Tert-Butyl esters of tripeptides based on Pro-Phe as organocatalysts for the asymmetric aldol reaction in aqueous or organic medium

Article abstract of DOI:10.1016/j.tet.2013.12.007

The enantioselective aldol reaction between ketones and aldehydes constitutes one the most common reaction models for the evaluation of novel organocatalysts. The last few years, it has been shown that the organocatalytic aldol reaction can be performed i

Full text of DOI:10.1016/j.tet.2013.12.007

Tetrahedron 70 (2014) 608e615
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
tert-Butyl esters of tripeptides based on Pro-Phe as organocatalysts
for the asymmetric aldol reaction in aqueous or organic medium
*
*
Anastasia Psarra, Christoforos G. Kokotos , Panagiota Moutevelis-Minakakis
Laboratory of Organic Chemistry, Department of Chemistry, 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:
The enantioselective aldol reaction between ketones and aldehydes constitutes one the most common
reaction models for the evaluation of novel organocatalysts. The last few years, it has been shown that
the organocatalytic aldol reaction can be performed in water. A family of tripeptides consisting of proline,
phenylalanine, and tert-butyl esters of amino acids was successfully employed in this asymmetric
transformation. The products of the reaction between various ketones and aldehydes were obtained in
high yields (up to 99%) with excellent diastereo- (up to 97:3 dr) and enantioselectivities (up to 99% ee).
The C-terminal amino acid determines the ability of the tripeptide (Pro-Phe-AA-OtBu) to act efficiently in
aqueous or organic medium.
Received 6 September 2013
Received in revised form 12 November 2013
Accepted 2 December 2013
Available online 7 December 2013
Keywords:
Aldol reaction
Organocatalysis
Prolinamides
Water
Ó 2013 Published by Elsevier Ltd.
Ureas
1. Introduction
The enantioselective aldol reaction is among the most com-
monly used CeC bond forming reactions in modern asymmetric
catalysis.1 With the recognition of organocatalysis as the third
branch of asymmetric catalysis, alongside the transition metal
complexes catalysis and biocatalysis,2,3 a significant increase in the
number of the studies concerning aldol reactions has been realized.
Since List, Lerner, and Barbas employed proline as the catalyst in
the intermolecular aldol reaction,4 proline, and proline derivatives
containing bioisosteric groups like sulfonamides and tetrazoles
have been frequently employed in organocatalytic trans-
formations.5 Nowadays, it is well accepted that organocatalysts
combining the prolinamide unit with functionalities able to act as
hydrogen bond donors are among the most successful classes of
catalysts employed in the aldol reaction. Representative examples
of such prolinamides that efficiently catalyze the aldol reactions are
shown in Fig. 1 (compounds 1e7).6e12 The five-membered sec-
ondary amine structure of the pyrrolidine ring enables the activa-
tion of carbonyl compounds through the formation of enamine
intermediates, while incorporation of a chiral template provides
extra interactions, while the bulky environment leads to enhanced
selectivity. Another important family of prolinamides that have
Fig. 1. Known prolinamide organocatalysts.
been less frequently exploited as potential organocatalysts are
peptides.13 Although peptides were among the first organocatalysts
employed in the aldol reaction, they found limited success, since in
* Corresponding authors. Tel.: þ30 210 7274484; fax: þ30 210 7274761 (P.M.-M.);
tel.: þ30 210 7274281; fax: þ30 210 7274761 (C.G.K.); e-mail addresses: ckokotos@
chem.uoa.gr (C.G. Kokotos), pminakak@chem.uoa.gr (P. Moutevelis-Minakakis).
0040-4020/$ e see front matter Ó 2013 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tet.2013.12.007

A. Psarra et al. / Tetrahedron 70 (2014) 608e615
609
most cases low to moderate enantioselectivities were obtained.14,15
In particular, the dipeptide Pro-Phe has been studied and when
DMSO is utilized as the solvent, moderate selectivities are obtai-
ned,14d except for a single case, where good enantioselectivities
were obtained.14h Unfortunately, when the solvent is switched to
water, the enantioselectivities and yields drop significantly.14c,f,h In
the last few years, reactions where water is used as the solvent have
attracted a great deal of attention because water is an abundant,
safe, and environmentally friendly medium to carry out reactions.16
Since the pioneering work from the groups of Hayashi and Barbas,17
a variety of catalysts have been developed for the organocatalytic
aldol reaction in the presence of water. Proline and proline de-
rivatives have been mainly designed and employed in aqueous
environment as the catalyst,9,18 but also a number of reports
exist on the use of the other amino acid derivatives.19
2. Results and discussion
Along with the catalytic activity of catalyst 5,10 the key factors
that are responsible for high catalytic activity in prolinamidee-
thioureas have been studied, concluding that catalyst 6 is an im-
proved catalyst for the aldol reaction in organic solvents and all
three potential hydrogen bond sites are involved and responsible
for the enantioselection observed.11 We have also demonstrated
that the combination of a prolinamide with an urea moiety pro-
vides similar modes of activation through hydrogen bonding as in
catalyst 7.12 Bearing these in mind, and our previous endeavors in
organocatalysis,20 we postulated that a tripeptide could be an ef-
ficient catalyst for the asymmetric aldol reaction. Coupled with the
potential for enamine activation of the nucleophile deriving from
the pyrrolidine ring of proline, a tripeptide possesses two potential
hydrogen bond sites that can activate the electrophile. Along the
same lines as our recent study,11 these additional activation can
lead to increased enantioselectivity (Fig. 2). Furthermore, tripep-
tides can adopt a stable conformation that is highly dependant on
the solvent and the containing amino acids. Thus, employing bulky
tert-butyl esters of various amino acids at the C-terminus of the
tripeptide, we could end up with tripeptides that will show cata-
lytic activities in different solvents. Having as a goal, the identifi-
cation of peptides that can catalyze the aldol reaction in either an
organic or an aqueous medium, (S)-benzyloxycarbonyl protected
proline (8) was coupled with (S)-methyl phenylalaninate (9) using
dicyclohexyl carbodiimide (DCC) as a condensing agent in the
presence of 1-hydroxybenzotriazole (HOBt). Saponification affor-
ded the N-protected dipeptide 10. To the resulting dipeptide, a se-
ries of tert-butyl ester of amino acids were added under
conventional peptide coupling conditions, affording the protected
tripeptides 11aef. Finally, deprotection via hydrogenation afforded
organocatalysts 12aef (Scheme 1).
Scheme 1. Synthesis of the tripeptides 12aef.
Table 1
Enantioselective aldol reaction of cyclohexanone with 4-nitrobenzaldehyde using
catalysts 12aa
Entry
Conditions
Yieldb (%)
drc
ee (%)d
1
2
3
4
5
6
Toluene, rt, 72 h
THF, rt, 72 h
MeOH, rt, 72 h
H2O, rt, 48 h
H2O/NaCl, rt, 48 h
H2O/Heptyl4NþCl-, rt, 48 h
H2O/NaBr, rt, 48 h
H2O/NaBr, rt, 24 h
H2O/NaBr, 0 ꢀC, 48 h
H2O/NaBr, 0 ꢀC, 24 h
H2O/NaBr, ꢁ10 ꢀC, 24 h
H2O/NaBr, 0 ꢀC, 24 h
58
31
42
>99
>99
>99
>99
>99
97
85:15
88:12
72:28
85:15
83:17
75:25
90:10
92:8
96:4
93:7
94:6
92:8
91
82
89
86
88
89
89
89
92
93
95
92
7
8e
9
10e,f
11e,f
12e,g
98
82
92
a
Catalyst (0.02 mmol) in solvent (1.0 mL), 4-NBA (0.014 mmol), aldehyde
(0.14 mmol), and cyclohexanone (1.00 mmol).
b
Isolated yield.
The diastereomeric ratio (dr) was determined by 1H NMR spectroscopy of the
c
crude reaction mixture.
d
The enantiomeric excess (ee) for the major isomer was determined by chiral
HPLC.
e
20 mol % additive.
2 equiv of cyclohexanone.
1.1 equiv of cyclohexanone, 4-NBA: 4-nitrobenzoic acid.
f
g
knowledge,12 toluene was employed as the solvent (entry 1, Table 1).
Although high selectivities were obtained, prolonged reaction times
were required to afford the products in mediocre yield. Other sol-
vents provided similar results (entries 2 and 3, Table 1, see also
Supplementary data). Fortunately, the use of water as the solvent led
to quantitative yield (entry 4, Table 1). Having identified the po-
tential to develop a tripeptide able to promote the aldol reaction in
aqueous medium in high selectivities, a thorough examination of
Fig. 2. Design of the peptide-organocatalysts used in this study.
