(2S,4R)-Hyp-(S)-Phe-OMe dipeptide supported on imidazolium tagged molecules as recoverable organocatalysts for asymmetric aldol reactions using water as reaction medium

Article abstract of DOI:10.1016/j.tet.2017.07.037

Four novel chiral imidazolium tagged molecules derived from dipeptide (2S,4R)-Hyp-(S)-Phe-OMe were prepared and evaluated as organocatalysts in the asymmetric aldol reaction using water as solvent. It was found that catalysts incorporating the hexanoyl linker are active down to 5 mol% and afford aldol products with up to 94% yield, up to 98:2 dr and up to 97:3 er. This chiral imidazolium catalyst was reused up to 6 times without any loss in the stereoselectivity of asymmetric aldol reactions. By contrast, organocatalysts containing an acetyl linker proved to be highly unstable in protic solvents, and for that reason they could not be recovered and reused.

Full text of DOI:10.1016/j.tet.2017.07.037

Accepted Manuscript
(2S,4R)-Hyp-(S)-Phe-OMe dipeptide supported on imidazolium tagged molecules as
recoverable organocatalysts for asymmetric aldol reactions using water as reaction
medium
Arturo Obregón-Zúñiga, Eusebio Juaristi
PII:
S0040-4020(17)30779-2
10.1016/j.tet.2017.07.037
TET 28869
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 7 June 2017
Revised Date: 20 July 2017
Accepted Date: 21 July 2017
Please cite this article as: Obregón-Zúñiga A, Juaristi E, (2S,4R)-Hyp-(S)-Phe-OMe dipeptide supported
on imidazolium tagged molecules as recoverable organocatalysts for asymmetric aldol reactions using
water as reaction medium, Tetrahedron (2017), doi: 10.1016/j.tet.2017.07.037.
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(2S,4R)-Hyp-(S)-Phe-OMe dipeptide supported on
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organocatalysts for asymmetric aldol reactions using water as reaction medium.
Arturo Obregón-Zúñiga,a and Eusebio Juaristi*a,b
b
aCentro de Investigación y de Estudios Avanzados, Av. IPN 2508, 07360 Ciudad de México. El Colegio
Nacional, Luis González Obregón No. 23, Ciudad de México, Mexico.

1
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Tetrahedron
journal homepage: www.elsevier.com
(2S,4R)-Hyp-(S)-Phe-OMe dipeptide supported on imidazolium tagged molecules
as recoverable organocatalysts for asymmetric aldol reactions using water as
reaction medium.
Arturo Obregón-Zúñiga,a and Eusebio Juaristi*a,b
aDepartamento de Química, Centro de Investigación y de Estudios Avanzados, Av. IPN 2508, 07360 Ciudad de México, México.
bEl Colegio Nacional, Luis González Obregón 23, Centro Histórico, 06020 Ciudad de México, México.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Four novel chiral imidazolium tagged molecules derived from dipeptide (2S,4R)-Hyp-(S)-Phe-
OMe were prepared and evaluated as organocatalysts in the asymmetric aldol reaction using
water as solvent. It was found that catalysts incorporating the hexanoyl linker are active down to
5 mol% and afford aldol products with up to 94% yield, up to 98:2 dr and up to 97:3 er. This
chiral imidazolium catalyst was reused up to 6 times without any loss in the stereoselectivity of
asymmetric aldol reactions. By contrast, organocatalysts containing an acetyl linker proved to be
highly unstable in protic solvents, and for that reason they could not be recovered and reused.
Available online
Keywords:
Dipeptide
Imidazolium tagged catalyst
Asymmetric organocatalysis
Aldol reaction
2009 Elsevier Ltd. All rights reserved
.
Recoverable organocatalyst
1. Introduction
In this regard, our group has made several contributions
consisting in the employment of dipeptides as organocatalysts
under solvent-free reaction conditions.4f,g,5e,11 Among those
The aldol reaction is one of the most versatile synthetic tools
available to simultaneously create carbon-carbon bonds and to
introduce a new stereogenic center supporting a hydroxyl group.1
Although it has been widely studied, the asymmetric version of
this reaction still proves to be a challenge, particularly in view of
present day interest in performing aldol reactions in media such
as water,2 brine,3 or even better, under solvent-free reaction
conditions.4 An alternative, interesting strategy involves the use
of recoverable organocatalysts to make the processes more
sustainable. Indeed, recyclable organocatalysts for the aldol
reaction have been prepared, for example by means of solid
supported organocalysts,5 or employing ion-tagged supported
catalysis.6 In this context, chiral imidazolium tagged molecules
(CITM), which are imidazolium compounds presenting a chiral
group as a side chain, have been extensively used in asymmetric
organocatalysis.7 Alternatively, the chiral moiety of the CITM
can be the chiral counteranion.8 This type of compounds can be
used in polar solvents such as water,9 and thus the ionic catalyst
can be recovered by simple extraction of the crude reaction
mixture with an organic solvent - the CITM remains dissolved in
the polar medium. This property makes imidazolium tagged
molecules attractive as recoverable organocatalysts, which
increases their usefulness.10
dipeptidic
organocatalysts,
(S)-Pro-(S)-Phe-OMe
proved
especially efficient.4g,12 Thus, we decided to use the
aforementioned dipeptide as a template for the preparation of
CITMs. In order to support the dipeptide on an imidazolium ionic
tag, (2S,4R)-hydroxyproline [(2S,4R)-Hyp] was used instead of
(S)-proline, which allows for derivatization through the hydroxyl
group.
2. Results and discussion
N-Cbz protected trans-hydroxyproline (2S,4R)-1 was coupled
to (S)-phenylalanine through the formation of a mixed anhydride,
to obtain the dipeptide (2S,4R,1’S)-2 in 88% yield. Subsequently,
acylation reactions allowed for the attachment of acetyl and
hexanoyl linkers. The acetyl linker was incorporated by means of
the reaction of bromoacetyl bromide with dipeptide (2S,4R,1’S)-
2, affording compound (2S,4R,1’S)-3, which was treated with 1-
methylimidazole at room temperature to obtain (2S,4R,1’S)-4 in
96% yield. On the other hand, 6-bromohexanoic acid was treated
with oxalyl chloride to generate the corresponding acyl chloride
derivative, which was then treated with dipeptide (2S,4R,1’S)-2
to produce (2S,4R,1’S)-5 in 75% yield. This bromide derivative
was treated with 1-methylimidazole at 70 °C to yield
imidazolium (2S,4R,1’S)-6 in 91% (Scheme 1).
In this report, we describe the synthesis of four novel CITMs
that incorporate a dipeptide as the chiral active component, and
that are able to function in asymmetric enamine organocatalysis.

2
Tetrahedron
ACCEPTED MANUSCRIPT
exhibited high stability toward hydrolysis and nucleophilic
attack.
Scheme 1. Synthetic route for the preparation of CITMs.
