Novel, Chiral, and Enantiopure C2-Symmetric Thioureas Promote Asymmetric Protio-Pictet-Spengler Reactions by Anion-Binding Catalysis

Article abstract of DOI:10.1002/ejoc.202001501

Although anion-binding processes are well-known for their crucial role in molecular recognition, they have only recently been utilized for catalysis. Herein, a new class of chiral, enantiopure C₂-symmetrical thioureas that, in combination with 4-methoxybenzoic acid, promotes the enantioselective protio-Pictet-Spengler reaction to provide unprotected tetrahydro-β-carbolines in good yields (40–93 %) and moderate-to-high enantioselectivities (34–95 % ee) in one step from tryptamine and aldehyde derivatives is described. The formation of a chiral catalyst-anion complex was explored by ¹H NMR.

Full text of DOI:10.1002/ejoc.202001501

Communications
doi.org/10.1002/ejoc.202001501
1
2
3
4
5
6
7
8
9
Novel, Chiral, and Enantiopure C2-Symmetric Thioureas
Promote Asymmetric Protio-Pictet-Spengler Reactions by
Anion-Binding Catalysis
Michele Retini,[a] Francesca Bartoccini,[a] Giovanni Zappia,[a] and Giovanni Piersanti*[a]
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
Dedicated to Professor Franco Cozzi, whose innovative studies on asymmetric organocatalytic reactions have enabled advances of
profound fundamental and practical value, on the occasion of his 70th birthday.
In the past two decades, anion-recognition chemistry has
emerged as a frontier of research in the field of molecular
recognition.[6] The greatest effort has focused on the develop-
ment of neutral receptors capable of complexing anions able to
detect the presence of poisonous substances in water or acting
as a carrier for ions through a membrane in vivo. In this context,
the synthesis and binding properties of some new symmetrical
hydrogen-bonding donor anion receptors based on a tertiary
amine base (tetraazacyclododecane scaffold), phenyl(thio)urea
(binding site for the anions by hydrogen bonding), and glycine
(linker) have been reported (Figure 1B).[7] These anion receptors
(1, 2) are able to adopt a conformation in which all binding
sites are positioned to build up a high degree of structural
organization in the presence of an anion such as carboxylate.
Given the strong interconnection between anion-recognition
chemistry and anion-binding catalysis[8] and considering the high
anion-binding properties of the previously reported nonchiral
receptors (1, 2), we aimed to synthesize and evaluate a possible
new chiral ligand/catalyst strictly connected to 2 by substituting
the glycine linker with an appropriate chiral amino acid. We
hypothesized that the binding properties and the conforma-
tional preorganization of 2 could be preserved even after the
introduction of chirality on the side chains of the tetraazacyclo-
dodecane scaffold. This class of catalysts would feature C2
symmetry, rigidity imparted by the conformational constraints,
and relatively simple diversification by changing the abundant
natural L-amino-acid building blocks (Figure 1B, 3).
Herein, we report a new class of chiral C2-symmetrical
anion-binding catalysts that, in combination with benzoic acid,
promotes the enantioselective protio-Pictet-Spengler reaction
to provide unprotected tetrahydro-β-carbolines[9] in good ee
and yield in one step from tryptamine and aldehyde derivatives.
A small focused library of new C2-symmetrical catalysts was
synthesized starting from commercial, protected, and enantio-
pure amino acids, such as N-Cbz-L-valine and N-Cbz-L-tert-
leucine, following the same synthetic approach described by
our group for the preparation of achiral anion receptors (2).[7a]
The choice to introduce isopropyl or t-butyl groups on the side
arms of the catalyst was motivated by the fact that these two
groups could have the appropriate characteristics to both
preserve the binding properties for anions and favor the
buildup of a well-organized structure due to their favorable
intrinsic conformational biases and interstrand sidechain-side-
Although anion-binding processes are well-known for their
crucial role in molecular recognition, they have only recently
been utilized for catalysis. Herein, a new class of chiral,
enantiopure C2-symmetrical thioureas that, in combination with
4-methoxybenzoic acid, promotes the enantioselective protio-
Pictet-Spengler reaction to provide unprotected tetrahydro-β-
carbolines in good yields (40–93%) and moderate-to-high
enantioselectivities (34–95% ee) in one step from tryptamine
and aldehyde derivatives is described. The formation of a chiral
catalyst-anion complex was explored by 1H NMR.
