Novel prolinamide-ureas as organocatalysts for the asymmetric aldol reaction

Article abstract of DOI:10.1016/j.tet.2012.08.023

Among the various versions of the aldol reaction, the enantioselective reaction between cyclic ketones and aldehydes constitutes a typical reaction model for the evaluation of novel organocatalysts. A multifunctional organocatalyst consisting of a prolinamide moiety, a gem diamine unit and a urea group was successfully employed in this asymmetric transformation. The products of the reaction between various ketones and aldehydes were obtained in high yields (up to 98%) with excellent diastereo- (up to >98:2 dr) and enantioselectivities (up to 99% ee).

Full text of DOI:10.1016/j.tet.2012.08.023

Tetrahedron 68 (2012) 8732e8738
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Novel prolinamideeureas as organocatalysts for the asymmetric aldol reaction
*
*
Panagiota Revelou, Christoforos G. Kokotos , Panagiota Moutevelis-Minakakis
Laboratory of Organic Chemistry, Department of Chemistry, University of Athens, Panepistimiopolis, Athens 15771, Greece
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 April 2012
Received in revised form 17 July 2012
Accepted 7 August 2012
Available online 15 August 2012
Among the various versions of the aldol reaction, the enantioselective reaction between cyclic ketones
and aldehydes constitutes a typical reaction model for the evaluation of novel organocatalysts. A mul-
tifunctional organocatalyst consisting of a prolinamide moiety, a gem diamine unit and a urea group was
successfully employed in this asymmetric transformation. The products of the reaction between various
ketones and aldehydes were obtained in high yields (up to 98%) with excellent diastereo- (up to >98:2
dr) and enantioselectivities (up to 99% ee).
Keywords:
Ó 2012 Elsevier Ltd. All rights reserved.
Aldol reaction
Organocatalysis
Prolinamides
Ureas
Asymmetric synthesis
1. Introduction
catalytic motives coupled with a chiral gem diamine derived from
an amino acid (Fig. 2). In comparison to catalyst 5, the novel family
Among the various CeC bond forming reactions in modern
asymmetric catalysis, aldol reaction possesses a pivotal role.1 With
the recognition of organocatalysis as the third branch of asym-
metric 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. Proline and
proline derivatives containing bioisosteric groups like sulfon-
amides and tetrazoles possess a prominent position among the
organocatalysts utilized.4 The five-membered secondary amine
structure of the pyrrolidine ring enables the activation of carbonyl
compounds through the formation of enamine intermediates,
while incorporation of a chiral template provides extra interactions
or a bulky environment leading to enhanced selectivity.
of catalysts lacks one of the chiral centres of the diamine backbone
of catalyst 5, while at the same time the prolinamide and the urea
group are closer to each other.
2. Results and discussion
(S)-Benzyloxycarbonyl protected proline (6) was coupled with
(S)-methyl phenylalaninate (7a), (S)-methyl phenylglycinate (7b) or
(R)-methyl phenylglycinate (7c) using dicyclohexylcarbodiimide
Since the pioneering work of List and co-workers,5 the aldol
reaction has been extensively studied. Nowadays, it is well accepted
that organocatalysts combining the prolinamide unit with func-
tionalities 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 cat-
alyze the aldol reactions are shown in Fig. 1 (compounds 1e5).6e10
Taking into account the high catalytic activity of catalyst 5,10 and
the assumption that the combination of a prolinamide with an urea
moiety should provide similar modes of activation through hy-
drogen bonding as in catalyst 5, we commenced a study on the
catalytic activity presented by compounds that combine these two
* Corresponding authors. Tel.: þ30 210 7274281; fax: þ30 210 7274761 (C.G.K);
tel.: þ30 210 7274484; fax: þ30 210 7274761 (P.M.-M.); e-mail addresses: ckokotos@
chem.uoa.gr (C.G. Kokotos), pminakak@chem.uoa.gr (P. Moutevelis-Minakakis).
Fig. 1. Known prolinamide organocatalysts.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.08.023

P. Revelou et al. / Tetrahedron 68 (2012) 8732e8738
8733
Table 1
Enantioselective aldol reaction of cyclohexanone with 4-nitrobenzaldehyde using
catalysts 10aec
Entry
Catalyst
Temperature (ꢀC)
Yielda (%)
drb
eec (%)
1
10a
10b
10c
10a
10b
10c
10a
510
ꢁ20
ꢁ20
ꢁ20
0
0
0
96
72
65
94
91
85
97
100
98:2
99:1
95:5
91:9
92:8
85:15
83:17
97:3
98
96
91
95
94
83
85
99
Fig. 2. Design of the organocatalysts used in this study.
2d
3d
4
(DCC) as
a
condensing agent in the presence of 1-
5d
6d
7
hydroxybenzotriazole (HOBt). Saponification afforded the N-pro-
tected dipeptides 8aec. The crucial step in the synthesis of the
catalyst is the formation of the isocyanate via a Curtius rear-
rangement11 of the acyl azide derived from the reaction of the
mixed anhydride of 8 with sodium azide. The Curtius rearrange-
ment was accomplished by sonication12,13 and the resultant iso-
cyanate was converted into the urea derivative when it was treated
with 3,5-bis(trifluoromethyl)aniline leading to the protected pro-
linamideeureas 9aec with retention of stereochemistry.14 Finally,
deprotection via hydrogenation afforded organocatalysts 10aec
(Scheme 1).
rt
ꢁ20
8
a
Yield of isolated product.
b
The diastereomeric ratio (dr) was determined by 1H NMR spectroscopy of the
crude reaction mixture.
c
The enantiomeric excess (ee) for the major isomer was determined by chiral
HPLC.
d
Reaction time 48 h. 4-NBA: 4-nitrobenzoic acid.
entry 2, Table 1). The combination of (S)-proline with (R)-phenyl-
glycine led to lower yield and selectivities, when it was used in-
stead of (S)-proline with (S)-phenylglycine, highlighting a clear
mismatch effect (entry 2 vs entry 3, Table 1). When the reaction was
carried out at 0 ꢀC, all three catalysts afforded the product in high
yields, however, the selectivities dropped (entries 3e6, Table 1).
