Proline dipeptides containing fluorine moieties as oganocatalysts for the asymmetric aldol reaction

Article abstract of DOI:10.1016/j.tet.2018.08.038

A series of dipeptide analogues consisting of proline, phenylalanine and aniline- or phenol-fluorine derivatives were synthesized. Their catalytic ability was evaluated in the intermolecular asymmetric aldol reaction, both in organic and aqueous media. Aniline-fluorine derivatives proved to be superior and the best results were obtained, when 2-CF₃ aniline was employed. A diverse substrate scope consisting of both aromatic and aliphatic aldehydes, as well as different ketones was demonstrated, where aromatic aldehydes afforded products in high yields (up to 100%) with excellent diastereo- (up to 95:5) and enantioselectivities (up to 97%), whereas the aliphatic aldehydes afforded also excellent selectivities, but relatively low yield. A simple addition of fluorine to a dipeptide analogue affords organocatalysts with new interesting properties that can catalyze the aldol reaction more efficiently.

Full text of DOI:10.1016/j.tet.2018.08.038

Tetrahedron xxx (2018) 1e9
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Tetrahedron
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Proline dipeptides containing fluorine moieties as oganocatalysts for
the asymmetric aldol reaction
Ardiol Ahmetlli, Nikoleta Spiliopoulou, Angeliki Magi-Oikonomopoulou,
Dimitrios-Triantaffylos Gerokonstantis, Panagiota Moutevelis-Minakakis**,
Christoforos G. Kokotos*
Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis 15771, Athens, Greece
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of dipeptide analogues consisting of proline, phenylalanine and aniline- or phenol-fluorine
derivatives were synthesized. Their catalytic ability was evaluated in the intermolecular asymmetric
aldol reaction, both in organic and aqueous media. Aniline-fluorine derivatives proved to be superior and
the best results were obtained, when 2-CF3 aniline was employed. A diverse substrate scope consisting of
both aromatic and aliphatic aldehydes, as well as different ketones was demonstrated, where aromatic
aldehydes afforded products in high yields (up to 100%) with excellent diastereo- (up to 95:5) and
enantioselectivities (up to 97%), whereas the aliphatic aldehydes afforded also excellent selectivities, but
relatively low yield. A simple addition of fluorine to a dipeptide analogue affords organocatalysts with
new interesting properties that can catalyze the aldol reaction more efficiently.
Received 15 July 2018
Received in revised form
21 August 2018
Accepted 23 August 2018
Available online xxx
Keywords:
Aldol reaction
Organocatalysis
Prolinamides
Dipeptides
© 2018 Elsevier Ltd. All rights reserved.
Fluorine
1. Introduction
widely accepted that prolinamides that contain functionalities able
to act as hydrogen bond donors are among the most effective cat-
Since the beginning of the millennium, small organic molecules
have been utilized as organocatalysts to promote asymmetric
organic transformations; this new and exciting field of Catalysis is
referred as Organocatalysis [1,2]. List, Barbas and Lerner were
among the first to reintroduce Organocatalysis, by employing
proline as the catalyst in the intermolecular aldol reaction between
acetone and 4-nitrobenzaldehyde (Scheme 1, A) [3], while Mac-
Millan and his coworkers employed imidazolidinones as catalysts
for cycloadditions and in Diels-Alder reaction more precisely
(Scheme 1, B) [4]. Organocatalysis went blooming and is now
considered to be among the traditional tools of Asymmetric Syn-
thesis. One of the most common reactions used in modern Asym-
alysts employed in the aldol reaction. Different types of organo-
catalysts have been developed through time, with each and every
one of them contributing something different in order to fully
understand all the parameters that affect the efficiency of the
asymmetric aldol reaction. Representative examples are shown in
Fig. 1 (compounds 1e9) [7]. The driving force behind the catalytic
potency of these prolinamides is the secondary amine of the five-
membered pyrrolidine ring, which can activate carbonyl com-
pounds via enamine formation, as well as the functional groups
that allow the formation of hydrogen bonds and enhance the se-
lectivities observed. Among the first examples of prolinamides able
to participate in multiple hydrogen bonding networks were com-
pounds 1 and 2, which required cryogenic conditions to induce
high levels of selectivities. Catalyst 4 was an improved version of
catalyst 3, while that study also highlighted the importance of the
chiral centers in the diamine moiety for the adopted conformation
of the catalyst in the assumed transition state. Peptides have been
explored for many years as organocatalysts [8], but the selectivities
that were obtained are anything but satisfactory in most cases
[9,10]. In addition, the low solubility that peptides display in
organic media is a limiting factor, while when aqueous solvents are
metric Catalysis, in order to form
a CeC bond, is the
enantioselective aldol reaction (Scheme 1, C) [5]. Since Organo-
catalysis' first days, proline and proline derivatives containing
different bioisosteric groups have undoubtedly been the most
efficient catalysts in organocatalytic transformations [6]. It is
* Corresponding author.
** Corresponding author.
E-mail address: ckokotos@chem.uoa.gr (C.G. Kokotos).
https://doi.org/10.1016/j.tet.2018.08.038
0040-4020/© 2018 Elsevier Ltd. All rights reserved.
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A. Ahmetlli et al. / Tetrahedron xxx (2018) 1e9
Scheme 1. Rebirth of Organocatalysis.
used, the selectivity drops significantly. Lately, more attention was
drawn towards reactions that are conducted in aqueous media,
which are considered to be in agreement with the principles of
Green Chemistry, as water is a safe, environmentally friendly and
abundant medium to carry out reactions. A milestone, for the use of
proline [7e,11] and many other aminoacids derivatives [12] in
aqueous media as catalysts for the aldol reaction, has been the work
from the groups of Hayashi and Barbas [13].
Recently, we have demonstrated that proline dipeptides with
tert-butyl esters of amino acids can be used as organocatalysts in
the aldol reaction [14]. A series of simple dipeptide and tripeptide
catalysts was introduced, where catalysts 6 and 7 proved to be the
most efficient ones, while providing a green alternative, since the
reaction could be performed in aqueous media. Very recently, we
have developed prolinamide derivatives bearing 2-pyrrolidinone,
like 8 and 9, which can also catalyze the aldol reaction. Carbon
materials in combination with amines have also been used to
promote aldol reactions. Taking into account all our previous en-
deavors in Organocatalysis [15], and in an effort to provide a cata-
lyst that is not only easy and cheap to synthesize, but also may
exhibit more interactions with the carbonyl compounds, we
questioned whether simple Pro-Phe dipeptides containing fluorine
moieties could be employed as organocatalysts in the aldol
reaction.
Fig. 1. Known prolinamide organocatalysts.
2. Results and discussion
(S)-Benzyloxycarbonyl-protected proline (10) was coupled with
(S)-methyl phenylalaninate using N-(3-Dimethyl-aminopropyl)-N0-
ethylcarbodiimide hydro-chloride (WSCI) as the condensing agent,
in the presence of 1-hydroxybenzotriazole (HOBt) (Scheme 2).
Saponification, under Schotten-Baumann conditions, afforded
dipeptide 11. To the resulting dipeptide, under conventional pep-
tide coupling conditions, aniline or 2-fluoro-aniline were added,
leading to peptide analogues 12a and 12b. Catalysts 13a and 13b
were obtained via catalytic hydrogenation (Scheme 2) [16].