Chiral anion-binding catalysis has attracted the interest of the
organic chemistry community as it is a powerful tool in the field
of asymmetric organocatalysis.[1] The formation of an asymmet-
ric catalytic system operating through close ion-pair interactions
of a chiral catalyst-anion complex and a cationic intermediate
enables discrimination of the enantiotopic faces of the charged
prochiral intermediate.[2,3]
Specific noncovalent interactions, from hydrogen bonding
to π-interactions, play a pivotal role in this context by
organizing the contact ion pairs for the activation of ionic
substrates.[4] Although it is difficult to define and translate novel
catalyst structural features, the ability of small organic mole-
cules containing urea, thiourea, and squaramide moieties to
interact with anions and enhance the reactivity of an ion pair
has been widely exploited in the last few years.[5] The structural
diversity of these anion-binding catalysts is immense; therefore,
the design of new chiral hydrogen-bond donor catalysts that
are able to promote enantioselective bond formation remains a
fascinating challenge. Additionally, most catalysts are C1
symmetric and constitute
flexibility (Figure 1A).
a wide spectrum of structural
[a] Dr. M. Retini, Dr. F. Bartoccini, Prof. G. Zappia, Prof. G. Piersanti
Dipartimento di Scienze Biomolecolari, Università degli studi di Urbino Carlo
Bo
P.zza del Rinascimento 6, 61029 Urbino, Italy
E-mail: giovanni.piersanti@uniurb.it
https://sites.google.com/uniurb.it/giovannipiersanti
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202001501
Part of the “Franco Cozzi’s 70th Birthday” Special Collection.
Eur. J. Org. Chem. 2021, 825–829
825
© 2021 Wiley-VCH GmbH

Communications
doi.org/10.1002/ejoc.202001501
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
Figure 1. A) Some C1-symmetrical (thio)urea organocatalysts. B) Structures of tetraazacyclododecane-derived anion receptors (1, 2) and a new C2-symmetrical
(thio)urea organocatalyst (3) derived from 2.
chain interactions,[10] which can be exploited for an asymmetric
transformation. Scheme 1 outlines the synthetic approach for
the easy and scalable preparation of catalysts 3a–d.
tive results reveal that the trifluoromethyl group not only
increases NÀ H acidity but also contributes to the conforma-
tional rigidity of the catalyst by polarizing the adjacent H atoms,
which in turn facilitates a hydrogen-bonding interaction with
the sulfur or oxygen atom in the (thio)urea.[12]
We selected the one-pot imine formation and asymmetric
protio-PictetÀ Spengler reaction between 6-methoxytryptamine
and p-chloro benzaldehyde in the presence of a Brønsted acid,
as a cocatalyst, as a model reaction (Table 1).
We were delighted to find that the Pictet-Spengler reaction,
carried out at a relatively low concentration (0.05 M) in toluene
and in the presence of the catalyst urea, L-t-leucine-based 3a,
and benzoic acid, gave the desired tetrahydro-β-carboline 10a,
albeit in a low yield and a modest stereoselectivity (Table 1,
entry 1). Reactions performed in different solvents (see the
supporting information) generally afforded worse results both
in terms of the yield and stereoselectivity, compared to toluene,
and revealed that the enantioselectivity is strongly dependent
on the type of solvent used. For example, no stereoselectivity
was achieved using a coordinating solvent such as THF,
suggesting that the catalyst in this type of solvent was not able
to bind to the carboxylate and activate the iminium ion, as
expected from an anion-binding mechanism.
