Article
Reference
Anion-π transaminase mimics
LIU, Le, MATILE, Stefan
Abstract
The possibility to stabilise anionic transition states on π-acidic aromatic surfaces has been explicitly demonstrated first in 2013. Since then, anion-π catalysis has been introduced to asymmetric enamine and iminium chemistry and to cascade processes, and the first anion-π enzyme has been created. Moving beyond systems that operate with nitronate-π interactions, this report adds transamination to the repertoire of anion-π catalysis. Whereas bioinspired approaches to transamination with pyridoxalphosphate appeared less obvious in this context, the base-catalyzed isomerisation of trifluoromethylimines contains suitable anionic transition states. Run on increasingly π-acidic aromatic surfaces in covalent and supramolecular trifunctional systems, we find that both rate and enantioselectivity of this reaction increase.
These results support that anion-π interactions with 2-azaallyl anion intermediates catalyse the isomerisation of trifluoromethylimines by cumulative asymmetric umpolung on π-acidic surfaces.
LIU, Le, MATILE, Stefan. Anion-π transaminase mimics. Supramolecular Chemistry , 2017, vol. 29, no. 10, p. 702-706
DOI : 10.1080/10610278.2016.1258118
Available at:
http://archive-ouverte.unige.ch/unige:95403
Disclaimer: layout of this document may differ from the published version.
Anion-π Transaminase Mimics
Le Liu and Stefan Matile*
Department of Organic Chemistry, University of Geneva, Geneva, Switzerland [email protected]
RECEIVED DATE
The possibility to stabilize anionic transition states on π-acidic aromatic surfaces has been explicitly demonstrated first in 2013. Since then, anion-π catalysis has been introduced to symmetric enamine and iminium chemistry and to cascade processes, and the first anion-π enzyme has been created. Moving beyond systems that operate with nitronate-π interactions, this report adds transamination to the repertoire of anion-π catalysis. Whereas bio-inspired approaches to transamination with pyridoxalphosphate appeared less obvious in this context, the base-catalyzed isomerization of trifluoromethylimines contains suitable anionic transition states. Run on increasingly π-acidic aromatic surfaces in covalent and supramolecular trifunctional systems, we find that both rate and enantioselectivity of this reaction increase. These results support that anion-π interactions with 2-azaallyl anion intermediates catalyze the isomerization of trifluoromethylimines by cumulative asymmetric umpolung on π-acidic surfaces.
Keyword: Anion-π interactions; catalysis; anionic transition states; transamination; imine isomerization; transaminase mimics; pyridoxalphosphate; rate enhancement; stereoselectivity; naphthalenediimides
Introduction
The idea to catalyze transamination with anion-π interactions does not appear meaningful on first view.
Transamination is an important reaction in biology (1–3).
For instance, transamination is the last step in the biosynthesis of amino acids and the first step in their degradation. Biological transamination of α-keto acids 1 is catalyzed by transaminases (Scheme 1). These enzymes contain pyridoxamine phosphate as a cofactor. Transfer of the amine from cofactor 2 to substrate 1 affords amino acid 3 and pyridoxal phosphate 4. This transfer is initiated by imine formation between substrate 1 and cofactor 2.
Deprotonation of intermediate 5 by a basic residue in the active site of the enzyme is enabled by the electron-deficient nitrogen of the pyridinium. In the resulting intermediate 6, the pyridinium is neutralized, but aromaticity is lost as well.
Rearomatization of the pyridinium ring drives the negative charge toward the imine, inverts the imine polarity (umpolung) (4) and has the now electrophilic imine carbon take up a proton from an acidic residue in the enzyme active site. In the resulting intermediate 7, the imine has isomerized with regard to the constitutional isomer 5. From 7, imine hydrolysis affords transamination products 3 and 4.
Transaminases have been used extensively for the synthesis of chiral amines in organic synthesis (5, 6). Moreover, a rich collection of transaminase mimics has been created, covering pioneering cyclodextrins (7), semisynthetic enzymes (8), and so on (1–3, 5–14).
The general idea to use anion-π interactions (15–20) in catalysis is to stabilize anionic transition states on π-acidic surfaces. This idea is complementary to the conventional cation-π catalysis, that is the stabilization of cationic reactive intermediates on π-basic aromatic surfaces, particularly carbocations, a strategy that is ubiquitous in biology and increasingly appreciated in chemistry (21).
