Reactivity and Selectivity of Iminium Organocatalysis Improved by a Protein Host

Article abstract of DOI:10.1002/anie.201806850

There has been growing interest in performing organocatalysis within a supramolecular system as a means of controlling reaction reactivity and stereoselectivity. Here, a protein is used as a host for iminium catalysis. A pyrrolidine moiety is covalently linked to biotin and introduced to the protein host streptavidin for organocatalytic activity. Whereas in traditional systems stereoselectivity is largely controlled by the substituents added to the organocatalyst, enantiomeric enrichment by the reported supramolecular system is completely controlled by the host. Also, the yield of the model reaction increases over 10-fold when streptavidin is included. A 1.1 ? crystal structure of the protein–catalyst complex and molecular simulations of a key intermediate reveal the chiral scaffold surrounding the organocatalytic reaction site. This work illustrates that proteins can be an excellent supramolecular host for driving stereoselective secondary amine organocatalysis.

Full text of DOI:10.1002/anie.201806850

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
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Accepted Article
Title: Reactivity and Selectivity of Iminium Organocatalysis Improved
by a Protein Host
Authors: Alexander R Nödling, Katarzyna Świderek, Raquel Castillo,
Jonathan W Hall, Antonio Angelastro, Louis C Morrill, Yi Jin,
Yu-Hsuan Tsai, Vicent Moliner, and Louis Y P Luk
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201806850
Angew. Chem. 10.1002/ange.201806850
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http://dx.doi.org/10.1002/ange.201806850

10.1002/anie.201806850
Angewandte Chemie International Edition
COMMUNICATION
Reactivity and Selectivity of Iminium Organocatalysis Improved
by a Protein Host
Alexander R. Nödling,[a] Katarzyna Świderek,[b] Raquel Castillo,[b] Jonathan W. Hall,[a] Antonio
Angelastro,[a] Louis C. Morrill,[a] Yi Jin,[a] Yu-Hsuan Tsai,[a] Vicent Moliner*,[b] Louis Y. P. Luk*[a]
Abstract: There has been growing interest in operating
organocatalysis within a supramolecular system as means of
controlling reaction reactivity and stereoselectivity. Here, a protein is
used as host for iminium catalysis; a pyrrolidine moiety is covalently
linked to biotin, introduced to the protein host streptavidin and tested
for organocatalytic activity. Whereas in traditional systems
stereoselectivity is largely controlled by the substituents added to the
organocatalyst, enantiomeric enrichment by the reported
supramolecular system is completely controlled by the host. Also, the
yield of the model reaction increases over 10-fold when streptavidin
is included. A 1.1-Å crystal structure of the protein-catalyst complex
and molecular simulations of a key intermediate reveal the chiral
scaffold surrounding the organocatalytic reaction site. This work
illustrates that proteins can be an excellent supramolecular host for
driving stereoselective secondary amine organocatalysis.
valeric acid sidechain can be chemically modified for other
applications, such as the production of artificial enzymes carrying
non-metal[1a, 7] or metal cofactors.[10] Herein, we have adapted this
technology and prepared Sav-based hybrid catalysts carrying
biotinylated secondary amine functionalities (Scheme 1). This
work demonstrates that Sav, as a water-soluble protein, can
provide
a microenvironment favorable for stereoselective
secondary amine organocatalysis.
Designing host-guest systems for organocatalysis has
increasingly interested chemists.[1] A molecular host provides a
specific environment that dictates both selectivity and reactivity of
the organocatalysis, thereby providing additional means for
reaction control. Nature provides such examples including
proteins. These present a hydrophobic and inherently chiral
scaffold favorable for organocatalysis.[2] Similar concepts have
been tested previously; small, metal-free reagents including
flavin,[3] thiazolium ylides,[4] pyridoxamine,[5] or selenocysteine[6]
have been added to a protein covalently for oxidation, C-C and C-
N bond formation reactions. Recently, a novel artificial enzyme
has been created using π-stacking organocatalysts whose
selectivity can be improved by modifying the protein scaffold.[1a, 7]
On the other hand, iminium formation by secondary amine has
transformed into a major mode of substrate activation in
organocatalysis,[8] but a protein-based host for this type of
catalysis has not been achieved.
Scheme 1. Model of the biotinylated organocatalysts anchored to the
surface of streptavidin (Sav, PDB 1STP).