The synthesized organocatalyst 12a was then evaluated in the
aldol reaction between cyclohexanone (13a) and 4-nitroben
zaldehyde (14a) (Table 1). Following previously acquired

610
A. Psarra et al. / Tetrahedron 70 (2014) 608e615
reaction conditions was undertaken (entries 5e12, Table 1 and
Supplementary data). Among a number of different aqueous solu-
tions, a saturated aqueous solution of NaBr provided the best results.
Careful selection of the reaction temperature and the amount of the
acid additive provided the best reaction conditions (entries 9e12,
Table 1). It has to be highlighted that only 2 equiv of ketone are
enough to afford the product in high yields and selectivities (entry
11, Table 1).
We then turned our attention in exploring the substrate scope of
the enantioselective aldol reaction by employing either catalyst 12a
in aqueous environment or catalyst 12c in toluene (Table 3). A va-
riety of substituted aromatic aldehydes can be employed with cy-
clohexanone leading to products from good to excellent yields and
selectivities (entries 1e16, Table 3). Electron-withdrawing groups
at any position of the aryl moiety led to good to excellent results
(entries 1e10, Table 3), while the use of benzaldehyde or aromatic
aldehydes para-substituted with halogens led to similar yields and
selectivities (entries 11e16, Table 3). In all cases higher diaster-
eoselectivities were obtained when the aqueous conditions along
with catalyst 12a were employed. On the other hand and in most
cases, slightly higher enantioselectivities were observed when
catalyst 12c in toluene was utilized. Tetrahydropyran-4-one and
tetrahydrothiopyran-4-one proved to be difficult substrates for
catalyst 12a leading to lower yields and selectivities, while catalyst
12c delivered the products in high yields and selectivities (entries
17e20, Table 3). Disubstituted cyclohexanone at the 4-position
required prolonged reaction time to deliver a mediocre yield and
lower enantioselectivity (entries 21 and 22, Table 3). The desym-
metrization of ketones is also possible utilizing organocatalyst 12a,
since 4-methyl cyclohexanone delivered the product in high yield
and with excellent selectivities, while catalyst 12c led to inferior
results (entries 23 and 24, Table 3). Cyclopentanone was also uti-
lized with some success, since very low enantioselectivities were
observed (entries 25 and 26, Table 3). Moreover, in order to broaden
the scope of this methodology, we investigated the reaction of ac-
etone with 4-nitrobenzaldehyde (entries 27 and 28, Table 3). In
aqueous environment no reaction took place, while the yield and
enantioselectivity observed were not satisfactory when catalyst 12c
was employed.
Once the optimum reaction conditions in aqueous medium were
identified, the catalytic behavior of the other tripeptides were
evaluated, since it was interesting to study how the incorporation
of other tert-butyl esters of amino acids on the catalyst backbone
would affect the catalytic efficiency. Thus, catalysts 12aef were
tested both in toluene and in aqueous conditions (Table 2). Tri-
peptide 12a, based on di-tert-butyl aspartate, provided the product
in high yields and selectivities only in aqueous medium, while in
toluene the yield was low (entries 1 and 2, Table 2). Although
catalyst 12b, based on (S)-tert-butyl phenylglycinate, catalyzed the
aldol reaction both in aqueous and organic media, it provided in-
ferior selectivities (entries 3 and 4, Table 2). Changing to (R)-tert-
butyl phenylglycinate, tripeptide 12c provided the product in
quantitative yield, but the selectivities were slightly inferior when
toluene was used as the solvent and compared to 12a (entry 5,
Table 2). Decreasing the excess of ketone to 2 equiv had a positive
impact in selectivities, while the yield remained high (entry 6 vs 5,
Table 2). This catalyst provided the best results in organic solvents
among the tripeptides bearing tert-butyl esters of amino acids
tested. Furthermore, catalyst 12c could be also employed in the
presence of water affording the product in slightly decreased se-
lectivities (entry 7, Table 2). Among the other catalysts, serine-
based 12d proved inferior in both reaction conditions, while cata-
lysts 12e and 12f led to a further decrease in the catalytic activity
(entries 8e13, Table 2).
A plausible transition-state model is proposed in Fig. 3. The
secondary amine of the pyrrolidine ring activates the ketone
through the formation of an enamine intermediate. It is likely that
the electrophile is activated through a multiple hydrogen bonding
network consisting of the two amide protons of the tripeptide.
Table 2
Enantioselective aldol reaction of cyclohexanone with 4-nitrobenzaldehyde using
catalysts 12aefa
3. Conclusions
In conclusion, the synthesis of tripeptides based on proline,
phenylalanine, and a series of tert-butyl esters of amino acids was
carried out. The design of these catalysts was based on the efficient
activation of ketones from the secondary amine of the proline
residue via enamine formation and the high level of organization of
the transition state when more than one potential hydrogen bond
sites exist in the molecule of the catalyst. The evaluation of these
tripeptides in the asymmetric aldol reaction was carried out. When
di-tert-butyl aspartate was utilized, the tripeptide provided the
aldol product in good to excellent yields and selectivities in satu-
rated aqueous solution. When the tert-butyl (R)-phenylglycinate
was utilized, the aldol product was obtained in similar high yields
and selectivities but in toluene. The nature of the amino acid
moiety at the C-terminus is of critical importance, since depending
on the amino acid, different reaction conditions can be employed.
Entry
Catalyst
Conditions
Yieldb (%)
drc
ee (%)d
1e
2
12a
12a
12b
12b
12c
12c
12c
12d
12d
12e
12e
12f
12f
A
B
A
B
A
A
B
A
B
A
B
A
B
17
82
98:2
94:6
95
95
75
88
94
96
93
92
83
n.d.
87
d
3e
4f
>99
>99
>99
99
>99
98
>99
12
63
70:30
80:20
83:17
88:12
88:12
90:10
86:14
87:13
90:10
d
5
6g
7
8
9
10f
11f
12e
13e
Traces
7
85:15
n.d.
4. Experimental section
a
Conditions A: catalyst (0.02 mmol) in toluene (1.0 mL), 4-NBA (0.03 mmol),
aldehyde (0.14 mmol), and cyclohexanone (1.40 mmol), ꢁ20 ꢀC, 24 h. Conditions B:
catalyst (0.02 mmol) in H2O/NaBr (1.0 mL), 4-NBA (0.03 mmol), aldehyde
(0.14 mmol), and cyclohexanone (0.28 mmol), ꢁ10 ꢀC, 24 h.
4.1. General information
b
Organic solutions were concentrated under reduced pressure on
Isolated yield.
c
The diastereomeric ratio (dr) was determined by 1H NMR spectroscopy of the
€
a Buchi rotary evaporator. Chromatographic purification of prod-
crude reaction mixture.
ucts was accomplished using column chromatography on Merck
Kieselgel 60 F254 230e400 mesh. Thin-layer chromatography (TLC)
was performed on aluminum backed silica plates (0.2 mm, 60 F254).
Visualization of the developed chromatogram was performed by
fluorescence quenching using ninhydrin stain. Melting points were
d
The enantiomeric excess (ee) for the major isomer was determined by chiral
HPLC.
e
Reaction time 72 h.
Reaction time 48 h.
2 equiv of cyclohexanone, 4-NBA: 4-nitrobenzoic acid, n.d.: not determined.
f
g

A. Psarra et al. / Tetrahedron 70 (2014) 608e615
611
Table 3
Enantioselective aldol reaction between ketones and aldehydes using catalyst 12a
or 12ca
Fig. 3. Proposed transition-state model for the aldol reaction.
Entry
Ketone
Ar/conditions
Yieldb (%)
drc
ee (%)d
€
determined on a Buchi 530 hot stage apparatus and are un-
corrected. IR spectra were recorded on a Nicolet 6700 FT-IR spec-
trometer and are reported in terms of frequency of absorption
(cmꢁ1). 1H and 13C NMR spectra were recorded on Varian Mercury
(200 or 600 and 50 or 125 MHz) as noted, and are internally ref-
erenced to residual solvent signals (CDCl3 or (CD3)2SO). Data for 1H
1
4-NO2C6H4/A
4-NO2C6H4/B
3-NO2C6H4/A
3-NO2C6H4/B
2-NO2C6H4/A
2-NO2C6H4/B
4-CF3C6H4/A
4-CF3C6H4/B
3-CNC6H4/A
3-CNC6H4/B
C6H5/A
C6H5/B
4-FC6H4/A
4-FC6H4/B
4-BrC6H4/A
4-BrC6H4/B
82 (15a)
99 (15a)
64 (15b)
67 (15b)
40 (15c)
47 (15c)
78 (15d)
80 (15d)
54 (15e)
58 (15e)
61 (15f)
86 (15f)
78 (15g)
62 (15g)
58 (15h)
53 (15h)
94:6
88:12
95:5
95
96
91
93
97
97
86
90
97
94
75
85
90
97
77
67
2
3e
4e
92:8
5e
89:11
90:10
94:6
88:12
93:7
88:12
90:10
88:12
97:3
86:14
93:7
6e
7f
8f
NMR spectroscopy are reported as follows: chemical shift (d parts
9f
per million), multiplicity (s¼singlet, d¼doublet, t¼triplet,
q¼quadruplet, m¼multiplet, br s¼broad signal, bs m¼broad signal
multiplet), integration, coupling constant and assignment. Wher-
ever rotamers exist, are presented in brackets. Diastereomeric ra-
tios were determined by 1H NMR spectroscopy (200 MHz). Data for
10f
11f
12f
13f
14f
15f
16f
13C NMR spectroscopy are reported in terms of chemical shift (
d
88:12
ppm). 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. High Perfor-
mance Liquid Chromatography (HPLC) was used to determine en-
antiomeric excesses and was performed on an Agilent 1100 Series
apparatus using ChiralpakÒ AD-H, OD-H and AS-H columns. Optical
rotations were measured on a Perkin Elmer 343 polarimeter. The
configuration of the products has been assigned by comparison to
literature data. Data for known compounds match literature data.
