Article Cite This: J. Am. Chem. Soc. 2017, 139, 15356-15362
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Influence of the Trans/Cis Conformer Ratio on the Stereoselectivity of Peptidic Catalysts Tobias Schnitzer and Helma Wennemers* Eidgenossische Technische Hochschule Zurich, Laboratory of Organic Chemistry, Vladimir-Prelog-Weg 3, Zurich 8093, Switzerland S Supporting Information *
ABSTRACT: Trans/cis isomerization of Xaa-Pro bonds is key for the structure and function of several enzymes. In recent years, numerous versatile peptidic catalysts have been developed that bear Xaa-Pro amide bonds. Due to the many degrees of freedom within even short peptides, the design and optimization of peptidic catalysts by rational structural modifications is difficult. We envisioned that control over the trans/cis amide bond ratio may provide a tool to optimize the catalytic performance of peptidic catalysts. Here, we investigated the influence of the amide bond conformation on the stereoselectivity of H-Pro-Pro-Xaa-NH2-type peptidic catalysts in conjugate addition reactions. The middle Pro residue within the tripeptides was replaced with analogues of varying ring sizes (azetidine carboxylic acid, Aze, and piperidine carboxylic acid, Pip) to produce different trans/cis ratios in different solvents. The studies revealed a direct correlation between the trans/cis amide bond ratio and the enantio- and diastereoselectivity of structurally related peptidic catalysts. These insights led to the identification of H-D-Pro-Pip-Glu-NH2 as a highly reactive and stereoselective amine-based catalyst that allows C−C bond formations to be performed in the presence of as little as 0.05 mol %, which is the lowest catalyst loading yet achieved for organocatalyzed reactions that rely on an enamine-based mechanism.
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INTRODUCTION Over the past two decades, numerous peptides have emerged as versatile catalysts for different asymmetric transformations.1−9 Several examples showed that peptides can be highly stereoselective and reactive as well as chemo- and regioselective catalysts.1−9 Thus, peptides enable the combination of features that may be difficult to achieve with other synthetic catalysts of comparable molecular weight. However, the many degrees of conformational freedom render a correlation between structural and catalytic features difficult.5 Thus, there is a need for design principles that facilitate the optimization of peptidic catalysts. Xaa-Pro bonds are common structural elements within numerous catalytically active peptides and can adopt trans and cis amide conformations (Scheme 1a).3−9 This trans/cis
different catalytic properties. Yet, little is known about the influence of cis and trans isomers on the performance of catalytically active peptides.4 We envisioned that control over the trans/cis ratio of Xaa-Pro bonds could provide a means to optimize the catalytic performance of peptidic catalysts. The effect of the trans/cis conformer ratio on the catalytic properties can be difficult to determine with long, complex peptides and when more than one Xaa-Pro bond is present in the catalytically active peptide. Peptides with the general structure Pro-Pro-Xaa are among the shortest Pro-containing peptidic catalysts (Scheme 1b).1 We therefore envisioned ProPro-Xaa-type catalysts as a good testing ground for probing the effect of the trans/cis conformer ratio on the reactivity and stereoselectivity of peptidic catalysts. These tripeptides are effective catalysts for aldol and conjugate addition reactions.6−9 For example, H-D-Pro-Pro-Glu-NH2 (A) and H-D-Pro-Pro-AsnNH2 (B) are potent catalysts for stereoselective addition reactions of aldehydes to β-nitroolefins and to maleimide, respectively.7,9 The peptidic catalysts provide the products in high yields and stereoselectivities and are also remarkably chemoselective and reactive. For example, only 1 mol % of tripeptide A suffices to obtain a range of different conjugate addition products in high yields and stereoselectivities, whereas other chiral amine-based catalysts require significantly higher catalyst loadings.13,14 Mechanistic studies showed that the conjugate addition reaction proceeds via an enamine
Scheme 1. (a) Trans/Cis Equilibrium of Xaa-Pro Amide Bonds; (b) Pro-Pro-Xaa-Type Catalysts
isomerization typically has a profound effect on the structure of peptides and proteins and is used in nature for regulation of, e.g., signal transduction, aggregation, as well as enzymatic processes.10−12 Catalytically active peptides with Xaa-Pro bonds are prone to adopt cis and trans amide conformers, which can be expected to have distinctly different structures and thereby © 2017 American Chemical Society
Received: June 19, 2017 Published: October 18, 2017 15356
DOI: 10.1021/jacs.7b06194 J. Am. Chem. Soc. 2017, 139, 15356−15362
Article
Journal of the American Chemical Society
conformer ratios. We reasoned that the different degrees of conformational flexibility of four- and six-membered analogues of proline19,21 would not suffice to disturb the overall steric and stereoelectronic features of the catalyst to a significant extent. Effect of Ring-Size Analogues of H-D-Pro-Pro-Glu-NH2 on the Trans/Cis Conformer Ratio and Stereoselectivity. We started our investigations by studying the effect of the trans/cis amide bond ratio on the catalytic performance of H-DPro-Pro-Glu-NH2 (A) in conjugate addition reactions of aldehydes to nitroolefins. Thus, we prepared analogues of A bearing azetidine carboxylic acid (Aze) and piperidine carboxylic (Pip)the four- and six-membered ring analogues of prolinein the middle position (Table 1). H-D-Pro-Aze-
intermediate (I) and that the subsequent C−C bond formation with the nitroolefin is the rate- and enantioselectivitydetermining step of the reaction (Scheme 2a).13,15,16 Crystal Scheme 2. (a) Catalytic Cycle of Conjugate Addition Reactions of Aldehydes to Nitroolefins Catalyzed by H-DPro-Pro-Glu-NH2 (A); (b) Trans and Cis Isomers of Enamine I
Table 1. Conjugate Addition Reaction of Butanal to (E)-Nitrostyrene Catalyzed by Peptides A4, A, and A6
a
Trans/cis conformer ratio in CDCl3/CD3OH 9:1. bConversion determined by 1H NMR spectroscopic analysis of the crude material. c Determined by chiral stationary phase SFC analysis.
