Combining prolinamides with 2-pyrrolidinone: Novel organocatalysts for the asymmetric aldol reaction

Article abstract of DOI:10.1016/j.tet.2018.03.054

Peptides and especially prolinamides have been identified as excellent organocatalysts for the aldol reaction. The combination of prolinamides with derivatives bearing the 2-pyrrolidinone scaffold, deriving from pyroglutamic acid, led to the identification of novel organocatalysts for the intermolecular asymmetric aldol reaction. The new hybrids were tested both in organic and aqueous media. Among the compounds tested, 22 afforded the best results in petroleum ether, while 25 afforded the products in brine in high yields and selectivities. Then, various ketones and aldehydes were utilized and the products of the aldol reaction were obtained in high yields (up to 100%) with excellent diastereo- (up to 97:3 dr) and enantioselectivities (up to 99% ee).

Full text of DOI:10.1016/j.tet.2018.03.054

Accepted Manuscript
Combining prolinamides with 2-pyrrolidinone: Novel organocatalysts for the
asymmetric aldol reaction
Ismini Vlasserou, Maria Sfetsa, Dimitrios-Triantafyllos Gerokonstantis, Christoforos G.
Kokotos, Panagiota Moutevelis-Minakakis
PII:
S0040-4020(18)30327-2
10.1016/j.tet.2018.03.054
TET 29394
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 18 January 2018
Revised Date: 19 March 2018
Accepted Date: 25 March 2018
Please cite this article as: Vlasserou I, Sfetsa M, Gerokonstantis D-T, Kokotos CG, Moutevelis-
Minakakis P, Combining prolinamides with 2-pyrrolidinone: Novel organocatalysts for the asymmetric
aldol reaction, Tetrahedron (2018), doi: 10.1016/j.tet.2018.03.054.
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Combining Prolinamides with 2-
Pyrrolidinone: Novel Organocatalysts for the
Asymmetric Aldol Reaction
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Ismini Vlasserou, Maria Sfetsa, Dimitrios-Triantafyllos Gerokonstantis, Christoforos G. Kokotos,*
Panagiota Moutevelis-Minakakis
Laboratory of Organic Chemistry, Department of Chemistry, University of Athens, Panepistimiopolis 15771,
Athens, Greece.

1
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Tetrahedron
journal homepage: www.elsevier.com
Combining Prolinamides with 2-Pyrrolidinone: Novel Organocatalysts for the
Asymmetric Aldol Reaction
Ismini Vlasserou,a Maria Sfetsa,a Dimitrios-Triantafyllos Gerokonstantis,a Christoforos G. Kokotos*a and
Panagiota Moutevelis-Minakakisa
a Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis 15771, Athens, Greece
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Peptides and especially prolinamides have been identified as excellent organocatalysts for the
aldol reaction. The combination of prolinamides with derivatives bearing the 2-pyrrolidinone
scaffold, deriving from pyroglutamic acid, led to the identification of novel organocatalysts for
the intermolecular asymmetric aldol reaction. The new hybrids were tested both in organic and
aqueous media. Among the compounds tested, 22 afforded the best results in petroleum ether,
while 25 afforded the products in brine in high yields and selectivities. Then, various ketones
and aldehydes were utilized and the products of the aldol reaction were obtained in high yields
(up to 100%) with excellent diastereo- (up to 97:3 dr) and enantioselectivities (up to 99% ee).
Available online
Keywords:
Aldol reaction
Organocatalysis
Prolinamides
Water
2009 Elsevier Ltd. All rights reserved
Dipeptides
1. Introduction
Since 2000, the year of its rebirth, asymmetric
Organocatalysis, the use of small organic molecules as catalysts
for the promotion of asymmetric organic transformations, has
provided elegant solutions to previously under-developed
reactions, complementary reactivities to transition-metal catalysis
and biocatalysis and new ways of thinking and solving chemical
problems.1,2 It is often acknowledged that the work of List,
Lerner and Barbas on the use of proline as the catalyst for the
intermolecular aldol reaction3 and the work by Macmillan on the
use of imidazolidinones as catalysts for cycloadditions4 had set
the first stones on building the field of Organocatalysis, that
nowadays is considered a common practice. The enantioselective
aldol reaction is among the most commonly employed C-C bond
forming reactions in modern asymmetric catalysis, and today is
considered a test reaction for novel organocatalysts.5 Since
Organocatalysis’ first days, it was evident that proline and
proline derivatives have
a prime role as catalysts in
organocatalytic transformations.6 Even today, research on the
identification of novel organocatalysts is vibrant and it is well
accepted that prolinamides containing functionalities able to act
as hydrogen bond donors are the most successful class of
organocatalysts. Representative examples are shown in Figure 1
(compounds 1-7).7 It is well accepted that the catalytic power of
Figure 1. Known prolinamide organocatalysts.
these compounds derives from the secondary amine of the
pyrrolidine ring, which can activate carbonyl compounds via
———
 Corresponding author. Tel.: +30-210-7274484; fax: +30-210-7274761;
e-mail: pminakak@chem.uoa.gr

2
Tetrahedron
ACCEPTED MANUSCRIPT
enamine formation, while the additional hydrogen bonding
interaction moieties on the molecules are responsible for the
enhanced selectivities observed. For many years, peptides have
been explored as potential organocatalysts,8 unfortunately, low or
moderate selectivities have been observed in most cases.9,10
A
very powerful step forward would be the use of water as the
solvent, since it will coincide with the principles of Green
Chemistry, since water is an abundant, safe and environmentally
friendly medium to carry out reactions. Unfortunately, proline
and most peptides fail to deliver high selectivities, until the
pioneering work of Hayashi and Barbas on the aldol reaction.11
Then, a number of amino acid derivatives12 and proline
derivatives7e,13 have been successfully developed for aldol
reactions being performed in aqueous media.
Scheme 2. Synthesis of 2-pyrrolidinone amines 13 and 14.
Recently, we have demonstrated that tripeptides of Pro-Phe with
a
tert-butyl ester from an amino acid are excellent
organocatalysts for the aldol reaction,14 while the use of
dipeptides can also be succeesful.7i,7j We have also attempted to
use carbon materials in combination with amines, in order to
promote aldol reactions.15 Having in mind our previous
endeavours in Organocatalysis,16 herein, we describe our efforts
to combine the prolinamide efficiency with the 2-pyrrolidinone
scaffold.
2. Results and Discussion
Scheme 3. Synthesis of 2-pyrrolidinone amine 15.
(S)-Benzyloxycarbonyl protected proline (8) was coupled with
either (S)-methyl phenylalaninate (9) or (R)-methyl
phenylalaninate (10) using dicyclohexylcarbodiimide (DCC) as
the coupling reagent, in the presence of 1-hydroxybenzotriazole
(HOBt).17
Saponification
afforded
the,
N-protected
diastereomeric dipeptides, 11 and 12, respectively. To the
resulting dipeptides, a series of amines (13-16), derived from
Scheme 4. Synthesis of 2-pyrrolidinone amine 16.
either (S)- or (R)- pyroglutamic acid, were added under
conventional peptide coupling conditions, affording the protected
amides 17-21. We have previously shown that no epimerization
is occurring at this step.14 Finally, deprotection via catalytic
hydrogenation, afforded organocatalysts 22-27 (Scheme 1).
For the synthesis of 2-pyrrolidinone amines 13-16, 2-
pyroglutamic acid was employed (Schemes 2-4). Starting from
alcohols 28-(S) and 29-(R),18 a convenient method that avoids
epimerization19 was selected for the synthesis of the
corresponding amines [13-(S) and 14-(R)]. This synthetic
approach combines mesyl ester activation, substitution from an
azide and Staundiger reaction (Scheme 2). In order to study the
efficiency of the additional hydrogen bonding, deriving from the
2-pyrrolidinone moiety, 2-pyrrolidinone amine 15, having an
extended alkyl chain between the 2-pyrrolidinone and the amine,
was synthesized from 28 (Scheme 3). Wittig reaction was
followed by hydrogenation and reduction in order to lead to
alcohol 34. Following the same route as before, alcohol 15 was
obtained (Scheme 3). Finally, starting from 36,20 benzylation
afforded compound 37. Deprotection under acidic conditions led
to alcohol 38. As above, this was selectively transformed to
amine 16.
Scheme 1. Synthesis of the organocatalysts 22-27.
The synthesized organocatalysts were then evaluated in the aldol

3
were tested (entries 9-12, Table 1). Unfortunately, in all cases
Table 1. Enantioselective aldol reaction of cyclohexanone
ACCEPTED MANUSCRIPT
with 4-nitrobenzaldehyde using compounds 22-27 as
lower yields and selectivities were obtained. As expected,
catalyst 27 possesing multiple hydrogen bonding sites, worked in
aqueous conditions, however, the conversion was low.
catalysts.a
After identifying catalyst 25 as a potent catalyst in brine, we
questioned whether we could find improved reaction conditions
for catalyst 22 in organic medium, since it was the catalyst that
provided the best enantioselectivity. Thus, a variety of solvents
and reaction conditions were tested with catalyst 22 (Table 2).
Initially, a number of organic solvents were utilized (entries 1-11,
Table 2). It seems that a small quantity of water is beneficial for
the catalysis, probably through facilitating the hydrolysis of the
product from the catalyst. Petroleum ether proved to be the best
solvent, along with diethyl ether and acetonitrile, leading to high
yield and selectivities of the product. Lowering the reaction
temperature, proved that petroleum ether afforded the best results
Yield
(%)b
ee
Entry Catalyst
Conditions
drc
(%)d
Pet. Ether,
H2O, 48 h
brine, 24 h
Pet. Ether,
H2O, 48 h
brine, 24 h
Pet. Ether,
H2O, 24 h
brine, 24 h
Pet. Ether,
H2O, 48 h
brine, 48 h
Pet. Ether,
H2O, 24 h
brine, 24 h
Pet. Ether,
H2O, 72 h
brine, 72 h
1
2
22
92
96
93:7
91:9
88:12
89:11
91:9
88:12
89:11
93:7
84:16
82:17
-
93
88
81
86
90
86
90
90
77
76
-
22
23
3
100
23
24
4
100
100
5
24
25
100
50
6
7
Table 2. Enantioselective aldol reaction of cyclohexanone
with 4-nitrobenzaldehyde using catalyst 22.a
25
26
100
100
100
0
8
9
26
27
10
11
12
27
43
93:7
91
Yield
(%)b
98
100
93
98
84
96
96
86
55
92
89
95
88
100
100
0
ee
(%)d
86
88
92
92
91
93
88
94
84
93
91
85
94
91
>99
-
drc
a
Entry
1e
2
3
4
Conditions
Catalyst (0.014 mmol) in solvent (1.0 mL) (Pet. Ether with 1
drop of water or brine), additive (0.018 mmol), aldehyde (0.09
mmol) and cyclohexanone (0.90 mmol). b Yield determined by 1H
NMR. c The diastereomeric ratio (dr) anti:syn was determined by
THF, 4-NBA
THF, 4-NBA
toluene, 4-NBA
AcOEt, 4-NBA
CH2Cl2, 4-NBA
Et2O, 4-NBA
85:15
95:5
90:10
96:4
82:18
95:5
91:9
93:7
88:12
93:7
89:11
84:16
97:3
90:10
95:5
-
1H NMR spectroscopy of the crude reaction mixture. The
d
5
enantiomeric excess (ee) for the anti diastereomer was
determined by chiral HPLC. 4-NBA: 4-nitrobenzoic acid.
6
7f
brine, 4-NBA
8
9
MeCN, 4-NBA
MeOH, 4-NBA
Pet. Eth., 4-NBA
CHCl3, 4-NBA
brine, 4-NBA
reaction between cyclohexanone and 4-nitrobenzaldehyde both in
organic and aqueous medium (Table 1). Initially, peptide 22,
based on Pro-Phe and 2-pyrrolidinone was tested, leading to high
yields in both reaction conditions (organic solvent of aqueous
conditions) with good diastereoselectivity and enantioselectivity
(entries 1 and 2, Table 1). Comparing the catalytic activity of 22
with the corresponding dipeptide Pro-Phe or H-Pro-Phe-tBu,7i
there is a significant increase on the catalytic activity that can be
attributed to the additional 2-pyrrolidinone ring. When the
development of a chiral catalyst requires the presence of more
than one chiral centers, matched and mis-matched effects might
be present. A mis-matched effect between Pro-Phe and the chiral
center of 2-pyrrolidinone was observed, when catalyst 23 was
tested (entries 3 and 4, Table 1). This effect was observed in
lesser extent, when the chiral center on the phenylalaline residue
was altered in catalyst 24 (entries 5 and 6, Table 1). The distance
on the linker between the Pro-Phe dipeptide backbone with 2-
pyrrolidinone, (catalyst 25) was then studied (entries 7 and 8,
Table 1). In the latter case, high diastereoselectivity and
enantioselectivity were observed. These results verify the
hypothesis that if the catalyst has additional hydrogen bonding
sites, it recognizes better the electrophile in the transition state
leading to higher levels of stereocontrol. In an effort to study the
substitution on the 2-pyrrolidinone moiety, catalysts 26 and 27
10
11
12g
13g
14e,g
15g
16h,g
17i,g
18j
19
20
21
22
23
Et2O, 4-NBA
MeCN, 4-NBA
Pet. Eth., 4-NBA
Pet. Eth., 4-NBA
Pet. Eth., 4-NBA
Pet. Eth., 4-NBA
Pet. Eth., AcOH
Pet. Eth., PhCOOH
Pet. Eth., TsOH
Pet. Eth., Z-Phe-OH
Pet. Eth., 4-FPO
0
62
traces
100
32
-
-
89
-
>99
93
-
88:12
-
83:17
65:35
-
0
51
70:30
96
a
Catalyst (0.014 mmol) in solvent (1.0 mL), additive (0.018
mmol), H2O (0.1 mL), aldehyde (0.09 mmol) and cyclohexanone
b
c
(0.90 mmol).
Yield determined by 1H NMR.
The
1
diastereomeric ratio (dr) anti:syn was determined by H NMR
d
spectroscopy of the crude reaction mixture. The enantiomeric
excess (ee) was determined by chiral HPLC. e No H2O. f Reaction
g
o
h
i
time 24 h. 0 C. 10 mol% catalyst. 10 mol% catalyst, 15
mol% 4-NBA.
j
2 equiv. of cyclohexanone. 4-NBA: 4-
nitrobenzoic acid. AcOH: acetic acid. TsOH: p-toluenesulfonic
acid. 4-FPO: 4-fluorophenol.