Scheme 1. The biosynthesis of amino acids by transamination.
In sharp contrast, anion-π catalysis is essentially ignored not only in biology but also in chemistry. This is understandable because a) anion-π interactions (15–20) and their functional relevance (22) have been introduced rather recently and b) strong π acidity (23) and/or precise positioning (24) are required to achieve significant stabilization of anionic transition states. At sufficient π acidity, however, anion-π interactions can become quite powerful. For example, changes up to ∆pKa = 5.5 found for enols on π–acidic surfaces correspond to the deprotonation of arginines in neutral water, a process that is considered as impossible in biology (23).
The possibility to stabilize anionic transition states on π-acidic aromatic surfaces has been explicitly demonstrated first with the Kemp elimination in 2013 (25). Since then, anion-π catalysis has been introduced to enolate (26), enamine (27) and iminium chemistry (28), conjugate additions, nitroaldol (Henry) condensations and cascade processes producing cyclohexane rings with five chiral
N H
5 N+
PO OH
R COO–
H
Enz-B N
6 N
PO OH
R COO–
H Enz-B+-H
N
7 N+
PO OH
R COO–
H
*
NH2
N
PO OH
O R COOH
1
2 +
O
N
PO OH
NH2 R COOH
3
4 + trans-
aminases
centers in one step (28). Moreover, the first anion-π enzyme has been created (29).
Considering this mechanism of transamination (Scheme 1), the idea to catalyze the reaction with anion-π interactions was not quite obvious. However, the isomerization of trifluoromethylimines has been achieved previously with tertiary amine catalysts. In 2007, 50 mol%
of conventional cinchona alkaloid catalysts 8 in chloroform have been shown to isomerize trifluoromethylimine 9 with 34% ee, and hydrolysis of imine 10 to the corresponding chiral amine was of course unproblematic (Scheme 2) (30).
By now, the asymmetric isomerization of trifluoromethylimines has been realized in many variations (30–34).
Contrary to the biological transamination with pyridoxamine 2, organocatalytic trifluoromethylimine isomerization proceeds with transition states without extensive delocalization. The intriguing 2-azaallyl anion intermediate is characterized by umpolung at both carbons bound to the central nitrogen, ready to pick up a proton to yield either substrate 9 or product 10. The prospect to stabilize this beautiful reactive intermediate on π-acidic aromatic surfaces was simply irresistible (Scheme 2).
Scheme 2. The design of asymmetric anion-π catalysts for the isomerization of trifluoromethylimines, with the expected structure of the reactive intermediate RI1, the 2-azaallyl anion, stabilized on the π- acidic surface of anion-π catalyst 11 (Figure 1, R1 = p-nitrophenyl) and the structure of a conventional tertiary amine catalyst 8.
Results and Discussion
Design. Anion-π transaminase mimics were designed around the π-acidic surface of a naphthalenediimide (NDI) (35). NDIs have emerged as privileged platforms for anion- π catalysis because their intrinsic quadrupole moment perpendicular to the plane is with Qzz = +18 B unusually strong (e.g., twice the Qzz = +9 B of the classical hexafluorobenzene), and it can be easily varied with substituents in the core (up to super-π-acids with Qzz = +39 B) (22, 23). Rigidified Leonard turns derived from cyclohexyldiamine have been introduced recently to position a tertiary amine base next to the π surface (24).
Hydrogen-bond assisted ion pairing with the conjugate ammonium acid positions anionic reactive intermediates firmly on the π surface, enabling also weaker anion-π interactions to contribute to transition-state stabilization, i.e.
anion-π catalysis (14). As mentioned in the introduction, the reactive intermediate of trifluoromethylimine isomerization is the 2-azaallyl anion (Scheme 2). The
delocalized negative charge in this intermediate was particularly appealing for anion-π catalysis because anion-π interactions are not limited by strong directionality and can be supported by π-π interactions. Examples for the power of such π-π enhanced anion-π interactions reach from nitrate recognition (36–39) to the catalysis of enolate chemistry (23, 24). In the envisioned reactive intermediate RI1, umpolung at both carbons bound to the central nitrogen is further supported not only by hydrogen-bond assisted ion pairing with the ammonium cation but also by another hydrogen bond to an amide donor at the other side of the π- acidic surface (Scheme 2, Figure 1).
