Helical Oligourea Foldamers as Powerful Hydrogen Bonding Catalysts for Enantioselective C-C Bond-Forming Reactions

Article abstract of DOI:10.1021/jacs.7b05802

Substantial progress has been made toward the development of metal-free catalysts of enantioselective transformations, yet the discovery of organic catalysts effective at low catalyst loadings remains a major challenge. Here we report a novel synergistic

Full text of DOI:10.1021/jacs.7b05802

Subscriber access provided by UNIVERSITY OF THE SUNSHINE COAST
Article
Helical Oligourea Foldamers As Powerful Hydrogen Bonding
Catalysts for Enantioselective C-C Bond-Forming Reactions
Diane Bécart, Vincent Diemer, Arnaud Salaün, Mikel Oiarbide, Yella-Reddy
Nelli, Brice Kauffmann, Lucile Fischer, Claudio Palomo, and Gilles Guichard
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b05802 • Publication Date (Web): 07 Aug 2017
Downloaded from http://pubs.acs.org on August 7, 2017
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 26
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Helical Oligourea Foldamers as Powerful Hydrogen Bonding
Catalysts for Enantioselective C-C Bond-Forming Reactions
Diane Bécart,a,b Vincent Diemer,a¶ Arnaud Salaün,a Mikel Oiarbide,b Yella Reddy Nelli,a
Brice Kauffmann,c Lucile Fischer,a Claudio Palomo,b* and Gilles Guicharda*
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a Univ. Bordeaux, CNRS, CBMN, UMR 5248, Institut Européen de Chimie et Biologie, 2 rue Robert Escarpit, F-
33607 Pessac, France ; b Departamento de Química Orgánica I, Facultad de Químicas, Universidad del País Vasco
UPV/EHU, Apdo. 1072, 20080 San Sebastián, Spain; c Univ. Bordeaux, CNRS, INSERM, UMS3033/US001, Institut
Européen de Chimie et Biologie, F-33607 Pessac, France
ABSTRACT: Substantial progress has been made towards the development of metal-free catalysts of enantioselective
transformations, yet the discovery of organic catalysts effective at low catalyst loadings remains a major challenge. Here
we report a novel synergistic catalyst combination system consisting of a peptide-inspired chiral helical (thio)urea
oligomer and a simple tertiary amine that is able to promote the Michael reaction between enolizable carbonyl
compounds and nitroolefins with excellent enantio-selectivities at exceptionally low (1/10000) chiral catalyst/substrate
molar ratios. In addition to high selectivity – which correlates strongly with helix folding – the system we report here is
also highly amenable to optimization, as each of its components can be fine-tuned separately to increase reaction rates
and/or selectivities. The predictability of the foldamer secondary structure coupled to the high-level of control over the
primary sequence results in a system with significant potential for future catalyst design.
expected to contribute to enhanced catalysis efficiency
through (i) cooperative substrate binding, (ii) specific
INTRODUCTION
The ability to synthesize sequence-based non-natural
oligomers that fold with high fidelity – foldamers –
raises new prospects for mimicking biopolymers and for
creating molecules with emergent functions tailored to
various applications.1 The structure-guided design of
foldamers that specifically recognize the surfaces of
target biomacromolecules2 or interact with small
molecular guests,3,4 as well as the fabrication of large
architectures consisting of multiple secondary structure
elements arranged in tertiary and quaternary
structures,5,6 represent significant recent achievements
in this direction. Bioinspired catalysis is another area in
which foldamers have far-reaching potential, yet little
progress has been made in this direction, despite the
(theoretical) suitability of foldamers as biomimetic
catalysts. For example, foldamer systems typically
exhibit long-range conformational (e.g. helical) order, a
property beyond the reach of small molecules and little
explored in enantioselective catalysis.
stabilization
of
charged
transition-states
and
intermediates and (iii) minimization of the entropic
cost of transition-state binding.8 Synthetic α-peptides
for example have received strong interest as bioinspired
catalysts.9,10 In general, the active site consists of an
array of reactive side chains pre-organized in space
through folding;9 more rarely, it involves main-chain
functional groups.11 However – and in contrast to
peptides which have gained a momentum as middle
size catalysts for
a
number of stereoselective,
regioselective and chemoselective transformations9-13
–
synthetic foldamers are yet to be fully explored as
asymmetric catalysts.14-19
Chiral aliphatic N,N’-linked oligoureas20-23 are robust
helical foldamers bearing structural resemblance to the
α-helical peptide backbone. Oligoureas typically
mediate molecular recognition events through arrays of
side chains displayed at the helix surface,24-26 yet the
main chain itself is highly-suited to bind small guest
molecules. In particular, urea NHs at the positive end of
the oligourea helix macrodipole have been shown to
readily bind anions.27,28 The finding that anion binding
occurs without helix unfolding suggested to us that
Enzymes are generally regarded as highly efficient
catalysts at low loading levels, and commonly act
through a mechanism involving multiple cooperative
interactions.7
Likewise,
pre-organization
of
multifunctional catalysts through folding would be
1
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 26
1
2
3
4
5
oligourea foldamers could be useful in hydrogen bond
catalysis.29
Herein, enantiopure helical oligo(thio)urea foldamers
have been investigated for the first time in the context
of enantioselective carbon-carbon bond forming
reactions. We provide evidence that short helically
folded aliphatic N,N’-linked oligoureas in combination
with a simple achiral Brønsted base cocatalyst do work
synergistically to promote the addition of carbonyl
pronucleophiles to nitroalkenes with high reactivity and
selectivity. A detailed structure-activity relationship
study including a chain length dependence test30
demonstrated the strong correlation between the
folding propensity of the oligomer (a property beyond
the reach of small molecule catalysts) and its catalytic
performance.
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
RESULTS AND DISCUSSION
Background, working hypothesis and design of
helical oligo(thio)urea H-bond donor catalysts. H-
bond catalysis has become a major strategy for the
activation of substrates in enantioselective organic
reactions.31 Among the suitable H-bond donor groups,
(thio)ureas have shown to be highly effective and
versatile, either as discrete catalyst or as integral part of
a bifunctional Brønsted base-H-bond catalyst unit (Fig.
1a, left).29,31-40 During the search of (thio)urea catalysts
with improved activity and/or selectivity, the Smith
laboratory discovered that thiourea catalysts featuring
cooperative intramolecular H-bonds were more
effective than simple thioureas in Mukaiyama-Mannich
reaction models (Fig. 1b).8 The Pihko group further
refined this concept and reported the design of tertiary
amine/bis(thio)urea
bifunctional
catalysts
with
improved activity in Mannich reactions of malonates
and ketoesters with imines.37,40 Also, Clayden has
reported an internally organized bifunctional
amine/thiourea catalyst that achieves remote
asymmetric induction.19 In addition to the benefits
resulting from pre-organization of multifunctional
catalysts through folding as noted above, it was
suggested that the cooperative intramolecular H-
bonding within the catalyst structure would (i) enhance
the H-bond-donor ability of the thiourea group and (ii)
liberate space around thiourea moiety for effective
substrate-catalyst coordination. Based on these
precedents, and inspired by the way enzymes engage
large networks of cooperative intramolecular H-bonds,
we hypothesized that chiral (thio)urea catalysts capable
of forming extended intramolecular H-bonding
networks – e.g. helical N,N’-linked oligoureas (Fig. 1c) -
should present a unique catalytic profile.
Figure 1. Rationale for the use of Helical oligo(thio)urea
foldamers as chiral components of binary catalytic systems.
(a) Bifunctional and synergistic activation with H-bond
donor catalysts;29,31-40 (b) di-(thio)urea catalysts forming
cooperative intramolecular H-bonds; (c) Representation of
the extended chain of an N,N’-linked oligourea and its
folded behavior22,27 illustrating the two accessible H-bond
donor sites near the positive pole of the helix macrodipole.
At the outset, we decided to validate this idea in the
context
of
synergistic
nucleophile/electrophile
activation strategy41 (Fig. 1a, right). Synergistic systems
are highly modular and allow for an easier optimization
2
ACS Paragon Plus Environment