Following a similar procedure, but utilizing pentafluorophenol,
catalyst 13c was also prepared (Scheme 3). Unfortunately com-
pounds 12d and 12e were not possible to synthesize under those
conditions and a different synthetic pathway was followed, using
triethyl amine (Et3N) and ethyl chloroformate via the mixed an-
hydride intermediate (Scheme 4). Finally, deprotection via catalytic
hydrogenation, afforded organocatalysts 13d and 13e.
Proline, although it is a powerful and archeotypical organo-
catalyst, is mostly insoluble in organic solvents (high catalyst
loading) and provides moderate enantioselectivities (<90% ee).
Also, it cannot be used in aqueous media. Prolinamides, like com-
pounds 1e9, are considered an improvement because they provide
multiple recognition sites, via hydrogen bonding interactions, with
the electrophile (aldehyde, see Fig. 2, top left). Thus, they provide a
more compact transition state, leading from moderate to high
enantioselectivities. Our hypothesis was to introduce fluorine
moieties on the organocatalyst backbone, in order to create more
and better hydrogen bonding interactions on the organocatalyst
and/or change the adopted conformation of the catalyst, due to the
fluorine, in the transition state (Fig. 2, top right and bottom). This
idea would lead to enhanced enantioselectivities, which could also
work in aqueous media.
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A. Ahmetlli et al. / Tetrahedron xxx (2018) 1e9
3
tested, and as postulated, excellent selectivity was observed, but
the yield dramatically dropped (entries 9 and 10, Table 1). These
results verify the hypothesis that if the catalyst has potent
hydrogen bonding sites, the interactions that occur during the
transition state with the electrophile are reinforced, leading to
higher levels of stereocontrol.
Once 13d was identified as the best catalyst, optimization of the
reaction conditions was carried out (Table 2). Wet petroleum ether,
CH2Cl2 and ether (Et2O) proved to be the best solvents, leading to
improved yield and selectivities of the product (entries 1e7,
Table 2). Brine was the only aqueous medium that was used,
affording the product in slightly lower enantioselectivity (entry 8,
Table 2). It is known that the asymmetric aldol reaction is suscep-
tible to the acid counterparts and thus, fine tuning is required, so
different acid additives were employed (entries 9 and 10, Table 2).
From the carboxylic acids tested, 4-nitrobenzoic acid yielded the
best selectivity. Other strong acids were not employed, since it is
known to promote salt formation with the catalyst, leading to its
deactivation.
Our attention was then turned to the exploration of the sub-
strate scope of the enantioselective aldol reaction employing
catalyst 13d (Table 3). Numerous substituted aromatic aldehydes
can be employed with cyclohexanone, affording products from
moderate to excellent yields and selectivities (entries 1e14,
Table 3). Electron-withdrawing groups at any position of the aryl
moiety led to moderate to excellent results (entries 1e5, Table 3),
while the use of halogen substituted aromatic aldehydes resulted in
high to excellent yields and selectivities (entries 6e11, Table 3). In
all cases, higher selectivities were observed with the ortho-
substituted aldehydes. However, the position of the substitution on
the aromatic ring did not alter the reaction outcome.
Heteroaromatic-substituted aldehydes and benzaldehyde, which
are notoriously known as difficult substrates, either leading to
lower yields or selectivities and/or requiring longer reaction times,
proved to be more challenging (entries 12e14, Table 3). Benzalde-
hyde and 3-thiophenyl carboxaldehyde led to excellent yields and
moderate to high selectivities, while 4-pyridinyl carboxaldehyde
proved to have a better yield, but moderate selectivity. Trying to
broaden the scope of substrates, different ketones were also
employed. Tetrahydropyran-4-one and tetrahydrothiopyran-4-one,
as expected from previous studies, required longer reaction time
(entries 15 and 16, Table 3). The desymmetrization of ketones is a
known process that can be achieved via organocatalytic aldol re-
Fig. 2. Possible transition states in the absence or presence of fluorine moieties.
The synthesized catalysts were then evaluated in the aldol re-
action between cyclohexanone and 4-nitrobenzaldehyde, both in
organic and aqueous media (Table 1). Initially, compound 13a, non-
containing fluorine moiety was tested, leading to an excellent yield
with good diastereoselectivity and 89% enantioselectivity in
organic medium, but in aqueous medium, no reaction was observed
(entries 1 and 2, Table 1). The addition of one fluorine substituent
led to dipeptide 13b, which was based on 2-fluoroaniline. When
13b was used, not only the yield and enantioselectivity improved in
organic medium, but also the reaction in brine resulted in excellent
yield and 91% enantioselectivity (entries 3 and 4, Table 1). In an
attempt to determine whether both the amide and fluorine moi-
eties are essential, the pentafluorophenol derivative 13c was tested.
Unfortunately, no product was obtained neither in organic, nor in
aqueous medium (entries 5 and 6, Table 1). These results highlight
the importance of both moieties, as only their combination yielded
improved results. Furthermore catalyst 13d, based on 2-
trifluoromethyl-aniline, was employed and afforded the best
selectivity, reaching 96% ee (entries 7 and 8, Table 1). Considering
all the above, these catalysts proved to be a cheap alternative to
proline, since the combination of two aminoacids with fluorine-
substituted aniline yields a potent organocatalyst for the aldol re-
action in different media, in which the solubility of proline is
limited. Trying to further improve the organocatalytic properties,
we surmised that the addition of another fluorine substituent
would limit the conformers and augment the acidity of the amide,
which could amplify the interactions with the substrates, as well as
improve the catalytic results in aqueous media. Catalyst 13e was
actions and herein constitutes
a
possibility, since 4-
methylcyclohexanone delivered excellent yield, but low selec-
tivity (entry 17, Table 3). Cyclopentanone, which is known to pro-
vide reversed anti:syn selectivity, was also utilized, despite the yield
being excellent, the diastereoselectivity was moderate and the
enantioselectivity low (entry 18, Table 3). Moreover, in order to
Scheme 2. Synthesis of catalysts 13a and 13b.
Scheme 3. Synthesis of catalyst 13c.
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4
A. Ahmetlli et al. / Tetrahedron xxx (2018) 1e9
Table 2
Enantioselective aldol reaction of cyclohexanone with 4-nitrobenzaldehyde using
catalyst 13d.a
Entry
Conditions
Yield (%)b
drc
ee (%)d
1
2
3
4
5
6
7
8
9
PE/H2O, 4-NBA
MeCN, 4-NBA
THF, 4-NBA
CH2Cl2, 4-NBA
AcOEt, 4-NBA
Et2O, 4-NBA
toluene, 4-NBA
brine, 4-NBA
PE/H2O, PhCO2H
PE/H2O, AcOH
100
88
85:15
71:29
65:35
85:15
66:34
85:15
70:30
86:14
81:19
85:15
96
96
96
96
95
96
94
91
95
92
100
100
100
100
100
100
91
Scheme 4. Synthesis of catalysts 13d and 13e.
10
84
4-NBA: 4-nitrobenzoic acid. PE: Petroleum ether.
a
Catalyst (0.015 mmol) in solvent (1.0 mL), additive (0.02 mmol), H2O (0.1 mL),
aldehyde (0.10 mmol) and cyclohexanone (1.00 mmol).
Table 1
Enantioselective reaction of cyclohexanone with 4-nitrobenzaldehyde using cata-
b
Isolated yield.
lysts 13a-e.a
c
The diastereomeric ratio (dr) anti:syn was determined by 1H NMR of the crude
reaction mixture.
d
The enantiomeric excess (ee) for the major isomer was determined by chiral
HPLC.