CITM (2S,4R,1’S)-7 containing an acetyl linker was obtained in
98% yield by removal of the Cbz protecting group in
(2S,4R,1’S)-4 via a hydrogenolytic reaction (Scheme 2).
On the other hand, imidazolium derivative (2S,4R,1’S)-4 was
subjected to
a
metathesis reaction with potassium
hexafluorophosphate to afford imidazolium hexafluorophosphate
(2S,4R,1’S)-8 in 63% yield. Attempted hydrogenolysis of
(2S,4R,1’S)-8 to obtain CITM (2S,4R,1’S)-9 afforded instead
dipeptide (2S,4R,1’S)-2 (Scheme 2).
In this regard, MS-TOF analysis provided evidence that
compound (2S,4R,1’S)-9 was indeed obtained, although in very
low yield. Furthermore, mass peaks corresponding to dipeptide
(2S,4R,1’S)-2 and the imidazolium fragment were observed,
which indicates that the anticipated product (2S,4R,1’S)-9 is
hydrolyzed under the reaction conditions (See Supporting
information). Furthermore, when NMR spectra of compound
(2S,4R,1’S)-7 were recorded several days after its preparation,
clear signs of decomposition were observed. It seems likely that
the same hydrolytic pathway that takes place in the hydrolysis of
(2S,4R,1’S)-9 (Scheme 2) is operative here. Apparently, this
hydrolysis reaction proceeds via activation by the imidazolium
group, which acts as an electron-withdrawing group that makes
the ester group more electrophilic, and therefore more susceptible
to a nucleophilic attack.13 This would explain the low stability of
CITMs containing the acetyl group towards moisture.
Hydrogenolysis of (2S,4R,1’S)-6 afforded CITM (2S,4R,1’S)-
10 in 99% yield. On the other hand, ionic exchange in aqueous
potassium hexafluorophosphate allowed the conversion of
(2S,4R,1’S)-6 to (2S,4R,1’S)-11 in 86% yield. Finally, CITM
(2S,4R,1’S)-12 was obtained in 97% yield after removal of the
protecting group in (2S,4R,1’S)-11 (Scheme 3). By contrast with
the (2S,4R,1’S)-7, CITMs (2S,4R,1’S)-10 and (2S,4R,1’S)-12
Scheme 2. Synthesis of CITM (2S,4R,1’S)-7.

3
Up to this point, an excess of cyclohexanone (10 equivalents)
ACCEPTED MANUSCRIPT
was being used, and it deemed convenient to determine whether
this amount of cyclohexanone could be reduced. Indeed, it was
observed that the stereoselectivity of the reaction is preserved
with reduced amounts of cyclohexanone (Table 3). Nevertheless,
when less than 4 equivalents of cyclohexanone were used the
yield decreased significantly (entries 1 and 2 in Table 3).
Table 1. Evaluation of CITMs (2S,4R,1’S)-10 and
(2S,4R,1’S)-12 as organocatalysts in the asymmetric aldol
reaction
Entry
CIL
Water
p-NBA
Yield
(%)a
95
96
85
95
96
95
95
drb
erc
1
2
3
4
5
6
7
(2S,4R,1’S)10
(2S,4R,1’S)10
(2S,4R,1’S)10
(2S,4R,1’S)10
(2S,4R,1’S)12
(2S,4R,1’S)12
(2S,4R,1’S)12
No
No
Yes
Yes
No
No
Yes
No
Yes
No
83:17
54:46
80:20
86:14
79:21
74:26
93:7
84:16
80:20
82:18
94:6
86:14
88:12
94:6
No
Yes
Yes
Yes
Scheme 3. Synthesis of CITMs (2S,4R,1’S)-10 and (2S,4R,1’S)-
12.
aDetermined after purification by flash chromatography. Determined by H
NMR from the crude reaction product. Major product: anti diastereomer.
cDetermined by HPLC with chiral stationary phase. Er for the anti isomer.
b
1
As in previous reports in this area,6,7 the purity of the final
CITMs was established by the usual spectroscopic techniques, in
particular 1H and 13C NMR and mass spectrometry (see the
Supporting Information). It should be mentioned that the water
1
signal present in H NMR spectra arises from the not totally
anhydrous DMSO-d6 employed for the recording of the high-
temperature NMR spectra.
Table 2. Evaluation of CITM and p-NBA additive loads in the
asymmetric aldol reaction catalyzed by (2S,4R,1’S)-12.
The efficiency of the CITMs (2S,4R,1’S)-10 and (2S,4R,1’S)-
12 as organocatalysts was evaluated in the asymmetric aldol
reaction between cyclohexanone and p-nitrobenzaldehyde. In
particular, the potential importance of two variables in the
reaction was examined, (1) presence of water in the reaction
medium, and (2) presence of p-nitrobenzoic acid (p-NBA) as an
additive (Table 1). The yield obtained in all cases was excellent,
ca. 95%. When the reaction was performed under neat conditions
(Table 1, entries 1 and 5), similarly moderate results in terms of
stereoselectivity were obtained with both CITMs. However,
when p-NBA was used as additive, the diastereoselectivity
obtained with CITM (2S,4R,1’S)-10 (Table 1, entry 2) decreased
dramatically, while the performance of CITM (2S,4R,1’S)-12 was
essentially identical to that observed under neat conditions (Table
1, entry 6). Lower yields were obtained when only water was
present as additive (Table 1, entry 3); nevertheless, the enantio-
and diastereoselectivity was maintained (compare entries 1-3 in
Table 1). On the other hand, when both water and p-nitrobenzoic
acid additives were employed, a significant improvement in
enantioselectivity was observed (Table 1, entry 4). Nevertheless,
the best result in terms of both diastereo- and enantioseletivity
was found with by (2S,4R,1’S)-12 as organocatalyst (Table 1,
entry 7), making it the organocatalyst of choice.
Entry
mol%
(2S,4R,1’S)12
and p-NBA
Yield
(%)a
dr
er
(anti/syn)b
(anti)c
1
2
3
5
10
15
95
95
94
94:6
92:8
91:9
94:6
94:6
94:6
aDetermined after purification by flash chromatography. Determined by H
NMR from the crude reaction product. cDetermined by HPLC with chiral
stationary phase.
b
1
Although results in aqueous media were satisfactory, a solvent
screening was performed to assess the reaction’s behavior in
other media. It was found that relative to water (entry 6 in Table
1) most organic solvents gave poorer results, both regarding yield
and stereoselectivity (Table 4, entries 1 to 4). When 1-butyl-3-
methylimidazolium hexafluorophosphate was used as solvent
(Table 4, entry 5), high yields were observed but stereoselectivity
Optimization of catalyst and additive loads confirmed that the
use of 5 mol% of catalyst and 5 mol% of p-NBA is most
convenient both in terms of observed yield and stereoselectivity
(Table 2).

4
Tetrahedron
ACCEPTED MANUSCRIPT
was low. Finally, when brine was used as reaction medium,
good stereoselectivity was obtained (Table 4, entry 7), but not
quite as good as that found in water solvent.
