Catalytic anions embedded into avidin: Importance of their chirality and the chiral environment on the stereocontrol of the aldol reaction

Article abstract of DOI:10.1021/jo5002406

Several catalytic anions bearing a pseudo-dipeptide scaffold, in combination with a biotinylated imidazolium cation, were prepared. The assembly of these salts with avidin resulted in the formation of stable biohybrid catalysts, active in ionic liquid/aqueous media for the aldol reaction. By using natural and non-natural amino alcohols as "side chains" for the proline derivative anion, we studied the cooperativity between the anion and its position in avidin. Taking advantage of the large freedom of movement of the anion inside avidin, we also investigated the substrate scope of this type of biohybrid catalyst.

Full text of DOI:10.1021/jo5002406

Article
pubs.acs.org/joc
Catalytic Anions Embedded into Avidin: Importance of Their Chirality
and the Chiral Environment on the Stereocontrol of the Aldol
Reaction
Vincent Gauchot and Andreea R. Schmitzer*
aDepartment of Chemistry, Universite
́ ́ ́ ́
de Montreal, C.P. 6128 Succursale Centre-ville, Montreal, Quebec H3C 3J7, Canada
S
* Supporting Information
ABSTRACT: Several catalytic anions bearing a pseudo-dipeptide scaffold, in
combination with a biotinylated imidazolium cation, were prepared. The assembly of
these salts with avidin resulted in the formation of stable biohybrid catalysts, active in
ionic liquid/aqueous media for the aldol reaction. By using natural and non-natural
amino alcohols as “side chains” for the proline derivative anion, we studied the
cooperativity between the anion and its position in avidin. Taking advantage of the large
freedom of movement of the anion inside avidin, we also investigated the substrate scope
of this type of biohybrid catalyst.
complex.11,12 Ward et al. elegantly showed that chemical
optimization of their ligands, combined with rational protein
engineering, can lead to the design of efficient artificial enzymes
tailored for specific reactions.13,14 Our group recently disclosed
the conception and design of biohybrid species by encapsulat-
ing inside avidin a biotinylated imidazolium salt bearing a
nonchiral pyrrolidine-based catalytic anion. The assembled
biohybrid catalyst was proven to be active in ionic liquid/water
mixtures, efficiently catalyzing asymmetric aldol reactions.15
While the reaction medium was shown to have a great influence
on the behavior of our catalyst, very little change was observed
when modifying the structure of the cationic core of the
imidazolium salt (Figure 1).
In order to gain a better understanding of how the anion
positions itself inside avidin, we prepared several proline-based
anions and combined them with the same biotinylated
imidazolium salt. The role of these anions in catalysis and the
tolerance of the optimized system to other substrates are
reported here.
INTRODUCTION
■
Over the last 50 years, enzymatic catalysis has proven itself to
be a marvelous tool for synthetic chemists. Since the first
discovery of enzymes almost two centuries ago, science has
done much to unveil the mechanisms behind their incredible
efficiency in doing specific chemical transformations and get a
better insight of their structure−activity relationship.1 The use
of native enzymes in organic synthesis has been extensively
studied over the past decades. Their field of applications ranges
from kinetic resolution2,3 to the introduction of specific
functionalities on small molecules.4 Enzymes are also tools of
choice for asymmetric reactions, such as selective reductions,
sometimes surpassing the best non-natural catalysts.5 However,
they suffer from major drawbacks. Among them, one can
pinpoint a low substrate scope, a poor tolerance to common
reaction conditions, and only a handful of possible
tranformations. Directed evolution has been one solution to
solve these issues, as native enzymes can be engineered to
overcome their substrate specificity and gain robustness over
somewhat harsh operating conditions.1 More recently, the
design of artificial enzymes has been another way to overcome
many of these issues.6 The design of these species relies mainly
on the covalent or noncovalent incorporation of a small catalyst
inside a biomolecule, such as a protein7 or DNA.8,9 These
macromolecules provide a natural and complex chiral environ-
ment around the encapsulated catalyst, thus leading to the
formation of a wide family of chiral biohybrid catalysts: namely,
artificial enzyme mimics or non-native enzymes. Among several
incorporation strategies, the pioneering work of Whitesides and
Wilson consisted of using the biotin−avidin technology to
anchor a biotinylated Rh complex inside avidin, leading to the
formation of an artificial.hydrogenase.10 This artifical metal-
loenzyme was used for the asymmetric reduction of N-
acetylalanine. Over the past decade, Ward et al. focused a
part of their research toward the development of numerous
artificial metalloenzymes based on the biotin−(strept)avidin
RESULTS AND DISCUSSION
■
A total of eight anions were prepared, each displaying different
physical and chemical properties. Our strategy was to keep the
pyrrolidine moiety, responsible for catalysis, and insert a spacer
between the amine site and the sulfate anion. We hypothesized
that (1) adding an alkyl spacer might give flexibility to the
anion and the length of this spacer might move the amine
moiety apart from the imidazolium cation, placing the anion in
a new chiral environment, (2) using chiral amino alcohols as
spacers might be beneficial due to their intrinsic chirality, and
(3) using specific amino alcohols might be interesting by
providing the anion with specific properties, such as steric
Received: January 30, 2014
Published: February 22, 2014
© 2014 American Chemical Society
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Figure 1. Modification of the anion structure.
bulkiness, conformational freedom, or π−π interaction proper-
ties. In this way, the anion could interact with specific residues
inside the avidin’s cavity, leading to new conformations and
positions when it is embedded in the protein (Figure 2).
experiments, aldol reactions without avidin were carried out,
with a substrate concentration 20 times higher in order to
overcome the high dilution conditions necessary to ensure
avidin solubilization ([substrate] = 5 × 10−2 M).15 Cyclo-
hexanone and p-nitrobenzaldehyde were the model substrates
used for these studies. From the results compiled in Table 1,
several observations can be drawn.