Several biotinylated organocatalysts were synthesized based on
known catalytically active secondary amine motifs (Figure 1),
including 4-imidazolidinone (1–4), proline (5 and 6) and
pyrrolidine (7 and 8) derivatives. Compounds 1–5 were prepared
by copper-catalyzed Huisgen 1,3-dipolar cycloadditions of
alkynylated biotin and azido functionalized precursors (5-47%
overall yield).[11] Catalysts 6–8 were synthesized by direct
coupling of biotin to the Boc protected amino-proline
or -pyrrolidine starting materials, followed by deprotection (48-
63% overall yield). Catalysts 1–3 and 5–8 were obtained as single
stereoisomers, but an inseparable 1:1 mixture of cis- and trans-
isomers was formed for 4.
Streptavidin (Sav) possesses a strong, non-covalent affinity to D-
biotin.[9] Since Sav mostly binds to the ureido moiety of biotin, the
[a]
[b]
Dr. A. R. Nödling, Mr J. W. Hall, Dr. A. Angelastro, Dr. L. C. Morrill,
Dr. Y. Jin, Dr. Y-H. Tsai and Dr L. Y. P. Luk.
School of Chemistry, Main Building
Cardiff University, Cardiff, CF10 3AT (UK)
E-Mail: lukly@cardiff.ac.uk
Dr. K. Świderek, Dr. R. Castillo, Prof. V. Moliner
Department de Química Física i Analítica
Universitat Jaume I
12071 Castelló (Spain)
E-Mail: moliner@uji.es
Figure 1. Biotinylated organocatalysts 1–8.
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201806850
Angewandte Chemie International Edition
COMMUNICATION
The newly prepared biotinylated catalysts were used in the
Michael addition of nitromethane to cinnamaldehyde (Table 1), a
type of 1,4-addition that is often used in pharmaceutical
synthesis.[12] Our previous analysis of this reaction indicates that
water can hamper the reaction progress when used as a solvent
but enhances turnover rate when used as an additive.[13] Hence,
this sets the basis on how a protein scaffold can affect the
efficiency of this organocatalytic reaction. For initial screening,
each biotinylated catalyst (20 mol%) was incubated with
cinnamaldehyde and five equivalents of nitromethane at 25 °C
(see Supporting Information). No activity was observed in
deionized water or in acidic buffer (pH 2.0–6.0). On the other hand,
at pH 7.0 and 8.0 the proline and pyrrolidine catalysts (5–8) were
able to mediate the Michael addition that could be detected by
GC-MS, whereas such observations were absent for 1-4. At pH
9.0, however, significant background reaction was observed
8
9
7
8
KPi
KPi
7
6
0.18
0.15
50:50
(S:R)
50:50
(S:R)
10
11
12
Sav-5
Sav-6
Sav-7
KPi
KPi
KPi
6
5
0.15
0.13
0.76
-
-
30
80:20
(S:R)
13
14
Sav-8
KPi
KPi
15
36
0.38
0.28
24:76
(S:R)
Sav-7[d]
80:20
(S:R)
15
16
17
18
19
20
21
Sav-7[e]
Sav-7[e]
Sav-7[e]
Sav-7[e]
Sav-7[e]
Sav-7[e]
Sav-7[e]
KPi:C6D6
KPi:CDCl3
KPi:THF[f,g]
KPi:EtOAc[f]
KPi:DMSO
KPi:MeCN
KPi:MeOH
<2
<2
-
rendering
this
condition
unfavorable
for
developing
stereoselective organocatalysis. In an acidic (< pH 7.0) or a non-
buffered aqueous environment, secondary amines are likely to be
protonated (pKa ≈ 8) and deprotonation of nitromethane (pKa ≈ 10)
is unfavorable; these factors likely stall the progress of the
organocatalysis.