4
Tetrahedron
reaction (entries 16-18, Table 2). Then, a variety of acid additives
Table 3. Enantioselective aldol reaction between ketones
ACCEPTED MANUSCRIPT
and aldehydes using catalyst 22 and 25.a
were employed, since it is known that these organocatalytic
reactions are sometimes sensitive to acid counterparts and fine
tuning is required (entries 19-23, Table 2). Only carboxylic acids
that have similar pKa with 4-nitrobenzoic acid led to similar
levels of reactivity (PhCOOH, entry 20, Table 2).
We then turned our attention in exploring the substrate scope of
the enantioselective aldol reaction by employing either catalyst
22 in petroleum ether or catalyst 25 in aqueous environment
(Table 3). A variety of substituted aromatic aldehydes can be
employed with cyclohexanone leading to products from good to
excellent yields and selectivities (entries 1-22, Table 3). Electron-
withdrawing groups at any position of the aryl moiety led to good
to excellent results, while the use of aromatic aldehydes
substituted with halogens led from moderate to high yields and
high to excellent selectivities. Benzaldehyde and heteroaromatic-
substituted aldehydes proved more problematic (entries 19-22,
Table 3). Tetrahydropyran-4-one and tetrahydrothiopyran-4-one
required longer reaction time (entries 23-26, Table 3).
Disubstituted cyclohexanone at the 4-position required prolonged
reaction time, and only catalyst 22 delivered the product in good
yield and high enantioselectivity (entries 27 and 28, Table 3).
The desymmetrization of ketones is also possible,6g,6i since 4-
methyl cyclohexanone delivered the product in high yield and
with excellent selectivities in the case where catalyst 25 was
employed (entries 29 vs 30, Table 3). Cyclopentanone was also
utilized with some success, since very low diastereoselectivities
were observed (entries 31 and 32, Table 3). Moreover, in order to
broaden the scope of this methodology, we investigated the
reaction of acetone with 4-nitrobenzaldehyde (entries 33 and 34,
Table 3).
Yield
(%)b
ee
Entry
Ketone
Ar/ Conditions
drc
(%)d
1
2
4-NO2C6H4/A
4-NO2C6H4/B
92(42a)
100(42a)
93:7
93:7
93
90
3
3-NO2C6H4/A
3-NO2C6H4/B
2-NO2C6H4/A
2-NO2C6H4/B
3-CNC6H4/A
3-CNC6H4/B
4-CF3C6H4/A
4-CF3C6H4/B
4-FC6H4/A
100(42b) 81:19
97(42b) 93:7
100(42c) 84:16
95(42c) 93:7
100(42d) 76:24
94(42d)
94(42e)
n.r.
20(42f)
89(42f)
90(42g)
92(42g)
89(42h)
100(42h) 79:21
85(42i) 97:3
100(42i) 77:23
89
92
97
96
86
70
92
-
92
92
70
90
74
88
88
86
83
99
76
95
4e
5
6e
7e
8f
83:17
83:17
-
83:17
88:12
95:5
9f
10f
11f
12f
13e
14g
15e
16e
17f
18g
19f
20g
21h
22
4-FC6H4/B
4-ClC6H4/A
4-ClC6H4/B
2-ClC6H4/A
2-ClC6H4/B
4-BrC6H4/A
4-BrC6H4/B
C6H5/A
C6H5/B
4-pyridinyl/A
4-pyridinyl /B
88:12
82:18
69(42j)
71(42j)
100(42k)
100(42k)
97:3
86:14
94:6
97:3
23f
24g
4-NO2C6H4/A
4-NO2C6H4/B
97(42l)
84(42l)
75:25
89:11
78
73
In an effort to further expand the possibilities of the catalytic
acitivity, a very difficult aldol reaction between acetone and
trifluoroacetophenone was tested (Scheme 5).21 The desired
25g
26g
4-NO2C6H4/A
4-NO2C6H4/B
100(42m) 84:16
100(42m) 85:15
83
90
27e
28e
4-NO2C6H4/A
4-NO2C6H4/B
100(42n) 86:14
90
-
n.r.
-
Scheme 5. Expanding the catalytic activity of 23.
29f
30e
4-NO2C6H4/A
4-NO2C6H4/B
92(42o)
100(42o) 78:22
71:29
37
90
31e
32e
4-NO2C6H4/A
4-NO2C6H4/B
100(42p) 40:60
100(42p) 32:68
76
36
33h
4-NO2C6H4/A
4-NO2C6H4/B
58(42q)
n.r.
-
-
89
-
34e
a
b
Conditions A: 22 in Pet. Eth./H2O Conditions B: 25 in brine.
c
Isolated yield.
The diastereomeric ratio (dr) anti:syn was
determined by 1H NMR spectroscopy of the crude reaction
mixture. d The enantiomeric excess (ee) for the major isomer was
determined by chiral HPLC. e Reaction time 72 h. f Reaction time
96 h. g Reaction time 120 h. h Reaction time 24 h.
Scheme 6. Study of the catalytic activity of 22 with aliphatic
aldehydes.
(entries 12-15, Table 2). Among other reaction conditions, none
proved better (entries 16-18, Table 2). Lowering the equivalents
of ketone or the catalyst loading had a dentrimental effect on the

5
product 44 was isolated in moderate yield with good
enantioselectivity. In an effort to further expand the reaction,
isobutyraldehyde (45) was employed. When 45 reacted with
acetone, 46 was obtained in very low yield and
enantioselectivity, while when reacted with cyclohexanone, 47
was obtained in low yield, but excellent diastereoselectivity and
enantioselectivity (Scheme 6).
We then turned our attention in revocery and reuse of catalyst
22 for the reaction between cyclohexanone and 4-
nitrobenzaldehyde. The catalyst was recovered succesfully
(73%), and then its activity was studied in an additional catalytic
cycle. The expected yield of the product remained high,
unfortunately, the enantioselectivity dropped (yield 82%, dr
81:19, ee 72%).
chromatogram was performed by fluorescence quenching using
ACCEPTED MANUSCRIPT
ninhydrin stain. Melting points were determined on a Büchi 530
hot stage apparatus. H, 19F and 13C NMR spectra were recorded
1
on Varian Mercury 200 MHz and are internally referenced to
residual solvent signals (CDCl3, CD3OD and DMSO-d6). Data for
1H NMR spectroscopy are reported as follows: chemical shift (δ
ppm), multiplicity (s = singlet, d = doublet, t = triplet, q =
quadruplet, m = multiplet, br s = broad signal), integration,
coupling constant and assignment. Wherever rotamers exist, are
presented in brankets. Diastereomeric ratios were determined by
1H NMR spectroscopy (200 MHz). Data for 13C NMR are
reported in terms of chemical shift (δ ppm). Wherever rotamers
exist, are cited in parenthesis. 19F spectra were recorded on
Varian Mercury (188 MHz) and are internally referenced to
trifluoroacetic acid. Mass spectra were recorded on a Finnigan
Surveyor MSQ Plus, with only molecular ions and major peaks
being reported with intensities quoted as percentages of the base
peak. HRMS spectra were recorded on Thermo® Orbitrap Velos
spectrometer. High Performance Liquid Chromatography
(HPLC) was used to determine enantiomeric excesses 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 The configuration of the products has been
assigned by comparison to literature data.7h Data for known
compounds match literature data. All new compounds were
assigned by analogy.
A plausible transition-state model is proposed in Figure 2. The
secondary amine of the pyrrolidine ring activates the ketone
through the formation of an enamine intermediate. The
electrophile is activated through a double hydrogen bonding
network consisting of the two amide protons of the catalyst,
while the bulkiness of the moiety of 2-pyrrolidinone ensures the
single orientation of the aldehyde.
3.2. General procedure for the synthesis of the catalysts
Figure 2. Proposed transition-state model for the aldol
Synthesis of amines 13-16
reaction.
3.2.1. (S)-5-(Aminomethyl)-1-benzylpyrrolidin-2-
In conclusion, the synthesis of peptides based on Pro-Phe and
2-pyrrolidinone moiety was carried out. Previously, we had
shown that dipeptides tripeptides based on proline having at their
C-terminus tert-butyl esters of amino acids provided excellent
organocatalysts for the aldol reaction. In this study, we have
shown that the addition of the 2-pyrrolidinone moiety affords
catalysts that have a better catalytic behavior. Matched and mis-
matched effects were observed. When catalyst 22 was utilized,
the aldol products were obtained in good to excellent yields and
selectivities in wet petroleum ether. When catalyst 25 was
employed, the aldol product was obtained in similar high yields
and selectivities but in brine. It is worth mentioning that both
catalysts work at room temperature and both have distinct
advantages compared to proline, since proline’s low solubility in
organic solvents and low selectivity obtained in aqueous media,
can be bypassed with these two catalysts. The catalytic activity of
these catalysts was demonstrated not only to aldol reaction
between ketones and aromatic aldehydes, but also in aldol
reactions of ketone with ketones.
one (13)
To a stirred solution of alcohol 2818 (0.66 g, 3.22 mmol) in
CH2Cl2 (3 mL) at 0 oC, Et3N (0.67 mL, 4.83 mmol) and
MeSO2Cl (0.38 mL, 4.83 mmol) were added. The reaction
o
mixture was left stirring at 0 C for 30 min, at room temperature
for 30 min, and then, the solvent was evaporated under reduced
pressure. The crude mixture was dissolved in AcOEt (10 mL)
and washed with aq. H2SO4 (5%, 10 mL), H2O (10 mL), aq.
NaHCO3 (5%, 10 mL) and brine (10 mL). After evaporation of
the solvent, the crude methanosulfonic ester was dissolved in dry
DMF (6 mL) and NaN3 (0.63 g, 9.66 mmol) was added. The
reaction mixture was left stirring at 55 oC overnight. After
evaporation of the solvent, the residue was dissolved in H2O (10
mL) and extracted with Et2O (3 x 5 mL). The combined organic
layers were washed with H2O (3 x 10 mL) and the solvent was
evaporated. Purification of the crude azide 30 was achieved using
column chromatography eluting with pet.ether/EtOAc (40:60).
Colorless oil, 645 mg, 87% yield; Rf (AcOEt/pet. ether 6:4) 0.40;
1
[α]D + 36.2 (c = 1.0, MeOH); H NMR (200 MHz, CDCl3) δ
7.34-7.18 (5H, m, ArH), 4.88 (1H, d, J = 15.2 Hz, NCHHPh),
4.07 (1H, d, J = 15.2 Hz, NCHHPh), 3.59-3.49 (1H, m, NCH),
3.41(1H, dd, J = 12.8 and 4.4 Hz, CHHN3), 3.27 (1H, dd, J =
12.8 and 3.6Hz, CHHN3), 2.63-2.26 (2H, m, COCH2), 2.12-1.97
(1H, m, CHH), 1.88-1.72 (1H, m, CHH); 13C NMR (50 MHz,
CDCl3) δ 175.2, 136.3, 128.7, 127.8, 127.6, 56.1, 52.9, 44.5,
29.7, 22.0. MS (ESI) m/z (%) 231 (100) ([M+H]+).
To a stirred solution of azide 30 (0.41 g, 1.78 mmol) in MeOH
(10 mL), 10% Pd/C (10 mol%) was added and the reaction
mixture was left stirring at room temperature for 2.5 h under
hydrogen atmosphere. After filtration through Celite, the solvent
was evaporated to afford the crude product. Purification of the
3. Experimental section
3.1. General Information
Organic solutions were concentrated under reduced pressure
on a Büchi rotary evaporator. Chromatographic purification of
products was accomplished using column chromatography on
Merck Kieselgel 60 F254 230-400 mesh. Thin-layer
chromatography (TLC) was performed on aluminum backed
silica plates (0.2 mm, 60 F254). Visualization of the developed