Subsequently, to evaluate the scope of the aldol reaction under
the optimum conditions, a screening with different ketones and
substituted benzaldehydes was performed (Table 6). When
cyclohexanone was used as the carbonyl substrate (Table 6,
entries 1 to 11), the observed stereoselectivities were good to
excellent (dr in the 85:15 to 98:2 range, while er varied from
82:18 to 97:3). Yields were good in most cases (above 70%)
(Table 6, entries 2, 4, and 6-8), although aldehydes with neutral
or electron-donating groups (Table 6, entries 1, 3, 5 and 9-11)
gave modest to poor results (≤ 52%) apparently as consequence
of their reduced electrophilicity. Regarding other cycloalkanones,
cyclopentanone gave good yield but low stereoselectivity (Table
6, entry 12), while cycloheptanone afforded an essentially
racemic aldol product in low yield but with good diastereomeric
ratio (Table 6, entry 13). Finally, aliphatic ketones generally
yielded poor results (Table 6, entries 14 to 17).
Because of the crucial role of additive p-NBA, it was deemed
convenient to carry out a screening of different Brønsted acid
additives (Table 5). In the event, benzoic acid and substituted
benzoic acid derivatives afforded similar results in
stereoselectivity (Table 5, entries 1 to 3) but lower yield (Table 5,
entry 2). Aliphatic carboxylic acids afforded similar
stereoselectivities with respect to benzoic acid derivatives (Table
5, entries 4 and 5), although the reaction proceeded in lower
yield. On the other hand, the effect of chiral Brønsted acids was
also explored using both enantiomers of mandelic acid14 (Table 5,
entries 6 and 7). Nevertheless, similar results were obtained
relative to the ones yielded with benzoic acids as additives (Table
5, entries 1 to 3). Furthermore, oxalic acid gave the lowest yield
and diastereomeric ratio (Table 5, entry 8). Thus, p-NBA was
confirmed as the most adequate Brønsted acid additive.
Table 5. Screening of Brønsted acid additives in the model
aldol reaction.
Table 3. Evaluation of the optimum amount of cyclohexanone
required in the model aldol reaction.
Entry
Additve
Yield
(%)a
88
92
86
80
75
90
91
dr
(anti/syn)b
94:6
95:5
94:6
94:6
94:6
94:6
94:6
er
(anti)c
94:6
95:5
94:6
95:5
95:5
94:6
93:7
94:6
Entry
Equiv
ketone
1
2
4
6
8
10
Yield
(%)a
80
85
93
94
93
94
dr
(anti/syn)b
92:8
93:7
95:5
93:7
93:7
94:6
er
1
2
3
4
5
6
7
8
Benzoic acid
p-NBA
Salicylic acid
Acetic acid
(anti)c
93:7
94:6
95:5
95:5
94:6
94:6
1
2
3
4
5
6
Formic acid
(S)-mandelic acid
(R)-mandelic acid
Oxalic acid
10
85:15
aDetermined after purification by flash chromatography. Determined by H
NMR from the crude reaction product. cDetermined by HPLC with chiral
stationary phase.
b
1
aDetermined after purification by flash chromatography. Determined by H
NMR from the crude reaction product. cDetermined by HPLC with chiral
stationary phase.
b
1
Table 4. Solvent screening in the model asymmetric aldol
reaction.
As indicated in the introduction, one advantage of CITMs is
that they can usually be recycled, especially when used in
water.8,10 The recyclability of (2S,4R,1’S)-12 in an aqueous
medium was assessed, finding that this CITM could be recycled
successfully following extraction from the crude reaction mixture
with ethyl acetate up to a fifth cycle, observing only a slight loss
in stereoselectivity. Nevertheless, the yield diminished
substantially, down to 45% in the fifth cycle. This decrease in
yield could be explained by the loss of a small quantity of CITM
in each extraction, as it has been observed with other CITM’s
systems.15 To overcome this problem, the recycling experiments
were performed using 10 mol% of CITM and additive (Table 7).
It was found that although the yield still decreased with each
cycle, the aldol product obtained in each cycle was higher than
when using only 5 mol% of CITM. Under these conditions, the
asymmetric aldol reaction could be performed up to 6 cycles with
no loss of stereoselectivity. Despite the increased yield on each
cycle when doubling the catalyst concentration, it was seen that
catalyst leaching remained. A plausible solution to this problem
could be the interchange of the metoxycarbonyl group in the
Entry
Solvent
Yield
(%)a
68
89
61
85
92
93
75
dr
(anti/syn)b
84:16
86:14
77:23
84:16
83:17
95:5
er
(anti)c
87:13
86:14
81:19
82:18
78:22
95:5
1
2
3
4
5
6
7
MeOH
Toluene
DMF
THF
BMImPF6
Water
Brine
90:10
94:6
aDetermined after purification by flash chromatography. Determined by H
NMR from the crude reaction product. cDetermined by HPLC with chiral
stationary phase.
b
1
dipeptide motif by
a
bulkier group, such as tert-

5
butyloxycarbonyl, in order to make the catalyst more resistant to
aDetermined after purification by flash chromatography. bDetermined by 1H
ACCEPTED MANUSCRIPT
the aqueous medium, as described previously by Kokotos, et al.16
NMR from the crude reaction product. cDetermined by HPLC with chiral
stationary phase.
3. Conclusions
Four (2S,4R)-Hyp-(S)-Phe-OMe chiral dipeptidic ion tagged
imidazolium molecules were prepared: two with an acetyl linker
and two with a hexanoyl linker. The two CITMs incorporating
the acetyl linker proved to be highly unstable towards moisture
and nucleophilic solvents, and were not tested in the aqueous
asymmetric aldol reaction. By contrast, the two CITMs with the
hexanoyl linker were stable to hydrolysis, and the one with
hexafluorophosphate as counter anion exhibited the best
performance in the presence of p-NBA as acid additive (both at at
5 mol%). With cyclohexanone as the carbonyl substrate, aldol
products were obtained in moderate to excellent yields and with
stereoselectivities varying from good to excellent. Finally,
recyclability of the CITM up to six cycles was demonstrated.
Table 6. Scope of the asymmetric aldol reaction catalyzed by
(2S,4R,1’S)-12.
Entry
R1
R2
R3
Yield
(%)a
drb
erc
4.1. General information
1
2
-(CH2)4-
-(CH2)4-
C6H5
4-CN-C6H4
52
94
94:6
96:4
84:16
93:7
Unless otherwise noted, all reagents were purchased from
Sigma-Aldrich and used without further purification. Reaction
progress was routinely monitored by TLC on silica gel 60
(precoated F254 Merck plates), and compounds were visualized
under a UV lamp (254 nm). Flash chromatography was
performed using silica gel (230−400 mesh). NMR spectra were
acquired on a JEOL ECA 500 and Bruker 400 Avance III HD.
