Merrifield resin supported dipeptides: Efficient and recyclable organo-catalysts for asymmetric aldol reactions under neat reaction conditions

Article abstract of DOI:10.1055/s-2008-1067104

A number of Merrifield resin supported dipeptide and tripeptide catalysts have been developed of which Pro-Ala-O-P, catalyst A, was found to be an efficient catalyst for asymmetric direct aldol reactions. Aldehydes and ketones underwent smooth aldol reaction in the presence of a catalytic amount of A at room temperature under neat reaction conditions and generated the corresponding products with excellent isolated yields (≤98%), good diastereoselectivities (dr ≥ 90:10) and enantioselectivities (≤95% ee). In addition, catalyst A could be used seven times without loss of its catalytic activity. Thieme Stuttgart.

Full text of DOI:10.1055/s-2008-1067104

PAPER
2065
Merrifield Resin Supported Dipeptides: Efficient and Recyclable Organo-
catalysts for Asymmetric Aldol Reactions under Neat Reaction Conditions
M
errifield
i
Resin
n
Supported D
c
ipeptides an Yan,a Lei Wang*a,b
a
Department of Chemistry, Huaibei Coal Teachers College, Huaibei, Anhui 235000, P. R. of China
Fax +86(561)3090518; E-mail: leiwang@hbcnc.edu.cn
b
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, P. R. of China
Received 3 March 2008; revised 4 April 2008
also can be carried out using an immobilized peptide, but
the reaction temperature is very strict and the enantio-
selectivity is low.10
Abstract: A number of Merrifield resin supported dipeptide and
tripeptide catalysts have been developed of which Pro-Ala-O–P,
catalyst A, was found to be an efficient catalyst for asymmetric di-
rect aldol reactions. Aldehydes and ketones underwent smooth aldol
reaction in the presence of a catalytic amount of A at room temper-
ature under neat reaction conditions and generated the correspond-
ing products with excellent isolated yields (£98%), good
diastereoselectivities (dr £ 90:10) and enantioselectivities (£95%
ee). In addition, catalyst A could be used seven times without loss
of its catalytic activity.
Although the organocatalyst systems have been extended
in asymmetric organic reactions, high enantioselective for
a comparably narrow range of substrates and requirement
of 20–30 mol% catalyst loading are observed in some
cases. Most recently, there are some reports on the asym-
metric aldol reaction using immobilized proline on PEG,
mesoporous support, and ionic liquids.11 It is desirable to
develop highly enantioselective and efficient chiral orga-
nocatalysts with broad substrate applicability and low cat-
alyst loading or recyclability in this field, especially for
the extremely limited scope of substrates when peptides
were used to catalyze aldol reactions.12
Key words: Merrifield resin, organocatalyst, aldol reaction, pep-
tide, neat reaction conditions
b-Hydroxy carbonyls are important building blocks in the
synthesis of polyfunctional compounds and natural prod-
ucts.1 Moreover, the b-hydroxy carbonyl unit is frequently
found in biologically active compounds, such as mac-
rolide antibiotics and anti-cancer drugs.2 Direct asymmet-
ric aldol reactions, which provide straightforward access
to optically active b-hydroxy carbonyl compounds, are
highly useful in organic synthesis and, thus, have received
much research interest.3 As a result, great advances have
been made in asymmetric direct aldol reactions, in partic-
ular, in those using L-proline and secondary amine based
organic molecules as catalysts.4 L-Proline was the first
small molecule used as an organocatalyst in direct aldol
reactions and its use was followed by 4-substituted-L-pro-
line,5 N-sulfonylcarboxamides,6a tetrazole,6b,c diamine-
protonic acid,6d axially chiral amino acids,6e,f pyrrolidine-
3-carboxylic acid,6g and prolinamides.7,8
Here we wish to report a novel Merrifield resin supported
dipeptide A that can be used in direct aldol reactions at
room temperature under neat reaction conditions and
gives high yields of products with good enantiomeric
excess (£95%) and diastereomeric ratio (£90:10)
(Scheme 1). In contrast, natural amino acids and other
peptides catalyzed the aldol reactions in low yields and
stereoselectivities, or the substrates are very limited.
Compared with the supported organocatalysts mentioned
above,11,12 the Merrifield resin supported catalysts pre-
pared in this paper can complete the aldol reaction very ef-
ficiently.
Merrifield resin supported peptides can be easily prepared
by the route shown in Scheme 2, a representative proce-
dure for the synthesis of catalyst A. Protected alanine 1
Peptides have the same units as enzymes, so they can be
used to mimic the qualities of enzymes and this feature
has been especially used in organocatalysis in recent
years. They can now be easily prepared due to develop-
ments in solid phase synthesis. On the other hand, the cat-
alytic mechanism of peptides is more facile than enzymes
and the catalyst loading is much lower. Peptides can be
used in a wide range of organocatalytic reactions, espe-
cially in the aldol reaction. In 2003, Reymond and other
groups reported that peptides were used as efficient cata-
lysts in the aldol reaction.9 Furthermore, aldol reactions
O
H
N
O
P
N
H
O
A
OH
O
O
10 mol%
CHO
+
R
R
neat, 24 h, r.t.
Up to 98% yield
Up to 95% ee
Up to 90:10 dr
SYNTHESIS 2008, No. 13, pp 2065–2072
x
x.
x
x
.
