Prolinamides bearing thiourea groups as catalysts for asymmetric aldol reactions

Article abstract of DOI:10.1002/ejoc.201001417

Organocatalysts based on α-amino acid amides (proline, valine, and threonine) and chiral diamines bearing thiourea groups were synthesized and their activities for aldol reactions were studied. The catalyst based on (S)-proline and (1S, 2S)-diphenylethyle

Full text of DOI:10.1002/ejoc.201001417

FULL PAPER
DOI: 10.1002/ejoc.201001417
Prolinamides Bearing Thiourea Groups as Catalysts for Asymmetric Aldol
Reactions
Stamatis Fotaras,[a] Christoforos G. Kokotos,[a] Evaggelia Tsandi,[a] and George Kokotos*[a]
Keywords: Aldol reactions / Asymmetric catalysis / Organocatalysis / Prolinamides / Thioureas
Organocatalysts based on α-amino acid amides (proline,
valine, and threonine) and chiral diamines bearing thiourea
groups were synthesized and their activities for aldol reac-
tions were studied. The catalyst based on (S)-proline and
(1S,2S)-diphenylethylenediamine proved to be an excellent
catalyst, providing the products of reactions between ketones
and aromatic aldehydes in high to quantitative yields and
with high stereoselectivities (up to 98:2 dr and 99% ee). The
presence of an acid additive (4-nitrobenzoic acid) has a con-
siderable impact on both yield and enantioselectivity.
Introduction
At the beginning of the 21st century, organocatalysis has
emerged as a new and powerful methodology for the syn-
thesis of enantiopure organic compounds.[1] The break-
through of proline-catalyzed asymmetric direct aldol reac-
tions reported by List, Lerner, and Barbas,[2] together with
the pioneering work of Jacobsen on catalytic thioureas[3]
and MacMillan on imidazolidinones,[4] opened new direc-
tions in asymmetric catalysis. The five-membered secondary
amine structure of proline is considered a “privileged”
structure capable of activating carbonyl compounds
through the formation of enamine intermediates. A number
of groups have thus successfully combined the proline scaf-
fold with functionalities capable of acting as hydrogen-bond
donors and have demonstrated the catalytic efficiency of
prolinamides.[5–13] Compounds 1–6 (Figure 1) are represen-
tative examples of prolinamides that efficiently catalyze
asymmetric aldol reactions.[6–11] In addition, primary
amino acids and derivatives such as alanine amides or
threonine and its derivatives have emerged as alternatives
to proline catalysts.[14,15] In recognition of the pivotal role
of extended hydrogen bonding networks in organocata-
lysis[16] and bearing in mind our recently reported primary
amine-thioureas, which were successfully used in Michael
reactions,[17] we thought of combining a thiourea group
with a prolinamide unit. We thus describe here the synthesis
of various α-amino acid amides based on chiral diamines
bearing thiourea groups and the evaluation of their cata-
lytic properties for aldol reactions.
Figure 1. Some prolinamide catalysts.
Results and Discussion
According to the proposed catalytic mechanism for the
known prolinamides 1–6, both the amide hydrogen and
either a hydroxy group or a sulfonamide hydrogen partici-
pate in simultaneous hydrogen bonding in the transition
state. Our concept was to combine either a prolinamide unit
or an α-amino acid moiety with a chiral unit bearing the
thiourea group, because it is a well-known double hydrogen
bond donor and chiral thioureas are known to be an impor-
tant class of organocatalysts.[18] By this reasoning, as start-
ing materials we used both the commercially available
(1S,2S)- and (1R,2R)-diphenylethylenediamines, as well as
various N-protected amino acids.
[a] Laboratory of Organic Chemistry, Department of Chemistry,
University of Athens,
The straightforward synthesis of our new catalysts is de-
picted in Scheme 1. Boc-l-proline (7a), Boc-l-valine (7b),
and Fmoc-l-threonine O-tert-butyl ether (7c) were each
coupled with (1S,2S)-diphenylethylenediamine with use of
Panepistimiopolis, Athens 15771, Greece
Fax: +30-210-727-4761
E-mail: gkokotos@chem.uoa.gr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001417.
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Eur. J. Org. Chem. 2011, 1310–1317

Asymmetric Aldol Reaction Catalysts
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (WSCI) efficiency in the aldol reaction. On comparison of the
as a condensing agent in the presence of hydroxybenzotri- prolinamide catalysts 10a and 11 it is obvious that the S
azole (HOBt). The amides 8a–c were then treated with the configuration of all three stereogenic centers leads to a
commercially available 3,5-bis(trifluoromethyl)phenyl iso- matched effect. The effect of the solvent was then studied
thiocyanate to give the thiourea derivatives 9a–c. The Boc at –20 °C for the catalyst 10a. However, none of the tested
group was removed from 9a and 9b by treatment with HCl solvents proved better than toluene (Entries 13 to 18,
in methanol, whereas the Fmoc group was removed by Table 1).
treatment with piperidine in DMF. Alternative synthetic
Table 1. Effect of temperature and solvent on the direct asymmetric
procedures to produce the desired organocatalysts were also
aldol reaction between acetone and 4-nitrobenzaldehyde in the
presence of catalysts 10a–c and 11.
explored, but none proved better (see the Supporting Infor-
mation). To explain the role of the stereochemistry of the
chiral diamine, the prolinamide 11, based on (1R,2R)-di-
phenylethylenediamine, was also synthesized by similar pro-
cedures.
Entry
Catalyst
Solvent, temp. [°C]
Yield [%][a]
ee [%][b]
1
2
3
4
5
6
7
8
10a
10a
10a
10b
10b
10b
10c
10c
10c
11
toluene, room temp.
toluene, –20
toluene, –50
toluene, room temp.
toluene, –20
toluene, –50
toluene, room temp.
toluene, –20
toluene, –50
toluene, room temp.
toluene, –20
toluene, –50
neat, –20
CH2Cl2, –20
CHCl3, –20
THF, –20
DMF, –20
50[c]
90
66
76
60
21
48
33
20
90
95
79
73
74
67
81
22
37
42
83
90
55
77
73
57
86
83
4
34
45
24
69
66
40
60
41
9
10
11
12
13
14
15
16
17
18
11
11
10a
10a
10a
10a
10a
10a
Et2O, –20
[a] Isolated yield after column chromatography. [b] The ee was de-
termined by HPLC with a Diacel Chiralpak AD-RH column.
[c] Reaction time: 18 h.
With toluene as the optimum solvent and the reaction
temperature set at –20 °C, a study on the effect of additives
and the catalyst loading was undertaken (Table 2). As has
been demonstrated, acid additives can influence the out-
come of enamine-mediated reactions,[20] although only a
few screening studies of acid co-catalysts are available in the
literature.[10,11,21,22] Weak Brønsted acids such as acetic
acid, benzoic acid, and mononitro-substituted benzoic acids
gave excellent results (Entries 1–4, Table 2). It has pre-
Scheme 1. Synthesis of the catalysts.