Pro-Phe, which is easy to prepare, combined with fluorine-
substituted aniline is a more powerful catalyst for the aldol reac-
tion. A fluorine substituent can instill new properties to the cata-
lyst, like increased acidity and can also interact with the substrate
and as a result the selectivity is improved. An alternative scenario
could be that it may also affect the adopted conformation of the
catalyst. The catalyst was evaluated both in organic and aqueous
media. When 13d was utilized, high to excellent yields and mod-
erate to excellent selectivities in wet petroleum ether were ob-
tained, even when the substrates were problematic. It is worth
mentioning that the catalyst works at room temperature and has
distinct advantages compared to proline, as it can bypass the low
solubility that proline displays in organic solvents and the low
selectivity it affords in aqueous media. Furthermore, expensive
chiral moieties are not required to be incorporated in the catalyst's
structure, since the chirality source is the Pro-Phe dipeptide,
coupled with commercially available 4-trifluoromethyl aniline.
Entry
Catalyst
Conditions
Yield (%)b
drc
ee (%)d
1
2
3
4
5
6
7
8
9
10
13a
13a
13b
13b
13c
13c
13d
13d
13e
13e
PE/H2O
Brine
PE/H2O
Brine
PE/H2O
Brine
PE/H2O
Brine
96
91:9
e
89
e
n.r.
100
100
n.r.
n.r.
100
100
24
85:15
86:14
e
91
91
e
e
e
85:15
86:14
85:15
88:12
96
91
96
93
PE/H2O
Brine
50
4-NBA: 4-nitrobenzoic acid. PE: Petroleum ether.
a
Catalyst (0.015 mmol) in solvent (1.0 mL), additive (0.02 mmol), H2O (0.1 mL),
aldehyde (0.10 mmol) and cyclohexanone (1.00 mmol).
b
Isolated yield.
c
The diastereomeric ratio (dr) anti:syn was determined by 1H NMR of the crude
reaction mixture.
d
The enantiomeric excess (ee) for the major isomer was determined by chiral
4. Experimental section
HPLC.
4.1. General information
broaden the scope of this methodology, we investigated the reac-
tion of acetone with 4-nitrobenzaldehyde. Unfortunately, this re-
action led to excellent yield, but moderate enantioselectivity (entry
19, Table 3).
Finally, the reaction between isobutyraldehyde and cyclohexa-
none was investigated (Scheme 5). Unfortunately, the desired
product was delivered in excellent selectivity, but in low yield.
Organic solutions were concentrated under reduced pressure on
a Buchi rotary evaporator. Chromatographic purification of prod-
ucts was accomplished using column chromatography on Merck
Kieselgel 60 F254 230e400 mesh. Thin-Layer chromatography (TLC)
was performed on aluminium backed silica plates (0.2 mm, 60
F254). Visualization of the developed chromatogram was performed
by fluorescence quenching using PMA stain. Melting points were
determined on a Buchi 530 hot stage apparatus. 1H, 19F and 13C NMR
spectra were recorded on Varian Mercury 200 MHz and are inter-
nally referenced to residual solvent signals (CDCl3 or CD3OD). Data
3. Conclusion
In conclusion, the synthesis of dipeptides containing fluorine
moieties was carried out. Previously, we had shown that the
addition of the hydrogen bonding sites provided excellent catalysts
for the aldol reaction. In this study, we have shown that dipeptide
for 1H NMR spectroscopy are reported as follows: chemical shift (
d
ppm), multiplicity (s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet,
m ¼ multiplet, br s ¼ broad signal), integration, coupling constant,
and assignment. Wherever rotamers exist, are cited. 19F NMR
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A. Ahmetlli et al. / Tetrahedron xxx (2018) 1e9
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Table 3
Chromatography (HPLC) was used to determine enantiomeric ex-
cesses and was performed on an Agilent 1100 Series apparatus
using Chiralpak® AD-H, OD-H and AS-H columns. Optical rotations
were measured on a Perkin Elmer 343 polarimeter. The syn:anti
ratio of the crude reaction mixture was assigned by comparison to
literature data [7h,7n]. The configuration of the products has been
assigned by comparison to literature data [7h,7n]. Data for known
compounds matched literature data. All new compounds were
assigned by analogy.
Enantioselective aldol reaction between ketones and aldehydes using catalyst 13d.
4.2. General procedure for the synthesis of the organocatalysts
Entry
Ketone
Aldehyde
Yield (%)a
drb
ee (%)c
1
4-NO2C6H4
3-NO2C6H4
2-NO2C6H4
4-CF3C6H4
3-CNC6H4
4-FC6H4
100 (16a)
100 (16b)
100 (16c)
100 (16d)
100 (16e)
88 (16f)
100 (16g)
90 (16h)
100 (16i)
84 (16j)
100 (16k)
84 (16l)
100 (16m)
77 (16n)
100 (16o)
85:15
88:12
91:9
80:20
79:21
88:12
95:5
89:11
89:11
83:17
89:11
83:17
67:33
74:26
74:26
96
93
97
87
56
90
97
87
93
89
95
89
84
76
88
4.2.1. General procedure for the synthesis of ((benzyloxy)carbonyl)-
L-prolyl-L-phenylalanine
2d
3d
4f
To a stirring solution of Cbz-Pro-OH (1.20 g, 4.81 mmol) in dry
CH2Cl2 (20 mL) at 0 ꢀC, HCl. H-Phe-OMe (1.10 g, 5.10 mmol),1-ethyl-
3-(3-dimethylamino) carbodiimide (0.83 g, 5.35 mmol), 1-
hydroxybenzotriazole (HOBt) (0.74 g, 4.83 mmol) and Et3N (2 mL,
15.51 mmol) were added consecutively. The reaction mixture was
left stirring at 0 ꢀC for 30 min and then warmed to room temper-
ature and left stirring overnight. The reaction mixture was diluted
with CH2Cl2 (30 mL) and washed with aq. HCl 1 N (2 ꢁ 25 mL), brine
(25 mL), aq. NaOH 1 N (2 ꢁ 25 mL) and brine (25 mL). The organic
layer was then dried over CaCl2, filtered and concentrated under
reduced pressure. The crude Cbz-Pro-Phe-OMe (1.60 g, 3.90 mmol)
was dissolved in dioxane (8 mL) and then an aqueous solution of
NaOH 2 N (2.4 mL, 4.80 mmol) was added. The reaction was left
stirring at room temperature, for approximately 1 h, until the re-
action was completed (determined by TLC). Dioxane was evapo-
rated under reduced pressure, and the residue was diluted with
water (40 mL) and extracted with Et2O (25 mL). The aqueous layer
was washed with aq. H2SO4 5% (30 mL) and was extracted with
EtOAc (3 ꢁ 25 mL). The combined organic layers were washed with
water (30 mL) and brine (30 mL), dried over CaCl2, filtered and
concentrated under reduced pressure to afford the free acid. The 1H
and 13C NMR data were in full agreement with literature [7h].