2
0
0
8
Advanced online publication: 21.05.2008
DOI: 10.1055/s-2008-1067104; Art ID: F04808SS
Scheme 1
© Georg Thieme Verlag Stuttgart · New York

2066
J. Yan, L. Wang
PAPER
O
O
O
(Boc)2O
CsHCO3
OH
O–Cs+
OH
t-BuOH, H2O
NH
Boc
NH
Boc
NH2
Boc-Ala-O–Cs+ (3)
Ala-OH (1)
Boc-Ala-OH (2)
O
O
TFA
Merrifield resin
NMP, DMF, 55 °C
O
P
O
P
CH2Cl2
NH
Boc
NH2
Boc-Ala-O–P (4)
Ala-O–P (5)
O
O
H
Boc-Pro-OH
N
P
N
HATU, DIPEA, DMF
O
Boc
Boc-Pro-Ala-O–P (6)
O
H
N
O
TFA
P
CH2Cl2
N
H
O
Pro-Ala-O–P (A)
Scheme 2 Preparation of catalyst A
O
O
H
N
H
N
O
O
O
O
P
P
P
P
N
N
H
O
H
O
A
B
O
O
H
N
O
H
N
P
N
N
H
H
O
O
NH2
Ph
O
C
D
O
H
N
O
O
N
H
N
H
O
N
O
P
N
H
F
E
O
O
O
H
H
N
O
P
N
N
N
H
H2N
O
P
O
O
H
G
Ph
O
O
O
O
O
H
H
H
N
N
H
N
N
N
O
P
N
O
H
P
H
O
Ph
J
I
Figure 1 The catalyst library screened in the reaction
Synthesis 2008, No. 13, 2065–2072 © Thieme Stuttgart · New York

PAPER
Merrifield Resin Supported Dipeptides
2067
was grafted onto Merrifield resin through standard meth- the amino acids. We also found that the catalysts that con-
odology to afford Boc-Ala-O–P (4) and this was reacted tain dipeptide units A–G are superior to the catalysts that
with trifluoroacetic acid in dichloromethane to form Ala- contain tripeptide units H–J. Among the catalysts
O–P (5). The obtained Ala-O–P (5) was reacted with Boc- screened in the model aldol reaction, catalyst A was found
Pro-OH in the presence of O-(7-azabenzotriazol-1-yl)- to be the best (98% yield, 95% ee, and dr 90:10).
N,N,N¢,N¢-tetramethyluronium
hexafluorophosphate
We next explored the effect of solvent on the reaction
(Table 2). Among the solvents investigated, polar sol-
vents showed better results than nonpolar ones (Table 2,
entries 1–4). In the presence of catalyst A (10 mol%),
when the reactions were performed in dimethyl sulfoxide,
tetrahydrofuran, and chloroform, the reactions generated
(HATU) and N,N-diisopropylethylamine in N,N-dimeth-
ylformamide to generate Boc-Pro-Ala-O–P (6) (peptide
coupling step), and followed by a standard deprotection
procedure (TFA–CH2Cl2) to afford the desired catalyst
Pro-Ala-O–P (A).
Catalysts B–G (Scheme 2) could be also prepared by the the corresponding product 7a in good yields and moderate
same procedures (Figure 1). By repeating the peptide cou- stereoselectivities (Table 2, entries 1–3). When the sol-
pling step once again, tripeptide catalysts H–J could be vent was changed to toluene, a significant decrease in the
easily obtained.
yield and stereoselectivity was found (Table 2, entry 4).
Table 2 Effect of Reaction Conditions on the Aldol Reactiona
For the initial investigation, we screened a library of cata-
lysts containing di- or tripeptides (10 mol%) in the model
asymmetric direct aldol reaction between 4-nitrobenzal-
dehyde and cyclohexanone under neat reaction conditions
and with no additive. As shown in Table 1, we found a re-
markable difference in the isolated yields of products, di-
astereoselectivities, and enantioselectivities between the
Merrifield resin supported peptide catalysts A–J and free
amino acid, L-proline and L-alanine, catalyzed reactions.
This remarkable difference may be as a result of differ-
ences between the structures of the peptide moieties and
OH
O
O
CHO
A
+
O2N
O2N
(2S,1′R)-7a
Entry Catalyst,
Additive
Solvent Yieldb
(%)
eec
(%)
drd
(anti/syn)
75:25
75:25
90:10
n.d
1
2
3
4
5
6
7
8
9
A (10 mol%)
DMSO
THF
85
88
75
72
70
78
n.d.
95
95
95
95
95
96
72
A (10 mol%)
A (10 mol%)
A (10 mol%)
A (10 mol%)
A (10 mol%)
A (30 mol%)
A (20 mol%)
A (5 mol%)
Table 1 Screening of the Catalyst Librarya
CHCl3
OH
O
O
catalyst
(10 mol%)
CHO
toluene <10
+
neat, r. t., 24 h
neat
neate
neat
neat
neat
neat
neat
98
98
97
98
82
73
85
90:10
90:10
90:10
90:10
90:10
90:10
75:25
O2N
O2N
(2S,1′R)-7a
drd (anti/syn)
90:10
Entry
1
Catalyst
Yieldb (%) eec (%)
A
98
91
92
43
90
90
90
72
92
90
65
36
95
76
81
55
82
53
80
55
62
55
45
51
2
B
60:40
3
C
60:40
10f A (10 mol%)
4
D
75:25
11 A (10 mol%),
TFA (2.5 mol%)
5
E
25:75
12 A (10 mol%),
neat
neat
neat
neat
92
95
62
83
90
94
32
79
60:40
60:40
75:25
86:14
6
F
70:30
AcOH (2.5 mol%)
7
G
60:40
13 A (10 mol%),
PhCO2H (2.5 mol%)
8
H
60:40
14 A (10 mol%),
9
I
75:25
TsOH (2.5 mol%)
10
11
12
J
60:40
15 A (10 mol%),
H2O (5.0 mol%)
L-Pro
50:50
a 4-Nitrobenzaldehyde (0.25 mmol), cyclohexanone (1.0 mL), cata-
lyst A, r.t., stirred, 24 h.
L-Ala
50:50
a 4-Nitrobenzaldehyde (0.25 mmol), cyclohexanone (1.0 mL), orga-
nocatalyst (contains 10 mol%), r.t., stirred, 24 h.
b Isolated yields.
b Isolated yields.
c Determined by HPLC using Chiralpak AD-H column.
d Determined by 1H NMR spectroscopy.
e Reaction time was 48 h.
c Determined by HPLC using Chiralpak AD-H column.
d Determined by 1H NMR spectroscopy.
f At 0 °C, 48 h.