6
Tetrahedron
desired amine 13 was achieved using column chromatography
MHz, CDCl3) δ 175.1, 136.2, 128.6, 127.6, 127.5, 56.0, 52.8,
ACCEPTED MANUSCRIPT
eluting with CHCl3/MeOH (80:20). Colorless oil; 244 mg; 67%
yield; Rf (CHCl3/MeOH 8:2) 0.42; [α]D + 25.7 (c = 1.0, MeOH);
1H NMR (200 MHz, CDCl3) δ 7.29-7.26 (5H, m, ArH), 4.86 (1H,
d, J = 15.0 Hz, CHHPh), 4.12 (1H, d, J = 15.0 Hz, CHHPh),
3.53-3.47 (1H, m, NCH), 2.87 (1H, dd, J = 12.4 and 5.4 Hz,
CHHNH2), 2.74 (1H, dd, J = 12.4 and 1.8 Hz, CHHNH2), 2.61-
2.32 (2H, m, COCH2), 2.17-1.83 (2H, m, CH2), 1.54 (2H, br s,
NH2); 13C NMR (50 MHz, CDCl3) δ 175.6, 136.6, 128.5, 127.7,
127.3, 58.8, 44.4, 42.9, 30.1, 21.3; MS (ESI) m/z (%) 205 (100)
([M+H]+); HRMS exact mass calculated for [M+H]+ (C12H17N2O)
requires m/z 205.1335, found m/z 205.1344.
44.4, 29.6, 21.9; MS (ESI) m/z (%) 231 (100) ([M+H]+).
The desired amine 14, enantiomer of amine 13, was obtained
following the same procedure as above, but starting from azide
31 (0.41 g, 1.78 mmol) Colorless oil; 225 mg, 62% yield; Rf
(CHCl3/MeOH 8:2) 0.39; [α]D -25.0 (c = 1.0, MeOH); 1H NMR
(200 MHz, CDCl3) δ 7.30-7.18 (5H, m, ArH), 4.80 (1H, d, J =
16.0 Hz, CHHPh), 4.07 (1H, d, J = 16.0 Hz, CHHPh), 3.47-3.43
(1H, m, NCH), 2.87 (1H, dd, J = 12.1 and 5.5Hz, CHHNH2),
2.74 (1H, dd, J = 12.1 and 1.6 Hz, CHHNH2), 2.51-2.35 (2H, m,
COCH2), 2.12-1.80 (2H, m, CH2), 1.52 (2H, br s, NH2); 13C
NMR (50 MHz, CDCl3) δ 175.4, 136.3, 128.3, 127.4, 127.1,
58.3, 44.1, 42.5, 29.9, 21.0; MS (ESI) m/z (%) 205 (100)
([M+H]+); HRMS exact mass calculated for [M+H]+ (C12H17N2O)
requires m/z 205.1335, found m/z 205.1342.
3.2.2. (R)-1-benzyl-5-(hydroxymethyl)pyrrolidin-2-
one (29)
Methyl (R)-pyroglutamate (4.50 g, 31.44 mmol) was dissolved in
dry THF (30 mL), followed by the addition of benzylbromide
(4.1 mL, 34.43 mmol). The reaction mixture was cooled at 0 C
3.2.4. Methyl (S, E)-3-(1-benzyl-5-oxopyrrolodin-
o
2-yl)acrylate (32)
and NaH (60% in paraffin oil, 1.89 g, 47.16 mmol) was added in
o
portions. The stirring was continued for 30 min at 0 C and 4 h at
To a stirred solution of alcohol 28 (0.60 g, 2.92 mmol) in a
mixture of dry toluene and dry DMSO 2:1 (3.5 mL), EDC.HCl
(1.46 g, 7.62 mmol) was added followed by the dropwise
addition of dry pyridine (0.66 mL, 8.18 mmol) and TFA (90 μL,
1.17 mmol) under argon. After stirring at room temperature for 2
h the reaction was quenched by the addition of CHCl3 (20 mL)
and the solution was washed with brine (10 mL) and H2O (10
mL). The solvent was evaporated and the resulting crude
aldehyde was subjected to Wittig reaction without further
purification. More specifically, it was dissolved in dry THF (5
mL), methyl (triphenylphosphoranylidene)acetate (0.97 g, 2.92
mmol) was added and the mixture was refluxed under argon for 1
h. The reaction was quenched by the addition of saturated
solution of NH4Cl (1 mL) and the solvent was evaporated. The
residue, dissolved in Et2O (30 mL), was successively washed
with saturated solution of NH4Cl (5 mL), brine (10 mL) and H2O
(10 mL). After evaporation of the solvent the crude alkene was
purified using column chromatography eluting with AcOEt.
Yellowish oil; 0.44 g, 58% yield; Rf (AcOEt) 0.50; [α]D +25.4 (c
room temperature. The reaction was quenched by the addition of
saturated solution of NH4Cl (10 mL), the organic solvent was
evaporated and the residue was dissolved in ethyl acetate (30
mL). The organic layer was washed with brine (30 mL) and the
solvent was evaporated to afford the crude ester. Purification was
achieved using column chromatography eluting with pet.
ether/EtOAc (40:60). Colorless oil; 4.99 g; 68% yield; Rf
(AcOEt/pet. ether 1:1) 0.30; [α]D -2.2 (c = 0.9, MeOH); 1H
NMR (200 MHz, CDCl3) δ 7.38-7.16 (5H, m, ArH), 4.99 (1H, d,
J = 15.2 Hz, CHHPh), 4.02-3.94 (2H, m, CHHPh & NCH), 3.64
(3H, s, OCH3), 2.60-1.96 (4H, m, 2 x CH2); 13C NMR (50 MHz,
CDCl3) δ 175.0, 172.2, 135.7, 128.7, 128.4, 127.7, 58.6, 52.3,
45.5, 29.5, 22.7.
In a two necked flask, LiBH4 (0.26 g, 11.68 mmol) was
suspended in dry THF (6 mL) under argon at room temperature.
A solution of the above mentioned (R)-methyl 1-benzyl-5-
oxopyrrolidine-2-carboxylate (2.72 g, 11.68 mmol) in dry THF
(5 mL) was added dropwise. The reaction was completed within
1 h and it was quenched by the addition of a 20% solution of
1
= 1.0, CHCl3); H NMR (200 MHz, CDCl3) δ 7.29-7.13 (5H, m,
ArH), 6.69 (1H, dd, J = 15.6 and 8.2 Hz, =CH), 5.83 (1H, d, J =
15.6 Hz, =CHCO), 5.02 (1H, d, J = 14.8 Hz, CHHPh), 4.04-3.94
(1H, m, NCH), 3.79-3.74 (4H, m, CHHPh & OCH3), 2.52-2.35
(2H, m, COCH2), 2.24-2.13 (1H, m, CHH), 1.87-1.73 (1H, m,
CHH); 13C NMR (50 MHZ, CDCl3) δ 174.9, 166.1, 146.3, 136.2,
128.8, 128.4, 127.8, 123.2, 58.0, 52.0, 44.7, 29.7, 24.7; MS (ESI)
m/z (%) 260 (100) ([M+H]+).
o
AcOH at 0 C, until the production of the gas was ceased. The
excess of acetic acid was neutralized by the addition of a small
quantity of Na2CO3. The organic solvent was evaporated under
reduced pressure and the residue was dissolved in EtOAc (30
mL). The organic phase was washed with brine (30 mL) and the
solvent was evaporated to afford the desired alcohol 29 as a white
o
solid; 1.75 g; 73% yield; mp 78-80 C; Rf (CHCl3/MeOH 9:1)
0.43; [α]D -106.1 (c = 1.0, MeOH); 1H NMR (200 MHz, CDCl3) δ
7.36-7.26 (5H, m, ArH), 5.00 (1H, d, J = 16.0 Hz, NCHHPh),
4.11 (1H, d, J = 16.0 Hz, NCHHPh), 3.83-3.78 (1H, m, NCH),
3.52-3.49 (2H, m, CH2OH), 2.65-2.28 (2H, m, COCH2), 2.07-
1.96 (2H, m, CH2); 13C NMR (50 MHz, CDCl3) δ 176.3, 136.5,
128.7, 127.9, 127.5, 61.9, 58.6, 44.3, 30.6, 21.0. MS (ESI) m/z
(%) 206 (100) ([M+H]+).
3.2.5. (R)-1-Benzyl-5-(3-
hydroxypropyl)pyrrolidin-2-one (34)
To a stirred solution of alkene 32 (0.44 g, 1.70 mmol) in MeOH
(5 mL), 10% Pd/C (10 mol%) was added and the reaction
mixture was left stirring at room temperature, overnight. After
filtration through Celite, the solvent was evaporated to afford the
desired product as colorless oil.
3.2.3. (R)-5-(Aminomethyl)-1-benzylpyrrolidin-2-
one (14)
To a two necked flask, LiBH4 (56 mg, 2.57 mmol) was
suspended in dry THF (8 mL) under argon at room temperature.
A solution of compound 33 (0.40 g, 1.53 mmol) in dry THF (2
mL) was added dropwise and the reaction mixture was stirred for
10 h. The reaction was quenched by the addition of a 20% aq.
Same procedure as above for the synthesis of the azide 30, but
utilizing alcohol 29 (0.66 g 3.22 mmol). The azide 31 was
obtained as a colorless oil; 556 mg, 75% yield; Rf (AcOEt/pet.
ether 6:4) 0.38; [α]D -35.8 (c = 1.0, MeOH); 1H NMR (200 MHz,
CDCl3) δ 7.32.-7.18 (5H, m, ArH), 4.87 (1H, d, J = 16.0 Hz,
CHHPh), 4.09 (1H, d, J = 16.0 Hz, CHHPh), 3.57-3.48 (1H, m,
NCH), 3.40 (1H, dd, J = 12.4 and 4.1 Hz, CHHN3), 3.26 (1H, dd,
J = 12.4 and 3.4 Hz, CHHN3), 2.62-2.26 (m, 2H, COCH2), 2.06-
2.01 (m, 1H, CHH), 1.87-1.71 (m, 1H, CHH); 13C NMR (50
o
solution of AcOH at 0 C until gas production was ceased. The
excess of acetic acid was neutralized by the addition of a small
quantity of Na2CO3. The solvent was evaporated and the residue
was dissolved in AcOEt (15 mL). The organic phase was washed