17g
18g
19f
20f
4-NO2C6H4/A
4-NO2C6H4/B
4-NO2C6H4/A
4-NO2C6H4/B
78 (15i)
92 (15i)
64 (15j)
92 (15j)
90:10
92:8
96:4
96:4
82
85
89
98
4.2. General procedure for the synthesis of the catalysts
21f
22f
4-NO2C6H4/A
4-NO2C6H4/B
41 (15k)
40 (15k)
82:18
89:11
72
85
4.2.1. (S)-2-[(S)-1-(Benzyloxycarbonyl)pyrrolidine-2-carboxamido]-
3-phenylpropanoic acid (10). An identical procedure was followed
and compound data in agreement with Ref. 12.
4.2.2. (S)-Di-tert-butyl 2-((S)-2-((S)-1-((benzyloxy)carbonyl)pyrroli-
dine-2-carboxamido)-3-phenylpropanamido)succinate (11a). To
a
stirred solution of dipeptide 10 (1.29 g, 3.26 mmol) in dry CH2Cl2
(20 mL) at 0 ꢀC,1-hydroxybenzotriazole (HOBt) (0.44 g, 3.26 mmol),
H-Asp(OtBu)-OtBu (0.92 g, 3.26 mmol), Et3N (0.70 mL, 5.00 mmol),
and dicyclohexyl carbodiimide (DCC) (0.72 g, 3.26 mmol) were
added consecutively. The reaction mixture was left stirring at 0 ꢀC
for 1 h and then warmed to rt 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 H2SO4 (5%, 20 mL), H2O (20 mL), aqueous
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 (30:70). Mixture of rotamers 60:40.
White solid; 1.80 g, 89% yield; Rf (AcOEt/Pet. Ether 7:3) 0.67; mp
23f
24e
25f
26e
27e
4-NO2C6H4/A
4-NO2C6H4/B
4-NO2C6H4/A
4-NO2C6H4/B
4-NO2C6H4/A
4-NO2C6H4/B
91 (15l)
43 (15l)
90 (15m)
98 (15m)
e (15n)
40 (15n)
97:3
70:30
37:63
37:63
d
99
82
12
27h
d
28e
d
71
92e94 ꢀC; ½a 2D5
ꢂ
ꢁ45.0 (c 1.0, CH3OH); IR (KBr) 3302, 2977, 2931,
a
1743, 1705, 1655, 1524, 1414, 1366, 1153 cmꢁ1
;
1H NMR (600 MHz,
Conditions A: 12a in H2O/NaBr. Conditions B: 12c in toluene.
b
c
Isolated yield.
DMSO-d6)
d
8.42 (0.6H, d, J¼7.9 Hz, NH), 8.27 (0.4H, d, J¼8.0 Hz,
The diastereomeric ratio (dr) was determined by 1H NMR spectroscopy of the
NH), 8.07 (0.6H, d, J¼8.5 Hz, NH), 7.96 (0.4H, d, J¼8.3 Hz, NH),
7.36e7.05 (10H, m, ArH), 5.08 (0.4H, d, J¼12.7 Hz, OCHH), 5.00
(0.4H, d, J¼12.7 Hz, OCHH), 4.94 (0.6H, d, J¼13.1 Hz, OCHH), 4.77
(0.6H, d, J¼13.1 Hz, OCHH), 4.58 (0.6H, ddd, J¼8.7, 8.5 and 3.9 Hz,
NCH), 4.52e4.41 (1.4H, m, NCH), 4.21e4.12 (1H, m, NCH), 3.38e3.25
(2H, m, 2ꢃ CHH), 3.04e2.92 (1H, m, CHH), 2.82e2.73 (1H, m, CHH),
2.66e2.58 (1H, m, CHH), 2.54e2.45 (1H, m, CHH), 2.08e2.00 (0.6H,
crude reaction mixture.
d
The enantiomeric excess (ee) for the major isomer was determined by chiral
HPLC.
e
Reaction time 48 h.
Reaction time 72 h.
Reaction time 120 h.
Major isomer syn: 27% ee, minor isomer anti: 97% ee.
f
g
h

612
A. Psarra et al. / Tetrahedron 70 (2014) 608e615
m, CHH), 2.00e1.92 (0.4H, m, CHH), 1.72e1.58 (3H, m, 3ꢃ CHH), 1.37
ArH), 5.08 (0.4H, d, J¼13.0 Hz, OCHH), 4.98 (0.4H, d, J¼13.0 Hz,
OCHH), 4.93 (0.6H, d, J¼13.4 Hz, OCHH), 4.77 (0.6H, d, J¼13.4 Hz,
OCHH), 4.72e4.53 (1H, m, NCH), 4.31e4.19 (1H, m, OCHH),
4.15e4.07 (1H, m, OCHH), 3.65e3.52 (1H, m, NCH), 3.47e3.18 (3H,
m, NCH and NCHH), 3.09e2.91 (1H, m, CHH), 2.86e2.69 (1H, m,
CHH), 2.05e1.96 (1H, m, CHH), 1.71e1.49 (3H, m, 3ꢃ CHH), 1.36 [9H,
s, (CCH3)3], 1.09 [9H, s, (CCH3)3]; 13C NMR (50 MHz, DMSO-d6)
[12.6H, s, (CCH3)3], 1.35 [5.4H, s, (CCH3)3]; 13C NMR (75 MHz,
DMSO-d6) d 172.2 (172.0), 171.5 (171.3), 170.0 (169.9), 169.6 (169.5),
154.7 (154.2), 138.2 (138.1), 137.5 (137.3), 129.6 (129.5), 128.8
(128.6), 128.4 (128.3), 127.9 (128.2), 127.3 (127.8), 126.6 (126.5),
81.4, 80.9, 66.0 (66.4), 59.7 (60.4), 53.7 (53.9), 49.8, 47.5 (46.9), 37.5
(38.0), 31.4 (30.1), 29.5 (29.2), 28.1, 28.0, 24.0 (23.2); MS 624
(MþHþ, 100); HRMS exact mass calculated for [MþH]þ
(C34H46N3O8) requires m/z 624.3279, found m/z 624.3284.
d
172.5 (172.3), 172.0 (171.8), 169.9 (170.0), 154.5 (154.9), 138.5
(138.7),137.7 (137.4),129.8 (129.9), 128.8 (129.1), 128.5 (128.6),128.1
(128.0), 127.6 (127.8), 126.8 (126.7), 81.3, 73.5, 66.3 (66.6), 62.3
(62.2), 60.0 (60.1), 58.4 (59.1), 54.1 (54.0), 47.7 (47.6), 37.9 (37.8), 31.7
(31.9), 28.3, 27.8, 23.4 (24.4); MS 596 (MþHþ, 42); HRMS exact mass
calculated for [MþH]þ (C33H46N3O7) requires m/z 596.3330, found
m/z 596.3341.