(a) The use of racemic anions 4 and 5 possessing superior
flexibility led to a lower stereocontrol of the corresponding
biohybrid catalyst (the notation X·Av will be used in this paper
to design the biotinylated catalyst obtained by the complexation
of avidin with the imidazolium cation bearing the anion X), in
comparison to our previously reported 3·Av. When the
corresponding biotinylated catalysts were not embedded into
avidin, no enantioselectivity was observed. It seems that too
much freedom in the avidin results in less steric discrimination,
perhaps due to the fact that the anion can occupy several places
inside the protein. Conversions in both cases (with and without
avidin) are very similar to those we already reported for the
aldol reaction.17
(b) When L-proline was used as the amine precursor (entry
4), a rise in selectivity up to 70% ee was observed for anion 6,
in comparison to the D,L-proline used in the case of anions 4
and 5. This might be a hint of a match−mismatch case between
avidin and the catalyst. More surprisingly in this case, when the
reaction was carried out without avidin, the selectivity was the
same.
Figure 2. Design of the anions.
The synthetic strategy is described in Scheme 1: the desired
chiral/achiral version of proline was first Boc-protected, and
then a standard peptidic coupling between Boc-Proline 1 and
the corresponding amino alcohol afforded the hydroxy
precursor 2, which was then sulfonated using chlorosulfonic
acid in CH2Cl2. Amino alcohols were obtained from the
corresponding amino acids following the procedure reported by
Meyers et al. (see the Supporting Information).16 Preparation
of the corresponding biotinylated catalysts and encapsulation
into avidin were carried out using our previously reported
procedures.
(c) With L-Proline kept as a precursor, adding a chiral side
chain derived from natural amino acids (L-phenylalanine for
compound 7 and L-valine for compound 8) led to better results
in terms of selectivity. However, the catalytic performances of
the free catalytic salts (without avidin) are similar to, if not
better than, those of the biohybrid catalysts. While it seems that
avidin does not change the performances of these catalysts,
there is no evidence of particular new interactions between the
All eight anion structures are reported in Figure 3, and the
results obtained by using them in the aldol reaction are
reported in Table 1. Anion 4, the one used in our previous
studies (Table 1, entry 1), was used as a means of comparison
with the second generation of the anions.
Each corresponding biotinylated catalyst was embedded into
avidin and tested under our optimized reaction conditions,
using a partitioned IL/aqueous buffer media. As control
Scheme 1. Preparation of the Anions
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Figure 3. The different zwitterions used as precursors for the biotinylated catalysts.
Table 1. Anion Screening
b
a
with avidin
without avidin
a
a
a
a
a
entry
anion
conversion (%)
dr (syn/anti)
ee (anti) (%)
conversion (%)
dr (syn/anti)
ee (anti) (%)
1
2
3
4
5
6
7
8
9
3
94
63
93
76
94
75
62
98
32/68
32/68
31/69
33/67
23/77
27/73
30/70
36/64
35/65
70
54
53
70
80
76
71
50
51
98
>99
94
36/64
35/65
36/64
35/65
24/76
27/73
54/46
35/65
20/80
rac
rac
rac
69
83
81
83
53
82
4
5
6
>99
>99
>99
58
7
8
9
10
11
89
93
98
a
b
Determined by chiral HPLC. [substrate] = 1 M.
side chains added to the L-proline and avidin for the complexed
catalysts.
In light of these results, it seems that no strict rule can be
applied toward the design of improved anions for our system,
even though chiral anions perform better than racemic ones.
We performed deeper investigations with the anion 7, in order
to get a better understanding of the possible match−mismatch
cases observed when anion 6 was used. In this case, all four
diastereoisomers of compound 7 were prepared (Figure 4) and
the corresponding biohybrid catalysts assembled.
Once again, their catalytic activity was assessed both with and
without avidin in the aldol reaction (Table 2). When catalytic
tests were carried out without avidin, the corresponding
biotinylated catalysts afforded the aldol products with excellent
conversion and good selectivities. The use of 7·Av and 14·Av
gave the best results in terms of selectivity, each enantiomer of
the anion affording each enantiomer of the aldol product with
the same ee value. Using 12·Av and 13·Av led to lower ee
values but once again expectedly led each to each enantiomer of
the aldol product. However, their behavior inside avidin is quite
(d) Lowering the number of possible conformations of the
anion inside avidin, as in the case of anion 9, based on a Pro-
Pro scaffold (entry 7), did not lead to a better stereocontrol of
the reaction, in comparison to anion 3. Adding steric hindrance
to the anion seems to lower the reactivity of the whole catalyst.
(e) We previously reported the use of a 1-butyl-3-
methylimidazolium salt bearing anions 10 and 11 as catalysts
for the aldol reaction.17 The use of trans-4-hydroxy-L-proline
derivatives in combination with the biotinylated imidazolium
cation allowed the displacement of the sulfate charge closer to
the amine site, in comparison to compounds 4−9. However,
the catalytic performances of the corresponding assembled
catalysts were still lower than those obtained with 3. Also, the
introduction of a hydrogen-bonding group on the anion 11 did
not enhance in any way the performance of the corresponding
11·Av biohybrid catalyst.
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aldehydes. The use of a bulky aldehyde (entry 5) led to good
results in terms of conversion and selectivity, despite a longer
reaction time. Fluorous aldehydes were also tested and afforded
the corresponding aldol products with excellent conversions
and selectivities (entries 6 and 7). 2-thiocarboxaldehyde,
however, displayed poor reactivity in spite of a good selectivity.
An intramolecular aldol reaction was also performed using 2-
(2-oxopropoxy)benzaldehyde (Table 3, entry 9). The dihy-
drobenzofuranol resulting from the intramolecular aldol is a
common motif found in several natural coumarins used for the
treatment of skin diseases, such as vitiligo and psoriasis. Enders
et al. used keto aldehyde derivatives (entry 9) to study this type
of intramolecular aldol reaction, using L-proline as catalyst, and
applied this procedure to the total synthesis of smyrindiol.18,19
In the presence of 7·Av, as well as 7 without avidin, we were
surprised to observe the exclusive formation of the con-
densation product despite the absence of dehydration
conditions, the formation of the aromatic benzofuranol being
quite favored.
Figure 4. Diastereomers of anion 7.
different. A trend emerges when looking at the results given in
Table 2.
The best results were achieved both in terms of selectivity
and conversion when 7·Av was used, but these results were
similar to those obtained without avidin. Nevertheless, the
influence of avidin was more pronounced when biohybrid
catalysts 12·Av−14·Av were used. Surprinsingly, better results
were achieved when only natural amino alcohols were used.