Asymmetric aldol reactions represent a powerful method viously been assumed that water can help the catalyst turn-
for the construction of C–C bonds in an enantioselective over by hydrolysis of the final product from the iminium
fashion.[19,20] The reaction between acetone and 4-nitro- intermediate, but in this case the addition of water has det-
benzaldehyde is a standard model reaction for study of the rimental effects both on yield and on enantioselectivity (En-
efficacies of new organocatalysts. The catalytic activities of try 5 vs. Entry 1, Table 2). The best results were obtained
10a–c and 11 were first studied at various temperatures in when 4-nitrobenzoic acid was used: on reduction of the re-
toluene as a solvent (Table 1). A strong dependence of the action time to 24 h the product was obtained in 95% yield
catalytic activity on the temperature was observed. In all and with 97% ee (Entry 3, Table 2). Although 2,4-dinitro-
cases, the best enantioselectivities were achieved at –20 or benzoic acid gave excellent enantioselectivity, the yield was
–50 °C. The prolinamide catalyst 10a (Entries 1 to 3, not satisfactory (Entry 6, Table 2). Strong acids such as tri-
Table 1) was more efficient than the valinamide catalyst 10b fluoroacetic acid, toluenesulfonic acid, and camphorsul-
(Entries 4 to 6, Table 1) and the threoninamide catalyst 10c fonic acid did not catalyze the reaction (Entries 7–9,
(Entries 7 to 10, Table 1), indicating that a secondary amino Table 2). A reduction in the catalyst loading to 5% afforded
group rather than a primary one is required for catalytic the product in high yield and enantioselectivity, whereas a
Eur. J. Org. Chem. 2011, 1310–1317
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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S. Fotaras, C. G. Kokotos, E. Tsandi, G. Kokotos
FULL PAPER
further decrease to 2% led to incomplete reagent consump- Table 3. Direct asymmetric aldol reactions between ketones and
various aldehydes in the presence of the catalyst 10a.
tion (Entries 10 and 11, Table 2). Reduction of the amount
of ketone used led to a slight decrease in the yield with the
same high level of enantioselectivity induction (Entry 12,
Table 2). When the reaction was performed at room tem-
perature, a quantitative yield was observed together with a
slight decrease in the enantioselectivity (Entry 13, Table 2).
Table 2. Effect of additive and catalyst loading on the direct asym-
metric aldol reaction between acetone and 4-nitrobenzaldehyde in
the presence of the catalyst 10a.
Entry
10a [%] Additive
Time [h] Yield [%][a]
ee [%][b]
1
2
3
4
5
6
7
8
10
10
10
10
10
10
10
10
10
5
AcOH
48
24
24
48
48
48
48
48
48
48
48
48
24
84
95
95
84
58
93
95
97
97
77
97
–
–
–
97
97
97
87
PhCOOH
4-NBA
2-NBA
AcOH, H2O
2,4-DNBA
TFA
TSA
CSA
4-NBA
4-NBA
4-NBA
4-NBA
42
traces
traces
traces
90
58
86
9
10
11
12[c]
13[d]
2
10
10
98
[a] Isolated yield after column chromatography. [b] The ee was de-
termined by HPLC with a Diacel Chiralpak AD-RH column.
[c] 5 equiv. of ketone were used. [d] The reaction was performed at
room temperature. TFA: trifluoroacetic acid. NBA: nitrobenzoic
acid. DNBA: dinitrobenzoic acid. TSA: p-toluenesulfonic acid.
CSA: (+)-camphorsulfonic acid.
The aldol reaction substrate scope for the new catalyst
10a was studied and the results are summarized in Table 3.
Electron-poor aldehydes such as 2-nitrobenzaldehyde, 4-tri-
fluoromethylbenzaldehyde, and 3-cyanobenzaldehyde re-
acted easily with acetone, providing the products in high to
quantitative yields (79–100%) and with high enantio-
selectivities (94–99%, Entries 1–3, Table 3). Benzaldehyde,
however, produced the product only in moderate yield, al-
though with high enantioselectivity (Entry 4, Table 3).
When cyclohexanone or cyclopentanone were used as the
donors and 4-nitrobenzaldehyde as the acceptor, the prod-
ucts were obtained both in quantitative yields and with ex-
cellent enantioselectivities (Entries 5 and 7, Table 3). In all
cases the reactions occurred with high anti stereoselectivity.
An unexpected reversal of the diastereoselectivity was ob-
served in the case of cyclopentanone, in which the syn prod-
uct was the predominant diastereomer. The product of the
reaction between cyclohexanone and 4-bromobenzaldehyde
was obtained in moderate yield and with slightly lower
enantioselectivity (Entry 6, Table 3). A number of cyclic
ketones reacted with 4-nitrobenzaldehyde to provide the
products in varying yields (61–98%), with high diastereo-
[a] Isolated yield after column chromatography. [b] The dia-
stereomeric ratio was determined by 1H NMR spectroscopy and
refers to the anti/syn ratio. [c] The ee was determined by chiral
HPLC. [d] 10 equiv. of ketone were used. [e] 99% ee for anti, 92%
ee for syn. [f] Reaction time 48 h. [g] 91% yield after 4 d.
It is clear that the combination of a prolinamide unit
selectivities (93:7 to 98:2)[23] and excellent enantioselectivi- with the thiourea functionality might provide useful new
ties (98–99% ee, Entries 8–10, Table 3).
organocatalysts. In the current study, the prolinamide 10a,
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Eur. J. Org. Chem. 2011, 1310–1317

Asymmetric Aldol Reaction Catalysts
bearing
a thiourea-group-substituted (1S,2S)-diphenyl-
Conclusions
ethylenediamine moiety, proved to be an excellent catalyst
for the direct aldol reaction. When proline or proline deriv-
atives, such as 4-substituted prolines,[24] tetrazoles,[25] and
sulfonamides,[25c,26] are used as catalysts, the catalytic
mechanism includes enamine formation and an internal
acid/hydrogen bond orienting the approach of the electro-
phile.[20] Prolinamides such as the catalysts 1 and 3, which
are regarded as the most active catalysts for direct aldol
reactions, as well as a pyrrolidinyl-camphor-based organo-
catalyst,[27] are believed to act through a double hydrogen
bonding activation mode. In the case of the new catalyst
10a, it is likely that the amide group and the thiourea func-
tionality form an extended hydrogen bonding network lead-
ing to high stereoselectivities. As illustrated in Figure 2
(model I), the pyrrolidine functionality activates the ketone
through the formation of an enamine intermediate, whereas
the aldehyde might be activated through the formation of a
double hydrogen bond involving the amide hydrogen and
In conclusion, in this work four catalysts based on amino
acid amides incorporating chiral diamines bearing thiourea
groups were synthesized and their catalytic activities in al-
dol reactions were studied. Proline-based amides showed
better catalytic activities than the amides of primary amino
acids (valine or threonine). A screening of various acid ad-
ditives revealed the great importance of their presence for
improving both the yield and the enantioselectivity. The cat-
alyst based on (S)-proline and (1S,2S)-diphenylethylenedia-
mine, in the presence of 4-nitrobenzoic acid, proved to be
an excellent catalyst, providing the products between
ketones and aromatic aldehydes in high to quantitative
yields and with high stereoselectivities (up to 98:2 dr and
99% ee).
