An efficient dipeptide-catalyzed direct asymmetric aldol reaction of equimolar reactants in solid media

Article abstract of DOI:10.1002/chir.20783

The direct asymmetric aldol reactions of equivalent molar amounts of aldehydes and ketones were carried out at -20 °C over alkaline Al ₂O₃ with 20 mol % of Pro-Trp as catalyst and 20 mol % of N-methylmorpholine or 1,4-diazabicyclo[2.

Full text of DOI:10.1002/chir.20783

CHIRALITY 22:580–586 (2010)
An Efficient Dipeptide-Catalyzed Direct Asymmetric
Aldol Reaction of Equimolar Reactants in Solid Media
*
*
MENG LEI, SHUAI XIA, JUNFENG WANG, ZEMEI GE, TIEMING CHENG, AND RUNTAO LI
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
ABSTRACT
The direct asymmetric aldol reactions of equivalent molar amounts of
aldehydes and ketones were carried out at 220 8C over alkaline Al2O3 with 20 mol % of
Pro-Trp as catalyst and 20 mol % of N-methylmorpholine or 1,4-diazabicyclo[2.2.2]octane
as additive. After simple and environmentally friendly work-up, moderate to high iso-
lated yields (up to 95%), good diastereoselectivities (>99:1), and enantioselectivities (up
to 98% ee) have been achieved for the reactions of different kinds of ketones with vari-
ous aldehydes. The catalytic system could be reused without decrease of activity by
addition of 10 mol % catalyst and base in the catalytic system. Chirality 22:580–586,
C
VV
2010.
2009 Wiley-Liss, Inc.
KEY WORDS: organocatalysis; asymmetric aldol reaction; dipeptide; solid media;
alkaline Al2O3
INTRODUCTION
were recorded on a Varian Mercury-300 spectrometer in
desired D-reagents with tetramethylsilane as an internal
standard. The maximum wavelength values were recorded
with a TU-1901-type UV-spectrophotometer. Enantiomeric
excess values of aldol products were determined by analyt-
ical HPLC using Daicel Chiralpak AD or AS analytical col-
umns with 2-propanol in hexane as the eluent.
The aldol reaction is one of the most powerful methods
for the formation of CꢀꢀC bonds in organic synthesis.1
Since the pioneering work of List and coworkers in
2000,2,3 the organocatalytic direct aldol reaction has
received much attention,4–8 and high diastereomeric and
enantiomeric selectivities have been achieved. However,
most of the reactions were carried out in organic solvents.
To seek more efficient and greener processes, more and
more researchers have recently focused their attention on
the application of green solvents, such as water,9–16 ionic
liquids,17,18 supercritical CO2,19 and heterogeneous cata-
lysts such as immobilized amino acids or even dipeptides
either on resins or inorganic solid supports.20–24 However,
under these reaction conditions, a huge excess of one of
the reactants (2–10 equivalents) was generally needed to
achieve satisfactory results. Herein, we wish to report a
highly efficient dipeptide-catalyzed direct asymmetric aldol
reaction over alkaline Al2O3, in which only equivalent
amount of aldehyde and ketone are required.
Representative Procedures for the Preparation of
catalysts 4–6
The catalysts 1–3 were obtained from GL Biochem
(Shanghai) and used directly without further purification.
The syntheses of catalysts 4–6 were carried out according
to the standard method of dipeptide preparation.25
General Procedure for Aldol Reactions
To a mixture of aldehyde acceptor (0.5 mmol) in 300
mg of alkaline Al2O3 were added the catalyst (20 mol %),
base (20 mol %), and ketone donor (0.5 mmol). The result-
ing solid powder mixture was rapidly stirred at 2208C for
the stated period of time. The reaction mixture was
washed with ethyl acetate, and the solution obtained was
condensed under reduced pressure. The residue was
recrystallized or isolated directly by flash silica gel chro-
matography using petroleum ether-ethyl acetate as the elu-
ent to afford the corresponding pure aldol adducts.
EXPERIMENTAL
General Procedures
Tetrahydrofuran (THF) was dried with P2O5 for 4 days
and refluxed over diphenylketone and sodium and then
˚
distilled on to 4 A molecular sieves after the reagent
Contract grant sponsor: National Natural Science Foundation of China;
Contract grant numbers: 20572004
Contract grant sponsor: National Key Technology R&D Program;
turned blue. Some reagents were redistilled before use.