The use of L-Proline as the first amino acid led to better results
in terms of conversion and enantioselectvity with L-phenyl-
alaninol, in comparison to those obtained when D-phenyl-
alaninol was used. Replacing L-proline by D-proline drastically
diminished the performances of the biohybrid catalyst, as ee
values decreased respectively to 6% and −9% (Table 2, entries
3 and 4), indicating that the chiral center closest to the amine
site is the most important for the stereocontrol of the reaction.
The drop of selectivity observed for D-proline and D-
phenylalaninol inside avidin may be the result of the
competition between the chiral induction of the avidin cavity
and the intrinsic chirality of the anion. This is a significant
evidence of a match−mismatch case, as the corresponding
catalyst in the absence of avidin afforded a better selectivity of
the reaction. The addition of a side chain also seems beneficial
for the stereocontrol of the reaction, and a fine-tuning process
for the design of new catalytic anions using other natural amino
alcohols is currently undergoing study in our group.
CONCLUSION
■
The preparation and catalytic studies of several anions in
combination with a biotinylated imidazolium salt assessed the
influence of the anion structure on the activity of biohybrid
catalysts obtained with avidin. Even though the observed effects
are still not completely understood, it has been shown that the
intrinsic chirality of the anion has an important influence on the
catalytic properties of the biohybrid species assembled with
avidin. A match−mismatch case was also identified, supporting
the hypothesis of cooperativity between avidin and the catalytic
salt itself, in terms of stereocontrol of the aldol reaction. The
substrate tolerance of the biohybrid catalyst was also put to use
through the use of several ketones/aldehydes in the aldol
reaction. Further optimization of the system could likely be
achieved through molecular modeling and docking studies to
identify the residues involved in the catalytic process. By
saturation mutagenesis and directed evolution, fine tuning
might also be achieved to further raise the cooperativity
between the catalyst and the avidin. The advantage of these
biohybrid system is that the catalyst and the protein could be
optimized independently, followed by screening all combina-
tions in a matrix format, if desired. The synthesis of other
anions with different catalytic properties may broaden the
scope of other possible reactions.
We also speculated that the use of a biohybrid catalyst in an
ionic liquid/aqueous mixture would be an asset in terms of
substrate tolerance, as the anion possesses a greater freedom of
movement inside avidin’s cavity, in comparison to a covalently
biotinylated amine catalyst. The biohybrid catalyst 7·Av was
used for substrate screening (Table 3). We were pleased to
observe that our biohybrid catalyst tolerates several ketones and
Table 2. Influence of the Chirality of the Anion
b
with avidin
without avidin
a
a
a
a
a
a
entry
anion
conversion (%)
dr (syn/anti)
ee (anti) (%)
conversion (%)
dr (syn/anti)
ee (anti) (%)
1
2
3
4
7 (L-Pro-L-Phe)
12 (L-Pro-D-Phe)
13 (D-Pro-L-Phe)
14 (D-Pro-D-Phe)
94
86
87
96
23/77
28/72
37/63
25/75
80
63
6
>99
>99
89
24/76
27/73
29/71
30/70
83
c
62
−63
c
c
−9
87
−79
a
b
c
Determined by chiral HPLC. [substrate] = 1 M. The enantiomer of the aldol product was obtained.
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Table 3. Substrate Scope
a
b
Determined by chiral HPLC. The reaction mixture was stirred for 5 days.
corresponding amino alcohol was then added to the reaction vessel,
and the suspension was refluxed overnight. Upon completion, the
reaction mixture was cooled to room temperature and filtered to
remove DCU. Methylene chloride was added to the filtrate, and the
organic phase was washed with water, dried with magnesium sulfate,
filtered, and concentrated in vacuo. The residue was purified by flash
chromatography on silica gel, affording the desired compound
tert-Butyl 2-((3-Hydroxypropyl)carbamoyl)pyrrolidine-1-carboxy-
late (1.4 and 1.6). Yields: white foam, 344.1 mg, 68% (compound
1.4); white foam, 308.6 mg, 61% (compound 1.6). 1H NMR (CDCl3,
400 MHz): δ 6.56−7.16 (m, 1 H), 4.24 (br s, 1 H), 3.16−3.71 (m, 7
H), 1.78−2.36 (m, 4 H), 1.62−1.75 (m, 2 H), 1.44 ppm (s, 9 H).
13C{1H} NMR (CDCl3, 75 MHz; mixture of rotamers): δ 173.9,
EXPERIMENTAL SECTION
■
Materials. All organic compounds were obtained commercially and
used without further purification. 1H and 13C NMR spectra were
recorded on 400, 300, 100, and 75 MHz spectrometers, in the
indicated solvent. Chemical shifts are reported in ppm with internal
reference to TMS, and J values are given in hertz. All HPLC analyses
were done using Chiralpak AD-H or OD columns, and absolute
configurations of the aldol products were based on previously reported
literature data.17 HRMS/ESI measurements were done on a Quantum
TSQ Ultra instruments.
Boc-proline was obtained following the procedure described by
Azizi et al.20
Representative Procedure for the Peptidic Coupling
between Proline and the Corresponding Amino Alcohol. The
1.X family of compounds refers to the Boc precursors of the
corresponding X zwitterion, as they are mentioned in the paper.