Experimental Section
one of the thiourea hydrogen atoms. The screening of the General Remarks: Chromatographic purification of products was
accomplished by forced-flow chromatography on Merck Kiesel-
gel 60 F254 (230–400 mesh). Thin-layer chromatography (TLC) was
performed on aluminum-backed silica plates (0.2 mm, 60 F254). Vi-
sualization of the developed chromatogram was performed by fluo-
rescence quenching with phosphomolybdic acid, anisaldehyde, or
ninhydrin stains. Melting points were determined with a Büchi 530
hot stage apparatus. Optical rotations were measured with a Per-
acid additives revealed that acids of medium acidity, such
as benzoic or 4-nitrobenzoic acid, might enhance the
enantioselectivity. These data indicate that the acid additive
might play a key role in the catalytic mechanism. A possible
activation mode involving the acid additive might be that
shown in Figure 2 (model II).
kin–Elmer 343 polarimeter. IR spectra were recorded with a Nico-
1
let 6700 FT-IR spectrometer and are reported in cm–1. H and 13
C
NMR spectra were recorded with a Varian Mercury instrument
(200 MHz or 50 MHz) and are internally referenced to residual
1
protio solvent signals (CDCl3). Data for H NMR are reported as
follows: chemical shift (δ, ppm), integration, multiplicity (s = sing-
let, d = doublet, t = triplet, q = quadruplet, m = multiplet, br. s =
broad singlet, br. m = broad multiplet), coupling constant, and
assignment. Wherever rotamers exist, they are presented in brack-
ets. Data for 13C NMR are reported in terms of chemical shift
(δ, ppm). Mass spectra were recorded with a Finnigan Surveyor
MSQ Plus instrument, with only molecular ions and major peaks
being reported, with intensities quoted as percentages of the base
peak. Chiral High Performance Liquid Chromatography (HPLC)
analyses were performed with an Agilent 1100 Series apparatus and
Chiralpak® AD-RH, AD-H, or AS-H columns. The configurations
of the aldol products were assigned by comparison with literature
data.
Figure 2. Proposed transition state model for the aldol reaction in
the absence (I) and in the presence of the acid additive (II).
During the course of our studies, Wang et al. reported General Procedure for the Synthesis of Compounds 8a–c: (1S,2S)-
Diphenylethylenediamine (0.60 g, 2.82 mmol), Et3N (0.44 mL,
3.10 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide
that prolinamides based on chiral diamines bearing thio-
urea groups catalyze Michael additions of α,α-disubstituted
aldehydes to β-nitroalkenes.[28] They found that the catalyst
based on (S)-proline and (1R,2R)-diphenylethylenediamine
showed the best enantioselectivity (up to 96% ee), but the
yields were moderate (47–71%). It has to be underlined that
in that study the presence of an acid additive led to de-
creases both in yield and in enantioselectivity.[28] In ad-
dition, prolinamide-thiourea catalysts have been success-
(WSCI) (0.59 g, 3.10 mmol), and hydroxybenzotriazole (HOBt,
0.43 g, 2.82 mmol) were added consecutively at 0 °C to a stirring
solution of the N-protected amino acid (2.82 mmol) in dry dichlo-
romethane (15 mL). The reaction mixture was left stirring at 0 °C
for 1 h, and was then allowed to warm to room temperature and
left stirring for 18 h. The solvent was evaporated under vacuum
and the crude product was purified by flash column chromatog-
raphy with elution with various CHCl3/MeOH or CH2Cl2/MeOH
fully used for α-amination of aldehydes.[29] Most recently, mixtures.
prolinamides derived either from a valine-based diamine or
tert-Butyl (S)-2-[(1S,2S)-2-Amino-1,2-diphenylethylcarbamoyl]pyr-
from 1,2-ethylenediamine,[30] as well as 4-acyloxy-l-prol-
ines,[31] have been reported to be efficient catalysts for aldol
reactions.
rolidine-1-carboxylate (8a): This compound was obtained from
Boc-(S)-proline and (1S,2S)-diphenylethylenediamine. White solid,
0.52 g, 45% yield; m.p. 68–70 °C. [α]D = –75.6 (c = 1.0, CH2Cl2).
Eur. J. Org. Chem. 2011, 1310–1317
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1313

S. Fotaras, C. G. Kokotos, E. Tsandi, G. Kokotos
FULL PAPER
1H NMR (200 MHz, CDCl3): δ = 8.12–7.96 (br. m, 0.5 H, NHCO),
7.34–7.17 (m, 10.5 H, ArH and NHCO), 5.11 (dd, J = 8.3 and
4.2 Hz, 1 H, NCH), 4.38–4.26 (m, 2 H, 2ϫ NCH), 3.42–3.26 (m,
1 H, NH), 8.35–7.82 (m, 3 H, 3ϫ ArH), 7.67–7.59 (m, 1 H, ArH),
7.31–6.95 (m, 11 H, ArH, NH and NCH), 6.45–6.15 (br. s, 0.5 H,
NH), 6.15–5.81 (br. s, 0.5 H, NH), 5.58–5.27 (m, 1 H, NCH), 4.39–
2 H, NCH2), 2.23–2.08 (s, 1 H, CHH), 1.88–1.62 (m, 5 H, 3ϫ 4.08 (m, 1 H, NCH), 3.39–3.18 (m, 2 H, NCH2), 2.41–1.60 (m, 4
CHH and NH2), 1.49 [s, 9 H, C(CH3)3] ppm. 13C NMR (50 MHz, H, 4ϫ CHH), 1.26 [s, 9 H, C(CH3)3] ppm. 13C NMR (50 MHz,
CDCl3): δ = 171.7 (172.0) (NHCO), 155.8 (OCONH), 142.0 (Ar), CDCl3): δ = 181.4 (181.3) (C=S), 174.1 (174.0) (NHCO), 155.6
140.5 (Ar), 128.3 (Ar), 128.2 (Ar), 127.3 (Ar), 127.1 (Ar), 126.8
(155.8) (OCONH), 140.2 (Ar), 137.9 (137.8) (Ar), 131.8 (q, J =
(Ar), 126.5 (Ar), 80.2 (80.1) [C(CH3)3], 60.0 (60.1) (NCH), 59.7
33.5 Hz, Ar), 128.8 (Ar), 128.4 (Ar), 128.1 (Ar), 128.0 (Ar), 127.8
(59.8) (NCH), 58.7 (58.8) (NCH), 46.9 (NCH2), 28.4 [C(CH3)], 27.6 (Ar), 127.7 (Ar), 127.4 (Ar), 123.9 (Ar), 123.1 (q, J = 272.8 Hz,
(27.9) (CH ), 24.5 (24.3) (CH ) ppm. IR (film): ν = 3310, 2974, CF3), 118.3 (Ar), 80.8 [C(CH3)3], 60.6 (60.5) (NCH), 60.4 (60.5)
˜
2
2
1693, 1400, 769, 701 cm–1. MS (ES): m/z (%) = 410 (100) [M +
H]+. C24H31N3O3 (409.52): calcd. C 70.39, H 7.63, N 10.26; found
C 70.10, H 7.84, N 10.17.