5e
6f
7e
2-FC6H4
8f
4-BrC6H4
2-BrC6H4
4-ClC6H4
2-ClC6H4
C6H5
4-pyridinyl
3-thiophenyl
4-NO2C6H4
9e
10f
11e
12f
13d
14f
15f
16e
17d
4-NO2C6H4
4-NO2C6H4
100 (16p)
100 (16q)
68:32
97
(30:29):41
24 (syn)
24 (anti)
18d
4-NO2C6H4
4-NO2C6H4
100 (16r)
100 (16s)
24:76
4
4.2.2. General procedure for the synthesis of catalysts (13a-c)
To a stirring solution of Cbz-Pro-Phe-OH (100 mg, 0.25 mmol) in
dry CH2Cl2 (1 mL) at 0 ꢀC, dicyclohexyl carbodiimide (62 mg,
0.30 mmol), 1-hydroxybenzotriazole (HOBt) (38 mg, 0.25 mmol)
and aniline or phenol (0.35 mmol) were added consecutively. The
reaction mixture was left stirring at 0 ꢀC for 30 min and then
warmed to room temperature and left stirring overnight. The re-
action mixture was filtered and the filtrate was concentrated and
then diluted with EtOAc (1 mL) left at 0 ꢀC for 10 min and then
filtered once again. The filtrate was diluted with EtOAc (10 mL) and
washed with aq. H2SO4 5% (2 ꢁ 10 mL), H2O (10 mL), aq. NaHCO3 5%
(2 ꢁ 10 mL) and brine (10 mL). The organic layer was dried over
CaCl2, filtered and concentrated under reduced pressure. The crude
product was purified by column chromatography eluting with
EtOAc/PE (1:1). The crude product was dissolved in absolute MeOH
(10 mL) and 10% Pd/C (10 w/w%) was added and the reaction
mixture was left stirring at room temperature for 2e24 h under
hydrogen atmosphere. After filtration through Celite, the solvent
was evaporated under vacuum to yield the desired product.
19
e
52
a
Isolated yield.
b
The diastereomeric ratio (dr) anti:syn was determined by 1H NMR of the crude
reaction mixture.
c
The enantiomeric excess (ee) for the major isomer was determined by chiral
HPLC.
d
Reaction time 72 h.
Reaction time 96 h.
e
f
Reaction time 120 h.
Scheme 5. Study of catalytic activity of 13d in the reaction of cyclohexanone with
isobutyraldehyde.
4.2.3. General procedure for the synthesis of catalysts (13d,e)
To a flame dried two-neck round bottom flask, Cbz-Pro-Phe-OH
(1.00 g, 2.54 mmol) was dissolved in dry THF (10 mL) at 0 ꢀC under
argon atmosphere. To the stirring solution, Et3N (0.4 mL,
2.92 mmol) and ethyl chloroformate (0.25 mL, 2.64 mmol) were
added and the reaction mixture was left stirring for 1 h at 0 ꢀC.
Finally, substituted aniline (0.67 mmol) was introduced to the re-
action mixture dropwise. The reaction mixture was stirred at 0 ꢀC
spectra were recorded on Varian Mercury (188 MHz). Mass spectra
were recorded on a Finnigan Surveyor MSQ Plus, with only mo-
lecular ions and major peaks being reported with intensities quoted
as percentages of the base peak. High Performance Liquid
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A. Ahmetlli et al. / Tetrahedron xxx (2018) 1e9
for 1 h, then warmed to room temperature for 2 h and finally heated
to reflux for 16 h. Then, the reaction mixture was filtered and
concentrated. The crude product was purified by column chroma-
tography eluting with EtOAc/PE (3:7). The deprotection of the
amino moiety of proline was performed similarly to the general
procedure that was followed for the synthesis of catalysts 13a-c.
4.2.8. (S)-N-((S)-1-((2,6-Difluorophenyl)amino)-1-oxo-3-
phenylpropan-2-yl)pyrrolidine-2-carboxamide (13e)
The product was obtained as a yellow oil. Yield: 52%; Rf (CHCl3/
MeOH 90:10) 0.33; [
CD3OD, mixture of rotamers)
a
]
25 ꢂ44.0 (c 0.25, CHCl3); 1H NMR (200 MHz,
D
d 7.70e7.63 (1H, m, NH), 7.38e7.16
(6H, m, ArH), 7.09e6.98 (2H, m, ArH), 5.17e4.99 (1H, m, NH),
4.58e4.50 (1H, m, NCH), 4.35e4.25 (1H, m, NCH), 3.55e3.39 (2H,
m, 2 ꢁ NCHH), 3.14e2.98 (2H, m, 2 ꢁ CHHPh), 2.29e1.85 (4H, m, 4 ꢁ
4.2.4. (S)-N-((S)-1-Oxo-3-phenyl-1-(pheynylamino)propan-2-yl)
pyrrolidine-2-carboxamide (13a) [17]
CHH); 13C (50 MHz, CD3OD)
d
174.6, 174.3, 159.7 (d, J ¼ 250.4 Hz),
The product was obtained as a white solid. Yield: 91%; mp
159.6 (d, J ¼ 250.6 Hz), 155.5, 138.4, 138.1e137.9 (m), 132.4,
130.5e127.8 (m), 113.0e112.8 (m), 112.5 (dd, J ¼ 5.8 Hz and 2.5 Hz),
62.2e60.6 (m), 57.4e52.7 (m), 47.4, 41.2e38.1 (m), 34.7e30.1 (m),
25
151e153 ꢀC; Rf (EtOAc/MeOH 80:20) 0.32; [
a
]
ꢂ52.8 (c 0.8,
D
CHCl3); 1H NMR (200 MHz, CD3OD)
d
8.81 (1H, d, J ¼ 6.3 Hz, NH),
7.50e7.05 (11H, m, ArH and NH), 4.84e4.73 (1H, m, NCH),
4.32e4.24 (1H, m, NCH), 3.50e3.32 (2H, m, NCH2), 3.21 (1H, dd,
J ¼ 14.0 and 6.7 Hz, CHHPh), 3.04 (1H, dd, J ¼ 14.0 and 8.4 Hz,
CHHPh), 2.51e2.37 (1H, m, CHH), 2.08e1.69 (4H, m, 3 ꢁ CHH and
27.6e23.3 (m); 19F NMR (188 MHz, CD3OD)
d
ꢂ73.8 (s); HRMS exact
mass calculated for [MþH]þ (C20H22F2N3O2) requires m/z 374.1680,
found m/z 374.1687.
NH); 13C NMR (50 MHz, CD3OD)
d
171.4, 169.5, 139.3, 137.9, 130.3,
4.3. General procedure for the aldol reaction
129.8, 129.5, 127.9, 125.4, 121.3, 60.9, 57.3, 47.5, 39.1, 31.1, 26.0;
HRMS exact mass calculated for [MþH]þ (C20H24N3O2) requires m/z
338.1869, found m/z 338.1875.
To a round-bottom flask, catalyst (0.015 mmol), 4-NBA (3 mg,
0.02 mmol) and aldehyde (0.10 mmol) were added. After the
addition of Petroleum Ether (PE) (1 mL) and H2O (0.1 mL), ketone
(1.00 mmol) was added and the reaction mixture was stirred at
room temperature for 24e120 h. The solvent was evaporated and
the crude product was purified by column chromatography. The
diastereomeric ratio was calculated by 1H NMR of the crude reac-
tion mixture and the enantiomeric excess was determined by chiral
HPLC. All known products from the asymmetric aldol reaction were
in full agreement with the literature [7i,7k].