Treatment of the N-Cbz amino acid with pentafluorophenyl
trifluoroacetate and pyridine in DMF gave the corresponding
activated ester 5a–b, which was immediately reacted with 1,7-
dimethyl-1,4,7,10-tetraazacyclododecane (6) in dry DMF with i-
Pr2EtN at room temperature to furnish 7a–b. Removal of the
benzyloxycarbonyl protecting group by catalytic hydrogenolysis
followed by treatment of the crude diamine (not isolated) with
2 equiv. of the corresponding isocyanate or isothiocynate in dry
CH2Cl2 allowed the preparation of the desired bis-(thio)ureas
(3a–d). The N-3,5-bis(trifluoro-methyl)phenyl group has been
popularly used in the design of thiourea-based organocatalysts
in the past.[11] The choice of two trifluoromethyl groups on the
aromatic moieties of the (thio)ureas, widely employed in
noncovalent organocatalysis,[3,4] was based on the ability of this
fragment to increase NH polarization of the (thio)urea and
prevent aggregation/self-association phenomena. The cumula-
Using toluene as the solvent and catalyst 3a (Table 1),
several Brønsted acids were tested, with the aim to improve the
enantioselectivity and to demonstrate that the stereochemical
outcome depends on the nature of the counter anion. As
expected, the Pictet-Spengler reaction did not proceed in the
absence of a Brønsted acid as a co-catalyst (entry 2), while
stronger acids, such as p-toluene sulfonic acid (PTSA) and
diphenyl phosphate, were detrimental to the catalytic activity,
providing the desired β-carboline without stereoselectivity
(entries 4–5). The same effect was obtained using weaker acids
like mandelic acid and a para-substituted phenol (entries 6–7).
Based on these preliminary outcomes, it appears that benzoic
acid has the optimal pKa (4.2) and structural features to
promote the reaction with this catalytic system. Next, we
envisioned that the introduction of a substituent, with the
appropriate electronic and steric properties, in the aromatic
ring of benzoic acid used as a co-catalyst could allow the
formation of a highly organized transition state through addi-
Scheme 1. Synthesis of new C2-symmetrical anion-binding catalysts.
Eur. J. Org. Chem. 2021, 825–829
www.eurjoc.org
826
© 2021 Wiley-VCH GmbH

Communications
doi.org/10.1002/ejoc.202001501
Table 1. Selected optimization studies.[a]
derived from L-valine, provided the tetrahydro-β-carboline
1
2
3
4
5
6
7
8
9
derivative in a good yield (93%) and excellent enantioselectivity
(92% ee) (entry 23). With optimized conditions in hand, various
commercially available aldehydes were explored to evaluate the
scope of the Pictet-Spengler reaction (Table 2). Generally, the
reaction of different aldehydes (9a–j) with 6-meth-
oxytryptamine (8) provided the desired product (10a–j) in good
yield and good-to-moderate enantioselectivity.
Different substituents on the aromatic moiety of the
aldehyde were well tolerated (10a–g), and the Pictet-Spengler
adducts were obtained in good-to-high yields with very high
control over the absolute stereochemistry (ee up to 95%),
except with the 4-fluorobenzaldehyde (10c). In particular,
replacing chlorine with bromine (10b,e) had no effect on the
yield or the stereochemical outcome of the reaction, while
introducing an electron-donating group on the aromatic ring
caused a slight decrease in the enantioselectivity. However, the
tetrahydro-β-carboline compounds (10d,g) were obtained in
75% and 78% yield, respectively. Using heteroaromatic alde-
hydes such as furan-2-carbaldehyde and thiophene-2-carbalde-
hyde, the respective tetrahydro-β-carboline compounds (10h,l)
were obtained in high yields but lower enantioselectivities,
likely due to the coordination effect of the oxygen and sulfur of
the aldehydes.
