Thieme Chemistry Journals Awardees - Where Are They Now? A Stereoselective Tripeptide Catalyst for Conjugate Addition Reactions of Acetophenones to Dicyanoolefins

Article abstract of DOI:10.1055/s-0036-1588964

Peptides of the type H-Pro-Pro-Xaa-NH ₂ were evaluated as catalysts for conjugate addition reactions of acetophenones to cyanoolefins. Tripeptide H- d -Pro-Pro-Glu-NH ₂ with a carboxylic acid moiety in the side chain of Xaa was ident

Full text of DOI:10.1055/s-0036-1588964

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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–E
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A
T. Schnitzer, H. Wennemers
Cluster
Synlett
Thieme Chemistry Journals Awardees – Where Are They Now?
A Stereoselective Tripeptide Catalyst for Conjugate Addition Reac-
tions of Acetophenones to Dicyanoolefins
O
Tobias Schnitzer
H
N
Helma Wennemers*
*
NH2
20 mol%
N
*
O
O
*
O
Ar2
ETH Zürich, Laboratory for Organic Chemistry, D-CHAB,
Vladimir-Prelog-Weg 1-5/10, 8093 Zürich, Switzerland
Helma.Wennemers@org.chem.ethz.ch
n
O
CN
CN
CN
Y
NH
Ar1
Ar2
+
Ar1
MeOH, r.t., 3 d
CN
up to 90% yield, 88:12 er
Received: 13.01.2017
Accepted after revision: 14.02.2017
Published online: 10.03.2017
DOI: 10.1055/s-0036-1588964; Art ID: st-2017-b0037-c
Abstract Peptides of the type H-Pro-Pro-Xaa-NH2 were evaluated as
catalysts for conjugate addition reactions of acetophenones to cya-
noolefins. Tripeptide H-D-Pro-Pro-Glu-NH2 with a carboxylic acid moi-
ety in the side chain of Xaa was identified as a catalyst that provides γ,γ-
dicyanoacetophenones in yields of up to 90% and stereoselectivies of up
to 88:12 er.
Key words peptides, organocatalysis, proline, nitriles, conjugate addi-
tion reactions
Nitriles are widespread in natural products1 and versa-
tile intermediates for the synthesis of amines, amides, and
carbonyl compounds.2 Hence, the introduction of cyano
groups into organic molecules is important. Organocatalyt-
ic conjugate addition reactions of carbonyl compounds to
α,β-unsaturated nitriles are an attractive means to access
enantiomerically enriched nitrile-containing products.
However, whereas numerous chiral amine-based catalysts
have been developed that activate aldehydes and ketones by
enamine formation for reactions with Michael acceptors
(e.g., nitroolefins, acrylates, α,β-unsaturated carbonyl com-
pounds),3 examples of related addition reactions to cya-
noolefins are rare.4 Since pioneering studies by Enders5 on
stoichiometric addition reactions of SAMP- and RAMP-hy-
drazones to dicyanoolefins only a few catalytic reactions
have been reported, which are typically part of cascade re-
actions.4 One challenge arises from the weak interaction of
cyanoolefins with hydrogen-bond donors, which renders
substrate activation difficult.6
Herein we explored amine-based catalysts of the type
Pro-Pro-Xaa bearing different functional groups in the side
chain of the Xaa residue as catalysts for conjugate addition
reactions between carbonyl compounds and cyanoolefins.
We show that the tripeptide H-D-Pro-Pro-Glu-NH2 cataly-
zes addition reactions between acetophenones and dicya-
noolefins and provides γ,γ-dicyanoacetophenones with
good yields and stereoselectivities.