4.2.5. (S)-N-((S)-1-((Fluorophenyl)amino)-1-oxo-3-phenylpropan-
2-yl)pyrrolidine-2-carboxamide (13b)
The product was obtained as a white solid. Yield: 89%; mp
117e119 ꢀC; Rf (CHCl3/MeOH 90:10) 0.36; [
a
]
D
25 ꢂ15.6 (c 0.5, DMF);
1H NMR (200 MHz, CD3OD)
d 7.77e7.68 (1H, m, ArH), 7.23e6.99
(8H, m, ArH), 4.80e4.76 (1H, m, NCH), 3.67e3.57 (1H, m, NCH),
3.23e3.11 (1H, m, NCHH), 2.99e2.74 (3H, m, NCHH and 2 ꢁ CHHPh),
2.04e1.90 (1H, m, CHH), 1.65e1.42 (3H, m, 3 ꢁ CHH); 13C NMR
(50 MHz, CD3OD)
d
176.3, 172.2, 155.8 (d, J ¼ 246.1 Hz), 138.0, 130.4,
4.3.1. (S)-2-[(R)-Hydroxy-(4-nitrophenyl)methyl]-cyclohexanone
129.5, 127.9, 127.3 (d, J ¼ 7.7 Hz), 126.6 (d, J ¼ 11.8 Hz), 125.7 (d,
(16a) [7i]
J ¼ 1.0 Hz), 125.3 (d, J ¼ 3.7 Hz), 116.4 (d, J ¼ 19.7 Hz), 61.3, 55.9, 47.9,
Colorless oil. Yield: 100%; 1H NMR (200 MHz, CDCl3) anti
d 8.20
39.2, 31.7, 26.6; 19F NMR (188 MHz, CD3OD)
d
ꢂ81.3 (s); MS (ESI)
(2H, d, J ¼ 8.8 Hz, ArH), 7.51 (2H, d, J ¼ 8.8 Hz, ArH), 4.87 (1H, d,
J ¼ 8.4 Hz, OCH), 4.09 (1H, br s, OH), 2.64e2.26 (3H, m, COCH and
2 ꢁ CHH), 2.17e1.29 (6H, m, 6 ꢁ CHH); 13C NMR (50 MHz, CDCl3)
356.22 ([MþH]þ, 100%); HRMS exact mass calculated for [MþH]þ
(C20H23FN3O2) requires m/z 356.1774, found m/z 356.1780.
d
214.6, 148.4, 127.9, 127.8, 123.4, 73.8, 57.0, 42.5, 30.6, 27.5, 24.5;
4.2.6. Perfluorophenyl L-prolyl-L-phenylalaninate (13c)
HPLC analysis: Diacel Chiralpak AD-H, hexane/iPrOH 90:10, flow
rate 1.0 mL/min, retention time: 32.79 (minor) and 38.87 (major),
96% ee.
The product was obtained as a colourless oil. Yield: 41%; Rf
25
(CHCl3/MeOH 95:5) 0.50; [
a
]
ꢂ61.0 (c 1.0, CHCl3); 1H NMR
D
(200 MHz, CDCl3, mixture of rotamers)
d 7.82 (1H, br s, NH),
7.38e7.15 (5H, m, ArH), 6.08 (1H, s, NH), 4.36e4.33 (1H, m, NCH),
4.18e4.08 (1H, m, NCH), 3.77e3.44 (2H, m, NCH2), 3.25e3.02 (1H,
m, CHHPh), 2.85 (1H, dd, J ¼ 14.0 and 10.0 Hz, CHHPh), 2.44e2.27
(1H, m, CHH), 2.05e1.70 (3H, m, 3 ꢁ CHH); 13C NMR (50 MHz,
4.3.2. (S)-2-[(R)-Hydroxy-(3-nitrophenyl)methyl]-cyclohexanone
(16b) [7i]
Colorless oil. Yield: 100%; 1H NMR (200 MHz, CDCl3) anti
d
8.23e8.14 (2H, m, ArH), 7.67 (1H, d, J ¼ 7.3 Hz, ArH), 7.55 (1H, d,
CDCl3)
d
172.8, 172.1, 167.7, 167.6, 156.5, 143.6e127.5 (m), 60.8e60.1
J ¼ 7.6 Hz, ArH), 4.90 (1H, d, J ¼ 8.4 Hz, OCH), 4.11 (1H, br s, OH),
2.68e2.31 (3H, m, COCH and 2 ꢁ CHH), 2.17e1.32 (6H, m, 6 ꢁ CHH);
(m), 53.1e52.6 (m), 49.5e47.0 (m), 37.5e37.2 (m), 33.8e30.7 (m),
27.9e23.3 (m); 19F NMR (188 MHz, CDCl3)
5.7 Hz), ꢂ122.6 to ꢂ122.8 (m), ꢂ128.0 (tt, J ¼ 22.1 and 5.8 Hz);
HRMS exact mass calculated for [MþH]þ (C20H18F5N2O3) requires
m/z 429.1238, found m/z 429.1244.
d
ꢂ120.9 (dd, J ¼ 18.0 and
13C NMR (50 MHz, CDCl3)
d 214.6, 148.2, 143.1, 133.1, 129.2, 122.7,
121.9, 74.0, 57.0, 42.6, 30.6, 27.6, 24.6; HPLC analysis: Diacel Chir-
alpak AD-H, hexane/iPrOH 95:5, flow rate 1.0 mL/min, retention
time: 66.49 (major) and 87.69 (minor), 93% ee.
4.2.7. (S)-N-((S)-1-Oxo-3-phenyl-1-((2-(trifluoromethyl)phenyl)
amino)propan-2-yl)pyrrolidine-2-carboxamide (13d)
4.3.3. (S)-2-[(R)-Hydroxy-(2-nitrophenyl)methyl]-cyclohexanone
(16c) [7i]
The product was obtained as a white solid. Yield: 49%; mp
Yellow solid. Yield: 100%; 1H NMR (200 MHz, CDCl3) anti
49e51 ꢀC; Rf (CHCl3/MeOH 90:10) 0.38; [
a
]
25 ꢂ37.8 (c 0.8, MeOH);
d
7.91e7.72 (2H, m, ArH), 7.63 (1H, t, J ¼ 6.6 Hz, ArH), 7.42 (1H, t,
D
1H NMR (200 MHz, CD3OD)
d
7.74e7.20 (9H, m, ArH), 4.89e4.84
J ¼ 6.6 Hz, ArH), 5.43 (1H, d, J ¼ 7.1 Hz, OCH), 4.16 (1H, br s, OH),
2.85e2.61 (1H, m, COCH), 2.55e2.08 (2H, m, 2 ꢁ CHH), 1.90e1.52
(1H, m, NCH), 3.79e3.67 (1H, m, NCH), 3.36e3.26 (1H, m, NCHH),
3.05e2.81 (3H, m, NCHH and 2 ꢁ CHHPh), 2.12e1.97 (1H, m, CHH),
(6H, m, 6 ꢁ CHH); 13C NMR (50 MHz, CDCl3)
d 214.9, 136.5, 133.0,
1.71e1.50 (3H, m, 3 ꢁ CHH); 13C (50 MHz, CD3OD)
d
176.5, 173.1,
128.9, 128.3, 124.0, 69.7, 57.2, 42.8, 31.1, 27.7, 24.9; HPLC analysis:
Diacel Chiralpak AD-H, hexane/iPrOH 95:5, flow rate 0.8 mL/min,
retention time: 61.80 (major) and 66.83 (minor), 97% ee.