Entry[a]
Catalyst 3
Acid
Yield (%)[b]
ee (%)[c]
1
2
3
4
5
6
7
8
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
b
c
C6H5CO2H
/
CH3CO2H
PTSA
40
/
56
/
25
12
16
12
<10
<10
31
67
25
50
20
45
49
33
53
20
<10
58
51
93
0
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
Diphenyl phosphate
D-Mandelic acid
4-MeOÀ C6H4OH
2-FÀ C6H4CO2H
4-FÀ C6H4CO2H
4-ClÀ C6H4CO2H
4-MeOÀ C6H4CO2H
4-NO2À C6H4CO2H
4-HOÀ C6H4CO2H
4-N(CH3)2À C6H4CO2H
4-CNÀ C6H4CO2H
4-CF3OÀ C6H4CO2H
4-AcOÀ C6H4CO2H
4-HO2CÀ C6H4CO2H
4-MeOÀ C6H4CO2H
4-MeOÀ C6H4CO2H
4-MeOÀ C6H4CO2H
10
16
40
40
65
35
70
14
12
48
28
41
56
7
9
10
11
12
13
14
15
16
19
20
21
22
23
50
50
92
d
[a] Reaction conditions: 8 (0.1 mmol), 9a (0.11 mmol, 1.1 equiv), 3a–d
(0.01 mmol, 0.1 equiv), Brønsted acid (0.02 mmol, 0.2 equiv). [b] isolated
yield. [c] determined by HPLC analysis of the N-Boc derivative on an ADÀ H
column.
Of note, a moderate yield (50%) and enantioselectivity
(75%) were detected when the reaction was conducted with an
aliphatic aldehyde such as butyraldehyde (10j). Since enolizable
aldehydes are very reactive as both nucleophiles and electro-
philes, controlling the competing pathways to avoid self-aldol
reactions and other potential side reactions associated with
tautomerization of aldehydes and/or imines is still an intrinsi-
cally unsolved challenge for the chemoselectivity.
tional nonbonding interactions, resulting in a higher yield and
stereoselectivity. Therefore, different substituted benzoic acids
were tested and revealed that the presence of a substituent in
the para position of benzoic acid provided higher yields and
stereoselectivities (entries 8–20).
Among the para-substituted benzoic acids tested, the
methoxy derivative was the best acidic cocatalyst for this
transformation (entry 11), providing 10a in 50% yield and 70%
ee. Furthermore, the Brønsted acid screening demonstrated
that the outcome of this reaction is strongly dependent on the
nature of the counter anion; this fact supports the hypothesis
that an anion-binding mechanism is involved in this trans-
formation.
Further optimization studies, in terms of temperature,
concentration, and stoichiometry of the reaction, did not lead
to substantial improvements (see the supporting information).
As expected, we found that the reaction concentration is a very
important parameter. For example, using [8]=0.1 M instead of
0.05 M resulted in a very impressive decrease in the yield and
enantioselectivity (20% and 55%, respectively). This phenomen-
on is not uncommon for thiourea-based catalytic systems[13] and
was rationalized by the self-aggregation of the catalyst, which
may determine the formation of monomer and dimer (or
higher) aggregates characterized by different catalytic and/or
stereoselective profiles. Under the best conditions, we tested all
of the newly synthesized C2-symmetrical anion-binding catalysts
(3b–d) (entries 21–23). Pleasingly, all the (thio)ureas tested
were able to catalyze this process; in particular, thiourea 3d,
Moreover, less nucleophilic tryptamines, such as 5-meth-
oxytryptamine and tryptophan methyl ester, were unreactive
Table 2. Scope of the Pictet-Spengler reaction.[a]
[a] Reaction conditions: 8 (0.2 mmol, 1 equiv), 9a–j (0.11 mmol, 1.1 equiv),
3d (0.02 mmol, 0.1 equiv), 4-MeOÀ C6H4COOH (0.04 mmol, 0.2 equiv).
Isolated yield. Enantiomeric excess was determined by HPLC analysis of
the N-Boc derivative on an ADÀ H column.