structures of D-Pro-Pro-Xaa type peptides all show a β-turn-like structure with a trans D-Pro-Pro amide bond.17 In solution, the thermodynamically favored trans conformer will be in equilibrium with the cis conformer of the catalyst. This rotation around the tertiary amide should significantly affect the overall three-dimensional structure of the catalyst, in particular since the enamine moiety will point into opposite direction, and should therefore have a profound influence on the stereoselectivity of the reaction (Scheme 2b). Herein, we used Pro-Pro-Xaa-catalyzed conjugate addition reactions of aldehydes to β-nitroolefins and maleimide as model reactions to examine the effect of trans/cis isomerization on the stereoselectivity of peptidic catalysts. Different trans/cis conformer ratios were achieved by changing the ring size of the middle residue in Pro-Pro-Xaa-type catalysts and by performing the reaction in different solvents. The results show that the trans/cis amide bond ratio of structurally closely related peptidic catalysts correlates with their enantio- and diastereoselectivity. These insights allowed for the development of an improved peptidic catalyst with respect to reactivity and stereoselectivity.
Glu-NH2 (A4) and H-D-Pro-Pip-Glu-NH2 (A6) were readily obtained as TFA salts by standard solid-phase peptide synthesis following the Fmoc/tBu strategy.22 As expected, the 1H NMR spectra of the TFA salts of A4, A, and A6 showed two spin systems that correspond to the trans and cis conformers around the tertiary amide. The major trans and minor cis isomers were unambiguously assigned on the basis of nuclear Overhauser effects (NOEs) between D-Pro-Hα and Pro-Hδ (Aze-Hγ and Pip-Hε) and D-Pro-Hα and Pro-Hα (Aze-Hα and Pip-Hα), respectively (Figure 1, see the Supporting Information for details). These initial NMR spectroscopic studies were performed using a mixture of CDCl3/CD3OH 9:1 to be as close as possible to the solvent CHCl3/iPrOH 9:1 that is optimal for the conjugate addition reaction catalyzed by A.6,23 The 1H NMR spectroscopic analyses revealed significantly different trans/cis conformer ratios of A4, A, and A6. The population of the trans conformer grows with increasing ringsize from Kt/c = 10 (A4·TFA), to Kt/c = 46 (A·TFA), and Kt/c = 71 (A6·TFA) (Table 1). Thus, the ring size of the cyclic amino acid in the middle position of H-D-Pro-Yaa-Glu-NH2 has a significant effect on the trans/cis conformer ratio of the tertiary amide bond. Next, we probed whether these differences in the trans/cis ratio are reflected in the stereoselectivity of the peptidic catalysts. The conjugate addition reaction between butanal 1a and (E)-nitrostyrene 2a in CHCl3/iPrOH 9:1 served as a test reaction (Table 1). Here, 1 mol % of the TFA salt of peptides A4, A, and A6 was used along with an equimolar amount of N-
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RESULTS AND DISCUSSION The trans/cis ratio of Xaa-Pro bonds can be influenced with substituents on the pyrrolidine ring of proline (e.g., F, OH, N3, alkyl) or with proline analogues of varying ring size.18,19 Substituents can also affect the steric and stereoelectronic properties of the proline residue,20 which would impede a direct correlation between the trans/cis amide bond ratio with the stereoselectivity of the peptidic catalysts. We therefore used analogues of proline with different ring sizes as tools to access structurally related catalysts that differ in their trans/cis 15357
DOI: 10.1021/jacs.7b06194 J. Am. Chem. Soc. 2017, 139, 15356−15362
Article
Journal of the American Chemical Society
cis ratio and the stereoselectivity of the peptidic catalysts, we performed the conjugate addition reaction between butanal and nitrostyrene with peptides A4, A, and A6 and determined the trans/cis conformer ratios of the catalysts in different solvents (Scheme 3). Aprotic solvents THF, 1,4-dioxane, MeCN, and