7
with brine (8 mL) and H2O (8 mL) and the solvent was
75.7, 75.4, 72.5, 71.9, 62.3, 59.8; MS (ESI) m/z (%) 328
ACCEPTED MANUSCRIPT
evaporated. The residue was purified with column
chromatography eluting with AcOEt and the product was
obtained as a yellowish oil, 268 mg, 75% yield; Rf (AcOEt) 0.22;
[α]D +38.6 (c = 1.0, CHCl3); 1H NMR (200 MHz, CDCl3) δ 7.34-
7.19 (5H, m, ArH), 4.95 (1H, d, J = 15.2 Hz, NCHHPh), 3.95
(1H, d, J = 15.2 Hz, NCHHPh), 3.71-3.36 (3H, m, CH2OH &
NCH), 2.54-1.99 (4H, m, 2 x CH2), 1.76-1.36 (4H, m, 2 x CH2);
13C NMR (50 MHz, CDCl3) δ 175.4, 136.7, 128.7, 128.0, 127.6,
62.3, 56.9, 44.2, 30.3, 29.1, 27.6, 23.9; MS (ESI) m/z (%) 234
(100) ([M+H]+).
(100%) ([M+H]+).
3.2.9. (3R, 4R, 5R)-5-(Aminomethyl)-3,4-
bis(benzyloxy)pyrrolidin-2-one (16)
Same procedure as above utilizing alcohol 38. Colorless oil, 81
mg, 73% yield; Rf (CHCl3/MeOH 80:20) 0.35; [α]D + 21.8 (c =
0.9, MeOH); H NMR (200 MHz, CDCl3) δ 7.43-7.26 (10H, m,
1
ArH), 6.36 (1H, br s, NH), 4.92 (1H, d, J = 11.8 Hz, OCHHPh),
4.74 (1H, d, J = 11.8 Hz, OCHHPh), 4.63 (1H, d, J = 11.6 Hz,
OCHHPh), 4.46 (1H, d, J = 11.6 Hz, OCHHPh), 4.04 (1H, d, J =
5.4 Hz, OCH), 3.81 (1H, t, J = 5.0 Hz, OCH), 3.74-3.67 (1H, m,
NCH), 2.98 (1H, dd, J = 13.6 and 3.8 Hz, CHHNH2), 2.59 (1H,
dd, J = 13.2 and 7.2 Hz, CHHNH2), 1.88 (2H, br s, NH2); 13C
NMR (50 MHz, CDCl3) δ 173.9, 137.9, 137.2, 128.5, 128.2,
128.0, 127.8, 127.5, 127.3, 77.8, 74.7, 73.9, 72.5, 54.8, 42.9; MS
(ESI) m/z (%) 327 (100%) ([M+H]+); HRMS exact mass
calculated for [M+H]+ (C26H29N2O3) requires m/z 417.2173,
found m/z 417.2180.
3.2.6. (R)-5-(3-Aminopropyl)-1-benzylpyrrolidin-
2-one (15)
Same procedure as above utilizing alcohol 34. Colorless oil; 130
1
mg, 90% yield; H NMR (200 MHz, CDCl3) δ 7.29-7.16 (5H, m,
ArH), 4.91 (1H, d, J = 15.2 Hz, NCHHPh), 3.93 (1H, d, J = 15.2
Hz, NCHHPh), 3.50-3.39 (1H, m, NCH), 2.71 (2H, br s, NH2),
2.48-2.41 (2H, m, CH2NH2) , 2.37-2.14 (2H, m, COCH2), 2.10-
1.96 (1H, m, CHH), 1.72-1.55 (2H, m, 2 x CHH), 1.41-1.21 (3H,
m, 3 x CHH); 13C NMR (50 MHz, CDCl3) δ 175.2, 136.7, 128.7,
127.9, 127.5, 56.8, 49.5, 44.2, 30.5, 30.3, 24.6, 23.8; MS (ESI)
m/z (%) 233.22 (35) ([M+H]+); HRMS exact mass calculated for
[M+H]+ (C14H21N2O) requires m/z 233.1648, found m/z
233.1654.
Synthesis of catalysts 22-27
3.2.10. (S)-2-[(S)-1-
(Benzyloxycarbonyl)pyrrolidine-2-
carboxamido] -3-phenylpropanoic acid (11)7 h
3.2.11. (R)-2-[(S)-1-
3.2.7. tert-Butyl (2R,3R,4R)-3,4-bis(benzyloxy)-2-
(((tert-butyldimethylsilyl)oxy)methyl)-5-
oxopyrrolidine-1-carboxylate (37)
(Benzyloxycarbonyl)pyrrolidine-2-
carboxamido] -3-phenylpropanoic acid (12)
To a stirred solution of alcohol 3620 (160 mg, 0.44 mmol) in
CH2Cl2 (3 mL) freshly prepared Ag2O22 (0.27 g, 1.19 mmol) was
added under argon, followed by the addition of benzylbromide
(157 μL, 1.32 mmol) at 0 oC. The reaction mixture was left
stirring at room temperature overnight. After filtration through
Celite, the solvent was evaporated and the crude residue was
purified using column chromatography eluting with
pet.ether/AcOEt (70:30). Colorless oil, 179 mg, 75% yield; Rf
To a stirred solution of Cbz-proline (8) (1.25 g, 5.00 mmol) in
dry CH2Cl2 (20 mL) at 0 oC, 1-hydroxybenzotriazole (HOBt)
(676 mg, 5.00 mmol), (R)-methylphenylalaninate hydrochloride
(10) (1.08 g, 5.00 mmol), Et3N (0.700 mL, 5.00 mmol) and
dicyclohexylcarbodiimide (DCC) (1.03 g, 5.00 mmol) were
added consecutively. The reaction mixture was left stirring at 0
oC for 1 h and then warmed to room temperature and left stirring
for 18 h. The solvents were evaporated under reduced pressure
and the crude product was dissolved in EtOAc (30 mL). After
filtration, the organic layer was washed with aq. H2SO4 (5%, 20
mL), H2O (20 mL), aq. NaHCO3 (5%, 20 mL) and brine (20 mL).
After evaporation of the solvent, the crude ester was purified
using column chromatography eluting with pet. ether/EtOAc
(50:50). White solid; 1.95 g, 95% yield; Rf (pet. ether/EtOAc 1:1)
0.20; mp 69-72 C; [α]D -11.3 (c = 1.0, MeOH); H NMR (200
MHz, CDCl3) δ 7.38-7.02 (10H, m, ArH), 6.35 (1H, br s, NH),
5.21 (2H, s, OCH2), 4.87-4.81 (1H, m, NCH), 4.41-4.35 (1H, m,
NCH), 3.73 (3H, s, OCH3), 3.50-3.41 (2H, m, NCH2), 3.14-3.00
(2H, m, CH2Ph), 2.24-2.06 (2H, m, CH2), 1.93-1.77 (2H, m,
CH2); 13C NMR (50 MHz, CDCl3) δ 171.6, 171.3, 155.8, 136.3,
135.7, 129.2, 129.0, 128.0, 127.8, 127.0, 67.2, 60.6, 52.2, 46.9,
37.6, 31.0, 28.8, 24.3.
1
(AcOEt/pet. ether 2:8) 0.40; [α]D + 16.2 (c = 1.0, CHCl3); H
NMR (200 MHz, CDCl3) δ 7.41-7.26 (10H, m, ArH), 5.01 (1H,
d, J = 12.4 Hz, OCHHPh), 4.83 (1H, d, J = 12.4 Hz, OCHHPh),
4.78 (1H, d, J = 12.0 Hz, OCHHPh), 4.65 (1H, d, J = 12.0 Hz,
OCHHPh), 4.41 (1H, d, J = 5.4 Hz, OCH), 4.10 (1H, m, OCH),
4.05 (1H, d, J = 5.4 Hz, NCH), 3.82 (1H, dd, J = 11.0 and 3.6 Hz,
CHHOSi), 3.66 (1H, dd, J = 11.0 and 2.2 Hz, CHHOSi), 1.52
[9H, s, OC(CH3)3], 0.75 [9H, s, SiC(CH3)3], -0.09 (6H, s, 2 x
CH3); 13C NMR (50 MHz, CDCl3) δ 171.4, 150.1, 137.7, 137.5,
128.4, 127.7, 76.7, 75.0, 72.6, 62.4, 61.7, 28.0, 25.7, 18.1, -5.7;
MS (ESI) m/z (%) 542 (100%) ([M+H]+).
o
1
3.2.8. (3R, 4R, 5R)-3,4-Bis(benzyloxy)-5-
(hydroxymethyl)-pyrrolidin-2-one (38)
To a stirred solution of compound 37 (520 mg, 0.96 mmol) in
AcOEt (10 mL), a 4N solution of HCl in dioxane (2.5 mL, 10.0
mmol) was added at 0 oC and the reaction mixture was left
stirring at room temperature for 2 h. After evaporation of the
solvent, the product was precipitated by the addition of Et2O/pet.
ether. White gummy solid; 250 mg, 80% yield; Rf (AcOEt) 0.17;
mp 53-56 oC; [α]D + 114.0 (c = 1.0, CHCl3); 1H NMR (200 MHz,
CDCl3) δ 7.37-7.26 (10H, m, ArH), 6.73 (1H, br s, NH), 4.86
(1H, d, J = 12.0 Hz, OCHHPh), 4.71 (1H, d, J = 12.0 Hz,
OCHHPh), 4.60 (1H, d, J = 11.4 Hz, OCHHPh), 4.49 (1H, d, J =
11.4 Hz, OCHHPh), 4.10 (1H, d, J = 4.6 Hz, OCH), 3.95-3.92
(1H, m, OCH), 3.73-3.66 (2H, m, NCH & OCHH), 3.51-3.44
(1H, m, OCHH), 2.37 (1H, br s, OH); 13C NMR (50 MHz,
CDCl3) δ 174.6, 137.2, 128.4, 128.3, 128.2, 128.1, 128.0, 127.9,
To a stirred solution of the protected dipeptide (0.20 g, 0.48
mmol) in dioxane (1 mL), an aq. solution of NaOH (2N, 3 mL)
was added. The reaction mixture was left stirring for 1 h at room
temperature. The crude mixture was extracted with Et2O (2 x 20
mL). The aqueous layer was acidified with aq. HCl (2N) until pH
2 and the crude product was extracted with EtOAc (2 x 15 mL).
The combined organic layers were washed with H2O (30 mL),
dried and the solvent was removed under reduced pressure. 12
was isolated as a white solid; 0.14 g, 76% yield; Rf (pet.
ether/EtOAc 30:70) 0.05; mp 53-56 oC; [α]D -76.7 (c = 2.5,
CHCl3); 1H NMR (200 MHz, CDCl3) δ 9.40 (1H, br s, COOH),
7.26-7.01 (10H, m, ArH), 6.79 (1H, br s, NH), 5.08 (2H, s,
OCH2), 4.87-4.81 (1H, m, NCH), 4.33-4.31 (1H, m, NCH), 3.46-