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J. Yan, L. Wang
PAPER
To our delight, when the reaction was carried out under the effects of various additives on the reaction were inves-
neat reaction conditions, that is to say, cyclohexanone tigated. Among the additives investigated, 2.5 mol% of
serves as reactant and solvent, the reaction was smooth acetic acid and benzoic acid were both helpful to the aldol
and excellent results were achieved (98% yield, 95% ee, reaction in isolated yields and enantioselectivities, but di-
and dr 90:10).
astereoselectivities decreased (Table 2, entries 12 and 13).
However, when 2.5 mol% of trifluoroacetic acid or 4-tol-
uenesulfonic acid was added to the reaction, the effect is
negative (Table 2, entries 11 and 14). It should be note
that in many cases of proline-catalyzed asymmetric aldol
reactions the addition of water accelerates dramatically
the reaction,14 but we did not find this effect in our inves-
tigation (Table 2, entry 15).
It was also found that the reaction was accomplished with-
in 24 hours, as using a reaction time of 48 hours gave the
same result (Table 2, entry 6). It should be noted that the
isolated yield of product and ee and dr were obtained with
good values when A with >10 mol% active units was add-
ed to the reaction mixture (Table 2, entries 7 and 8). A
lower yield of the aldol reaction product was isolated
when A with <10 mol% loading was used in the reaction To examine the generality of the reaction, we extended
(Table 2, entry 9). Moreover, almost the same enantiose- our studies to a variety of aldehydes and ketones. As
lectivity and diastereoselectivity were achieved when the shown in Table 3, aromatic aldehydes bearing electron-
reaction temperature was lowered to 0 °C, but there was a withdrawing groups (electron-deficient aromatic alde-
significant decrease in the reaction rate (Table 2, entry hydes), such as cyano, trifluoromethyl, chloro, and nitro
10).
groups, were able to undergo smoothly aldol condensation
with cyclohexanone in the presence of A (10 mol%) at
room temperature. The reactions generated the corre-
sponding aldol products 7a–g in good yields (72–98%)
and good enantioselectivities and diastereoselectivities
Additives are a key effect factor in some cases of organo-
catalysis. Generally strong acidic additives such as tri-
fluoroacetic acid,13a trifluoromethanesulfonic acid,13b
acetic acid,13c etc. were essential for catalysis. Of course,
Table 3 Aldol Reaction Catalyzed by Merrifield Resin Supported Dipeptide Aa
O
O
OH
R1
A (10 mol%)
R1CHO
+
R2
R2
neat, r.t., 24 h
R3
R3
7
Entry
1
R1
R2
R3
Product
7a
Yieldb (%)
eec (%)
95
drd (anti/syn)
90:10
80:20
80:20
75:25
40:60
60:40
80:20
75:25
60:40
40:60
80:20e
20:80
–
4-O2NC6H4
3-O2NC6H4
2-O2NC6H4
4-F3CC6H4
4-NCC6H4
2-Cl-5-O2NC6H3
4-Cl-3-O2NC6H3
1-naphthyl
2-naphthyl
4-O2NC6H4
4-O2NC6H4
4-O2NC6H4
4-O2NC6H4
Ph
–(CH2)4–
98
87
85
80
84
92
72
68
63
85
86
95
65
52
trace
2
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
Me
7b
7c
81
3
94
4
7d
7e
86
5
90
6
7f
85
7
7g
80
8
7h
7i
82
9
76
10
11
12
13
14
15
OH
Me
7j
80
–(CH2)2SCH2–
–(CH2)3–
Me
7k
7l
92
75
7m
7n
7o
82
–(CH2)4–
–(CH2)4–
80
80:20
n.d.
4-MeOC6H4
n.d.
a Aldehyde (0.25 mmol), ketones (1.0 mL), A (contains 10 mol%), r.t. stirred, 24 h.
b Isolated yields.
c Determined by HPLC using Chiralpak column.
d Determined by 1H NMR spectroscopy.
e DMSO (1.0 mL) was added as solvent.
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PAPER
Merrifield Resin Supported Dipeptides
2069
(80–95% ee and dr 60:40–90:10, Table 3, entries 1–7). In summary, catalyst A containing a dipeptide unit has
However, the use of aromatic aldehydes bearing an elec- been developed for the asymmetric direct intermolecular
tron-neutral or electron-donating group, such as hydrogen aldol reaction between aldehydes and ketones. The reac-
or methoxy, in the aldol condensation with cyclohexanone tions were performed in the presence of catalyst A (10
under standard reaction conditions gave the products 7n,o mol% active loading) at room temperature under neat re-
in lower yields (£52%, Table 3, entries 14 and 15). Fortu- action conditions. The reactions generated the corre-
nately, naphthaldehydes, including 1-naphthaldehyde and sponding aldol products with high isolated yields (£98%
2-naphthaldehyde could also react with cyclohexanone yield) and good enantioselectivities and diastereoselectiv-
under these reaction conditions to give 7h,i with moderate ities (£95% ee and dr £90:10). In addition, catalyst A
isolated yields (63–68%) and good enantioselectivities could be used for seven times with only a minor decrease
and diastereoselectivities (76–82% ee and dr 60:40– in product yields, but with maintained stereoselectivities.
75:25, Table 3, entries 8 and 9). Under the present reac-
tion conditions, 4-nitrobenzaldehyde also reacted with
Melting points were recorded on a WRS-2B melting point apparatus
1
other ketones, such as acetone, cyclopentanone, tetrahy-
drothiopyran-4-one, and hydroxyacetone, to generate the
corresponding aldol condensation products 7j–m in good
yields and with good enantioselectivities and diastereo-
selectivities (Table 3, entries 10–13).
and are uncorrected. All H NMR spectra were recorded on a 300
MHz Bruker FT-NMR spectrometer with TMS as internal standard.