4.2.3. (S)-Benzyl 2-(((S)-1-(((S)-2-(tert-butoxy)-2-oxo-1-
phenylethyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamoyl)pyrroli-
dine-1-carboxylate (11b). Same procedure as above, but utilizing H-
Phg-OtBu (1.00 mmol). Mixture of rotamers 60:40. White solid;
0.50 g, 87% yield; Rf (AcOEt/Pet. Ether 1:1) 0.38; mp 99e101 ꢀC;
½
a 2D5
1648, 1535, 1414, 1358, 1151 cmꢁ1
8.67 (0.6H, d, J¼6.9 Hz, NH), 8.48 (0.4H, d, J¼7.0 Hz, NH), 8.07
ꢂ
ꢁ9.1 (c 1.0, CH3OH); IR (KBr) 3281, 2918, 2850, 1738, 1707,
4.2.6. (S)-Benzyl 2-(((S)-1-(((2S,3R)-1,3-di-tert-butoxy-1-oxobutan-
2-yl)amino)-1-oxo-3-phenylpropan-2-yl)carbamoyl)pyrrolidine-1-
carboxylate (11e). Same procedure as above, but utilizing H-
Thr(tBu)-OtBu (0.50 mmol). Mixture of rotamers 60:40. White solid;
0.28 g, 91% yield; Rf (AcOEt/Pet. Ether 7:3) 0.75; mp 105e107 ꢀC;
;
1H NMR (600 MHz, DMSO-d6)
d
(0.6H, d, J¼8.5 Hz, NH), 7.97 (0.4H, d, J¼8.5 Hz, NH), 7.41e7.31 (7H,
m, ArH), 7.31e7.18 (5H, m, ArH), 7.16e7.06 (3H, m, ArH), 5.23 (0.4H,
d, J¼7.0 Hz, NCH), 5.20 (0.6H, d, J¼7.0 Hz, NCH), 5.00 (0.4H, d,
J¼12.7 Hz, OCHH), 4.92 (0.6H, d, J¼13.0 Hz, OCHH), 4.86 (0.4H, d,
J¼12.7 Hz, OCHH), 4.76 (0.6H, d, J¼13.0 Hz, OCHH), 4.70 (0.6H, td,
J¼9.6 and 4.2 Hz, NCH), 4.64 (0.4H, ddd, J¼9.7, 9.6 and 4.1 Hz, NCH),
4.16e4.06 (1H, m, NCH), 3.40e3.34 (1H, m, NCHH), 3.32e3.24 (1H,
m, NCHH), 3.09 (0.4H, dd, J¼13.6 and 3.6 Hz, CHH), 3.02 (0.6H, dd,
J¼13.9 and 4.0 Hz, CHH), 2.86e2.79 (1H, m, CHH), 2.06e1.97 (0.6H,
m, CHH), 1.96e1.88 (0.4H, m, CHH), 1.68e1.61 (1H, m, CHH),
1.61e1.52 (2H, m, 2ꢃ CHH), 1.33 [3.6H, s, (CCH3)3], 1.32 [5.4H, s,
½
a 2D5
1517, 1415, 1364, 1160 cmꢁ1; 1H NMR (200 MHz, CDCl3)
ꢂ
ꢁ37.4 (c 0.8, CH3OH); IR (KBr) 3315, 2975, 2933, 1740, 1702,
d
7.48e7.09
(11H, m, ArH and NH), 6.61e6.41 (1H, m, NH), 5.22e4.92 (2H, m,
OCHH), 4.81e4.62 (1H, m, OCH), 4.39e4.07 (3H, m, 3ꢃ NCH),
3.52e2.85 (4H, m, NCHH and CHH), 2.29e2.12 (0.6H, m, CHH),
2.08e1.62 (3.4H, m, 3.4ꢃ CHH),1.46 [9H, s, (CCH3)3],1.17e1.05 [12H,
m, (CCH3)3 and CH3]; 13C NMR (50 MHz, CDCl3)
d 171.4 (171.8), 170.7
(170.6), 169.4 (169.5), 156.9 (156.8), 136.7 (136.6), 136.3 (136.4),
129.3, 128.5 (128.6), 128.3 (128.4), 128.0 (128.1), 127.9 (128.0), 126.6
(126.9), 81.9, 73.8, 67.3, 67.1, 60.5 (60.7), 58.4 (56.7), 53.8 (53.7),
46.8 (47.3), 38.1 (38.2), 30.8 (30.9), 28.6, 28.1, 24.3 (23.2), 20.6
(21.1); MS 610 (MþHþ, 49); HRMS exact mass calculated for
[MþH]þ (C34H48N3O7) requires m/z 610.3487, found m/z 610.3496.
(CCH3)3]; 13C NMR (125 MHz, DMSO-d6)
d 172.3 (172.1), 171.6
(171.4), 169.8 (169.7), 154.2 (154.8), 138.3 (138.2), 137.5 (137.3),
136.7 (136.6), 129.7 (129.6), 129.0 (129.1), 128.8 (128.7), 128.6
(128.7), 128.3 (128.4), 128.1 (128.2), 128.1 (127.8), 127.4 (127.8),
126.6 (126.5), 81.6, 66.0 (66.4), 59.8 (60.5), 57.6, 53.6 (53.7), 47.5
(46.9), 37.8 (37.5), 31.4 (30.1), 27.9, 23.2 (24.0); MS 586 (MþHþ, 52);
HRMS exact mass calculated for [MþH]þ (C34H40N3O6) requires m/z
586.2912, found m/z 586.2927.
4.2.7. (S)-Benzyl 2-(((S)-1-(((S)-1-(tert-butoxy)-1-oxo-3-(1-trityl-
1H-imidazol-4-yl)propan-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)
carbamoyl)pyrrolidine-1-carboxylate (11f). Same procedure as
above, but utilizing H-His(Trt)-OtBu (0.50 mmol). White solid;
4.2.4. (S)-Benzyl 2-(((S)-1-(((R)-2-(tert-butoxy)-2-oxo-1-
phenylethyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamoyl)pyrroli-
dine-1-carboxylate (11c). Same procedure as above, but utilizing
(R)-H-Phg-OtBu (2.90 mmol). White solid; 1.56 g, 92% yield; Rf
0.33 g, 80% yield; Rf (AcOEt/Pet. Ether 8:2) 0.75; mp 75e78 ꢀC; ½a D25
ꢂ
ꢁ40.3 (c 0.67, CH3OH); IR (KBr) 3311, 2979, 2927, 1738, 1705, 1672,
1495, 1415, 1357, 1154 cmꢁ1; 1H NMR (200 MHz, CDCl3)
d 7.80e7.52
(1H, m, NH), 7.41e7.21 (16H, m, ArH), 7.21e6.97 (11H, m, ArH),
6.61e6.52 (1H, m, NH), 5.15 (1H, d, J¼12.1 Hz, OCHH), 5.01 (1H, d,
J¼12.1 Hz, OCHH), 4.85e4.69 (1H, m, NCH), 4.68e4.56 (1H, m,
NCH), 4.31e4.17 (1H, m, NCH), 3.41e3.18 (3H, m, NCHH and CHH),
2.99e2.82 (3H, m, 3ꢃ CHH), 1.99e1.52 (4H, m, 4ꢃ CHH), 1.36 [9H, s,
(AcOEt/Pet. Ether 6:4) 0.55; mp 100e102 ꢀC; ½a D25
ꢁ75.3 (c 1.0,
ꢂ
CH3OH); IR (KBr) 3301, 2978, 2852, 1735, 1697, 1651, 1523, 1415,
1356, 1152 cmꢁ1 1H NMR (200 MHz, CDCl3)
; d 7.41e6.82 (17H, m,
ArH and 2ꢃ NH), 5.46e5.29 (1H, m, NCH), 5.22e4.92 (2H, m,
OCHH), 4.71e4.57 (1H, m, NCH), 4.29e4.21 (1H, m, NCH),
3.49e3.29 (2H, m, NCHH), 3.29e2.81 (2H, m, CHH), 2.11e1.89 (2H,
m, 2ꢃ CHH), 1.89e1.55 (2H, m, 2ꢃ CHH), 1.36 [9H, s, (CCH3)3]; 13C
(CCH3)3]; 13C NMR (50 MHz, CDCl3)
d 171.6 (171.4), 170.5 (170.3),
169.8 (169.9), 156.0 (155.9), 142.1, 140.5, 138.5 (138.4), 136.5 (136.4),
136.4 (136.3),129.7,129.5,128.4,128.1,126.4,119.3, 81.4, 70.3 (70.2),
67.3 (67.2), 60.6 (60.6), 53.6 (53.7), 53.0 (52.9), 46.7, 37.9 (38.0), 36.9
(37.0), 29.7, 28.0, 24.2; MS 832 (MþHþ, 38); HRMS exact mass
calculated for [MþH]þ (C51H54N5O6) requires m/z 832.4069, found
m/z 832.4078.
NMR (50 MHz, CDCl3)
d 171.6 (171.8), 169.9 (170.0), 169.5 (169.7),
156.1 (156.0), 136.6, 136.5, 136.3, 129.1, 129.2, 128.6 (128.8), 128.5,
128.4, 128.1, 127.3 (127.1), 127.1 (127.0), 126.7 (126.9), 82.5 (82.6),
67.4 (67.3), 60.7 (60.4), 57.0 (56.9), 53.8 (53.7), 47.0 (47.4), 37.8
(37.7), 28.7 (28.6), 27.7, 24.3 (23.2); MS 586 (MþHþ, 54); HRMS
exact mass calculated for [MþH]þ (C34H40N3O6) requires m/z
586.2912, found m/z 586.2925.