Common solvents were used as purchased without further
purification. Thin-layer chromatography (TLC) was per-
formed on silica gel 60 F254 glass backed plates. Melting
points were measured on an X4-type micro-melting point
apparatus and were uncorrected. Mass spectrometric anal-
yses were performed on a ZAB-2F spectrometer. High Re-
Contract grant numbers: 2007BAI34B00
*Correspondence to: Runtao Li or Zemei Ge, State Key Laboratory of Nat-
ural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking
University, Beijing 100191, People’s Republic of China.
E-mail: lirt@mail.bjmu.edu.cn or zmge@bjmu.edu.cn
Received for publication 19 March 2009; Accepted 4 August 2009
DOI: 10.1002/chir.20783
solution of Mass Spectrum (HRMS) analyses were carried
Published online 6 November 2009 in Wiley InterScience
out on Bruker Apex IV. H NMR and 13C NMR spectra (www.interscience.wiley.com).
1
C
VV
2009 Wiley-Liss, Inc.

ALDOL REACTION OF EQUIMOLAR REACTANTS
581
The Characterizations of Catalysts 4–6
and the Aldol Products
2-[Hydroxyl(4-methoxyphenyl)methyl]cyclohexanone
(9g).26 White powder; 40% yield; m.p. 74–76 8C. 79% ee
(anti) [Daicel Chiralpak AD-H column, n-hexane/i-propa-
nol 5 98:2, 1.8 ml/min, 218 nm; tR (anti) 5 41.25 min
(major) and 38.46 min, tR (syn) 5 23.76 min (major) and
19.60 min].
L-Val-L-ValOH (4).26 White powder. m.p. 257–2598C.
[a]2D2 5 2158 (c 5 1, HCl aq.).
L-Pro-L-PheOH (5).26 White powder. m.p. 236–
2378C. [a]2D2 5 2508 (c 5 2, HCl aq.).
2-[Hydroxyl(2-chlorophenyl)methyl]cyclohexanone
(9h).26 White powder; 74% yield; m.p. 89–918C. 74% ee
(anti) [Daicel Chiralpak AD-H column, n-hexane/i-propa-
nol 5 92:8, 1.0 ml/min, 210 nm; tR (anti) 5 13.93 min and
12.29 min (major), tR (syn) 5 7.88 min and 7.09 min
(major)].
L-Pro-L-TrpOH (6).26 White powder. m.p. 183–1848C.
[a]2D2 5 2328 (c 5 1, HCl aq.).
2-[Hydroxyl(4-nitrophenyl)methyl]cyclohexanone
(9a).26 White powder; 83% yield; m.p. 129–1308C. 98%
ee (anti) (Daicel Chiralpak AD-H column, n-hexane/i-pro-
panol 5 92:8, 1.0 ml/min, 268 nm; tR (anti) 5 43.09 min
(major) and 32.00 min, tR (syn) 5 28.80 min and 23.64 min
(major).
2-[Hydroxyl(5-nitrofuran-2-yl)methyl]cyclohexanone
(9i).21 Yellow oil; 83% yield. 79% ee (anti) [Daicel Chiral-
pak AD-H column, n-hexane/i-propanol 5 92:8, 1.0 ml/
min, 316 nm; tR (anti) 5 28.18 min and 23.46 min (major),
tR (syn) 5 19.45 min and 18.21 min (major)]. 1H NMR
(300 MHz, CDCl3): d (ppm): 7.30 (q, J 5 3.9 Hz, 1H, Ph),
6.59–6.61 (m, 1H, Ph), 4.81–5.37 (m, 1H, CH), 2.92–3.02
(m, 1H, CHCO), 2.40–2.46 (m, 2H, CH2CO), 2.12–2.16 (m,
1H, CH2), 1.60–1.94 (m, 5H, CH2). HRMS: Calcd. for
C11H13NO5 [M 1 H] 1: 240.0866; found 240.0871.