-
34[h]
38[h]
<2
-
92:8 (S:R)
-
To see if the performance of organocatalysis can be improved by
anchoring to a protein surface, catalysts 5–8 were introduced to
streptavidin (Sav). For proline derivatives 5 and 6, the reaction
yields at pH 7.0 were not affected by the addition of Sav and
remains at ~5–6% (Table 1 and supporting information). In
contrast, the reactivity of pyrrolidines 7 and 8 was significantly
improved when Sav was included, showing about 5- and 2-fold
increase in reaction yields at pH 7.0, respectively (Table 1,
kcat/kuncat = 10 and ΔΔG‡ = 5.71 kJ × mol−1 for Sav-7). No reaction
enhancement was observed in control reactions with L-proline,
pyrrolidine or Sav-biotin; this highlights the synergistic effect
observed by the introduction of 7 and 8 into the protein scaffold
(Figure 2). While these two diastereomeric catalysts differ by one
stereoconfiguration at the 3' position, the yield of the reaction
catalyzed by Sav-7 is slightly higher. Indeed, the reactivity of Sav-
7 is comparable to that of a water-compatible derivative of the
Jørgensen-Hayashi catalyst in that a similar reaction yield per mol%
of catalyst was obtained.[12c]
<2
-
80
4.4
91:9 (S:R)
[a] Reactions carried out for 42 h on a 3.3 µmol scale, using nitromethane
(16.5 µmol), catalyst (1.0 mol%, additionally 0.2 mol% Sav, 1.2 mol% active
sites, for entries 4 and 10–14) in 500 µL of solvent. KPi = 10 mM potassium
phosphate buffer at pH 7.0 and 25 °C. [b] Conversion determined by 1H
NMR spectroscopy for 5–8 and Sav-5–Sav-8. [c] Determined by chiral LC
of the reduced product 11a (Chiralpak IB, see SI). [d] Reaction was carried
out at 4 °C for 136 h. [e] Reactions were carried out for 18 h instead of 42 h,
using 1:1 mixtures of buffer to organic solvent. [f] Cinnamic acid was
observed as side product. [g] Unidentified side products and the 1,2-addition
product were observed in significant amounts up to 50%. [h] Range of yield
observed in multiple runs in these solvents.
Whereas many traditional organocatalysts such as the MacMillan
and Jørgensen-Hiyashi catalysts contain bulky or H-bonding
groups adjacent to the reacting nitrogen atom for stereoselectivity
control, these substituents are absent in 7 and 8. However, the
transformation taking place on the surface of the inherently chiral
Sav is anticipated to improve the stereoselectivity. This
hypothesis is examined by chiral LC analyses of the catalytically
enhanced reactions. In the absence of Sav, no enantioselectivity
was observed. In the Sav-7 reaction, the majority of the product
contains an S configuration at the C-3 position giving an
enantiomeric ratio of 80:20. Conversely, the R stereoisomer was
preferentially formed in the Sav-8 reaction (Table 1, Entries 12 &
13). These results clearly indicate that the binding of the catalysts
to Sav causes noticeable improvement in enantioselectivity.
Table 1. Catalyst screening for the reaction of nitromethane with
cinnamaldehyde.[a]
Entry
Catalyst
Solvent
Yield
(%)[b]
TOF
(x h-1)
er[c]
1
2
3
4
5
6
7
None
Pyrrolidine
Proline
Sav-biotin
1-4
KPi
KPi
KPi
KPi
KPi
KPi
KPi
3
3
3
3
3
4
5
-
-
-
-
-
-
-
-
-
-
-
-
-
5
6
0.13
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10.1002/anie.201806850
Angewandte Chemie International Edition
COMMUNICATION
Molecular dynamics (MD) simulations were performed to
investigate the origin of reaction stereoselectivity (see Supporting
Information for details). Our previous computational analysis
indicates that the iminium and deprotonated nitromethane
intermediates are formed in one step and thus they are extremely
transient before forming a stereogenic center at the C-3
position.[13] Hence, the reaction stereoselectivity is most likely
dictated by the hemiaminal tetrahedral intermediate which forms
prior to the iminium/deprotonated nitromethane pair. The C-1
position of the hemiaminal tetrahedral intermediate can be either
R or S, which exerts a strong effect on how the C-3 is being
exposed for nucleophilic reaction (Scheme S1&2). Interestingly, a
representative snapshot of the 1-(S) intermediate from the MD
simulation of Sav-7 overlays well with the crystal structure
complex (Figure 3). According to the population analysis obtained
from the MD simulations, this 1-(S) intermediate dictates the
stereoselectivity of the reaction. Upon dehydration, this
intermediate will be converted into the iminium intermediate which
exposes the C-3 Si face for nucleophilic addition, whereas the
opposite face is shielded by the protein (Figure 4); consequently,
formation of the stereoisomer S-10a is favored. Similarly, for the
iminium derived from the 1-(R) intermediate, the C-3 Si face of the
iminium intermediate is exposed for reaction. In the case where 8
is used, formation of the 1-(R) intermediate is favored and the
product stereoisomer is reversed (Figure S7). However, this
intermediate is noticeably more flexible; analysis of the MD
trajectory of this complex indicates that, while the majority of the
conformers (ca. 90%) yield the 3-R adduct, there is a population
of conformers that yield the opposite stereoisomer (see
geometrical analysis and animation movies deposited in the
Supporting Information).
Figure 2. GC-MS traces of the non-catalyzed reaction and reactions catalyzed
by Sav-biotin, pyrrolidine, catalyst 7 and Sav-7 at pH 7.0.
