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ScienceDirect Asymmetric catalysis with short-chain peptides Bartosz Lewandowski and Helma Wennemers Within this review article we describe recent developments in asymmetric catalysis with peptides. Numerous peptides have been established in the past two decades that catalyze a wide variety of transformations with high stereoselectivities and yields, as well as broad substrate scope. We highlight here catalytically active peptides, which have addressed challenges that had thus far remained elusive in asymmetric catalysis: enantioselective synthesis of atropoisomers and quaternary stereogenic centers, regioselective transformations of polyfunctional substrates, chemoselective transformations, catalysis in-flow and reactions in aqueous environments. Addresses Laboratory of Organic Chemistry, ETH Zurich, Vladimir-Prelog-Weg 3, 8093 Zurich, Switzerland Corresponding author: Wennemers, Helma ([email protected])
Current Opinion in Chemical Biology 2014, 22:40–46 This review comes from a themed issue on Synthetic biomolecules Edited by Paul F Alewood and Stephen BH Kent For a complete overview see the Issue and the Editorial Available online 30th September 2014 http://dx.doi.org/10.1016/j.cbpa.2014.09.011 1367-5931/# 2014 Elsevier Ltd. All rights reserved.
Introduction Peptides fulfil a multitude of different functions in nature and everyday life as, hormones, neurotransmitters, toxins, therapeutics against numerous diseases, and artificial sweeteners [1]. Despite this functional versatility, the value of peptides for asymmetric catalysis has only been recognized in the past two decades [2,3]. Apart from early reports on cyclic dipeptides and polyleucines for catalytic asymmetric hydrocyanations [4] and epoxidations [5], respectively, the field remained dormant until the late 1990s. The establishment of numerous effective peptidic catalysts since then, is closely connected to the development of smart combinatorial screening methods that allowed the discovery of lead structures by overcoming the challenge of rationally designing potent catalyst structures [6]. Nowadays, the palette of reactions for which peptidic catalysts are available is broad and includes, for example, stereoselective acylations, phosphorylations, brominations, epoxidations, aldol, and numerous other C–C bond forming reactions [2,3]. Recent advances in the field also revealed that the structural and functional Current Opinion in Chemical Biology 2014, 22:40–46
diversity of peptides offers unique opportunities for tackling challenges that are difficult to address by other less modular catalyst structures. These include the development of catalysts for highly challenging enantioselective reactions, regioselective and chemoselective transformations, as well as metal-free catalysis at low catalyst loadings and in continuous flow. Within this report we will showcase these features with a focus on latest highlights that have not been covered in previous reviews [2,3].
Challenging enantioselective reactions Whereas numerous metalorganic and metal-free catalysts have been developed for enantioselective formations of stereogenic centers, the stereoselective installation of axial chirality has proven to be significantly more difficult. Miller provided a solution to this challenge with a tetrapeptidic catalyst that brominates substituted, tertiary benzamides to yield atropoisomeric tribromo products with excellent enantioselectivities [7]. Using the same tetrapeptide 1 the group also achieved dynamic kinetic resolution of atropoisomers of unsymmetrical tertiary benzamides with two axes of chirality; one defined through the benzamide structure, the other associated with the different substituents on the amide nitrogen (Figure 1a) [8]. The interplay of kinetic and thermodynamic parameters of the enantioselective bromination and isomerisation of the amide bond led to a product distribution with equal stereochemical enrichment of both the cis and trans amide isomers. This impressive control over the dynamics of the system not only allowed to obtain the target compound with high stereoselectivity but is also potentially of great value for the design of molecular switches or motors as well as ligands for metalbased asymmetric catalysts [9]. Acyclic compounds containing all-carbon, quaternary stereocenters represent another class of challenging molecules for asymmetric synthesis [10]. Kudo tackled this challenge with the 11-mer helical peptide 2 that catalyzes Michael reactions between nitromethane and b,b-disubstituted aldehydes (Figure 1b) [11]. Wennemers accessed the same type of g-nitroaldehydes with two consecutive stereogenic centers by conjugate addition reactions between aliphatic aldehydes and b,b-disubstituted nitroolefins, promoted by the H-d-Pro-Pro based catalyst 3 (Figure 1c) [12]. Of note, side reactions such as homo-aldol reactions, which had impeded the development of effective catalysts for this conjugate addition reaction, occur in the presence of tripeptide 3 only to a minor extent. This shows the high level of chemoselectivity of 3. The target g-nitroaldehydes were obtained in very high yields as well as enantioselectivities and www.sciencedirect.com
Asymmetric catalysis with short-chain peptides Lewandowski and Wennemers 41
Figure 1
(a)
O HO
N
10 mol% 1 DMBDH (1.5 equiv)
Br
CHCl3, 24 h N Boc 57:43 trans:cis racemic
(b)
O
HO
N
N N
Boc 94% yield 76:24 trans:cis 79:21 e.r. (for both the trans and cis isomer)
H-Pro-D-Pro-Aib-Trp-Trp-[Leu]6 R2
O
Ph OMe
1
R2 CHO
R1
MeOH/H2O (1:2) rt, 24 h
+ MeNO2 10 examples
H
O
NO2
2, 20 mol% CHO
R1
O O HN
N
Br
Br
H N
NBoc
64–82% yield, 95–99% ee
(c) O H R1
10 mol% 3·TFA, NMM
R3 +
R2
12 examples
H N
O R3 R2
NO2
NO 2
H tBuOH, 72 h
N
R1 82–90% yield 3:1–10:1 dr, 90–97% ee
O NH
O 3
Current Opinion in Chemical Biology
Enantioselective peptide-catalyzed reactions providing access to structurally challenging molecules: (a) dynamic kinetic resolution of atropoisomers of a tertiary benzamide with tetrapeptide catalyst 1; (b,c) conjugate addition reactions providing acyclic g-nitroaldehydes with all-carbon stereogenic centers.
diastereoselectivities. Their synthetic versatility was additionally demonstrated by conversion to a range of useful, chiral building blocks [12].