2-[Hydroxyl(pyridin-4-yl)methyl]cyclohexanone
(9b).21 White powder; 94% yield; m.p. 108–1098C. 87%
ee (anti) [Daicel Chiralpak AD-H column, n-hexane/i-pro-
panol 5 92:8, 1.0 ml/min, 254 nm; tR (anti) 5 31.20 min
(major) and 28.67 min, tR (syn) 5 24.13 min and 20.74 min
1
(major)]. H NMR (300 MHz, CDCl3): d (ppm): 8.55–8.59
(m, 2H, CH¼¼N), 7.24–7.27 (m, 2H, CH¼¼C), 4.77–5.39 (m,
1H, CH), 2.31–2.64 (m, 3H, CH2CO 1 CHCO), 2.09–2.14
(m, 1H, CH2), 1.82–1.86 (m, 1H, CH2), 1.59–1.76 (m, 3H,
CH2), 1.34–1.56 (m, 1H, CH2). HRMS: Calcd. for
C12H15NO2 [M 1 H]1: 206.1175; found 206.1178.
(E)-2-(1-Hydroxy-3-phenylallyl)cyclohexanone
(9j).27 White powder; 62% yield; m.p. 119–121 8C. 75%
ee (anti) [Daicel Chiralpak AD-H column, n-hexane/i-pro-
panol 5 92:8, 1.0 ml/min, 255 nm; tR (anti) 5 20.59 min
and 17.78 min (major), tR (syn) 5 16.92 min and 14.39 min
1
(major)]. H NMR (300 MHz, CDCl3): d (ppm): 7.36–7.39
2-[Hydroxyl(2-nitrophenyl)methyl]cyclohexanone
(9c).26 Yellow powder; 73% yield; m.p. 116–1188C. 91%
ee (anti) [Daicel Chiralpak AD-H column, n-hexane/i-pro-
panol 5 92:8, 1.0 ml/min, 209 nm; tR (anti) 5 26.02 min
and 24.29 min (major)].
(m, 2H, Ph), 7.31 (t, J 5 7.8 Hz, 2H, Ph), 7.20–7.26 (m,
1H, Ph), 6.58–6.66 (m, 1H, CH¼¼CH), 6.15–6.25 (m, 1H,
CH¼¼CH), 4.43 (t, J 5 4.8 Hz, 1H, CH), 2.31–2.59 (m, 3H,
CHCO 1 CH2CO), 2.07–2.13 (m, 2H, CH2), 1.87–1.94 (m,
1H, CH2), 1.63–1.78 (m, 3H, CH2).
2-[Hydroxyl(3-nitrophenyl)methyl]cyclohexanone
(9d).26 White powder; 83% yield; m.p. 69–718C. 78%
ee (anti) [Daicel Chiralpak AD-H column, n-hexane/i-pro-
panol 5 92:8, 1.0 ml/min, 263 nm; tR (anti) 5 31.60 min
and 24.82 min (major), tR (syn) 5 22.07 min (major) and
20.28 min].
(E)-2-(3-(2-Chlorophenyl)-1-hydroxyallyl)cyclohexa-
none (9k). Yellow oil; 68% yield. 76% ee (anti) [Daicel
Chiralpak OD-H column, n-hexane/i-propanol 5 95:5, 1.l0l
ml/min, 258 nm; tR (anti) 5 50.35 min and 27.41 min
1
(major), tR (syn) 5 40.79 min and 29.60 min (major)]. H
NMR (300 MHz, CDCl3): d (ppm): 7.52–7.55 (m, 1 H, Ph),
7.33–7.37 (m, 1H, Ph), 7.18–7.26 (m, 2H, Ph), 6.96–7.01
(m, 1H, CH¼¼CH), 6.14–6.22 (m, 1H, CH¼¼CH), 4.48 (t, J
5 7.5 Hz, 1H, CH), 3.68 (t, J 5 3.0 Hz, 1H, OH), 2.31–2.56
(m, 3H, CHCO 1 CH2CO), 2.04–2.18 (m, 2H, CH2), 1.90–
1.94 (m, 1H, CH2), 1.43–1.75 (m, 3H, CH2). HRMS: Calcd.
for C15H17ClO2 [M 1 Na]1: 287.0815; found 287.0825.