Eur. J. Org. Chem. 2021, 825–829
www.eurjoc.org
827
© 2021 Wiley-VCH GmbH

Communications
doi.org/10.1002/ejoc.202001501
under these conditions. The basis for this intriguing difference
formers in solution on the NMR time scale. However, the
resonances of the side arms collapsed in only one and sharp
pattern of signals at 353 K, resulting from C2v symmetry
mediated on the NMR time scale. The 1H NMR experiments
carried out in the presence of benzoate showed similar
behavior, although the spectra were sharper and shifted. These
data suggest a cooperative H-bond to the carboxylate anion,
which is accommodated inside the rigidified structure cavity of
the catalyst.
1
2
3
4
5
6
7
8
9
in reactivity is not well understood. For a substrate such as 5-
methoxytryptamine, the use of a more acidic additive was
necessary, but the reaction proceeded in low ee and in modest
yield.
The absolute configuration of the major enantiomer of 10a
(96:4 er) was determined to be R by comparison of polarimetry
data reported for the same enantiopure compound.[9i] Assuming
the same behavior of the catalytic system, the configuration of
the other tetrahydro-β-carboline products 10b–j was also
assigned as R.
In conclusion, a novel, chiral, and enantiopure hydrogen-
bond donor C2-symmetrical thioura-based compound has been
developed as an anion-binding catalyst for the asymmetric
protio-Pictet-Spengler reaction. These catalysts transfer the
chirality effectively to the unprotected tetrahydro-β-carbolines
in one step from 6-methoxy tryptamine and aldehyde deriva-
tives to form a close chiral anion-pair complex with an iminium
ionic substrate formed in situ between tryptamine and the
aldehyde. Cooperative binding of the catalyst’s hydrogen bond
in its cavity to the benzoate anion and the reinforced catalyst
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
To obtain a better understanding of the activity and
1
behavior of the catalysts, a H NMR titration of 3a in DMSO-d6
at 298 K with sodium benzoate was carried out. As shown in
Figure 2, the proton signals of the NÀ H bonds of the urea were
clearly shifted downfield after the addition of at least 1 equiv.
of the benzoate. Slight changes in the chemical shifts of other
aromatic H atoms were also observed. In particular, the
opposite shift was exhibited by Ho with respect to the Hp
protons in the presence of the interacting anions. In contrast,
by adding an excess of OHÀ , i.e., deprotonating the urea units,
both Ho and Hp exhibited upfield shifts, respectively (data not
shown). The shift of both sets of hydrogens (ureido and
aromatic) is in agreement with the statement that the host-
guest interaction occurs at the ureido group. Interestingly, 3a
1
structure upon this coordination were confirmed by H-NMR.
The unique features of the presented organocatalysts might
also unveil further interesting applications in asymmetric anion-
binding catalysis.
exhibited a complex number of signals in DMSO-d6 and other Conflict of Interest
deuterated solvents (i.e., the signals were very broad), suggest-
ing the existence of two or more slowly interchanging con-
The authors declare no conflict of interest.
Figure 2. 1H NMR spectra of 3a in DMSO-d6 at 298 K by adding 1 or 2 equiv. of sodium benzoate with respect to 3a.
Eur. J. Org. Chem. 2021, 825–829
www.eurjoc.org
828
© 2021 Wiley-VCH GmbH

Communications
doi.org/10.1002/ejoc.202001501
d) S. Asmus, S. Beckendorf, M. Zurro, C. Mück-Lichtenfeld, O. Gar-
cía Mancheñ, Chem. Asian J. 2014, 9, 2178; e) Y. Liu, W. Zhao, C.-H.
Chen, A. H. Flood, Science 2019, 365, 159–161; f) R. Dorel, B. L. Feringa,
Angew. Chem. Int. Ed. 2020, 59, 785–789.
Keywords: Anion-binding
Pictet-Spengler reaction · Synthetic methods
· Organocatalysis · Ion-pairing ·
1
2
3
4
5
6
7
8
9
[6] For reviews, see: a) P. A. Gale, Chem. Commun. 2011, 47, 82–86; b) P.
Molina, F. Zapata, A. Caballero, Chem. Rev. 2017, 117, 9907–9972; c) L.