Boc-proline (1 equiv) and N-hydroxysuccinimide (1 equiv) were
dissolved in acetonitrile (1 mL/mmol of proline). Dicyclohexylcarbo-
diimide (1 equiv) was then added to the reaction mixture, and the
formation of a precipitate (DCU) was observed after 10 min. The
173.4, 155.6, 154.6, 80.5, 61.2, 60.1, 59.2, 47.1, 36.1 (br s), 32.3, 31.2
(br s), 28.4, 24.6, 23.7 ppm. HRMS (ESI): m/z [M + H]+ calcd for
C13H25N2O4, 273.1809; found, 273.1802.
tert-Butyl 2-((5-Hydroxypentyl)carbamoyl)pyrrolidine-1-carboxy-
1
late (1.5). Yield: pale yellow foam, 362.4 mg, 65%. H NMR (CDCl3,
400 MHz): δ 6.02−7.02 (m, 1 H), 4.26 (br s, 1 H), 3.65 (t, J = 6.0 Hz,
2 H), 3.07−3.51 (m, 4 H), 1.89 (br s, 2 H), 1.77 (br s, 3 H), 1.36−
1.64 ppm (m, 15 H). 13C{1H} NMR (CDCl3, 75 MHz; mixture of
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rotamers): δ 173.8, 173.5, 155.7, 154.7, 80.7, 61.2, 60.1, 59.2, 47.1,
36.2 (br s), 32.2, 31.1 (br s), 28.4, 24.6, 23.6 ppm. HRMS (ESI): m/z
[M + H]+ calcd for C15H29N2O4, 301.2122; found, 301.2116.
tert-Butyl 2-((1-Hydroxy-3-phenylpropan-2-yl)carbamoyl)-
pyrrolidine-1-carboxylate (1.7 and 1.14). Yields: white foam, 394.9
mg, 61% (compound 1.7); white foam, 284.8 mg, 44% (compound
to 0 °C. Chlorosulfonic acid (1 equiv) was added dropwise to the
reaction mixture, and the reaction mixture was stirred for an additional
2 h at room temperature. After the reaction, the solvent was discarded
and purification by achieved by flash chromatography on silica gel
(CH2Cl2/MeOH 8/2), affording the desired compound.
3-(Pyrrolidin-1-ium-2-carboxamido)propyl Sulfate (4 and 6).
Yields: white sticky foam, 173.8 mg, 53% (compound 4); white sticky
1
1.14). H NMR (CDCl3, 400 MHz): δ 7.13−7.33 (m, 5 H), 6.24−
1
6.80 (m, 1 H), 4.19 (br s, 2 H), 3.49−3.74 (m, 2 H), 3.17−3.46 (m, 3
H), 2.66−3.02 (m, 2 H), 1.55−2.24 (m, 4 H), 1.44 ppm (br s, 9 H).
13C{1H} NMR (CDCl3, 75 MHz; mixture of rotamers): δ 173, 172.1,
foam, 147.5 mg, 62% (compound 6). H NMR (D2O, 400 MHz): δ
4.26 (dd, J = 8.3, 6.6 Hz, 1 H), 4.02 (t, J = 6.0 Hz, 2 H), 3.23−3.41 (m,
4 H), 2.35 (d, J = 8.4 Hz, 1 H), 1.92−2.04 (m, 3 H), 1.80−1.89 ppm
(m, 2 H). 13C{1H} NMR (D2O, 75 MHz): δ 169.5, 66.7, 59.8, 46.4,
36.5, 29.6, 27.7, 23.8 ppm. HRMS (ESI): m/z [M + H]+ calcd for
C8H16N2O5S, 253.0853; found, 253.0855.
155.7, 154.6, 137.7 (br s), 129.1, 128.5, 126.5, 80.7, 64.3, 63.8, 61.2,
60.5, 52.7, 52.4, 47. (br s), 37, 33.9, 30.9 (br s), 28.7, 28.3, 24.3, 23.3
ppm. HRMS (ESI): m/z [M + H]+ calcd for C19H29N2O4, 349.2122;
found, 349.2120.
5-(Pyrrolidin-1-ium-2-carboxamido)pentyl Sulfate (5). Yield: pale
yellow sticky foam, 147.4 mg, 42%. 1H NMR (D2O, 400 MHz): δ 4.25
(t, J = 7.2 Hz, 1 H), 3.97 (t, J = 6.1 Hz, 2 H), 3.08−3.42 (m, 4 H),
2.30−2.43 (m, 1 H), 1.89−2.02 (m, 3 H), 1.61 (quin, J = 6.7 Hz, 2 H),
1.49 (quin, J = 7.0 Hz, 2 H), 1.33 ppm (quin, J = 7.5 Hz, 2 H).
13C{1H} NMR (D2O, 75 MHz): δ 168.9, 68.8, 59.4, 46.1, 39, 29.4,
tert-Butyl 2-((1-Hydroxy-3-phenylpropan-2-yl)carbamoyl)-
pyrrolidine-1-carboxylate (1.12 and 1.13). Yields: white foam,
439.7 mg, 68% (compound 1.12); white foam, 405.3 mg, 63%
1
(compound 1.13). H NMR (CDCl3, 400 MHz): δ 7.12−7.36 (m, 5
H), 6.72 (br s, 1 H), 4.08−4.23 (m, 2 H), 3.22−3.76 (m, 5 H), 2.88
(d, J = 7.7 Hz, 2 H), 1.69−2.21 (m, 4 H), 1.44 ppm (br s, 9 H).,
13C{1H} NMR (CDCl3, 75 MHz; mixture of rotamers): δ 173.2,
27.5, 27.1, 23.4, 21.7 ppm. HRMS (ESI): m/z [M + H]+ calcd for
C10H21N2O5S, 281.1166; found, 281.1160.
172.7, 155.6, 154.6, 137.9, 129.2, 128.5, 126.5, 80.6, 63.4, 61.2, 60.3,
53.1, 52.7, 47.1, 46.8, 36.9, 31.1, 28.9, 28.4, 24.6, 23.6 ppm. HRMS
(ESI): m/z [M + H]+ calcd for C19H29N2O4, 349.2122; found,
349.2125.
(S)-tert-Butyl 2-(((S)-1-Hydroxy-3-methylbutan-2-yl)carbamoyl)-
pyrrolidine-1-carboxylate (1.8). Yield: white foam, 312.2 mg, 56%.
Spectroscopic data were in accordance with literature data.21
3-Phenyl-2-(pyrrolidin-1-ium-2-carboxamido)propyl Sulfate (7
and 14). Yields: white solid, 381.9 mg, 92% (compound 7); white
solid, 268.6 mg, 69% (compound 14). These compounds can be
1
purified by recrystallization in ethanol. H NMR (D2O, 400 MHz): δ
7.17−7.38 (m, 5 H), 4.27−4.38 (m, 1 H), 4.11−4.20 (m, 1 H), 4.03−
4.10 (m, 1 H), 3.90−4.01 (m, 1 H), 3.17−3.39 (m, 2 H), 2.88−2.98
(m, 1 H), 2.68−2.79 (m, 1 H), 2.24−2.38 (m, 1 H), 1.94 ppm (d, J =
6.4 Hz, 3 H). 13C{1H} NMR (D2O, 75 MHz): δ 170, 138.4, 130.1,
129.5, 127.7, 70, 60.4, 51.7, 473, 36.5, 30.7, 24.4 ppm. HRMS (ESI):
m/z [M + H]+ calcd for C14H20N2O5S, 329.1166; found, 329.1173.