Figure 1. Structure of catalysts used in this study.
Synthesis. Anion-π catalyst 11 was readily accessible following previously reported procedures (Figure 1) (24).
The synthesis of the required control molecules 12-16 was similarly straightforward. Experimental details and characterization of all new compounds can be found in the Supporting Online Information.
Evaluation. Reactions were performed with 500 mM substrate 9, 20 mol% catalyst 11 at 20 ºC. The progress of the reactions was followed by 1H NMR spectroscopy (Figure S1). Reaction times were adjusted to usually reach completion (Table 1). Enantiomeric excess (ee) was determined by chiral HPLC of product 10 (Figures S2-S5).
Initial solvent screening gave best results in CDCl3
(Table 1). After 40 h in the presence of catalyst 11, product 10 was obtained with 94% conversion and 22% ee. Control catalyst 12 was prepared to probe for contributions from
N
N O
O O
O N H
S H N F3C
Ph
R1
O N
RI1 Ph
N R1 F3C
9
Ph N R1 F3C
10
*
N
N
OR
8
O S
NH O
O N
S O N N O
O NH O
O N O
N NO
O HN
O S
NH O
O N
S O N O
O
O O
O O
HN
O S
NH O
O N
S O N O
N S
O
O N
S O N NO
11
13
14
15
16 12
O OH 17
3 anion-π interactions. This catalyst was tested together with amide 13. Used together, amine 12 and amide 13 reproduce the structure of catalyst 11 as precisely as possible except for the π-acidic NDI surface (Figure 1). However, compared to 11, the reaction catalyzed by 12 and 13 was much slower and reached only 23% conversion in 60 h, and enatioselectivity dropped to half (Table 2, entries 1, 2;
Figure S6). Comparison of the initial rates calculated to a transition-state stabilization by catalyst 11 exceeding that of 12 by ∆Ea = –3.8 kJ mol-1 (Table 2, entry 2).
The catalysis of the imine isomerization by amine 12 was faster in the presence of NDI 14 than in the presence of amide 13 (Table 2, entries 1, 3). Moreover, stereoselectivity increased slightly from 12% ee to 15% ee. NDI 14 contains an amide on both sides of the π-acidic surface to eventually assist the stabilization of the anionic reactive intermediate RI1 by anion-π interactions. However, contrary to NDI 11, NDI 14 does not contain a tertiary amine base to produce the anionic intermediate RI1 from substrate 9. The rate enhancements observed in the presence of NDI 14 thus suggested that amine 12 and NDI 14 operate together as non-covalent anion-π catalyst, with amine 12 generating and NDI 14 stabilizing the 2-azaallyl anion in RI1.
This conclusion was important because anion-π catalysis has been successful only with covalent, bi- or trifunctional catalysts such as 11 (24–28). In clear contrast, supramolecular anion-π catalysis with multicomponent systems has remained elusive so far. To test for the existence of supramolecular anion-π catalysis, the two sulfides in the core of NDI 14 were oxidized to sulfones. In the obtained NDI 15, the strongly withdrawing sulfones lower the energy of the LUMO level and thus increase the π acidity of the NDI with otherwise minimal global structural change (24–28). Together with amine 12, imine isomerization was faster with the more π-acidic NDI 15 than with the less π-acidic NDI 14 (Table 2, entries 3, 4). The obtained increase in transition-state stabilization ∆Ea = –0.9 kJ mol–1 was about as expected for the underlying increase in π acidity. In line with the fundamental principles of asymmetric catalysis, stereoselectivity increased with transition state recognition from 15% ee for amine 12 with the less π-acidic 14 to 20% ee for amine 12 with the more π- acidic 15. Control experiments confirmed that NDIs 14 and 15 are inactive in the absence of amine 12 (Table 2, entries
5, 6). Increasing rate and stereoselectivity with increasing π acidity and π basicity is generally accepted as experimental evidence as strong as possible in support of operational anion-π and cation-π catalysis, respectively (40). The existence of supramolecular anion-π catalysts can thus, with all due caution, be considered as presumably confirmed.