Helma Wennemers studied chemistry at the Johann-Wolfgang-Goethe
University in Frankfurt before moving to Columbia University, New York,
where she received her Ph.D. degree for studies with W. Clark Still in
1996. Following postdoctoral studies at Nagoya University with Hisashi
Yamamoto (1997–1998), she joined the faculty of Basel University as
the Bachem-endowed Assistant Professor in 1999. She was promoted
to Associate Professor (2004) at the University of Basel before moving
to ETH Zurich in the fall of 2011 where she is Professor of Organic
Chemistry. Her research focuses on the development of small molecules
with functions that are fulfilled in nature by large macromolecules. She
utilizes the power of organic synthesis to access functionalities that na-
ture might have not had in the repertoire of building blocks. The focus
is both on practical applications and an understanding of the properties
on the molecular level. This scope includes the development of bioin-
spired asymmetric catalysts, functionalizable collagen, the controlled
formation of metal nanoparticles as well as the use of molecular scaf-
folds for applications in supramolecular and biological chemistry (e.g.,
cell-penetrating peptides, and tumor targeting). Helma is a fellow of
ChemPubSoc Europe and the Royal Society of Chemistry and received
several other recognitions for her research, including the Thieme
Chemistry Journal Award (2001), Göring Visiting Professorship, Univer-
sity of Wisconsin–Madison (2004), Leonidas Zervas Award (2010), Da-
vid Ginsburg Lectureship (2010), Holger Erdtman Lectureship (2010),
Auer von Welsbach Lectureship (2011), Novartis Lectures [University of
Columbia (2011), University of Wisconsin, Madison (2012), University
of Illinois–Champaign (2015), University of Pennsylvania (2017)], Euro-
pean Journal of Organic Chemistry Lectureship (2014), Pedler Award
(2016), JSPS Distinguished Lectureship (2016), and most recently Cal-
vin Lectureship (University of California at Berkeley), Chemical Record
Lectureship (2017), and the Inhoffen Medal (2017).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

B
T. Schnitzer, H. Wennemers
Cluster
Synlett
Peptidic catalysts of the Pro-Pro-Xaa-type are attractive
for C–C bond formations that proceed via enamine activa-
tion of carbonyl compounds.7–10 Highly stereoselective ca-
talysts for aldol and conjugate addition reactions have been
developed that require, compared to other secondary amine
based catalysts, only low catalyst loadings for obtaining
the products in high yields (Scheme 1).7–11 Tailoring of the
C-terminal amino acid (Xaa) and the absolute configuration
of the stereogenic centers allowed for tuning of the reactiv-
ity, stereoselectivity, and notably also the chemoselectivity
of the tripeptidic catalysts.7–10 Even challenging substrates
such as α,β- or β,β-disubstituted nitroolefins react in the
presence of an appropriate tripeptidic catalyst to provide
products with three consecutive stereogenic centers and a
quaternary stereogenic center, respectively.10 We therefore
reasoned that Pro-Pro-Xaa-type catalysts provide a good
testing ground for evaluating the effect of functional groups
within secondary amine based catalysts on the reactivity of
carbonyl compounds with cyanoolefins.
that bear different proteinogenic and non-proteinogenic
amino acids in the Xaa position (Scheme 2). The functional
groups in the side chain of Xaa include proton donors, hy-
drogen-bond donors and acceptors, as well as aromatic
moieties.
Initial trials to react monocyanoolefins (e.g., monocya-
nostyrene) with aldehydes in the presence of A–K showed
little or no conversion. Conversely, reactions of aliphatic al-
dehydes and ketones (e.g., butanal, acetone, pentanone)
with dicyanoolefins in the presence of the tripeptides pro-
vided products but in a fast and uncontrolled manner. We
therefore turned to reactions between dicyanoolefins and
acetophenones, which are particularly challenging sub-
strates for catalysts that rely on the activation of carbonyl
compounds by enamine formation.12
The reaction between acetophenone (1a) and dicyano-
styrene (2a) served as a model reaction. The peptides were
used as trifluoroacetic acid (TFA) salts and an equivalent
amount of N-methylmorpholine (NMM) was added to liber-
ate the secondary amine. These conditions were chosen for
ease of synthesis of the peptides that were cleaved off the
solid support by TFA, while keeping in mind that the pres-
ence of TFA can affect their catalytic performance.13 The ini-
tial reactions were performed in methanol since all pep-
tides were soluble in this solvent. Using equimolar amounts
Previous work:
1 mol%
O
O
OH
O
+
H-Pro-Pro-Asp-NH2
Ar
H
Ar
0.1–1 mol%
O
O
O
R2
H-D-Pro-Pro-Glu-NH2
NO2
NO2
O
NO2
R2
H
H
H
Ph
10 mol%
H-DPro-Pro-Xaa-NH2
10 mol% NMM
R1
O
Ph
⋅
TFA
1a
R2
(1 equiv.)