methylmorpholine (NMM) to liberate the N-terminal amine. (Note that previous studies had shown that the presence of TFA/NMM does not affect the performance of the peptidic catalyst A.15) The desired product 3a was obtained cleanly in the presence of all three peptides in less than 12 h, but with significantly different stereoselectivities. Peptide A4 had the lowest population of the trans conformer (Kt/c = 10, ∼90% trans amide) and exhibited the lowest enantio- and diastereoselectivity (92% ee, dr 26:1) followed by catalyst A (97% ee, dr 35:1; Kt/c = 46, ∼98% trans amide). Catalyst A6 had the highest population of the trans conformer and provided the product in almost perfect stereoselectivity (99% ee, dr 50:1; Kt/c = 71, ∼98.5% trans amide). Structural Similarity of H-D-Pro-Yaa-Glu-NH2 Catalysts. The peptidic catalysts A4, A, and A6 need to be structurally similar in order to support the correlations observed between their trans/cis conformer ratios and their stereoselectivities. Reassuringly, crystal structures of the TFA salts of A and A6 that were obtained by crystallization in MeOH/THF are almost identical (Figure 1a). The overlay of
Scheme 3. Correlation between the Amount of Trans Conformer of Peptides A4, A, and A6 with Their (a) Enantioselectivity and (b) Diastereoselectivity As Examined in Different Solvents
Figure 1. (a) Overlay of the crystal structures of the TFA salts of A (green) and A6 (blue). (b) Non-vicinal NOEs of the TFA salts of A4 (n = 0), A (n = 1), and A6 (n = 2) observed in CDCl3/CD3OH 9:1.
the two structures shows that the bond angles and lengths of the peptide backbone as well as the side chains of the Nterminal D-Pro and the C-terminal Glu residues are hardly influenced by the ring size of the amino acid in the middle position. Both peptides adopt β-turn structures with a hydrogen bond between the CO of D-Pro and the C-terminal amide. In addition, the TFA anion is coordinated by hydrogen bonds to the N-terminal amino group of D-Pro and the amide N−H of Glu. NOEs measured by NMR spectroscopic experiments of the major trans isomers in solutions of CDCl3/CD3OH 9:1 further supported that the structures of A4, A, and A6 are closely related. The same pattern of NOEs was observed in the spectra of the three peptides (only the major trans conformer was fully assigned, Figure 1b). Aside from the NOEs that are indicative of the trans amide bond, NOEs between Glu-HNH and the protons of the middle residue as well as those between Glu-Hα with Glu-HNH, Glu-HCONH2, and Glu-Hγ occur in the spectra of all three peptides and are in agreement with the turn conformation observed in the crystal structures. Thus, the ring size of the residue in the middle position of peptides A4, A, and A6 does not influence their overall structure to a significant extent. This finding corroborates that the observed differences in stereoselectivity of A4, A, and A6 arise from their different trans/cis conformer ratios. Effect of Solvents on the Trans/Cis Conformer Ratio and Stereoselectivity of Peptidic Catalysts A4, A, and A6. Solvent can affect the trans/cis conformer ratio of Xaa-Pro bonds.24,25 To further probe the correlation between the trans/
DMF as well as the protic solvents MeOH and CHCl3/MeOH 9:1 were used. This choice of solvent was made to cover the largest possible polarity range in which the peptides are still soluble. The TFA salts of the peptides were used since they are generally more soluble than the “desalted” peptides.26 These studies revealed significant differences in the trans/cis conformer ratios (from Kt/c = 2.1, ∼68% trans to Kt/c = 71, ∼98.5% trans) as well as the diastereo- and enantioselectivity of the three peptidic catalysts in the different solvents. In all solvents examined, a higher trans/cis conformer ratio of the catalyst correlated with a higher enantioselectivity (Scheme 3a). Most remarkably, linear correlations between the amount of trans conformer of the peptidic catalysts and their enantio- and diastereoselectivities were observed in each of the solvents (Scheme 3a,b). Higher enantioselectivity goes in all solvents hand in hand with higher trans/cis conformer ratios of the catalysts (Scheme 3a). The same trend was also observed for the diastereoselectivity with the exception of MeOH and DMF, where a higher content of the trans conformer correlates with lower diastereoselectivity (Scheme 3b). Note that the amount 15358
DOI: 10.1021/jacs.7b06194 J. Am. Chem. Soc. 2017, 139, 15356−15362
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Journal of the American Chemical Society
Table 2. Equilibrium Constants Ktrans/cis of the TFA Salt of A and the Enamine Derived from Peptide A and Phenylacetaldehyde in Different Solventsa