The stereoselectivity obtained with the more π-acidic supramolecular catalyst 12+15 is almost as good as the 22%
ee obtained with the covalent bifunctional anion-π catalyst 11 (Table 2, entries 2, 4).
Catalyst 16 contains two tertiary amines, one on each side of the π surface. Compared to the original catalyst 11 with one amine and one amide, diamine catalyst 16 was much faster but clearly less enantioselective (Table 2, entry 7). Consistent with the activity of diamides 14 and 16, this finding supported the importance of Leonard-turned24 neutral amide hydrogen-bond donors to position the anionic reactive intermediate RI1 on the π surface for stabilization by operational anion-π interactions (Scheme 2). The addition of pivalic acid 17 to diamine NDI 16 was expected to regenerate a hydrogen-bond donor as in 13 without significant binding of the bulky pivaloate anion to the π surface. In the presence of one equivalent of 17, NDI catalyst 16 proceeded slower and with decreased enantioelectivity (Table 2, entry 8). These trends were consistent with reducing the total concentration of amines inactivation on the one hand and stabilization and protonation of the anionic umpolung intermediate in the π surface by two proximal ammonium cations on the other.
Trifluoromethylimine isomerization with anion-π catalyst 13 in the presence of an excess tetrabutylammonium nitrate was slightly accelerated rather than decelerated (i.e., the isomerization was complete in 12 h rather than 40 h).
This failure to inhibit anion-π catalysis of transamination with nitrate was interesting because nitrate inhibition has previously been established as valuable experimental support for operational anion-π interactions (28, 29). In these reactions, nitrate inhibitors competed directly with nitronate intermediates for anion-π interactions. In the present transamination, the situation is different. Namely, anion-π interactions in the 2-azaallyl anion are supported and directed by hydrogen-bond assisted ion pairing with an ammonium cation (Scheme 2). This cation forms together with the anionic reactive intermediate RI1, by proton transfer from the substrate to the catalyst. Compared to this,
Table 2. Catalyst characterization.a
Entry Cat b ∆vinic ∆Ea (kJ mol–1)d η (%)e ee (%)f
1 12+13 - - 23 12
2 11 12.1 –3.8 94 22
3 12+14 6.2 –2.6 98g 15
4 12+15 10.4 –3.5 70 20
5 14 <0.1h - - -
6 15 <0.1h - - -
7 16 23.2 –5.1 94 13
8 16+17 17.3 –4.5 90 8
aReactions were carried out with substrate 9 (0.5 M) in the presence of 20 mol%
of catalyst at 20 ºC in CDCl3, usually measured after t = 60 h. bCatalyst, see Figure 1. cRate enhancement relative to 12+13. dTransition-state stabilization relative to 12+13, from ∆vini. eConversion based on crude 1H NMR spectroscopy with 1,1,2,2-tetrachloroethane as internal standard. fEnantiomeric excess. gt = 96 h. hinactive.
Table 1. Solvent screening for anion-π transaminase mimic 11.a Entry Solvent t (h) b η (%) c ee (%) d
1 CD2Cl2 40 88 18
2 THF-d8 40 92 17
3 DMF-d7 40 100 12
4 CD3CN 40 100 12
5 CDCl3 72 94 22
6 e CDCl3 40 10 -
7 DMSO-d6 40 100 8
8 Toluene-d8 40 40 9
9 C6D6 60 98 7
10 PhNO2 24 100 11
11 C6F6 40 60 11
aReactions were carried out with substrate 9 (0.5 M) in the presence of 20 mol%
of catalyst 11 at 20 ºC. bReaction time the reported data refer to. cConversion based on crude 1H NMR spectroscopy with 1,1,2,2-tetrachloroethane as internal standard. dEnantiomeric excess. eThe reaction was run at 5 ºC, ee was not detected.
nitrate-π interactions (37–40) would have to occur with the neutral catalyst, without support from hydrogen-bond assisted ion pairing. It was thus meaningful that they are not competitive and fail to inhibit the process. Several explanations were conceivable for the loss of enantioselectivity in the presence of excess nitrate, including ordinary solvent effects (Table 1) and disturbances unrelated to anion-π interactions as observed previously, for example, with the Jørgenson-Hayashi catalyst (28).