(NCH), 59.5 (NCH), 47.2 (NCH2), 29.7 (CH2), 28.1 [C(CH3)], 24.3
(CH ) ppm. IR (film): ν = 3301, 2931, 1670, 1529, 1278, 1176, 1136,
˜
2
769, 700 cm–1. MS (ES): m/z (%) = 681 (100) [M + H]+.
C33H34F6N4O3S (680.70): calcd. C 58.23, H 5.03, N 8.23; found C
57.98, H 5.27, N 8.40.
tert-Butyl (S)-1-[(1S,2S)-2-Amino-1,2-diphenylethylamino]-3-meth-
yl-1-oxobutan-2-ylcarbamate (8b): This compound was obtained
from Boc-(S)-valine and (1S,2S)-diphenylethylenediamine. White
solid, 0.96 g, 83% yield; m.p. 161–163 °C. [α]D = –39.6 (c = 1.0,
CHCl3). 1H NMR (200 MHz, CDCl3): δ = 7.44–7.05 (m, 11 H,
ArH and NH), 5.12 (dd, J = 8.2 and 3.0 Hz, 1 H, NCH), 5.18–
4.95 (m, 1 H, NH), 4.44 (d, J = 3.0 Hz, 1 H, NCH), 3.86 (dd, J =
9.1 and 6.9 Hz, 1 H, NCH), 1.95–1.71 (m, 1 H, CH), 1.45 [s, 9 H,
C(CH3)3], 1.40 (s, 2 H, NH2), 0.68 (d, J = 6.8 Hz, 3 H, CH3), 0.62
(d, J = 6.9 Hz, 3 H, CH3) ppm. 13C NMR (50 MHz, CDCl3): δ =
171.2 (NHCO), 155.9 (OCONH), 141.8 (Ar), 140.2 (Ar), 128.6
(Ar), 128.4 (Ar), 127.5 (Ar), 127.3 (Ar), 126.3 (Ar), 126.2 (Ar), 79.5
[C(CH3)3], 60.2 (NCH), 59.0 (NCH), 58.7 (NCH), 30.6 (CH), 28.3
tert-Butyl
(S)-1-[(1S,2S)-2-{[3,5-Bis(trifluoromethyl)phenyl]thio-
ureido}-1,2-diphenylethylamino]-3-methyl-1-oxobutan-2-ylcarbamate
(9b): White solid, 0.45 g, 97% yield; m.p. 191–193 °C. [α]D = –3.8
(c = 1.0, CHCl3). 1H NMR (200 MHz, CDCl3): δ = 9.23 (br. s, 0.4
H, NH), 8.92 (br. s, 0.6 H, NH), 8.11–7.76 (m, 3 H, 2ϫ ArH and
NH), 7.60 (s, 1 H, ArH), 7.28–7.01 (m, 11 H, ArH and NH), 6.73
(0.4, br. s, NH), 6.02 (br. s, 0.6 H, NH), 5.48–5.25 (m, 1 H, NCH),
5.28–4.87 (m, 1 H, NCH), 4.00 (dd, J = 8.0 and 5.8 Hz, 1 H, NCH),
2.21–1.98 (m, 1 H, CH), 1.33 [s, 9 H, C(CH3)3], 0.97–0.71 (m, 6 H,
2ϫ CH3) ppm. 13C NMR (50 MHz, CDCl3): δ = 181.1 (181.0)
(C=S), 173.2 (172.7) (NHCO), 156.1 (155.9) (OCONH), 139.9
(140.0) (Ar), 138.0 (138.1) (Ar), 137.7 (137.8) (Ar), 131.9 (q, J =
34.0 Hz, Ar), 128.6 (Ar), 128.5 (Ar), 128.1 (Ar), 127.9 (Ar), 127.7
(Ar), 127.6 (Ar), 123.7 (Ar), 123.0 (q, J = 272.8 Hz, CF3), 118.4
(Ar), 80.4 [80.5, C(CH3)3], 63.0 (NCH), 60.3 (NCH), 59.6 (NCH),
30.3 (CH), 28.1 [C(CH3)], 19.2 (CH3), 17.3 (CH3) ppm. IR (film):
[C(CH )], 19.1 (CH ), 17.6 (CH ) ppm. IR (film): ν = 3322, 2922,
˜
3
3
3
1727, 1663, 1497, 760, 700 cm–1. MS (ES): m/z (%) = 412 (100) [M
+ H]+. C24H33N3O3 (411.54): calcd. C 70.04, H 8.08, N 10.21;
found C 69.91, H 8.35, N 10.11.
(9H-Fluoren-9-yl)methyl (2S,3R)-1-[(1S,2S)-2-Amino-1,2-diphenyl-
ethylamino]-3-tert-butoxy-1-oxobutan-2-ylcarbamate (8c): This
compound was obtained from Fmoc-(S)-threonine and (1S,2S)-di-
phenylethylenediamine. White solid, 1.22 g, 73% yield; m.p. 72–
ν = 3266, 2962, 1686, 1656, 1529, 1279, 1177, 1137, 758, 700 cm–1.
˜
MS (ES): m/z (%) = 683 (100) [M + H]+. C33H36F6N4O3S (682.72):
calcd. C 58.06, H 5.31, N 8.21; found C 57.79, H 5.55, N 8.31.
1
74 °C. [α]D = –1.6 (c = 1.0, CHCl3). H NMR (200 MHz, CDCl3):
(9H-Fluoren-9-yl)methyl
(2S,3R)-1-[(1S,2S)-2-{[3,5-Bis(trifluoro-
δ = 8.35 (d, J = 7.5 Hz, 1 H, NH), 7.76 (d, J = 7.4 Hz, 2 H, ArH),
7.60 (d, J = 7.3 Hz, 2 H, ArH), 7.54 (d, J = 7.4 Hz, 2 H, ArH),
7.44–7.23 (m, 12 H, ArH), 6.02 (d, J = 4.7 Hz, 1 H, NH), 5.20 (dd,
J = 7.5 and 2.8 Hz, 1 H, NCH), 4.46–4.32 (m, 3 H, OCH and
OCH2), 4.32–4.11 (m, 3 H, 2ϫ NCH and CHCH2O), 1.43 [s, 11
H, C(CH3)3 and NH2], 0.77 (d, J = 6.3 Hz, 3 H, CH3) ppm. 13C
NMR (50 MHz, CDCl3): δ = 168.6 (NHCO), 155.9 (OCONH),
143.8 (Ar), 143.6 (Ar), 141.9 (Ar), 141.2 (Ar), 141.1 (Ar), 140.9
(Ar), 128.6 (Ar), 128.2 (Ar), 127.6 (Ar), 127.4 (Ar), 127.0 (Ar),
126.9 (Ar), 126.2 (Ar), 125.1 (Ar), 119.8 (Ar), 77.2 [C(CH3)3], 75.4
(OCH), 66.8 (OCH2), 59.7 (NCH), 59.5 (NCH), 58.8 (NCH), 47.0
methyl)phenyl]thioureido}-1,2-diphenylethylamino]-3-tert-butoxy-1-
oxobutan-2-ylcarbamate (9c): White solid, 0.57 g, 97% yield; m.p.