Chen, S. N. Berry, X. Wu, E. N. W. Howe, P. A. Gale, Chem 2020, 6, 61–
141.
[7] a) M. Formica, V. Fusi, E. Macedi, P. Paoli, G. Piersanti, P. Rossi, G. Zappia,
P. Orlando, New J. Chem. 2008, 32, 1204–1214; b) M. Formica, V. Fusi, L.
Giorgi, E. Macedi, G. Piersanti, M. A. Varrese, G. Zappia, Supramol. Chem.
2010, 22, 365–379.
[8] Z. Zhang, P. R. Schreiner, Chem. Soc. Rev. 2009, 38, 1187–1198.
[9] For representative reviews and publications on the Pictet-Spengler
reactions, see: a) A. Pictet, T. Spengler, Ber. Dtsch. Chem. Ges. 1911, 44,
2030–2036; b) E. D. Cox, J. M. Cook, Chem. Rev. 1995, 95, 1797–1842;
c) N. Glinsky-Olivier, X. Guinchard, Synthesis 2017, 49, 2605–2620; d) J.
Stockigt, A. P. Antonchick, F. R. Wu, H. Waldmann, Angew. Chem. Int. Ed.
2011, 50, 8538–8564; Angew. Chem. 2011, 123, 8692–8719; e) A.
Calcaterra, L. Mangiardi, G. Delle Monache, D. Quaglio, S. Balducci, S.
Berardozzi, A. Iazzetti, R. Franzini, B. Botta, F. Ghirga, Molecules 2020, 25,
414–496; f) M. S. Taylor, E. N. Jacobsen, J. Am. Chem. Soc. 2004, 126,
10558–10559; g) J. Seayad, A. M. Seayad, B. List, J. Am. Chem. Soc. 2006,
128, 1086–1087; h) M. J. Wanner, R. N. S. van der Haas, K. R. de Cuba,
J. H. van Maarseveen, H. Hiemstra, Angew. Chem. Int. Ed. 2007, 46, 7485–
7487; Angew. Chem. 2007, 119, 7629–7631; i) R. S. Klausen, E. N.
Jacobsen, Org. Lett. 2009, 11, 887–890; j) D. Huang, F. Xu, X. Lin, Y.
Wang, Chem. Eur. J. 2012; 18, 3148–3152; k) N. Mittal, D. X. Sun, D.
Seidel, Org. Lett. 2014; 16, 1012–1015; l) R. S. Klausen, C. R. Kennedy,
A. M. Hyde, E. N. Jacobsen, J. Am. Chem. Soc. 2017, 139, 12299–12309;
m) M. Odagi, H. Araki, C. Min, E. Yamamoto, T. J. Emge, M. Yamanaka, D.
Seidel, Eur. J. Org. Chem. 2019, 486–492.
[1] Selected reviews on anion-binding catalysis: a) K. Brak, E. N. Jacobsen,
Angew. Chem. Int. Ed. 2013, 52, 534–561; Angew. Chem. 2013, 125, 558–
588; b) N. Busschaert, C. Caltagirone, W. van Rossom, P. A. Gale, Chem.
Rev. 2015, 115, 8038–8155; c) S. Beckendorf, S. Asmus, O. G. Mancheño,
ChemCatChem 2012, 4, 926–936; d) M. Mahlau, B. List, Angew. Chem. Int.
Ed. 2013, 52, 518–533; Angew. Chem. 2013, 125, 540–556; e) R. J. Phipps,
G. L. Hamilton, F. D. Toste, Nat. Chem. 2012, 4, 603–614; f) P. Nagorny, Z.
Sun, Beilstein J. Org. Chem. 2016, 12, 2834–2848.
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
[2] M. Kotke, P. R. Schreiner, Tetrahedron 2006, 62, 434–439.