Peptide-catalyzed regioselective reactions Enzymes typically discriminate near-perfectly not only between different substrates but also different reactive sites within a given substrate. In contrast, traditional synthetic catalysts discriminate poorly between identical functional groups within the same molecule that differ only by their chemical environment [13]. Miller and coworkers showed that peptidic catalysts, while being of significantly lower molecular weight than enzymes, have the right degree of complexity to distinguish between the same type of functional group and favor reactions also at intrinsically less reactive sites. Initial studies showed impressive levels of discrimination by peptidic acylation and phosphorylation catalysts between hydroxyl groups within complex natural products such as erythromycin and teicoplanin [14,15]. Recently, pentapeptide 4 and tripeptide 5 were developed for site-selective thiocarbonylations of vancomycin (Figure 2a) [16]. Both bear a reactive methyl-imidazole (Me-Imi) group that activates www.sciencedirect.com
and transfers the thiocarbonyl moiety to the preferred hydroxyl group, which can then be selectively removed. The resulting derivatives are highly valuable for deciphering the mode of action of vancomycin. Whereas peptide 4 thiocarbonylates preferentially the more reactive benzylic alcohol and enhances the intrinsic reactivity to a 9:1 product ratio, peptide 5 reacts preferentially with the less reactive primary hydroxyl group of the sugar moiety and provides the products in a 27:1 ratio. Whereas peptide 4 was the result of screening a small collection of 25 Me-Imi containing peptides, 5 was rationally designed based on the dipeptide motif D-Ala-D-Ala, which is present in bacterial cell walls and binds to vancomycin selectively. The replacement of one D-Ala moiety by D-(Me)His allowed for catalytic turnover, yet, high catalyst loadings of 20 mol% were necessary [16]. In a related study the group used a D-Ala-D-Ala containing tripeptide for siteselective brominations of vancomycin that yielded previously unknown monobromo-vancomycin, dibromo-vancomycin and a tribromo-vancomycin derivative [17]. However due to the high affinity of D-Ala-D-Ala for both the vancomycin substrate and the product stoichiometric amounts of the peptide were required. Current Opinion in Chemical Biology 2014, 22:40–46
42 Synthetic biomolecules
Figure 2
(a)
H N
N N
catalyst 5, 27:1, 97% conv.
O O HN
N O
OtBu
N H O
thiocarbonylation
OtBu Ph
4 O
OMe
O CbzHN
H N
N H
CbzHN
O O – +Bu 4N
catalyst 4, 9:1, 88% conv.
H HO 2C
N
N
11
7
3
2
O H N H H NH
O
O
O
Cl H N
O O
N H H
Cl OH H N
OH BocHN
O
81% yield, 86% ee (100:1:1 regioselectivity)
O
Ph
O
N
N H O
O
CO2H
NHMe H
O NH 2
H N
N
NH
H O
OH OH
HO
CH 2Cl 2, 4 oC, 7 h
6
HO
NH 2
O O
O HO
O
10 mol% 6 1 equiv HOBt /DMAP/DIC 2 equiv H2 O 2
10
HO HO
20 mol%catalyst 1.5 equiv PCTF, 2 equiv PEMP THF/CH2Cl2 rt, 24 h
O 5
(b)
OH O
O
O
O
NH O
TrtHN
OH
TrtHN
6
O
OMe
O NHTrt 10 mol% 7 10 mol% HOBt /DMAP 1.1 equiv DIC, 2 equiv H 2O 2 CHCl 3, -12oC, 24 h
O
H N
OH N
43% yield, ee n.d. (8.2:1:1 regioselectivity)
BocHN
O
O
CO2H
O N H OBn 7
H N O
O N H
OMe O O tBu
Current Opinion in Chemical Biology
Site-selective catalysis with peptidic catalysts: (a) site-selective transformations of vancomycin; (b) regioselective epoxidation of farnesol.
The Miller group also developed aspartic acid-based pentapeptide catalysts for site-selective and enantioselective epoxidations of electron-rich alkenes (Figure 2b). Peptides 6 and 7 were identified in a one-bead-onecompound combinatorial screening and catalyze epoxidation of farnesol to the corresponding 2,3-monoepoxide and 6,7-monoepoxide derivatives, respectively, with excellent regiocontrol [18]. The active site of both catalysts is the carboxylic acid group of the N-terminal amino acid that is activated by hydrogen peroxide in a mixture of DIC, DMAP and HOBt to form a peracid that transfers the oxygen to the double bond. The 6,7-selectivity over 10,11-selectivity is particularly noteworthy as the two double bonds are almost impossible to distinguish with any other synthetic method [19]. Mechanistic investigations, aimed at explaining the catalyst–substrate interactions responsible for the observed reaction outcome, showed that the complexity of the system is too high to draw definite conclusions [20]. Also noteworthy is a report by Kudo and coworkers who used a resin-bound 11-mer peptide to promote Current Opinion in Chemical Biology 2014, 22:40–46
regioselective 1,6- and 1,4-addition reactions of aromatic thiols to a,b,g,d-unsaturated aldehydes [21]. Good yields and enantioselectivities of either the kinetic 1,4-addition or the thermodynamic 1,6-addition product were achieved after careful optimization of the reaction conditions. A similar system was also successfully applied to the regioselective reduction of similar substrates [22].
Peptide catalysts with high chemoselectivity and reactivity Metal-free catalysis with small molecules has become a highly attractive tool for numerous transformations and is a useful alternative to enzyme or metal-based catalysis [23]. Yet, many organocatalysts suffer from low reactivity that has hampered their practical utility [24]. For example, numerous chiral secondary amines that were developed as catalysts for aldol and related reactions typically require high catalyst loadings of 10–30 mol% to provide the desired products in good yields and stereoselectivities [25]. In addition, comparatively little research has been invested into elucidating the mechanism of organocatalytic www.sciencedirect.com
Asymmetric catalysis with short-chain peptides Lewandowski and Wennemers 43
reactions, which often enables optimization of the reaction conditions.
peptides of the type H-Pro-Pro-Xaa showcased that the modular nature of peptidic catalysts allows not only for tuning their reactivity and stereoselectivity but also their chemoselectivity. Structural and functional variations enabled tailoring of the properties of H-Pro-Pro-Xaa type peptides to accommodate the requirements of even ‘difficult’ substrates. This afforded peptides 10 and 3 as catalysts for addition reactions with a,b-disubstituted and b,b-disubstituted nitroolefins [12,30]. These electrophiles are significantly less inclined to engage in 1,4addition reactions than, for example, b-nitroolefins and consequently homo-aldol reactions are typical side, if not main, reactions when other chiral amine based catalysts are used. Peptides 10 and 3 favor the desired conjugate addition pathway and provided g-nitroaldehydes with three consecutive stereogenic centers and an all-carbon quaternary adjacent to a tertiary stereocenter, respectively, in high yields and stereoselectivities (Figure 3).