For 1H NMR and 13C NMR, CDCl3 (7.26 and 77.0 ppm,
respectively) or DMSO-d6 (2.50 and 39.5 ppm, respectively)
were used as internal references. Chemical shifts (δ) are reported
in parts per million (ppm). Multiplicity was abbreviated as
follows: s = singlet, bs = broad singlet, d = doublet, dd = doublet
of doublets, t = triplet, q = quartet, quint = quintet, sext = sextet,
hept = septet, m = multiplet. High resolution mass spectra were
recorded on an HPLC 1100 coupled to a MSD-TOF Agilent
series HR-MSTOF model 1969 A. IR spectra were acquired on
an ATR-IR Varian and are expressed in wave number (cm-1).
3
4
5
6
7
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)3-
-(CH2)5-
4-Me-C6H4
3-NO2-C6H4
4-Ph-C6H4
2-Cl-C6H4
4-Br-C6H4
2-CF3-C6H4
1-Naph
41
90
36
75
72
70
16
49
15
82
42
48
12
nr
96:4
94:6
93:7
95:5
95:5
98:2
89:11
85:15
91:9
33:67d
85:15
-
82:18
94:6
92:8
96:4
92:8
97:3
92:8
91:9
92:8
75:25e
57:43
80:20
54:46e
-
8
9
10
11
12
13
14
15
16
17
2-MeO-C6H4
2-Furyl
4-NO2-C6H4
4-NO2-C6H4
4-NO2-C6H4
4-NO2-C6H4
4-NO2-C6H4
4-NO2-C6H4
Me
H
OH
H
Me
Ph
Et
47:53d
-
Me
nr
-
-
aDetermined after purification by flash chromatography. Determined by H
NMR from the crude reaction product. Major product: anti isomer
cDetermined by HPLC with chiral stationary phase. Er for the anti isomer.
dMajor product: syn isomer. eEr for the enantiomer (2S, 1’S).
b
1
4.2. Synthesis of chiral ionic liquids
4.2.1. (2S,4R)-Benzyl 4-hydroxy-2-(((S)-1-methoxy-1-oxo-3-
phenylpropan-2-yl)carbamoyl)pyrrolidine-1-carboxylate
[(2S,4R,1’S)-2].
Table 7. Evaluation of CITM (2S,4R,1’S)-12 recyclability in the
model asymmetric aldol reaction.
In a 250 mL round bottom flask, (2S,4R,1’S)-1 (4.0 g, 15.08
mmol), triethylamine (2.3 mL, 16.58 mmol), and a magnetic
stirring bar were placed. Then, 88 mL of dry THF were added
and the flask was submerged in an ice bath and purged with
nitrogen. After that, ethyl chloroformate (1.5 mL, 15.84 mmol)
was added dropwise via syringe for 10 minutes. Subsequently,
the mixture was left to react for 20 minutes at 0 °C, and then a
solution of (S)-phenylalanine methyl ester (3.25 g, 15.08 mmol),
triethylamine (2.3 mL, 16.58 mmol), and DMF (8 mL) in 60 mL
of dry dichloromethane was added dropwise to the chilled flask
through a syringe for 10 minutes. Then, the reaction was allowed
to react for 2 hours at 0 °C and then at room temperature for 18
hours. The reaction was filtered under vacuum and the isolated
solid was washed with 80 mL of THF. The filtrate was
concentrated, 40 mL of water were added and then extracted with
EtOAc (3x60 mL). Then, the organic phase was washed with 1N
HCl (1x40 mL), with a saturated solution of NaHCO3 (1x40 mL)
and with brine (1x40 mL). Finally, the organic phase was dried
with anhydrous Na2SO4, concentrated, and recrystallized from
hexane/EtOAc to afford pure dipeptide (2S,4R,1’S)-2. Yield: 5.65
(S, R, S)ꢀ12
10 mol%
CHO
NO2
O
O
OH
+
pꢀNBA 10 mol%
H2O (100 equiv)
24 h
NO2
(2S, 1'S)ꢀ13a
4 equiv 1 equiv
Cycle
Yield
(%)a
93
dr
(anti/syn)b
95:5
er
(anti)c
1
2
3
4
5
6
93:7
94:6
93:7
92:8
93:7
94:6
89
95:5
88
95:5
81
93:7
77
94:6
72
94:6

6
Tetrahedron
1
g (88%), white solid; mp = 114 – 116 °C; H NMR (500.16
with vigorous stirring for 24 h at ambient temperature. The crude
product (yellow viscous precipitate) was decanted and washed
with additional EtOAc (3x0.5 mL) to remove the excess of 1-
methylimidazole. The product was dissolved in MeOH (1 mL)
and then precipitated with Et2O (10 mL). The heterogeneous
mixture was left standing for 90 minutes to ensure complete
precipitation of the product. The upper layer was removed and
the pure product was dried under vacuum until constant weight to
obtain pure (2S, 4R,1’S)-4. Yield: 0.55 g (96%) as a light yellow
ACCEPTED MANUSCRIPT
MHz, DMSO-d6, 120 °C): δ 7.83 (bs, 1H, NH), 7.35-7.05 (m,
10H, Ph), 5.10-4.88 (dd, 2H, J = 12.7 Hz, J = 21.6 Hz, PhCH2O),
4.65 (bs, 1H, OH), 4.56-4.45 (q, 1H, J = 7.06 Hz, NCHCO),
4.39-4.27 (t, 1H, J = 7.42 Hz, NHCHCO), 4.21 (bs, 1H, CHOH),
3.55 (s, 3H, OCH3), 3.48-3.42 (dd, 1H, J = 4.94 Hz, J = 11.0 Hz,
NCHHCH), 3.38-3.31 (dd, 1H, J = 4.94 Hz, J = 11.0 Hz,
NCHHCH), 3.04-2.97 (dd, 2H, J = 6.36 Hz, J = 14.1 Hz,
PhCH2CH), 2.08-1.97 (m, 1H, CHCHHCH), 1.91-1.77 (m, 1H,
CHCHHCH) ppm; 13C NMR (125.76 MHz, DMSO-d6, 120 °C):
δ 172.4, 172.1, 155.0, 137.7, 137.6, 129.5, 128.7, 128.6, 128.1,
127.7, 126.9, 68.8, 66.6, 59.4, 55.6, 54.0, 52.1, 37.5, 30.5 ppm;
IR (neat): νmax 3424, 3275, 2974, 1751, 1686, 1660, 1538, 1437,
1361, 1211, 1172, 1112, 1077 cm-1; Elemental analysis
calculated for C23H26N2O6: C, 64.78; H, 6.15; N, 6.57, found: C,
65.14; H, 6.12; N, 6.50; HRMS (MS-TOF): calcd for C23H27N2O6
1
hygroscopic solid; mp = 97 – 98 °C; H NMR (399.78 MHz,
DMSO-d6, 120 °C): δ 9.10 (s, 1H, +NCHN), 8.05 (d, 1H, J = 7.22
+
Hz, NH), 7.66 (d, 2H, J = 10.4 Hz, NCHCHN), 7.35-7.10 (m,
10H, Ph), 5.30 (bs, 1H, CHOH), 5.21 (s, 2H, NCH2CO), 5.10-
4.98 (dd, 2H, J = 12.9 Hz, J = 30.7 Hz, PhCH2O), 4.57-4.50 (q,
1H, J = 7.67 Hz, NCHCO), 4.48-4.39 (t, 1H, J = 7.22 Hz,
NHCHCO), 3.91 (bs, 3H, CH3N), 3.75-3.68 (dd, 1H, J = 5.19 Hz,
J = 12.4 Hz, NCHHCH), 3.65-3.58 (m, 1H, NCHHCH), 3.57 (s,
3H, OCH3), 3.17-3.11 (m, 1H, PhCHHCH), 2.99-2.96 (m, 1H,
PhCHHCH), 2.42-2.28 (m, 1H, CHCHHCH), 2.19-2.07 (m, 1H,
CHCHHCH) ppm; 13C NMR (100.52 MHz, DMSO-d6, 120 °C):
δ 172.0, 171.8, 166.5, 154.7, 138.5, 137.6, 137.3, 129.5, 128.8,
128.7, 128.3, 127.8, 127.0, 124.3, 124.0, 74.8, 67.0, 58.9, 54.1,
52.6, 52.2, 50.4, 37.5, 36.6, 36.2 ppm; IR (neat): νmax 3463,
3152, 3033, 2954, 1745, 1698, 1561, 1539, 1497, 1418, 1353,
1201, 1172, 1123, 1061 cm-1; HRMS (MS-TOF): calcd for
(M+H)+ 427.1864, found 427.1865. [α]D = −28.7°, c = 1.00,
CHCl3.