2-[Hydroxyl(4-cyanophenyl)methyl]cyclohexanone
(9e).26 White powder; 76% yield; m.p. 82–838C. 87% ee
(anti) [Daicel Chiralpak AD-H column, n-hexane/i-propa-
nol 5 92:8, 1.0 ml/min, 267 nm; tR (anti) 5 39.02 min
(major) and 30.75 min, tR (syn) 5 26.46 min and 21.87 min
(major)].
2-[Hydroxy(6-nitro-1,3-dihydroisobenzofuran-5-yl)
(E)-4-(3-Hydroxy-3-(2-oxocyclohexyl)prop-1-enyl)-
methyl]cyclohexanone (9f).21 Light yellow powder; benzonitrile (9l). Light yellow oil; 75% yield. 78% ee
59% yield; m.p. 165–1668C. 97% ee (anti) [Daicel Chiralpak (anti) [Daicel Chiralpak OD-H column, n-hexane/i-propa-
AD-H column, n-hexane/i-propanol 5 92:8, 1.0 ml/min, nol 5 95:5, 1.0 ml/min, 270 nm; tR (anti) 5 45.14 min and
214 nm; tR (anti) 5 62.92 min and 49.01 min (major), tR 42.94 min (major), tR (syn) 5 38.42 min (major) and 35.49
1
1
(syn) 5 36.15 min (major) and 32.86 min]. H NMR (300 min]. H NMR (300 MHz, CDCl3): d (ppm): 7.60 (d, J 5
MHz, CDCl3): d (ppm): 7.61 (s, 1H, Ph), 7.26 (s, 1H, Ph), 8.4 Hz, 2H, Ph), 7.46 (d, J 5 8.1 Hz, 2H, Ph), 6.65 (d, J 5
6.22 (s, 2H, OCH2O), 5.69 (d, J 5 7.5 Hz, 1H, CH), 5.57 15.9 Hz, 1H, CH¼¼CH), 6.35 (q, J 5 7.2 Hz, 1H, CH¼¼CH),
(br, 1H, OH), 2.39–2.51 (m, 2H, CHCO 1 CH2CO), 2.17– 4.46 (t, J 5 7.2 Hz, 1H, CH), 3.72 (br, 1H, OH), 2.30–2.56
2.26 (m, 1H, CH2CO), 1.92–2.09 (m, 6H, CH2). HRMS: (m, 3H, CHCO 1 CH2CO), 2.03–2.17 (m, 2H, CH2), 1.87–
Calcd. for C14H15NO6 [M 1 Na]1: 316.0791; found 1.94 (m, 1H, CH2), 1.47–1.72 (m, 3H, CH2). HRMS: Calcd.
316.0794.
for C16H17NO2 [M 1Na]1: 278.1157; found 278.1166.
Chirality DOI 10.1002/chir

582
LEI ET AL.
TABLE 1. The screening of the reaction conditions in the direct asymmetric aldol reaction between cyclohexanone
and 4-nitrobenzaldehyde catalyzed by Pro-Trp in the solid mediaa
Entry
T (8C)
Time (h)
7a:8a
Solid media
no
Yieldb (%)
drcanti:syn
eec(%) R/S
1
2
3
4
5
6
7
8
9
0
0
0
16
16
16
30
30
30
30
30
30
4:1
1:1
1:1
1:1
4:1
1:1
1:1
1:1
1:1
90
65
83
82
85
72
65
58
72
93:7
92:8
82:18
93:7
94:6
93:7
92:8
94:6
86:14
93/–
92/–
93/–
97/–
96/–
91/–
85/–
93/–
93/–
no
Alkaline Al2O3
Alkaline Al2O3
Alkaline Al2O3
Neutral Al2O3
Silica gel
220
220
220
220
220
220
Bentonite
b-cyclo dextrin
aReaction was performed in 300 mg solid media with DABCO as the base.
bIsolated yield of the corresponding product.
cDetermined by chiral-phase HPLC.
3-(Hydroxy(pyridin-4-yl)methyl)-tetrahydrothio- 47.9. HRMS: Calcd. for C16H21NO9 [M 1 Na]1: 394.1114;
pyran-4-one (9m). Yellow oil; 71% yield. 87% ee [Daicel found 394.1115.