Finally, organocatalyst 10a that afforded the best results, was also
tested at room temperature (entry 7, Table 1). Unfortunately, the
selectivity of the reaction dropped even more.
A survey on the reaction solvent and the acid additive was then
undertaken (Table 2). Unfortunately, no other solvent or additive
delivered better results (entries 1e6, Table 2). When the catalyst
loading was reduced to 5 mol %, the reaction time had to be in-
creased to afford similar results (entry 7, Table 2). Also, once the
amount of ketone was reduced to 5 equiv, the reaction time had to
be extended to obtain high yields and selectivities (entry 8,
Table 2).
Table 2
Enantioselective aldol reaction of cyclohexanone with 4-nitrobenzaldehyde using
catalyst 10a
Scheme 1. Synthesis of the organocatalysts 10aec.
Entry
Conditions
Yielda (%)
drb
eec (%)
The synthesized organocatalysts were then evaluated in the
aldol reaction between cyclohexanone (11a) and 4-
nitrobenzaldehyde (12a) (Table 1). The reaction conditions that
were used for the initial comparison of the three catalysts were the
optimum reaction conditions for catalyst 5 (entry 8, Table 1),10 since
our expectations were to adopt similar activation modes. At low
temperatures, all three organocatalysts afforded the product in
good to excellent yields, high to excellent diastereoselectivities and
high to excellent enantioselectivities (entries 1e3, Table 1).
Comparing organocatalysts 10a with 10b, it is obvious that the
aromatic ring of the gem diamine spacer needs to be a carbon atom
away from the stereogenic centre (phenylalanine instead of phe-
nylglycine) in order to get faster reaction rates and thus higher
yields, while in both cases the selectivities are excellent (entry 1 vs
1
2
3
4
Toluene, 4-NBA
CH2Cl2, 4-NBA
THF, 4-NBA
96
74
86
42
84
94
88
84
98:2
97:3
97:3
95:5
97:3
98:2
98:2
98:2
98
79
52
55
94
96
98
98
Et2O, 4-NBA
5
Toluene, AcOH
Toluene, PhCOOH
Toluene, 4-NBA
Toluene, 4-NBA
6
7d
8e
a
Yield of isolated product.
b
The diastereomeric ratio (dr) was determined by 1H NMR spectroscopy of the
crude reaction mixture.
c
The enantiomeric excess (ee) for the major isomer was determined by chiral
HPLC.
d
Catalyst (5 mol%) was used, reaction time 48 h.
Ratio of ketone to aldehyde 5:1, reaction time 48 h. 4-NBA: 4-nitrobenzoic acid,
e
AcOH: acetic acid.

8734
P. Revelou et al. / Tetrahedron 68 (2012) 8732e8738
The scope and the limitations of the organocatalyst 10a were also
methylcyclohexanone delivered the product in high yield and with
excellent selectivities (entry 12, Table 3). Cyclopentanone was also
utilized with some success (entry 13, Table 3). Moreover, in order to
broaden the scope of this methodology, we investigated the reaction
of acetone with 4-nitrobenzaldehyde (entry 14, Table 3). Although
a high yield was obtained, the enantioselectivity observed was not
satisfactory. Comparing catalyst 10a with parent catalyst 5,10 it is
obvious that 10a behaves similarly with 5 when cyclic ketones are
used as the nucleophile. Unfortunately, when less bulky ketones are
utilized, like acetone, 10a leads to inferior results compared to 5.10
It is clear that an organocatalyst combining the prolinamide unit
tested (Table 3). Avariety of substituted aromatic aldehydes could be
utilized affording the products in good to excellent yields and high to
excellent selectivities (entries 1e8, Table 3). Electron-withdrawing
groups at any position of the aryl moiety led to excellent results,
while the use of benzaldehyde or aromatic aldehydes para-
substituted with halogens led to lower yields, albeit with excellent
selectivities. Tetrahydropyran-4-one and tetrahydrothiopyran-4-
one proved to be difficult substrates and required longer reaction
times in order to deliver the products in highyields (entries 9 and 10,
Table 3). Disubstituted cyclohexanone at the 4-position required
prolonged reaction time to deliver a mediocre yield and lower dia-
stereoselectivity (entry 11, Table 3). The desymmetrization of ke-
tones is also possible utilizing organocatalyst 10a, since 4-
with a chiral diamine spacer derived from an a-amino acid and an
aryl urea moiety provides the products of the aldol reaction be-
tween cyclic ketones and aromatic aldehydes in excellent yields
and selectivities. Nowadays, it is well accepted that when proline
derivatives are used as catalysts, the catalytic mechanism includes
activation of the nucleophile via an enamine intermediate, while
the approach of the electrophile is governed by an internal acid/
hydrogen bonding. Similarly to catalyst 5,10 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 comprised from the
amide and the urea functionality (Fig. 3, I). An alternative pathway
could be also envisaged where the acid co-catalyst participates in
the transition state of the reaction (Fig. 3, II).
Table 3
Enantioselective aldol reaction between ketones and aldehydes using catalyst 10a
Entry
1
Ketone
Ar
Yielda (%)
drb
eec (%)
98
4-NO2C6H4
96 (13a)
98:2
2
3-NO2C6H4
2-NO2C6H4
4-CF3C6H4
3-CNC6H4
C6H5
87 (13b)
90 (13c)
77 (13d)
98 (13e)
51 (13f)
47 (13g)
30 (13h)
96:4
96
98
97
97
96
97
95
3d
4e
5d
6e
7d
8d
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
4-FC6H4
4-BrC6H4
9f
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
90 (13i)
90 (13j)
42 (13k)
95:5
92:8
84:16
92
97
92
10d
11d
Fig. 3. Proposed transition-state models for the aldol reaction in the absence (I) and in
the presence of the acid co-catalyst (II).