of the trans conformer increases in CHCl3/MeOH 9:1, THF, dioxane, and MeCN in the order A4 (Aze) < A (Pro) < A6 (Pip), whereas the order changes to A6 (Pip) < A4 (Aze) < A (Pro) in MeOH and A4 (Aze) < A6 (Pip) < A (Pro) in DMF. The reasons for these different trends in the trans/cis ratios are difficult to rationalize since multiple factors, e.g., n → π* interactions, dipole moments, and solvation, are responsible for this conformer equilibrium.18,19,24,25 It is also significant to note that comparably small differences in trans/cis ratios can translate into remarkable differences in the enantioselectivity. For example, in MeCN the differences in the trans/cis ratios of 24:1 and 57:1 (ΔG° = 0.5 kcal mol−1) result in differences in enantioselectivity of 60% versus 92% ee (ΔΔG⧧ = 1.1 kcal mol−1). The observed correlation highlights the fact that the trans/cis ratio of the tertiary amide is a key factor for the enantio- and diastereoselectivity of the catalysts.27,28 The results also show that the trans conformer of the peptides is the more stereoselective catalyst compared to the cis conformer. Trans/Cis Conformer Ratio of the Enamine Intermediate. The previous mechanistic studies had shown that the enamine formed by the tripeptidic catalyst and the aldehyde is involved in the rate- and enantioselectivity determining step of the conjugate addition reaction.15,16 Thus, the trans/cis ratio of the enamine intermediate is ultimately key to the stereochemical outcome of the reaction. The observed correlation between the trans/cis ratio of the TFA salts of the catalysts with their stereoselectivity entails that also the trans/cis ratio of the catalyst−enamines correlates with the stereoselectivity. Yet, the relative population of the trans and cis conformers of the catalyst−enamines is likely different from that of the TFA salts. We therefore attempted to prepare enamines derived from the peptidic catalysts. Enamines formed by amine-based catalysts that bear a carboxylic acid moiety are highly reactive and therefore difficult to characterize, in particular, in protic solvents.29 Thus, analyses of the trans/cis conformer ratios of enamines formed by catalysts A4, A, and A6 are not trivial, which is why we performed the systematic analysis in the different solvents with the unmodified peptides. We succeeded in obtaining enamines derived from catalyst A that were sufficiently stable to determine their trans/cis ratio in DMSO-d6, CDCl3, and CDCl3/CD3OH 9:1 by using phenylacetaldehyde, which forms a conjugated and thereby stabilized enamine with secondary amines, in the presence of molecular sieves (3 Å) (Table 2). As seen for the TFA salts, a significant influence of the solvent on the trans/cis conformer ratios was observed with values that range from 2.6:1 in DMSO-d6 to 20:1 in CDCl3/CD3OH 9:1. The trans/cis ratios of the enamines are generally lower compared to those of the corresponding TFA salt of peptide A. However, to our satisfaction, the general trend of the conformer ratio in the different solvents is the same for the enamine and the TFA salt. These results further corroborate the influence of the trans/ cis amide bond ratio on the stereoselectivity of the peptidic catalysts, in particular since isomerization around Xaa-Pro bonds is slow (kcis→trans ∼ 0.005 s−1)30 compared to the catalytic reaction under standard reaction conditions (turnover frequency ∼0.025 s−1).15,31 Effect of the Trans/Cis Ratio of H-D-Pro-Pro-Xaa-NH2 on the Addition Reaction of Aldehydes to Maleimide. Next, we probed the generality of the correlation between the trans/cis conformer ratio and the stereoselectivity of the peptidic catalysts and used the addition reaction of aldehydes
a
Determined at a concentration of 15 mM using molecular sieves (3 Å).
to maleimide as a testing ground. The tripeptide H-D-Pro-ProAsn-NH2 (B) is an effective catalyst for this transformation.9 We therefore prepared H-D-Pro-Pip-Asn-NH2 (B6) with a sixmembered pipecolic acid residue in the middle position and compared the properties of this analogue with those of B (Table 3). A solvent mixture of CDCl3/CD3OH 1:1 was used Table 3. Conjugate Addition Reaction of Aldehydes to Maleimide in the Presence of H-D-Pro-Pro-Asn-NH2 (B) and H-D-Pro-Pip-Asn-NH2 (B6)
a
Yield of the isolated product. bDetermined by 1H NMR spectroscopy of the crude reaction mixture. cDetermined by chiral stationary-phase HPLC analysis. dData taken from ref 9.