138.2 (q, J ¼ 8.5 Hz), 138.1, 135.8 (q, J ¼ 1.8 Hz), 134.0, 130.5 (q,
J ¼ 3.9 Hz), 130.4, 129.5, 128.1 (q, J ¼ 12.3 Hz), 127.5 (q, J ¼ 5.2 Hz),
126.6 (q, J ¼ 29.9 Hz), 125.4 (q, J ¼ 272.8 Hz), 61.3, 55.7, 47.9, 38.8,
31.7, 26.6; 19F NMR (188 MHz, CD3OD)
d
ꢂ16.1 (s); MS (ESI) 406.25
4.3.4. (S)-2-[(R)-Hydroxy-(4-(trifluoromethyl)phenyl)methyl]-
cyclohexanone (16d) [7i]
([MþH]þ, 100%); HRMS exact mass calculated for [MþH]þ
(C20H22F3N3O2) requires m/z 406.1742, found m/z 406.1747.
White solid. Yield: 100%; mp 73e75 ꢀC; 1H NMR (200 MHz,
Please cite this article in press as: A. Ahmetlli, et al., Proline dipeptides containing fluorine moieties as oganocatalysts for the asymmetric aldol
reaction, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.08.038

A. Ahmetlli et al. / Tetrahedron xxx (2018) 1e9
7
CDCl3) anti
d
7.61 (2Н, d, J ¼ 8.2 Hz, ArH), 7.44 (2H, d, J ¼ 8.2 Hz,
hexane/iPrOH 98:2, flow rate 1.0 mL/min, retention time: 15.58
(major) and 18.51 (minor), 93% ee.
ArH), 4.84 (1H, d, J ¼ 8.6 Hz, OCH), 4.03 (1H, br s, OH), 2.69e2.02
(4H, m, COCH and 3 ꢁ CHH), 1.90e1.39 (5H, m, 5 ꢁ CHH); 13C NMR
(50 MHz, CDCl3)
d
215.1, 144.9, 129.6 (q, J ¼ 31.2 Hz), 127.3, 125.3 (q,
4.3.10. (S)-2-[(R)-Hydroxy-(4-(chlorophenyl)methyl]-
cyclohexanone (16j) [7i]
J ¼ 8.1 Hz), 123.9 (q, J ¼ 271.4 Hz), 74.2, 57.2, 42.6, 30.7, 27.6, 24.7;
19F NMR (188 MHz, CDCl3)
d
ꢂ7.50 (s); HPLC analysis: Diacel Chir-
White solid. Yield: 84%; mp 96e98 ꢀC; 1H NMR (200 MHz,
alpak AD-H, hexane/iPrOH 90:10, flow rate 0.5 mL/min, retention
time: 25.83 (minor) and 31.87 (major), 87% ee.
CDCl3) anti
d
7.32 (2H, d, J ¼ 8.5 Hz, ArH), 7.24 (2H, d, J ¼ 8.5 Hz,
ArH), 4.76 (1H, d, J ¼ 8.7 Hz, OCH), 3.98 (1H, br s, OH), 2.63e2.28
(3H, m, COCH and 2 ꢁ CHH), 2.19e2.01 (1H, m, CHH), 1.88e1.42 (5H,
4.3.5. (R)-3-[Hydroxy-(2-(S)-oxocyclohexyl)methyl]-benzonitrile
(16e) [7i]
m, 5 ꢁ CHH); 13C NMR (50 MHz, CDCl3)
d 215.3, 139.5, 133.6, 128.5,
128.4, 74.2, 57.4, 42.7, 30.7, 27.7, 24.7; HPLC analysis: Diacel Chir-
alpak OD-H, hexane/iPrOH 95:5, flow rate 1.0 mL/min, retention
time: 19.30 (major) and 25.59 (minor), 89% ee.
Colorless oil. Yield: 100%; 1H NMR (200 MHz, CDCl3) anti
d
7.68e7.38 (4H, m, ArH), 4.81 (1H, d, J ¼ 8.5 Hz, OCH), 4.01 (1H, br s,
OH), 2.65e2.03 (4H, m, COCH and 3 ꢁ CHH), 1.87e1.22 (5H, m, 5 ꢁ
CHH); 13C NMR (50 MHZ, CDCl3)
214.6, 142.6, 131.5, 130.6, 129.1,
d
4.3.11. (S)-2-[(R)-Hydroxy-(2-(chlorophenyl)methyl]-
cyclohexanone (16k) [7i]
118.7, 112.4, 73.9, 57.1, 42.6, 30.6, 27.6, 24.6; HPLC analysis: Diacel
Chiralpak AD-H, hexane/iPrOH 95:5, flow rate 1.0 mL/minm
retention time: 40.98 (minor) and 62.07 (major), 56% ee.
Pale yellow solid. Yield: 100%; mp 88e90 ꢀC; 1H NMR (200 MHz,
CDCl3) anti
d
7.54 (1H, dd, J ¼ 7.8 and 1.9 Hz, ArH), 7.36e7.16 (3H, m,
ArH), 5.34 (1H, d, J ¼ 8.2 Hz, OCH), 3.86 (1H, br s, OH), 2.77e2.61
(1H, m, COCH), 2.54e2.22 (2H, m, 2 ꢁ COCHH), 2.17e2.02 (1H, m,
CHH), 1.86e1.42 (5H, m, 5 ꢁ CHH); 13C NMR (50 MHz, CDCl3)
4.3.6. (S)-2-[(R)-Hydroxy-(4-(fluorophenyl)methyl]-cyclohexanone
(16f) [7i]
White solid. Yield: 88%; mp 84e86 ꢀC; 1H NMR (200 MHz,
d 215.3, 139.1, 132.9, 129.2, 128.7, 128.3, 127.3, 70.5, 57.6, 42.7, 30.4,
CDCl3) anti
d
7.33e7.27 (2H, m, ArH), 7.03 (2H, d, J ¼ 8.7 Hz, ArH),
27.8, 24.9; HPLC analysis: Diacel Chiralpak OD-H, hexane/iPrOH
95:5, flow rate 1.0 mL/min, retention time: 20.68 (major) and 23.63
(minor), 95% ee.
4.77 (1H, d, J ¼ 8.4 Hz, OCH), 4.03 (1H, br s, OH), 2.65e2.31 (3H, m,
COCH and CHH), 2.08e1.22 (6H, m 6 ꢁ CHH); 13C NMR (50 MHz,
CDCl3)
d
215.4, 162.3 (d, J ¼ 246.2 Hz), 136.6, 128.5 (d, J ¼ 5.1 Hz),
115.2 (d, J ¼ 20.0 Hz), 74.1, 57.4, 42.6, 30.7, 27.7, 24.6; 19F NMR
4.3.12. (S)-2-[(R)-Hydroxy-(phenyl)methyl]-cyclohexanone (16l)
(188 MHz, CDCl3)
d
ꢂ59.49 HPLC analysis: Diacel Chiralpak AD-H,
[7i]
hexane/iPrOH 90:10, flow rate 0.5 mL/min, retention time: 36.52
(minor), 40.21 (major), 90% ee.