122–124 °C. [α]D = +19.7 (c = 1.0, CHCl3). 1H NMR (200 MHz,
CDCl3): δ = 8.99 (br. s, 1 H, NH), 8.48 (br. s, 1 H, NH), 8.00 (s, 2
H, ArH), 7.89 (d, J = 8.7 Hz, 1 H, NH), 7.75 (dd, J = 7.4 and
3.0 Hz, 2 H, ArH), 7.61–7.53 (m, 2 H, ArH), 7.44–7.12 (m, 15 H,
ArH), 6.22 (br. s, 1 H, NH), 5.78 (d, J = 6.6 Hz, 1 H, NCH), 5.45
(dd, J = 10.5 and 9.4 Hz, 1 H, NCH), 4.42–4.05 (m, 5 H, OCH,
OCH2, NCH and CHCH2O), 1.19 (d, J = 6.3 Hz, 3 H, CH3), 0.82
[s, 9 H, C(CH3)3] ppm. 13C NMR (50 MHz, CDCl3): δ = 181.6
(C=S), 172.2 (NHCO), 156.4 (OCONH), 144.3 (Ar), 142.8 (Ar),
141.3 (Ar), 141.2 (Ar), 140.3 (Ar), 138.3 (Ar), 137.7 (Ar), 131.7 (q,
J = 33.4 Hz, Ar), 128.7 (Ar), 128.5 (Ar), 128.3 (Ar), 128.0 (Ar),
127.8 (Ar), 127.7 (Ar), 127.0 (Ar), 126.9 (Ar), 125.7 (Ar), 125.0
(Ar), 124.4 (Ar), 123.0 (q, J = 272.9 Hz, CF3), 119.9 (Ar), 118.4
(Ar), 77.2 [C(CH3)3], 74.8 (OCH), 67.7 (OCH2), 62.8 (NCH), 60.5
(NCH), 59.1 (NCH), 46.7 (OCH2CH), 27.8 [C(CH3)], 19.4
(OCH CH), 28.3 [C(CH )], 16.3 (CH ) ppm. IR (film): ν = 3324,
˜
2
3
3
2922, 1721, 1667, 1490, 757, 701 cm–1. MS (ES): m/z (%) = 592
(100) [M + H]+. C37H41N3O4 (591.74): calcd. C 75.10, H 6.98, N
7.10; found C 74.86, H 7.18, N 6.82.
General Procedure for the Synthesis of Compounds 9a–c: A solution
of an isothiocyanate (0.18 g, 0.68 mmol) in dry dichloromethane
(2 mL) was added to a stirring solution of an amine 8a–c
(0.68 mmol) in dry dichloromethane (6 mL). The reaction mixture
was left stirring at room temperature for 18 h. The solvent was
evaporated under vacuum and the crude product was purified by
flash column chromatography with elution with various mixtures
of petroleum ether (40–60 °C)/EtOAc.
(CH ) ppm. IR (film): ν = 3312, 2977, 1721, 1650, 1541, 1278, 1179,
˜
3
1136, 757, 701 cm–1. MS (ES): m/z (%) = 863 (100) [M + H]+.
C46H44F6N4O4S (862.93): calcd. C 64.03, H 5.14, N 6.49; found C
63.80, H 5.42, N 6.61.
General Procedure for the Synthesis of Compounds 10a, 10b, and 11:
A solution of HCl/MeOH (6 n, 2.4 mL) was added to a stirring
solution of an N-Boc-protected derivative 9 (0.29 mmol) in meth-
tert-Butyl (S)-2-[(1S,2S)-2-{3-[3,5-Bis(trifluoromethyl)phenyl]thio-
ureido}-1,2-diphenylethylcarbamoyl]pyrrolidine-1-carboxylate (9a): anol (3 mL). The reaction mixture was left stirring at room tem-
White solid, 0.44 g, 95% yield; m.p. 106–108 °C. [α]D = –41.7 (c = perature for 1 h. The pH of the mixture was adjusted to 8 with a
1.0, CH2Cl2). H NMR (200 MHz, CDCl3): δ = 9.31–9.08 (br. m, solution of NaHCO3 (10%). The resulting mixture was extracted
1
1314
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1310–1317

Asymmetric Aldol Reaction Catalysts
with CH2Cl2 (3ϫ10 mL). The combined organic layers were dried (2S,3R)-2-Amino-N-[(1S,2S)-2-{[3,5-bis(trifluoromethyl)phenyl]thio-
with Na2SO4 and the solvent was evaporated to afford the desired
product.
ureido}-1,2-diphenylethylamino]-3-tert-butoxybutanamide
(10c):
White solid, 100 mg, 98% yield; m.p. 63–65 °C. [α]D = –9.8 (c =
0.5, CHCl3). 1H NMR (200 MHz, CDCl3): δ = 8.60 (br. d, J =
8.5 Hz, 1 H, NH), 7.95 (br. s, 1 H, NH), 7.61 (s, 1 H, NH), 7.41–
6.99 (m, 13 H, ArH), 6.11–5.87 (m, 1 H, OCH), 5.35 (t, J = 9.2 Hz,
1 H, NCH), 3.99–3.71 (m, 1 H, NCH), 3.36–3.18 (m, 1 H, NCH),
1.12 (d, J = 5.8 Hz, 3 H, CH3), 0.99 [s, 9 H, C(CH3)3] ppm. 13C
NMR (50 MHz, CDCl3): δ = 181.3 (C=S), 175.1 (NHCO), 140.4
(Ar), 138.6 (Ar), 138.0 (Ar), 131.8 (q, J = 33.2 Hz, Ar), 128.9 (Ar),
128.7 (Ar), 128.3 (Ar), 128.2 (Ar), 127.8 (Ar), 127.6 (Ar), 124.3
(Ar), 123.1 (q, J = 273.0 Hz, CF3), 118.4 (Ar), 77.2 [C(CH3)3], 74.4
(OCH), 67.6 (NCH), 59.8 (NCH), 59.4 (NCH), 28.2 [C(CH3)], 19.3
(S)-N-[(1S,2S)-2-{3-[3,5-Bis(trifluoromethyl)phenyl]thioureido}-1,2-
diphenylethyl]pyrrolidine-2-carboxamide (10a): White solid, 167 mg,
99% yield; m.p. 151–153 °C. [α]D = +17.8 (c = 1.0, CH3OH). 1H
NMR (200 MHz, CDCl3): δ = 10.08–9.95 (br. m, 1 H, NH), 8.92–
8.81 (m, 2 H, 2ϫ NH), 8.04 (s, 2 H, ArH), 7.60 (s, 1 H, ArH),
7.35–7.01 (m, 11 H, ArH and NH), 6.37–6.17 (m, 1 H, NCH), 5.41
(t, J = 9.4 Hz, 1 H, NCH), 3.81–3.58 (m, 1 H, NCH), 2.98–2.61
(m, 2 H, NCH2), 2.05–1.81 (m, 1 H, CHH), 1.79–1.45 (m, 3 H, 3ϫ
CHH) ppm. 13C NMR (50 MHz, CDCl3): δ = 181.6 (C=S), 176.1
(NHCO), 140.9 (Ar), 137.9 (Ar), 137.8 (Ar), 131.6 (q, J = 33.2 Hz,
Ar), 128.8 (Ar), 128.5 (Ar), 128.2 (Ar), 127.9 (Ar), 127.6 (Ar), 127.4
(Ar), 123.5 (Ar), 123.1 (q, J = 272.7 Hz, CF3), 118.0 (Ar), 62.6
(NCH), 60.5 (NCH), 59.5 (NCH), 46.8 (NCH2), 30.4 (CH2), 25.5
(CH ) ppm. IR (film): ν = 3310, 2950, 1725, 1650, 1536, 1278, 1178,
˜
3
1134, 759, 700 cm–1. MS (ES): m/z (%) = 641 (100) [M + H]+.