12
13
4-NO2C6H4
90 (13l)
99:1
99
3. Conclusions
In conclusion, the synthesis and the evaluation of novel proli-
namide compounds bearing an aryl urea moiety were carried out.
When a chiral gem diamine spacer easily derived from the natural
4-NO2C6H4
4-NO2C6H4
97 (13m)
91 (13n)
30:70
75g
66
a-amino acid phenylalanine was used, the best results were ob-
tained. This novel organocatalyst provided the products of the re-
action between cyclic ketones with aromatic aldehydes in excellent
yields and selectivities in the presence of 4-nitrobenzoic acid as the
acid co-catalyst.
14e
d
a
Yield of isolated product.
b
The diastereomeric ratio (dr) was determined by 1H NMR spectroscopy of the
4. Experimental section
crude reaction mixture.
c
The enantiomeric excess (ee) for the major isomer was determined by chiral
HPLC.
4.1. General information
d
Reaction time 72 h.
Reaction time 48 h.
Reaction time 120 h.
e
f
Organic solutions were concentrated under reduced pressure on
g
€
Major isomer syn: 75% ee, minor isomer anti: 80% ee.
a Buchi rotary evaporator. Chromatographic purification of products

P. Revelou et al. / Tetrahedron 68 (2012) 8732e8738
8735
was accomplished using column chromatography on Merck Kie-
selgel 60 F254 230e400 mesh. Thin-layer chromatography (TLC) was
performed on aluminium backed silica plates (0.2 mm, 60 F254).
Visualization of the developed chromatogram was performed by
fluorescence quenching using ninhydrin stain. Melting points were
6.5 Hz, NCH), 4.32e4.25 (1H, m, NCH), 3.41e3.11 (3H, m, PhCHH
and NCH2), 3.09e2.89 (1H, m, PhCHH), 2.37e2.05 (1H, m, CHH),
2.01e1.62 (3H, m, 3ꢂCHH); 13C NMR (50 MHz, CDCl3)
d 173.8, 171.8,
156.0, 135.9, 135.7, 129.2, 128.3, 128.2, 128.0, 127.8, 126.8, 67.4, 60.2,
52.9, 46.7, 37.2, 28.2, 24.1.
€
determined on a Buchi 530 hot stage apparatus and are uncorrected.
IR spectra were recorded on a Nicolet 6700 FT-IR spectrometer and
4.2.2. (S)-2-[(S)-1-(Benzyloxycarbonyl)pyrrolidine-2-carboxamido]-
2-phenylacetic acid (8b). Same procedure as above, but utilizing
are reported in terms of frequency of absorption (cmꢁ1). 1H and 13
C
NMR spectra were recorded on Varian Mercury (200 or 50 MHz) as
noted, and are internally referenced to residual solvent signals
(CDCl3). Data for 1H NMR spectroscopy are reported as follows:
(S)-methyl
5.00 mmol). White solid; 1.529 g, 80% yield; Rf (n-butanol/AcOH/
H2O 4:1:1) 0.73; mp 194e195 ꢀC; [
þ19.4 (c 1.0, CH3OH); IR
(KBr) 3313, 3062, 2960, 1732, 1662, 717, 695, 648 cmꢁ1
(200 MHz, CD3OD) 8.70 (1H, br s, NH), 7.48e7.18 (10H, m, ArH),
phenylglycinate
hydrochloride
(7b)
(1.00 g,
a
]
D
chemical shift (
d
ppm), multiplicity (s¼singlet, d¼doublet, t¼triplet,
;
1H NMR
q¼quadruplet, m¼multiplet, bs¼broad signal, bs m¼broad signal
multiplet), integration, coupling constant and assignment. Wher-
ever rotamers exist, are presented in brackets. Diastereomeric ratios
d
5.39 (1H, br s, NCH), 5.11e5.01 (2H, m, OCH2), 4.40 (1H, dd, J¼8.3,
3.9 Hz, NCH), 3.63e3.43 (2H, m, NCH2), 2.36e2.15 (1H, m, CHH),
were determined by 1H NMR spectroscopy (200 MHz). Data for 13
C
2.11e1.82 (3H, m, 3ꢂCHH); 13C NMR (50 MHz, CD3OD)
d 174.9,
NMR spectroscopy are reported in terms of chemical shift (
d
ppm).
173.5, 157.1, 137.7, 137.6, 129.8, 129.7, 129.5, 129.2, 128.9, 128.7, 68.2,
60.9, 58.2, 47.7, 32.5, 24.6; MS 381 (MꢁHþ, 100); HRMS exact mass
calculated for [MꢁH]þ (C21H21N2O5) requires m/z 381.4025, found
m/z 381.4016.
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 performance liquid
chromatography (HPLC) was used to determine enantiomeric ex-
cesses 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 and only when the
diastereomeric ratio of the product was >99:1. The configuration of
the products has been assigned by comparison to literature data.
Data for known compounds match literature data.