8
Tetrahedron
ACCEPTED MANUSCRIPT
3.36 (2H, m, NCH2), 3.12-2.87 (m, 2H, CH2Ph), 2.03-1.89 (2H,
172.4, 171.7, 155.3, 137.1, 136.5, 136.2, 129.1, 128.7, 128.5,
m, CH2), 1.89-1.75 (2H, m, CH2); 13C NMR (50 MHz, CDCl3) δ
173.7, 172.2, 155.8, 136.1, 135.9, 129.5, 128.6, 128.5, 128.2,
127.9, 127.0, 67.6, 60.4, 52.8, 47.0, 37.6, 29.8, 24.3; MS (ESI)
m/z (%) 397 (100) ([M+H]+).
128.5, 128.1, 127.7, 127.5, 127.4, 126.8, 67.0, 60.8, 56.5, 54.2,
46.9, 44.0, 40.1, 36.9, 30.1, 29.5, 24.6, 21.5; MS (ESI) m/z (%)
1165 (100) ([2M+H]+).
3.2.15. Benzyl (S)-2-(((S)-1-((3-((R)-1-benzyl-5-
oxopyrrolidin-2-yl)propyl)amino)-1-oxo-3-
phenylpropan-2-yl)carbamoyl)pyrrolidine-1-
carboxylate (20)
3.2.12. Benzyl (S)-2-(((S)-1-((((S)-1-benzyl-5-
oxopyrrolidin-2-yl)methyl)amino)-1-oxo-3-
phenylpropan-2-yl)carbamoyl)pyrrolidine-1-
carboxylate (17)
Same procedure as above, utilizing dipeptide 11 and amine 15
(1.8 mmol). Eluent EtOAc/pet. ether 90:10; Colorless oil; 0.78 g,
65% yield; Rf (EtOAc/pet. ether 9:1) 0.55; [α]D -42.0 (c = 1,
MeOH); 1H NMR (200 MHz, CDCl3) δ 7.96-7.08 (15H, m, ArH),
6.55-6.43 (2H, m, 2 x NH), 5.08-4.83 (3H, m, OCH2 & NCH),
4.65-4.54 (1H, m, NCH), 4.22-4.16 (1H, m, NCH), 4.06 (1H, d, J
= 15.0 Hz, NCHHPh), 3.94 (1H, d, J = 15.0 Hz, NCHHPh),
3.53-2.98 (6H, m, 2 x NCH2 & CH2), 2.46-2.34 (2H, m, CH2),
2.29-1.24 (10H, m, 5 x CH2); 13C NMR (50 MHz, CDCl3) δ
175.3, 171.5, 170.6, 156.1, 136.8, 136.1, 129.2, 129.0, 128.7,
128.4, 128.1, 128.0, 127.8, 127.5, 127.1, 67.6, 61.3, 56.7, 53.8,
47.2, 44.2, 39.5, 37.2, 30.3, 30.1, 28.7, 24.4, 23.8, 12.9; MS
(ESI) m/z (%) 611 (100) ([M+H]+).
To a stirred solution of dipeptide 11 (1.29 g, 3.26 mmol) in dry
CH2Cl2 (20 mL) at 0 C, 1-hydroxybenzotriazole (HOBt) (0.44 g
3.26 mmol), compound 13 (0.67 g, 3.26 mmol) and dicyclohexyl
o
carbodiimide (DCC) (0.72 g, 3.26 mmol) were added
o
consecutively. The reaction mixture was left stirring at 0 C for 1
h and then warmed to room temperature and left stirring for 18 h.
The solvents were evaporated under reduced pressure and the
crude product was dissolved in EtOAc (30 mL). After filtration,
the organic layer was washed with aqueous aq. H2SO4 (5%, 20
mL), H2O (20 mL), aq. NaHCO3 (5%, 20 mL) and brine (20 mL).
After evaporation of the solvent, the crude product was purified
using column chromatography eluting with CHCl3/MeOH
(90:10). Colorless oil; 1.46 g, 77% yield; Rf (CHCl3/MeOH 9:1)
1
0.50; [α]D -48.7 (c = 0.9, MeOH); H NMR (200 MHz, CDCl3) δ
3.2.16. Benzyl (S)-2-(((S)-1-((((2R,3R,4R)-3,4-
bis(benzyloxy)-5-oxopyrrolidin-2-
7.34-7.07 (15H, m, ArH), 6.67 (1H, br s, NH), 6.45 (1H, br s,
NH), 5.08-4.88 (3H, m, CH2O & NCH), 4.63-4.54 (1H, m,
NCH), 4.25-4.18 (1H, m, NCH), 4.06 (1H, d, J = 15.4 Hz,
NCHHPh), 3.52-3.04 (7H, m, NCHHPh, 2 x NCH2 & CH2),
2.46-2.25 (2H, m, CH2), 2.07-1.67 (6H, m, 3 x CH2); 13C NMR
(50 MHz, CDCl3) δ 175.4, 171.5, 171.3, 156.0, 136.6, 136.0,
129.0, 128.7, 128.5, 128.5, 128.2, 127.9, 127.6, 127.5, 126.9,
67.4, 61.1, 56.2, 53.8, 47.1, 44.2, 40.5, 36.9, 29.9, 29.2, 24.3,
21.7; MS (ESI): m/z= 583 (100) ( M+H+ ).
yl)methyl)amino)-1-oxo-3-phenylpropan-2-
yl)carbamoyl)pyrrolidine-1-carboxylate (21)
Same procedure as above, utilizing dipeptide 11 and amine 16
(0.60 mmol). Eluent EtOAc/MeOH 90:10; Colorless oil; 0.33 g,
78% yield; Rf (EtOAc/MeOH 9:1) 0.32; [α]D -5.9 (c = 1, CHCl3);
1H NMR (200 MHz, CDCl3) δ 7.35-7.08 (20Η, m, ArH) , 6.89
(1H, br s, NH), 6.67-6.48 (2H, m, 2 x NH), 5.08 (1H, d, J = 12.2
Hz, OCHHPh), 4.93 (1H, d, J = 12.2 Hz, OCHHPh), 4.80 (1H, d,
J = 11.4 Hz, OCHHPh), 4.69 (1H, d, J = 11.4 Hz, OCHHPh),
4.61-4.51 (3H, m, OCH2 & OCH), 4.18 (1H, dd, J =8.2 and 4.0
Hz, OCH), 3.93-3.91 (1H, m, NCH), 3.74-3.72 (2H, m, 2 x
NCH), 3.50-3.08 (6H, m, 2 x NCH2 & CH2), 2.04-1.57 (4H, m, 2
x CH2); 13C NMR (50 MHz, CDCl3) δ 172.8, 171.4, 171.3, 156.4,
137.6, 137.5, 136.5, 135.8, 129.1, 128.8, 128.8, 128.6, 128.5,
128.4, 128.2, 128.1, 127.9, 127.8, 127.3, 127.2, 74.2, 72.1, 68.0,
61.5, 57.7, 53.8, 47.4, 41.3, 36.7, 34.1, 29.7, 25.7, 25.1; MS
(ESI) m/z (%) 705 (100%) ([M+H]+)
3.2.13. Benzyl (S)-2-(((S)-1-((((R)-1-benzyl-5-
oxopyrrolidin-2-yl)methyl)amino)-1-oxo-3-
phenylpropan-2-yl)carbamoyl)pyrrolidine-1-
carboxylate (18)
Same procedure as above, utilizing dipeptide 11 and amine 14 (1
mmol). Eluent AcOEt/MeOH 90:10; Colorless oil; 0.41 g, 70%
yield; Rf (AcOEt/MeOH 9:1) 0.45; [α]D -65.8 (c = 1, MeOH); 1H
NMR (200 MHz, CDCl3) δ 7.32-7.00 (15H, m, ArH), 6.77 (1H,
br s, NH), 6.73 (1H, br s, NH), 5.09-4.91 (3H, m, CH2O &
NCH), 4.66,-4.56 (1H, m, NCH), 4.22-4.16 (1H, m, NCH), 4.04
(1H, d, J = 14.2 Hz, NCHHPh), 3.48-3.06 (7H, m, NCHHPh, 2 x
NCH2 & CH2), 2.47-2.22 (2H, m, CH2), 2.10-1.67 (6H, m, 3 x
CH2); 13C NMR (50 MHz, CDCl3) δ 175.4, 171.5, 171.3, 156.0,
136.6, 136.0, 129.0, 128.7, 128.5, 128.5, 128.2, 127.9, 127.6,
127.5, 126.9, 67.4, 61.1, 56.2, 53.8, 47.1, 44.2, 40.5, 36.9, 29.9,
29.2, 24.3, 21.7; MS (ESI) m/z (%) 583 (100) ([M+H]+).
3.2.17. (S)-N-((S)-1-((((S)-1-benzyl-5-
oxopyrrolidin-2-yl)methyl)amino)-1-oxo-3-
phenylpropan-2-yl)pyrrolidine-2-
carboxamide (22)
To a stirred solution of compound 17 (0.87 g, 1.50 mmol) in dry
methanol (30 mL), 10% Pd/C (10 mol%) was added and the
reaction mixture was left stirring at room temperature for 2.5 h
under hydrogen atmosphere. After filtration through Celite, the
solvent was evaporated to afford the desired product. Colorless
oil; 0.55 g, 82% yield; Rf (CHCl3/MeOH 7:3) 0.53; [α]D -8.9 (c =
3.2.14. Benzyl (S)-2-(((R)-1-((((S)-1-benzyl-5-
oxopyrrolidin-2-yl)methyl)amino)-1-oxo-3-
phenylpropan-2-yl)carbamoyl)pyrrolidine-1-
carboxylate (19)
1
1, MeOH); H NMR (200 MHz, DMSO) δ 8.91 (1H, br s, NH),
8.87 (1H, br s, NH), 8.37-7.23 (10H, m, ArH), 4.77 (1H, d, J =
15.4 Hz, NCHHPh), 4.59-4.48 (1H, m, NCH), 4.14-4.12 (1H, m,
NCH), 4.04 (1H, d, J = 15.4 Hz, NCHHPh), 3.35-3.15 (3H, m,
NCH & NCH2), 2.99-2.76 (2H, m, NCH2), 2.33-2.15 (2H, m,
CH2), 1.94-1.00 (8H, m, 4 x CH2); 13C NMR (50 MHz, DMSO) δ
174.3, 172.7, 171.3, 137.4, 137.2, 129.2, 128.6, 128.0, 127.6,
127.2, 126.4, 59.7, 55.7, 53.3, 46.4, 43.3, 30.1, 29.4, 29.2, 25.2,
21.4, 16.9; MS 449 (M+H+ 100); HRMS exact mass calculated
Same procedure as above, utilizing dipeptide 12 and amine 13
(1.5 mmol). Eluent AcOEt; White solid; 0.63 g, 72% yield; Rf
o
1
(EtOAc) 0.30; mp 161-163 C; [α]D -2.6 (c = 1.0, MeOH); H
NMR (200 MHz, CDCl3) δ 7.33-7.20 (15H, m, ArH), 6.77-6.73
(2H, m, 2 x NH), 5.04-4.95 (3H, m, CH2O & NCH), 4.74-4.63
(1H, m, NCH), 4.09-3.97 (2H, m, NCH & NCHHPh), 3.94-3.05
(7H, m, NCHHPh, 2 x NCH2 & CH2), 2.42-2.23 (2H, m, CH2),
1.99-1.74 (6H, m, 3 x CH2); 13C NMR (50 MHz, CDCl3) δ 175.6,