Conclusions
In this report, the first transaminase mimic that operates with anion-π interactions is described.
Trifluoromethylimine isomerization is initiated by a tertiary amine, the cumulated umpolung in the resulting 2-azaallyl anion intermediate is then stabilized on π-acidic aromatic surface. Increasing rates and enantioselectivities with presence and π acidity of this surface provide strong experimental support for operational anion-π interactions.
Besides the well precedented multifunctional covalent systems (24–28), non-covalent catalytic systems with separate tertiary amines and π-acidic surfaces are active as well. This is one of the first explicit examples for operational supramolecular anion-π catalysts. Anion-π catalysis of reactions that do not include nitronate intermediates (24–28) is similarly rare. Clearly improvable are enantioselectivities. Steadily increasing ee’s from quite modest beginnings also with conventional catalysts (30–36) indicate that this can be done, presumably also for anion-π catalysis. We are particularly interested in the integration on anion-π transamination into more complex systems (41, 42).
Supporting Information Experimental details.
Acknowledgements
We thank the NMR and the Sciences Mass Spectrometry (SMS) platforms for services, and the University of Geneva, the National Centre of Competence in Research (NCCR) Chemical Biology, the NCCR Molecular Systems Engineering, and the Swiss NSF for financial support.
References
(1) Martell, A. E. Acc. Chem. Res. 1989, 22, 115–124.
(2) Waser, M.; Novacek, D. J. Angew. Chem. Int. Ed. 2015, 54, 14288–14231.
(3) Xie, Y.; Pan, H.; Liu, N.; Xiao, X.; Shi, Y. Chem. Soc. Rev. 2015, 44, 1740–1748.
(4) Seebach, D. Angew. Chem. Int. Ed. 1979, 18, 239–336.
(5) Koszelewski, D.; Lavandera, I.; Clay, D.; Guebitz, G. M.;
Rozzell, D.; Kroutil, W. Angew. Chem. Int. Ed. 2008, 47, 9337–
9340.
(6) Truppo, M. D.; Rozzell, J. D.; Turner, N. J. Org. Process Res.
Dev. 2010, 14, 234–237.
(7) Breslow, R.; Canary, J. W.; Varney, M.; Waddell, S. T.; Yang, D.
J. Am. Chem. Soc. 1990, 112, 5212–5219.
(8) Qi, D.; Tann, C. M.; Haring, D.; Distefano, M. D. Chem Rev.
2001, 101, 3081–3112.
(9) Schaufelberger, F.; Hu, L.; Ramstrom, O. Chem. Eur. J. 2015, 21, 9776–9783.
(10) Limanto, J.; Ashley, E.; Yin, J.; Brendan, G. L.; Grau, B. T.;
Kassim, A. M.; Kim, M. M. Liu, Z.; Strotman, H. R.; Truppo, M.
D. Org. Lett. 2014, 16, 2716–2719.
(11) Kowalczyk, D.; Albrecht, L. Chem. Commun. 2015, 51, 3981–
3984.
(12) Pressnitz, D.; Fuchs, C. S.; Sattler, J. H.; Knaus, T.; Macheroux, P.; Mutti, F. G.; Kroutil, W. ACS Catal. 2013, 3, 555–559.
(13) Giustinano, M; Pirali, T.; Massarotti, A.; Biletta, B.; Novellion, E.; Campiglia, P.; Sorba, G.; Tron, G. Synthesis 2010, 23, 4107–
4188.
(14) Lan, X.; Tao, C.; Liu, X.; Zhang, A.; Zhao, B. Org. Lett. 2016, 18, 3658–3661.
(15) Frontera, A.; Gamez, P.; Mascal, M.; Mooibroek, T. J.; Reedijk, J.
Angew. Chem. Int. Ed. 2011, 50, 9564–9583.
(16) Giese, M.; Albrecht, M.; Rissanen, K. Chem. Commun. 2016, 52, 1778–1795.
(17) Chifotides, H. T.; Dunbar, K. R. Acc. Chem. Res. 2013, 46, 894–
906.
(18) Wang, D.-X.; Wang, M.-X. Chimia 2011, 65, 939–943.