to determine the trans/cis ratio since the highest stereoselectivities had been observed in CHCl3/iPrOH 1:1 with catalyst B.9 The trans/cis ratios of B and B6 are similar in this solvent with a slightly higher ratio observed for the fivemembered ring analog (Kt/c = 10 and 8, Table 3). This trend is comparable to that observed for peptides A and A6 in methanol where the Pro derivative has a higher trans content compared 15359
DOI: 10.1021/jacs.7b06194 J. Am. Chem. Soc. 2017, 139, 15356−15362
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Journal of the American Chemical Society to the Pip derivative (Scheme 3). On the basis of the trans/cis conformer ratio, the six-membered ring analogue B6 was expected to be less enantioselective compared to the parent compound. Indeed, when three different aldehydes were reacted with maleimide in the presence of 5 mol % of the peptides, the succinimides 5a−c were obtained with higher enantio- and diastereoselectivity with B compared to B6 (Table 3).32 Performance of H-D-Pro-Pip-Glu-NH2 in Conjugate Addition Reactions of Aldehydes to Nitroolefins. The effectiveness of H-D-Pro-Pip-Glu-NH2 (A6) in the conjugate addition reaction of butanal to (E)-nitrostyrene encouraged us to explore its catalytic properties further as compared to the parent catalyst H-D-Pro-Pro-Glu-NH2. We chose to focus on aldehydes and nitroolefins that are difficult to react with each other (Table 4).33 Such examples include propanal and β-disubstituted aldehydes (Table 4, entries 2, 4, and 7) and nitroolefins bearing acetal, aliphatic, or electron-rich aromatic moieties (Table 4, entries 5−7). All reactions provided the desired product γ-nitroaldehydes 3a−g in the presence of the
Pip derivative A6 with higher enantio- and diastereoselectivities compared to A and other secondary amine-based organocatalysts.33 Finally, we compared the reactivity of peptide A6 with that of A. React IR was used for in situ monitoring of product formation from the conjugate addition reaction of butanal to (E)-nitrostyrene in the presence of A and A6 (Scheme 4). The Scheme 4. Conjugate Addition Reaction of Butanal to (E)-Nitrostyrene Catalyzed by A (Blue) and A6 (Green) Monitored by IR Spectroscopy (1 mol % Catalyst, CHCl3/iPrOH 9:1 at 20 °C)
Table 4. Comparison of Peptides A and A6 as Catalysts in Conjugate Addition Reactions of Challenging Substrates
shape of the rate profiles of both reactions is comparable, which indicates that the C−C bond formation is the rate- and enantioselectivity-determining step for both catalysts.15 However, the relative rate of product formation differed. In the presence of peptidic catalyst A 50% conversion was reached after 38 min, whereas half of the time (20 min) sufficed to reach the same level of conversion when the Pip analogue A6 was used. These results led us to investigate whether the catalyst loading can be reduced. High catalyst loadings of 5−30 mol % are common for reactions catalyzed by secondary amines and a major drawback for practical applications.14,33 Previous studies with the parent peptidic catalyst A had shown that 0.1 mol % of A suffice when an excess of nitroolefin relative to the aldehyde is reacted in dry solvents.13 Under these conditions, only 0.05 mol % of peptide A6 was necessary to obtain the γnitroaldehyde 3a in 95% yield with a diastereoisomeric ratio of 60:1 (syn/anti) and an enantioselectivity of 99% ee on a multigram scale (8.6 g) (Scheme 5). This catalyst loading is the lowest so far achieved in organocatalytic reactions using secondary amine-based catalysts. Thus, H-D-Pro-Pip-Glu-NH2 (A6) is an extraordinarily Scheme 5. Gram-Scale Synthesis of 3a Using 0.05 mol % of H-D-Pro-Pip-Glu-NH2 (A6)
a
Yield of the isolated product. bDetermined by 1H NMR spectroscopy of the crude reaction mixture. cDetermined by chiral stationary-phase SFC or HPLC analysis. dUse of 2 mol % of catalyst and NMM. e Reaction was performed in pure CHCl3. fData taken from ref 7b. 15360