Page 3 of 26
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
of each catalyst component separately. Our second
assumption was that while relatively high
configuration with different proteinogenic side chains
(Me, iPr and iBu) to enable an unambiguous assignment
of all backbone protons.
a
concentration of (achiral) base may be required for the
activation of the C–H pronucleophile (to reach
threshold concentration of the actual nucleophile),
conversely relatively low amounts of the (chiral) H–
bond donor catalyst might suffice if, during the
subsequent C–C bond-forming (and stereochemistry-
determining) step, a cooperative H-bond network with
strong stereo-directing power operates.
Crystals suitable for X-ray diffraction of both
oligomers 1a and 2a were obtained, and the structures
solved by direct methods in the P21 and P1 space
groups, respectively. The crystal structures of 1a and 2a
(Fig. 2) which contain four and two independent
molecules in the asymmetric units, respectively, (see
Supplementary Fig. 1a,b) show that both oligomers have
right-handed (P) helicity with both carbonyl and/or
thiocarbonyl groups of the first two (thio)urea units
engaged in intramolecular H-bonding. As expected,42
the main differences between 1a and 2a resides in the
geometry of the first intramolecular hydrogen bond
between the terminal C=X and the NHs of the third
urea group (the C=X•••N distance increases from an
average 2.90 Å in 1a to 3.42 Å distance in 2a) that leads
to a slight rearrangement of the first residue and of the
3,5-bis(trifluoromethyl)phenyl moiety.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In this work, we focused on 6-mer oligoureas which
are known to adopt a well-defined helical conformation
in both polar and non-polar solvents.27,42 To
differentiate the two sites available for substrate
recognition and catalysis (Fig. 1c), we increased the
polarity and the polarizability of the first urea group by
introducing
a
3,5-bis(trifluoromethyl)phenyl group
(oligomer 1a) and/or replacing the urea moiety by a
thiourea (oligomer 2a) moiety (Fig. 2). The primary
structure (i.e. the sequence) of both oligomers is similar
and consists of the repeat of three residues of (S)–
Figure 2. Foldamer-based chiral catalysts. Primary sequence of (thio)urea hexamers 1a and 2a and view along and down helical
axis of their X-ray crystal structures showing accessibility of H-bond donor sites. The two helices are colored separately (1a, left
and 2a, right). The asymmetric units of 1a and 2a contain four and two independent molecules, respectively, of which only one
is represented here (see supplementary Fig. S1 for a structural alignment of all independent molecules in the asymmetric unit).
A
synergistic catalytic system at low chiral
resultant γ-nitro carbonyl adducts can be easily
transformed into γ-amino acids, γ-butyrolactams and
pyrrolidines, all of which are interesting building blocks
for pharmaceutical developments.46 Initial catalytic
activities (addition of diethyl malonate 3a to
nitrostyrene 4a) were measured at different
catalyst/substrate ratio. The conjugate addition43 of
malonate ester (e.g. 3) to nitroalkenes (e.g. 4),44 was
selected to assess the viability of the approach. This
reaction is synthetically interesting due in part to the
rich chemistry of the nitro group,45 and also because the
3
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 26
1
2
3
4
5
6
7
8
9
concentrations (from 1 to 0.00025 mol%) of 1a (or 2a) in
The combination of 1a (0.1 mol%) and Et3N (10 mol%)
non-polar solvents in the presence of a fixed amount of
Brønsted base (Et3N, 10 mol%). Several interesting
trends were observed from this first series of
experiments (Table 1, entries 1-13, Supplementary Table
1 and Supplementary Fig. 2a).
in toluene at -20 °C was found to provide complete
conversion and excellent enantioselectivities (95% ee47),
thus denoting that separate Brønsted base and chiral H-
bond donor work synergistically (Table 1, entry 2 and
Supplementary Table 1, entry 1).48 There was almost no
conversion in the absence of 1a (Et3N alone, entry 1).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 1. Optimization of the foldamer/base catalytic system and structure-activity relationship study.
Entry
Chiral
Foldamer
Temperature Reaction Et3N
Conversion (%)
Yield (%)
ee (%)
Catalyst Loading
(°C)
Time (h) (mol%)
(mol%)
1
-
-
-20
-20
-20
-20
-20
-20
-20
-20
-20
-20
RT
-20
RT
48
10
10
10
10
10
10
1
7
n.d.
86 (63)
85
0
2
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
2a
2a
0.1
48 (24)
48
100 (99)
100
98
95 (94)
94
3
0.05
0.01
0.005
0.001
0.1
4
5
48
82
91
48
93
82
84
6
7
48
67
49
74
48
56
43
95
8
9
10
11
12
13
0.1
48
5
100
100
100
98
85
95
0.1
48
20
30
10
10
10
83
93
0.1
16
78
93
0.1
48
75
89
0.1
48 (24)
48
98 (94)
94
80 (59)
74
93 (88)
86
0.1
Reactions were performed with 0.5 mmol of 4a and 1.0 mmol of 3a. Yields correspond to isolated compound after chromatographic
purification. The enantiomeric excess (ee) was determined by chiral HPLC analysis. Absolute configuration (R) or (S) was known or assigned by
analogy.
Remarkably, the reactivity and the selectivity of the
catalytic system (1a/Et3N) remained largely unaffected
when the chiral catalyst/substrate ratio was decreased
to levels as low as 1:10000 (Table 1, entries 2-4 and
Supplementary Fig. 2a). When as little as 0.01 mol% of
1a was employed, the Michael adduct 5 was still
obtained in a yield of 82% with 91% ee (Table 1, entry 4).
Note that just 0.05 mg of 1a (0.01 mol%) is needed in
this case to convert 0.5 mmol of nitrostyrene, whereas a
similar conversion with common small molecule
bifunctional catalyst would typically require >20 mg (10
mol%) of catalyst. As initially hypothesized, the
the reaction rate is significantly impacted at 1 mol% of
Et3N (Table 1, entries 7 and 8). Conversely, increasing
the concentration of Et3N to 20 and 30 mol% is well
tolerated and allows shorter reaction times (Table 1,
entries 9 and 10). The reaction with 1a/Et3N was slightly
less selective at RT (89% ee, entry 11). The synthetic
utility of 1a was further demonstrated by performing
the reaction on a larger scale. Gram quantities of the
Michael adduct (0.95 g after purification) and excellent
ee (95% ee) were obtained when the reaction was
conducted on a 3.3 mmol scale with 3.4 mg of 1a (0.1
mol%).
catalytic
process
requires
a
relatively
high
Hexamer 2a, which contains a thiourea at the first
position, also performed well but was systematically less
concentration of base relative to the chiral catalyst, as
4
ACS Paragon Plus Environment