25
4.2.2. (2S,4R)-Benzyl 4-(2-bromoacetoxy)-2-(((S)-1-methoxy-
1-oxo-3-phenylpropan-2-yl)carbamoyl)pyrrolidine-1-
carboxylate [(2S,4R,1’S)-3].
To a 50 mL round bottom flask equipped with an addition
funnel, was added (2S,4R,1’S)-2 (0.5 g, 1.17 mmol),
triethylamine (0.2 mL, 1.41 mmol), dichloromethane (10 mL),
and a magnetic stirring bar. The reaction flask was fitted with an
addition funnel containing a solution of bromoacetyl bromide
(0.11 mL, 1.29 mmol) in dichloromethane (10 mL). The flask
was placed in an ice bath, and when the temperature reached 0 °C
the acylation solution was added dropwise for 15 minutes. After
that, the reaction was allowed to react for 6 hours at room
temperature. Subsequently, water (10 mL) and saturated solution
of NH4Cl (5 mL) were added and the resulting immiscible phases
were separated. The aqueous phase was extracted with
dichloromethane (20 mL) and the organic layers were mixed and
washed with HCl 1N (1x20 mL) and saturated solution of
potassium sodium tartrate tetrahydrate (1x20 mL). Finally, the
organic phase was dried with anhydrous Na2SO4, concentrated,
and purified by flash chromatography, using hexane/EtOAc (7:3
to 1:1) as the mobile phase to afford pure (2S,4R,1’S)-3. Yield:
C29H33N4O7 (M)+ 549.2344, found 549.2335. [α]D = −13.39°, c
= 1.12, MeOH.
25
4.2.4. (2S,4R)-Benzyl 4-((6-bromohexanoyl)oxy)-2-(((S)-1-
methoxy-1-oxo-3-phenylpropan-2-yl)carbamoyl)pyrrolidine-
1-carboxylate ((2S,4R,1’S)-5).
To a 10 mL round bottom flask with a magnetic stirring bar, a
solution of 6-bromohexanoic acid (0.192 g, 0.985 mmol), DMF
(2 drops) and dry dichloromethane (2 mL) was added. The
reaction flask was purged with nitrogen and placed in an ice bath.
Afterwards, oxalyl chloride (0.1 mL, 1.182 mmol) was added
dropwise via a syringe. After that, the ice bath was removed and
the reaction was allowed to react for 3 hours at room
temperature. After this time, the reaction was concentrated to
remove the excess of oxalyl chloride, and then a solution of the
crude acyl chloride was prepared by dissolving it in dry
dichloromethane (6 mL), which was placed in an addition funnel.
On the other hand, to a 25 mL round bottom flask with a
magnetic stirring bar, a solution of the dipeptide (2S,4R,1’S)-2
(0.4 g, 0.938 mmol) and triethylamine (0.16 mL, 1.126 mmol) in
dry dichloromethane (10 mL) was added. Subsequently, the
reaction flask was placed in an ice bath and fitted with the
addition funnel containing the acyl chloride solution. Once
chilled, the acyl chloride solution was added dropwise for 20
minutes, and then the reaction was allowed to react for 18 hours
at room temperature. After this time, water (10 mL) and saturated
solution of NH4Cl (5 mL) were added and the resulting
immiscible phases were separated. The aqueous phase was
extracted with dichloromethane (20 mL) and the organic layers
were mixed and washed with 1N HCl (1x20 mL) and a saturated
solution of potassium sodium tartrate tetrahydrate (1x20 mL).
Finally, the organic phase was dried with anhydrous Na2SO4,
concentrated, and purified by flash chromatography, using
hexane/EtOAc (7:3 to 1:1) as the mobile phase to afford pure
(2S,4R,1’S)-5. Yield: 0.424 g (75%) as a light yellow viscous
1
0.515 g (80%) as a light yellow viscous liquid; H NMR (500.16
MHz, DMSO-d6, 120 °C): δ 7.99 (bs, 1H, NH), 7.32-7.11 (m,
10H, Ph), 5.18 (bs, 1H, CHOH), 5.04-4.80 (dd, 2H, J = 12.4 Hz,
J = 14.1 Hz, PhCH2O), 4.53-4.49 (q, 1H, J = 7.06 Hz, NCHCO),
4.39-4.36 (t, 1H, J = 7.42 Hz, NHCHCO), 3.95 (bs, 1H,
BrCHHCO), 3.68-3.62 (dd, 1H, J = 4.94 Hz, J = 12.0 Hz,
NCHHCH), 3.57-3.50 (m, 1H, NCHHCH), 3.55 (s, 3H, OCH3),
3.28 (bs, 1H, BrCHHCO), 3.02-2.87 (ddd, 2H, J = 6.00 Hz, J =
14.4 Hz,
J = 34.0 Hz, PhCH2CH), 2.28-2.18 (m, 1H,
CHCHHCH), 2.10-2.02 (m, 1H, CHCHHCH) ppm; 13C NMR
(125.76 MHz, DMSO-d6, 120 °C): δ 172.5, 172.0, 171.8, 154.7,
137.6, 137.3, 129.5, 128.7, 128.6, 128.1, 127.7, 127.0, 72.8, 66.8,
60.5, 58.9, 54.0, 52.8, 52.1, 37.4, 36.4 ppm; IR (neat): νmax 3320,
3029, 2954, 1738, 1703, 1530, 1497, 1416, 1353, 1274, 1208,
1170, 1113, 1061 cm-1; HRMS (MS-TOF): calcd for
C25H28N2O7Br (M+H)+ 547.1074, found 547.1079. [α]D
=
25
−9.50°, c = 1.20, CHCl3.