4.2.3. (S)-2-[(R)-1-(Benzyloxycarbonyl)pyrrolidine-2-carboxamido]-
2-phenylacetic acid (8c). Same procedure as above, but utilizing
(R)-methyl
5.00 mmol). White solid; 1.472 g, 77% yield; Rf (n-butanol/AcOH/
H2O 4:1:1) 0.83; mp 185e186 ꢀC; [
ꢁ138.0 (c 1.0, CH3OH); IR
(KBr) 3379, 3063, 2953, 1733, 1666, 719, 697, 639 cmꢁ1
(200 MHz, CD3OD) 7.51e7.21 (10H, m, ArH), 5.44 (1H, br s,
phenylglycinate
hydrochloride
(7c)
(1.00 g,
a
]
D
;
1H NMR
d
4.2. General procedure for the synthesis of the catalysts
NCH), 5.15e5.04 (2H, s, OCH2), 4.42e4.31 (1H, m, NCH),
3.63e3.43 (2H, m, NCH2), 2.39e2.13 (1H, m, CHH), 2.13e1.75
4.2.1. (S)-2-[(S)-1-(Benzyloxycarbonyl)pyrrolidine-2-carboxamido]-
3-phenylpropanoic acid (8a). To a stirred solution of Cbz-proline
(6) (1.20 g, 5.00 mmol) in dry CH2Cl2 (20 mL) at 0 ꢀC, 1-
hydroxybenzotriazole (HOBt) (0.670 g, 5.00 mmol), (S)-methyl
phenylalaninate hydrochloride (7a) (1.07 g, 5.00 mmol), Et3N
(0.700 mL, 5.00 mmol) and dicyclohexylcarbodiimide (DCC)
(1.10 g, 5.00 mmol) were added consecutively. The reaction mix-
ture was left stirring at 0 ꢀC for 1 h and then warmed to room
temperature and left stirring for 18 h. The solvents were evapo-
rated 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 (30:70). White solid;15 1.90 g, 92% yield; Rf (pet. ether/
(3H, m, 3ꢂCHH); 13C NMR (50 MHz, CD3OD)
d 174.6, 173.1, 156.4,
138.4, 137.8, 129.7, 129.5, 129.4, 129.2, 128.9, 128.5, 68.2, 61.2,
57.8, 47.6, 32.4, 24.5; MS 381 (MþHþ, 100); HRMS exact mass
calculated for [MꢁH]þ (C21H21N2O5) requires m/z 381.4025,
found m/z 381.4014.
4.2.4. (S)-Benzyl
iodo]-2-phenylethylcarbamoyl}pyrrolidine-1-carboxylate
2-{(R)-1-[3-(3,5-bis(trifluoromethyl)phenyl)ure-
(9a). To
a stirred solution of dipeptide 8a (0.476 g, 1.20 mmol) in dry THF
(6 mL) at ꢁ15 ꢀC, N-methylmorpholine (NMM) (0.145 mL,
1.32 mmol) and ethyl chloroformate (ECF) (0.126 mL, 1.32 mmol)
were added. The reaction mixture was left stirring at ꢁ10 ꢀC for
15 min. The reaction mixture was warmed to ꢁ5 ꢀC and a solution
of NaN3 (0.195 g, 3 .00 mmol) in H2O (2 mL) was added. The re-
action mixture was left stirring for 5 min and then, the solvents
were evaporated under reduced pressure. The crude material was
dissolved in CH2Cl2 (20 mL) and washed with aq NaHCO3 (5%,
20 mL), H2O (20 mL), aq citric acid (10%, 20 mL), brine (20 mL),
dried (Na2SO4) and the solvents were evaporated. The crude
product was dissolved in dry toluene (6 mL) and N-methyl-
morpholine (NMM) (0.145 mL, 1.32 mmol) and 3,5-
bis(trifluoromethyl)aniline (0.187 mL, 1.20 mmol) were added.
The reaction mixture was put in an ultrasound bath for 2 h. Then, it
was left to stir at room temperature for 48 h. After evaporation of
the solvent, the crude product was purified using column chro-
matography eluting with pet. ether/EtOAc (10:90). White solid;
0.38 g, 52% yield; Rf (AcOEt/pet. ether 9:1) 0.69; mp 169e170 ꢀC;
EtOAc 7:3) 0.67; mp 66e68 ꢀC; [
a]
D ꢁ32.8 (c 1.0, CH3OH) {lit.: [
a]
D
ꢁ35.4 (c 1.0, CH3OH)15b}; 1H NMR (200 MHz, CDCl3)
d 7.44e6.94
(10H, m, ArH), 6.35 (1H, br s, NH), 5.12 (2H, s, OCH2), 4.83 (1H, dd,
J¼13.5, 6.7 Hz, NCH), 4.31 (1H, t, J¼8.5 Hz, NCH), 3.68 (3H, s,
OCH3), 3.42e3.31 (2H, m, NCH2), 3.21e3.05 (1H, m, PhCHH),
2.97(1H, dd, J¼13.3, 6.9 Hz, PhCHH), 2.39e2.01 (1H, m, CHH),
1.99e1.65 (3H, m, 3ꢂCHH); 13C NMR (50 MHz, CDCl3)
d 171.0,
170.5, 155.1, 135.9, 135.5, 128.6, 127.8, 127.3, 127.2, 127.1, 126.2, 66.4,
59.6, 52.6, 51.5, 46.1, 37.1, 27.6, 23.7.
To a stirred solution of the dipeptide (0.200 g, 0.48 mmol) in
dioxane (1 mL), an aq solution of NaOH (2 N, 0.3 mL) was added.
The reaction mixture was left stirring for 1 h at room temperature.
The crude mixture was extracted with Et2O (2ꢂ20 mL). The aque-
ous layer was acidified with aq HCl (2 N) until pH 2 and the crude
product was extracted with EtOAc (2ꢂ30 mL). The combined or-
ganic layers were washed with H2O (30 mL), dried and the solvent
was removed under reduced pressure. The product 8a was isolated
as a white solid;16 0.162 g, 85% yield; Rf (n-butanol/AcOH/H2O
[a
]
D ꢁ22.6 (c 1.0, CHCl3); IR (KBr) 3328, 1664, 1576, 1388, 1129, 880,
732, 699, 681 cmꢁ1; 1H NMR (200 MHz, CDCl3)
d
7.90 (2H, s, ArH),
7.42 (1H, s, ArH), 7.42e7.03 (12H, m, ArH and 2ꢂNH), 6.61e6.20
(1H, br s, NH), 5.58e5.39 (1H, m, NCH), 5.18e4.87 (2H, m, OCH2),
4.32e4.17 (1H, m, NCH), 3.62e2.81 (4H, m, NCH2 and PhCH2),
2.15e1.55 (4H, m, 4ꢂCHH); 13C NMR (50 MHz, CDCl3)
d 173.7, 156.1,
4:1:1) 0.80; mp 124e126 ꢀC; [
a
]
ꢁ49.0 (c 2.5, CHCl3) {lit.: [
a
]
154.8, 141.0, 135.8, 131.7 (q, J¼33.0 Hz), 129.2, 128.9, 128.6, 128.5,
D
D
ꢁ49.0 (c 2.5, CHCl3)}; 1H NMR (200 MHz, CDCl3)
d 7.43e7.03 (10H,
128.2, 127.8,127.0,123.3 (q, J¼272.6 Hz),118.4,115.4, 67.5, 60.7, 58.7,
m, ArH), 6.48 (1H, br s, NH), 5.09 (2H, s, OCH2), 4.82 (1H, dd, J¼12.2,
46.9, 40.0, 29.7, 24.1; 19F NMR (188 MHz, CDCl3)
d 9.47 (s); MS 623

8736
P. Revelou et al. / Tetrahedron 68 (2012) 8732e8738
(MþHþ, 100); HRMS exact mass calculated for [MþH]þ
(C30H29F6N4O4) requires m/z 623.2088, found m/z 623.2068.