Page 5 of 26
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
effective than 1a for the addition of malonate 3a to the
nitroolefin 4a (Table 1, entry 12 vs entry 2 (at 24h) and
entry 13 vs entry 11 (at RT)), suggesting a subtle
interplay of acidity49 and conformation in controlling
the catalytic efficiency of the system. One plausible
explanation is that the benefit of increasing the acidity
by replacing the oxygen of the first urea by a sulfur
atom may be counterbalanced by unfavorable
conformational change and dynamics at the positive
pole of the helix where catalysis takes place.42
solvents.50 The helix dipole is also expected to increase
with the length of the helix, possibly suggesting a more
pronounced interaction of longer oligomers with
charged intermediates during the catalytic process. To
gain more specific information about the helix forming
propensity of oligoureas 1a-e, we recorded their
electronic circular dichroism (ECD) spectra in
trifluoroethanol (Fig. 3b). As expected, the tetramer
(1c), pentamer (1b) and hexamer (1a), but not dimer 1d
and monomer 1e, displayed the characteristic ECD
signature of (P)-2.5-helical oligoureas, with a positive
maximum at ∼203 nm whose intensity (mean residue
ellipticity) increases with the number of residues in the
chain. This observation was further supported by the
degree of anisochronicity of NMR signals arising from
diastereotopic protons in the chiral units of 1a-1e
(Supplementary Table 2). We obtained an X-ray crystal
structure of 5-mer 1b. This oligomer is fully helical in
the crystal and an overlay with the structure of 1a (Fig.
3c) by fitting the first five pairs of carbonyl C atoms
indicates a very close match between the two helices
including at the active site (root-mean-square deviation
(RMSD) = 0.150 Å).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Catalysis upon folding: Chain-length dependence
and temperature effects. To investigate whether the
helical conformation of oligo(thio)ureas 1a and 2a is
critical
to
achieve
rate
acceleration
and
enantioselectivities reported in Table 1, we next
prepared two series of shorter analogues (1b-e and 2c-e)
ranging from 1 to 5 monomeric (NHCH(R)-CH2-NHCO)
units, and sharing the same terminal bis(thio)urea
segment and 3,5-bis(trifluoromethyl)phenyl moiety
(Fig. 3a). Whereas analogues consisting of one (1e and
2e) and two (1d and 2d) monomeric units are too short
to adopt a helical conformation, longer analogues are
expected to gradually populate the 2.5-helical
conformation in non-polar and moderately polar
Figure 3. Catalysis and chain length dependence. a, Primary sequence of analogues of 1a and 2a ranging in size from monomer
to pentamer. b, Electronic circular dichroism (ECD) analysis of oligoureas 1a-1e in trifluoroethanol. Molar residual ellipticity in
deg.cm2.dmol-1.residue-1. c, Structural alignment of the crystal structures of 1a (carbon atoms in sand) and 1b (carbon atoms in
light blue). d, Enantiomeric excess of the Michael adduct 5 determined by chiral HPLC analysis after purification for reactions
conducted in the presence of 1a-e and 2a-e. Reactions were performed at RT for 24h, with 0.1 mol% catalyst, 10 mol% Et3N, on
0.67 mmol scale.
All foldamers were then tested for their ability to
catalyze the reaction between diethylmalonate 3a with
nitrostyrene 4a at low chiral catalyst loading using
conditions reported in Table 1, entry 11 (chiral catalyst
0.1 mol%, Et3N 10 mol%, RT, 48 h). A strong chain
length dependence effect was observed (Fig. 3d and
5
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 26
1
2
3
4
5
6
7
8
9
Supplementary Table 3) with almost no enantio-control
reaction outcome could be significantly improved by
in the presence of monomers (1e and 2e) and dimers
(1d and 2d) and the highest reactivity (94-98%
conversion) and selectivity (86-89 % ee) for helically
folded 5- and 6-mers (1a > 1b > 2a). Intermediate
selectivities (36-63 % ee) were obtained with partially
folded 4-mers and in this case, conversion and
stereocontrol were significantly higher with the
thiourea containing derivative 2c, suggesting that
increased acidity of the catalyst could compensate for
the limited conformational control. Overall these
results support the view that a well-defined helical
conformation is required for efficient stereocontrol in
the catalytic process, and furthermore that even
relatively short helices (e.g. 5-mer 1b) display an
employing trialkylamine bases with increasing alkyl
chain length or bulkiness. Although we do not yet have
a full explanation for this result, the data in Table 2
show that among the bases tested, iPr2EtN (DIPEA)
gave the best enantioselectivity for the addition
reactions with acetylacetone 7 and 1,3-diphenylpropane-
1,3-dione 8 with ee’s between 83 and >99 % (Table 2,
entries 6, 9, 12 and 15).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 2. Suitability of several 1,3-dicarbonyl
compounds as nucleophiles and influence of the
nature
of
the
amine
base
cocatalyst.
excellent
catalytic
activity
profile
at
low
oligomer/substrate ratio. Because the 2.5-helix of
oligoureas is robust and shows significant thermal
stability in non-polar and moderately polar solvents,51
we decided to evaluate to which extent the activity of
the catalytic system 1a/Et3N persists at high
temperature. Although the selectivity gradually
decreased between -20 and 80 °C the reactivity was not
significantly affected, with the reaction at 80 °C still
producing the Michael adduct in a satisfactory yield of
78% and 69% ee. This indicates that the active site as
well as supramolecular interactions are largely
Entry Product
1
Amine
base
Time Yield ee
(h)
(%)
(%)
9
Et3N
40
72
98*
maintained over
a
wide temperature range
2
Et3N
16
16
92
90
78
72
70
82
98
90
87
80
82
64
99
67
63
73
(Supplementary Fig. 2b).
3
nBu3N
Scope of the reaction and fine tuning of the
selectivity. We next addressed the substrate scope of
the reactions catalyzed by oligourea 1a by applying it to
other 1,3-dicarbonyl compounds and to a variety of
nitroalkenes (Tables 2 and 3). The effectiveness of the
catalyzed addition of malonate esters to nitrostyrene, in
terms of reactivity and selectivity, inversely correlates
with the size of the ester group; dimethyl malonate 3b
giving the fastest conversion and a remarkable 97% ee,
and tert-butyl malonate 3e being the least reactive
(Supplementary Table 4, entries 1-5). When using cyclic
ketoester 6 as a nucleophile, the resulting adduct 9
bearing a stereogenic quaternary center was formed
with a high 98% ee and complete diastereoselectivity
(Table 2, entry 1). As noted above, a distinctive feature
of this synergistic approach as compared to the
bifunctional catalyst approach is that variation of each
catalyst component can be performed independently of
the other. Thus, catalyst optimization may be simply
achieved by modifying the nature of the associated
Brønsted base. For example, during the initial scope of
Michael donors, we observed that the reaction of
acetylacetone 7 with nitrostyrene 4a to produce adduct
10a, (Table 2, entry 2) proceeded with a low 63% ee
under our established conditions. However, the
R’:H
(10a)
4
nHex3N 120
nOct3N 120
iPr2EtN 16
76
83
92
80
66
86
56
69
83
91
5
6
7
Et3N
16
R’: Me
(10b)
8
nOct3N 120
iPr2EtN 16
9
10
11
12
13
14
15
Et3N
16
R’: Cl
(10g)
nOct3N 120
iPr2EtN 16
Et3N
16
nOct3N 72
iPr2EtN 16
95
>99
11
Reactions were performed on 1 mmol scale with 2 equiv. of
diketone. Yields correspond to isolated compound after
chromatographic purification. The ee was determined by chiral
HPLC analysis. Absolute configuration (R) or (S) was known or
assigned by analogy. *dr (2R/2S) : 0:100
As shown in Table 3, the catalyzed reaction of
dimethyl malonate 3b with an array of nitroalkenes 4
was found to be quite independent of the electronic
6
ACS Paragon Plus Environment