4.2.3.
1-(2-(((2R,4S)-1-((Benzyloxy)carbonyl)-5-(((S)-1-
methoxy-1-oxo-3-phenylpropan-2-yl)carbamoyl)pyrrolidin-3-
yl)oxy)-2-oxoethyl)-3-methyl-1H-imidazol-3-ium
[(2S,4R,1’S)-4].
bromide
1
liquid; H NMR (399.78 MHz, DMSO-d6, 120 °C): δ 7.95 (bs,
1H, NH), 7.32-7.12 (m, 10H, Ph), 5.13 (bs, 1H, CHOH), 5.05-
4.96 (dd, 2H, J = 12.6 Hz, J = 22.2 Hz, PhCH2O), 4.55-4.49 (q,
1H, J = 7.67 Hz, NCHCO), 4.40-4.36 (t, 1H, J = 7.22 Hz,
NHCHCO), 3.65-3.60 (dd, 1H, J = 4.97 Hz, J = 12.1 Hz,
NCHHCH), 3.56 (s, 3H, OCH3), 3.55-3.49 (m, 1H, NCHHCH),
To a 25 mL round bottom flask provided with a magnetic stirring
bar, a solution of bromoamide (2S,4R,1’S)-3 (0.5 g, 0.91 mmol)
in EtOAc (2 mL) was added. 1-Methylimidazole (0.11 mL, 1.37
mmol) was then added and the reaction mixture was left to react

7
3.46-3.37 (dt, 2H, J = 6.55 Hz, J = 18.1 Hz, CH2CH2Br), 3.04-
4.2.6.1.
1-(2-(((3R,5S)-1-((Benzyloxy)carbonyl)-5-(((S)-1-
ACCEPTED MANUSCRIPT
2.88 (ddd, 2H, J = 6.10 Hz, J = 14.0 Hz, J = 34.4 Hz, PhCH2CH),
2.38-2.18 (m, 3H, CH2CH2CO and CHCHHCH), 2.10- 2.01 (m,
1H, CHCHHCH), 1.83-1.74 (m, 1H, CHHCH2Br), 1.58-1.48 (m,
2H, CHHCH2Br and CHHCH2CO), 1.45-1.36 (m, 2H,
CHHCH2CO and CH2CHHCH2), 1.36-1.26 (m, 1H,
CH2CHHCH2) ppm; 13C NMR (100.52 MHz, DMSO-d6, 120 °C):
δ 173.1, 172.0, 171.9, 154.9, 137.5, 137.3, 129.4, 128.8, 128.7,
128.2, 127.7, 127.0, 72.5, 66.9, 61.3, 58.9, 54.0, 52.8, 52.2, 37.5,
36.4, 34.2, 32.4, 25.5, 24.8 ppm; IR (neat): νmax 3322, 2946,
1735, 1705, 1529, 1415, 1353, 1252, 1206, 1171, 1120, 1064 cm-
1; HRMS (MS-TOF): calcd for C29H36N2O7Br (M+H)+ 603.1700,
found 603.1696. [α]D25 = −5.83°, c = 1.20, CHCl3.
methoxy-1-oxo-3-phenylpropan-2-yl)carbamoyl)pyrrolidin-3-
yl)oxy)-2-oxoethyl)-3-methyl-1H-imidazol-3-ium
hexafluorophosphate [(2S,4R,1’S)-8].
The general procedure was followed to afford (2S,4R,1’S)-8
as a white waxy solid; yield: 87 mg (63%); mp = 67 - 69 °C; 1H
NMR (399.78 MHz, DMSO-d6, 120 °C): δ 9.00 (bs, 1H,
+NCHN), 7.96 (d, 1H, J = 7.00 Hz, NH), 7.63 (bs, 2H,
+NCHCHN), 7.38-7.103 (m, 10H, Ph), 5.30 (bs, 1H, CHOH),
5.17 (bs, 2H, NCH2CO), 5.11-4.97 (dd, 2H, J = 12.6 Hz, J = 30.6
Hz, PhCH2O), 4.60-4.51 (q, 1H, J = 7.67 Hz, NCHCO), 4.45-
4.38 (t, 1H, J = 7.00 Hz, NHCHCO), 3.90 (bs, 3H, CH3N), 3.76-
3.69 (dd, 1H, J = 5.19 Hz, J = 12.1 Hz, NCHHCH), 3.65-3.60
(m, 1H, NCHHCH), 3.58 (bs, 3H, OCH3), 3.14-3.06 (m, 2H,
PhCH2CH), 2.38-2.27 (m, 1H, CHCHHCH), 2.20-2.09 (m, 1H,
CHCHHCH) ppm; 13C NMR (100.52 MHz, DMSO-d6, 120 °C):
δ 172.0, 171.7, 166.5, 154.7, 138.4, 137.6, 137.3, 129.5, 128.8,
128.7, 128.3, 127.9, 127.0, 124.2, 124.0, 74.8, 67.0, 58.9, 54.0,
52.5, 52.2, 50.3, 37.5, 36.6, 36.2 ppm; 31P NMR (161.83 MHz,
DMSO-d6): δ -142.73 ppm (hept, JP-F = 709.6 Hz); IR (neat): νmax
2956, 2925, 1748, 1699, 1688, 1525, 1418, 1354, 1202, 1175,
1123, 1175 cm-1; HRMS (MS-TOF): calcd for C29H33N4O7 (M)+
549.2344, found 549.2344, calcd PF6 (M)- 144.9647, found
144.9645. [α]D25 = −13.5°, c = 1.10, MeOH.
4.2.5.
1-(6-(((2R,4S)-1-((Benzyloxy)carbonyl)-5-(((S)-1-
methoxy-1-oxo-3-phenylpropan-2-yl)carbamoyl)pyrrolidin-3-
yl)oxy)-6-oxohexyl)-3-methyl-1H-imidazol-3-ium
[(2S,4R,1’S)-6].
bromide
To a 10 mL round bottom flask equipped with a magnetic stirring
bar and a condenser, a solution of bromoamide (2S,4R,1’S)-5
(0.567 g, 0.94 mmol) in EtOAc (2 mL) was added. Then, 1-
methylimidazole (0.11 mL, 1.41 mmol) was added and the
reaction mixture was heated to 70 °C and allowed to react for 48
h. After this time, the reaction mixture was left standing until it
reached ambient temperature. The crude product (yellow viscous
precipitate) was decanted and washed with additional EtOAc
(3x0.5 mL) to remove the excess of 1-methylimidazole. The
product was dissolved in MeOH (1 mL) and then precipitated
with Et2O (10 mL). The heterogeneous mixture was left standing
for 90 minutes to ensure complete precipitation of the product.
The upper layer was removed and the pure product was dried
under vacuum until constant weight to obtain pure (2S,4R,1’S)-6.