Utilizing combinatorial screenings and rational design, our group established tripeptides of the general type HPro-Pro-Xaa as effective catalysts for aldol and conjugate addition reactions (Figure 3) [12,26–30]. Their reactivity is so high that only 1 mol% of the peptides H-ProPro-Asp-NH2 (8) and H-d-Pro-Pro-Glu-NH2 (9) are necessary to catalyze aldol and conjugate addition reactions between aldehydes and b-nitrolefins, respectively, and provide the desired products for a large range of substrate combinations in excellent yields and stereoselectivities (Figure 3) [26–29]. Studies with numerous analogs showed that the secondary amine, the carboxylic acid moiety as well as a turn conformation with the right balance between rigidity and flexibility are critical for the high efficiency of 8 and 9 [27,29]. Further studies with
Figure 3
(a) N * NH
O
(c)
1 mol% H-Pro-Pro-Asp-NH 2 (8)
H N * Y
*
OH
O
80–98% yield up to 90% ee
acetone
O
Z 0.1-1 mol% H-D-Pro-Pro-Glu-NH 2 (9)
H-Pro-Pro-Xaa
O
R1
H 5 mol% H-Pro-Pro-D-Gln-OH (10)
R1
R2
O
R1
R3
R3
O R3 R2
10 mol% 3
70–90% yield 3:1–10:1 dr 90–97% ee
NO 2
H R1
R3
>600 TON
59–98% yield up to 87:8:4:1 dr 92–99% ee
NO 2
H
NO 2
R2
65–98% yield 6:1– >99:1 dr 81–99% ee
NO 2
H
NO 2
R2
R2
O
NO 2
R2
O
R2 NO 2
H
(b)
O
O
* XH/Y
N
H R1
R1
H 2O
R2 X H
*
* XH/Y
N
O
R1 * X
* N O H
O
R2 * * R1
NO 2
R1 *
H
piston pump
+
A
NH
R1
NO 2
R2
R1
*
N O
R1
*
R2
B
B
>450 mmol, >100 g
Y
N
or
NO 2
O *
N O
*
=
O NH. TFA
R2
H N
N O
O N H CO 2H
H N 5 O 9-TG/PS
N O
*
R2
*
E
H 2O
N C
XH = proton donor, Y = no proton donor
* R1
Y *
NO 2 * * R2
Current Opinion in Chemical Biology
(a) Chemoselective reactions catalyzed by H-Pro-Pro-Xaa tripeptides; (b) proposed catalytic cycle; (c) stereoselective conjugate additions catalyzed by immobilized peptide 9-TG/PS in continuous flow (TON = turnover number). www.sciencedirect.com
Current Opinion in Chemical Biology 2014, 22:40–46
44 Synthetic biomolecules
These results highlight the ease with which the chemoselectivity of peptides of the type Pro-Pro-Xaa can be finetuned by subtle structural modifications to accommodate the requirements of different substrate combinations and favor a desired reaction pathway. Whereas, each of the four peptides is selective for a given substrate type combination, within the substrate type the scope of tolerated compounds is broad. Thus, these tripeptides have features that are reminiscent of enzymes (chemoselectivity) and others that are typical and desirable for synthetic catalysts (broad substrate scope). Mechanistic studies revealed that the conjugate addition reactions proceed via the formation of an enamine between the peptidic catalyst and the aldehydes and showed that the subsequent C–C bond formation with the nitroolefin is the stereoselectivity-determining and rate-limiting step in the catalytic cycle [31–33]. This insight allowed for further optimizing the reaction conditions and reducing the catalyst loading to as little as 0.1%, which is the lowest catalyst loading achieved in enamine catalysis to date [31]. The mechanistic studies also showed that the reaction pathway and the rate limiting step depend on the presence or absence of a suitably positioned intramolecular proton donor within the catalyst (Figure 3b) [32]. These insights provided a general guide for catalyst design and optimization of the reaction conditions and are therefore highly relevant for enamine catalysis in general. More recently, the group showed that the peptidic catalysts are so robust that an immobilized variant of 9, H-DPro-Pro-Glu-NH-TentaGel (9-TG), can be reused after a
simple filtration for at least 30 times without loss in activity and stereoselectivity [34]. Reactions catalyzed by 9-TG are so clean and high yielding that simple removal of all volatiles under reduced pressure suffices to provide the desired products in excellent yields, stereoselectivities and purities that do not require column chromatographic purification [34]. The immobilized catalyst can even be used in a flow system: 0.8 mmol of 9-PS allowed for the continuous synthesis of more than 100 g (>450 mmol) of conjugate addition products with very high to excellent stereoselectivities (Figure 3c) [35]. After more than 600 turnovers the catalyst still had the same high stereoselectivity and activity comparable to the freshly prepared one. Since tripeptides can be easily prepared in multi-kilogram scales, these results open the way for practical applications of peptide catalyzed reactions on an industrial scale.
Catalysis in water As described above, several peptidic catalysts have features, such as site-selectivity, chemoselectivity and stereoselectivity that are reminiscent of enzymes. Yet, whereas the active site of many enzymes is often hydrophobic and resembles an organic solvent environment, a hallmark of enzyme catalysis is the use of water as a solvent. Inspired by the early polyleucine and polyalanine epoxidation catalysts by Julia and Colonna [5], Kudo developed resinbound helical peptides that have repeating tryptophan and/ or leucine residues at their core and catalytically active Pro-Pro moiety at the N-terminus (Figures 1b and 4a). The solid-supported peptides catalyzed in THF/water mixtures a remarkably broad range of different stereoselective transformations of a,b-unsaturated aldehydes, for
Figure 4
(a)
O
Me H
R + N Me
20. mol% 11. TFA rt, 24–144 h H 2O
HN
N NaBH 4 1h
OH
N
R
5 examples
O
76–84% yield, 89–91% ee
+
H R1
R2
9 examples
NO 2
3 mol% 9a 3 mol% NMM rt, 5–24 h H 2O
NO 2
H R1
H N
76–99% yield, 84–94% ee
N O NH. TFA
H N
O 6
O 2
11
NH
R2
O
N H
O
(b) O
O
H N
O
O N H CO 2H
9a Current Opinion in Chemical Biology
Peptide catalysts promoting enantioselective reactions in aqueous environments: (a) Friedel–Crafts reactions of a,b-unsaturated aldehydes; (b) conjugate addition reactions in aqueous emulsions. Current Opinion in Chemical Biology 2014, 22:40–46
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Asymmetric catalysis with short-chain peptides Lewandowski and Wennemers 45
example, reductions [22], epoxidations [36], Friedel–Crafts alkylations [37], Michael reactions [11], and cyclopropanations [38]. Provided that 20 mol% of the catalyst was used, good to very high enantioselectivities were obtained. A detailed structure–activity relationship study of the resin-supported peptide catalyst 11 for Friedel–Crafts reactions showed that the helical C-terminal end of the peptide as well as the N-terminal Pro-Pro moiety are important for the catalytic performance [37]. The Miller group derived a peptide from their acylation and epoxidation catalysts where the replacement of the carboxylic acid moiety by a trifluoromethyl ketone group as the catalytically active site allowed for enantioselective epoxidations of electron-rich alkenes in mixtures of tamyl alcohol/water. The oxidation products were formed in good yields but only moderate enantiomeric ratios [39]. Wennemers and coworkers created the highly active and stereoselective amphiphilic catalyst H-D-Pro-Pro-GluNHCOC12H25 9a for conjugate addition reactions in aqueous emulsions by attaching a long alkyl chain to the C-terminus of catalyst 9 (Figure 4b) [40]. The catalytic reactivity and stereoselectivity of 9a in water are only slightly lower compared to that of the parent peptide in organic solvents [29]. These results suggest that the catalytically active peptide is shielded from the surrounding water within a hydrophobic microenvironment, which is reminiscent of the hydrophobic pockets often found within the active sites of enzymes. This also points to the possibility that hydrophobic compartments containing reactants and catalytically active short peptides could have played a critical role in the evolution of enzymes.