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Migianu-Griffoni, E.; Deschamp, J.; Lecouvey, M. Adv. Synth. Catal. 2016, 358, 34. (3) For examples of peptidic catalysts without a Xaa-Pro bond, see: (a) Wende, R. C.; Seitz, A.; Niedek, D.; Schuler, S. M. M.; Hofmann, C.; Becker, J.; Schreiner, P. R. Angew. Chem., Int. Ed. 2016, 55, 2719. (b) Müller, C. E.; Zell, D.; Schreiner, P. R. Chem. - Eur. J. 2009, 15, 9647. (c) Weyer, A.; Diaz, D.; Nierth, A.; Schlörer, N. E.; Berkessel, A. ChemCatChem 2012, 4, 337. (d) Freund, M.; Schenker, S.; Tsogoeva, S. B. Org. Biomol. Chem. 2009, 7, 4279. (e) Martin, H. J.; List, B. Synlett 2003, 12, 1901. (4) (a) D'Elia, V.; Zwicknagl, H.; Reiser, O. J. Org. Chem. 2008, 73, 3262. (b) De la Torre, A. F.; Rivera, D. G.; Ferreira, M. A. B.; Correa, A. G.; Paixao, M. W. J. Org. Chem. 2013, 78, 10221. (5) Metrano, A. J.; Abascal, N. C.; Mercado, B. Q.; Paulson, E. K.; Hurtley, A. E.; Miller, S. J. J. Am. Chem. Soc. 2017, 139, 492. (6) Krattiger, P.; Kovasy, R.; Revell, J. D.; Ivan, S.; Wennemers, H. Org. Lett. 2005, 7, 1101. (7) (a) Wiesner, M.; Revell, J. D.; Wennemers, H. Angew. Chem., Int. Ed. 2008, 47, 1871. (b) Wiesner, M.; Neuburger, M.; Wennemers, H. Chem. - Eur. J. 2009, 15, 10103. (8) (a) Wiesner, M.; Revell, J. D.; Tonazzi, S.; Wennemers, H. J. Am. Chem. Soc. 2008, 130, 5610. (b) Duschmale, J.; Wennemers, H. Chem. - Eur. J. 2012, 18, 1111. (c) Kastl, R.; Wennemers, H. Angew. Chem., Int. Ed. 2013, 52, 7228. (d) Schnitzer, T.; Wennemers, H. Synlett 2017, 28, 1282. (9) Grünenfelder, C.; Kisunzu, J.; Wennemers, H. Angew. Chem., Int. Ed. 2016, 55, 8571. (10) (a) Fischer, G. Chem. Soc. Rev. 2000, 29, 119. (b) Dugave, C.; Demange, L. Chem. Rev. 2003, 103, 2475. (11) For reviews, see: (a) Craveur, P.; Joseph, A. P.; Poulain, P.; de Brevern, A. G.; Rebehmed, J. Amino Acids 2013, 45, 279. (b) Shoulders, M. D.; Raines, R. T. Annu. Rev. Biochem. 2009, 78, 929. (c) Andreotti, A. H. Biochemistry 2003, 42, 9515. (d) VanHoof, G.; Goossens, F.; De Meester, I.; Hendriks, D.; Scharpe, S. FASEB J. 1995, 9, 736. (12) For examples, see: (a) Nelson, C. J.; Santos-Rosa, H.; Kouzarides, T. Cell 2006, 126, 905. (b) Pastorino, L.; Sun, A.; Lu, P.-J.; Zhou, X. Z.; Balastik, M.; Finn, G.; Wulf, G.; Lim, J.; Li, S.-H.; Li, X.; Xia, W.; Nicholson, L. K.; Lu, K. P. Nature 2006, 440, 528. (c) Videau, L. L.; Arendall, W. B., III; Richardson, J. S. Proteins: Struct., Funct., Genet. 2004, 56, 298. (d) Lummis, S. C. R.; Beene, D. L.; Lee, L. W.; Lester, H. A.; Broadhurst, R. W.; Dougherty, D. A. Nature 2005, 438, 248. (e) Arnold, U.; Hinderaker, M. P.; Köditz, J.; Golbik, R.; Ulbrich-Hofmann, R.; Raines, R. T. J. Am. Chem. Soc. 2003, 125, 7500. (f) Golbik, R.; Yu, C.; Weyher-Stingl, E.; Huber, R.; Moroder, L.; Budisa, N.; Schiene-Fischer, C. Biochemistry 2005, 44, 16026. (g) Holzberger, B.; Marx, A. J. Am. Chem. Soc. 2010, 132, 15708. (13) Wiesner, M.; Upert, G.; Angelici, G.; Wennemers, H. J. Am. Chem. Soc. 2010, 132, 6. (14) (a) List, B.; Lerner, R. A.; Barbas, C. F., III J. Am. Chem. Soc. 2000, 122, 2395. (b) For a review, see: Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471. (c) Science of Synthesis, Asymmetric Organocatalysis; List, B., Maruoka, K., Eds.; Georg Thieme Verlag: Stuttgart, 2012. (15) Duschmale, J.; Wiest, J.; Wiesner, M.; Wennemers, H. Chem. Sci. 2013, 4, 1312. (16) Bächle, F.; Duschmale, J.; Ebner, C.; Pfaltz, A.; Wennemers, H. Angew. Chem., Int. Ed. 2013, 52, 12619. (17) Grünenfelder, C. E.; Kisunzu, J. K.; Trapp, N.; Kastl, R.; Wennemers, H. Biopolymers 2017, 108, e22912. (18) For examples of substituted proline derivatives, see: (a) Pandey, A. K.; Naduthambi, D.; Thomas, K. M.; Zondlo, N. J. J. Am. Chem. Soc. 2013, 135, 4333. (b) Bretscher, L. E.; Jenkins, C. L.; Taylor, K. M.; DeRider, M. L.; Raines, R. T. J. Am. Chem. Soc. 2001, 123, 777. (c) Renner, C.; Alefelder, S.; Bae, J. H.; Budisa, N.; Huber, R.; Moroder, L. Angew. Chem., Int. Ed. 2001, 40, 923. (d) Sonntag, L.-S.; Schweizer, S.; Ochsenfeld, C.; Wennemers, H. J. Am. Chem. Soc. 2006, 128, 14697. (19) For examples of ring-size analogues of proline, see: (a) Jhon, J. S.; Kang, Y. K. J. Phys. Chem. B 2007, 111, 3496. (b) Melis, C.; Bussi,
reactive and stereoselective amine-based catalyst for conjugate addition reactions of aldehydes to nitroolefins.