A crystal structure at a resolution of 1.1 Å was obtained to pinpoint
the interactions between the secondary amine catalyst and
protein scaffold. The amide bond in the valeric moiety undergoes
hydrogen bonding with Ser88, which is frequently seen when
biotin is functionalized via amide bond formation.[10f,
previous Sav-based artificial metalloenzyme, the location of the
metal catalyst is often unclear, because the ligand is inherently
flexible or the metal catalyst dissociated during crystallography.[10f,
10h, 10j] In contrast, the location of the secondary amine catalyst is
clearly revealed in this work. The pyrrolidinyl moiety forms a
10h, 10j]
In
hydrogen bond with Ser112, which has been shown to be
important in artificial metalloenzyme design.[10f,
10h, 10j]
Other
residues surrounding the organocatalytic reaction are also
revealed, including Leu124 and Lys121. Notably, Lys121 was
also found to play critical role in the development of the Sav-
based anion-π enzyme dictating the activity of the catalytically
important tertiary amine.1a However, this residue likely plays a
different role here, as it is distant from the catalytic amine atom
(8.1 and ca. 7.3 Å based on the X-ray and MD simulations,
respectively). Since Lys121 is located in proximity to the C-3 and
phenyl moiety of the intermediate (4-5 Å), it likely dictates how the
nucleophile approaches the iminium intermediate for reaction.
Figure 4. (Top) tetrahdral intermediates 1-(R)- and 1-(S)-intermediate derived
from QM/MM studies, and (Bottom) schematic representation of the orientation
of the iminium intermediate. A denotes residues within one subunit, D denotes
residues from the other subunit, red refers to hypothetical hydrogen bonding
interactions.
Figure 3. Overlay of the 1.1-Å crystal structure of Sav-7 (green) and the
hemiaminal tetrahedral intermediates obtained from the MD simulations
(yellow); blue dashed lines denote proposed hydrogen-bonding interactions.
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10.1002/anie.201806850
Angewandte Chemie International Edition
COMMUNICATION
Attempts to further enhance the reaction yield were made by
prolonging the reaction time or raising the pH, but no improvement
2
3
4
5
6
7
(4’-Me)-C6H4, H; 9b
(4’-OMe)-C6H4, H; 9c
(4’-Cl)-C6H4, H; 9d
(4’-NO2)-C6H4, H; 9e
(3’-Py), H; 9f
37
39
13:87
14:86
11:89
24:76
nd[d]
was found. Instead, there was
a substantial amount of
precipitation observed after 6–42 h which can be caused by imine
formation between free amines of the protein and the aldehyde
moieties or by aggregation due to surface binding of the
hydrophobic reactants. To suppress the precipitation, different
organic solvents were included as additives (Table 1). They can
be separated into three categories: unpolar (C6D6, CDCl3,), polar
aprotic (EtOAc, THF, DMSO, MeCN) and polar protic (MeOH)
solvents.[10i, 14] In all cases precipitate formation was suppressed
but the reaction yield was improved only when THF, EtOAc or
MeOH were included. However, reaction yield fluctuated severely
when THF or EtOAc was used, and cinnamic acid was observed
as side product. Also, in THF up to 50% of 1,2-addition product
was observed. The presence of MeOH enhances the reaction
yield up to an average value of 80% within 18 hours per mol%
79
10
62
(4’-X)-C6H4, CH3;
(X = Cl; 12d, NO2; 12e,
CF3; 12g)
< 2-5
nd
[a] Reactions carried out for 18 h on a 3.3 µmol scale, using nitromethane
(16.5 µmol), catalyst (1.0 mol%, additionally 0.2 mol% Sav, 1.2 mol% active
sites) in 500 µL of mixed solvent, KPi/MeOH = 1:1, KPi = 10 mM, pH 7.0, and
25 °C. [b] Conversion determined by 1H NMR spectroscopy. [c] Determined
by chiral LC of reduced products 11a–11f (see SI). [d] The corresponding
product was found to be degraded during purification, and thus the er was
not determined. nd = not determined.
catalyst used. This transforms into a rate enhancement (kcat/kuncat
)
of 8 and a ΔΔG‡ = 5.12 kJ × mol−1 with 10% additional side
products observed in the uncatalyzed background reaction. Such
efficiency has not been seen in previously reported aqueous
organocatalytic system.[12c, 15] Furthermore, while the previously
reported Sav-based π-stacking organocatalytic system operates
best at low pH,[1a] in the Sav-7 system such conditions were found
to be detrimental for catalysis (~5% at pH 5.0 and no product
observed at pH 3.0).