IR spectra were obtained on a Nicolet NEXUS 470 spectrophoto-
meter. The CHN analysis was performed on a Vario El III elemen-
tary analyzer. Enantiomeric excesses were determined on Agilent
1100 HPLC using Daicel Chiralpak AS-H, AD-H, and Chiralcel
OJ-H, OD-H columns with racemic products as standards. Products
To screen the recyclability of catalyst A, we reused it sev-
eral times under standard reaction conditions. When 4-ni- were purified by flash chromatography on 230–400 mesh silica gel.
trobenzaldehyde was treated with cyclohexanone in the
presence of A (10 mol% loading) at room temperature for
24 hours, the desired aldol condensation product 7a was
obtained in 98% yield with 95% ee and dr 90:10. After
carrying out a reaction, isolating the product from the re-
action mixture, washing with solvents, drying, and recov-
ering catalyst A, fresh starting materials were charged into
the reaction system. The reactions still proceeded very
well and catalyst A was recycled through seven repetitive
cycles with only a slightly decrease in product yields, but
the ee and dr values were maintained (Table 4). The re-
used catalyst A surface loading was determined by ele-
mental analysis and was found to be proportional to the
isolated yield of product in each recycling experiment.
The chemicals and solvents were purchased from commercial sup-
pliers either from Aldrich, Fluka, Fisher Scientific and Novabio-
chem, USA, or Shanghai Chemical Company, China and were used
without purification prior to use.
Preparation of Merrifield Resin Supported Dipeptide Cata-
lysts; Typical Procedures
Boc-Ala-OH (1)
A flask was charged with a soln of NaOH (4.4 g, 0.11 mol) in H2O
(100 mL). Stirring was initiated and L-alanine (8.9 g, 0.10 mol) was
added at r.t. and then the mixture was diluted with t-BuOH (75 mL).
To the soln, (Boc)2O (22.3 g, 0.10 mol) was added dropwise over 1
h. The reaction was brought to completion by further stirring over-
night at r.t. The mixture was extracted with pentane (2 × 50 mL) and
the combined aqueous layers were acidified to pH 1–1.5 by addition
of a soln of KHSO4 (22.4 g, 0.165 mol) in H2O (100 mL). The turbid
mixture was then extracted with Et2O (4 × 30 mL). The combined
organic layers were washed with H2O (2 × 20 mL), dried (anhyd
Na2SO4), and filtered. The solvent was removed under reduced
pressure using a rotary evaporator at a bath temperature not exceed-
ing 30 °C. The yellowish oil was treated with hexane (50 mL) and
allowed to stand overnight. Within 1 d the following portions of
hexane were added with stirring to the partially crystallized product:
2 × 10 mL, 4 × 20 mL, and 1 × 50 mL. The soln was placed in a re-
frigerator overnight; the white precipitate was collected and washed
with cold pentane. The solid was dried under reduced pressure at r.t.
to constant weight to give the first crop. The mother liquor was
evaporated to dryness leaving yellowish oil, which was treated in
the same manner as described above, giving a second crop. The total
yield of pure white Boc-Ala-OH (1) (17.2 g, 91%); mp 82.7–83.0
°C (Lit.15 82.0–83.0 °C).
Table 4 Recyclability of the Catalyst Aa
OH
O
O
reused A
(10 mol%)
CHO
+
neat, 24 h, r.t.
O2N
O2N
(2S,1′R)-7a
Entry
Yieldb (%)
eec (%)
95
drd (anti/syn)
90:10
1
2
3
4
5
6
7
98
95
92
94
89
88
86
95
90:10
94
90:10
95
90:10
Boc-Ala-O–P (4)
To the vessel was added H2O (10 mL) and CsHCO3 (0.362 g, 2.0
mmol) and then MeOH (10 mL) and Boc-Ala-OH (1, 0.355 g, 1.88
mmol) was added. At this time, the pH decreased to 7.0 and CO2
was released. After evaporated, Boc-Ala-O–Cs+ (3) was obtained as
a dry powder. To the Boc-Ala-O–Cs+ (3), DMF (13 mL), Merrifield
resin (0.639 g, 1.599 mmol; loading: 2.5 mmol/g), and NMP (7 mL)
were added and the mixture was reacted at 55 °C for 19 h under N2.
After completion of the reaction, it was washed as follow: DMF
(3 × 5 mL), DMF–H2O (7:3, 3 × 5 mL), DMF (3 × 5 mL), DMF–
H2O (9:1, 3 × 5 mL), DMF–AcOH (10:1, 3 × 5 mL), DMF–H2O
(9:1, 3 × 5 mL), DMF (3 × 5 mL), CH2Cl2 (3 × 5 mL). Finally, it
94
90:10
95
90:10
94
90:10
a 4-Nitrobenzaldehyde (0.25 mmol), cyclohexanone (1.0 mL), cata-
lyst A (contains 0.025 mmol loading), r.t., stirred, 24 h.
b Isolated yields.
c Determined by HPLC using Chiralpak AD-H column.
d Determined by 1H NMR spectroscopy.
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J. Yan, L. Wang
PAPER
(2S)-2-[(R)-Hydroxy(2-nitrophenyl)methyl]cyclohexanone
was dried to constant weight and Boc-Ala-O–P (4) (0.952 g) was
obtained. The surface catalyst loading was readily determined by el-
emental analysis and was found to be 2.45 mmol/g.
[(2S,1¢R)-7c]
White powder;16 anti-diastereomer; 94% ee [HPLC (Daicel Chiral-
cel OD-H, i-PrOH–hexane, 10:90), UV 254 nm, flow rate 1.0 mL/
min): tR (major) = 31.5 min, tR (minor) = 36.7 min].
Ala-O–P (5)
The N-Boc protecting group was removed by treating Boc-Ala-O–
P (4, 1.30 g) with TFA–CH2Cl2 (1:1, 5 mL) for 2 h. Then the resin
was filtered, washed with CH2Cl2 (2 × 5 mL), Et3N–CH2Cl2 (1:1) (2
× 5 mL), and CH2Cl2 (2 × 5 mL), and dried in vacuo to give Ala-O–
P (5) (1.18 g). The surface catalyst loading was readily determined
by elemental analysis and was found to be 2.08 mmol/g.
IR (KBr): 3524, 3012, 1705, 1616, 1512, 1346, 767 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.46–1.75 (m, 6 H), 2.16–2.41 (m,
2 H), 2.62–2.68 (m, 1 H), 4.10 (s, 1 H), 5.44 (d, J = 7.2 Hz, 1 H),
7.42 (t, J = 8.1 Hz, 2 H), 7.71 (d, J = 8.1 Hz, 2 H).