Summary and future perspectives Since their revival in the late 1990s, catalytically active peptides have been shown to solve challenges that are difficult to tackle with enzymes or traditional metalorganic or metal-free synthetic catalysts. Their modular nature allows for tailoring of the catalytic performance of peptides. This enabled the development of catalysts with excellent stereoselectivities and reactivities as well as site-selectivities and chemoselectivities. Combined with the ease of synthesis of, in particular, short-chain peptides on large scale, several peptidic catalysts are attractive for applications in organic synthesis and even on an industrial scale. Aside from the practical utility of catalytically active peptides, research in the field also raises the intriguing question as to their role in the chemical evolution of enzymes. Since they have features reminiscent of both enzymes (chemoselectivity, siteselectivity) and synthetic catalysts (comparable, or lower molecular weight, broad substrate scope) it is highly probable that peptides were fundamental in the development of the complex enzymes we know today. Intriguing future directions may involve the development of www.sciencedirect.com
bi-catalytic or multicatalytic systems [41] as well as the control of the catalytic performance of peptides by aggregation [42,43]. It can be expected that these strategies will further enable the development of many more peptidic catalysts for synthetically useful transformations and catalytic concepts in the next decade.
Acknowledgements Support from the Swiss National Science Foundation (Grant no. 2-7786613) is gratefully acknowledged. We thank the European Union’s 7th Framework Marie-Curie Intra European Fellowship Program for a fellowship for BL.
References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as: of special interest of outstanding interest 1.
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Julia´ S, Guixer J, Masana J, Rocas J, Colonna S, Annunziata R, Molinari H: Synthetic enzymes. Part 2. Catalytic asymmetric epoxidation by means of polyamino-acids in a triphase system. J Chem Soc Perkin Trans I 1982:1317-1324.
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Revell JD, Wennemers H: Peptidic catalysts developed by combinatorial screening methods. Curr Opin Chem Biol 2007, 11:269-278.
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Barrett KT, Miller SJ: Enantioselective synthesis of atropisomeric benzamides through peptide-catalyzed bromination. J Am Chem Soc 2013, 135:2963-2966.
8.
Barrett KT, Metrano AJ, Rablen PR, Miller SJ: Spontaneous transfer of chirality in an atropisomerically enriched two-axis system. Nature 2014, 509:71-75. The first example of an enantioselective bromination of tertiary benzamides to yield atropoisomers with two axes of chirality catalyzed by a tetrapeptide. Careful optimization of reaction conditions allowed a high degree of control over the dynamics of the system and led to equal stereoenrichment of both cis and trans amide isomers.
9.
Wang J, Feringa B: Dynamic control of chiral space in a catalytic asymmetric reaction using a molecular motor. Science 2011, 331:1429-1432.
10. Das JP, Marek I: Enantioselective synthesis of all-carbon quaternary stereogenic centers in acyclic systems. Chem Commun 2011, 47:4593-4623. 11. Akagawa K, Kudo K: Construction of an all-carbon quaternary stereocenter by the peptide-catalyzed asymmetric Michael addition of nitromethane to b-disubstituted a,b-unsaturated aldehydes. Angew Chem Int Ed 2012, 51:12786-12789. Synthesis of acyclic compounds with all-carbon quaternary stereogenic centers in high yields and stereoselectivities. 12. Kastl R, Wennemers H: Peptide-catalyzed stereoselective conjugate addition reactions generating all-carbon quaternary stereogenic centers. Angew Chem Int Ed 2013, 52:7228-7232. Highly enantioselective conjugate addition reactions that yield for the first time g-nitroaldehydes with consecutive tertiary and quaternary stereogenic centers. The synthetically challenging products were obtained in excellent yields, chemo-selectivities and stereoselectivities. Current Opinion in Chemical Biology 2014, 22:40–46
46 Synthetic biomolecules
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16. Fowler BS, Laemmerhold KM, Miller SJ: Catalytic site-selective thiocarbonylations and deoxygenations of vancomycin reveal hydroxyl-dependent conformational effects. J Am Chem Soc 2012, 134:9755-9761. Site-selective thiocarbonylation of specific hydroxyl groups in vancomycin catalyzed by short peptides. 17. Pathak TP, Miller SJ: Site-selective bromination of vancomycin. J Am Chem Soc 2012, 134:6120-6123. 18. Lichtor PA, Miller SJ: Combinatorial evolution of site- and enantioselective catalysts for polyene epoxidation. Nat Chem 2012, 4:990-996. Site-selective and enantioselective epoxidation of farnesol catalyzed by hexapeptides with a carboxylic acid moiety as an active site. Unprecedented control over selective functionalization of alkenes within comparable chemical environments. 19. Gnanadesikan V, Corey EJ: A strategy for position-selective epoxidation of polyprenols. J Am Chem Soc 2008, 130: 8089-8093. 20. Lichtor PA, Miller SJ: Experimental lineage and functional analysis of a remotely directed peptide epoxidation catalyst. J Am Chem Soc 2014, 136:5301-5308. 21. Akagawa K, Nishi N, Sen J, Kudo K: Peptide-catalyzed consecutive 1,6- and 1,4-additions of thiols to a,b,g,dunsaturated aldehydes. Org Biomol Chem 2014, 12:3581-3585. 22. Akagawa K, Sen J, Kudo K: Peptide-catalyzed regio- and enantioselective reduction of a,b,g,d-unsaturated aldehydes. Angew Chem Int Ed 2013, 52:11585-11588. 23. Berkessel A, Gro¨ger H (Eds): Asymmetric Organocatalysis, edn 1. Wiley VCH; 2005. 24. MacMillan DWC: The advent and development of organocatalysis. Nature 2008, 455:304-308. 25. Mukherjee S, Yang JW, Hoffmann S, List B: Asymmetric enamine catalysis. Chem Rev 2007, 107:5471-5569. 26. Krattiger P, Kovasy R, Revell JD, Ivan S, Wennemers H: Increased structural complexity leads to higher activity: peptides as efficient and versatile catalysts for asymmetric aldol reactions. Org Lett 2005, 7:1101-1103. 27. Revell JD, Wennemers H: Investigating sequence space: how important is the spatial arrangement of functional groups in the asymmetric aldol reaction catalyst H-Pro-Pro-Asp-NH2? Adv Synth Catal 2008, 350:1046-1052. 28. Wiesner M, Revell JD, Wennemers H: Tripeptides as efficient asymmetric catalysts for 1,4-addition reactions of aldehydes to nitroolefins — a rational approach. Angew Chem Int Ed 2008, 47:1871-1874. 29. Wiesner M, Neuburger M, Wennemers H: Tripeptides of the type H-D-Pro-Pro-Xaa-NH2 as catalysts for asymmetric 1,4addition reactions: structural requirements for high catalytic efficiency. Chem Eur J 2009, 15:10103-10109. 30. Duschmale J, Wennemers H: Adapting to substrate challenges: peptides as catalysts for conjugate addition reactions of