Yield: 0.585 g (91%), white highly hygroscopic solid, mp = 48 -
50 °C; 1H NMR (399.78 MHz, DMSO-d6, 120 °C): δ 9.06 (s, 1H,
+NCHN), 8.00 (d, 1H, J = 6.77 Hz, NH), 7.65 (bs, 1H,
4.2.6.2.
1-(6-(((2R,4S)-1-((Benzyloxy)carbonyl)-5-(((S)-1-
methoxy-1-oxo-3-phenylpropan-2-yl)carbamoyl)pyrrolidin-3-
yl)oxy)-6-oxohexyl)-3-methyl-1H-imidazol-3-ium
hexafluorophosphate [(2S,4R,1’S)-11].
The general procedure was followed to afford (2S,4R,1’S)-11
as a white solid; yield: 129 mg (86%); mp = 53 - 56 °C; 1H NMR
(399.78 MHz, DMSO-d6, 120 °C): δ 8.95 (bs, 1H, +NCHN), 7.96
(d, 1H, J = 6.77 Hz, NH), 7.62 (bs, 1H, +NCHCHN), 7.58(bs, 1H,
+NCHCHN), 7.35-7.13 (m, 10H, Ph), 5.15 (bs, 1H, CHOH),
5.10-4.97 (dd, 2H, J = 12.9 Hz, J = 24.8 Hz, PhCH2O), 4.59-4.51
(q, 1H, J = 7.67 Hz, NCHCO), 4.43-4.35 (t, 1H, J = 7.45 Hz,
NHCHCO), 4.17-4.10 (t, 2H, J = 7.22 Hz, CH2CH2N+), 3.85 (bs,
3H, CH3N), 3.70-3.62 (dd, 1H, J = 4.74 Hz, J = 12.0 Hz,
NCHHCH), 3.58 (bs, 3H, OCH3), 3.55-3.48 (m, 1H, NCHHCH),
2.99-2.91 (m, 2H, PhCH2CH), 2.31-2.24 (t, 2H, J = 7.22 Hz,
CH2CH2CO), 2.24-2.18 (dd, 1H, J = 3.84 Hz, J = 8.58 Hz,
CHCHHCH), 2.13- 2.03 (m, 1H, CHCHHCH), 1.85-1.76 (quint,
2H, J = 7.45 Hz, CH2CH2N), 1.61-1.52 (quint, 2H, J = 7.45 Hz,
CH2CH2CO), 1.35-1.24 (m, 2H, CH2CH2CH2) ppm; 13C NMR
(100.52 MHz, DMSO-d6, 120 °C): δ 172.8, 172.0, 171.8, 154.9,
137.6, 137.4, 137.1, 129.5, 128.8, 128.7, 128.2, 127.8, 127.0,
124.2, 122.9, 72.6, 66.9, 59.0, 54.0, 52.8, 52.1, 49.5, 37.5, 36.3,
36.2, 33.9, 29.4, 25.5, 24.1 ppm; 31P NMR (161.83 MHz,
DMSO-d6): δ -142.75 ppm (hept, JP-F = 709.6 Hz); IR (neat): νmax
2949, 1732, 1698, 1568, 1529, 1498, 1417, 1355, 1207, 1169,
1125 cm-1; Elemental analysis calculated for C33H41F6N4O7P: C,
52.80; H, 5.51; N, 7.46, found: C, 52.62; H, 5.60; N, 7.73;
+
+NCHCHN), 7.61(bs, 1H, NCHCHN), 7.42-7.03 (m, 10H, Ph),
5.15 (bs, 1H, CHOH), 5.09-4.95 (dd, 2H, J = 12.6 Hz, J = 24.1
Hz, PhCH2O), 4.59-4.49 (q, 1H, J = 7.67 Hz, NCHCO), 4.40-
4.36 (t, 1H, J = 7.45 Hz, NHCHCO), 4.22-4.11 (m, 2H,
CH2CH2N+), 3.86 (bs, 3H, CH3N), 3.69-3.62 (dd, 1H, J = 4.97
Hz, J = 12.1 Hz, NCHHCH), 3.57 (bs, 3H, OCH3), 3.55-3.48 (m,
1H, NCHHCH), 3.01-2.91 (m, 2H, PhCH2CH), 2.35-2.17 (m, 3H,
CH2CH2CO and CHCHHCH), 2.14- 2.02 (m, 1H, CHCHHCH),
1.89-1.76 (m, 2H, CH2CH2N), 1.63-1.51 (m, 2H, CH2CH2CO),
1.39-1.24 (m, 2H, CH2CH2CH2) ppm; 13C NMR (100.52 MHz,
DMSO-d6, 120 °C): δ 172.9, 172.0, 171.9, 154.8, 137.6, 137.4,
137.1, 129.5, 128.8, 128.7, 128.2, 127.7, 127.0, 124.2, 122.9,
72.6, 66.9, 59.0, 54.1, 52.8, 52.2, 49.5, 37.5, 36.5, 36.4, 33.9,
29.4, 25.5, 24.2 ppm; IR (neat): νmax 3464, 3149, 3032, 1731,
1702, 1681, 1562, 1543, 1417, 1354, 1206, 1167, 1125, 1064 cm-
1; HRMS (MS-TOF): calcd for C33H41N4O7 (M)+ 605.2970, found
605.2968. [α]D25 = −21.3°, c = 1.20, MeCN.
4.2.6. General metathesis procedure: preparation of
compounds (2S,4R,1’S)-8 and (2S,4R,1’S)-11.
HRMS (MS-TOF): calcd for C33H41N4O7 (M)+ 605.2970, found
605.2969, calcd PF6 (M)- 144.9647, found 144.9643. [α]D
=
25
−20.5°, c = 1.03, MeCN.
In a 10 mL round bottom flask equipped with a magnetic
stirring bar, the imidazolium salt [(2S,4R,1’S)-4 or (2S,4R,1’S)-6]
(0.2 mmol) was placed and dissolved in water (2 mL). The
resulting solution was treated with KPF6 (40.5 mg, 0.22 mmol)
was added (the resulting reaction mixture turned cloudy). The
reaction mixture was vigorously stirred for 12 hours.
Subsequently, the upper layer was decanted and the precipitated
product was washed with water (2x1 mL). Finally, the product
was dried under vacuum until constant weight. No further
purification was required.
4.2.7. General method for the hydrogenolysis reaction:
preparation of compounds (2S,4R,1’S)-7, (2S,4R,1’S)-10 and
(2S,4R,1’S)-12.
In a 25 mL round bottom flask equipped with a magnetic
stirring bar, the imidazolium compound [(2S,4R,1’S)-4, or
(2S,4R,1’S)-6, or (2S,4R,1’S)-11) (0.5 mmol) was dissolved in
MeOH (5 mL) before the addition of 20 wt% of Pd/C. The
reaction flask was sealed with a septum cap, purged with H2, and
allowed to react for 24 hours at ambient temperature with

8
Tetrahedron
ACCEPTED MANUSCRIPT
vigorous stirring and under H2 atmosphere. The heterogeneous
(m, 2H, PhCHHCH and NCHHCH), 2.70-2.59 (dd, 1H, J = 3.39
mixture was filtered through Celite to remove the Pd/C catalyst,
and the solvent was removed under vacuum until constant weight
of the product.