Page 7 of 26
Journal of the American Chemical Society
1
2
3
4
5
properties of the aryl ring of the nitroalkene.
Compound 4a as well as nitroalkenes with electron
Table 3. Scope of the enantioselective conjugate
addition of dimethylmalonate to nitroalkenes
catalyzed by 1a
donating β-aryl groups such as 4b, 4c, 4d and 4e led to
the corresponding adducts 12a-e with excellent
chemical and stereochemical results, regardless of their
o-, m- or p-substitution pattern. Likewise, nitroalkenes
4f, 4g and 4h with inductively electron withdrawing
fluoro, chloro and bromo groups afforded Michael
adducts 12f-h with good yields and ee’s up to 92%.
Somewhat inferior results were observed for the
reaction of 4i and 4j, bearing electron poor β-aryl
groups, which provided adducts 12i and 12j with 62% ee
and 86% ee, respectively. In these cases, the
enantioselectivity was largely improved by using DIPEA
as a base (96% and 93% ee, respectively) instead of
Et3N. Nitroalkenes with heteroaromatic β-substituents
such as 4k and 4l are also good acceptors, and provide
the corresponding adducts 12k and 12l in 98% ee and
97% ee, respectively. Conjugated nitroalkenes 4m-4p
led to the respective adducts 12m-p, although long
reaction times were required. Again, the combination of
DIPEA with 1a proved superior to the use of Et3N in
terms of stereocontrol (e.g. 12n-12p). Importantly, only
0.1 mol % of catalyst loading was needed in the majority
of the cases in order to achieve good yields of isolated
product and high enantioselectivities. To the best of our
knowledge, this represents the lowest catalyst/substrate
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ratio employed in Brønsted base catalyzed Michael
33,52,53
reaction of malonate esters to nitroalkenes.
Most
significantly, the recalcitrant β-alkyl nitroalkenes such
as 4q and 4r, which generally lead to sluggish reactions
and poor ee’s,34,35 provided the corresponding adducts
with ee’s up to 81% at 0.1 mol% catalyst loading and -20
°C. In these cases, the enantioselectivity could be
substantially improved by increasing the amount of
catalyst to 0.3 mol% and decreasing the reaction
temperature to -30 °C. As shown in Table 3, extension to
nitroalkenes 4s-w with short, large and ramified β-alkyl
chains is equally tolerated and provided adducts 12s-w
in good yields and high ee’s.
Structure-reactivity/enantioselectivity
relationship and mechanistic studies. We
conducted analysis by 1H NMR in toluene-d8 of
mixtures of 1a, Et3N, 3a and 4a in order to generate
information concerning the kinetics of the foldamer-
catalyzed addition reaction of malonate to nitroolefin
(Supplementary Figure 3). Using the method of flooding
with [3a] = 10 ꢀ [4a], we confirm that the reaction
exhibits a first-order with respect to nitrostyrene. The
method of initial rates was used to determine the order
in foldamer, base and malonate 3a.54 We found that the
reaction is first order with respect to base and malonate
3a and also exhibit a first order dependence in foldamer
at concentrations below ≈ 0.2 mol%.
Reactions were performed on 0.5 mmol scale with 2 equiv. of
3b.
Yields
correspond
to
isolated
compound
after
chromatographic purification and are given in per cent. The ee
was determined by chiral HPLC analysis. Absolute configuration
(R) or (S) was known or assigned by analogy. §The reaction was
performed using DIPEA as base (30 mol%); *Reaction conducted
at −30 °C using 0.3 mol% catalyst.
7
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 8 of 26
1
2
3
4
5
6
7
8
9
The deviations from first order kinetics at higher
geometry of the 2.5-helix is compatible with the
concentrations of 1a could be rationalized by a possible
aggregation of the foldamer, an explanation which is
also supported by the small but substantial non-linear
effect which is observed at 0.1 mol% when the ee of the
catalyst is varied by mixing 1 and its enantiomer ent-1 in
defined proportions (Supplementary Fig. 4).
introduction of a pyrrolidine unit. In the crystal, the
CO−N−Cβ−Cα angle (ϕ) of the pyrrolidine units adopts
a value (≈ −96°) close to that of standard residues in
helical oligoureas and the carbonyl group of the
pyrrolidine unit is engaged in typical H-bonds with urea
NHs of canonical residues. Helix formation is also
supported in solution by anisochronicities measured in
the chiral units of compounds 13-15, although with
some local perturbation at the site of the pyrrolidine
insertion (Fig. 4c). Despite the overall structural
similarity between 14 / 15 and 1a / 2a respectively, we
found that the pyrrolidine residues in 14 and 15 were
detrimental to the catalytic activity (≈ 35% and 15%
conversion, respectively) supporting a key role of the
second urea site in catalysis (Table 4, entries 2 and 3).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
We next introduced sequence variations into 1a and
2a in order to interrogate the role of the first two
(thio)urea moieties and gain additional insight into the
principles governing the catalytic activity of oligoureas
as a mean to improve next generation foldamer-based
catalysts (Fig. 4). Pyrrolidine units in compounds 13-15
were used to selectively block the first or second
accessible urea groups. The crystal structures of 15 (Fig.
4b) and of the Boc-protected precursor of 14
(compound 20, Supplementary Fig. 1c) show that the
Table 4. Correlation of the foldamer structure with the catalytic activity.
Entry
Chiral
Foldamer
Temperature Reaction Et3N
Conversion (%)
Yield (%)
ee (%)
Catalyst Loading
(°C)
Time (h) (mol%)
(mol%)
1
13
14
15
16
17
18
19
0.1
0.1
0.1
0.1
0.1
0.1
0.1
-20
-20
-20
-20
-20
-20
-20
48
48
48
48
48
48
48
10
10
10
10
10
10
10
72
35
15
47
29
n.d.
48
75
57
5
2
3
4
5
6
7
15
62
92
45
94
68
83
35
88
40
75
Reactions were performed with 0.5 mmol of 4a and 1.0 mmol of 3a. Yields correspond to isolated compound after chromatographic purification. The
enantiomeric excess (ee) was determined by chiral HPLC analysis. Absolute configuration (R) or (S) was known or assigned by analogy.
The combination of oligourea 13 and Et3N was more
active, providing the Michael adduct in a moderate
yield and 57% ee (Table 4, entry 1) which suggests that
the replacement of the first chiral residue with a
pyrrolidine unit is less critical to catalytic activity. The
role of the first urea group in the catalytic process was
further investigated by decreasing its acidic strength
(Table 4, entry 4). These data support a cooperative role
of both ureas in the catalytic process.
We next probed the contribution of the stereocenter
of the first chiral residue on the catalytic process by
either removing the branched side-chain (17 and 18) or
replacing it with a benzyl group (19). The combination
of two potentially destabilizing elements at the end of
the helix, i.e. a flexible achiral 1,2-diaminoethyl residue55
and a thiourea termination42 (Fig. 4a) in 18 was
deleterious for the catalytic efficiency and resulted in
poor conversion and stereocontrol (Table 4, entry 6).
Interestingly, oligourea 17 which has a urea termination,
still produces the Michael adduct in good yield and
through
replacement
of
the
3,5-
bis(trifluoromethyl)phenyl termination with a 4-Br-
phenyl group. This modification (16) leads to a similar
outcome as to the pyrrolidine ring insertion at the first
urea position (13), with a moderate yield and 68 % ee
8
ACS Paragon Plus Environment

