En
N S
8
H Ph
15 9
O
10 N
11
N Si
H Ph
6
12
16
13
Figure 3. Nucleophilicities of enamines derived from phenylacetaldehyde with diverse secondary amines. O H Si
Ph sc-exo conformation
The pioneering works already established that the catalyst performance can be tuned by the introduction of substituents on the 3 and 5-position of the aryl rings.1,12 In concordance with the Taft´s Es values,13 increasing the size of the substituents from methyl in 12 to trifluoromethyl in 13 improved the enantiocontrol in -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.
The same group measured the electrophilicity (E) of various iminium ions using silyl ketene acetals (Figure 4).14b In this case, the iminium ion 20 revealed 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 towards nucleophilic attack (see e.g. Scheme 5 and 19). However, the overall reaction rate is not only determined by the electrophilicity of the iminium ion intermediate, but also by its rate of formation and concentration.
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Im
tuning the electronic properties O
O N
Ph 17
-9.5
18
Ph
19
-9.0
O
H
H
H Ph
N
N
N
H
N Ph
Si
-8.5 E
Ph
-8.0
a)
-7.5
O
catalyst (10 mol%) PhO2S
21
H
Im
SO2Ph
SO2Ph
toluene, rt
22
PhO2S
23
CF3
F3C
CF3 N H 2
O
Si
90% yield 71% ee increasing steric demand
N H
O Si 13
15% yield 80% ee
N H CF3
b)
24
N
-7.0
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 trimethyl silyl (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 Scheme 4. The effect of the silyl substituents in the Michael addition of bis(phenylsulfonyl)methane to ,-unsaturated aldehydes
H
Im
En
Im
20
Figure 4. Electrophilicities of iminium ions derived from diverse secondary amines.
O
nitromethane to enals (Figure 5c); and (iii) -functionalization of aldehydes via enamine activation (Figure 5d). In these cases, the smaller TMS protecting group of 2 provides enough steric shielding to confer high enantiocontrol.
H
7
Ph
N
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O Si
88% yield 83% ee 90% ee @ 0 °C, 48 h higher enantiocontrol
After X-ray and computational conformational analyses of the diverse iminium ions intermediates, the authors concluded that with catalyst 24, the -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 - and -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
H Nu
Ph
O Si CH3 -Re-face
Ph
25 -position shielded in 1,4-addition manifold c)
O H
Im
N C
O H Ph
and position participate in the TS of cycloadditon reactions d)
O CH3 H Si H3C CH3 -Re-face N
7 orientation effect by electrostatic interaction
O CH3 Si H H3C CH3 -Re-face 7 N
En
O CH3 Si CH3 Ph Re-face E 6 reactive -position shielded in enamine intermediate N
H H 3C
Figure 5. Schematic approaches of the reactants.
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 27catalyzed by two different catalytic systems proceed through diverse reaction pathways, furnishing either the [4+2]-cycloadduct 28 or the Michael product 29 (Scheme 5). The reaction catalyzed by 13 under strong 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 electronwithdrawing 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 promote the intended reactivity. In fact, the strong trifluoroacetic acid (TFA) increases the iminium ion 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 determine divergent reaction pathways. The same concept was exploited using remotely enolizable dicyanodienes as pro-vinylogous nucleophiles.19 Scheme 5. Divergent reaction pathways via iminium ion intermediates depending on the catalyst structure and reaction conditions
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Ar
CF3
O
Si OHC
13 (10 mol%) a)
Ph 28 80% yield exo/endo 84/16 97% ee
O
H 27
26
N
CF3COO
O
H
En
Im
toluene TFA (20 mol%)
Ph
CF3
Ar
N H
MeOH p-nitrophenol (20 mol%)
CF3
Si
Ph 31
increasing iminium ion concentration
O
H
Im Ph
b) 30 (10 mol%) Ph Ph N O H Si
N
O
H
29
81% yield 92% ee 2 isomers
Ph
Si
32
anionic nucleophile addition
2.2. Catalyst Performances – TON vs TOF. One of the weak points of organocatalytic transformations is the need of 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 accounts with low TON, owing to catalysts 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 ethers catalysts under different reactions conditions (Figure 6).22
the catalyst degradation under the effect of different acidic 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 hours. Taking into account that the 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 measure by a single NMR analysis and in situ optimize in order to maximize the catalyst performance.
solvent N H a)
N H
acidic additives in DMSO
O Si 2
OH 1
C6D12 |