C31H34F6N4O2S (640.68): calcd. C 58.11, H 5.35, N 8.74; found C
57.83, H 5.51, N 8.58.
(CH ) ppm. IR (film): ν = 3303, 2921, 1732, 1636, 1527, 1276, 1178,
˜
2
1135, 759, 698 cm–1. MS (ES): m/z (%) = 581 (100) [M + H]+.
C28H26F6N4OS (580.59): calcd. C 57.92, H 4.51, N 9.65; found C
57.61, H 4.75, N 9.48.
General Procedure for the Aldol Reaction: 4-Nitrobenzoic acid
(2.5 mg, 0.0138 mmol) was added to a stirring solution of the cata-
lyst 10a (8 mg, 0.0138 mmol) in toluene (1.1 mL). The aldehyde
(0.138 mmol) was added at –20 °C, followed by the ketone
(3.70 mmol). The reaction mixture was left stirring at –20 °C until
the reaction was complete (by TLC). The solvent was evaporated
and the crude product was purified by flash column chromatog-
raphy with elution with various mixtures of petroleum ether (40–
60 °C)/EtOAc to afford the desired product.
(S)-2-Amino-N-[(1S,2S)-2-{3-[3,5-bis(trifluoromethyl)phenyl]thio-
ureido}-1,2-diphenylethyl]-3-methylbutanamide (10b): White solid,
164 mg, 97% yield; m.p. 99–101 °C. [α]D = +16.2 (c = 1.0, CHCl3).
1H NMR (200 MHz, CDCl3): δ = 9.76 (br. s, 1 H, NH), 8.94–8.76
(m, 1 H, NH), 8.37 (d, J = 8.8 Hz, 1 H, NH), 7.99 (s, 2 H, ArH),
7.61 (s, 1 H, ArH), 7.34–7.08 (m, 10 H, ArH), 6.42–6.32 (m, 1 H,
NCH), 5.54 (t, J = 9.8 Hz, 1 H, NCH), 3.37–3.22 (m, 1 H, NCH),
2.28–1.98 (m, 3 H, CH and NH2), 0.95–0.82 (m, 6 H, 2 ϫ
CH3) ppm. 13C NMR (50 MHz, CDCl3): δ = 181.6 (C=S), 175.5
(NHCO), 140.6 (Ar), 138.2 (Ar), 135.2 (Ar), 131.7 (q, J = 33.5 Hz,
Ar), 128.8 (Ar), 128.5 (Ar), 128.2 (Ar), 127.9 (Ar), 127.6 (Ar), 127.3
(Ar), 123.9 (Ar), 123.1 (q, J = 272.9 Hz, CF3), 118.2 (Ar), 62.3
(NCH), 60.1 (NCH), 59.8 (NCH), 31.3 (CH), 19.4 (CH3), 15.6
(R)-4-Hydroxy-4-(4-nitrophenyl)butan-2-one:[26d] Table 1, Entry 1.
1
27 mg, 95% yield. H NMR (200 MHz, CDCl3): δ = 8.20 (d, J =
7.0 Hz, 2 H, ArH), 7.52 (d, J = 7.0 Hz, 2 H, ArH), 5.25 (m, 1 H,
OCH), 3.56 (br. s, 1 H, OH), 3.01–2.71 (m, 2 H, CHHCO), 2.21
(s, 3 H, CH3CO) ppm. 13C NMR (50 MHz, CDCl3): δ = 208.6
(C=O), 149.9 (Ar), 147.4 (Ar), 126.4 (Ar), 123.8 (Ar), 68.9 (OCH),
51.5 (CH2), 30.7 (CH3) ppm. HPLC analysis: Diacel Chi-
ralpak AD-RH, MeCN/H2O 20:80, flow rate 0.5 mLmin–1, reten-
tion time: 35.45 (major) and 46.45 (minor).
(R)-4-Hydroxy-4-(2-nitrophenyl)butan-2-one:[32] Table 3, Entry 1.
29 mg, 100% yield. 1H NMR (200 MHz, CDCl3): δ = 8.05–7.85
(m, 2 H, ArH), 7.72–7.61 (m, 1 H, ArH), 7.49–7.38 (m, 1 H, ArH),
5.68 (d, J = 9.3 Hz, 1 H, OCH), 3.76 (br. s, 1 H, OH), 3.15 (d, J
= 17.8 Hz, 1 H, CHHCO), 2.73 (dd, J = 17.8 and 9.3 Hz, 1 H,
CHHCO), 2.25 (s, 3 H, CH3CO) ppm. 13C NMR (50 MHz,
CDCl3): δ = 208.7 (C=O), 148.1 (Ar), 144.6 (Ar), 131.8 (Ar), 129.4
(Ar), 122.5 (Ar), 120. 6 (Ar), 68.6 (OCH), 51.4 (CH2), 30.7
(CH3) ppm. HPLC analysis: Diacel Chiralpak AS-H, hexane/iP-
rOH 80:20, flow rate 0.8 mLmin–1, retention time: 15.41 (major)
and 22.94 (minor).