Current Opinion in Chemical Biology 2014, 22:40–46
33. Ba¨chle F, Duschmale´ J, Ebner C, Pfaltz A, Wennemers H: Organocatalytic asymmetric conjugate addition of aldehydes to nitroolefins: identification of catalytic intermediates and the stereoselectivity-determining step by ESI-MS. Angew Chem Int Ed 2013, 52:12619-12623. 34. Arakawa Y, Wiesner M, Wennemers H: Efficient recovery and reuse of an immobilized peptidic organocatalyst. Adv Synth Catal 2011, 353:1201-1206. 35. Arakawa Y, Wennemers H: Enamine catalysis in flow with an immobilized peptidic catalyst. ChemSusChem 2013, 6:242-245. Unprecedented catalytic performance of an immobilized organocatalyst (H-D-Pro-Pro-Glu-NH-resin) that provided Michael reaction products on a 100 g scale in a continuous flow system with excellent yields and stereoselectivities for a broad range of different substrates. 36. Akagawa K, Kudo K: Asymmetric epoxidation of a,bunsaturated aldehydes in aqueous media catalyzed by resinsupported peptide-containing unnatural amino acids. Adv Synth Catal 2011, 353:843-847. 37. Akagawa K, Suzuki R, Kudo K: Effect of the helical tether of a resin-supported peptide catalyst for Friedel–Crafts-type alkylation in water. Adv Synth Catal 2012, 354:1280-1286. Enantioselective Friedel–Crafts reactions in an aqueous environment catalyzed by a resin-bound helical undeca-peptide. A structure–activity relationship study determined the importance of helical and turn motifs for catalyst efficiency. 38. Akagawa K, Takigawa S, Nagamine IS, Umezawa R, Kudo K: Peptide-catalyzed diastereo- and enantioselective cyclopropanation of aromatic a,b-unsaturated aldehydes. Org Lett 2013, 15:4964-4967. 39. Romney DK, Miller SJ: A peptide-embedded trifluoromethyl ketone catalyst for enantioselective epoxidation. Org Lett 2012, 14:1138-1141. 40. Duschmale´ J, Kohrt S, Wennemers H: Peptide catalysis in aqueous emulsions. Chem Commun 2014, 50:8109-8112. Conjugate addition reactions catalyzed by an amphiphilic peptide in aqueous emulsions. The products formed in high yields and stereoselectivities, presumably in hydrophobic pockets, reminiscent of the active sites of enzymes. 41. Hofmann C, Schuler SMM, Wende RC, Schreiner PR: En route to multicatalysis: kinetic resolution of trans-cycloalkane-1,2diols via oxidative esterification. Chem Commun 2014, 50: 1221-1223. 42. Rodriguez-Llansola F, Escuder B, Miravet JF: Switchable performance of an L-proline-derived basic catalyst controlled by supramolecular gelation. J Am Chem Soc 2009, 131:1147811484. 43. Rufo CM, Moroz YS, Moroz OV, Sto¨hr J, Smith TA, Hu X, DeGrado WF, Korendovych IV: Short peptides self-assemble to produce catalytic amyloids. Nat Chem 2014, 6:303-309.
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ScienceDirect Asymmetric catalysis with short-chain peptides Bartosz Lewandowski and Helma Wennemers Within this review article we describe recent developments in asymmetric catalysis with peptides. Numerous peptides have been established in the past two decades that catalyze a wide variety of transformations with high stereoselectivities and yields, as well as broad substrate scope. We highlight here catalytically active peptides, which have addressed challenges that had thus far remained elusive in asymmetric catalysis: enantioselective synthesis of atropoisomers and quaternary stereogenic centers, regioselective transformations of polyfunctional substrates, chemoselective transformations, catalysis in-flow and reactions in aqueous environments. Addresses Laboratory of Organic Chemistry, ETH Zurich, Vladimir-Prelog-Weg 3, 8093 Zurich, Switzerland Corresponding author: Wennemers, Helma ([email protected])
Current Opinion in Chemical Biology 2014, 22:40–46 This review comes from a themed issue on Synthetic biomolecules Edited by Paul F Alewood and Stephen BH Kent For a complete overview see the Issue and the Editorial Available online 30th September 2014 http://dx.doi.org/10.1016/j.cbpa.2014.09.011 1367-5931/# 2014 Elsevier Ltd. All rights reserved.
Introduction Peptides fulfil a multitude of different functions in nature and everyday life as, hormones, neurotransmitters, toxins, therapeutics against numerous diseases, and artificial sweeteners [1]. Despite this functional versatility, the value of peptides for asymmetric catalysis has only been recognized in the past two decades [2,3]. Apart from early reports on cyclic dipeptides and polyleucines for catalytic asymmetric hydrocyanations [4] and epoxidations [5], respectively, the field remained dormant until the late 1990s. The establishment of numerous effective peptidic catalysts since then, is closely connected to the development of smart combinatorial screening methods that allowed the discovery of lead structures by overcoming the challenge of rationally designing potent catalyst structures [6]. Nowadays, the palette of reactions for which peptidic catalysts are available is broad and includes, for example, stereoselective acylations, phosphorylations, brominations, epoxidations, aldol, and numerous other C–C bond forming reactions [2,3]. Recent advances in the field also revealed that the structural and functional Current Opinion in Chemical Biology 2014, 22:40–46
diversity of peptides offers unique opportunities for tackling challenges that are difficult to address by other less modular catalyst structures. These include the development of catalysts for highly challenging enantioselective reactions, regioselective and chemoselective transformations, as well as metal-free catalysis at low catalyst loadings and in continuous flow. Within this report we will showcase these features with a focus on latest highlights that have not been covered in previous reviews [2,3].