[3] Selected examples of asymmetric anion-binding catalysis: a) S. E. Reis-
man, A. G. Doyle, E. N. Jacobsen, J. Am. Chem. Soc. 2008, 130, 7198–
7199; b) C. K. De, E. G. Klauber, D. Seidel, J. Am. Chem. Soc. 2009, 131,
17060–17061; c) H. Xu, S. J. Zuend, M. G. Woll, Y. Tao, E. N. Jacobsen,
Science 2010, 327, 986–990; d) M. Zurro, S. Asmus, S. Becken- dorf, C.
Mück-Lichtenfeld, O. García Mancheño, J. Am. Chem. Soc. 2014, 136,
13999–14002; e) O. García Mancheño, S. Asmus, M. Zurro, T. Fischer,
Angew. Chem. Int. Ed. 2015, 54, 8823–8827; Angew. Chem. 2015, 127,
8947–8951; f) Y. Park, K. C. Harper, N. Kuhl, E. E. Kwan, R. Y. Liu, E. N.
Jacobsen, Science 2017, 355, 162–166; g) A. E. Wendlandt, P. Vangal,
E. N. Jacobsen, Nature 2018, 556, 447–451.
[4] Selected review on hydrogen bonding catalysis: a) P. R. Schreiner,
Chem. Soc. Rev. 2003, 32, 289–296; b) Y. Takemoto, Org. Biomol. Chem.
2005, 3, 4299–4306; c) M. S. Taylor, E. N. Jacobsen, Angew. Chem. Int. Ed.
2006, 45, 1520–1543; Angew. Chem. 2006, 118, 1550–1573; d) S. J.
Connon, Chem. Eur. J. 2006, 12, 5418–5427; e) A. G. Doyle, E. N.
Jacobsen, Chem. Rev. 2007, 107, 5713–5743; f) Hydrogen Bonding in
Organic Synthesis, (Eds.: P. M. Pihko), Wiley-VCH, Weinheim, 2009; g) R.
Knowles, E. N. Jacobsen, Proc. Natl. Acad. Sci. USA 2010, 107, 2067–
20685; h) M. Raynal, P. Ballester, A. Vidal-Ferran, P. W. N. M. van Leeu-
wen, Chem. Soc. Rev. 2014, 43, 1660–1733; i) Y. Zhao, Y. Cotelle, L. Liu, J.
López-Andarias, A.-B. Bornhof, M. Akamatsu, N. Sakai, S. Matile, Acc.
Chem. Res. 2018, 51, 2255–2263; j) Y. Nishikawa, Tetrahedron Lett. 2018,
59, 216–223.
[10] S. T. Phillips, G. Piersanti, P. A. Bartlett, Proc. Natl. Acad. Sci. USA 2005,
102, 13737–13742.
[11] P. R. Schreiner, A. Wittkopp, Org. Lett. 2002, 4, 217–220.
[12] D. P. Curran, L. H. Kuo, J. Org. Chem. 1994, 59, 3259–3261.
[13] H. B. Jang, H. S. Rho, J. S. Oh, E. H. Nam, S. E. Park, H. Y. Bae, C. E. Song,
Org. Biomol. Chem. 2010, 8, 3918–3922.
[5] For a review, see: a) M. D. Visco, J. Attard, Y. Guan, A. E. Mattson,
Tetrahedron Lett. 2017, 58, 2623–2628; For a review of chiral silanediols
in anion-binding catalysis see: b) A. G. Schafer, J. M. Wieting, T. J. Fisher,
A. E. Mattson, Angew. Chem. Int. Ed. 2013, 52, 11321–11324; Angew.
Chem. 2013, 125, 11531–11534; For selected examples of chiral triazoles
in anion-binding catalysis see: c) S. Beckendorf, S. Asmus, C. Mück-
Lichtenfeld, O. García Mancheño, Chem. Eur. J. 2013, 19, 1581–1585;
Manuscript received: November 16, 2020
Revised manuscript received: January 1, 2021
Accepted manuscript online: January 16, 2021
Eur. J. Org. Chem. 2021, 825–829
www.eurjoc.org
829
© 2021 Wiley-VCH GmbH