4.2.8. (S)-Di-tert-butyl 2-((S)-3-phenyl-2-((S)-pyrrolidine-2-carbo
xamido)propanamido)succinate (12a). To a stirred solution of com-
pound 11a (1.70 g, 2.70 mmol) in dry methanol (60 mL), 10% Pd/C
(10 mol %) was added and the reaction mixture was left stirring at
rt for 2 h under hydrogen atmosphere. After filtration through Celite,
the solvent was evaporated to afford the desired product. Colorless
4.2.5. (S)-Benzyl 2-(((S)-1-(((S)-1,3-di-tert-butoxy-1-oxopropan-2-yl)
amino)-1-oxo-3-phenylpropan-2-yl)carbamoyl)pyrrolidine-1-
carboxylate (11d). Same procedure as above, but utilizing H-
Ser(tBu)-OtBu (2.16 mmol). Mixture of rotamers 60:40. White solid;
1.10 g, 85% yield; Rf (AcOEt/Pet. Ether 7:3) 0.59; mp 106e108 ꢀC;
oil; 1.10 g, 85% yield; Rf (nBuOH/AcOH/H2O 4:1:1) 0.62; ½a D25
ꢁ16.4 (c
ꢂ
1.0, CH3OH); IR (KBr) 3296, 2975, 2926, 1731, 1654, 1513, 1392, 1367,
½
a 2D5
1655, 1524, 1415, 1363, 1193 cmꢁ1
8.15 (0.4H, d, J¼7.2 Hz, NH), 8.09 (0.6H, d, J¼8.3 Hz, NH), 8.05 (0.6H,
d, J¼6.8 Hz, NH), 7.95 (0.4H, d, J¼8.3 Hz, NH), 7.38e7.05 (10H, m,
ꢂ
ꢁ35.5 (c 1.0, CH3OH); IR (KBr) 3310, 2974, 2931, 1736, 1699,
1152 cmꢁ1; 1H NMR (600 MHz, DMSO-d6)
d
8.55 (1H, d, J¼8.1 Hz, NH),
;
1H NMR (200 MHz, DMSO-d6)
8.06 (1H, d, J¼8.9 Hz, NH), 7.23e7.16 (2H, m, ArH), 7.17e7.13 (3H, m,
ArH), 4.57 (1H, td, J¼9.0 and 4.5 Hz, NCH), 4.52e4.43 (1H, m, NCH),
3.44 (1H, dd, J¼8.8 and 4.9 Hz, NCH), 3.01 (1H, dd, J¼13.8 and 4.3 Hz,
d

A. Psarra et al. / Tetrahedron 70 (2014) 608e615
613
CHH), 2.80e2.72 (2H, m, CHH and CHH), 2.64 (1H, dd, J¼16.3 and
5.9 Hz, CHH), 2.59e2.47 (2H, m, 2ꢃ CHH), 1.85e1.75 (1H, m, CHH),
1.48e1.38 (2H, m, 2ꢃ CHH), 1.38e1.32 (2H, m, CHH and NH), 1.37 [9H,
s, (CCH3)3], 1.36 [9H, s, (CCH3)3]; 13C NMR (125 MHz, DMSO-d6)
NMR (200 MHz, CDCl3)
d
7.82e7.59 (1H, m, NH), 7.36e7.08 (5H, m,
ArH), 6.68e6.52 (1H, m, NH), 4.91e4.41 (2H, m, OCH and NCH),
4.40e4.06 (2H, m, 2ꢃ NCH), 3.58e3.17 (2H, m, NCHH), 3.11e2.77
(2H, m, CHH), 2.31 (1H, br s, NH), 2.21e1.61 (4H, m, 4ꢃ CHH), 1.45
[9H, s, (CCH3)3], 1.18e1.08 [12H, m, (CCH3)3 and CH3]; 13C NMR
d
173.8, 171.2, 170.1, 169.6, 137.6, 129.8, 128.3, 126.8, 81.5, 80.9, 60.3,
52.8, 49.7, 47.0, 38.6, 37.5, 30.7, 28.1, 28.0, 25.9; MS 490 (MþHþ, 100);
HRMS exact mass calculated for [MþH]þ (C26H40N3O6) requires m/z
490.2912, found m/z 490.2897.
(50 MHz, CDCl3) d 171.1 (171.2), 170.4 (170.8), 169.4 (169.5), 136.8
(136.7), 129.3 (129.5), 128.4 (128.2), 126.8 (126.7), 82.0 (82.2), 73.9,
67.1 (68.1), 58.4 (58.3), 57.6 (56.2), 54.1 (53.6), 46.5 (50.7), 38.0
(37.9), 30.2 (27.3), 28.6, 28.0, 23.9 (24.0), 20.7 (20.8); MS 476
(MþHþ, 100); HRMS exact mass calculated for [MþH]þ
(C26H42N3O5) requires m/z 476.3119, found m/z 476.3108.
4.2.9. (S)-tert-Butyl 2-phenyl-2-((S)-3-phenyl-2-((S)-pyrrolidine-2-
carboxamido)propanamido)acetate (12b). Same procedure as
above, but utilizing 11b (0.77 mmol). Colorless oil; 0.29 g, 84% yield;
Rf (nBuOH/AcOH/H2O 4:1:1) 0.63; ½a 2D5
ꢂ
þ5.9 (c 1.0, CH3OH); IR (KBr)
4.2.13. (S)-tert-Butyl 2-((S)-3-phenyl-2-((S)-pyrrolidine-2-carbox
amido)propanamido)-3-(1-trityl-1H-imidazol-4-yl)propanoate
(12f). Same procedure as above, but utilizing 11f (0.26 mmol) (no
cleavage of the Trt-protecting group was observed under the reaction
conditions employed). Yellow oil; 0.13 g, 72% yield; Rf (CHCl3/CH3OH
3299, 2976, 2928, 1735, 1649, 1517, 1392, 1369, 1152 cmꢁ1; 1H NMR
(600 MHz, DMSO-d6)
d
8.88 (1H, d, J¼7.2 Hz, NH), 8.09 (1H, d,
J¼8.9 Hz, NH), 7.42e7.32 (5H, m, ArH), 7.22e7.14 (5H, m, ArH), 5.24
(1H, d, J¼7.2 Hz, NCH), 4.69 (1H, td, J¼9.1 and 4.4 Hz, NCH), 3.44
(1H, dd, J¼8.9 and 5.0 Hz, NCH), 3.05 (1H, dd, J¼13.7 and 4.3 Hz,
NCHH), 2.81 (1H, dd, J¼13.7 and 9.3 Hz, NCHH), 2.77 (1H, dt, J¼10.1
and 6.6 Hz, CHH), 2.57 (1H, dt, J¼10.1 and 6.3 Hz, CHH), 1.85e1.75
(1H, m, CHH), 1.48e1.36 (2H, m, 2ꢃ CHH), 1.36e1.28 (2H, m, CHH
and NH), 1.34 [9H, s, (CCH3)3]; 13C NMR (125 MHz, DMSO-d6)
9:1) 0.29; ½a 2D5
ꢂ
ꢁ17.4 (c 0.6, CH3OH); IR (KBr) 3300, 2975, 2928, 1733,
1665, 1522, 1367, 1154 cmꢁ1; 1H NMR (200 MHz, CDCl3)
d
8.65e7.63
(4H, m, ArH and NH), 7.42e6.95 (19H, m, ArH), 6.69e6.55 (1H, m,
NH), 5.55e5.33 (1H, m, NCH), 4.91e4.52 (2H, m, 2ꢃ NCH), 3.51e3.19
(2H, m, NCHH), 3.19e2.81 (4H, m, 4ꢃ CHH), 2.41e2.31 (1H, m, CHH),
2.27e2.07 (2H, m, CHH and NH), 1.81e1.51 (2H, m, 2ꢃ CHH), 1.41
[3.6H, s, (CCH3)3], 1.34 [5.4H, s, (CCH3)3]; 13C NMR (50 MHz, CDCl3)
d
173.8, 171.3, 169.9, 137.7, 136.8, 129.8, 129.1, 128.7, 128.3, 128.1,
126.7, 81.7, 60.3, 57.4, 52.8, 47.0, 38.6, 30.7, 28.0, 25.8; MS 452
(MþHþ, 100); HRMS exact mass calculated for [MþH]þ
(C26H34N3O4) requires m/z 452.2544, found m/z 452.2537.
d
170.9 (171.2), 169.7 (169.8), 166.5 (165.2), 141.8, 138.1, 137.2, 137.0,
135.2, 129.7, 129.4, 128.4, 128.3, 128.2, 128.1, 126.2, 120.0, 81.7 (81.1),
67.8 (66.3), 55.7 (56.1), 53.5 (54.5), 53.0 (52.8), 44.6, 40.5 (40.6), 38.3,
30.1 (29.4), 27.9, 23.6; MS 698 (MþHþ, 100); HRMS exact mass cal-
culated for [MþH]þ (C43H48N5O4) requires m/z 698.3701, found m/z
698.3692.