140.8, 133.2 (q, J¼33.2 Hz), 129.8, 129.3, 127.1, 124.6 (q, J¼250.2 Hz),
119.3, 116.0, 61.7, 60.3, 48.0, 32.1, 27.0; 19F NMR (188 MHz, CD3OD)
d
9.45 (s); MS 475 (MþHþ, 100); HRMS exact mass calculated for
4.2.5. (S)-Benzyl
2-{(R)-3-[3-(3,5-bis(trifluoromethyl)phenyl)ure-
[MþH]þ (C21H21F6N4O2) requires m/z 475.1563, found m/z 475.1546.
iodo](phenyl)methylcarbamoyl}pyrrolidine-1-carboxylate
(9b). Same procedure as above, but utilizing 8b; 0.37 g, 50% yield;
4.2.9. (S)-N-{(S)-1-[3-(3,5-Bis(trifluoromethyl)phenyl)ureiodo]-2-
phenylmethyl}pyrrolidine-1-carboxyamide (10c). Same procedure
as above, but utilizing 9c; 0.15 g, 97% yield; Rf (n-butanol/AcOH/H2O
Rf (AcOEt/pet. ether 7:3) 0.58; mp 190e191 ꢀC; [
a
]
ꢁ26.3 (c 1.0,
D
DMF); IR (KBr) 3331, 2967, 2893, 1678, 1572, 1542, 1128, 879, 769,
735, 698 cmꢁ1 1H NMR (200 MHz, DMSO)
;
d
9.47 (1H, br s, NH),
4:1:1) 0.38; mp 177e178 ꢀC; [
a
]
D
ꢁ10.0 (c 1.0, CH3OH); IR (KBr)
8.86 (1H, s, NH), 8.04 (2H, s, ArH), 7.59 (1H, s, ArH), 7.46e7.11 (11H,
m, ArH and NH), 6.59e6.41 (1H, m, NCH), 5.21e4.88 (2H, m, OCH2),
4.37e4.19 (1H, m, NCH), 3.58e3.31 (2H, m, NCH2), 2.31e2.03 (1H,
m, CHH), 2.01e1.72 (3H, m, 3ꢂCHH); 13C NMR (50 MHz, DMSO)
3280, 3095, 1679, 1655, 1582, 1130, 844, 751, 696, 681 cmꢁ1
;
1H
NMR (200 MHz, CD3OD) 8.01 (2H, s, ArH), 7.51 (1H, s, ArH),
d
7.51e7.24 (5H, m, ArH), 6.65 (1H, s, NCH), 3.81e3.75 (1H, m, NCH),
3.14e2.89 (2H, m, NCH2), 2.29e2.06 (1H, m, CHH), 1.92e1.67 (3H,
d
171.7 (171.4), 153.6 (153.8), 153.5 (153.8), 142.0, 140.3, 136.7, 130.6
m, 3ꢂCHH); 13C NMR (50 MHz, CD3OD)
d 174.1, 154.9, 141.9, 139.4,
131.9 (q, J¼32.3 Hz), 128.9, 128.1, 125.9, 123.5 (q, J¼249.8 Hz), 117.9,
(q, J¼32.2 Hz), 128.2, 128.1, 127.5, 127.3, 126.8, 125.8, 123.1 (q,
J¼265.1 Hz), 117.2, 113.9, 65.8, 59.8 (59.3), 57.9 (57.6), 47.0 (46.5),
114.7, 60.3, 59.1, 46.7, 30.8, 25.5; 19F NMR (188 MHz, CD3OD)
d 9.45
31.9 (29.8), 23.0 (23.8); 19F NMR (188 MHz, DMSO)
d
9.45 (s); MS
(s); MS 475 (MþHþ, 100); HRMS exact mass calculated for [MþH]þ
(C21H21F6N4O2) requires m/z 475.1563, found m/z 475.1547.
609 (MþHþ, 50); HRMS exact mass calculated for [MþH]þ
(C29H27F6N4O4) requires m/z 609.1931, found m/z 609.1913.
4.3. General procedure for the aldol reaction
4.2.6. (S)-Benzyl
2-{(S)-3-[3-(3,5-bis(trifluoromethyl)phenyl)ure-
iodo](phenyl)methylcarbamoyl}pyrrolidine-1-carboxylate
To a stirred solution of catalyst (0.014 mmol) in toluene (1.0 mL),
4-nitrobenzoic acid (2.3 mg, 0.014 mmol) was added. The reaction
mixture was cooled to ꢁ20 ꢀC. The aldehyde (0.140 mmol) was
added, followed by the ketone (1.40 mmol). The reaction mixture
was left stirring at ꢁ20 ꢀC for 24e120 h. The solvent was evapo-
rated and the crude product was purified using column chroma-
tography eluting with the appropriate mixture of petroleum ether
(40e60 ꢀC)/EtOAc to afford the desired product.