Challenging enantioselective reactions Whereas numerous metalorganic and metal-free catalysts have been developed for enantioselective formations of stereogenic centers, the stereoselective installation of axial chirality has proven to be significantly more difficult. Miller provided a solution to this challenge with a tetrapeptidic catalyst that brominates substituted, tertiary benzamides to yield atropoisomeric tribromo products with excellent enantioselectivities [7]. Using the same tetrapeptide 1 the group also achieved dynamic kinetic resolution of atropoisomers of unsymmetrical tertiary benzamides with two axes of chirality; one defined through the benzamide structure, the other associated with the different substituents on the amide nitrogen (Figure 1a) [8]. The interplay of kinetic and thermodynamic parameters of the enantioselective bromination and isomerisation of the amide bond led to a product distribution with equal stereochemical enrichment of both the cis and trans amide isomers. This impressive control over the dynamics of the system not only allowed to obtain the target compound with high stereoselectivity but is also potentially of great value for the design of molecular switches or motors as well as ligands for metalbased asymmetric catalysts [9]. Acyclic compounds containing all-carbon, quaternary stereocenters represent another class of challenging molecules for asymmetric synthesis [10]. Kudo tackled this challenge with the 11-mer helical peptide 2 that catalyzes Michael reactions between nitromethane and b,b-disubstituted aldehydes (Figure 1b) [11]. Wennemers accessed the same type of g-nitroaldehydes with two consecutive stereogenic centers by conjugate addition reactions between aliphatic aldehydes and b,b-disubstituted nitroolefins, promoted by the H-d-Pro-Pro based catalyst 3 (Figure 1c) [12]. Of note, side reactions such as homo-aldol reactions, which had impeded the development of effective catalysts for this conjugate addition reaction, occur in the presence of tripeptide 3 only to a minor extent. This shows the high level of chemoselectivity of 3. The target g-nitroaldehydes were obtained in very high yields as well as enantioselectivities and www.sciencedirect.com
Asymmetric catalysis with short-chain peptides Lewandowski and Wennemers 41
Figure 1
(a)
O HO
N
10 mol% 1 DMBDH (1.5 equiv)
Br
CHCl3, 24 h N Boc 57:43 trans:cis racemic
(b)
O
HO
N
N N
Boc 94% yield 76:24 trans:cis 79:21 e.r. (for both the trans and cis isomer)
H-Pro-D-Pro-Aib-Trp-Trp-[Leu]6 R2
O
Ph OMe
1
R2 CHO
R1
MeOH/H2O (1:2) rt, 24 h
+ MeNO2 10 examples
H
O
NO2
2, 20 mol% CHO
R1
O O HN
N
Br
Br
H N
NBoc
64–82% yield, 95–99% ee
(c) O H R1
10 mol% 3·TFA, NMM
R3 +
R2
12 examples
H N
O R3 R2
NO2
NO 2
H tBuOH, 72 h
N
R1 82–90% yield 3:1–10:1 dr, 90–97% ee
O NH
O 3
Current Opinion in Chemical Biology
Enantioselective peptide-catalyzed reactions providing access to structurally challenging molecules: (a) dynamic kinetic resolution of atropoisomers of a tertiary benzamide with tetrapeptide catalyst 1; (b,c) conjugate addition reactions providing acyclic g-nitroaldehydes with all-carbon stereogenic centers.
diastereoselectivities. Their synthetic versatility was additionally demonstrated by conversion to a range of useful, chiral building blocks [12].
Peptide-catalyzed regioselective reactions Enzymes typically discriminate near-perfectly not only between different substrates but also different reactive sites within a given substrate. In contrast, traditional synthetic catalysts discriminate poorly between identical functional groups within the same molecule that differ only by their chemical environment [13]. Miller and coworkers showed that peptidic catalysts, while being of significantly lower molecular weight than enzymes, have the right degree of complexity to distinguish between the same type of functional group and favor reactions also at intrinsically less reactive sites. Initial studies showed impressive levels of discrimination by peptidic acylation and phosphorylation catalysts between hydroxyl groups within complex natural products such as erythromycin and teicoplanin [14,15]. Recently, pentapeptide 4 and tripeptide 5 were developed for site-selective thiocarbonylations of vancomycin (Figure 2a) [16]. Both bear a reactive methyl-imidazole (Me-Imi) group that activates www.sciencedirect.com
and transfers the thiocarbonyl moiety to the preferred hydroxyl group, which can then be selectively removed. The resulting derivatives are highly valuable for deciphering the mode of action of vancomycin. Whereas peptide 4 thiocarbonylates preferentially the more reactive benzylic alcohol and enhances the intrinsic reactivity to a 9:1 product ratio, peptide 5 reacts preferentially with the less reactive primary hydroxyl group of the sugar moiety and provides the products in a 27:1 ratio. Whereas peptide 4 was the result of screening a small collection of 25 Me-Imi containing peptides, 5 was rationally designed based on the dipeptide motif D-Ala-D-Ala, which is present in bacterial cell walls and binds to vancomycin selectively. The replacement of one D-Ala moiety by D-(Me)His allowed for catalytic turnover, yet, high catalyst loadings of 20 mol% were necessary [16]. In a related study the group used a D-Ala-D-Ala containing tripeptide for siteselective brominations of vancomycin that yielded previously unknown monobromo-vancomycin, dibromo-vancomycin and a tribromo-vancomycin derivative [17]. However due to the high affinity of D-Ala-D-Ala for both the vancomycin substrate and the product stoichiometric amounts of the peptide were required. Current Opinion in Chemical Biology 2014, 22:40–46
42 Synthetic biomolecules
Figure 2
(a)
H N
N N
catalyst 5, 27:1, 97% conv.
O O HN
N O
OtBu
N H O
thiocarbonylation
OtBu Ph
4 O
OMe
O CbzHN
H N
N H
CbzHN
O O – +Bu 4N
catalyst 4, 9:1, 88% conv.
H HO 2C
N
N
11
7
3
2
O H N H H NH
O
O
O
Cl H N
O O
N H H
Cl OH H N
OH BocHN
O
81% yield, 86% ee (100:1:1 regioselectivity)
O
Ph
O
N
N H O
O
CO2H
NHMe H
O NH 2
H N
N
NH
H O
OH OH
HO
CH 2Cl 2, 4 oC, 7 h
6
HO
NH 2
O O
O HO
O
10 mol% 6 1 equiv HOBt /DMAP/DIC 2 equiv H2 O 2
10
HO HO
20 mol%catalyst 1.5 equiv PCTF, 2 equiv PEMP THF/CH2Cl2 rt, 24 h
O 5
(b)
OH O
O
O
O
NH O
TrtHN
OH
TrtHN
6
O
OMe
O NHTrt 10 mol% 7 10 mol% HOBt /DMAP 1.1 equiv DIC, 2 equiv H 2O 2 CHCl 3, -12oC, 24 h
O
H N
OH N
43% yield, ee n.d. (8.2:1:1 regioselectivity)
BocHN
O
O
CO2H
O N H OBn 7
H N O
O N H
OMe O O tBu
Current Opinion in Chemical Biology
Site-selective catalysis with peptidic catalysts: (a) site-selective transformations of vancomycin; (b) regioselective epoxidation of farnesol.