+
CN
5 mol%
Ph
R2
H-Pro-Pro-D-Gln-OH
MeOH, rt, 3 d
CN
NO2
NO2
CN
3a
Ph
R3
O
CN
2a
R1
R2
R3
R4
(1 equiv.)
+
H
10 mol%
H-D-Pro-Pro-R
R4
Xaa:
R1
O
O
O
O
NO2
H
N
H
H
H
N
R2
O
R = CH(Ph)CH2(pTol)
N
N
R1
O
CO2H
5 mol%
H
N
NH
O
CO2H
O
CO2H
O
NH2
H-D-Pro-Pro-Asn-NH2
O
A
B
D
C
H
61:39 er
87:13 er
64:36 er
59:41 er
R1
O
O
O
O
H
N
H
N
H
H
N
N
This work:
O
H
N
OH
OH
*
NH2
N
*
O
NH
HO
O
O
E
F
G
H
O
Ar2
*
NH
HN
NH2
n
rac.
rac.
26:74 er
52:48 er
Ar
+
Y
CN
Ar
O
O
O
CN
CN
Ar2
H
N
H
N
H
N
CN
NH
Scheme 1 Addition reactions catalyzed by Pro-Pro-Xaa-type peptides
N
NH
NO2
I
J
K
52:48 er
47:53 er
56:44 er
Pro-Pro-Xaa catalysts with different residues in the Xaa
position are easily accessible by solid-phase peptide syn-
thesis. We therefore started by synthesizing peptides A–K
Scheme 2 Testing of catalysts A–K in conjugate addition reactions be-
tween acetophenone 1a and dicyanostyrene 2a
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

C
T. Schnitzer, H. Wennemers
Cluster
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of acetophenone and dicyanostyrene and 10 mol% of the
peptidic catalysts, the formation of the conjugate addition
product 3a was observed for all evaluated peptides, albeit
typically with conversions of less than 20%. In light of the
low reactivity of acetophenone, this poor conversion was
not surprising and the performance of the catalysts was
therefore mainly evaluated based on their enantioselectivi-
ty. In the presence of peptides bearing aliphatic or aromatic
alcohol (F–H), aromatic (H–K), or amide (D) moieties γ,γ-
dicyanoacetophenone (3a) was formed, but was essentially
racemic (Scheme 2). Higher enantiomeric ratios were ob-
tained when peptides with hydrogen-bond donors such as
carboxylic acid (A–C) or guanidinium (E) moieties were
used. H-D-Pro-Pro-Glu-NH2 (B) exhibited the highest stereo-
selectivity and was therefore further investigated.