In conclusion, a hybrid organocatalytic system based on the
streptavidin-biotin technology was developed in this work. This
system facilitates secondary amine-catalyzed reactions.
Surprisingly, by simply exploiting the scaffold of the wild type
streptavidin, a sparsely substituted cyclic secondary amine can
be used to catalyze reactions with high enantioselectivity. This
approach bypasses the need of striking a balance between
reactivity and stereoselectivity as frequently seen in traditional
organocatalyst design.[8] Molecular simulations and protein
crystallography have been particularly insightful, as they reveal
how the protein dictates the orientation of the substrate and
reaction stereoselectivity. This work lays the basis for protein
engineering in which a designated scaffold can be modified for
optimal organocatalysis.[10d, 10f, 10g, 10i-k, 16] Furthermore, since this
work enables organocatalysis in an isolated environment of a
supramolecular complex, its compatibility with other species
including reagents, other catalysts, and intermediates are greatly
enhanced.[1a, 1c] Hence, this protein-based organocatalytic system
will facilitate the development of tandem reaction sequences and
hybrid catalysts as tools in chemical biology.[17]
Since MeOH proved to be the most productive co-solvent, the
ratio of this solvent to buffer was screened for optimal reaction
yield and enantioselectivity. Increasing the amount of MeOH
steadily enhances both the yield and enantioselectivity of the
model reaction (Figure S8). A ratio of 1:1 of buffer-MeOH at pH
7.0 proved to be the optimal condition. In the control experiment
where the Sav protein scaffold is omitted, no enantioselectivity
was observed. Together, this indicates the stereoselectivity
originates from the binding between Sav and 7 which remains
intact even in the presence of a significant amount of MeOH.
The applicability of the Sav-7 system was explored by testing
cinnamaldehyde derivatives and the respective ketones as
alternative substrates (Table 2). Almost all of the employed
aldehydes are tolerated by Sav-7 giving acceptable to good yields
(>35%) and enantioselectivities (entries 1–7). The low yield of 4’-
nitrocinnamaldehyde (entry 5) is most likely caused by its low
solubility in the buffer-MeOH mix. In contrast, all of the ketone
counterparts give poor yield, and only the ones shown in Table 2
afford a detectable yield.
Acknowledgements
We thank Professor Nigel G.J. Richards for his helpful
discussions and useful suggestions during the development of
this project and Dr Pierre Rizkallah for his assistance with protein
crystallography data collection. We thank Diamond Light Source
for access to beamline IO4 (Proposal Number mx-1881) that
contributed to the results presented here. This work was
supported by Cardiff University through the Centre of Doctoral
Training for Catalysis sabbatical scholarship to J.W.H., startup
fund provided by the Cardiff School of Chemistry, the Leverhulme
Trust through grant to L.Y.P.L (RPG-2017-195), the Royal Society
through grant to L.C.M. (RG150466), the UK’s Wellcome Trust
through grants to L.Y.P.L (202056/Z/16/Z) and to Y.H.T
Table 2. Exploration of substrate scope in the reaction of nitromethane with
α,β-unsaturated
carbonyl
compounds
and
Sav-7.[a]
(200730/Z/16/Z), the Spanish Ministerio de Economía
y
Competitividad through project CTQ2015-66223-C2 and a Juan
de la Cierva–Incorporación contract to K.Ś. (IJCI-2016-27503)
and Universitat Jaume I (Project UJI·B2017- 31).
Entry
1
R1, R2
Yield(%)[b]
80
er[c]
Ph, H; 9a
9:91
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10.1002/anie.201806850
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COMMUNICATION
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Keywords: hybrid catalyst • organocatalysis • computational
enzymology • artificial enzyme • supramolecular chemistry
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10.1002/anie.201806850
Angewandte Chemie International Edition
COMMUNICATION
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COMMUNICATION
Alexander R. Nödling, Katarzyna
Świderek, Raquel Castillo, Jonathan W.
Hall, Antonio Angelastro, Louis C.
Morrill, Yi Jin, Yu-Hsuan Tsai, Vicent
Moliner*, Louis Y. P. Luk*
Page No. – Page No.
The perfect host: A supramolecular system for stereoselective secondary amine
organocatalysis was developed based on the streptavidin-biotin technology. The
results combined from catalyst screening, protein crystallography and molecular
simulations clearly reveal that both the reactivity and stereoselectivity are dictated by
the protein host. Text for Table of Contents
Reactivity and Selectivity of Iminium
Catalysis Controlled by a Protein
Host
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