3-Phenyl-2-(pyrrolidin-1-ium-2-carboxamido)propyl Sulfate (12
and 13). Yields: white solid, 281 mg, 62% (compound 12); white
solid, 221.8 mg, 68% (compound 13). These compounds can be
Preparation of (S)-tert-Butyl 2-((S)-2-(Hydroxymethyl)-
pyrrolidine-1-carbonyl)pyrrolidine-1-carboxylate (1.9). Under
a nitrogen atmosphere, Boc-protected L-proline (1 g, 4.646 mmol, 1.05
equiv) and L-proline methyl ester hydrochloride22 (1 equiv) were
suspended in 25 mL of dry CH2Cl2, and DIPEA (3 equiv) was added.
The limpid solution was cooled to 0 °C, and a solution of DCC (1.2
equiv) in dry DCM (5 mL) was slowly added. The solution was stirred
for 30 min at 0 °C and then overnight at room temperature. After
completion of the reaction, the DCU was filtered and the organic
phase was washed with water, dried with magnesium sulfate, filtered,
and evaporated in vacuo. The residue was purified by flash
chromatography on silica gel (CH2Cl2/MeOH: 99/1 then 95/5) to
afford the desired Pro-Pro derivative 1.9-A as a sticky foam (1.04 g,
63%). 1H NMR (CDCl3, 400 MHz): δ 4.34−4.63 (m, 2 H), 3.77 (d, J
= 9.5 Hz, 1 H), 3.67−3.72 (m, 3 H), 3.33−3.66 (m, 3 H), 1.77−2.25
(m, 8 H), 1.33−1.49 ppm (m, 9 H), 13C{1H} NMR (CDCl3, 75 MHz;
mixture of rotamers): δ 172.9, 172.6, 171.6, 171.1, 154.6, 153.7, 79.5,
79.4, 58.7 (d), 57.8, 57.7, 52.2, 52.0, 46.9,46.7, 46,5 (d), 30, 29.0, 28.8,
28.7, 28.5, 28.4, 25 (d), 24.1, 23.6 ppm. HRMS (ESI): m/z [M + H]+
calcd for C16H27N2O5, 327.1914; found, 327.1914. Compound 1.9 was
then prepared following a procedure reported by De Souza et al.23 In a
three-neck flask, compound 1.9-A (659.2 mg) was dissolved in THF
(10 mL), and NaBH4 (6 equiv) was added. The mixture was stirred at
reflux for 15 min, and then methanol (6 mL) was slowly added using
an addition funnel over 30 min, inducing effervescence in the flask.
The reaction was stirred at reflux for 1 h more. After TLC completion,
excess hydride was slowly quench edusing H2O and the mixture was
extracted three times with CH2Cl2. The combined organic phases were
dried over magnesium sulfate, filtered, and evaporated in vacuo to
1
purified by trituration in cold ethanol. H NMR (D2O, 400 MHz): δ
7.13−7.38 (m, 5 H), 4.40 (m, 1 H), 4.07−4.23 (m, 2 H), 3.96−4.04
(m, 1 H), 3.18 (t, J = 7.1 Hz, 2 H), 2.99 (dd, J = 14.2, 4.1 Hz, 1 H),
2.67 (m, 1 H), 2.09 (m, 1 H), 1.80 (m, 1 H), 1.58 (m, 1 H), 1.34 ppm
(m, 1 H). 13C{1H} NMR (D2O, 75 MHz): δ 169.9, 138.2, 130.1,
129.4, 127.6, 70.4, 60.4, 51.3, 47.1, 36.9, 30.6, 24.2 ppm. HRMS (ESI):
m/z [M + H]+ calcd for C14H20N2O5S, 329.1166; found, 329.1173.
(S)-3-Methyl-2-((S)-pyrrolidin-1-ium-2-carboxamido)butyl Sul-
1
fate (8). Yield: white foam, 218.8 mg, 42%; H NMR (D2O, 400
MHz): δ 4.29 (dd, J = 8.3, 6.7 Hz, 1 H), 4.02−4.10 (m, 1 H), 3.94−
4.01 (m, 1 H), 3.79 (td, J = 7.3, 3.6 Hz, 1 H), 3.21−3.42 (m, 2 H),
2.29−2.41 (m, 1 H), 1.90−2.09 (m, 3 H), 1.74−1.85 (m, 1 H), 0.86
ppm (dd, J = 16.8, 6.7 Hz, 6 H). 13C{1H} NMR (D2O, 75 MHz): δ
170.1, 69.5, 59.8, 55, 46.5, 30.1, 28.5, 23.7, 18.5, 18 ppm. HRMS
(ESI): m/z [M + H]+ calcd for C10H20N2O5S, 281.1166; found,
281.1174.
((S)-1-((S)-Pyrrolidin-1-ium-2-carbonyl)pyrrolidin-2-yl)methyl Sul-
1
fate (9). Yield: white solid, 134 mg, 28%; H NMR (D2O, 500 MHz;
mixture of rotamers): δ 5.03−5.32 (m, 1 H), 4.80−4.88 (m, 1 H), 4.75
(dd, J = 10.3, 4.8 Hz, 1 H), 4.46−4.59 (m, 1 H), 4.08−4.15 (m, 1 H),
3.97−4.05 (m, 2 H), 3.92 (tt, J = 10.8, 7.0 Hz, 1 H), 2.97−3.10 (m, 1
H), 2.37−2.66 ppm (m, 7 H). 13C{1H} NMR (D2O, 100 MHz;
mixture of rotamers): δ 168.9, 168.4, 69.6, 68.1, 60.1, 59.9, 57.6, 57.4,
48.1, 47.6, 47.4, 46.8, 29.4, 29.1, 18.2, 27.1, 24.5, 24.3(9), 24.3(6), 21.6
ppm. HRMS (ESI): m/z [M + H]+ calcd for C5H9N2O5S−, 209.02377;
found, 209.02386.