(2S)-2-{(R)-Hydroxy[4-(trifluoromethyl)phenyl]methyl}cyclo-
hexanone [(2S,1¢R)-7d]
Boc-Pro-Ala-O–P (6)
White powder;16 anti-diastereomer; 86% ee [HPLC (Daicel Chiral-
pak AD-H, i-PrOH–hexane, 10:90, UV 254 nm, flow rate 1.0 mL/
min): tR (major) = 32.6 min, tR (minor) = 35.3 min].
To a reaction vessel with HATU (2.37 g, 6.24 mmol) and Ala-O–P
(5, 1.00 g, loading: 2.08 mmol/g of acid groups), DMF (0.3 mL) was
added to dissolve them for pre-activation. After shaking for 0.5 h,
DIPEA (805 mg, 6.24 mmol) and Boc-Pro-OH (1.52 g, 6.24 mmol)
in DMF (10 mL) was added. After shaking for 24 h, the resin was
collected by filtration, washed with DMF (2 × 5 mL), i-PrOH (2 ×
5 mL), and CH2Cl2 (2 × 5 mL), and dried in vacuo to give Boc-Pro-
Ala-O–P (6) (1.38 g). The loading was readily quantified by CHN
microanalysis and was found to be 1.79 mmol/g based on the per-
centage of nitrogen.
IR (KBr): 3513, 2935, 1698, 1453, 1312, 768 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.48–2.37 (m, 6 H), 2.45–2.55 (m,
1 H), 2.69–2.81 (m, 1 H), 4.03 (t, J = 3.0 Hz, 1 H), 5.30 (d, J = 9.3
Hz, 1 H), 7.40 (t, J = 7.2 Hz, 1 H), 7.55–7.74 (m, 3 H).
(2S)-2-[(R)-(4-Cyanophenyl)(hydroxy)methyl]cyclohexanone
[(2S,1¢R)-7e]
White powder;16 syn-diastereomer; 90% ee [HPLC (Daicel Chiral-
pak AD-H, i-PrOH–hexane, 10:90, UV 254 nm, flow rate 1.0 mL/
min): tR (major) = 39.8 min, tR (minor) = 31.5 min].
Pro-Ala-O–P (A)
The N-Boc protecting group was removed by treating Boc-Pro-Ala-
O–P (6) with the same procedure as above described. The loading
was readily quantified by CHN microanalysis and was found to be
1.71 mmol/g based on the percentage of nitrogen.
IR (KBr): 3425, 2943, 2860, 2225, 1689, 1608, 1447, 1133 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.64–2.20 (m, 6 H), 2.44–2.51 (m,
2 H), 2.53–2.59 (m, 1 H), 3.27 (d, J = 3.3 Hz, 1 H), 5.52 (s, 1 H),
7.52 (d, J = 8.4 Hz, 2 H), 7.72 (d, J = 8.1 Hz, 2 H).
Catalysts B–J
Catalysts B–J were easily prepared using the typical procedures for
A.
(2S)-2-[(R)-(2-Chloro-5-nitrophenyl)(hydroxy)methyl]cyclo-
hexanone [(2S,1¢R)-7f]
White powder; anti-diastereomer; 85% ee [HPLC (Daicel Chiralcel
OJ-H, i-PrOH–hexane, 10:90, UV 254 nm, flow rate 1.0 mL/min):
tR (major) = 14.5 min, tR (minor) = 16.7 min].
The Recyclability of the Catalyst
After carrying out the reaction, the mixture was vacuum filtered us-
ing a sintered glass funnel and washed with CH2Cl2 (3 mL), Et2O (3
mL), EtOH (3 mL), and hexane (3 mL). The catalyst was oven dried
and then it could be reused directly without further purification.
IR (KBr): 3426, 2949, 2867, 1698, 1577, 1526, 1346, 743 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.64–2.12 (m, 6 H), 2.37–2.52 (m,
2 H), 3.34 (d, J = 3.3 Hz, 1 H), 4.20 (d, J = 3.9 Hz, 1 H), 5.39 (d,
J = 7.2 Hz, 1 H), 7.49–7.53 (m, 1 H), 8.06–8.10 (m, 1 H), 8.44–8.48
(m, 1 H).
(2S)-2-[(R)-Hydroxy(4-nitrophenyl)methyl]cyclohexanone
[(2S,1¢R)-7a]; Typical Procedure
To the catalyst A (contains 0.025 mmol loading), 4-nitrobenzalde-
hyde (0.25 mmol), and cyclohexanone (1.0 mL) were added. The
mixture was stirred for 24 h (monitored by TLC). The reaction was
quenched with sat. NH4Cl soln (5 mL) and extracted with EtOAc
(3 × 5 mL). The combined organic layers were dried (Na2SO4) and
concentrated in vacuo. The crude product was purified by flash col-
umn chromatography to give pure aldol adduct 7a as a white pow-
der;16 anti-diastereomer; 95% ee [HPLC (Daicel Chiralpak AD-H,
i-PrOH–hexane, 10:90, UV 254 nm, flow rate 1.0 mL/min): tR (ma-
jor) = 32.6 min, tR (minor) = 25.3 min].
Anal. Calcd for C13H14ClNO4: C, 55.04; H, 4.97; N, 4.94. Found: C,
55.18; H, 5.05; N, 4.78.
(2S)-2-[(R)-(4-Chloro-3-nitrophenyl)(hydroxy)methyl]cyclo-
hexanone [(2S,1¢R)-7g]
White powder; anti-diastereomer; 80% ee [HPLC (Daicel Chiralcel
OJ-H, i-PrOH–hexane, 10:90, UV 254 nm, flow rate 1.0 mL/min):
tR (major) = 19.5 min, tR (minor) = 23.7 min].
IR (KBr): 3493, 3100, 2867, 1691, 1529, 1482, 1198, 833 cm–1.