Chiralpak AD-H column, n-hexane/i-propanol 5 80:20, 1.0
ml/min, 260 nm; tR (anti) 5 22.77 min and 15.01 min
1
(major), tR (syn) 5 11. 85 min and 9.75 min (major)]. H
RESULTS AND DISCUSSION
NMR (300 MHz, CDCl3): d (ppm): 8.60 (t, J 5 5.1 Hz, 2H,
In our previous work,26 we studied direct asymmetric
organocatalytic aldol reactions catalyzed by dipeptide Pro-
Trp in the presence of water and obtained some encourag-
ing results. In a search for more economic and environ-
CH¼¼N), 7.27–7.30 (m, 2H, CH¼¼C), 4.93–5.42 (m, 1H,
CH), 2.82–3.18 (m, 4H, CHCO 1 CH2S), 2.51–2.81 (m, 3H,
CH2CO 1 CH2), HRMS: Calcd. for C11H13NO2S [M 1
H]1: 224.0745; found 224.0745.
mentally friendly reaction conditions, we initially investi-
4-Hydroxy-4-(4-nitrophenyl)butan-2-one (9n).26
White powder; 83% yield; m.p. 59–618C. 41% ee [Daicel
gated the reaction of 4-nitrobenzaldehyde (8a) with four
equivalents of cyclohexanone (7a) utilizing 1,4-diazabicy-
clo[2.2.2]octane (DABCO) as an additive and the dipeptide
Chiralpak AS-H column, n-hexane/i-propanol 5 70:30, 1.0
Pro-Trp as the catalyst in the absence of any solvent at 08C
ml/min, 254 nm; tR 5 13.87 min (major) and 11.09 min].
and obtained good yield and high stereoselectivity (Table
4-Hydroxy-4-(2-nitrophenyl)butan-2-one (9o).26
Light yellow powder; 91% yield; m.p. 59–618C. 49% ee
[Daicel Chiralpak AS-H column, n-hexane/i-propanol 5
70:30, 1.0 ml/min, 209 nm; tR 5 7.69 min and 10.11 min
1, entry 1). However, when the molar ratio of the reactants
was reduced to 1:1, the yield decreased from 90% to 65%,
although the stereoselectivity was retained (Table 1, entry
2). The decrease of yield may be because of thickening,
leading to insufficient stirring. Inspired by the applications
(major)].
of solid media in organic reactions,28,29 we attempted to
solve the above problem by using solid media in the reac-
tion. A preliminary examination of alkaline Al2O3 was per-
4-Hydroxy-4-(6-nitrobenzo[d][1,3]dioxol-5-yl)butan-
2-one (9p).19 Yellow powder; 61% yield; m.p. 99–1018C.
formed (Table 1, entry 3) utilizing equivalent of 8a and 7a
94% ee [Daicel Chiralpak AS-H column, n-hexane/i-propa-
as the reactants at 08C to obtain the corresponding aldol
nol 5 70:30, 1.0 ml/min, 242 nm; tR 5 15.68 min and 19.88
1
product 9a in 83% yield with 93% ee, albeit the diastereose-
min (major)]. H NMR (300 MHz, CDCl3): d (ppm): 7.56
(s, 1H, Ph), 7.26 (s, 1H, Ph), 6.21 (d, J 5 5.1 Hz, 2H,
OCH2O), 5.67 (m, 1H, CH), 5.43–5.54 (m, 1H, OH), 2.62–
2.77(m, 2H, CH2CO), 2.13 (s, 3H, CH3CO).
4-Hydroxy-4-(4-nitrophenyl)-1-(1-b-glucosyl)propan-
2-one (9q). Yellow oil; 46% yield. 70% ee [Daicel Chiral-
pak AS-H column, n-hexane/i-propanol 5 75:25, 1.0 ml/
1
min, 254 nm; tR 5 11.32 min and 17.34 min (major)]. H
NMR (300 MHz, D2O): d (ppm): 8.05 (d, J 5 8.7 Hz, 2H,
Ph), 7.42 (d, J 5 8.7 Hz, 2H, Ph), 5.17–5.13 (m, 1H, CH),
3.62–3.52 (m, 2H, CH2OH), 3.48–3.43 (m, 1H, CHOH),
3.31–3.21 (m, 1H, CHOH), 3.19–3.15 (m, 2H, CH2CO),
3.05–2.85 (m, 3H, CHOH), 2.80 (dd, J 5 3.0 Hz, 16.5 Hz,
1H, CH2CO), 2.60–2.49 (m, 1H, CH2CO). 13C NMR (75
MHz, D2O): d (ppm): 213.2, 153.0, 149.7, 129.6, 129.5,
126.5, 126.5, 82.1, 79.8, 77.8, 75.6, 72.3, 71.1, 63.3, 53.3,
Chirality DOI 10.1002/chir
Fig. 1. The structures of the catalysts 1–6.