9
for [M-H]- (C26H31N4O3) requires m/z 447.2402, found m/z
447.2398.
Same procedure but utilizing compound 21 (0.18 mmol).
ACCEPTED MANUSCRIPT
Reaction time 2 h; gummy solid; 59.6 mg, 58% yield; Rf
(CHCl3/MeOH 8:2) 0.20; [α]D +9.4 (c = 1.0, MeOH); 1H NMR
(200 MHz, CDCl3) δ 8.19-8.15 (2H, m, 2 x NH), 7.90-7.82 (1H,
m, NH), 7.31-7.13 (15H, m, ArH), 4.80 (1H, d, J = 11.6 Hz,
OCHHPh), 4.64 (1H, d, J = 11.6 Hz, OCHHPh), 4.51 (1H, d, J =
11.4 Hz, OCHHPh), 4.41 (1H, d, J = 11.4 Hz, OCHHPh), 3.88
(1H, d, J = 5.0 Hz, OCH), 3.73-3.43 (4H, m, OCH & 3 x NCH),
3.09-2.77 (4H, m, 2 x NCH2), 2.67- 2.44 (3H, m, NH & CH2),
1.50-1.18 (4H, m, 2 x CH2); 13C NMR (50 MHz, CDCl3) δ 176.1,
173.1, 172.2, 137.5, 137.4, 136.8, 129.3, 128.6, 128.6, 128.5,
128.4, 128.2, 128.2, 128.1, 127.0, 74.5, 72.1, 60.3, 57.6, 54.4,
47.1, 40.8, 37.5, 30.6, 25.9, 21.2, 14.3; MS 571 (M+H+ 100);
HRMS exact mass calculated for [M-H]- (C33H37N4O5) requires
m/z 569.2769, found m/z 569.2754.
3.2.18. (S)-N-((S)-1-((((R)-1-benzyl-5-
oxopyrrolidin-2-yl)methyl)amino)-1-oxo-3-
phenylpropan-2-yl)pyrrolidine-2-
carboxamide (23)
Same procedure as above but utilizing 18 (0.84 mmol). Reaction
o
time 2 h; white solid; 0.37 g, 99% yield; mp 118-120 C; Rf
1
(CHCl3/MeOH 7:3) 0.61; [α]D -47.2 (c = 1.0, CHCl3); H NMR
(200 MHz, CDCl3) δ 8.24 (1H, br s, NH), 8.20 (1H, br s, NH),
7.77-7.14 (10H, m, ArH), 4.92-4.84 (1H, d, J = 15.2 Hz,
NCHHPh), 4.60-4.49 (1H, m, NCH), 4.03-3.95 (1H, d, J = 15.2
Hz, NCHHPh), 3.80-3.73 (1H, m, NCH), 3.51-3.40 (1H, m,
NCH), 3.23-2.71 (6H, m, 2 x NCH2 & CH2), 2.46-2.19 (2H, m,
CH2), 1.99-1.24 (6H, m, 3 x CH2); 13C NMR (50 MHz, CDCl3) δ
175.8, 175.3, 172.1, 137.0, 136.5, 129.3, 128.9, 128.6, 128.0,
127.7, 126.9, 60.2, 56.8, 54.3, 47.1, 44.5, 40.1, 37.3, 30.6, 30.2,
25.7, 21.7; MS 449 (M+H+ 100); HRMS exact mass calculated
for [M-H]- (C26H31N4O3) requires m/z 447.2402, found m/z
447.2402.
3.2.22. (S)-N-((S)-1-((((2R,3R,4R)-3,4-dihydroxy-5-
oxopyrrolidin-2-yl)methyl)amino)-1-oxo-3-
phenylpropan-2-yl)pyrrolidine-2-
carboxamide (27)
Same procedure but utilizing compound 21 (0.22 mmol).
Reaction time 5.5 h; gummy solid; 84.2 mg, 98% yield; Rf
1
(EtOAc/MeOH 9:1) 0.45; [α]D +22.2 (c = 0.9, MeOH); H NMR
3.2.19. (S)-N-((R)-1-((((S)-1-benzyl-5-
oxopyrrolidin-2-yl)methyl)amino)-1-oxo-3-
phenylpropan-2-yl)pyrrolidine-2-
carboxamide (24)
(200 MHz, DMSO-d6 & CD3OD) δ 8.13-8.09 (2H, m, 2 x NH),
7.64-6.91 (5H, m, ArH), 6.32 (1H, br s, NH), 5.27-4.99 (2H, m, 2
x OCH), 4.35-4.27 (1H, m, NCH), 4.07-3.76 (2H, m, 2 x NCH,
3.21-2.77 (6H, m, 2 x NCH2 & CH2), 2.66-1.38 (6H, 2 x OH & 2
x CH2), 0.94 (1H, br s, NH); 13C NMR (50 MHz, DMSO-d6 &
CD3OD) δ 168.4, 164.4, 160.2, 128.6, 120.7, 120.1, 118.5, 62.1,
61.6, 51.7, 51.5, 47.7, 37.9, 32.4, 28.9, 21.4, 15.6; MS 391
(M+H+ 100); HRMS exact mass calculated for [M-H]-
(C19H25N4O5) requires m/z 389.1830, found m/z 389.1948.
Same procedure as above but utilizing 19 (0.78 mmol). Reaction
o
time 1.5 h; white solid; 0.31 g, 90% yield; mp 116-119 C; Rf
1
(CHCl3/MeOH 7:3) 0.53; [α]D -5.4 (c = 1.0, MeOH); H NMR
(200 MHz, CDCl3) δ 8.28-8.24 (2H, br m, 2 x NH), 7.36-7.10
(10H, m, ArH), 4.90-4.83 (1H, d, J = 15.0 Hz NCHHPh), 4.59-
4.48 (1H, m, NCH), 4.19-4.15 (1H, m, NCH), 4.04-3.96 (1H, d, J
= 15.0 Hz, NCHHPh, 3.84-3.77 (1H, m, NCH), 3.52-3.44 (2H,
m, NCH2), 3.38-2.86 (4H, m, NCH2 & CH2), 2.46-2.31 (2H, m,
CH2), 2.10-1.65 (6H, m, 3 x CH2); 13C NMR (50 MHz, CDCl3) δ
175.6, 174.8, 171.9, 136.9, 136.4, 129.2, 128.8, 128.4, 127.9,
127.6, 126.8, 60.2, 56.5, 54.6, 47.0, 44.2, 40.1, 37.8, 30.6, 30.1,
25.8, 21.7; MS 449 (M+H+ 100); HRMS exact mass calculated
for [M-H]- (C26H31N4O3) requires m/z 447.2402, found m/z
447.2401.
4. General procedure for the aldol reaction
Conditions A: To a round-bottom flask, 22 (10 mg, 0.021 mmol),
4-NBA (4.7 mg, 0.028 mmol) and aldehyde (0.14 mmol) were
added. After the addition of Petroleum ether (1 mL) and H2O (0.1
mL), ketone (1.40 mmol) was added and the reaction mixture
was stirred for 24-120 h at room temperature. The solvent was
evaporated and the crude product was purified using flash
column chromatography eluting with the appropriate mixture of
o
petroleum ether (40-60 C)/ethyl acetate to afford the desired
3.2.20. (S)-N-((S)-1-((3-((R)-1-benzyl-5-
oxopyrrolidin-2-yl)propyl)amino)-1-oxo-3-
phenylpropan-2-yl)pyrrolidine-2-
carboxamide (25)
product. Conditions B: To a round-bottom flask, 25 (10 mg,
0.021 mmol), 4-NBA (4.7 mg, 0.028 mmol) and aldehyde (0.14
mmol) were added. After the addition of brine (1 mL), ketone
(1.40 mmol) was added and the reaction mixture was stirred for
24-120 h at room temperature. The solvent was evaporated and
the crude product was purified using flash column
chromatography eluting with the appropriate mixture of
Same procedure but utilizing compound 20 (0.25 mmol).
Reaction time 3 h; colorless oil; 0.12 g, 100% yield; Rf
1
(CHCl3/MeOH 7:3) 0.28; [α]D -1.6 (c = 1.0, MeOH); H NMR
(200 MHz, CDCl3) δ 8.52 (2H, br s, 2 x NH), 7.35-7.14 (10H, m,
ArH), 4.97 (1H, m, NCH), 4.86 (1H, d, J = 15.4 Hz, NCHHPh),
4.63 (1H, m, NCH), 4.05 (1H, d, J = 15.4 Hz, NCHHPh), 3.94
(1H, d, J = 15.0 Hz, NCH), 3.90-2.95 (7H, m, 2 x NCH2, CH2 &
NH), 2.52-2.21 (4H, m, COCH2 & CH2), 2.12-1.98 (2H, m, CH2),
1.80-1.23 (6H, m, 3 x CH2); 13C NMR (50 MHz, CDCl3) δ 175.3,
170.2, 167.9, 136.7, 135.9, 129.9, 128.9, 128.7, 128.3, 127.9,
127.5, 56.7, 56.0, 44.7, 44.1, 39.7, 30.3, 29.9, 28.6, 24.4, 24.2,
23.8, 23.4, 12.8; MS 477 (M+H+ 100); HRMS exact mass
calculated for [M+Na]+ (C28H36N4O3Na) requires m/z 499.2680,
found m/z 499.2696.
o
petroleum ether (40-60 C)/ethyl acetate to afford the desired
product.
4.1. (S)-2-[(R)-Hydroxy-(4-nitrophenyl)methyl] -
cyclohexanone (42a, Table 3, entry 1)1 4
Colorless oil, 32 mg, 92% yield; Rf (AcOEt:Pet. Ether 3:7) 0.56;
1H NMR (200 MHz, CDCl3) anti δ 8.20 (2H, d, J = 8.8 Hz, ArH),
7.51 (2H, d, J = 8.8 Hz, ArH), 4.87 (1H, d, J = 8.4 Hz, OCH),
4.09 (1H, br s, OH), 2.64-2.26 (3H, m, COCH & 2 x CHH), 2.17-
1.29 (6H, m, 6 x CHH); 13C NMR (50 MHz, CDCl3) δ 214.6,
148.4, 127.9, 127.8, 123.4, 73.8, 57.0, 42.5, 30.6, 27.5, 24.5;
HPLC analysis: Diacel Chiralpak AD-H, hexane:iPrOH 90:10,
flow rate 1.0 mL/min, retention time: 33.07 (minor) and 44.02
(major), 93% ee.
3.2.21. (S)-N-((S)-1-((((2R,3R,4R)-3,4-
bis(benzyloxy)-5-oxopyrrolidin-2-
yl)methyl)amino)-1-oxo-3-phenylpropan-2-
yl)pyrrolidine-2-carboxamide (26)