(R)-4-Hydroxy-4-[4-(trifluoromethyl)phenyl]butan-2-one:[33] Table 3,
Entry 2. 32 mg, 100% yield. 1H NMR (200 MHz, CDCl3): δ =
7.62–7.52 (m, 2 H, ArH), 7.48–7.38 (m, 2 H, ArH), 5.17 (t, J =
5.9 Hz, 1 H, OCH), 3.62 (br. s, 1 H, OH), 2.85–2.77 (m, 2 H,
CHHCO), 2.17 (s, 3 H, CH3CO) ppm. 13C NMR (50 MHz,
CDCl3): δ = 208.8 (C=O), 146.6 (Ar), 129.6 (q, J = 31.0 Hz, Ar),
125.8 (Ar), 125.3 (Ar), 123.9 (q, J = 271.0 Hz, Ar), 69.0 (OCH),
51.6 (CH2), 30.6 (CH3) ppm. HPLC analysis: Diacel Chiralpak AS-
H, hexane/iPrOH 80:20, flow rate 0.5 mLmin–1, retention time:
11.17 (major) and 12.88 (minor).
(CH ) ppm. IR (film): ν = 3261, 2921, 1729, 1665, 1547, 1278, 1179,
˜
3
1136, 760, 700 cm–1. MS (ES): m/z (%) = 583 (100) [M + H]+.
C28H28F6N4OS (582.60): calcd. C 57.72, H 4.84, N 9.62; found C
57.45, H 5.02, N 9.71.
(S)-N-[(1R,2R)-2-{3-[3,5-Bis(trifluoromethyl)phenyl]thioureido}-1,2-
diphenylethyl]pyrrolidine-2-carboxamide (11): White solid, 167 mg,
99% yield; m.p. 173–174 °C. [α]D = –78.5 (c = 1.0, CHCl3). 1H
NMR (200 MHz, CDCl3): δ = 8.98 (d, J = 9.9 Hz, 1 H, NH), 8.53
(d, J = 9.1 Hz, 1 H, NH), 8.10 (s, 2 H, ArH), 7.59 (s, 1 H, ArH),
7.32–7.08 (m, 12 H, ArH and 2ϫ NH), 6.46 (t, J = 9.8 Hz, 1 H,
NCH), 5.46 (t, J = 9.8 Hz, 1 H, NCH), 3.70 (dd, J = 8.1 and
5.1 Hz, 1 H, NCH), 3.28–2.87 (m, 2 H, NCH2), 2.11–1.52 (m, 4 H,
4ϫ CHH) ppm. 13C NMR (50 MHz, CDCl3): δ = 181.5 (C=S),
176.4 (NHCO), 141.0 (Ar), 138.1 (Ar), 137.8 (Ar), 131.6 (q, J =
33.5 Hz, Ar), 129.0 (Ar), 128.7 (Ar), 128.6 (Ar), 128.5 (Ar), 127.9
(Ar), 127.7 (Ar), 123.1 (q, J = 272.9 Hz, CF3), 122.9 (Ar), 117.6
(Ar), 61.7 (NCH), 60.4 (NCH), 58.6 (NCH), 47.2 (NCH2), 31.1
(CH ), 26.0 (CH ) ppm. IR (film): ν = 3264, 2921, 1734, 1638,
˜
2
2
1528, 1275, 1176, 1132, 758, 700 cm–1. MS (ES): m/z (%) = 581
(100) [M + H]+. C28H26F6N4OS (580.59): calcd. C 57.92, H 4.51,
N 9.65; found C 57.67, H 4.69, N 9.53.
General Procedure for the Synthesis of Compound 10c: A solution
of piperidine in DMF (50%, 2 mL) was added to a stirring solution
of the N-Fmoc-protected derivative 9c (0.14 g, 0.16 mmol) in DMF
(R)-3-(1-Hydroxy-3-oxobutyl)benzonitrile: Table 3, Entry 3. Pale
(1 mL). The reaction mixture was left stirring at room temperature yellow oil, 21 mg, 79% yield. [α]D = +51.9 (c = 1.0, CHCl3). 1H
for 1 h. After completion of the reaction, the solvents were removed
in vacuo. The resulting crude was dried with P2O5 and purified by
flash column chromatography with elution initially with petroleum
ether/EtOAc (40:60), followed by CH2Cl2/CH3OH (70:30).
NMR (200 MHz, CDCl3): δ = 7.74–7.68 (m, 1 H, ArH), 7.65–7.54
(m, 2 H, ArH), 7.52–7.40 (m, 1 H, ArH), 5.19 (t, J = 6.4 Hz, 1 H,
OCH), 3.61 (br. s, 1 H, OH), 2.84 (d, J = 6.4 Hz, 2 H, CHHCO),
2.22 (s, 3 H, CH3CO) ppm. 13C NMR (50 MHz, CDCl3): δ = 208.5
Eur. J. Org. Chem. 2011, 1310–1317
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1315

S. Fotaras, C. G. Kokotos, E. Tsandi, G. Kokotos
FULL PAPER
(C=O), 144.3 (Ar), 131.1 (Ar), 130.1 (Ar), 129.2 (Ar), 129.1 (Ar),
118.6 (CN), 112.3 (Ar), 68.6 (OCH), 51.5 (CH2), 30.6 (CH3) ppm.
MS (ES): m/z (%) = 188 (33) [M – H]+, 170 (100) [M – H2O]+.
C11H11NO2 (189.21): calcd. C 69.83, H 5.86, N 7.40; found C
(S)-3-[(R)-Hydroxy-(4-nitrophenyl)methyl]dihydro-2H-thiopyran-
4(3H)-one:[34] Table 3, Entry 9. 23 mg, 61 % yield. 1H NMR
(200 MHz, CDCl3, anti): δ = 8.21 (d, J = 8.3 Hz, 2 H, ArH), 7.53
(d, J = 8.3 Hz, 2 H, ArH), 5.04 (d, J = 7.9 Hz, 1 H, OCH), 3.65
69.58, H 6.10, N 7.20. HPLC analysis: Diacel Chiralpak AD-RH, (br. s, 1 H, OH), 3.13–2.91 (m, 3 H, CH and CHH), 2.87–2.70 (m,
MeCN/H2O 40:60, flow rate 1.0 mLmin–1, retention time: 7.58
(major) and 9.04 (minor).
2 H, 2ϫ CHH), 2.68–2.42 (m, 2 H, 2ϫ CHH) ppm. 13C NMR
(50 MHz, CDCl3): δ = 211.2 (C=O), 147.7 (Ar), 147.6 (Ar), 127.7
(Ar), 123.8 (Ar), 73.1 (OCH), 59.4 (CH), 44.7 (CH2), 32.8 (CH2),
30.7 (CH2) ppm. HPLC analysis: Diacel Chiralpak AD-H, hexane/
iPrOH 90:10, flow rate 1 mLmin–1, retention time: 54.77 (minor)
and 75.12 (major).