ALDOL REACTION OF EQUIMOLAR REACTANTS
583
TABLE 2. The screening of catalysts for the direct asymmet-
ric aldol reaction of 7a with 8aa
the best efficiencies (Table 3, entry 1 and entry 3). How-
ever, in the absence of base, only a trace amount of prod-
uct was detected by TLC, even when the reaction time
was prolonged to 48 h (Table 3, entry 2). We speculate
that is because of the acid catalyst neutralising the alkaline
Al2O3 in the absence of amine that leads to the loss of cata-
lytic activity. Thus, the base is one of the critical factors
for the improvement of the yield and stereoselectivity.
After identifying the suitable reaction conditions for the
asymmetric aldol reactions catalyzed by Pro-Trp in the
alkaline Al2O3 medium, the scope of the process was
explored under these optimized reaction conditions
(namely, equivalent mole of aldehyde and ketone, 20 mol
% of catalyst, 20 mol % of NMM or DABCO, at 2208C) (Ta-
ble 4). All the reactions proceeded smoothly and gave sat-
isfactory results, with NMM usually showing a slightly
better efficiency than DABCO. In the case of cyclohexa-
none 7a as aldol substrate, a variety of aldehydes 8,
including aromatic, heteroaromatic, and substituted cin-
namyl aldehydes, gave excellent diastereoselectivities
(88:12 to >99:1) and good to excellent enantioselectivities
(70–98% ee) (Table 4, entries 1–24). The properties of sub-
stituents on the aromatic aldehydes have significant influ-
ence on the reaction rate, yield, and enantioselectivity,
such as, 4-nitrobenzaldehyde (8a) (entry 1, 30 h, 82%
yield, anti:syn 5 93:7, 97% ee) and 4-methoxybenzaldehyde
(8g) (entry 13, 180 h, 35% yield, anti:syn 5 97:3, 77% ee).
On the contrary, the substitution pattern of aromatic alde-
hydes (para-, meta-, or ortho-) does not obviously affect
yield or diastereoselectivity but significantly affects the
Yieldb
(%)
drc
anti:syn
eec (%)
R/S
Entry
Catalyst
Proline (1)
(R)-thiazolidine-4-carboxylic
acid (2)
1
2
78
15
47:53
60:40
36/11
19/10
3
4
5
6
7
8
9
Tryptophan (3)
Val-Val (4)
Pro-Phe (5)
Pro-Trp (6, 20 mol %)
Pro-Trp (6, 10 mol %)
Pro-Trp (6, 30 mol %)
Pro-Trp (6, 50 mol %)
61
51
68
82
76
82
79
55:45
81:19
85:15
93:7
80:20
91:9
34/27
89/–
86/–
97/–
82/–
96/–
96/–
92:8
aReaction was performed at 0.5 mmol scale of aldehyde and 0.5 mmol
scale of ketone with 20 mol % catalyst in 300 mg alkaline Al2O3 media at
2208C, unless otherwise stated.
bIsolated yield of the corresponding product.
cDetermined by chiral-phase HPLC.
lectivity slightly decreased (anti:syn 5 82:18) compared
with the case of solvent-free (anti:syn 5 92:8; Table 1,
entry 2). Notably, a satisfactory result was obtained when
the reaction was performed at 2208C for 30 h (Table 1,
entry 4, 82% yield, anti:syn 5 93:7, 97% ee). These results
further verified the feasibility of the reaction in solid
media. We then screened a variety of common inorganic
solid media (Table 1, entries 5–8) and found that the alka-
line Al2O3 was the best. We speculate that the hydroxyl
groups on the surface of alkaline Al2O3 could form inter-
molecular hydrogen bonds with reactants and catalyst that
might be favorable for the reaction.