IR (KBr): 3513, 2938, 1693, 1606, 1523, 1510, 1344 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.60–2.10 (m, 6 H), 2.31–2.61 (m,
3 H), 4.07 (d, J = 3.0 Hz, 1 H), 4.82–4.86 (m, 1 H), 7.46–7.54 (m, 2
H), 7.87 (s, 1 H).
1H NMR (300 MHz, CDCl3): d = 1.52–2.26 (m, 6 H), 2.46–2.52 (m,
2 H), 2.58–2.74 (m, 1 H), 4.17 (d, J = 2.7 Hz, 1 H), 5.01 (t, J = 8.1
Hz, 1 H), 7.61 (d, J = 8.1 Hz, 2 H), 8.31 (d, J = 8.4 Hz, 2 H).
Anal. Calcd for C13H14ClNO4: C, 55.04; H, 4.97; N, 4.94. Found: C,
55.24; H, 5.01; N, 4.86.
(2S)-2-[(R)-Hydroxy(3-nitrophenyl)methyl]cyclohexanone
[(2S,1¢R)-7b]
White powder;16 anti-diastereomer; 81% ee [HPLC (Daicel Chiral-
pak AD-H, i-PrOH–hexane, 10:90, UV 254 nm, flow rate 1.0 mL/
min): tR (major) = 35.3 min, tR (minor) = 37.8 min].
(2S)-2-[(R)-Hydroxy(1-naphthyl)methyl]cyclohexanone
[(2S,1¢R)-7h]
White powder;17 anti-diastereomer; 82% ee [HPLC (Daicel Chiral-
pak AD-H, i-PrOH–hexane, 20:80, UV 254 nm, flow rate 1.0 mL/
min): tR (major) = 39.5 min, tR (minor) = 23.8 min].
IR (KBr): 3513, 2938, 1692, 1606, 1510, 1345, 857 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.50–2.10 (m, 6 H), 2.34–2.49 (m,
2 H), 2.59–2.62 (m, 1 H), 4.05 (d, J = 3.0 Hz, 1 H), 4.88 (m, 1 H),
7.49 (d, J = 8.7 Hz, 2 H), 8.18 (d, J = 8.7 Hz, 2 H).
IR (KBr): 3525, 2943, 2861, 1692, 1597, 804 cm–1.
Synthesis 2008, No. 13, 2065–2072 © Thieme Stuttgart · New York

PAPER
Merrifield Resin Supported Dipeptides
2071
1H NMR (300 MHz, CDCl3): d = 1.22–1.39 (m, 6 H), 1.64–2.02 (m,
3 H), 4.15 (d, J = 3.3 Hz, 1 H), 5.56 (m, 1 H), 7.42–7.56 (m, 4 H),
7.77–7.86 (m, 2 H), 8.25 (t, J = 9.0 Hz, 1 H).
Acknowledgement
We gratefully acknowledge financial support by the National Natu-
ral Science Foundation of China (No. 20772043, 20572031), and
the Key Project of Science and Technology, Department of Educa-
tion, Anhui, China (No. ZD2007005–1).
(2S)-2-[(R)-Hydroxy(2-naphthyl)methyl]cyclohexanone
[(2S,1¢R)-7i]
White powder;18 anti-diastereomer; 76% ee [HPLC (Daicel Chiral-
pak AS-H, i-PrOH–hexane, 10:90, UV 254 nm, flow rate 1.0 mL/
min): tR (major) = 36.5 min, tR (minor) = 43.9 min].
References
IR (KBr): 3426, 2908, 1702, 1693, 1679, 833 cm–1.
(1) (a) Mukaiyama, T. Tetrahedron 1999, 55, 8609.
(b) Nicolaou, K. C.; Vourloumis, D.; Wissinger, N.; Baran,
P. S. Angew. Chem. Int. Ed. 2000, 39, 44. (c) Evans, D. A.;
Ratz, A. M.; Huff, B. E.; Sheppard, G. S. J. Am. Chem. Soc.
1995, 117, 3448. (d) Narasaka, K.; Pai, F.-C. Tetrahedron
1984, 40, 2233. (e) Keck, G. E.; Wager, C. A.; Sell, T.;
Wager, T. T. J. Org. Chem. 1999, 64, 2172.
(2) (a) Scheidt, K. A.; Bannister, T. D.; Tasaka, A.; Wendt, M.
D.; Savall, B. M.; Fegley, G. J.; Roush, W. R. J. Am. Chem.
Soc. 2002, 124, 6981. (b) White, J. D.; Blakemore, P. R.;
Green, N. J.; Hauser, E. B.; Holoboski, M. A.; Keown, L. E.;
Kolz, C. S. N.; Phillips, B. W. J. Org. Chem. 2002, 67,
7750. (c) Gerber-Lemaire, S.; Vogel, P. Eur. J. Org. Chem.
2003, 2959.
1H NMR (300 MHz, CDCl3): d = 1.36–1.80 (m, 5 H), 2.10–2.65 (m,
4 H), 4.19 (s, 1 H), 5.07 (d, J = 8.7 Hz, 1 H), 7.60 (d, J = 7.2 Hz, 3
H), 7.87 (s, 1 H), 7.94–7.97 (m, 3 H).
(3S,4R)-3,4-Dihydroxy-4-(4-nitrophenyl)butan-2-one [(3S,4R)-
7j]
White powder;19 syn-diastereomer; 80% ee [HPLC (Daicel Chiral-
cel OD-H, i-PrOH–hexane, 10:90, UV 254 nm, flow rate 1.0 mL/
min): tR (major) = 31.5 min, tR (minor) = 36.7 min].
IR (KBr): 3411, 1705, 1606, 1515, 1348, 1097 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.34 (s, 3 H), 3.67–3.73 (m, 1 H),
4.39–4.45 (m, 1 H), 5.07–5.21 (m, 1 H), 7.59 (d, J = 9.0 Hz, 2 H),
8.22 (d, J = 8.4 Hz, 2 H).
(3) (a) Comprehensive Organic Synthesis, Vol. 2; Trost, B. M.;
Fleming, I., Eds.; Pergamon: Oxford, 1991. (b) Mahrwald,
R. Modern Aldol Reactions, Vols. 1 and 2; Wiley-VCH:
Weinheim, 2004.