(9c). Same procedure as above, but utilizing 8c; 0.36 g, 49% yield; Rf
(AcOEt/pet. ether 7:3) 0.61; mp 189e190 ꢀC; [
a
]
D ꢁ28.0 (c1.0, DMF);
IR (KBr) 3329, 2961, 2891, 1678, 1571, 1541, 1127, 879, 768, 735,
697 cmꢁ1 1H NMR (200 MHz, DMSO)
9.55e9.45 (1H, m, NH),
;
d
8.94e8.77 (1H, m, NH), 8.03e8.00 (2H, m, ArH), 7.56 (1H, s, ArH),
7.38e7.07 (11H, m, ArH and NH), 6.56e6.41 (1H, m, NCH), 5.12e4.83
(2H, m, OCH2), 4.32e4.18 (1H, m, NCH), 3.54e3.33 (2H, m, NCH2),
2.21e2.03 (1H, m, CHH), 1.88e1.65 (3H, m, 3ꢂCHH); 13C NMR
(50 MHz, DMSO)
d
171.5 (171.7), 153.7 (154.0), 153.6 (153.8), 142.0,
4.3.1. (S)-2-[(R)-Hydroxy-(4-nitrophenyl)methyl]-cyclohexanone
140.3, 136.7, 130.6 (q, J¼32.5 Hz), 128.2, 127.6, 127.3, 126.8, 125.9,
125.7,123.1 (q, J¼265.1 Hz),117.2,113.9, 65.8, 59.8 (59.3), 57.9 (57.6),
47.0 (46.5), 31.0 (30.0), 23.0 (23.8); 19F NMR (188 MHz, DMSO)
(13a, Table 3, entry 1).10 Colourless oil, 34 mg, 96% yield; Rf (AcOEt/
pet. ether 4:6) 0.10; 1H NMR (200 MHz, CDCl3) anti
d 8.20 (2H, d,
J¼8.8 Hz, ArH), 7.51 (2H, d, J¼8.8 Hz, ArH), 4.87 (1H, d, J¼8.4 Hz,
d
9.42 (s); MS 609 (MþHþ, 45); HRMS exact mass calculated for
OCH), 4.09 (1H, br s, OH), 2.64e2.26 (3H, m, COCH and CHH),
[MþH]þ (C29H27F6N4O4) requires m/z 609.1931, found m/z 609.1912.
2.17e1.29 (6H, m, 6ꢂCHH); 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 min (minor) and 33.10 min (major), 98% ee.
4.2.7. (S)-N-{(R)-1-[3-(3,5-Bis(trifluoromethyl)phenyl)ureiodo]-2-
phenylethyl}pyrrolidine-1-carboxyamide (10a). To a stirred solution
of compound 9a (0.195 g, 0.320 mmol) in dry THF (10 mL), 10% Pd/C
(10 mol %) was added and the reaction mixture was left stirring at
room temperature for 24 h under hydrogen atmosphere. After fil-
tration through Celite, the solvent was evaporated to afford the
desired product. White solid; 0.15 g, 96% yield; Rf (n-butanol/AcOH/
4.3.2. (S)-2-[(R)-Hydroxy-(3-nitrophenyl)methyl]-cyclohexanone
(13b, Table 3, entry 2).17 Colourless oil, 31 mg, 87% yield; Rf (AcOEt/
pet. ether 4:6) 0.20; 1H NMR (200 MHz, CDCl3) anti
d 8.23e8.14 (2H,
m, ArH), 7.67 (1H, d, J¼7.3 Hz, ArH), 7.55 (1H, d, J¼7.6 Hz, ArH), 4.90
(1H, d, J¼8.4 Hz, OCH), 4.11 (1H, br s, OH), 2.68e2.31 (3H, m, COCH
and CHH), 2.17e1.32 (6H, m, 6ꢂCHH); 13C NMR (50 MHz, CDCl3)
H2O 4:1:1) 0.58; mp 183e185 ꢀC; [
3266, 1695, 1638, 1132, 879, 729, 701, 680 cmꢁ1; 1H NMR (200 MHz,
DMSO)
a
]
D
þ24.1 (c 1.0, THF); IR (KBr)
d
8.41 (1H, d, J¼8.6 Hz, NH), 8.05 (2H, s, ArH), 7.57 (1H, s,
d 214.6, 148.2, 143.1, 133.1, 129.2, 122.7, 121.9, 74.0, 57.0, 42.6, 30.6,
ArH), 7.35e7.15 (6H, m, ArH and NH), 6.92 (1H, d, J¼7.6 Hz, NH),
5.66e5.46 (1H, m, NCH), 3.46 (1H, dd, J¼8.6, 4.2 Hz, NCH), 3.11e2.95
(2H, m, NCH2), 2.88e2.73 (1H, m, PhCHH), 2.69e2.57 (1H, m,
PhCHH),1.93e1.72 (1H, m, CHH),1.54e1.28 (4H, m, NH and 3ꢂCHH);
27.6, 24.6; HPLC analysis: Diacel Chiralpak AD-H, hexane/iPrOH
92:8, flow rate 1.0 mL/min, retention time: 25.15 min (major) and
31.99 min (minor), 96% ee.
13C NMR (50 MHz, DMSO)
d
173.8, 153.6, 142.2, 137.2, 130.5 (q,
4.3.3. (S)-2-[(R)-Hydroxy-(2-nitrophenyl)methyl]-cyclohexanone
J¼32.5 Hz), 129.2, 128.1, 126.2, 123.3 (q, J¼272.1 Hz), 117.3, 113.8,
(13c, Table 3, entry 3).17 Yellow solid, 31 mg, 90% yield; Rf (AcOEt/
59.9, 57.0, 46.5, 40.6, 30.2, 25.5; 19F NMR (188 MHz, DMSO)
d
9.46 (s);
pet. ether 3:7) 0.25; [
a
]
þ16.6 (c 1.5, CHCl3); 1H NMR (200 MHz,
D
MS 489 (MþHþ, 100); HRMS exact mass calculated for [MþH]þ
(C22H23F6N4O2) requires m/z 489.1720, found m/z 489.1704.