1
afford the desired product as a pale yellow foam (92%). H NMR
(CDCl3, 400 MHz): δ 4.80−5.04 (m, 1 H), 4.02−4.55 (m, 2 H),
3.34−3.91 (m, 6 H), 1.50−2.31 (m, 8 H), 1.32−1.48 ppm (m, 9 H).
13C{1H} NMR (CDCl3, 75 MHz; mixture of rotamers): δ 174.2,
Representative Procedure for the Preparation of Biotiny-
lated Salts Biot-4−Biot-11. The Biot-X family of compounds refers
to the corresponding biotinylated imidazolium salts bearing the anion
X. These compounds are NOT designated as such in the paper, to
avoid confusion with the biohybrid catalysts.
The biotinylated imidazolium bromide salt precursor was
synthesized following our reported procedure. The preparation of
the catalytic biotinylated imidazolium salts is based on our published
procedure, with minor modifications.
173.8, 171.6, 154.9, 154.2, 153.3, 79.8, 79.2, 67.2, 67.1, 66.2, 61.2, 60.8,
59.3, 57.6, 57.2, 47.2, 46.9, 46.5, 46.3, 45.3, 30.3, 29.5 (d), 28.9, 28.1,
28, 27.6, 27.4, 24.3, 24.2, 23.9, 23.3, 21.9 ppm. HRMS (ESI): m/z [M
+ H]+ calcd for C15H27N2O4, 299.1965; found, 299.1963. NMR of this
compound in dmso-d6 was carried out at different temperatures to
confirm the presence of rotamers (see the Supporting Information).
Representative Procedure for the Preparation of Zwitter-
ions 4−9 and 13−15. Under nitrogen, the corresponding alcohol
1.X was dissolved in dry dichloromethane (3 mL/mmol) and cooled
2699
dx.doi.org/10.1021/jo5002406 | J. Org. Chem. 2014, 79, 2694−2701

The Journal of Organic Chemistry
Article
The biotinylated imidazolium bromide salt (50 mg, 0.102 mmol)
was dissolved in MeOH (2 mL) and passed through an IRA-400 HO
form exchange resin (1.5 g). The resin was then washed with MeOH
(2 × 3 mL), and zwitterion 6 (1.05 equiv) was added to the reaction
vessel. The mixture was stirred overnight at room temperature. The
methanol and resulting water were removed under reduced pressure,
and the residue was dissolved in 1 mL of CH3CN/MeOH (95/5) and
cooled to −8 °C for 3 h. The resulting solid was filtered, and the
filtrate was evaporated under reduced pressure and dried under
vacuum to give the desired product as a yellow foam.
3-Butyl-1-(3-(5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]-
imidazol-4-yl)pentanamido)propyl)-1H-imidazol-3-ium 3-(Pyrroli-
dine-2-carboxamido)propyl Sulfate (Biot-4 and Biot-6). Yields:
47.8 mg, 71% (compound Biot-4); 51.8 mg, 77% (compound Biot-6).
1H NMR (D2O, 400 MHz): δ 7.44 (s, 2 H), 4.53 (dd, J = 7.6, 4.9 Hz,
yl-2-((S)-pyrrolidine-2-carboxamido)butyl Sulfate (Biot-8). Yield:
68.7 mg, 98%. H NMR (D2O, 400 MHz): δ 7.44 (s, 2H), 4.52 (br
1
s, 1 H), 4.33 (br s, 1 H), 4.14 (dt, J = 13.2, 6.6 Hz, 4 H), 3.97−4.03
(m, 2 H), 3.77 (d, J = 5.7 Hz, 2 H), 3.11−3.30 (m, 3 H), 2.85−3.05
(m, 3 H), 2.67 (d, J = 13.0 Hz, 1 H), 1.96−2.24 (m, 5 H), 1.18−1.85
(m, 14 H), 0.72−0.93 ppm (m, 9 H). 13C{1H} NMR (D2O, 75 MHz):
δ 176.8, 175.4, 165.3, 122.5, 122.3, 68.5, 62.11, 60.25, 60.1, 5..5, 54.4,
49.4, 47, 46.5, 39.7, 35.8, 35.4, 31.2, 30.63, 28.9, 28.6, 28, 27.7, 25.1,
24.9, 18.8, 18.6, 17.9, 12.7 ppm. HRMS (ESI): m/z [M*]+ calcd for
C20H34N5O2S+, 408.2428; found, 408.2435; m/z [M*]− calcd for
C10H19N2O5S−, 279.1020; found, 279.1028.
3-Butyl-1-(3-(5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]-
imidazol-4-yl)pentanamido)propyl)-1H-imidazol-3-ium ((S)-1-((S)-
Pyrrolidine-2-carbonyl)pyrrolidin-2-yl)methyl Sulfate (Biot-9).
1
Yield: 231 mg, 33%. H NMR (D2O, 400 MHz): δ 7.44 (s, 2 H),
1 H), 4.34 (dd, J = 7.8, 4.5 Hz, 1 H), 4.14 (dt, J = 13.8, 7.0 Hz, 4 H),
4.01 (t, J = 6.0 Hz, 2 H), 3.73 (d, J = 6.6 Hz, 1 H), 3.22−3.31 (m, 2
H), 3.12−3.20 (m, 2 H), 2.83−3.02 (m, 3 H), 2.68 (d, J = 13.0 Hz, 1
H), 1.99−2.25 (m, 5 H), 1.16−1.88 (m, 16 H), 0.85 ppm (t, J = 7.4
Hz, 3 H). 13C{1H} NMR (D2O, 75 MHz): δ 176.9, 175.8, 165.3,
122.5, 122.3, 66.7, 62.1, 60.2, 60.1, 55.5, 49.4, 47, 46.4, 39.7, 36.1, 35.8,
35.4, 31.2, 30.3, 28.9, 28, 27.9, 27.7, 25.1, 25, 18,8, 12.6 ppm. HRMS
(ESI): m/z [M*]+ calcd for C20H34N5O2S+, 408.2428; found,
408.2436; m/z [M*]− calcd for C8H15N2O5S−, 251.0707; found,
251.0713.