TABLE 3. Efficiency of different base additives for the direct
asymmetric aldol reaction of 7a with 8a in the solid mediaa
Subsequently, we also tested some other structurally
simple and synthetically accessible catalysts (Fig. 1), such
as the simple amino acids (S)-proline (1), (S)-thiazolidine-
4-carboxylic acid (2),2 and tryptophan (3),30 as well as the
dipeptides Val-Val (4),27,31,32 Pro-Phe (5),33 and Pro-Trp
(6),25 which showed effective catalytic activities for the
direct asymmetric aldol reactions in liquid media. It is
clear that the dipeptides showed significantly better cata-
lytic activities than the amino acids, and Pro-Trp (6) was
the most potent catalyst (Table 2, entry 6). Then, the effect
of the amount of the catalyst Pro-Trp on the reaction was
examined (Table 2, entries 7–9). The results reveal that 20
mol % of catalyst is suitable.
Time Yieldc
drd
anti:syn
eed (%)
R/S
Entry
Baseb
DABCO
no
NMM
Et3N
HMTA
iPr2EtN
N-methylpiperidine
1-methylpyrrolidine
(h)
(%)
1
2
3
4
5
6
7
8
30
48
30
30
30
30
30
30
82
trace
83
75
58
55
61
63
93:7
n.d.
91:9
86:14
91:9
88:12
73:27
79:21
97/–
n.d.
98/–
92/–
96/–
82/–
75/–
90/–
aReaction catalyzed by Pro-Trp was performed at 0.5 mmol scale of alde-
hyde and 0.5 mmol scale of ketone in 300 mg alkaline Al2O3 media at
2208C.
We next screened a variety of bases using the reaction
of 7a and 8a (1:1) catalyzed by Pro-Trp (20 mol %) over
alkaline Al2O3 at 2208C as the model reaction. As shown
in Table 3, all the bases gave good to excellent yields and
bNMM, N-methylmorpholine; HMTA, hexamethylenetetramine; DABCO,
1,4-diazabicyclo[2.2.2]octane.
cIsolated yield of the corresponding product.
stereoselectivities with both DABCO and NMM exhibiting dDetermined by chiral-phase HPLC.
Chirality DOI 10.1002/chir

584
LEI ET AL.
TABLE 4. Reactions of aliphatic and cyclic ketones with various aldehydes catalyzed by 6 in the solid mediaa
Time Yieldb drc anti: eec (%)
Entry
R1, R2
R
Product
Base
(h)
(%)
syn
R/S
1
2
3
4
5
6
7
8
ꢀꢀ(CH2)4ꢀ (7a)
(7a)
(7a)
(7a)
(7a)
(7a)
(7a)
(7a)
(7a)
(7a)
(7a)
(7a)
(7a)
(7a)
(7a)
(7a)
(7a)
(7a)
(7a)
(7a)
(7a)
(7a)
(7a)
(7a)
4-nitrophenyl (8a)
(8a)
pyridin-4-yl (8b)
(8b)
2-nitrophenyl (8c)
(8c)
3-nitrophenyl (8d)
(8d)
9a
9a
9b
9b
9c
9c
9d
9d
9e
9e
9f
DABCO
NMM
DABCO
NMM
DABCO
NMM
DABCO
NMM
30
30
12
12
36
36
36
36
50
50
82
83
95
94
77
73
83
81
69
76
57
59
35
38
69
74
77
83
56
62
68
64
75
74
70
71
83
81
89
91
55
61
46
93:7
91:9
88:12
92:8
>99:1
>99:1
90:10
95:5
96:4
94:6
94:6
93:7
97:3
98:2
>99:1
>99:1
92:8
93:7
88:12
89:11
98:2
98:2
88:12
92:8
67:33
64:36
–
97/–
98/–
85/–
87/–
89/–
91/–
77/–
78/–
81/–
87/–
95/–
97/–
77/–
79/–
70/–
74/–
79/–
79/–
71/–
75/–
75/–
76/–
71/–
78/–
87/66
83/64
40
9
4-cyanophenyl (8e)
(8e)
6-nitro-1,3-dihydroisobenzofuran-5-yl (8f)
DABCO
NMM
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31d
32
33d
DABCO 180
NMM 180
DABCO 180
NMM 180
DABCO 180
NMM
DABCO
NMM
DABCO
NMM
DABCO
NMM
DABCO
NMM
DABCO
NMM
DABCO
NMM
DABCO
NMM
DABCO
NMM
DABCO
(8f)
9f