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 (6H, m, 6ꢂCHH); 13C
4.2.8. (S)-N-{(R)-1-[3-(3,5-Bis(trifluoromethyl)phenyl)ureiodo]-2-
phenylmethyl}pyrrolidine-1-carboxyamide (10b). Same procedure
as above, but utilizing 9b. White solid; 0.14 g, 94% yield; Rf (n-bu-
NMR (50 MHz, CDCl3) d 214.9,136.5,133.0,128.9, 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
min (major) and 42.92 min (minor), 98% ee.
tanol/AcOH/H2O 4:1:1) 0.43; mp 170e171 ꢀC; [
a
]
ꢁ18.9 (c 1.0,
D
CH3OH); IR (KBr) 3280, 3097, 1683, 1626, 1583, 1129, 883, 751, 696,
681 cmꢁ1; 1H NMR (200 MHz, CD3OD)
d
8.02 (2H, s, ArH), 7.52 (1H, s,
4.3.4. (S)-2-[(R)-Hydroxy-(4-(trifluoromethyl)phenyl)methyl]-cyclo-
hexanone (13d, Table 3, entry 4).18 White solid, 29 mg, 77% yield; Rf
ArH), 7.52e7.19 (5H, m, ArH), 6.59 (1H, s, NCH), 3.83e3.65 (1H, m,
NCH), 3.08e2.85 (2H, m, NCH2), 2.27e2.03 (1H, m, CHH), 1.97e1.57
(AcOEt/pet. ether 4:6) 0.48; [
(200 MHz, CDCl3) anti
a
]
þ2.0 (c 0.5, CHCl3); 1H NMR
D
(3H, m, 3ꢂCHH); 13C NMR (50 MHz, CD3OD)
d
176.4, 156.1, 143.1,
d
7.61 (2H, d, J¼8.2 Hz, ArH), 7.44 (2H, d,

P. Revelou et al. / Tetrahedron 68 (2012) 8732e8738
8737
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 3ꢂCHH), 1.90e1.39 (5H, m, 5ꢂCHH);
J¼7.9 Hz, OCH), 3.63 (1H, br s, OH), 3.07e2.91 (3H, m, COCH and
CHH), 2.87e2.70 (2H, m, 2ꢂCHH), 2.68e2.42 (2H, m, 2ꢂCHH); 13C
13C NMR (50 MHz, CDCl3)
d
215.1, 144.9, 129.6 (q, J¼31.2 Hz), 127.3,
NMR (50 MHz, CDCl3) d 211.2, 147.7, 147.6, 127.7, 123.8, 73.1, 59.4,
125.3 (q, J¼8.1 Hz), 123.9 (q, J¼271.4 Hz), 74.2, 57.2, 42.6, 30.7, 27.6,
44.7, 32.8, 30.7; HPLC analysis: Diacel Chiralpak AD-H, hex-
ane/iPrOH 90:10, flow rate 1.0 mL/min, retention time: 51.85 min
(minor) and 73.77 min (major), 97% ee.
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, re-
tention time: 22.16 min (minor) and 27.63 min (major), 97% ee.
4.3.11. (S)-7-[(R)-Hydroxy-4-(nitrophenyl)methyl]-1,4-dioxospiro
[4.5]decan-8-one (13k, Table 3, entry 11).10 White solid, 18 mg, 42%
yield; Rf (AcOEt/pet. ether 3:7) 0.06; 1H NMR (200 MHz, CDCl3) anti
4.3.5. (R)-3-[Hydroxy-(2-(S)-oxocyclohexyl)methyl]-benzonitrile
(13e, Table 3, entry 5).19 Yellowsolid, 32 mg, 98%yield;Rf (AcOEt/pet.
ether 3:7) 0.17; [
a
]
D þ20.2 (c 1.1, CHCl3); 1H NMR (200 MHz, CDCl3)
d
8.21 (2H, d, J¼8.8 Hz, ArH), 7.49 (2H, d, J¼8.8 Hz, ArH), 4.92 (1H, d,
anti
d
7.68e7.38 (4H, m, ArH), 4.81 (1H, d, J¼8.5 Hz, OCH), 4.01 (1H, br
J¼7.5 Hz, OCH), 4.04 (1H, br s, OH), 3.98e3.68 (4H, m, 4ꢂOCHH),
2.91e2.74 (1H, m, COCH), 2.66e2.54 (1H, m, CHH), 2.51e2.42 (1H,
m, CHH), 2.07e1.55 (3H, m, 3ꢂCHH), 1.54e1.44 (1H, m, CHH); 13C
s, OH), 2.65e2.03 (4H, m, COCH and 3ꢂCHH), 1.87e1.22 (5H, m,
5ꢂCHH); 13C NMR (50 MHz, CDCl3)
d 214.6, 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 min (minor) and 42.58 min (major), 97% ee.
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: 10.16
min (syn minor) and 15.08 min (syn major), 11.96 min (anti minor)
and 18.97 min (anti major), 92% ee.
4.3.6. (S)-2-[(R)-Hydroxy-(phenyl)methyl]-cyclohexanone (13f, Table
3, entry 6).18 Colourless oil, 15 mg, 51% yield; Rf (AcOEt/pet. ether
4:6) 0.42; [
a
]
D þ23.1 (c 1.0, CHCl3); 1H NMR (200 MHz, CDCl3) anti
4.3.12. (2S,4R)-2-[(R)-Hydroxy-(4-(nitrophenyl)methyl)]-4-
d
7.51e7.21 (5H, m, ArH), 4.78 (1H, d, J¼8.8 Hz, OCH), 3.84 (1H, br s,
methylcyclohexanone (13l, Table 3, entry 12).21 Yellow solid, 33 mg,
OH), 2.70e2.31 (3H, m, COCH and CHH), 2.15e1.24 (6H, m, 6ꢂCHH);
90% yield; Rf (AcOEt/pet. ether 3:7) 0.15; [
NMR (200 MHz, CDCl3) anti
a
]
D ꢁ6.8 (c 1.0, CHCl3); 1H
13C NMR (50 MHz, CDCl3)
d
215.5, 140.8, 128.3, 127.8, 125.7, 74.7,
d
8.22 (2H, d, J¼8.8 Hz, ArH), 7.51 (2H,
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: 17.73
min (major) and 24.49 min (minor), 96% ee.