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CONCLUSIONS The trans/cis ratio of the tertiary amide bond was found to have a significant effect on the stereochemical outcome of reactions catalyzed by H-Pro-Pro-Xaa-NH2-type peptides. Our investigations revealed a direct correlation between the trans/cis amide bond ratio and the enantio- and diastereoselectivity of the tripeptidic catalysts in a range of different protic and aprotic solvents. The value of tuning the conformer ratio for the optimization of peptidic catalysts was showcased by the development of H-D-Pro-Pip-Glu-NH2, a catalyst with an enhanced population of the trans conformer that outperforms the Pro analogue. Since Xaa-Pro is a common motif in catalytically active peptides, control over the trans/cis amide ratioby incorporation of ring-size analogues of proline or solvent variationscould become a general tool for improving the stereoselectivity and reactivity of peptidic catalysts.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.7b06194. Experimental details on the syntheses and analyses of the presented compounds (PDF) Crystal structure of peptide A (CIF) Crystal structure of peptide A6 (CIF)
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AUTHOR INFORMATION
Corresponding Author
*
[email protected] ORCID
Helma Wennemers: 0000-0002-3075-5741 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank the Fonds der Chemischen Industrie (Germany) for a Kekulé Fellowship for T.S. and the Swiss National Science Foundation (Grant No. 200020_169423) for financial support. This publication is dedicated to Prof. Dieter Seebach on the occasion of his 80th birthday.
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REFERENCES
(1) For reviews, see: (a) Davie, E. A. C.; Mennen, S. M.; Xu, Y.; Miller, S. J. Chem. Rev. 2007, 107, 5759. (b) Wennemers, H. Chem. Commun. 2011, 47, 12036. (c) Lewandowski, B.; Wennemers, H. Curr. Opin. Chem. Biol. 2014, 22, 40. (d) Shugrue, C. R.; Miller, S. J. Chem. Rev. 2017, 117, 11894. (2) For recent examples of peptidic catalysts with a Xaa-Pro bond, see: (a) Gustafson, J. L.; Lim, D.; Miller, S. J. Science 2010, 328, 1251. (b) Barrett, K. T.; Metrano, A. J.; Rablen, P. R.; Miller, S. J. Nature 2014, 509, 71. (c) Shugrue, C. R.; Miller, S. J. Angew. Chem., Int. Ed. 2015, 54, 11173. (d) Alford, J. S.; Abascal, N. C.; Shugrue, C. R.; Colvin, S. M.; Romney, D. K.; Miller, S. J. ACS Cent. Sci. 2016, 2, 733. (e) Romney, D. K.; Colvin, S. M.; Miller, S. J. J. Am. Chem. Soc. 2014, 136, 14019. (f) Mbofana, C. T.; Miller, S. J. J. Am. Chem. Soc. 2014, 136, 3285. (g) Lichtor, P. A.; Miller, S. J. Nat. Chem. 2012, 4, 990. (h) Han, S.; Miller, S. J. J. Am. Chem. Soc. 2013, 135, 12414. (i) Akagawa, K.; Sakai, N.; Kudo, K. Angew. Chem., Int. Ed. 2015, 54, 1822. (j) Akagawa, K.; Kudo, K. Angew. Chem., Int. Ed. 2012, 51, 12786. (k) Cortes-Clerget, M.; Gager, O.; Monteil, M.; Pirat, J.-L.; 15361
DOI: 10.1021/jacs.7b06194 J. Am. Chem. Soc. 2017, 139, 15356−15362
Article
Journal of the American Chemical Society G.; Lummis, S. C. R.; Molteni, C. J. Phys. Chem. B 2009, 113, 12148. (c) Kern, D.; Schutkowski, M.; Drakenberg, T. J. Am. Chem. Soc. 1997, 119, 8403. (d) Thomas, W. A.; Williams, M. K. Org. Magn. Reson. 