Page 9 of 26
Journal of the American Chemical Society
1
2
3
4
5
selectivity (83% ee), providing evidence that the
(Table 4, entry 5). In line with this result, catalyst 19 was
found to behave similarly to 1a but with a slightly lower
degree of stereocontrol (Table 4, entry7).
stereochemical outcome of the reaction largely depends
on the helical nature of the catalyst and is not
significantly controlled locally by the first chiral unit
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 4. Oligomer sequences for structure-reactivity/enantioselectivity relationship study. a, Analogues of 1a and 2a bearing
various sequence variations at the first two positions: pyrrolidine residue replacements (13-15), terminal aromatic group
modification (16), achiral 1,2-diaminoethyl residue replacement (17, 18) and benzyl side chain replacement (19). b, Crystal
structure of compound 15 with a pyrrolidine residue at the second position viewed down helix axis and superimposition with
the structure of 2a (RMSD = 0.460 Å by fitting the seven pairs of (thio)carbonyl C atoms). The pyrrolidine residue is colored in
green. c, Anisochronicity in the residues of catalysts 13-15 and 17-18 compared to that of catalysts 1a and 2a. The values have
been measured in CD3OH for all compounds except 17 for which NMR analysis was conducted in DMSO-d6.
Conclusions
introducing urea → thiourea replacements. This
structure/activity relationship study revealed a strong
correlation between the oligomer catalyst efficiency and
its folding propensity in apolar and moderately polar
solvents. It also supports a key role for the first two
(thio)ureas close to the positive pole of the helix
macrodipole, which is reminiscent of the role of amide
NHs at the positive pole (N-terminus) of the helical
polyleucine catalyst used in the Juliá–Colonna
epoxidation.11,57
We report here the first successful development of
customizable foldamers
−
aliphatic N,N’-linked
oligoureas – as critical chiral components of synergistic
catalytic systems (achiral base/chiral H–bond donor
foldamer catalyst) for enabling efficient simultaneous
activation of the nucleophile and the electrophile at
extremely low catalyst/substrate molar ratios. As little
as 0.01 mol% of foldamer 1a in combination with 10 mol
% Et3N was shown to be sufficient to catalyze the
addition of 1,3-dicarbonyl substrates to nitroalkenes in
high yield and enantioselectivity. This system is highly
robust and, crucially, enables facile optimization, due to
the separation of base and H-bond donor components
of the catalyst system. For example, the use of DIPEA
(instead of Et3N) in combination with 1a was
The chiral oligourea foldamers studied here combine
a number of unique and positive features – such as
synthetic accessibility, functional capability, sequence
modularity, and high folding fidelity – which could be
further applied to catalysis of other C-C bond forming
reactions, or even turned into distinct practical and
scalable technologies. Overall the present development
provides new insights into the factors that govern
catalysis of organic reactions by middle size molecules
and thus constitutes a new step towards approaching
the efficiency of enzymes.
subsequently
found
to
substantially
increase
enantioselectivity in the most difficult cases. Other
modular binary systems albeit non chiral, such as a
simple (thio)urea and a base component have proven
particularly versatile in macromolecular catalysis for
ring opening polymerization of lactide.52,56 Furthermore,
we gained insight into the mechanisms and origins of
the high selectivity observed by varying the chiral
catalyst primary sequence, folding propensity, and by
Methods
General procedure for the synthesis of
oligo(thio)ureas. Oligomers 1, 2 and 13-19 and ent-1
9
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 10 of 26
1
2
3
4
5
6
7
8
9
were synthesized in solution using a stepwise approach
consumption of the nitroalkene, the reaction mixture
and N-Boc protected succinimidyl carbamate building
blocks following previously reported procedures.27,55
Full details of chemical synthesis and purification can
be found in the Supplementary Information.
was quenched with 1N hydrochloric acid solution,
extracted three times with dichloromethane, washed
with brine, dried over magnesium sulfate, filtered and
concentrated. The crude material was purified on silica
gel chromatography as described in Supporting
Information. The enantiomeric excess was determined
by chiral HPLC as described in Supplementary
Information.
Hexamer 1a. Trifluoroacetic acid (2 mL) was added
to a solution of the corresponding Boc-protected
oligourea hexamer (800 mg, 0.88 mmol) in
dichloromethane (2 mL) and the reaction mixture was
stirred at room temperature for 4 h. After completion of
the reaction, trifluoroacetic acid and dichloromethane
were evaporated under reduced pressure. DIPEA (0.48
mL, 2.72 mmol) and 3,5-bis(trifluoromethyl)phenyl
isocyanate (0.24 mL, 1.36 mmol) were successively
added to the resulting TFA salt dissolved in DMF (4
mL). The reaction mixture was stirred at room
temperature for 16 h. Sodium bicarbonate solution (30
mL) was added which led to gel formation which was
recovered after filtration, then dissolved in methanol,
concentrated and dried under high vacuum. The
recovered orange solid was triturated in acetonitrile to
led to the titled oligourea 1a as a white solid (731 mg,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Circular Dichroism. ECD experiments were
performed on a Jasco J-815 spectrometer. Measurements
on oligoureas 1a-e and 2a-e were performed at 2 mM in
trifluoroethanol. Solutions with different ratios 1a / ent-
1a were obtained from a mixture of stock solutions of 1a
and ent-1a to lead to a final concentration of 2 mM in
oligourea. Data were recorded at 20 °C between
wavelengths of 180 and 250 nm at 0.5 nm intervals at a
speed of 50 nm min–1 with an integration time of two
seconds.
X-ray diffraction. Atomic coordinates and structure
factors have been deposited in the Cambridge
Crystallographic Data Centre with accession codes:
1534525, 1534527, 1534523, 1534528, and 1534526, for
structures 1a, 1b, 2a, 15, and 20 respectively, and can be
1
81%). H NMR (400 MHz, CD3OH) δ (ppm) 9.01 (s, 1H),
8.00 (brs, 2H), 7.52 (brs, 1H), 6.56 (dd, J = 10.2 and 2.7
Hz, 1H), 6.50 (dd, J = 9.8 and 2.3 Hz, 1H), 6.37-6.45 (m,
2H), 6.26 (d, J = 10.7 Hz, 1H), 6.24 (d, J = 10.3 Hz, 1H),
6.21 (q, J = 4.9 Hz, 1H), 6.03-6.11 (m, 2H), 6.00 (dd, J =
9.6 and 3.6 Hz, 1H), 5.97 (d, J = 10.6 Hz, 1H), 5.93 (d, J =
10.6 Hz, 1H), 5.86 (d, J = 10.1 Hz, 1H), 4.00-4.15 (m, 1H),
3.75-4.00 (m, 4H), 3.48-3.75 (m, 7H), 2.70 (d, J = 4.8 Hz,
3H), 2.57-2.74 (m, 2H), 2.24-2.47 (m, 4H), 1.64-1.85 (m,
3H), 1.49-1.64 (m, 1H), 1.12-1.32 (m, 4H), 1.00-1.06 (m,
9H), 0.98 (d, J = 7.0 Hz, 3H), 0.88-0.95 (m, 15 H), 0.86
(d, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CD3OH) δ (ppm)
162.1 (C), 162.0 (C), 161.8 (C), 161.6 (C), 161.4 (C), 160.9
(C), 158.2 (C), 143.2 (C), 133.1 (q, J = 33 Hz, 2 × C), 124.6
(q, J = 270 Hz, 2 × C), 118.8-119.1 (m, 2 × CH), 115.5-115.8
(m, CH), 56.7 (CH), 56.2 (CH), 49.4 (CH), 49.1 (CH),
48.2 (2 × CH2), 47.3 (CH2), 46.8 (CH), 46.3 (CH2), 46.1
(CH), 44.7 (CH2), 44.4 (CH2), 43.8 (CH2), 42.7 (CH2),
31.91 (CH), 31.88 (CH), 26.8 (CH3), 26.1 (CH), 25.8 (CH),
23.6 (CH3), 23.5 (CH3), 22.7 (CH3), 22.4 (CH3), 20.1
(CH3), 20.0 (CH3), 18.7 (CH3), 18.5 (CH3), 18.3 (CH3),
18.2 (CH3); 19F NMR (376 MHz, CD3OH) δ (ppm) -64.6
obtained
free
of
charge
upon
request
(www.ccdc.cam.ac.uk/data_request/).
ASSOCIATED CONTENT
*Supporting Information
Additional experimental procedures and characterization
data of all compounds, supplemental Figures S1−S19 and
Tables S1−S23 (PDF)
Crystallographic data for 1a (CIF)
Crystallographic data for 1b (CIF)
Crystallographic data for 2a (CIF)
Crystallographic data for 15 (CIF)
Crystallographic data for 20 (CIF)
AUTHOR INFORMATION
Corresponding Author
ppm; HRMS (ES+, MeOH) calcd for C44H76F6N14O7
1027.59984; found 1027.60173.
=
General
procedure
for
the
catalytic
* g.guichard@iecb.u-bordeaux.fr
* claudio.palomo@ehu.es
ORCID
enantioselective conjugate addition of dimethyl
malonate to nitroalkenes (Table 3). To a vial charged
with 1a (0.51 mg, 0.5 µmol) were added the nitroalkene
(0.5 mmol) and a solution of freshly distilled dimethyl
malonate (0.11 mL, 1.0 mmol) in dry toluene (0.5 mL).
The reaction mixture was cooled down to -20 °C and
tertiary amine (0.15 mmol) was added. After complete
Gilles Guichard: 0000-0002-2584-7502
Claudio Palomo: 0000-0001-9809-2799
10
ACS Paragon Plus Environment