(19) Ballester, P. Acc. Chem. Res. 2013, 46, 874–884.
(20) S. Kumar, M. R. Ajayakumar, G. Hundal and P. Mukhopadhyay, J. Am. Chem. Soc., 2014, 136, 12004-12010.
(21) Kennedy, C. R.; Lin, S.; Jacobsen, E. N. Angew. Chem. Int. Ed.
2016, 55, 12596–12624.
(22) Gorteau, V.; Bollot, G.; Mareda, J.; Perez-Velasco, A.; Matile, S.
J. Am. Chem. Soc. 2006, 128, 14788–14789.
(23) Miros, F. N.; Zhao, Y.; Sargsyan, G.; Pupier, M.; Besnard, C.;
Beuchat, C.; Mareda, J.; Sakai, N.; Matile, S. Chem. Eur. J. 2016, 22, 2648–2657.
(24) Cotelle, Y.; Benz, S.; Avestro, A.-J.; Ward, T. R.; Sakai, N.;
Matile, S. Angew. Chem. Int. Ed. 2016, 55, 4275–4279.
(25) Zhao, Y.; Domoto, Y.; Orentas, E.; Beuchat, C.; Emery, D.;
Mareda, J.; Sakai, N.; Matile, S. Angew. Chem. Int. Ed. 2013, 52, 9940–9943.
(26) Zhao, Y.; Benz, S.; Sakai, N.; Matile, S. Chem. Sci. 2015, 6, 6219–6223.
(27) Zhao, Y.; Cotelle, Y.; Avestro, A.-J.; Sakai, N.; Matile, S. J. Am.
Chem. Soc. 2015, 137, 11582–11585.
(28) Liu, L.; Cotelle, Y.; Avestro, A.-J.; Sakai, N.; Matile, S. J. Am.
Chem. Soc. 2016, 138, 7876–7879.
(29) Cotelle, Y.; Lebrun, V.; Sakai, N.; Ward, T. R.; Matile, S. ACS Cent. Sci. 2016, 2, 388–393.
(30) Soloshonok, V. A.; Yasumoto, M. J. Fluorine Chem. 2007, 128, 170–173.
(31) Soloshonok, V. A.; Ono, T.; Soloshonok, I. V. J. Org. Chem.
1997, 62, 7538–75399.
(32) Michaut, V.; Metz, F.; Paris, J.-M.; Plaquevent, J.-C. J. Fluorine Chem. 2007, 128, 500–506.
(33) Liu, M.; Li, J.; Xiao, X.; Shi, Y. Chem. Commun. 2013, 49, 1404–
1406.
(34) Wu, Y.; Hu, L.; Li, Z.; Deng, L. Nature 2015, 523, 445–450.
(35) Al Kobaisi, M.; Bhosale, Si. V.; Latham, K.; Raynor, A. M.;
Bhosale, Sh. V. Chem. Rev. 2016, 116, 11685–11796.
(36) Wang, D.-X.; Wang, M.-X. J. Am. Chem. Soc. 2013, 135, 892–
897.
(37) Watt, M. M.; Zakharov, L. N.; Haley, M. M.; Johnson, D. W.
Angew. Chem. Int. Ed. 2013, 52, 10275–10280.
(38) Giese, M.; Albrecht, M.; Ivanova, G.; Valkonen, A.; Rissanen, K.
Supramol. Chem. 2012, 24, 48–55.
(39) Adriaenssens, L.; Estarellas, C.; Vargas Jentzsch, A.; Martinez Belmonte, M.; Matile, S.; Ballester, P. J. Am. Chem. Soc. 2013, 135, 8324–8330.
5 (40) Zhao, Y.; Cotelle, Y.; Sakai, N.; Matile, S. J. Am. Chem. Soc.
2016, 138, 4270–4277.
41 Baumeister, B.; Sakai, N.; Matile, S. Org. Lett. 2001, 3, 4229–
4232.
42 Cotelle, Y.; Lebrun, V.; Sakai, N.; Ward, T. R.; Matile, S. ACS Cent. Sci. 2016, 2, 388–393.
TOC graphic:
N
N O
O O
O N H
S
H N F3C
Ph
R1
O N
Ph N R1 F3C
asymmetric
anion-π catalyst Ph N R1 F3C