In previous studies the absolute configuration of cata-
lysts of the type H-Pro-Pro-Xaa had been found to affect
their reactivity and stereoselectivity.7–10 We therefore pre-
pared all diastereoisomers of B and evaluated their catalytic
performance. Peptide H-Pro-D-Pro-Glu-NH2 (14:86 er) per-
formed equally well as B (87:13 er) but with opposite enan-
tioselectivity. Such a switch in the enantioselectivity of di-
astereoisomeric catalysts had also been observed for other
conjugate addition reactions catalyzed by H-Pro-Pro-Xaa
peptides and is likely due to opposite turn conformations of
the diastereoisomeric peptides.8a The other two diastereo-
mers were less stereoselective (H-D-Pro-D-Pro-Glu-NH2,
43:57 er and H-Pro-Pro-Glu-NH2, 63:37 er) and also less re-
active. We therefore continued the studies with H-D-Pro-
Pro-Glu-NH2 (B) and sought to optimize the reaction condi-
tions further.14
Since the conformational properties of peptides and in-
termolecular interactions can be significantly affected by
the solvent,7b we next performed a thorough testing of dif-
ferent solvents. To overcome the low conversions (<20%)
observed in the initial trial, the catalyst loading was in-
creased to 20 mol% and a fivefold excess of acetophenone
was used. Reassuringly, the enantioselectivity of peptide B
was maintained at 87:13 er under these conditions and the
conversion increased to 72% (Table 1, entry 1). Testing of ar-
omatic solvents, CHCl3, THF, dioxane, EtOAc, MeCN, DMF,
DMSO, and an ionic liquid (Table 1, entries 2–13) resulted in
lower enantiomeric ratios compared to that obtained in
MeOH and hardly any conversion of the starting materials
into the product was observed. We therefore tested addi-
tional linear and branched alcohols (Table 1, entries 14–30)
as solvents for the addition reaction.
Table 1 Solvent Screening
O
20 mol%
Ph
H-D-Pro-Pro-Glu-NH2 (B) ⋅ TFA
1a
O
Ph
20 mol% NMM
(5 equiv)
CN
+
Ph
solvent, r.t., 3 d
CN
CN
3a
Ph
CN
2a
(1 equiv)
Entry
Solvent
era
Conv. (%)b
1
2e
MeOH
87:13
56:44
67:33
68:32
53:47
75:25
44:55
69:30
71:29
73:27
62:38
62:38
80:20
86:14
85:15
83:17
84:16
68:32
76:24
71:29
76:24
78:22
82:18
80:20
72
<5
<5
<5
<5
<5
<5
5
benzene
anisole
3e
4e
nitrobenzene
C6F6
5e
6e
CHCl3
7
THF
8
1,4-dioxane
EtOAc
9e
<5
<5
n.d.c
12
18
83
76
76
60
5
10
11
12
13
14
15
16
17
18e
19
20
21
22
23
24
25
26
27
28
29
30
MeCN
DMF
DMSO
BmimPF6
EtOH
n-PrOH
i-PrOH
n-BuOH
i-BuOH
(S)-s-BuOH
(R)-s-BuOH
t-BuOH
18
>95
65
>95
33
18
t-amyl alcohol
n-HexOH
n-OctOH
TCE
d
d
–
–
d
d
TFE
–
–
d
d
HFIP
–
–
cyclohexanol
propargyl alcohol
ethylene glycol
81:19
81:19
82:18
>95
48
55
In most of the alcoholic solvents conversions of more
than 50% and enantiomeric ratios of higher than 80:20
were observed. In general, higher stereoselectivities were
obtained in saturated linear alcohols (Table 1, entries 1, 14,
15, 17, 23, 24) compared to the corresponding branched al-
a Determined by chiral stationary phase SFC analysis.
b Estimated by 1H NMR spectroscopy of the crude product, error ±5%.
c Decomposition of the starting material/product was observed.
d No product was formed.
e Poor solubility of the dicyanoolefin and/or peptide.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

D
T. Schnitzer, H. Wennemers
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cohols with the same chain length (Table 1, entries 16, 18–
22). In addition, the enantioselectivity was overall higher in
alcohols with short linear aliphatic chains. This led us to
hypothesize that solvents with OH acidity are beneficial for
higher stereoselectivities. Yet, chlorinated and fluorinated
alcohols were too acidic and suppressed the reaction (Table
1, entries 25–27). Also ethylene glycol, propargyl alcohol,
and cyclohexanol as representatives of diols, unsaturated,
and cyclic alcohols were tested but did not lead to improved
stereoselectivities (Table 1, entries 28–30).