(2S)-3-[(R)-Hydroxy(4-nitrophenyl)]methyl]tetrahydrothio-
pyran-4-one [(2S,1¢R)-7k]
(4) For pioneering work using proline as a catalyst, see:
(a) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39,
1615. (b) Eder, U.; Sauer, R.; Wiechert, R. Angew. Chem.,
Int. Ed. Engl. 1971, 10, 496. (c) List, B.; Lerner, R. A.;
Barbas, C. F. III J. Am. Chem. Soc. 2000, 122, 2395.
(d) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F. III J. Am.
Chem. Soc. 2001, 123, 5260. (e) Notz, W.; List, B. J. Am.
Chem. Soc. 2000, 122, 7386. For reviews on direct aldol
reactions catalyzed by secondary amine-based organic
molecules, see: (f) List, B. Acc. Chem. Res. 2004, 37, 548.
(g) Notz, W.; Tanaka, F.; Barbas, C. F. III Acc. Chem. Res.
2004, 37, 580. (h) Saito, S.; Yamamoto, H. Acc. Chem. Res.
2004, 37, 570. (i) List, B. Chem. Commun. 2006, 819.
(5) (a) Benaglia, M.; Cinquini, M.; Cozzi, F.; Puglisi, A.;
Celentano, G. Adv. Synth. Catal. 2002, 344, 533. (b) Shen,
Z.-X.; Chen, W.-H.; Jiang, H.; Ding, Y.; Luo, X.-Q.; Zhang,
Y.-W. Chirality 2005, 17, 119. (c) Gruttadauria, M.; Riela,
S.; Aprile, C.; Meo, P. L.; D’Anna, F.; Noto, R. Adv. Synth.
Catal. 2006, 348, 82. (d) Bellis, E.; Kokotos, G.
White powder;8a anti-diastereomer; 92% ee [HPLC (Daicel Chiral-
pak AD-H, i-PrOH–hexane, 10:90, UV 254 nm, flow rate 1.0 mL/
min): tR (major) = 63.0 min, tR (minor) = 43.5 min].
IR (KBr): 3425, 2943, 2860, 2225, 1689, 1608, 1447, 1133 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.57–2.10 (m, 4 H), 2.30–2.67 (m,
3 H), 4.10 (d, J = 3.0 Hz, 1 H), 4.90 (m, 1 H), 7.60 (m, 2 H), 8.18 (t,
J = 9.3 Hz, 2 H).
(2R)-2-[(R)-Hydroxy(4-nitrophenyl)methyl]cyclopentanone
[(2R,1¢R)-7l]
White powder;16 syn-diastereomer; 75% ee [HPLC (Daicel Chiral-
pak AS-H, i-PrOH–hexane, 10:90, UV 254 nm, flow rate 1.0 mL/
min): tR (major) = 31.3 min, tR (minor) = 25.8 min].
IR (KBr): 3447, 2952, 1729, 1605, 1515, 1347, 1104 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.60–2.05 (m, 4 H), 2.35–2.75 (m,
2 H), 2.73 (d, J = 3.6 Hz, 1 H), 5.42 (d, J = 3.6 Hz, 1 H), 4.84 (d,
J = 4.6 Hz, 1 H), 7.53 (d, J = 8.7 Hz, 2 H), 8.20 (d, J = 8.4 Hz, 2 H).
Tetrahedron 2005, 61, 8669.
(4R)-4-Hydroxy-4-(4-nitrophenyl)butan-2-one [(4R)-7m]
White powder;16 82% ee [HPLC (Daicel Chiralpak AS-H, i-PrOH–
hexane, 30:70, UV 254 nm, flow rate 1.0 mL/min): R-isomer,
tR (major) = 13.6 min, S-isomer, tR (minor) = 17.0 min].
(6) (a) Berkessel, A.; Koch, B.; Lex, J. Adv. Synth. Catal. 2004,
346, 1141. (b) Hartikka, A.; Arvidsson, P. I. Tetrahedron:
Asymmetry 2004, 15, 1831. (c) Torii, H.; Nakadai, M.;
Ishihara, K.; Saito, S.; Yamamoto, H. Angew. Chem. Int. Ed.
2004, 43, 1983. (d) Nakadai, M.; Saito, S.; Yamamoto, H.
Tetrahedron 2002, 58, 8167. (e) Kano, T.; Takai, J.;
Tokuda, O.; Maruoka, K. Angew. Chem. Int. Ed. 2005, 44,
3055. (f) Kano, T.; Tokuda, O.; Maruoka, K. Tetrahedron
Lett. 2006, 47, 7423. (g) Mitsumori, S.; Zhang, H.; Cheong,
P. H.-Y.; Houk, K. N.; Tanaka, F.; Barbas, C. F. III J. Am.
Chem. Soc. 2006, 128, 1040.
(7) (a) Tang, Z.; Jiang, F.; Cui, X.; Gong, L.-Z.; Mi, A.-Q.;
Jiang, Y.-Z.; Wu, Y.-D. Proc. Natl. Acad. Sci. U.S.A. 2004,
101, 5755. (b) Tang, Z.; Yang, Z.-H.; Chen, X.-H.; Cun, L.-
F.; Mi, A.-Q.; Jiang, Y.-Z.; Gong, L.-Z. J. Am. Chem. Soc.
2005, 127, 9285.
IR (KBr): 3452, 2907, 1713, 1599, 1520, 1341, 1106 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.22 (s, 3 H), 2.86 (t, J = 7.2 Hz,
2 H), 3.62 (d, J = 3.3 Hz, 1 H), 5.25 (s, 1 H), 7.55 (d, J = 8.7 Hz, 2
H), 8.20 (d, J = 8.7 Hz, 2 H).
(2S)-2-[(R)-Hydroxy(phenyl)methyl]cyclohexanone [(2S,1¢R)-
7n]
White powder;8a anti-diastereomer; 80% ee [HPLC (Daicel Chiral-
cel OD-H, i-PrOH–hexane, 10:90, UV 254 nm, flow rate 1.0 mL/
min): tR (major) = 21.5 min, tR (minor) = 26.7 min].