4.53 (dd, J = 7.8, 4.9 Hz, 1 H), 4.06−4.37 (m, 7 H), 3.95 (dd, J = 9.6,
2.8 Hz, 1 H), 3.37−3.58 (m, 2 H), 2.86−3.30 (m, 6 H), 2.68 (d, J =
13.0 Hz, 1 H), 1.13−2.39 (m, 23 H), 0.84 ppm (t, J = 7.3 Hz, 3 H).
13C{1H} NMR (D2O, 75 MHz): δ 177, 171.3, 165.3, 122.5, 122.3,
68.9, 67.5, 32.1, 60.2, 28,9, 28.7, 26.7, 56.4, 55.4, 55.4, 49.4, 47.4, 47,
46.8, 46.6, 46.1, 39.7, 35.8, 35.4, 31.2, 29.4, 29.2, 28.9, 28, 27.7, 27.5,
26.5, 25, 24.8, 24.7, 23.8, 21, 18.8, 12.6 ppm. HRMS (ESI): m/z
[M*]+ calcd for C20H34N5O2S+, 408.2428; found, 408.2436; m/z
[M*]− calcd for C10H17N2O5S−, 277.0864; found, 277.0869.
3-Butyl-1-(3-(5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]-
imidazol-4-yl)pentanamido)propyl)-1H-imidazol-3-ium (3R,5S)-5-
(Methoxycarbonyl)pyrrolidin-3-yl Sulfate (Biot-10). Yield: 58.7 mg,
3-Butyl-1-(3-(5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]-
imidazol-4-yl)pentanamido)propyl)-1H-imidazol-3-ium 5-(Pyrroli-
dine-2-carboxamido)pentyl Sulfate (Biot-5). Yield: 48.4 mg, 69%.
1H NMR (D2O, 400 MHz): δ 7.44 (s, 2 H), 4.46−4.56 (m, 1 H), 4.33
1
91%. H NMR (D2O, 400 MHz): δ 8.71 (s, 1 H), 7.44 (s, 2 H), 4.99
(br s, 1 H), 4.48−4.56 (m, 1 H), 4.30−4.37 (m, 1 H), 4.08−4.25 (m, 5
H), 3.71 (s, 4 H), 3.08−3.33 (m, 5 H), 2.86−2.94 (m, 1 H), 2.68 (d, J
= 12.8 Hz, 1 H), 2.46−2.55 (m, 1 H), 2.18 (t, J = 7.3 Hz, 3 H), 2.04 (t,
J = 6.8 Hz, 2 H), 1.16−1.83 (m, 9 H), 0.84 ppm (t, J = 7.4 Hz, 3 H).
13C{1H} NMR (D2O, 75 MHz): δ 176.9, 174, 165.3, 135.3, 122.5,
12.3, 79.3, 62.1, 60.3, 58, 55.5, 53.1, 51.9, 49.4,47.1, 39.7, 35.9, 35.8,
35.4, 32.2, 28.9, 28, 27.7, 25.1, 18.8, 12.6 ppm. HRMS (ESI): m/z
[M*]+ calcd for C20H34N5O2S+, 408.2428; found, 408.2240; m/z
[M*]− calcd for C6H10NO6S−, 224.0234; found, 224.0234.
3-Butyl-1-(3-(5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]-
imidazol-4 yl)pentanamido)propyl)-1H-imidazol-3-ium (3R,5S)-5-
Carbamoylpyrrolidin-3-yl Sulfate (Biot-11). Yield: 55.5 mg, 88%.
1H NMR (D2O, 400 MHz): δ 8.72 (s, 1 H), 7.44 (s, 2 H), 4.95 (br s, 1
H), 4.50−4.56 (m, 1 H), 4.31−4.37 (m, 1 H), 4.14 (dt, J = 13.9, 7.1
Hz, 4 H), 3.94 (s, 1 H), 3.13−3.30 (m, 4 H), 3.10 (d, J = 4.0 Hz, 1 H),
2.89 (d, J = 5.0 Hz, 1 H), 2.68 (d, J = 13.0 Hz, 1 H), 2.40−2.48 (m, 1
H), 2.18 (t, J = 7.2 Hz, 2 H), 1.95−2.09 (m, 3 H), 1.72−1.83 (m, 2
H), 1.43−1.71 (m, 4 H), 1.24 (d, J = 7.7 Hz, 4 H), 0.85 ppm (t, J = 7.4
Hz, 3 H). 13C{1H} NMR (D2O, 75 MHz): δ 178.4, 177, 165.3, 135.3,
122.5, 122.3, 80.8, 62.1, 62.3, 58.5, 55.4, 52.3, 49.4, 47, 39.7, 7.1, 35.8,
35.4, 31.22, 28.9, 28, 27.7, 25.1, 18.8, 12.6. HRMS (ESI): m/z [M*]+
calcd for C20H34N5O2S+, 408.2428; found, 408.2436; m/z [M*]− calcd
for C5H9N2O5S−, 209.0238; found, 209.0239.
Representative Procedure for the Aldol Reaction. The aldol
reaction is carried in 100 μL of a 8/2 solution of [Bmim]Br and Tris
buffer solution. Stock solutions of starting materials and catalysts were
prepared: S1 refers to a 0.2 M solution of aldehyde in [Bmim]Br, S2
refers to a 2 M solution of cyclohexanone in [Bmim]Br, and S3 refers
to a 0.03 M solution catalyst in Tris buffer solution (pH 3). In a vial,
12 mg of avidin (13.8 U/mg, binds 0.678 μmol of biotynilated catalyst,
1.13 equiv compared to catalyst) was suspended in 60 μL of
[Bmim]Br. A 10 μL portion of S2 (20 μmol, 10 equiv) and 20 μL of S3
(0.6 μmol, 30 mol %) were added. Avidin was dissolved in the reaction
medium, and the reaction vial was stirred for 15 min at room
temperature to allow the preformation of the catalytic species. A 10 μL
portion of S1 (2 μmol, 1 equiv) was added, and the reaction mixture
was stirred for 48 h at 4 °C. Ether (0.5 mL) was then added, and the
vial was vortexed for 1 min. The ethereal phase was analyzed by chiral
HPLC (ChiralPak AD-H column, hexanes/IPA 95/5, 0.5 mL/min, λ
254 nm): tR(anti isomer) = 47.10 (minor), 63.90 (major), tR(syn
isomer) = 32.14 (minor), 42.81 min (major).