4.2.10. (R)-tert-Butyl 2-phenyl-2-((S)-3-phenyl-2-((S)-pyrrolidine-2-
carboxamido)propanamido)acetate (12c). Same procedure as above,
but utilizing 11c (2.39 mmol). Colorless oil; 0.89 g, 83% yield; Rf
(nBuOH/AcOH/H2O 4:1:1) 0.62; ½a 2D5
ꢂ
ꢁ84.2 (c 1.1, CH3OH); IR (KBr)
3297, 2975, 2927, 1735, 1651, 1513, 1368, 1152 cmꢁ1
;
1H NMR
4.3. General procedure for the aldol reaction
(200 MHz, CDCl3)
d
8.12 (0.8H, d, J¼8.0 Hz, NH), 7.77 (0.2H, d,
J¼8.5 Hz, NH), 7.34e7.04 (11H, m, ArH and NH), 5.37 (1H, d,
J¼7.2 Hz, NCH), 4.69 (1H, td, J¼8.3 and 4.1 Hz, NCH), 3.75 (1H, dd,
J¼8.2 and 4.8 Hz, NCH), 3.25e2.86 (3H, m, NCHH and CHH), 2.67
(1H, dt, J¼10.1 and 6.1 Hz, CHH), 2.12e1.91 (2H, m, CHH and NH),
1.72e1.36 (3H, m, 3ꢃ CHH), 1.35 [9H, s, (CCH3)3]; 13C NMR (50 MHz,
Conditions A: To a stirred solution of catalyst 12a (10 mg,
0.02 mmol) in saturated aqueous NaBr (1.0 mL), 4-nitrobenzoic acid
(4.6 mg, 0.028 mmol) was added. The reaction mixture was cooled
to ꢁ10 ꢀC. The aldehyde (0.14 mmol) was added, followed by the
ketone (0.28 mmol). The reaction mixture was left stirring at ꢁ10 ꢀC
for 24e120 h. The solvent was evaporated and the crude product
was purified using column chromatography eluting with the ap-
propriate mixture of petroleum ether (40e60 ꢀC)/EtOAc to afford
the desired product. Conditions B: To a stirred solution of catalyst
12c (9.3 mg, 0.02 mmol) in toluene (1.0 mL), 4-nitrobenzoic acid
(4.6 mg, 0.028 mmol) was added. The reaction mixture was cooled
to ꢁ20 ꢀC. The aldehyde (0.14 mmol) was added, followed by the
ketone (0.28 mmol). The reaction mixture was left stirring at
ꢁ20 ꢀC for 24e120 h. The solvent was evaporated and the crude
product was purified using column chromatography eluting with
the appropriate mixture of petroleum ether (40e60 ꢀC)/EtOAc to
afford the desired product.
CDCl3)
d 175.4, 170.1, 169.5, 136.7, 136.6, 129.2, 128.7, 128.5, 128.1,
127.1, 126.7, 82.5, 60.1, 56.9, 53.8, 47.0, 37.0, 30.6, 27.7, 25.8; MS 452
(MþHþ, 100); HRMS exact mass calculated for [MþH]þ
(C26H34N3O4) requires m/z 452.2544, found m/z 452.2535.
4.2.11. (S)-tert-Butyl 3-(tert-butoxy)-2-((S)-3-phenyl-2-((S)-pyrroli-
dine-2-carboxamido)propanamido)propanoate (12d). Same pro-
cedure as above, but utilizing 11d (1.60 mmol). Colorless oil; 0.64 g,
87% yield; Rf (nBuOH/AcOH/H2O 4:1:1) 0.67; ½a 2D5
ꢁ21.2 (c 0.76,
ꢂ
CH3OH); IR (KBr) 3301, 2973, 2929, 1736, 1656, 1513, 1393, 1365,
1161 cmꢁ1; 1H NMR (200 MHz, CDCl3)
d
8.05 (0.5H, d, J¼8.5 Hz, NH),
7.72 (0.5H, d, J¼8.9 Hz, NH), 7.38e7.05 (5H, m, ArH), 6.78e6.62 (1H,
m, NH), 4.71e4.59 (1H, m, OCHH), 4.59e4.41 (1H, m, OCHH),
3.79e3.61 (1H, m, NCH), 3.58e3.42 (1H, m, NCH), 3.29e2.62 (5H,
m, NCH, NCHH and CHH), 2.18e1.81 (3H, m, 2ꢃ CHH and NH),
1.71e1.22 (2H, m, 2ꢃ CHH), 1.44 [9H, s, (CCH3)3], 1.11 [9H, s,
4.3.1. (S)-2-[(R)-Hydroxy-(4-nitrophenyl)methyl]-cyclohexanone
(15a, Table 3, entry 2).12 Colorless oil, 34 mg, 99% yield; Rf (AcOEt/
Pet. Ether 4:6) 0.10; 1H NMR (200 MHz, CDCl3) anti
d 8.20 (2H, d,
(CCH3)3]; 13C NMR (50 MHz, CDCl3)
d
174.5 (174.4), 170.5 (170.6),
J¼8.8 Hz, ArH), 7.51 (2H, d, J¼8.8 Hz, ArH), 4.87 (1H, d, J¼8.4 Hz,
169.0 (168.9), 136.5 (136.6), 129.4 (129.3), 128.5 (128.4), 126.9
(126.8), 82.0 (81.9), 77.2, 64.5 (68.5), 62.0 (61.8), 53.5 (53.6), 53.2
(53.4), 47.0 (52.2), 38.0 (41.6), 30.2 (30.6), 28.0, 27.3, 24.1 (25.7); MS
462 (MþHþ, 100); HRMS exact mass calculated for [MþH]þ
(C25H40N3O5) requires m/z 462.2962, found m/z 462.2951.
OCH), 4.09 (1H, br s, OH), 2.64e2.26 (3H, m, COCH and CHH),
2.17e1.29 (6H, m, 6ꢃ CHH); 13C NMR (50 MHz, CDCl3)
d 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: 25.15 (minor) and 33.10 (major), 96% ee.
4.2.12. (2S,3R)-tert-Butyl
pyrrolidine-2-carboxamido)propanamido)butanoate
3-(tert-butoxy)-2-((S)-3-phenyl-2-((S)-
(12e). Same
4.3.2. (S)-2-[(R)-Hydroxy-(3-nitrophenyl)methyl]-cyclohexanone
(15b, Table 3, entry 4).12 Colorless oil, 23 mg, 67% yield; Rf (AcOEt/
procedure as above, but utilizing 11e (0.31 mmol). Yellow oil; 0.13 g,
Pet. Ether 4:6) 0.20; 1H NMR (200 MHz, CDCl3) anti
d 8.23e8.14 (2H,
88% yield; Rf (CHCl3/CH3OH 9:1) 0.34; ½a D25
ꢂ
ꢁ32.5 (c 0.89, CH3OH);
m, ArH), 7.67 (1H, d, J¼7.3 Hz, ArH), 7.55 (1H, d, J¼7.6 Hz, ArH), 4.90
IR (KBr) 3298, 2974, 2929, 1730, 1655, 1515, 1366, 1155 cmꢁ1
;
1H
(1H, d, J¼8.4 Hz, OCH), 4.11 (1H, br s, OH), 2.68e2.31 (3H, m, COCH

614
A. Psarra et al. / Tetrahedron 70 (2014) 608e615
and CHH), 2.17e1.32 (6H, m, 6ꢃ CHH); 13C NMR (50 MHz, CDCl3)
anti
d
7.47 (2H, d, J¼8.5 Hz, ArH), 7.20 (2H, d, J¼8.5 Hz, ArH), 4.75
d
214.6, 148.2, 143.1, 133.1, 129.2, 122.7, 121.9, 74.0, 57.0, 42.6, 30.6,
(1H, d, J¼8.6 Hz, OCH), 3.94 (1H, br s, OH), 2.61e2.13 (3H, m, COCH
27.6, 24.6; HPLC analysis: Diacel Chiralpak AD-H, hexane/iPrOH
92:8, flow rate 1.0 mL/min, retention time: 25.15 (major) and 31.98
(minor), 93% ee.
and CHH), 2.11e2.01 (1H, m, CHH), 1.88e1.24 (5H, m, 5ꢃ CHH); 13
C
NMR (50 MHz, CDCl3)
d 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, hex-
ane/iPrOH 90:10, flow rate 0.5 mL/min, retention time: 30.57 (mi-
nor) and 35.29 (major), 77% ee.