(R)-4-Hydroxy-4-phenylbutan-2-one:[33] Table 3, Entry 4. 11 mg,
1
48% yield. H NMR (200 MHz, CDCl3): δ = 7.37–7.21 (m, 5 H,
ArH), 5.21–5.07 (m, 1 H, OCH), 3.27 (br. s, 1 H, OH), 2.88–2.77
(m, 2 H, CHHCO), 2.15 (s, 3 H, CH3CO) ppm. 13C NMR
(50 MHz, CDCl3): δ = 209.0 (C=O), 142.5 (Ar), 128.3 (Ar), 127.6
(Ar), 125.5 (Ar), 69.6 (OCH), 51.9 (CH2), 30.6 (CH3) ppm. HPLC
analysis: Diacel Chiralpak AS-H, hexane/iPrOH 90:10, flow rate
0.8 mLmin–1, retention time: 14.58 (major) and 17.15 (minor).
(S)-7-[(R)-Hydroxy-(4-nitrophenyl)methyl]-1,4-dioxospiro[4.5]decan-
8-one:[36] Table 3, Entry 10. 27 mg, 64% yield. 1H NMR (200 MHz,
CDCl3, anti): δ = 8.20 (d, J = 8.8 Hz, 2 H, ArH), 7.49 (d, J =
8.8 Hz, 2 H, ArH), 4.83 (d, J = 7.5 Hz, 1 H, OCH), 4.04 (br. s, 1
H, OH), 3.98–3.68 (m, 4 H, 4ϫ OCHH), 2.91–2.74 (m, 1 H, CH),
2.66–2.54 (m, 1 H, CHH), 2.51–2.42 (m, 1 H, CHH), 2.07–1.55 (m,
3 H, 3ϫ CHH), 1.54–1.44 (m, 1 H, CHH) ppm. 13C NMR
(50 MHz, CDCl3): δ = 213.1 (C=O), 147.9 (Ar), 127.8 (Ar), 126.5
(Ar), 123.6 (Ar), 106.7 [C(OCH2)2], 73.8 (OCH), 64.6 (OCH2), 64.5
(OCH2), 52.9 (CH), 38.8 (CH2), 37.8 (CH2), 34.3 (CH2) ppm.
HPLC analysis: Diacel Chiralpak AS-H, hexane/iPrOH 70:30, flow
rate 1 mLmin–1, retention time: 10.11 (minor) and 14.95 (major).
(S)-2-[(R)-Hydroxy-(4-nitrophenyl)methyl]cyclohexanone:[34] Table 3,
Entry 5. 34 mg, 100% yield. 1H NMR (200 MHz, CDCl3): anti δ
= 8.20 (d, J = 8.8 Hz, 2 H, ArH), 7.51 (d, J = 8.8 Hz, 2 H, ArH),
4.87 (d, J = 8.4 Hz, 1 H, OCH), 4.09 (br. s, 1 H, OH), 2.64–2.26
(m, 3 H, CH and CHH), 2.17–1.29 (m, 6 H, 6ϫ CHH) ppm. 13C
NMR (50 MHz, CDCl3): δ = 214.6 (C=O), 148.4 (Ar), 127.9 (Ar),
127.8 (Ar), 123.4 (Ar), 73.8 (OCH), 57.0 (CH), 42.5 (CH2), 30.6
(CH2), 27.5 (CH2), 24.5 (CH2) ppm. HPLC analysis: Diacel Chi-
ralpak AS-H, hexane/iPrOH 80:20, flow rate 0.5 mLmin–1, reten-
tion time: 26.75 (minor) and 34.89 (major).
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details, NMR spectra and HPLC data.
(S)-2-[(R)-(4-Bromophenyl)-hydroxymethyl]cyclohexanone:[35] Table 3,
Entry 6. 24 mg, 62% yield. H NMR (200 MHz, CDCl3, anti): δ =
1
Acknowledgments
7.46 (d, J = 8.4 Hz, 2 H, ArH), 7.19 (d, J = 8.4 Hz, 2 H, ArH),
4.74 (d, J = 8.7 Hz, 1 H, OCH), 3.98 (br. s, 1 H, OH), 2.61–2.11
(m, 3 H, CH and CHH), 2.13–2.07 (m, 1 H, CHH), 1.81–1.43 (m,
5 H, 5ϫ CHH) ppm. 13C NMR (50 MHz, CDCl3): δ = 215.2
(C=O), 140.0 (Ar), 131.5 (Ar), 128.7 (Ar), 121.7 (Ar), 74.2 (OCH),
57.3 (CH), 42.7 (CH2), 30.7 (CH2), 27.7 (CH2), 24.7 (CH2) ppm.
HPLC analysis: Diacel Chiralpak AD-H, hexane/iPrOH 90:10,
flow rate 0.5 mLmin–1, retention time: 28.70 (minor) and 33.59
(major).
This project was co-funded by the European Social Fund and
National Resources (EPEAK II).
[1] For books, see: a) A. Berkessel, H. Groger, in: Asymmetric Or-
ganocatalysis – From Biomimetic Concepts to Powerful Methods
for Asymmetric Synthesis (Ed.: A. Berkessel), Wiley-VCH,
Weinheim, 2005; P. I. Dalko, in: Enantioselective Organocata-
lysis: Reactions and Experimental Procedures (Ed.: P. I. Dalko),
Wiley-VCH, Weinheim, Germany, 2007.
(S)-2-[(R)-Hydroxy-(4-nitrophenyl)methyl]cyclopentanone:[34] Table 3,
Entry 7. 33 mg, 100% yield. 1H NMR (200 MHz, CDCl3): δ = 8.20
(d, J = 8.8 Hz, 2 H, ArH), 7.15 (d, J = 8.8 Hz, 2 H, ArH), 5.41 (s,
1 H, OCH syn), 4.83 (d, J = 9.2 Hz, 1 H, OCH anti), 4.76 (br. s, 1
H, OH anti), 2.69 (br. s, 1 H, OH syn), 2.52–2.18 (m, 3 H, CH
and CHH), 2.15–1.83 (m, 2 H, 2ϫ CHH), 1.78–1.55 (m, 2 H, 2ϫ
CHH) ppm. 13C NMR (50 MHz, CDCl3): δ = 214.6 (C=O), 213.4
(C=O), 149.2 (Ar), 147.9 (Ar), 147.4 (Ar), 147.3 (Ar), 127.2 (Ar),
126.5 (Ar), 123.0 (Ar), 122.9 (Ar), 73.5 (OCH), 69.8 (OCH), 57.0
(CH), 56.3 (CH), 42.5 (CH2), 30.2 (CH2), 27.7 (CH2), 25.5 (CH2),
24.6 (CH2), 24.3 (CH2) ppm. HPLC analysis: Diacel Chi-
ralpak AD-H, hexane/iPrOH 95:5, flow rate 1 mLmin–1, retention
time: 27.50 (syn major) and 38.01 (syn minor), 47.94 (anti minor)
and 49.63 (anti major).
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CDCl3, anti): δ = 8.21 (d, J = 8.8 Hz, 2 H, ArH), 7.50 (d, J =
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Received: October 17, 2010
Published Online: January 11, 2011
Eur. J. Org. Chem. 2011, 1310–1317
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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