(dd, J = 7.5, 4.4 Hz, 1 H), 4.14 (dt, J = 14.0, 7.0 Hz, 4 H), 3.97 (t, J =
6.1 Hz, 2 H), 3.77 (d, J = 6.6 Hz, 1 H), 3.07−3.32 (m, 5 H), 2.85−
3.06 (m, 3 H), 2.67 (d, J = 13.0 Hz, 1 H), 2.08−2.23 (m, 3 H), 2.03
(m, 2 H), 1.42−1.83 (m, 13 H), 1.16−1.37 (m, 6 H), 0.84 ppm (t, J =
7.3 Hz, 3 H). 13C{1H} NMR (D2O, 75 MHz): δ 176.9, 174.7, 165.3,
122.5, 122.3, 69.1, 621, 60.3, 60.1, 55.5, 49.4, 47, 46.4, 39.7, 39.1, 35.9,
35.4, 31.2, 30.4, 28.9, 28, 28, 27.8, 27.7, 25.1, 24.9, 22.3, 18.8, 12.7
ppm. HRMS (ESI): m/z [M*]+ calcd for C20H34N5O2S, 409.2506;
found, 409.2489; m/z [M*]− calcd for C10H19N2O5S−, 279.1027;
found, 279.1027.
3-Butyl-1-(3-(5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]-
imidazol-4-yl)pentanamido)propyl)-1H-imidazol-3-ium 3-Phenyl-2-
(pyrrolidine-2-carboxamido)propyl Sulfate (Biot-7 and Biot-14).
Yields: 73.5 mg, 98% (compound Biot-7); 53.3 mg, 71% (compound
Biot-14). 1H NMR (D2O, 400 MHz): δ 7.41 (s, 2 H), 7.13−7.33 (m,
5 H), 4.43−4.53 (m, 1 H), 4.22−4.35 (m, 2 H), 4.05−4.17 (m, 4 H),
3.89−4.05 (m, 2 H), 3.70 (dd, J = 8.2, 6.3 Hz, 1 H), 3.09−3.26 (m, 3
H), 2.81−2.96 (m, 4 H), 2.59−2.78 (m, 2 H), 2.15 (t, J = 7.2 Hz, 2
H), 1.95−2.10 (m, 3 H), 1.39−1.81 (m, 9 H), 1.16−1.38 (m, 4 H),
0.83 ppm (t, J = 7.3 Hz, 3 H). 13C{1H} NMR (D2O, 75 MHz): δ
176.8, 174.4, 165.2, 137.6, 129.3, 128.6, 126.8, 122.5, 122.3, 69.2, 60.2,
59.9, 55.5, 50.3, 49.4, 47, 46.4, 39.7, 36.1, 35.8, 34.4, 31.2, 30.3, 28.9,
28, 27.7, 25.1, 24.7, 19.9, 12.7 ppm. HRMS (ESI): m/z [M*]+ calcd
for C20H34N5O2S+, 408.2428; found, 408.2438; m/z [M*]− calcd for
C14H19N2O5S, 327.1020; found, 327.1029.
3-Butyl-1-(3-(5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]-
imidazol-4-yl)pentanamido)propyl)-1H-imidazol-3-ium 3-Phenyl-2-
(pyrrolidine-2-carboxamido)propyl Sulfate (Biot-12 and Biot-13).
Yields: 63.3 mg, 91% (compound Biot-12); 61.5 mg, 82% (compound
Biot-13). 1H NMR (D2O, 400 MHz): δ 7.41 (s, 2 H), 7.15−7.30 (m,
5 H), 4.49 (s, 1 H), 4.25−4.36 (m, 2 H), 3.94−4.17 (m, 6 H), 3.66−
3.74 (m, 1 H), 3.17−3.27 (m, 1 H), 3.10−3.16 (m, 2 H), 2.81−2.97
(m, 4 H), 2.60−2.71 (m, 2 H), 2.16 (t, J = 7.2 Hz, 2 H), 2.00 (dd, J =
14.2, 7.4 Hz, 3 H), 1.70−1.81 (m, 2 H), 1.41−1.69 (m, 6 H), 1.15−
1.39 (m, 5 H), 0.83 ppm (t, J = 7.4 Hz, 3 H). 13C{1H} NMR (D2O, 75
MHz): δ 176.5, 173.5, 164.9, 137.2, 129, 128.2, 126.4, 122.1, 121.9,
69.1, 61.7, 59.9, 59.4, 55.1, 49.8, 49, 46.6, 45.8, 39.3, 35.8, 35.4, 35,
30.8, 28.5, 27.6, 27.3, 24.7, 24.1, 18.4, 12.3 ppm. HRMS (ESI): m/z
[M*]+ calcd for C20H34N5O2S+, 408.2428; found, 408.2432; m/z
[M*]− calcd for C14H19N2O5S−, 327.1020; found, 327.1024.
3-Butyl-1-(3-(5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]-
imidazol-4-yl)pentanamido)propyl)-1H-imidazol-3-ium (S)-3-Meth-
2700
dx.doi.org/10.1021/jo5002406 | J. Org. Chem. 2014, 79, 2694−2701

The Journal of Organic Chemistry
Article
ASSOCIATED CONTENT
■
S
* Supporting Information
Figures giving 1H and 13C NMR spectra and HPLC traces. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail for A.R.S.: ar.schmitzer@umontreal.ca.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the Natural Sciences and
Engineering Research Council of Canada, the Fonds Queb
de la Recherche sur la Nature et les Technologies, the Centre of
Green Chemistry and Catalysis and the Canada Foundation for
■
́
ec
́
ois
́ ́
Innovation, and the Universite de Montreal. The authors thank
Sylvie Bilodeau for the variable-temperature NMR experiments
and colleagues for careful discussions of this paper.
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