10
Tetrahedron
ACCEPTED MANUSCRIPT
4.7.
(S)-2-[(R)-Hydroxy-(4-
(chlorophenyl)methyl] -cyclohexanone (42g,
4.2 (S)-2-[(R)-Hydroxy-(3-nitrophenyl)methyl] -
Table 3, entry 14)7 i
cyclohexanone (42b, Table 3, entry 4)1 4
o
White solid, 31 mg, 92% yield; mp 96-98 C; Rf (AcOEt:Pet.
Colourless oil, 34 mg, 97% yield; Rf (AcOEt:Pet. Ether 3:7) 0.48;
1H NMR (200 MHz, CDCl3) anti δ 8.23-8.14 (2H, m, ArH), 7.67
(1H, d, J = 7.3 Hz, ArH), 7.55 (1H, d, J = 7.6 Hz, ArH), 4.90
(1H, d, J = 8.4 Hz, OCH), 4.11 (1H, br s, OH), 2.68-2.31 (3H, m,
COCH & 2 x CHH), 2.17-1.32 (6H, m, 6 x CHH); 13C NMR (50
MHz, CDCl3) δ 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
Chiralpak AD-H, hexane:iPrOH 95:5, flow rate 1.0 mL/min,
retention time: 53.41 (major) and 69.16 (minor), 92% ee.
Ether 3:7) 0.38; 1H NMR (200 MHz, CDCl3) anti δ 7.32 (2H, d, J
= 8.5 Hz, ArH), 7.24 (2H, d, J = 8.5 Hz, ArH), 4.76 (1H, d, J =
8.7 Hz, OCH), 3.98 (1H, br s, OH), 2.63-2.28 (3H, m, COCH &
2 x CHH), 2.19-2.01 (1H, m, CHH), 1.88-1.42 (5H, m, 5 x
CHH); 13C NMR (50 MHz, CDCl3) δ 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
Chiralpak OD-H, hexane:iPrOH 95:5, flow rate 1.0 mL/min,
retention time: 19.34 (major) and 31.10 (minor), 90% ee.
4.8.
(S)-2-[(R)-Hydroxy-(2-
4.3.
(S)-2-[(R)-Hydroxy-(2-nitrophenyl)methyl] -
cyclohexanone (42c, Table 3, entry 5)1 4
(chlorophenyl)methyl] -cyclohexanone (42h,
Table 3, entry 16)7 i
Yellow solid, 35 mg, 100% yield; Rf (AcOEt:Pet. Ether 3:7)
0.46; 1H NMR (200 MHz, CDCl3) anti δ 7.91-7.72 (2H, m, ArH),
7.63 (1H, t, J = 6.5 Hz, ArH), 7.42 (1H, t, J = 6.6 Hz, ArH), 5.43
(1H, d, J = 7.1 Hz, OCH), 4.16 (1H, br s, OH), 2.85-2.61 (1H, m,
COCH), 2.55-2.08 (2H, m, 2 x CHH), 1.90-1.52 (6H, m, 6 x
CHH); 13C NMR (50 MHz, CDCl3) δ 214.9, 136.5, 133.0, 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: 60.85 (major) and 65.23 (minor), 97%
ee.
Pale yellow solid, 33 mg, 100% yield; mp 60-62 oC; Rf
(AcOEt:Pet. Ether 3:7) 0.42; 1H NMR (200 MHz, CDCl3) anti δ
7.54 (1H, dd, J = 7.8 and 1.9 Hz, ArH), 7.36-7.16 (3H, m, ArH),
5.34 (1H, d, J = 8.2 Hz, OCH), 3.86 (1H, br s, OH), 2.77-2.61
(1H, m, COCH), 2.54-2.22 (2H, m, COCHH), 2.17-2.02 (1H, m,
CHH), 1.86-1.42 (5H, m, 5 x CHH); 13C NMR (50 MHz, CDCl3)
δ 215.3, 139.1, 132.9, 129.2, 128.7, 128.3, 127.3, 70.5, 57.6,
42.7, 30.4, 27.8, 24.9; HPLC analysis: Diacel Chiralpak OD-H,
hexane:iPrOH 95:5, flow rate 1.0 mL/min, retention time: 14.29
(major) and 18.86 (minor), 88% ee.
4.4.
(R)-3-[Hydroxy-(2-(S)-
4.9.
(S)-2-[(R)-Hydroxy-(4-
oxocyclohexyl)methyl] -benzonitrile (42d,
Table 3, entry 7)1 4
(bromophenyl)methyl] -cyclohexanone (42i,
Table 3, entry 17)7 i
o
White solid, 32 mg, 100% yield; mp 66-68 C; Rf (AcOEt:Pet.
Ether 3:7) 0.42; H NMR (200 MHz, CDCl3) anti δ 7.68-7.38
o
1
White solid, 34 mg, 85% yield; mp 89-91 C; Rf (AcOEt:Pet.
Ether 3:7) 0.42; 1H NMR (200 MHz, CDCl3) anti δ 7.47 (2H, d, J
= 8.5 Hz, ArH), 7.20 (2H, d, J = 8.5 Hz, ArH), 4.75 (1H, d, J =
8.6 Hz, OCH), 3.94 (1H, br s, OH), 2.61-2.13 (3H, m, COCH &
2 x CHH), 2.11-2.01 (1H, m, CHH), 1.88-1.24 (5H, m, 5 x
CHH); 13C NMR (50 MHz, CDCl3) δ 215.2, 140.0, 131.5, 128.7,
121.7, 74.2, 57.3, 42.6, 30.7, 27.7, 24.7; HPLC analysis: Diacel
Chiralpak AD-H, hexane:iPrOH 90:10, flow rate 0.5 mL/min,
retention time: 41.79 (minor) and 49.33 (major), 88% ee.
(4H, m, ArH), 4.81 (1H, d, J = 8.5 Hz, OCH), 4.01 (1H, br s,
OH), 2.65-2.03 (4H, m, COCH & 3 x CHH), 1.87-1.22 (5H, m, 5
x CHH); 13C NMR (50 MHz, CDCl3) δ 214.6, 142.6, 131.5,
130.6, 129.1, 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/min, retention time: 46.07 (minor) and 68.80
(major), 87% ee.
4.5.
(S)-2-[(R)-Hydroxy-(4-
4.10.
(S)-2-[(R)-Hydroxy-(phenyl)methyl] -
(trifluoromethyl)phenyl)methyl] -
cyclohexanone (42j, Table 3, entry 20)1 4
cyclohexanone (42e, Table 3, entry 9)1 4
o
Colourless oil, 58 mg, 71% yield; Rf (AcOEt:Pet. Ether 7:3) 0.42;
1H NMR (200 MHz, CDCl3) anti δ 7.51-7.21 (5H, m, ArH), 4.78
(1H, d, J = 8.8 Hz, OCH), 3.84 (1H, br s, OH), 2.70-2.31 (3H, m,
COCH & CHH), 2.15-1.24 (6H, m, 6 x CHH); 13C NMR (50
MHz, CDCl3) δ 215.5, 140.8, 128.3, 127.8, 125.7, 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: 22.91
(major) and 32.08 (minor), 99% ee.
White solid, 36 mg, 94% yield; mp 73-75 C; Rf (AcOEt:Pet.
Ether 3:7) 0.48; 1H NMR (200 MHz, CDCl3) anti δ 7.61 (2H, d, J
= 8.2 Hz, ArH), 7.44 (2H, d, J = 8.2 Hz, ArH), 4.84 (1H, d, J =
8.6 Hz, OCH), 4.03 (1H, br s, OH), 2.69-2.02 (4H, m, COCH &
3 x CHH), 1.90-1.39 (5H, m, 5 x CHH); 13C NMR (50 MHz,
CDCl3) δ 215.1, 144.9, 129.6 (q, J = 31.2 Hz), 127.3, 125.3 (q, J
= 8.1 Hz), 123.9 (q, J = 271.4 Hz), 74.2, 57.2, 42.6, 30.7, 27.6,
24.7; 19F NMR (188 MHz, CDCl3) δ -7.50 (s); HPLC analysis:
Diacel Chiralpak AD-H, hexane:iPrOH 90:10, flow rate 0.5
mL/min, retention time: 27.39 (minor) and 33.61 (major), 92%
ee.
4.11.
(S)-2-[(R)-Hydroxy-(pyridine-4-yl)methyl] -
cyclohexanone (42k, Table 3, entry 22)7 i
White solid, 29 mg, 100% yield; mp 107-109 oC; Rf (AcOEt:Pet.
1
4.6.
(S)-2-[(R)-Hydroxy-(4-
Ether 4:6) 0.23; H NMR (200 MHz, CDCl3) anti δ 8.58-8.52
(fluorophenyl)methyl] -cyclohexanone (42f,
(2H, m, ArH), 7.27-7.21 (2H, m, ArH), 4.78 (1H, d, J = 8.1 Hz,
OCH), 3.19 (1H, br s, OH), 2.67-2.25 (3H, m, COCH & CHH),
2.18-2.01 (1H, m, CHH), 1.87-1.35 (5H, m, 5 x CHH); 13C NMR
(50 MHz, CDCl3) δ 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: 35.88
(minor) and 47.63 (major), 95% ee.
Table 3, entry 12)1 4
o
White solid, 28 mg, 89% yield; mp 66-68 C; Rf (AcOEt:Pet.
1
Ether 3:7) 0.52; H NMR (200 MHz, CDCl3) anti δ 7.33-7.27
(2H, m, ArH), 7.03 (2H, t, J = 8.7 Hz, ArH), 4.77 (1H, d, J = 8.4
Hz, OCH), 4.03 (1H, br s, OH), 2.65-2.31 (3H, m, COCH & 2 x
CHH), 2.08-1.22 (6H, m, 6 x CHH); 13C NMR (50 MHz, CDCl3)
δ 215.4, 162.3 (d, J = 246.2 Hz), 136.6, 128.5 (d, J = 5.1 Hz),
115.2 (d, J = 20.0 Hz), 74.1, 57.4, 42.6, 30.7, 27.7, 24.6; 19F
NMR (188 MHz, CDCl3) δ -59.49 (m); HPLC analysis: Diacel
Chiralpak AD-H, hexane:iPrOH 90:10, flow rate 0.5 mL/min,
retention time: 36.72 (minor) and 40.35 (major), 92% ee.
4.12.
(S)-3-[(R)-Hydroxy-[4-
(nitrophenyl)methyl]dihydro-2H-pyran-
4(3H)-one (42l, Table 3, entry 23)1 4

11
Pale yellow solid, 34 mg, 97% yield; mp 116-118 oC; Rf
(AcOEt:Pet. Ether 4:6) 0.16; H NMR (200 MHz, CDCl3) anti δ
ACCEPTED MANUSCRIPT
1
4.17. (S)-4-Hydroxy-4-(4-nitrophenyl)-butan-2-
one (42q, Table 3, entry 33)1 4
8.21 (2H, d, J = 8.8 Hz, ArH), 7.50 (2H, d, J = 8.8 Hz, ArH),
4.97 (1H, d, J = 8.2 Hz, OCH), 4.28-4.09 (1H, m, OCHH), 3.90-
3.64 (3H, m, 2 x OCHH & OH), 3.44 (1H, dd, J = 11.4 and 9.8
Hz, OCHH), 3.02-2.41 (3H, m, 3 x CHH); 13C NMR (50 MHz,
CDCl3) δ 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: 23.53
(minor) and 33.52 (major), 78% ee.
Colourless oil, 17 mg, 58 % yield; Rf (AcOEt:Pet. Ether 4:6)
0.14; H NMR (200 MHz, CDCl3) δ 8.20 (2H, d, J = 7.0 Hz,
1
ArH), 7.52 (2H, d, J = 7.0 Hz, ArH), 5.25 (1H, m, OCH), 3.56
(1H, br s, OH), 3.01-2.71 (2H, m, CHHCO), 2.21 (3H, s,
CH3CO); 13C NMR (50 MHz, CDCl3) δ 208.6, 149.9, 147.4,
126.4, 123.8, 68.9, 51.5, 30.7; HPLC analysis: Diacel Chiralpak
AS-H, hexane:iPrOH 85:15, flow rate 1.0 mL/min, retention
time: 28.59 (minor) and 35.28 (major), 89% ee.
4.13. (S)-3-[(R)-Hydroxy-[4-
(nitrophenyl)methyl]dihydro-2H-thiopyran-
4(3H)-one (42m, Table 3, entry 26)1 4
5.0. General procedure for the aldol reaction for the
Yellow solid, 37 mg, 100% yield; mp 137-139 oC; Rf
synthesis of 44
1
(AcOEt:Pet. Ether 3:7) 0.39; H NMR (200 MHz, CDCl3) anti δ
(R)-5,5,5-trifluoro-4-hydroxy-4-phenylpentan-2-one (44)21
8.23 (2H, d, J = 8.3 Hz, ArH), 7.53 (2H, d, J = 8.3 Hz, ArH),
5.04 (1H, d, J = 7.9 Hz, OCH), 3.63 (1H, br s, OH), 3.07-2.91
(3H, m, COCH & CHH), 2.87-2.70 (2H, m, 2 x CHH), 2.68-2.42
(2H, m, 2 x CHH); 13C NMR (50 MHz, CDCl3) δ 211.2, 147.7,
147.6, 127.7, 123.8, 73.1, 59.4, 44.7, 32.8, 30.7; HPLC analysis:
Diacel Chiralpak AD-H, hexane:iPrOH 90:10, flow rate 1.0
mL/min, retention time: 89.93 (minor) and 108.34 (major), 90%
ee.
To a round-bottom flask, 23 (10 mg, 0.021 mmol), 4-NBA (4.7
mg, 0.028 mmol) and 2,2,2-trifluoroacetophenone (24 mg, 0.14
mmol) were added. After the addition of Petroleum ether (1 mL)
and H2O (0.1 mL), acetone (1 mL) was added and the reaction
mixture was stirred for 96 h at room temperature. The solvent
was evaporated and the crude product was purified using flash
column chromatography eluting with the appropriate mixture of
o
4.14. (S)-7-[(R)-Hydroxy-4-(nitrophenyl)methyl] -
1,4-dioxospiro[4.5]decan-8-one (42n, Table
3, entry 27)1 4
petroleum ether (40-60 C)/ethyl acetate to afford the desired
product.21 Colorless oil, 21 mg, 63% yield; Rf (AcOEt:Pet. Ether
1
3:7) 0.56; H NMR (200 MHz, CDCl3) δ 7.62-7.52 (2H, m),
o
White solid, 43 mg, 100% yield; mp 89-91 C; Rf (AcOEt:Pet.
7.46-7.34 (3H, m), 5.46 (1H, br s), 3.39 (1H, d, J = 17.2 Hz),
3.21 (1H, d, J = 17.2 Hz), 2.22 (3H, s); 13C NMR (50 MHz,
CDCl3) δ 209.1, 137.3, 128.7, 128.4, 126.0, 124.4 (q, J = 284.9
Hz), 75.9 (q, J = 29.1 Hz), 44.8, 31.8; 19F NMR (188 MHz,
CDCl3) δ -13.97 (s); HPLC analysis: Diacel Chiralpak AS-H,
hexane:iPrOH 95:5, flow rate 0.7 mL/min, retention time: 12.34
(minor) and 17.06 (major), 70% ee.
Ether 3:7) 0.20; 1H NMR (200 MHz, CDCl3) anti δ 8.21 (2H, d, J
= 8.8 Hz, ArH), 7.49 (2H, d, J = 8.8 Hz, ArH), 4.92 (1H, d, J =
7.5 Hz, OCH), 4.04 (1H, br s, OH), 3.98-3.68 (4H, m, 4 x
OCHH), 2.91-2.74 (1H, m, COCH), 2.66-2.54 (1H, m, CHH),
2.51-2.42 (1H, m, CHH), 2.07-1.55 (3H, m, 3 x CHH), 1.54-1.44
(1H, m, CHH); 13C NMR (50 MHz, CDCl3) δ 213.1, 147.9,
127.8, 126.5, 123.6, 106.6, 73.8, 64.8, 64.5, 52.9, 38.8, 37.8,
34.3; HPLC analysis: Diacel Chiralpak AS-H, hexane:iPrOH
70:30, flow rate 1.0 mL/min, retention time: 17.08 (minor) and
26.70 (major), 90% ee.
5.1 (S)-4-Hydroxy-5-methylhexan-2-one (46)23
To a round-bottom flask, 22 (13.4 mg, 0.03 mmol), 4-NBA (6.9
mg, 0.04 mmol) and isobutyraldehyde (15 mg, 0.21 mmol) were
added. After the addition of Petroleum ether (3 mL) and H2O (0.1
mL), acetone (1 mL) was added and the reaction mixture was
stirred for 120 h at room temperature. The solvent was
evaporated and the crude product was purified using flash
column chromatography eluting with petroleum ether (40-60
oC)/ethyl acetate (70:30). Colourless oil, 1.1 mg, 4%, yield; Rf
(AcOEt:Pet. Ether 3:7) 0.66; 1H NMR (200 MHz, CDCl3) δ 3.87-
3.77 (1H, m, OCH), 2.93 (1H, br s, OH), 2.57–2.53 (2H, m,
COCH2), 2.21 (3H, s, CH3), 1.77–1.60 (1H, m, CH), 1.00–0.80
(6H, m, 2 x CH3); 13C NMR (50 MHz, CDCl3) δ 210.4, 72.2,
46.9, 33.0, 30.9, 18.4; HPLC analysis: Diacel Chiralpak AD-H,
hexane:iPrOH 98:2, flow rate 0.5 mL/min, retention time: 26.06
(minor) and 31.64 (major), 44% ee.
4.15. (2S,4R)-2-[(R)-Hydroxy-(4-
(nitrophenyl)methyl] -4-methylcyclohexanone
(42o, Table 3, entry 30)1 4
Pale yellow solid, 37 mg, 100% yield; mp 99-101 oC; Rf
1
(AcOEt:Pet. Ether 4:6) 0.22; H NMR (200 MHz, CDCl3) anti δ
8.22 (2H, d, J = 8.8 Hz, ArH), 7.51 (2H, d, J = 8.8 Hz, ArH),
4.92 (1H, d, J = 8.6 Hz, OCH), 3.99-3.87 (1H, br s, OH), 2.81-
2.29 (3H, m, COCH & CHH), 2.15-1.29 (5H, m, 4 x CHH &
CH); 1.07 (3H, d, J = 7.1 Hz, CH3); 13C NMR (50 MHz, CDCl3)
δ 214.8, 148.4, 147.5, 127.8, 123.7, 73.9, 52.9, 38.3, 36.1, 33.0,
26.5, 18.2; HPLC analysis: Diacel Chiralpak OD-H,
hexane:iPrOH 95:5, flow rate 1.0 mL/min, retention time: 46.34
(minor) and 54.23 (major), 90% ee.
5.2 (S)-2-((R)-1-Hydroxy-2-methylpropyl)cyclohexanone (47)24
To a round-bottom flask, 22 (13.4 mg, 0.03 mmol), 4-NBA (6.9
mg, 0.04 mmol) and isobutyraldehyde (15 mg, 0.21 mmol) were
added. After the addition of Petroleum ether (3 mL) and H2O (0.1
mL), cyclohexanone (206 mg, 2.10 mmol) was added and the
reaction mixture was stirred for 120 h at room temperature. The
solvent was evaporated and the crude product was purified using
flash column chromatography eluting with petroleum ether (40-
60 oC)/ethyl acetate (50:50) Oil, 3.6 mg, 10%, yield, Rf
4.16. (S)-2-[(R)-Hydroxy-(4-(nitrophenyl)methyl] -
cyclopentanone (42p, Table 3, entry 31)1 4
Colourless oil, 33 mg, 100% yield; Rf (AcOEt:Pet. Ether 4:6)
1
0.23; H NMR (200 MHz, CDCl3) δ 8.21 (2H, d, J = 8.8 Hz,
ArH), 7.52 (2H, d, J = 8.8 Hz, ArH), 5.42 (1H, s, OCH syn), 4.84
(1H, d, J = 9.2 Hz, OCH anti), 4.76 (1H, br s, OH anti), 2.69
(1H, br s, OH syn), 2.52-2.18 (3H, m, COCH & CHH), 2.15-1.83
(2H, m, 2 x CHH), 1.78-1.55 (2H, m, 2 x CHH); 13C NMR (50
MHz, CDCl3) δ 214.6, 213.4, 149.2, 147.9, 147.4, 147.3, 127.2,
126.5, 123.0, 122.9, 73.5, 69.8, 57.0, 56.3, 42.5, 30.2, 27.7, 25.5,
24.6, 24.3; HPLC analysis: Diacel Chiralpak AD-H,
hexane:iPrOH 95:5, flow rate 1.0 mL/min, retention time: 40.32
(syn major) and 57.11 (syn minor), 72.75 (anti minor) and 76.19
(anti major), 90% ee.
1
(AcOEt:Pet. Ether 1:1) 0.70; H NMR (200 MHz, CDCl3) δ 3.52
(1H, m, OCH), 3.27 (1H, d, J = 4.8 Hz, COCHH), 2.42-2.34 (3H,
m, 3 x COCHH), 2.35-2.25 (2H, m, 2 x CHH), 2.04-1.62 (5H, m,
5 x CHH), 0.98 (3H, d, J = 6.8 Hz, CH3), 0.88 (3H, d, J = 6.8 Hz,
CH3); 13C NMR (50 MHz, CDCl3) δ 216.1, 75.6, 53.7, 42.9, 30.6,