Page 11 of 26
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
(20)
Burgess, K.; Ibarzo, J.; Linthicum, D. S.; Russell, D. H.;
Present Address:
Shin, H.; Shitangkoon, A.; Totani, R.; Zhang, A. J. J. Am. Chem.
Soc. 1997, 119, 1556-1564.
(21)
Briand, J.-P.; Marraud, M.; Guichard, G. Angew. Chem. Int. Ed.
2002, 41, 1893-1895.
(22)
¶ Current address: UMR CNRS 8161 Pasteur Institute of
Lille, Univ Lille, 1 rue du Pr Calmette, 59021 Lille, France
Semetey, V.; Rognan, D.; Hemmerlin, C.; Graff, R.;
Notes
Fischer, L.; Guichard, G. Org. Biomol. Chem. 2010, 8,
The authors declare no competing financial interest.
3101-3117.
(23)
Fremaux, J.; Mauran, L.; Pulka-Ziach, K.; Kauffmann,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACKNOWLEDGEMENTS
B.; Odaert, B.; Guichard, G. Angew. Chem. Int. Ed. 2015, 54, 9816-
This work is dedicated to Prof. Dieter Seebach on the
occasion of his 80th Birthday. The work was funded in part
by the CNRS, ANR (ANR-10-PDOC-0022), Conseil Regional
d’Aquitaine (Project #2014-1R10208), UREkA and in part by
9820.
(24)
Collie, G. W.; Pulka-Ziach, K.; Lombardo, C. M.;
Fremaux, J.; Rosu, F.; Decossas, M.; Mauran, L.; Lambert, O.;
Gabelica, V.; Mackereth, C. D.; Guichard, G. Nat. Chem. 2015, 7,
871-878.
MEC (CTQ2014-62203-EXP, Spain).
A
pre-doctoral
(25)
Teyssières, E.; Corre, J.-P.; Antunes, S.; Rougeot, C.;
fellowship from the IDEX of Univ. Bordeaux to D. B. is
gratefully acknowledged (funding from the French
National Research Agency - Program ANR No.-10-IDEX-
03-02). This work has benefited from the facilities and
expertise of IECB Biophysical and Structural Chemistry
platform (BPCS), CNRS UMS3033, Inserm US001, Univ.
Bordeaux.
Dugave, C.; Jouvion, G.; Claudon, P.; Mikaty, G.; Douat, C.;
Goossens, P. L.; Guichard, G. J. Med. Chem. 2016, 59, 8221-8232.
(26)
M.; Mauran, L.; Taib-Maamar, N.; Dessolin, J.; Mackereth, C. D.;
Guichard, G. J. Am. Chem. Soc. 2017, 139, 6128-6137.
(27)
Chem. Eur. J. 2016, 22, 15684-15692.
(28)
Clayden, J. Angew. Chem. Int. Ed. 2016, 55, 9657-9661.
(29)
1187-1198.
(30)
Res. 2006, 39, 11-20.
(31)
5713-5743.
(32)
124, 12964-12965.
(33)
2003, 125, 12672-12673.
(34)
Y. J. Am. Chem. Soc. 2005, 127, 119-125.
(35)
Collie, G. W.; Bailly, R.; Pulka-Ziach, K.; Lombardo, C.
Diemer, V.; Fischer, L.; Kauffmann, B.; Guichard, G.
Wechsel, R.; Raftery, J.; Cavagnat, D.; Guichard, G.;
REFERENCES
Zhang, Z.; Schreiner, P. R. Chem. Soc. Rev. 2009, 38,
(1)
Guichard, G.; Huc, I. Chem. Commun. 2011, 47, 5933-
5941.
(2)
Stone, M. T.; Heemstra, J. M.; Moore, J. S. Acc. Chem.
Checco, J. W.; Gellman, S. H. Curr. Opin. Struc. Biol.
2016, 39, 96-105.
Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107,
(3)
Chandramouli, N.; Ferrand, Y.; Lautrette, G.;
Kauffmann, B.; Mackereth, C. D.; Laguerre, M.; Dubreuil, D.; Huc,
I. Nat Chem 2015, 7, 334-341.
Wenzel, A. G.; Jacobsen, E. N. J Am Chem Soc 2002,
(4)
Juwarker, H.; Suk, J. M.; Jeong, K. S. Chem. Soc. Rev.
Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc.
2009, 38, 3316-3325.
(5)
Wang, P. S. P.; Schepartz, A. Chem. Commun. 2016, 52,
Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto,
7420-7432.
(6)
(7)
(8)
Horne, W. S. Nat. Chem. 2015, 7, 858-859.
Ringe, D.; Petsko, G. A. Science 2008, 320, 1428-1429.
Jones, C. R.; Pantos, G. D.; Morrison, A. J.; Smith, M.
(a) McCooey, S. H.; Connon, S. J. Angew. Chem. Int. Ed.
2005, 44, 6367-6370; (b) Ye, J.; Dixon, D. J.; Hynes, P. S. Chem.
Commun. 2005, 4481-4483; (c) Vakulya, B.; Varga, S.; Csámpai,
A.; Soós, T. Org. Lett. 2005, 7, 1967-1969.
D. Angew. Chem. Int. Ed. Engl. 2009, 48, 7391-7394.
(9) Davie, E. A. C.; Mennen, S. M.; Xu, Y.; Miller, S. J.
Chem. Rev. 2007, 107, 5759-5812.
(36)
Palomo, C.; Oiarbide, M.; Lopez, R. Chem. Soc. Rev.
2009, 38, 632-653.
(37)
Rissanen, K.; Neuvonen, A.; Pihko, P. M. Angew. Chem. Int. Ed.