4.3.3. (S)-2-[(R)-Hydroxy-(2-nitrophenyl)methyl]-cyclohexanone
(15c, Table 3, entry 6).12 Yellow solid, 16 mg, 47% yield; mp
114e116 ꢀC {lit.: mp 116e11821}; Rf (AcOEt/Pet. Ether 3:7) 0.25; 1H
4.3.9. (S)-3-[(R)-Hydroxy-[4-(nitrophenyl)methyl]dihydro-2H-py-
ran-4(3H)-one (15i, Table 3, entry 18).12 Pale yellow solid, 32 mg,
92% yield; mp 116e118 ꢀC; Rf (AcOEt/Pet. Ether 4:6) 0.16; 1H NMR
NMR (200 MHz, CDCl3) anti
d 7.91e7.72 (2H, m, ArH), 7.63 (1H, t,
J¼6.5 Hz, ArH), 7.42 (1H, t, J¼6.6 Hz, ArH), 5.43 (1H, d, J¼7.1 Hz,
OCH), 4.16 (1H, br s, OH), 2.85e2.01 (3H, m, COCH, CHH), 1.90e1.52
(200 MHz, CDCl3) anti
d
8.21 (2H, d, J¼8.8 Hz, ArH), 7.50 (2H, d,
(6H, m, 6ꢃ CHH); 13C NMR (50 MHz, CDCl3)
d
214.9, 136.5, 133.0,
J¼8.8 Hz, ArH), 4.97 (1H, d, J¼8.2 Hz, OCH), 4.28e4.09 (1H, m,
OCHH), 3.90e3.64 (3H, m, 2ꢃ OCHH and OH), 3.44 (1H, dd, J¼11.4,
9.8 Hz, OCHH), 3.02e2.41 (3H, m, 3ꢃ CHH); 13C NMR (50 MHz,
128.9, 128.3, 128.2, 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: 40.77 (major) and 42.92 (minor),
97% ee.
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: 19.03 (minor) and 27.46 (major),
85% ee.
4.3.4. (S)-2-[(R)-Hydroxy-(4-(trifluoromethyl)phenyl)methyl]-cyclo-
hexanone (15d, Table 3, entry 8).12 White solid, 30 mg, 80% yield;
mp 73e75 ꢀC; Rf (AcOEt/Pet. Ether 4:6) 0.48; 1H NMR (200 MHz,
4.3.10. (S)-3-[(R)-Hydroxy-[4-(nitrophenyl)methyl]dihydro-2H-thio-
pyran-4(3H)-one (15j, Table 3, entry 20).12 Yellow solid, 34 mg, 92%
yield; mp 137e139 ꢀC {lit.: mp 140e14122}; Rf (AcOEt/Pet. Ether
CDCl3) anti
d
7.61 (2H, d, J¼8.2 Hz, ArH), 7.44 (2H, d, J¼8.2 Hz, ArH),
4.84 (1H, d, J¼8.6 Hz, OCH), 4.03 (1H, br s, OH), 2.69e2.02 (4H, m,
COCH and 3ꢃ CHH), 1.90e1.39 (5H, m, 5ꢃ CHH); 13C NMR (50 MHz,
3:7) 0.13; 1H NMR (200 MHz, CDCl3) anti
d
8.23 (2H, d, J¼8.3 Hz,
CDCl3)
d
215.1, 144.9, 129.6 (q, J¼31.2 Hz), 127.3, 125.3 (q, J¼8.1 Hz),
ArH), 7.53 (2H, d, J¼8.3 Hz, ArH), 5.04 (1H, d, J¼7.9 Hz, OCH), 3.63
(1H, br s, OH), 3.07e2.91 (3H, m, COCH and CHH), 2.87e2.70 (2H, m,
2ꢃ CHH), 2.68e2.42 (2H, m, 2ꢃ CHH); 13C NMR (50 MHz, CDCl3)
123.9 (q, J¼271.4 Hz), 74.2, 57.2, 42.6, 30.7, 27.6, 24.7; 19F NMR
(188 MHz, CDCl3)
d 3.89 (S); HPLC analysis: Diacel Chiralpak AD-H,
hexane/iPrOH 90:10, flow rate 0.5 mL/min, retention time: 22.19
d 211.2, 147.7, 147.6, 127.7, 123.8, 73.1, 59.4, 44.7, 32.8, 30.7; HPLC
(minor) and 27.37 (major), 90% ee.
analysis: Diacel Chiralpak AD-H, hexane/iPrOH 90:10, flow
rate 1.0 mL/min, retention time: 48.22 (minor) and 71.13 (major),
98% ee.
4.3.5. (R)-3-[Hydroxy-(2-(S)-oxocyclohexyl)methyl]-benzonitrile
(15e, Table 3, entry 9).12 Yellow solid, 17 mg, 54% yield; mp
66e68 ꢀC {lit.: mp 69e7218o}; Rf (AcOEt/Pet. Ether 3:7) 0.17; 1H
4.3.11. (S)-7-[(R)-Hydroxy-4-(nitrophenyl)methyl]-1,4-dioxospiro
[4.5]decan-8-one (15k, Table 3, entry 22).12 White solid, 17 mg, 40%
yield; mp 89e91 ꢀC; Rf (AcOEt/Pet. Ether 3:7) 0.06; 1H NMR
NMR (200 MHz, CDCl3) anti
d 7.68e7.38 (4H, m, ArH), 4.81 (1H, d,
J¼8.5 Hz, OCH), 4.01 (1H, br s, OH), 2.65e2.03 (4H, m, COCH and 3ꢃ
CHH),1.87e1.22 (5H, m, 5ꢃ CHH); 13C NMR (50 MHz, CDCl3)
d
214.6,
(200 MHz, CDCl3) anti
d
8.21 (2H, d, J¼8.8 Hz, ArH), 7.49 (2H, d,
142.6, 131.5, 130.6, 129.1, 129.0, 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: 28.15 (minor) and 42.58
(major), 97% ee.
J¼8.8 Hz, ArH), 4.92 (1H, d, J¼7.5 Hz, OCH), 4.04 (1H, br s, OH),
3.98e3.68 (4H, m, 4ꢃ OCHH), 2.91e2.74 (1H, m, COCH), 2.66e2.54
(1H, m, CHH), 2.51e2.42 (1H, m, CHH), 2.07e1.55 (3H, m, 3ꢃ CHH),
1.54e1.44 (1H, m, CHH); 13C NMR (50 MHz, CDCl3)
d 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: 16.34 (anti minor) and 26.41 (anti
major), 85% ee.
4.3.6. (S)-2-[(R)-Hydroxy-(phenyl)methyl]-cyclohexanone (15f, Table
3, entry 12).12 Colorless oil, 25 mg, 86% yield; Rf (AcOEt/Pet. Ether
4:6) 0.42; 1H NMR (200 MHz, CDCl3) anti
d 7.51e7.21 (5H, m, ArH),
4.78 (1H, d, J¼8.8 Hz, OCH), 3.84 (1H, br s, OH), 2.70e2.31 (3H, m,
COCH and CHH), 2.15e1.24 (6H, m, 6ꢃ CHH); 13C NMR (50 MHz,
4.3.12. (2S,4S)-2-[(R)-Hydroxy-(4-(nitrophenyl)methyl)]-4-methyl
CDCl3)
d
215.5, 140.8, 128.3, 127.8, 125.7, 74.7, 57.4, 42.6, 30.8, 27.8,
cyclohexanone (15l, Table 3, entry 23).23 Yellow solid, 34 mg, 91%
24.7; HPLC analysis: Diacel Chiralpak OD-H, hexane/iPrOH 90:10,
flow rate 0.5 mL/min, retention time: 18.87 (major) and 27.38
(minor), 85% ee.
yield; mp 99e101 ꢀC; Rf (AcOEt/Pet. Ether 3:7) 0.15; ½a 2D5
ꢁ6.8 (c 1.0,
ꢂ
CHCl3); 1H NMR (200 MHz, CDCl3) anti
d
8.22 (2H, d, J¼8.8 Hz, ArH),
7.51 (2H, d, J¼8.8 Hz, ArH), 4.92 (1H, d, J¼8.6 Hz, OCH), 3.99e3.87
(1H, br s, OH), 2.81e2.29 (3H, m, COCH and CHH), 2.15e1.29 (5H, m,
4ꢃ CHH, CH); 1.07 (3H, d, J¼7.1 Hz, CH3); 13C NMR (50 MHz, CDCl3)
4.3.7. (S)-2-[(R)-Hydroxy-(4-(fluorophenyl)methyl])-cyclohexanone
(15g, Table 3, entry 14).12 White solid, 19 mg, 62% yield; mp
66e68 ꢀC; Rf (AcOEt/Pet. Ether 4:6) 0.16; 1H NMR (200 MHz, CDCl3)
d
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: 48.43 (minor) and 54.58
(major), 99% ee.
anti
d
7.33e7.27 (2H, m, ArH), 7.03 (2H, t, J¼8.7 Hz, ArH), 4.77 (1H, d,
J¼8.4 Hz, OCH), 4.03 (1H, br s, OH), 2.65e2.31 (3H, m, COCH and
CHH), 2.08e1.22 (6H, m, 6ꢃ CHH); 13C NMR (50 MHz, CDCl3)
d
215.4, 162.3 (d, J¼246.2 Hz), 136.6, 128.5 (d, J¼5.1 Hz), 115.2 (d,
4.3.13. (S)-2-[(R)-Hydroxy-(4-(nitrophenyl)methyl)]-cyclopentanone
J¼20.0 Hz), 74.1, 57.4, 42.6, 30.7, 27.7, 24.6; 19F NMR (188 MHz,
(15m, Table 3, entry 26).12 Pale yellow oil, 32 mg, 98% yield; Rf
CDCl3)
d
ꢁ48.12 (S); HPLC analysis: Diacel Chiralpak AD-H, hex-
(AcOEt/Pet. Ether 4:6) 0.23; 1H NMR (200 MHz, CDCl3)
d 8.21 (2H, d,
ane/iPrOH 90:10, flow rate 0.5 mL/min, retention time: 26.65 (mi-
J¼8.8 Hz, ArH), 7.52 (2H, d, J¼8.8 Hz, ArH), 5.42 (1H, s, OCH syn),
4.84 (1H, d, J¼9.2 Hz, OCH anti), 4.76 (1H, br s, OH anti), 2.69 (1H, br
s, OH syn), 2.52e2.18 (3H, m, COCH and CHH), 2.15e1.83 (2H, m, 2ꢃ
nor) and 29.59 (major), 97% ee.