IR (KBr): 3524, 3012, 1705, 1616, 1512, 1346, 767 cm–1.
(8) (a) Chen, J.-R.; Lu, H.-H.; Li, X.-Y.; Chen, L.; Wan, J.;
Xiao, W.-J. Org. Lett. 2005, 7, 4543. (b) Chimni, S. S.;
Mahajan, D.; Suresh, B. V. V. Tetrahedron Lett. 2005, 46,
5617. (c) Gryko, D.; Lipinski, R. Adv. Synth. Catal. 2005,
1H NMR (300 MHz, CDCl3): d = 1.29–2.00 (m, 6 H), 2.35–2.64 (m,
3 H), 4.88 (d, J = 6.0 Hz, 1 H), 7.31–7.42 (m, 5 H).
Synthesis 2008, No. 13, 2065–2072 © Thieme Stuttgart · New York

2072
J. Yan, L. Wang
PAPER
347, 1948. (d) Córdova, A.; Zou, W.-B.; Ibrahem, I.; Reyes,
E.; Engqvist, M.; Liao, W.-W. Chem. Commun. 2005, 3586.
(e) Samanta, S.; Liu, J.-Y.; Dodda, R.; Zhao, C.-G. Org. Lett.
2005, 7, 5321. (f) Cheng, C.-L.; Sun, J.; Wang, C.; Zhang,
Y.; Wei, S.-Y.; Jiang, F.; Wu, Y.-D. Chem. Commun. 2006,
215.
(11) (a) Benaglia, M.; Celentano, G.; Cozzi, F. Adv. Synth. Catal.
2001, 343, 171. (b) Calderon, F.; Fernandez, R.; Sanchez,
F.; Fernandez-Mayoralas, A. Adv. Synth. Catal. 2005, 347,
1395. (c) Miao, W.-S.; Chan, T. H. Adv. Synth. Catal. 2006,
348, 1711. (d) Zhou, L.; Wang, L. Chem. Lett. 2007, 36,
628.
(9) (a) Kofoed, J.; Nielsen, J.; Reymond, J. L. Bioorg. Med.
Chem. Lett. 2003, 13, 2445. (b) Tang, Z.; Jiang, F.; Yu, L.-
T.; Cui, X.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z.; Wu, Y.-D.
J. Am. Chem. Soc. 2003, 125, 5262. (c) Tang, Z.; Yang, Z.-
H.; Cun, L.-F.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z. Org.
Lett. 2004, 6, 2285. (d) Luppi, G.; Cozzi, G.; Monari, M.;
Kaptein, B.; Broxterman, Q. B.; Tomasin, C. J. Org. Chem.
2005, 70, 7418. (e) Krattiger, P.; Kovasy, R.; Revell, J. D.;
Ivan, S.; Wennermers, H. Org. Lett. 2005, 7, 1101.
(f) Revell, J. D.; Gantenbein, D.; Krattigei, P.; Wennermers,
H. Biopolymer 2006, 84, 105. (g) Zou, W.-B.; Ibrahem, I.;
Dziedzic, P.; Sunden, H.; Córdova, A. Chem. Commun.
2005, 4946. (h) Córdova, A.; Zou, W.-B.; Dziedzic, P.;
Ibrahem, I.; Reyes, E.; Xu, Y. Chem. Eur. J. 2006, 12, 5383.
(i) Dziedzic, P.; Zou, W.-B.; Hafren, J.; Córdova, A. Org.
Biomol. Chem. 2006, 4, 38. (j) Tsogoeva, S. B.; Wei, S. W.
Tetrahedron: Asymmetry 2005, 16, 1947. (k) Tsogoeva,
S. B.; Jagtap, S. B.; Ardemasova, Z. A. Tetrahedron:
Asymmetry 2006, 17, 989.
(12) Akagawa, K.; Sakamoto, S.; Kudo, K. Tetrahedron Lett.
2005, 46, 8185.
(13) (a) Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.;
Tanaka, F.; Barbas, C. F. III J. Am. Chem. Soc. 2006, 128,
734. (b) Luo, S.-Z.; Xu, H.; Li, J.-Y.; Zhang, L.; Cheng, J.-
P. J. Am. Chem. Soc. 2007, 129, 3074. (c) Chen, J.-R.; Li,
X.-Y.; Xing, X.-N.; Xiao, W.-J. J. Org. Chem. 2006, 71,
8198.
(14) (a) Brogan, A. P.; Dickerson, T. J.; Janda, K. D. Angew.
Chem. Int. Ed. 2006, 45, 8100. (b) Hayashi, Y. Angew.
Chem. Int. Ed. 2006, 45, 8103. (c) Blackmond, D. G.;
Armstrong, A.; Coombe, V.; Wells, A. Angew. Chem. Int.
Ed. 2007, 46, 3798.
(15) Oskar, K.; Walter, E. K.; Gert, L.; Gernot, W.; Thomas, G.;
Mark, A. S.; Clayton, H. H. Org. Synth. Coll. Vol. VII; John
Wiley & Sons: London, 1990, 70.
(16) Lei, M.; Shi, L.-X.; Li, G.; Chen, S.-L.; Fang, W.-H.; Ge, Z.-
M.; Cheng, T.-M.; Li, R.-T. Tetrahedron 2007, 63, 7892.
(17) Carrea, G.; Ottolina, G.; Lazcano, A.; Pironti, V.; Colonna,
S. Tetrahedron: Asymmetry 2007, 18, 1265.
(10) Andreae, M. R. M.; Davis, A. P. Tetrahedron: Asymmetry
2005, 16, 2487.
(18) Gruttadauria, M.; Giacalone, F.; Mossuto Marculescu, A.;
Lo Meo, P.; Riela, S.; Noto, R. Eur. J. Org. Chem. 2007, 28,
4688.
(19) Gu, Q.; Wang, X.-F.; Wang, L.; Wu, X.-Y.; Zhou, Q.-L.
Tetrahedron: Asymmetry 2006, 17, 1537.
Synthesis 2008, No. 13, 2065–2072 © Thieme Stuttgart · New York