4-methoxylphenyl (8g)
(8g)
2-chlorophenyl (8h)
(8h)
5-nitrofuran-2-yl (8i)
(8i)
styryl (8j)
(8j)
2-chlorostyryl (8k)
(8k)
9g
9g
9h
9h
9i
9i
9j
9j
180
36
36
80
80
68
68
60
60
10
10
45
45
36
36
60
60
60
9k
9k
9l
4-cyanostyryl (8l)
(8l)
9l
ꢀꢀ(CH2)2S(CH2)2ꢀꢀ(7b) pyridin-4-yl (8b)
9m
9m
9n
9n
9o
9o
9p
9p
9q
(7b)
(8b)
4-nitrophenyl (8a)
(8a)
2-nitrophenyl (8c)
(8c)
6-nitro-1,3-dihydroisobenzofuran-5-yl (8f)
(8f)
H, CH3 (7c)
(7c)
(7c)
(7c)
(7c)
–
–
–
–
–
–
41
45
49
92
94
70
(7c)
(7d)
4-nitrophenyl (8a)
aReaction was performed at 0.5 mmol scale of aldehyde and 0.5 mmol scale of ketone in 300 mg alkaline Al2O3 at 2208C.
bIsolated yield of the corresponding product.
cDetermined by chiral-phase HPLC.
dThe reaction was performed at r.t.
enantioselectivity, such as 4-nitrobenzaldehyde (8a) 33). To the best of our knowledge, this is the first example
(entry 2, 98% ee), 2-nitrobenzaldehyde (8c) (entry 6, 91% of a ketone bearing saccharide group as an aldol substrate.
ee), and 3-nitrobenzaldehyde (8d) (entry 8, 78% ee). The
Much to our delight, these products can easily be iso-
acetone (7c) as aldol substrate usually gave the aldol lated from the reaction system by simply washing with
products in good yields and moderate enantioselectivities ethyl acetate, and meanwhile, most of the catalyst still
(entries 27–30). However, the reaction of acetone with 6- remained on the alkaline Al2O3, which opens the possibil-
nitro-1,3-dihydroisobenzofuran-5-yl aldehyde (8f) afforded ity of the reuse of the catalytic system. As shown in Table
the corresponding aldol product in over 90% ee (entries 5, the catalytic activity did not obviously decrease with
31 and 32). To extend the scope of aldol substrates, reuse of the catalytic system, with the addition of 10 mol %
the 1-(3,4,5-trihydroxy-6-(hydroxymethyl)-tetrahydro 22H- more catalyst and DABCO before reuse each time.
pyran-2-yl)propan-2-one (7d) was also selected to react with
In summary, we have developed an efficient direct
8a to afford the product 9q in 46% yield with 70% ee (entry asymmetric aldol reaction catalyzed by dipeptide Pro-Trp
Chirality DOI 10.1002/chir

ALDOL REACTION OF EQUIMOLAR REACTANTS
585
TABLE 5. The reuse of the catalytic system and catalytic efficiencya
Cycle
Yieldb (%)
drcanti:syn
eec (%) R/S
Cycle
Yieldb (%)
drcanti:syn
eec (%) R/S
0
82
76
93:7
79:21
97/–
90/–
0
82
83
80
79
93:7
92:8
91:9
89:11
97/–
96/–
96/–
95/–
1d
1e
2e
3e
aReaction was performed at 0.5 mmol scale of aldehyde and 0.5 mmol scale of ketone in 300 mg alkaline Al2O3 at 2208C.
bIsolated yield of the corresponding product.
cDetermined by chiral-phase HPLC.
dReused directly.
eAfter every cycle, 10 mol % more catalyst and DABCO were added in the reaction.
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included the green solid reaction media, equivalent molar
ratio of reactants, reuse of catalytic system, simple work-
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1624.
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