4.3.8. (S)-2-[(R)-Hydroxy-(4-(bromophenyl)methyl)]-cyclohexanone
(15h, Table 3, entry 15).12 White solid, 23 mg, 58% yield; mp
89e91 ꢀC; Rf (AcOEt/Pet. Ether 3:7) 0.24; 1H NMR (200 MHz, CDCl3)
CHH),1.78e1.55 (2H, m, 2ꢃ CHH); 13C NMR (50 MHz, CDCl3)
d 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

A. Psarra et al. / Tetrahedron 70 (2014) 608e615
615
Chiralpak AD-H, hexane/iPrOH 95:5, flow rate 1.0 mL/min, re-
tention time: 30.01 (syn major) and 41.68 (syn minor), 54.22
(anti minor) and 56.18 (anti major), syn isomer 27% ee, anti isomer
97% ee.
9. Wang, B.; Chen, G.-H.; Liu, L.-Y.; Chang, W.-X.; Li, J. Adv. Synth. Catal. 2009, 351,
2441e2448.
10. Fotaras, S.; Kokotos, C. G.; Tsandi, E.; Kokotos, G. Eur. J. Org. Chem. 2011,
1310e1317.
11. Fotaras, S.; Kokotos, C. G.; Kokotos, G. Org. Biomol. Chem. 2012, 10, 5613e5619.
12. Revelou, P.; Kokotos, C. G.; Moutevelis-Minakakis, P. Tetrahedron 2012, 68,
8732e8738.
13. For reviews, see: (a) Colby Davie, E. A.; Mennen, S. M.; Xu, Y.; Miller, S. J. Chem.
Rev. 2007, 107, 5759e5812; (b) Wennemers, H. Chem. Commun. 2011,
12036e12041.
14. For proline-based peptides, see: (a) Martin, H. J.; List, B. Synlett 2003,
1901e1902; (b) Kofoed, J.; Nielsen, J.; Reymond, J.-L. Bioorg. Med. Chem. Lett.
2003, 13, 2445e2447; (c) Tang, Z.; Tang, Z.-H.; Cun, L.-F.; Gong, L.-Z.; Mi, A.-Q.;
Jiang, Y.-Z. Org. Lett. 2004, 6, 2285e2287; (d) Shi, L.-X.; Sun, Q.; Ge, Z. M.; Zhu,
Y.-Q.; Cheng, T.-M.; Li, R.-T. Synlett 2004, 2215e2217; (e) Krattiger, P.; Kovasy,
R.; Revell, J. D.; Ivan, S.; Wennemers, H. Org. Lett. 2005, 7, 1101e1103; (f) Lei, M.;
Shi, L.; Li, G.; Chen, S.; Fang, W.; Ge, Z.; Cheng, T.; Li, R. Tetrahedron 2007, 63,
7892e7898; (g) Revell, J. D.; Wennemers, H. Adv. Synth. Catal. 2008, 350,
1046e1052; (h) Chen, Y.-H.; Sung, P.-H.; Sung, K. Amino Acids 2010, 38,
839e845.
4.3.14. (S)-4-Hydroxy-4-(4-nitrophenyl)-butan-2-one (15n, Table 3,
entry 28).21 Colorless oil, 12 mg, 40% yield; Rf (AcOEt/Pet. Ether 4:6)
25
0.14; [
a]
þ36.9 (c 1.4, CHCl3); 1H NMR (200 MHz, CDCl3)
d 8.20
D
(2H, d, J¼7.0 Hz, ArH), 7.52 (2H, d, J¼7.0 Hz, ArH), 5.25 (1H, m, OCH),
3.56 (1H, br s, OH), 3.01e2.71 (2H, m, 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, hexane/iPrOH
85:15, flow rate 1.0 mL/min, retention time: 32.69 (minor) and
42.78 (major), 71% ee.
15. For peptides not containing proline, see: (a) Tsogoeva, S. B.; Wei, S. Tetrahedron:
Asymmetry 2005, 16, 1947e1951; (b) Zou, W.; Ibrahem, I.; Dziedzic, P.; Sunden,
H.; Cordova, A. Chem. Commun. 2005, 4946e4948; (c) Dziedzic, P.; Zou, W.;
Hafren, J.; Cordova, A. Chem. Commun. 2006, 38e40; (d) Cordova, A.; Zou, W.;
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16. (a) Lindstrom, U. M. Chem. Rev. 2002, 102, 2751e2772; (b) Li, C.-J. Chem. Rev.
2005, 105, 3095e3166.
17. (a) Hayashi, Y.; Sumiya, T.; Takahashi, J.; Gotoh, H.; Urushima, T.; Shoji, M.
Angew. Chem., Int. Ed. 2006, 45, 958e961; (b) Mase, N.; Nakai, Y.; Ohara, N.;
Yoda, H.; Takabe, K.; Tanaka, F.; Barbas, C. F., III. J. Am. Chem. Soc. 2006, 128,
734e735.
Acknowledgements
C.G.K. gratefully acknowledges the Operational Program ‘Edu-
cation and Lifelong Learning’ for financial support through the
NSRF program ‘ENISXYSH METADIDAKTOPUN EPEYNHTUN’
(PE 2431) co-financed by ESF and the Greek State.
Supplementary data
18. (a) Guillena, G.; Hita, M. C.; Najera, C. Tetrahedron: Asymmetry 2006, 17,
1493e1497; (b) Wu, Y.; Zhang, Y.; Yu, M.; Zhao, G.; Wang, S. Org. Lett. 2006, 8,
4417e4420; (c) Font, D.; Jimeno, C.; Pericas, M. A. Org. Lett. 2006, 8,
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N.; Sumiya, T.; Shoji, M.; Hayashi, Y. Chem.dEur. J. 2007, 13, 10246e10256; (h)
Zu, L.; Xie, H.; Li, H.; Wang, J.; Wang, W. Org. Lett. 2008, 10, 1211e1214; (i) Zhao,
J.-F.; He, L.; Jiang, J.; Tang, Z.; Cun, L.-F.; Gong, L.-Z. Tetrahedron Lett. 2008, 49,
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2009, 351, 2791e2796; (k) Zhang, S.-P.; Fu, X.-K.; Fu, S.-D. Tetrahedron Lett.
2009, 50, 1173e1176; (l) Giacalone, F.; Gruttadauria, M.; Agrigento, P.; Lo Meo,
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19. For tryptophan-catalyzed aldol reaction, see: (a) Jiang, Z.; Liang, Z.; Wu, X.; Lu,
Y. Chem. Commun. 2006, 2801e2803; (b) Amedjkouh, M. Tetrahedron: Asym-
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Jiang, Z.; Shen, H.-M.; Lu, Y. Adv. Synth. Catal. 2007, 349, 812e816 For serine-
catalyzed aldol reaction, see: (d) Teo, Y.-C. Tetrahedron: Asymmetry 2007, 18,
1155e1158; (e) Wu, C.; Fu, X.; Li, S. Tetrahedron 2011, 67, 4283e4290 For
chitosan-catalyzed aldol reaction, see: (f) Gioia, C.; Ricci, A.; Bernardi, L.;
Bourahla, K.; Tanchoux, N.; Robitzer, M.; Quignard, F. Eur. J. Org. Chem. 2013,
588e594.
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.12.007.
References and notes
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20. (a) Kokotos, C. G.; Limnios, D.; Triggidou, D.; Trifonidou, M.; Kokotos, G. Org.
Biomol. Chem. 2011, 9, 3386e3395; (b) Kokotos, C. G. J. Org. Chem. 2012, 77,
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