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, 4ꢂCHH,
CH); 1.07 (3H, d, J¼7.1 Hz, CH3); 13C NMR (50 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
i
4.3.7. (S)-2-[(R)-Hydroxy-(4-(fluorophenyl)methyl)]-cyclohexanone
(13g, Table 3, entry 7).20 White solid, 17 mg, 47% yield; Rf (AcOEt/
analysis: Diacel Chiralpak AD-H, hexane/ PrOH 90:10, flow rate
1.0 mL/min, retention time: 28.87 min (major) and 31.22 min (mi-
nor), 99% ee.
pet. ether 4:6) 0.16; [
a
]
þ22.5 (c 0.9, CHCl3); 1H NMR (200 MHz,
D
CDCl3) 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
4.3.13. (S)-2-[(R)-Hydroxy-(4-(nitrophenyl)methyl)]-cyclopentanone
and CHH), 2.08e1.22 (6H, m, 6ꢂCHH); 13C NMR (50 MHz, CDCl3)
(13m, Table 3, entry 13).10 Pale yellow oil, 32 mg, 97% yield; Rf
d
215.4, 162.3 (d, J¼246.2 Hz), 136.6, 128.5 (d, J¼5.1 Hz), 115.2 (d,
(AcOEt/pet. ether 4:6) 0.23; 1H NMR (200 MHz, CDCl3)
d 8.21 (2H, d,
J¼20.0 Hz), 74.1, 57.4, 42.6, 30.7, 27.7, 24.6; 19F NMR (188 MHz,
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, 2ꢂCHH),
CDCl3)
d
ꢁ48.12 (s); HPLC analysis: Diacel Chiralpak AD-H, hex-
ane/iPrOH 90:10, flow rate 0.5 mL/min, retention time: 26.65 min
(minor) and 29.59 min (major), 97% ee.
1.78e1.55 (2H, m, 2ꢂCHH); 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 Chiralpak
AD-H, hexane/iPrOH 95:5, flow rate 1.0 mL/min, retention time:
26.51 min (syn major) and 37.88 min (syn minor), 48.25 min (anti
minor) and 50.49 min (anti major), syn isomer 75% ee, anti isomer
80% ee.
4.3.8. (S)-2-[(R)-Hydroxy-(4-(bromophenyl)methyl)]-cyclohexanone
(13h, Table 3, entry 8).10 White solid, 12 mg, 30% yield; Rf (AcOEt/
pet. ether 3:7) 0.24; [
CDCl3) anti
a
]
þ18.3 (c 0.5, CHCl3); 1H NMR (200 MHz,
D
d
7.47 (2H, d, J¼8.5 Hz, ArH), 7.20 (2H, d, J¼8.5 Hz, ArH),
4.75 (1H, d, J¼8.6 Hz, OCH), 3.94 (1H, br s, OH), 2.61e2.13 (3H, m,
COCH and CHH), 2.11e2.01 (1H, m, CHH), 1.88e1.24 (5H, m,
5ꢂCHH); 13C NMR (50 MHz, CDCl3)
d
215.2, 140.0, 131.5, 128.7, 121.7,
4.3.14. (R)-4-Hydroxy-4-(4-nitrophenyl)-butan-2-one (13n, Table 3,
entry 14).10 Colourless oil, 27 mg, 91% yield; Rf (AcOEt/pet. ether
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: 29.89
min (minor) and 34.91 min (major), 95% ee.
4:6) 0.14; [
a
]
D þ36.9 (c 1.4, CHCl3); 1H NMR (200 MHz, CDCl3)
d 8.20
(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);
4.3.9. (S)-3-[(R)-Hydroxy-[4-(nitrophenyl)methyl]dihydro-2H-py-
ran-4(3H)-one (13i, Table 3, entry 9).10 Pale yellow solid, 32 mg, 90%
yield; Rf (AcOEt/pet. ether 4:6) 0.16; 1H NMR (200 MHz, CDCl3) anti
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 AD-RH, MeCN/H2O
30:70, flow rate 0.5 mL/min, retention time: 20.25 min (major) and
25.14 min (minor), 66% ee.
d
8.21 (2H, d, J¼8.8 Hz, ArH), 7.50 (2H, d, J¼8.8 Hz, ArH), 4.97 (1H, d,
J¼8.2 Hz, OCH), 4.28e4.09 (1H, m, OCHH), 3.90e3.64 (3H, m,
2ꢂOCHH and OH), 3.44 (1H, dd, J¼11.4, 9.8 Hz, OCHH), 3.02e2.41
Acknowledgements
(3H, m, 3ꢂCHH); 13C NMR (50 MHz, 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 Chir-
alpak AD-H, hexane/iPrOH 80:20, flow rate 1.0 mL/min, retention
time: 20.34 min (minor) and 23.74 min (major), 92% ee.
Financial support from the EPEAEK Program ‘Organic Synthesis
and Applications in Chemical Industry’ as well as from the Special
Research Account of the University of Athens is highly appreciated.
4.3.10. (S)-3-[(R)-Hydroxy-[4-(nitrophenyl)methyl]dihydro-2H-thio-
pyran-4(3H)-one (13j, Table 3, entry 10).10 Yellow solid, 34 mg, 90%
yield; Rf (AcOEt/pet. ether 3:7) 0.13; 1H NMR (200 MHz, CDCl3) anti
Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2012.08.023.
d
8.23 (2H, d, J¼8.3 Hz, ArH), 7.53 (2H, d, J¼8.3 Hz, ArH), 5.04 (1H, d,

8738
P. Revelou et al. / Tetrahedron 68 (2012) 8732e8738
6. (a) Tang, Z.; Jiang, F.; Yu, L. T.; Cui, X.; Gong, L. Z.; Mi, A. Q.; Jiang, Y. Z. J. Am.
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