The Miller group also developed aspartic acid-based pentapeptide catalysts for site-selective and enantioselective epoxidations of electron-rich alkenes (Figure 2b). Peptides 6 and 7 were identified in a one-bead-onecompound combinatorial screening and catalyze epoxidation of farnesol to the corresponding 2,3-monoepoxide and 6,7-monoepoxide derivatives, respectively, with excellent regiocontrol [18]. The active site of both catalysts is the carboxylic acid group of the N-terminal amino acid that is activated by hydrogen peroxide in a mixture of DIC, DMAP and HOBt to form a peracid that transfers the oxygen to the double bond. The 6,7-selectivity over 10,11-selectivity is particularly noteworthy as the two double bonds are almost impossible to distinguish with any other synthetic method [19]. Mechanistic investigations, aimed at explaining the catalyst–substrate interactions responsible for the observed reaction outcome, showed that the complexity of the system is too high to draw definite conclusions [20]. Also noteworthy is a report by Kudo and coworkers who used a resin-bound 11-mer peptide to promote Current Opinion in Chemical Biology 2014, 22:40–46
regioselective 1,6- and 1,4-addition reactions of aromatic thiols to a,b,g,d-unsaturated aldehydes [21]. Good yields and enantioselectivities of either the kinetic 1,4-addition or the thermodynamic 1,6-addition product were achieved after careful optimization of the reaction conditions. A similar system was also successfully applied to the regioselective reduction of similar substrates [22].
Peptide catalysts with high chemoselectivity and reactivity Metal-free catalysis with small molecules has become a highly attractive tool for numerous transformations and is a useful alternative to enzyme or metal-based catalysis [23]. Yet, many organocatalysts suffer from low reactivity that has hampered their practical utility [24]. For example, numerous chiral secondary amines that were developed as catalysts for aldol and related reactions typically require high catalyst loadings of 10–30 mol% to provide the desired products in good yields and stereoselectivities [25]. In addition, comparatively little research has been invested into elucidating the mechanism of organocatalytic www.sciencedirect.com
Asymmetric catalysis with short-chain peptides Lewandowski and Wennemers 43
reactions, which often enables optimization of the reaction conditions.
peptides of the type H-Pro-Pro-Xaa showcased that the modular nature of peptidic catalysts allows not only for tuning their reactivity and stereoselectivity but also their chemoselectivity. Structural and functional variations enabled tailoring of the properties of H-Pro-Pro-Xaa type peptides to accommodate the requirements of even ‘difficult’ substrates. This afforded peptides 10 and 3 as catalysts for addition reactions with a,b-disubstituted and b,b-disubstituted nitroolefins [12,30]. These electrophiles are significantly less inclined to engage in 1,4addition reactions than, for example, b-nitroolefins and consequently homo-aldol reactions are typical side, if not main, reactions when other chiral amine based catalysts are used. Peptides 10 and 3 favor the desired conjugate addition pathway and provided g-nitroaldehydes with three consecutive stereogenic centers and an all-carbon quaternary adjacent to a tertiary stereocenter, respectively, in high yields and stereoselectivities (Figure 3).
Utilizing combinatorial screenings and rational design, our group established tripeptides of the general type HPro-Pro-Xaa as effective catalysts for aldol and conjugate addition reactions (Figure 3) [12,26–30]. Their reactivity is so high that only 1 mol% of the peptides H-ProPro-Asp-NH2 (8) and H-d-Pro-Pro-Glu-NH2 (9) are necessary to catalyze aldol and conjugate addition reactions between aldehydes and b-nitrolefins, respectively, and provide the desired products for a large range of substrate combinations in excellent yields and stereoselectivities (Figure 3) [26–29]. Studies with numerous analogs showed that the secondary amine, the carboxylic acid moiety as well as a turn conformation with the right balance between rigidity and flexibility are critical for the high efficiency of 8 and 9 [27,29]. Further studies with
Figure 3
(a) N * NH
O
(c)
1 mol% H-Pro-Pro-Asp-NH 2 (8)
H N * Y
*
OH
O
80–98% yield up to 90% ee
acetone
O
Z 0.1-1 mol% H-D-Pro-Pro-Glu-NH 2 (9)
H-Pro-Pro-Xaa
O
R1
H 5 mol% H-Pro-Pro-D-Gln-OH (10)
R1
R2
O
R1
R3
R3
O R3 R2
10 mol% 3
70–90% yield 3:1–10:1 dr 90–97% ee
NO 2
H R1
R3
>600 TON
59–98% yield up to 87:8:4:1 dr 92–99% ee
NO 2
H
NO 2
R2
65–98% yield 6:1– >99:1 dr 81–99% ee
NO 2
H
NO 2
R2
R2
O
NO 2
R2
O
R2 NO 2
H
(b)
O
O
* XH/Y
N
H R1
R1
H 2O
R2 X H
*
* XH/Y
N
O
R1 * X
* N O H
O
R2 * * R1
NO 2
R1 *
H
piston pump
+
A
NH
R1
NO 2
R2
R1
*
N O
R1
*
R2
B
B
>450 mmol, >100 g
Y
N
or
NO 2
O *
N O
*
=
O NH. TFA
R2
H N
N O
O N H CO 2H
H N 5 O 9-TG/PS
N O
*
R2
*
E
H 2O
N C
XH = proton donor, Y = no proton donor
* R1
Y *
NO 2 * * R2
Current Opinion in Chemical Biology
(a) Chemoselective reactions catalyzed by H-Pro-Pro-Xaa tripeptides; (b) proposed catalytic cycle; (c) stereoselective conjugate additions catalyzed by immobilized peptide 9-TG/PS in continuous flow (TON = turnover number). www.sciencedirect.com
Current Opinion in Chemical Biology 2014, 22:40–46
44 Synthetic biomolecules
These results highlight the ease with which the chemoselectivity of peptides of the type Pro-Pro-Xaa can be finetuned by subtle structural modifications to accommodate the requirements of different substrate combinations and favor a desired reaction pathway. Whereas, each of the four peptides is selective for a given substrate type combination, within the substrate type the scope of tolerated compounds is broad. Thus, these tripeptides have features that are reminiscent of enzymes (chemoselectivity) and others that are typical and desirable for synthetic catalysts (broad substrate scope). Mechanistic studies revealed that the conjugate addition reactions proceed via the formation of an enamine between the peptidic catalyst and the aldehydes and showed that the subsequent C–C bond formation with the nitroolefin is the stereoselectivity-determining and rate-limiting step in the catalytic cycle [31–33]. This insight allowed for further optimizing the reaction conditions and reducing the catalyst loading to as little as 0.1%, which is the lowest catalyst loading achieved in enamine catalysis to date [31]. The mechanistic studies also showed that the reaction pathway and the rate limiting step depend on the presence or absence of a suitably positioned intramolecular proton donor within the catalyst (Figure 3b) [32]. These insights provided a general guide for catalyst design and optimization of the reaction conditions and are therefore highly relevant for enamine catalysis in general. More recently, the group showed that the peptidic catalysts are so robust that an immobilized variant of 9, H-DPro-Pro-Glu-NH-TentaGel (9-TG), can be reused after a
simple filtration for at least 30 times without loss in activity and stereoselectivity [34]. Reactions catalyzed by 9-TG are so clean and high yielding that simple removal of all volatiles under reduced pressure suffices to provide the desired products in excellent yields, stereoselectivities and purities that do not require column chromatographic purification [34]. The immobilized catalyst can even be used in a flow system: 0.8 mmol of 9-PS allowed for the continuous synthesis of more than 100 g (>450 mmol) of conjugate addition products with very high to excellent stereoselectivities (Figure 3c) [35]. After more than 600 turnovers the catalyst still had the same high stereoselectivity and activity comparable to the freshly prepared one. Since tripeptides can be easily prepared in multi-kilogram scales, these results open the way for practical applications of peptide catalyzed reactions on an industrial scale.