Next, we compared the performance of the TFA salt of B
in the presence of NMM with that of peptide B where the
TFA had been removed by ion-exchange chromatography. In
the presence of this ‘desalted’ peptidic catalyst B full con-
version to γ,γ-dicyanoacetophenone (3a) was observed
with maintained stereoselectivity (88:21 er), and 3a was
isolated in a yield of 85% (Table 2, entry 1). These optimized
conditions were then used for reactions between a couple
of acetophenones and dicyanoolefins.15 These experiments
showed that peptidic catalyst B catalyzes reactions of dicy-
anoolefins bearing electron-deficient aromatic substituents
(Table 2, entries 2 and 3) with product yields of up to 90%
and enantiomeric ratios of up to 88:12. Dicyanoolefins
bearing electron-rich moieties (Table 2, entries 4 and 5) and
substituted acetophenone derivatives (Table 2, entries 6
and 7) were converted with good enantiomeric ratios of up
to 87:13 but only poor conversions of less than 40%.
In summary, the testing of a collection of amine-based
catalysts bearing different functional groups revealed the
peptide H-D-Pro-Pro-Glu-NH2 as a good catalyst for conju-
gate addition reactions of acetophenones to dicyanoolefins.
The conjugate addition products formed in stereoselectivi-
ties of up to 88:12 er and 90% yield. The study showed that
even challenging addition reaction donors such as ace-
tophenone, with an intrinsically low reactivity, can be acti-
vated by peptidic catalysts to engage in conjugate addition
reactions. Yet, the research also showed that the efficient
activation of cyanoolefins remains a challenge.
Acknowledgment
This research was supported by the Swiss National Science Founda-
tion. T.S. thanks the Fonds der Chemischen Industrie for a Kekulé Fel-
lowship.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588964.
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References and Notes
(1) Fleming, F. F. Nat. Prod. Rep. 1999, 16, 597.
(2) Carey, F. C.; Sundberg, R. J. In Advanced Organic Chemistry, Part
B, 5th ed.; Springer: New York, 2008.
(3) Vicario, J. L.; Badia, D.; Carrillo, L.; Reyes, E. In Organocatalytic
Enantioselective Conjugate Addition Reactions: A Powerful Tool
for the Stereocontrolled Synthesis of Complex Molecules; RSC Pub-
lishing: Cambridge, 2010.
Table 2 Investigation of the Substrate Scope Using Optimized Condi-
tions for the Michael Addition of Acetophenones 1 to Dicyanoolefins 2
O
(4) For examples, see: (a) Huang, H.; Bihani, M.; Zhao, J. C.-G. Org.
Biomol. Chem. 2016, 14, 1755. (b) Penon, O.; Carlone, A.;
Mazzanti, A.; Locatelli, M.; Sambri, L.; Bartoli, G.; Melchiorre, P.
Chem. Eur. J. 2008, 14, 4788.
(5) Enders, D.; Demir, A. S.; Rendenbach, B. E. M. Chem. Ber. 1987,
120, 1731.
(6) Gilli, P.; Pretto, L.; Bertolasi, V.; Gilli, G. Acc. Chem Res. 2008, 42,
33.
(7) (a) Krattiger, P.; Kovasy, R.; Revell, J. D.; Ivan, S.; Wennemers, H.
Org. Lett. 2005, 7, 1101. (b) Messerer, M.; Wennemers, H. Synlett
2011, 499.
Ar1
Ar2
1
O
20 mol%
H-D-Pro-Pro-Glu-NH2 (B)
(5 equiv)
CN
Ar1
+
MeOH, r.t., 3 d
CN
CN
3
Ar2
CN
2
(1 equiv)
Entry
Ar1
Ar2
era
Yield/Conv. (%)b,c
(8) (a) Wiesner, M.; Neuburger, M.; Wennemers, H. Chem. Eur. J.
2009, 15, 10103. (b) Wiesner, M.; Upert, G.; Angelici, G.;
Wennemers, H. J. Am. Chem. Soc. 2010, 132, 6. (c) Wiesner, M.;
Revell, J. D.; Tonazzi, S.; Wennemers, H. J. Am. Chem. Soc. 2008,
130, 5610.
(9) Grünenfelder, C. E.; Kisunzu, J. K.; Wennemers, H. Angew. Chem.