2012, 51, 8495-8499.
(38)
2: Bronsted Base and Acid Catalysts, and Additional Topics;
Maruoka, K., Ed.; Thieme Publishing Group Stuttgart, Germany,
2012.
(10)
Lewandowski, B.; Wennemers, H. Curr. Opin. Chem.
Probst, N.; Madarász, Á.; Valkonen, A.; Pápai, I.;
Biol. 2014, 22, 40-46.
(11)
Berkessel, A.; Gasch, N.; Glaubitz, K.; Koch, C. Org.
Lett. 2001, 3, 3839-3842.
Science of Synthesis: Asymmetric Organocatalysis Vol.
(12)
Akagawa, K.; Kudo, K. Angew. Chem. Int. Ed. 2012, 51,
12786-12789.
(13)
Burton, A. J.; Thomson, A. R.; Dawson, W. M.; Brady,
R. L.; Woolfson, D. N. Nat. Chem. 2016, 8, 837-844.
(39)
Kennedy, C. R.; Lehnherr, D.; Rajapaksa, N. S.; Ford, D.
(14)
J.; Smith, J. A. Chem. Commun. 2001, 2330-2331.
(15) Hasegawa, T.; Furusho, Y.; Katagiri, H.; Yashima, E.
Angew. Chem. Int. Ed. 2007, 46, 5885-5888.
(16) Maayan, G.; Ward, M. D.; Kirshenbaum, K. Proc. Nat.
Acad. Sci. U.S.A. 2009, 106, 13679-13684.
(17) Müller, M. M.; Windsor, M. A.; Pomerantz, W. C.;
Coffey, P. E.; Drauz, K.-H.; Roberts, S. M.; Skidmore,
D.; Park, Y.; Jacobsen, E. N. J. Am. Chem. Soc. 2016, 138, 13525-
13528.
(40)
Pihko, P. M. ACS Catal. 2017, 7, 3284-3294.
(41)
633-658.
(42)
S.; Kauffmann, B.; Douat, C.; Guichard, G. Chem. Eur. J. 2015, 21,
2870-2880.
(43)
Reactions: A Powerful Tool for the Stereocontrolled Synthesis of
Complex Molecules; Vicario, J. L.; Badia, D.; Carrillo, L.; Reyes,
E., Eds.; The Royal Society of Chemistry: Cambridge, 2010; Vol.
5.
Neuvonen, A. J.; Földes, T.; Madarász, Á.; Pápai, I.;
Allen, A. E.; MacMillan, D. W. C. Chem. Sci. 2012, 3,
Nelli, Y. R.; Antunes, S.; Salaün, A.; Thinon, E.; Massip,
Gellman, S. H.; Hilvert, D. Angew. Chem. Int. Ed. 2009, 48, 922-
925.
(18)
Wang, P. S. P.; Nguyen, J. B.; Schepartz, A. J. Am.
Organocatalytic Enantioselective Conjugate Addition
Chem. Soc. 2014, 136, 6810-6813.
(19)
Le Bailly, B. A. F.; Byrne, L.; Clayden, J. Angew. Chem.
Int. Ed. 2016, 55, 2132-2136.
11
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 12 of 26
1
2
3
4
5
6
7
8
(44)
Journal of Organic Chemistry 2002, 2002, 1877-1894.
(45) Aitken, L. S.; Arezki, N. R.; Dell’Isola, A.; Cobb, A. J.
A. Synthesis 2013, 45, 2627-2648.
Berner, Otto M.; Tedeschi, L.; Enders, D. European
(46)
Sukhorukov, A. Y.; Sukhanova, A. A.; Zlotin, S. G.
Tetrahedron 2016, 72, 6191-6281.
(47)
Right-handed (P) foldamers 1a and 2a provided the (S)-
9
adduct.
(48)
It is noteworthy that the present synergistic catalysis
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
system appears to be more efficient than standard bifunctional
Brønsted base/H-bond catalysts for this particular transformation.
See the Supplementary Information for details.
(49)
Schreiner, P. R. Org. Lett. 2012, 14, 1724-1727.
(50) Violette, A.; Lancelot, N.; Poschalko, A.; Piotto, M.;
Jakab, G.; Tancon, C.; Zhang, Z.; Lippert, K. M.;
Briand, J. P.; Raya, J.; Elbayed, K.; Bianco, A.; Guichard, G.
Chem. Eur. J. 2008, 14, 3874-3882.
(51)
Hemmerlin, C.; Marraud, M.; Rognan, D.; Graff, R.;
Semetey, V.; Briand, J.-P.; Guichard, G. Helv. Chim. Acta 2002,
85, 3692-3711.
(52)
Lin, B.; Waymouth, R. M. J. Am. Chem. Soc. 2017, 139,
1645-1652.
(53)
Giacalone, F.; Gruttadauria, M.; Agrigento, P.; Noto, R.
Chem. Soc. Rev. 2012, 41, 2406-2447.
(54)
Quintard, A.; Cheshmedzhieva, D.; Sanchez Duque, M.
d. M.; Gaudel-Siri, A.; Naubron, J.-V.; Génisson, Y.; Plaquevent,
J.-C.; Bugaut, X.; Rodriguez, J.; Constantieux, T. Chem. Eur. J.
2015, 21, 778-790.
(55)
Pendem, N.; Douat, C.; Claudon, P.; Laguerre, M.;
Castano, S.; Desbat, B.; Cavagnat, D.; Ennifar, E.; Kauffmann, B.;
Guichard, G. J. Am. Chem. Soc. 2013, 135, 4884-4892.
(56)
Zhang, X.; Jones, G. O.; Hedrick, J. L.; Waymouth, R.
M. Nat Chem 2016, 8, 1047-1053.
(57)
Kelly, D. R.; Roberts, S. M. Chem. Commun. 2004,
2018-2020.
12
ACS Paragon Plus Environment