Hz, J = 13.0 Hz, NCHHCH), 2.36-2.17 (m, 4H, NH, CH2CH2CO
and CHCHHCH), 1.94-1.80 (quint, 2H, J = 7.22 Hz, CH2CH2N),
1.80-1.70 (m, 1H, CHCHHCH), 1.65-1.55 (quint, 2H, J = 7.67
Hz, CH2CH2CO), 1.38-1.25 (m, 2H, CH2CH2CH2) ppm; 13C
NMR (100.52 MHz, CDCl3): δ 174.0, 173.1, 172.1, 136.2, 136.1,
129.3, 128.6, 127.2, 123.7, 122.2, 76.3, 59.7, 52.8, 52.6, 52.5,
49.8, 38.1, 36.1, 36.2, 33.8, 29.5, 25.4, 23.9 ppm; 31P NMR
(161.83 MHz, CDCl3): δ -143.22 ppm (hept, JP-F = 712.1 Hz); IR
(neat): νmax 3350, 3164, 2954, 1729, 1660, 1572, 1514, 1440,
1362, 1200, 1169 cm-1; HRMS (MS-TOF): calcd for C25H35N4O5
(M)+ 471.2602, found 471.2603, calcd PF6 (M)- 144.9647, found
144.9648. [α]D25 = +6.83°, c = 0.97, MeCN.
4.2.7.1.
1-(2-(((2R,4S)-5-(((S)-1-Methoxy-1-oxo-3-
phenylpropan-2-yl)carbamoyl)pyrrolidin-3-yl)oxy)-2-
oxoethyl)-3-methyl-1H-imidazol-3-ium bromide ((2S,4R,1’S)-
7).
The general procedure was followed to afford (2S,4R,1’S)-7
1
as a slightly yellow viscous liquid; yield: 0.243 g (98%); H
NMR (399.78 MHz, CDCl3): δ 9.92 (bs, 1H, NCHN), 8.13 (d,
1H, J = 8.58 Hz, NHCO), 7.62 (bs, 1H, NCHCHN), 7.44 (bs,
1H, NCHCHN), 7.26-7.19 (m, 3H, Ph), 7.12-7.06 (m, 2H, Ph),
+
+
+
4.3. General procedure for recyclable asymmetric aldol
5.47 (bs, 2H, NCH2CO), 4.84-4.75 (m, 1H, NCHCO), 4.25 (bs,
1H, CHOH), 4.03 (bs, 3H, CH3N), 3.93-3.86 (t, 1H, J = 8.35 Hz,
NHCHCO), 3.72 (bs, 3H, OCH3), 3.20-3.12 (dd, 1H, J = 5.64 Hz,
J = 13.8 Hz, PhCHHCH), 3.04-2.91 (m, 2H, PhCHHCH and
NCHHCH), 2.73-2.54 (bs, 1H, NH), 2.54-2.45 (dd, 1H, J = 3.16
Hz, J = 12.5 Hz, NCHHCH), 2.20-2.10 (dd, 1H, J = 8.80 Hz, J =
13.8 Hz, CHCHHCH), 1.66-1.55 (m, 1H, CHCHHCH) ppm; 13C
NMR (100.52 MHz, CDCl3): δ 174.9, 172.2, 166.8, 138.4, 136.2,
129.3, 128.6, 127.1, 124.0, 123.1, 73.2, 59.6, 55.4, 53.6, 52.5,
50.3, 39.9, 38.2, 36.9 ppm; HRMS (MS-TOF): calcd for
C21H27N4O5 (M)+ 415.1976, found 415.1976. [α]D25 = -26.8°, c =
1.03, MeOH.
reactions.
To a small vial, CIL (0.025 mmol), p-NBA (4.2 mg, 0.025
mmol), aldehyde (0.5 mmol), ketone (2.0 mmol) and water (0.9
mL) was added. The reaction mixture was stirred at room
temperature for 24 hours. Subsequently, the reaction was
extracted with ethyl acetate (3x1 mL) and the aqueous phase was
subjected to the next reaction cycle, by means of the addition of
additive and substrates. The crude organic phase was subjected to
flash chromatography using silica gel as the stationary phase and
hexane/EtOAc (9:1 to 1:1) as the mobile phase to afford the pure
aldol products.
4.2.7.2.
1-(6-(((2R,4S)-5-(((S)-1-Methoxy-1-oxo-3-
Acknowledgements
phenylpropan-2-yl)carbamoyl)pyrrolidin-3-yl)oxy)-6-
oxohexyl)-3-methyl-1H-imidazol-3-ium bromide [(2S,4R,1’S)-
10).
We are indebted to CONACYT for financial support via grant
220945. A. Obregón-Zúñiga thanks CONACYT for scholarship
283367. We also thank Teresa Cortez-Picasso for her assistance
in the acquisition of NMR spectra.
The general procedure was followed to afford (2S,4R,1’S)-10
1
as a white hygroscopic waxy solid; yield: 0.273 g (99%); H
References
+
NMR (399.78 MHz, CDCl3): δ 10.36 (bs, 1H, NCHN), 8.02 (d,
+
1H, J = 8.35 Hz, NHCO), 7.46-7.39 (m, 2H, NCHCHN), 7.26-
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7.20 (m, 3H, Ph), 7.12-7.05 (m, 2H, Ph), 5.11-5.05 (t, 1H, J =
3.84 Hz, CONHCHCO), 4.84-4.75 (m, 1H, CHOH), 4.39-4.31
(ddd, 2H, J = 1.81 Hz, J = 7.00 Hz, J = 6.66 Hz, CH2CH2N+),
4.06 (bs, 3H, CH3N), 3.90-3.83 (t, 1H, J = 8.35 Hz, NHCHCO),
3.72 (bs, 3H, OCH3), 3.24-3.15 (dd, 1H, J = 5.64 Hz, J = 13.8
Hz, PhCHHCH), 3.06-2.95 (m, 2H, PhCHHCH and NCHHCH),
2.65-2.56 (dd, 1H, J = 3.61 Hz, J = 13.1 Hz, NCHHCH), 2.35-
2.25 (bs, 1H, NH), 2.31-2.25 (t, 2H, J = 7.22 Hz, CH2CH2CO),
2.24-2.15 (dd, 1H, J = 8.35 Hz, J = 14.5 Hz, CHCHHCH), 1.99-
1.88 (quint, 2H, J = 7.22 Hz, CH2CH2N), 1.80-1.70 (m, 1H,
CHCHHCH), 1.69-1.58 (quint, 2H, J = 7.45 Hz, CH2CH2CO),
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ACCEPTED MANUSCRIPT
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