Int. Ed. 2016, 55, 8571.
(10) (a) Duschmalé, J.; Wennemers, H. Chem Eur. J. 2012, 18, 1111.
(b) Kastl, R.; Wennemers, H. Angew. Chem. Int. Ed. 2013, 52,
7228.
1
2
3
4
5
6
7
Ph
Ph
Ph
Ph
Ph
Ph
88:12
87:13
69:31
85
90
78
4-O2NC6H4
4-ClC6H4
4-MeC6H4
4-MeOC6H4
Ph
87:13 (37)
87:13 (14)
87:13 (24)
52:48 (<5)
4-MeOC6H4
3,5-(CF3)2C6H4
Ph
(11) For an early report on aldol and conjugate addition reactions
catalyzed by peptides, see: Martin, H. J.; List, B. Synlett 2003,
1901.
(12) For examples of reactions between acetophenones and cya-
noolefins, see: (a) Moirangthem, N.; Thingom, B.; Moirangthem,
S. D.; Laitonjam, W. S. Indian J. Chem., Sect. B: Org. Chem. Incl.
a Determined by chiral stationary phase SFC analysis.
b Yield of the isolated products.
c Conversions listed in parentheses were estimated by 1H NMR of the crude
product, error ±5%. Products were only isolated in reactions with >50%
conversion.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

E
T. Schnitzer, H. Wennemers
Cluster
Synlett
Med. Chem. 2013, 937. (b) Wei, Y.; Guo, R.; Dang, Y.; Nie, J.; Ma,
J.-A. Adv. Synth. Catal. 2016, 358, 2721. (c) Yue, L.; Du, W.; Liu,
Y.-K.; Chen, Y.-C. Tetrahedron Lett. 2008, 49, 3881. (d) Kojima, S.;
Suzuki, M.; Watanabe, A.; Ohkata, K. Tetrahedron Lett. 2006, 47,
9061. For examples of amine-catalyzed addition reactions with
acetophenones, see: (e) Liu, K.; Cui, H.-F.; Nie, J.; Li, X.-J.; Ma, J.-
A. Org. Lett. 2007, 9, 923. (f) Liu, J.; Yang, Z.; Liu, X.; Wang, Z.;
Liu, Y.; Bai, S.; Lin, L.; Feng, X. Org. Biomol. Chem. 2009, 7, 4120.
(g) Li, W.; Wu, W.; Yang, J.; Liang, X.; Ye, J. Synthesis 2011, 1085.
(h) Liu, T.-Y.; Cui, H.-L.; Zhang, Y.; Jiang, K.; Du, W.; He, Z.-Q.;
Chen, Y.-C. Org. Lett. 2007, 9, 3671.
(14) Notably, this peptide is also a powerful catalyst for conjugate
addition reactions between aldehydes and β-nitroolefins (ref. 8).
(15) The peptide catalyst B (0.2 equiv, 20 μmol) was dissolved in
MeOH (400 μL). The acetophenone 1 (5 equiv, 500 μmol) and
dicyanostyrene 2 (1 equiv, 100 μmol) were added, and the reac-
tion mixture was stirred for 3 d. The reaction mixture was sub-
jected to flash chromatography (hexane–EtOAc, 20:1 to 4:1) to
isolate the product after removal of all volatiles under reduced
pressure.
(S)-2-(3-Oxo-1,3-diphenylpropyl)malononitrile (Table 2,
Entry 1)
(13) Duschmalé, J.; Wiest, J.; Wiesner, M.; Wennemers, H. Chem. Sci.
2013, 4, 1312.
1H NMR (300 MHz, CDCl3): δ = 8.01–7.92 (m, 2 H), 7.71–7.58
(m, 1 H), 7.51 (dd, J = 8.3, 6.9 Hz, 2 H), 7.41 (s, 3 H), 4.63 (d, J =
5.0 Hz, 1 H), 3.95 (dt, J = 8.2, 5.3 Hz, 1 H), 3.75–3.56 (m, 2 H).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E