Catalysis in water As described above, several peptidic catalysts have features, such as site-selectivity, chemoselectivity and stereoselectivity that are reminiscent of enzymes. Yet, whereas the active site of many enzymes is often hydrophobic and resembles an organic solvent environment, a hallmark of enzyme catalysis is the use of water as a solvent. Inspired by the early polyleucine and polyalanine epoxidation catalysts by Julia and Colonna [5], Kudo developed resinbound helical peptides that have repeating tryptophan and/ or leucine residues at their core and catalytically active Pro-Pro moiety at the N-terminus (Figures 1b and 4a). The solid-supported peptides catalyzed in THF/water mixtures a remarkably broad range of different stereoselective transformations of a,b-unsaturated aldehydes, for
Figure 4
(a)
O
Me H
R + N Me
20. mol% 11. TFA rt, 24–144 h H 2O
HN
N NaBH 4 1h
OH
N
R
5 examples
O
76–84% yield, 89–91% ee
+
H R1
R2
9 examples
NO 2
3 mol% 9a 3 mol% NMM rt, 5–24 h H 2O
NO 2
H R1
H N
76–99% yield, 84–94% ee
N O NH. TFA
H N
O 6
O 2
11
NH
R2
O
N H
O
(b) O
O
H N
O
O N H CO 2H
9a Current Opinion in Chemical Biology
Peptide catalysts promoting enantioselective reactions in aqueous environments: (a) Friedel–Crafts reactions of a,b-unsaturated aldehydes; (b) conjugate addition reactions in aqueous emulsions. Current Opinion in Chemical Biology 2014, 22:40–46
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Asymmetric catalysis with short-chain peptides Lewandowski and Wennemers 45
example, reductions [22], epoxidations [36], Friedel–Crafts alkylations [37], Michael reactions [11], and cyclopropanations [38]. Provided that 20 mol% of the catalyst was used, good to very high enantioselectivities were obtained. A detailed structure–activity relationship study of the resin-supported peptide catalyst 11 for Friedel–Crafts reactions showed that the helical C-terminal end of the peptide as well as the N-terminal Pro-Pro moiety are important for the catalytic performance [37]. The Miller group derived a peptide from their acylation and epoxidation catalysts where the replacement of the carboxylic acid moiety by a trifluoromethyl ketone group as the catalytically active site allowed for enantioselective epoxidations of electron-rich alkenes in mixtures of tamyl alcohol/water. The oxidation products were formed in good yields but only moderate enantiomeric ratios [39]. Wennemers and coworkers created the highly active and stereoselective amphiphilic catalyst H-D-Pro-Pro-GluNHCOC12H25 9a for conjugate addition reactions in aqueous emulsions by attaching a long alkyl chain to the C-terminus of catalyst 9 (Figure 4b) [40]. The catalytic reactivity and stereoselectivity of 9a in water are only slightly lower compared to that of the parent peptide in organic solvents [29]. These results suggest that the catalytically active peptide is shielded from the surrounding water within a hydrophobic microenvironment, which is reminiscent of the hydrophobic pockets often found within the active sites of enzymes. This also points to the possibility that hydrophobic compartments containing reactants and catalytically active short peptides could have played a critical role in the evolution of enzymes.
Summary and future perspectives Since their revival in the late 1990s, catalytically active peptides have been shown to solve challenges that are difficult to tackle with enzymes or traditional metalorganic or metal-free synthetic catalysts. Their modular nature allows for tailoring of the catalytic performance of peptides. This enabled the development of catalysts with excellent stereoselectivities and reactivities as well as site-selectivities and chemoselectivities. Combined with the ease of synthesis of, in particular, short-chain peptides on large scale, several peptidic catalysts are attractive for applications in organic synthesis and even on an industrial scale. Aside from the practical utility of catalytically active peptides, research in the field also raises the intriguing question as to their role in the chemical evolution of enzymes. Since they have features reminiscent of both enzymes (chemoselectivity, siteselectivity) and synthetic catalysts (comparable, or lower molecular weight, broad substrate scope) it is highly probable that peptides were fundamental in the development of the complex enzymes we know today. Intriguing future directions may involve the development of www.sciencedirect.com
bi-catalytic or multicatalytic systems [41] as well as the control of the catalytic performance of peptides by aggregation [42,43]. It can be expected that these strategies will further enable the development of many more peptidic catalysts for synthetically useful transformations and catalytic concepts in the next decade.
Acknowledgements Support from the Swiss National Science Foundation (Grant no. 2-7786613) is gratefully acknowledged. We thank the European Union’s 7th Framework Marie-Curie Intra European Fellowship Program for a fellowship for BL.
References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as: of special interest of outstanding interest 1.
Sewald N, Jakubke H-D (Eds): Peptides: Chemistry and Biology, edn 2. Wiley VCH; 2009.
2.
Davie EAC, Mennen SM, Xu Y, Miller SJ: Asymmetric catalysis mediated by synthetic peptides. Chem Rev 2007, 107:57595812.
3.
Wennemers H: Asymmetric catalysis with peptides. Chem Commun 2011, 47:12036-12041.
4.
Oku J-I, Ito N, Inoue S: Asymmetric cyanohydrin synthesis catalysed by synthetic peptides. Makromol Chem 1979, 180:1089-1091.
5.
Julia´ S, Guixer J, Masana J, Rocas J, Colonna S, Annunziata R, Molinari H: Synthetic enzymes. Part 2. Catalytic asymmetric epoxidation by means of polyamino-acids in a triphase system. J Chem Soc Perkin Trans I 1982:1317-1324.
6.
Revell JD, Wennemers H: Peptidic catalysts developed by combinatorial screening methods. Curr Opin Chem Biol 2007, 11:269-278.
7.
Barrett KT, Miller SJ: Enantioselective synthesis of atropisomeric benzamides through peptide-catalyzed bromination. J Am Chem Soc 2013, 135:2963-2966.
8.
Barrett KT, Metrano AJ, Rablen PR, Miller SJ: Spontaneous transfer of chirality in an atropisomerically enriched two-axis system. Nature 2014, 509:71-75. The first example of an enantioselective bromination of tertiary benzamides to yield atropoisomers with two axes of chirality catalyzed by a tetrapeptide. Careful optimization of reaction conditions allowed a high degree of control over the dynamics of the system and led to equal stereoenrichment of both cis and trans amide isomers.
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