Page 13 of 26
Journal of the American Chemical Society
1
2
3
TOC
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 14 of 26
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
High resolution Figure 1
124x254mm (300 x 300 DPI)
ACS Paragon Plus Environment

Page 15 of 26
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
High resolution Figure 2
250x134mm (300 x 300 DPI)
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 16 of 26
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
High resolution Figure 3
254x124mm (300 x 300 DPI)
ACS Paragon Plus Environment

Page 17 of 26
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
High resolution Figure 4
245x99mm (300 x 300 DPI)
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 18 of 26
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
High resolution Table of Content graphic
79x47mm (300 x 300 DPI)
ACS Paragon Plus Environment

Page 19 of 26
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
High res (600 dpi) scheme for Table 1
30x8mm (300 x 300 DPI)
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 20 of 26
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
High res (600 dpi) scheme for Table 2
35x9mm (300 x 300 DPI)
ACS Paragon Plus Environment

Page 21 of 26
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
High res (600 dpi) formula 9 for Table 2
29x29mm (300 x 300 DPI)
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 22 of 26
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
High res (600 dpi) formula10 for Table 2
27x20mm (300 x 300 DPI)
ACS Paragon Plus Environment

Page 23 of 26
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
High res (600 dpi) formula 11 for Table 2
25x23mm (300 x 300 DPI)
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 24 of 26
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
High res (600 dpi) scheme for Table 3
25x5mm (300 x 300 DPI)
ACS Paragon Plus Environment

Page 25 of 26
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
High res (600 dpi) scope for Table 3
237x406mm (300 x 300 DPI)
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 26 of 26
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
High res (600 dpi) scheme for Table 4
30x8mm (300 x 300 DPI)
ACS Paragon Plus Environment