1972, 4, 145. (e) Galardy, R. E.; Alger, J. R.; Liakopoulou-Kyriakides, M. Int. J. Pept. Protein Res. 1982, 19, 123. (f) Hayashi, T.; Asai, T.; Ogoshi, H. Tetrahedron Lett. 1997, 38, 3039. (20) Variations in the overall structure of the peptidic catalyst, e.g., by changes of the absolute configuration of the stereogenic centers or the linker length between the backbone and the carboxylic acid, influence the reactivity and stereoselectivity of Pro-Pro-Xaa-type catalysts. See, for example, refs 6 and 7. (21) For conformational studies on monomeric piperidine and azetidine amides, see: (a) Coombs, T. C.; Lushington, G. H.; Douglas, J.; Aube, J. Angew. Chem., Int. Ed. 2011, 50, 2734. (b) Szostak, R.; Aube, J.; Szostak, M. J. Org. Chem. 2015, 80, 7905. (c) Liu, C.; Achtenhagen, M.; Szostak, M. Org. Lett. 2016, 18, 2375. (d) Otani, Y.; Nagae, O.; Naruse, Y.; Inagaki, S.; Ohno, M.; Yamaguchi, K.; Yamamoto, G.; Uchiyama, M.; Ohwada, T. J. Am. Chem. Soc. 2003, 125, 15191. (22) For details, see the Supporting Information. (23) The NMR spectroscopic studies were performed at a peptide concentration of 5 mM. The same concentration was used for the catalytic reactions. (24) Siebler, C.; Maryasin, B.; Kuemin, M.; Erdmann, R. S.; Rigling, C.; Grünenfelder, C.; Ochsenfeld, C.; Wennemers, H. Chem. Sci. 2015, 6, 6725. (25) (a) Grathwohl, C.; Wüthrich, K. Biopolymers 1976, 15, 2043. (b) Hunston, R. N.; Gerothanassis, I. P.; Lauterwein, J. J. Am. Chem. Soc. 1985, 107, 2654. (c) Sugawara, M.; Tonan, K.; Ikawa, S.-I. Spectrochim. Acta, Part A 2001, 57, 1305. (26) The trans/cis ratio of the “desalted” peptide H-D-Pro-Pro-GluNH2 A is Kt/c > 100:1 in CDCl3/CD3OH 9:1. (27) Note that peptidic catalyst H-D-Pro-Ala-Glu-NH2 C bearing only trans-configured secondary amides catalyzed the conjugate addition of butanal to nitrostyrene but was less reactive and stereoselective (56% conv, 90% ee, 45:1 dr after 24 h under standard reaction conditions) compared to catalysts A4, A, and A6. This result shows that not only the trans/cis amide ratio but also the Ψ- and Φangles of the D-Pro-Pro/Aze/Pip motif are key to the performance of the catalysts. (28) The observed slight deviations from a linear correlation may be caused by differences in the flexibility of four-, five-, and six-membered rings; see ref 21. (29) For examples of enamines of secondary amine-based organocatalysts, see: (a) Haindl, M. H.; Hioe, J.; Gschwind, R. M. J. Am. Chem. Soc. 2015, 137, 12835. (b) Seebach, D.; Sun, X.; Ebert, M.-O.; Schweizer, W. B.; Purkayastha, N.; Beck, A. K.; Duschmalé, J.; Wennemers, H.; Mukaiyama, T.; Benohoud, M.; Hayashi, Y.; Reiher, M. Helv. Chim. Acta 2013, 96, 799. (30) (a) Grathwohl, C.; Wüthrich, K. Biopolymers 1981, 20, 2623. (b) Reimer, U.; Scherer, G.; Drewello, M.; Kruber, S.; Schutkowski, M.; Fischer, G. J. Mol. Biol. 1998, 279, 449. (31) The turnover frequency of TOF ∼ 0.025 s−1 was derived from the observed initial rates (t < 20 min) of the reaction under standard reaction conditions based on experimental data described in ref 15. (32) Note that the difference of the trans/cis ratios observed for B and B6 is small, which suggests that also other factors play an important role for the reaction. (33) For examples, see: (a) Ishikawa, H.; Suzuki, T.; Hayashi, Y. Angew. Chem., Int. Ed. 2009, 48, 1304. (b) Wang, W.; Wang, J.; Li, H. Angew. Chem., Int. Ed. 2005, 44, 1369. (c) Palomo, C.; Vera, S.; Mielgo, A. Angew. Chem., Int. Ed. 2006, 45, 5984. (d) Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew. Chem., Int. Ed. 2005, 44, 4212. (e) Lalonde, M. P.; Chen, Y.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 6366. For a recent review, see: (f) Alonso, D. A.; Baeza, A.; Chinchilla, R.; Gomez, C.; Guillena, G.; Pastor, I. M.; Ramon, D. J. Molecules 2017, 22, 895.
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