12
Tetrahedron
ACCEPTED MANUSCRIPT
6564-6568; h) Tsandi, E.; Kokotos, C. G.; Kousidou, S.;
29.2, 27.8, 25.0, 20.1, 15.2; HPLC analysis: Diacel Chiralpak
AD-H, hexane:iPrOH 97:3, flow rate 0.5 mL/min, retention time:
25.08 (minor) and 37.71 (major), 97% ee.
Ragoussis, V.; Kokotos, G. Tetrahedron 2009, 65, 1444-1449; i)
El-Hamdouni, N.; Companyo, X.; Rios, R.; Moyano, A. Chem.
Eur. J. 2010, 16, 1142-1148.
7. For selected examples, see: a) Tang, Z.; Jiang, F.; Yu, L. T.; Cui,
X.; Gong, L. Z.; Mi, A. Q.; Jiang, Y. Z. J. Am. Chem. Soc. 2003,
125, 5262-5263; b) Tang, Z.; Jiang, F.; Cui, X.; Gong, L. Z.; Mi,
A. Q.; Jiang, Y. Z.; Wu, Y. D. Proc. Natl. Acad. Sci. U. S. A.
2004, 101, 5755-5760; c) Tang, Z.; Yang, Z. H.; Chen, X. H.;
Cun, L. F.; Mi, A. Q.; Jiang, Y. Z.; Gong, L. Z. J. Am. Chem. Soc.
2005, 127, 9285-9289; d) Gandgi, S.; Singh, V. K. J. Org. Chem.
2008, 73, 9411-9416; e) Wang, B.; Chen, G.-H.; Liu, L.-Y.;
Chang, W.-X.; Li, J. Adv. Synth. Cat. 2009, 351, 2441-2448; f)
Fotaras, S.; Kokotos, C. G.; Tsandi, E.; Kokotos, G. Eur. J. Org.
Chem., 2011, 1310-1317; g) Fotaras, S.; Kokotos, C. G.; Kokotos,
G. Org. Biomol. Chem. 2012, 10, 5613-5619; h) Revelou, P.;
Kokotos, C. G.; Moutevelis-Minakakis, P. Tetrahedron 2012, 68,
8732-8738; i) Triandafillidi, I.; Bisticha, A.; Voutyritsa, E.;
Galiatsatou, G.; Kokotos, C. G. Tetrahedron 2015, 71, 932-940; j)
Bisticha, A.; Triandafillidi, I.; Kokotos, C. G. Tetrahedron:
Asymmetry 2015, 26, 102-108.
For the recovery of catalyst 22, after completion of the reaction,
the petroleum ether was evapotated and the residue, dissolved in
CHCl3 and acidified with 2N HCl (1 mL). The aqueous layer was
evaporated in high vacuum and the evaporation was repeated
twice, after the addition of toluene (2 x 1 mL). After drying,
catalyst 22 was isolated as the hydrochloride salt and identified
by 1H , 13C NMR , measurement of optical activity and MS; yield
73% (7.4 mg). The recovered catalyst, was further subjected in
an identical second catalytic reaction after the addition of the
appropriate Et3N (2 μL, 0.015 mmol). The desired compound 42a
was finally isolated in 82 % yield; dr 81:19 and ee 72%.
8. For reviews, see: a) Colby Davie, E. A.; Mennen, S. M.; Xu, Y.;
Miller, S. J. Chem. Rev. 2007, 107, 5759-5812; b) Wennemers, H.
Chem. Commun. 2011, 47, 12036-12041.
6
Acknowledgments
9. For selected examples of organocatalytic transformations utilizing
peptides not containing proline, see: a) Tsogoeva, S. B.; Wei, S.
Tetrahedron: Asymmetry 2005, 16, 1947-1951; b) Zou, W.;
Ibrahem, I.; Dziedzic, P.; Sunden, H.; Cordova, A. Chem.
Commun. 2005, 4946-4948; c) Dziedzic, P.; Zou, W.; Hafren, J.;
Cordova, A. Chem. Commun. 2006, 4, 38-40; d) Cordova, A.;
Zou, W.; Dziedzic, P.; Ibrahem, I.; Reyes, E.; Xu, Y. Chem. Eur.
J. 2006, 12, 5383-5397
10. For selected examples of organocatalytic transformations utilizing
proline-based peptides, see: a) Martin, H. J.; List, B. Synlett 2003,
1901-1902; b) Kofoed, J.; Nielsen, J.; Reymond, J.-L. Bioorg.
Med. Chem. Lett. 2003, 13, 2445-2447.; c) Tang, Z.; Tang, Z.-H.;
Cun, L.-F.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z. Org. Lett. 2004,
6, 2285-2287; d) Shi, L.-X.; Sun, Q.; Ge, Z. M.; Zhu, Y.-Q.;
Cheng, T.-M.; Li, R.-T. Synlett 2004, 2215-2217; e) Krattiger, P.;
Kovasy, R.; Revell, J. D.; Ivan, S.; Wennemers, H. Org. Lett.
2005, 7, 1101-1103; f) Lei, M.; Shi, L.; Li, G.; Chen, S.; Fang,
W.; Ge, Z.; Cheng, T.; Li, R. Tetrahedron 2007, 63, 7892-7898; g)
Revell, J. D.; Wennemers, H. Adv. Synth. Catal. 2008, 350, 1046-
1052; h) Chen, Y.-H.; Sung, P.-H.; Sung, K. Amino Acids 2010,
38, 839-845
C. G. K. gratefully acknowledges the Operational Program
“Education and Lifelong Learning” for financial support through
the NSRF program “ΕΝΙΣΧΥΣΗ ΜΕΤΑΔΙΔΑΚΤΟΡΩΝ
ΕΡΕΥΝΗΤΩΝ” (PE 2431)” co-financed by ESF and the Greek
State. P. M. M. acknowledges Dr K. Georgikopoulou for the
synthesis of compound 34 and G. Michas (MSc.) for the
synthesis of compounds 37 and 38. Dr M. Kokotou is
acknowledged for acquiring HRMS data.
7
References and notes
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Organocatalysis
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Experimental Procedure, Wiley-VCH: Weinheim, 2007; c) Dalko,
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catalyzed aldol reaction, see: d) Teo, Y.-C. Tetrahedron:
Asymmetry 2007, 18, 1155-1158; e) Wu, C.; Fu, X.; Li, S.
Tetrahedron 2011, 67, 4283-4290; for chitosan-catalyzed aldol
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Tanchoux, N.; Robitzer, M.; Quignard, F. Eur. J. Org. Chem.
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Torii, H.; Nakadai, M.; Ishihara, K.; Saito, S.; Yamamoto, H.
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2006, 17, 1493-1497; b) Wu, Y.; Zhang, Y.; Yu, M.; Zhao, G.;
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