Colorless oil. Yield: 84%; 1H NMR (200 MHz, CDCl3) anti
d
7.51e7.21 (5H, m, ArH), 4.78 (1H, d, J ¼ 8.8 Hz, OCH), 3.84 (1H, br s,
OH), 2.70e2.31 (3H, m, COCH and 2 ꢁ CHH), 2.15e1.24 (6H, m, 6 ꢁ
CHH); 13C NMR (50 MHz, CDCl3)
215.5, 140.8, 128.3, 127.8, 125.7,
4.3.7. (S)-2-[(R)-Hydroxy-(2-(fluorophenyl)methyl]-cyclohexanone
(16g) [7i]
d
74.7, 57.4, 42.6, 30.8, 27.8, 24.7; HPLC analysis: Diacel Chiralpak OD-
H, hexane/iPrOH 90:10, flow rate 0.5 mL/min, retention time: 20.32
(major) and 26.21 (minor), 89% ee.
Colorless oil. Yield: 100%; 1H NMR (200 MHz, CDCl3) anti
d 7.48
(1H, td, J ¼ 7.4 and 1.9 Hz, ArH), 7.36e7.14 (2H, m, ArH), 7.02 (1H,
ddd, J ¼ 10.2, 8.0 and 1.6 Hz, ArH), 5.18 (1H, d, J ¼ 8.7 Hz, OCH), 4.00
(1H, br s, OH), 2.74e2.62 (1H, m, COCH), 2.52e2.28 (2H, m, 2 ꢁ
4.3.13. (S)-2-[(R)-Hydroxy-(pyridine-4-yl)methyl]-cyclohexanone
(16m) [7i]
COCHH), 2.19e2.03 (1H, m, CHH), 1.89e1.38 (5H, m, 5 ꢁ CHH); 13
C
NMR (50 MHz, CDCl3)
d
215.2, 159.9 (d, J ¼ 245.8 Hz), 129.1 (d,
White solid. Yield: 100%; mp 107e109 ꢀC; 1H NMR (200 MHz,
J ¼ 8.3 Hz), 128.2 (d, J ¼ 4.3 Hz), 128.0, 124.3 (d, J ¼ 3.4 Hz), 115.0 (d,
CDCl3) anti d 8.58e8.52 (2H, m, ArH), 7.27e7.21 (2H, m, ArH), 4.78
J ¼ 22.3 Hz), 67.8, 57.0, 42.5, 30.1, 27.6, 24.6; 19F NMR (188 MHz,
(1H, d, J ¼ 8.1 Hz, OCH), 3.19 (1H, br s, OH), 2.67e2.225 (3H, m,
CDCl3)
d
ꢂ62.92 (s); HPLC analysis: Diacel Chiralpak AD-H, hex-
COCH and 2 ꢁ CHH), 2.18e2.01 (1H, m, CHH), 1.87e1.35 (5H, m, 5 ꢁ
ane/iPrOH 95:5, flow rate 0.5 mL/min, retention time: 40.98 (major)
and 54.35 (minor), 97% ee.
CHH); 13C NMR (50 MHz, CDCl3)
d 214.5, 150.1, 149.7, 122.1, 73.3,
57.0, 42.6, 30.8, 27.7, 24.7; HPLC analysis: Diacel Chiralpak AD-H,
hexane/iPrOH 92:8, flow rate 1.0 mL/min, retention time: 28.47
(minor) and 38.70 (major), 84% ee.
4.3.8. (S)-2-[(R)-Hydroxy-(4-(bromophenyl)methyl]-
cyclohexanone (16h) [7i]
White solid. Yield: 90%; mp 89e91 ꢀC; 1H NMR (200 MHz,
4.3.14. (S)-2-[(R)-Hydroxy-(thiophen-3-yl)methyl]-cyclohexanone
(16n) [7i]
CDCl3) anti
d
7.47 (2H, d, J ¼ 8.5 Hz, ArH), 7.20 (2H, d, J ¼ 8.5 Hz,
ArH), 4.75 (1H, d, J ¼ 8.6 Hz, OCH), 3.94 (1H, br s, OH), 2.61e2.13
(3H, m, COCH and 2 ꢁ CHH), 2.11e2.01 (1H, m, CHH), 1.88e1.24 (5H,
Pale yellow oil. Yield: 77%; 1H NMR (200 MHz, CDCl3) anti
d
7.36e7.26 (1H, m, ArH), 7.19 (1H, d, J ¼ 2.4 Hz, ArH), 7.08 (1H, d,
m, 5 ꢁ CHH); 13C NMR (50 MHz, CDCl3)
d
215.2, 140.0, 131.5, 128.7,
J ¼ 5.0 Hz, ArH), 4.92 (1H, d, J ¼ 8.4 Hz, OCH), 3.90 (1H, br s, OH),
2.74e2.22 (3H, m, COCH and 2 ꢁ CHH), 2.17e2.04 (1H, m, CHH),
121.7, 74.2, 27.3, 42.6, 30.7, 27.7, 24.7; HPLC analysis: Diacel Chir-
alpak AD-H, hexane/iPrOH 90:10, flow rate 0.5 mL/min, retention
time: 37.83 (minor) and 44.00 (major), 87% ee.
1.86e1.44 (5H, m, 5 ꢁ CHH); 13C NMR (50 MHz, CDCl3)
d 215.3,
142.3, 126.0, 125.9, 122.2, 70.6, 57.1, 42.6, 30.8, 27.8, 24.7; HPLC
analysis: Diacel Chiralpak AD-H, hexane/iPrOH 90:10, flow rate
1.0 mL/min, retention time: 14.01 (minor) and 19.43 (major), 76%
ee.
4.3.9. (S)-2-[(R)-Hydroxy-(2-(bromophenyl)methyl]-
cyclohexanone (16i) [7i]
White solid. Yield: 100%; mp 103e105 ꢀC; 1H NMR (200 MHz,
CDCl3) anti
d
7.56e7.46 (2H, m, ArH), 7.34 (1H, t, J ¼ 7.4 Hz, ArH),
4.3.15. (S)-3-[(R)-Hydroxy-[4-(nitrophenyl)methyl]dihydro-2H-
pyran-4(3H)-one (16o) [7i]
7.18e7.06 (1H, m, ArH), 5.30 (1H, d, J ¼ 7.9 Hz, OCH), 4.02 (1H, br s,
OH), 2.78e2.61 (1H, m, COCH), 2.52e2.25 (2H, m, 2 ꢁ COCHH),
2.18e2.01 (1H, m, CHH), 1.88e1.36 (5H, m, 5 ꢁ CHH); 13C NMR
Pale yellow solid. Yield: 100%; mp 116e118 ꢀC; 1H NMR
(200 MHz, CDCl3) anti
J ¼ 8.8 Hz, ArH), 4.97 (1H, d, J ¼ 8.2 Hz, OCH), 4.28e4.09 (1H, m,
d
8.21 (2H, d, J ¼ 8.8 Hz, ArH), 7.50 (2H, d,
(50 MHz, CDCl3)
d
215.2, 140.7, 132.5, 129.1, 128.5, 127.9, 123.4, 72.9,
57.6, 42.7, 30.6, 27.8, 25.0; HPLC analysis: Diacel Chiralpak AD-H,
OCHH), 3.90e3.64 (3H, m, 2 ꢁ OCHH and OH), 3.44 (1H, dd, J ¼ 11.4
Please cite this article in press as: A. Ahmetlli, et al., Proline dipeptides containing fluorine moieties as oganocatalysts for the asymmetric aldol
reaction, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.08.038

8
A. Ahmetlli et al. / Tetrahedron xxx (2018) 1e9
and 9.8 Hz, OCHH), 3.02e2.41 (3H, m, 3 ꢁ CHH); 13C NMR (50 MHz,
Acknowledgments
CDCl3)
d 209.2, 147.7, 147.4, 127.4, 123.8, 71.2, 69.7, 68.2, 57.5, 42.7;
HPLC analysis: Diacel Chiralpak AD-H, hexane/iPrOH 80:20, flow
rate 1.0 mL/min, retention time: 18.86 (minor) and 27.00 (major),
88% ee.
We would like to thank the Special Account for Research Grants
of the National and Kapodistrian University of Athens for the
funding. G.T.D. greatly appreciates financial support from the Hel-
lenic Foundation for Research and Innovation (ELIDEK).
4.3.16. (S)-3-[(R)-Hydroxy-[4-(nitrophenyl)methyl]dihydro-2H-
thiopyran-4(3H)-one (16p) [7i]
Appendix A. Supplementary data
Yellow solid. Yield: 100%; mp 137e139 ꢀC; 1H NMR (200 MHz,
CDCl3) anti
d
8.23 (2H, d, J ¼ 8.3 Hz, ArH), 7.53 (2H, d, J ¼ 8.3 Hz,
Supplementary data related to this article can be found at
https://doi.org/10.1016/j.tet.2018.08.038.
ArH), 5.04 (1H, d, J ¼ 7.9 Hz, OCH), 3.63 (1H, br s, OH), 3.07e2.91
(3H, m, COCH and 2 ꢁ CHH), 2.87e2.70 (2H, m, 2 ꢁ CHH), 2.68e2.42
(2H, m, 2 ꢁ CHH); 13C NMR (50 MHz, CDCl3)
d 211.2, 147.7, 147.6,
References
127.7, 123.8, 73.1, 59.4, 44.7, 32.8, 30.7; HPLC analysis: Diacel Chir-
alpak AD-H, hexane/iPrOH 90:10, flow rate 1.0 mL/min, retention
time: 51.83 (minor) and 73.77 (major), 97% ee.
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4.3.17. (2S,4S)-2-[(R)-Hydroxy-(4-(nitrophenyl)methyl]-4-
methylcyclohexanone (16q) [7l,7m]
White solid. Yield: 100%; mp 109e111 ꢀC; 1H NMR (200 MHz,
CDCl3)
d 8.23e8.18 (2H, m, ArH), 7.52e7.47 (2H, m, ArH), 5.48 (1H,
br s, syn OCH), 4.92 (1H, d, J ¼ 8.6 Hz, anti, OCH), 3.89e3.82 (1H, br
s, OH), 2.78e2.72 (1H, m, anti, COCH), 2.72e2.66 (1H, m, syn,
COCH), 2.50e2.48 (1H, m, CHH), 2.43e2.36 (1H, m, CHH),
2.09e2.07 (1H, m, CHH), 1.93 (1H, m, CH), 1.81e1.78 (1H, m, CHH)
1.60e1.54 (1H, m, CHH), 1.33 (1H, m, CHH) 1.05 (3H, d, J ¼ 6.9 Hz,
CH3); 13C NMR (50 MHz, CDCl3)
d 214.9, 148.4, 147.6, 127.8, 123.6,
74.1, 52.8, 38.1, 36.0, 32.9, 26.6,18.1; HPLC analysis: Diacel Chiralpak
OD-H, hexane/iPrOH 95:5, flow rate 1.0 mL/min, retention time:
27.42 (syn minor), 32.70 (syn major), 45.19 (anti major) and 54.59
(anti minor), 24% (anti) and 24% (syn) ee.
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4.3.18. (R)-2-[(R)-Hydroxy-(4-(nitrophenyl)methyl]-
cyclopentanone (16r) [7n]
Colourless oil. Yield: 100%; 1H NMR (200 MHz, CDCl3)
d 8.21 (2H,
d, J ¼ 8.7 Hz, ArH), 7.52 (2H, d, J ¼ 8.7 Hz, ArH), 5.42 (1H, s, syn,
OCH), 4.84 (1H, d, J ¼ 9.1 Hz, anti, OCH), 4.77 (1H, s, anti, COCH),
2.95 (1H, s, syn, COCH), 2.55e1.90 (5H, m, OH and 4 ꢁ CHH),
1.75e1.72 (2H, m. 2 ꢁ CHH); 13C NMR (50 MHz, CDCl3)
d syn 219.6,
150.2, 147.0, 126.3, 123.6, 70.3, 56.0, 38.8, 22.2, 20.2. anti 222.8,
148.5, 147.2, 127.3, 123.5, 74.3, 55.0, 38.5, 26.7, 20.2; HPLC analysis:
Diacel Chiralpak AD-H, hexane/iPrOH 95:5, flow rate 1.0 mL/min,
retention time: 29.99 (syn minor), 41.76 (syn major), 54.57 (anti
minor) and 55.83 (anti major), 4% ee.
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4.3.19. (R)-4-Hydroxy-4-(4-nitrophenyl)-butan-2-one (16s) [7i]
Colourless oil. Yield: 100%; 1H NMR (200 MHz, CDCl3)
d 8.20 (2H,
d, J ¼ 7.0 Hz, ArH), 7.52 (2H, d, J ¼ 7.0 Hz, ArH), 5.25 (1H, m, OCH),
3.56 (1H, br s, OH), 3.01e2.71 (2H, m, 2 ꢁ CHHCO), 2.21 (3H, s,
CH3CO); 13C NMR (50 MHz, CDCl3)
d 208.6, 149.9, 147.4, 126.4, 123.8,
68.9, 51.5, 30.7; HPLC analysis: Diacel Chiralpak AS-H, hex-
ane/iPrOH 85:15, flow rate 1.0 mL/min, retention time: 31.93 (ma-
jor) and 42.52 (minor), 52% ee.
k) I. Vlasserou, M. Sfetsa, D.T. Gerokonstantis, C.G. Kokotos, P. Moutevelis-
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4.3.20. (S)-2-((S)-1-Hydroxy-2-methylpropyl)cyclohexan-1-one
(16t) [7k]
Colorless oil. Yield: 17%; 1H NMR (200 MHz, CDCl3)
d 3.52 (1H,
m, OCH), 3.27 (1H, d, J ¼ 4.8 Hz, COCH), 2.42e2.34 (3H, m, 3 ꢁ
COCHH and CH), 2.35e2.25 (2H, m, 2 ꢁ CHH), 2.04e1.62(5H, m, 4 ꢁ
CHH and OH), 0.98 (3H, d, J ¼ 6.8 Hz, CH3), 0.88 (3H, d, J ¼ 6.8 Hz,
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d 216.1, 75.6, 53.7, 42.9, 30.6, 29.2,
27.8, 25.0, 20.1, 15.2; HPLC analysis: Diacel Chiralpak AD-H, hex-
ane/iPrOH 97:3, flow rate 0.5 mL/min, retention time: 25.08 (minor)
and 37.77 (major), 91% ee.
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Please cite this article in press as: A. Ahmetlli, et al., Proline dipeptides containing fluorine moieties as oganocatalysts for the asymmetric aldol
reaction, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.08.038

A. Ahmetlli et al. / Tetrahedron xxx (2018) 1e9
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Please cite this article in press as: A. Ahmetlli, et al., Proline dipeptides containing fluorine moieties as oganocatalysts for the asymmetric aldol
reaction, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.08.038