Dehydrative cyclization of serine, threonine, and cysteine residues catalyzed by molybdenum(VI) oxo compounds

Article abstract of DOI:10.1016/j.tet.2008.12.074

Commercially available molybdenum(VI) oxides such as (NH₄)₂MoO₄, (NH₄)₆Mo₇O₂₄·4H₂O, MoO₂(acac)₂, and MoO₂(TMHD)₂ are highly

Full text of DOI:10.1016/j.tet.2008.12.074

Tetrahedron 65 (2009) 2102–2109
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Dehydrative cyclization of serine, threonine, and cysteine residues catalyzed by
molybdenum(VI) oxo compounds
,
Akira Sakakura a, Rei Kondo b, Shuhei Umemura b, Kazuaki Ishihara b
*
a EcoTopia Science Institute, Nagoya University, Chikusa, Nagoya 464-8603, Japan
b Graduate School of Engineering, Nagoya University, Chikusa, Nagoya 464-8603, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Commercially available molybdenum(VI) oxides such as (NH4)2MoO4, (NH4)6Mo7O24$4H2O, MoO2(acac)2,
Received 3 December 2008
Received in revised form 24 December 2008
Accepted 24 December 2008
Available online 31 December 2008
and MoO2(TMHD)2 are highly effective dehydrative cyclization catalysts for the synthesis of a variety of
oxazolines. The reaction proceeds with a complete retention of configuration at the b-position. For the
dehydrative cyclization of cysteine derivatives, bis(2-ethyl-8-quinolinolato)dioxomolybdenum(VI) shows
remarkable catalytic activity and gives thiazolines without a significant loss of stereochemical integrity at
the C2-exomethine positions.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
thiazolines, biomimetic retentive cyclization is more desirable.
However, most reactions that use stoichiometric dehydrating re-
Oxazolines, oxazoles, thiazolines, and thiazoles are important
constituents of numerous bioactive natural products of peptide
origin.1 Their wide range of antitumor, antiviral, and antibiotic ac-
tivities has fueled numerous synthetic investigations. The bio-
synthesis of many naturally occurring oxazolines and thiazolines
appears to involve the dehydrative cyclization of serine, threonine,
and cysteine residues (Scheme 1).1c Oxazoles and thiazoles are
synthesized by the oxidation of oxazolines and thiazolines,
respectively.
agents proceed with an inversion of configuration at the
Therefore the conventional synthesis using stoichiometric dehy-
drating reagents requires expensive -allo-threonine for the syn-
thesis of
-threonine-derived oxazolines.10,11 In addition, for the
b-position.
L
L
synthesis of thiazolines, the use of N-(b-hydroxyethyl)thioamides is
required.2a,d,f
HX
Me
Me
CO2Me
retention
biomimetic
O
X
X
+
+
H2O
ð1Þ
ð2Þ
Although several methods have been reported for the synthesis
of oxazolines and thiazolines using stoichiometric dehydrating
reagents,2 few dehydrating catalysts are known to be effective for
R
R
N
CO2Me
R
R
cyclization
N
N
H
the dehydrative cyclization of N-(
mercaptoethyl)amides to oxazolines or thiazolines: 3-nitro-
phenylboric acid,3 tetranuclear zinc cluster,4
lanthanide
b-hydroxyethyl)amides or N-(b-
HO
Me
Me
CO2Me
inversion
dehydrating
X
a
a
H2O
chloride,5 a zeolite,6 TiCl4,7 TsOH,8 etc. However, these catalytic
methods are limited to simple substrates derived from an amino
alcohol or a monopeptide (amino acid). Since oxazolines and
thiazolines readily epimerize at the C2-exomethine position under
both acidic and basic conditions,7a,9 the synthesis of oxazolines and
thiazolines must be conducted under mild and weakly acidic or
basic conditions.
N
CO2Me
reagents
H
(X = O, S)
For the synthesis of oxazoline- and/or thiazoline-containing
bioactive natural compounds, a more effective catalytic method for
the dehydrative cyclization of serine, threonine, and cysteine resi-
There are two known methodologies for the chemical synthesis
dues that proceeds with a retention of configuration at the b-po-
of oxazolines and thiazolines: retentive cyclization at the
(biomimetic cyclization) (Eq. 1), and its invertive cyclization (Eq. 2).
For the chemical synthesis of naturally occurring oxazolines and
b
-position
sition is needed. In this report, we describe a detailed investigation
of molybdenum(VI) oxo compounds as highly effective catalysts for
the dehydrative cyclization of serine, threonine, and cysteine resi-
dues.12,13 To the best of our knowledge, this is the first successful
example of the catalytic dehydrative cyclization of dipeptide sub-
strates for the biomimetic synthesis of oxazolines and thiazolines.
The present method is highly useful for the synthesis of common
* Corresponding author. Tel.: þ81 52 789 3331; fax: þ81 52 789 3222.
E-mail address: ishihara@cc.nagoya-u.ac.jp (K. Ishihara).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.12.074

A. Sakakura et al. / Tetrahedron 65 (2009) 2102–2109
2103
Table 2
Base
BaseH
Catalytic activities of molybdenum oxo compounds for the dehydrative cyclization
H
X
BaseH
HO
of 1a
R'
R'
O
HO
R
O
X
H
N
H
N
O
catalyst (10 mol %)
toluene
azeotropic reflux
N
H
N
H
Ph
N
H
CO2Me
R
R
O
1a: R = H
Base
R
1b: R = Me
O
R'
R'
R
O
X
X
[O]
Ph
+
–H2O
N
H
N
H
O
N
O
R
N
N
O
Ph
CO2Me
N
R
O
R
O
Ph
N
H
CO2Me
X = O: oxazolines
X = S: thiazolines
X = O: oxazoles
X = S: thiazoles
2a: R = H
2b: R = Me
3a: R = H
3b: R = Me
Scheme 1. Proposed biosynthesis of oxazolines, thiazolines, oxazoles, and thiazoles.
building blocks for various bioactive natural products14,15 and chiral
oxazoline ligands for asymmetric synthesis.16
Entry
Catalyst
1a/2a
1b/2b
Time (h)
Yieldb,c (%)
Time (h)
Yieldb,c (%)
1
2
3
4
5
6
7
8
9
MoO2
MoO3
(NH4)6Mo7O24$4H2O
(NH4)2MoO4
MoO2(acac)2
CoMoO4
FeMoO4
3-(NO2)C6H4B(OH)2
No catalyst
8
8
4
4
1
86 (10)
78 (5)
87 (11)
89 (11)
87 (7)
d
8
8
2
2
1
4
4
8
8
97 (0)
99 (0)
97 (0)
95 (0)
90 (0)
96 (0)
96 (0)
4 (0)
2. Results and discussion
2.1. Catalytic dehydrative cyclization of serine and threonine
derivatives
d
8
8
3 (0)
0 (0)
0 (0)
Our initial studies focused on the catalytic activities of various
metal compounds (10 mol %) for the dehydrative cyclization of N-
a
The reaction of
1 (0.5 mmol) was conducted in the presence of catalyst
(10 mol %) in toluene (50 mL for 1a and 10 mL for 1b) under azeotropic reflux with
(3-phenylpropionyl)-L-serine methyl ester (1a) in toluene under
the removal of water.
reflux conditions for 2 h (Table 1). Commercially available molyb-
denum oxides such as (NH4)6Mo7O24$4H2O, MoO2, and MoO3
showed high catalytic activities (51–68% yield, entries 1–3). Per-
rhenic acid (HOReO3) and trimethylsilylperrhenate (TMSOReO3)
also gave good results (49% yields, entries 6 and 7). In contrast, the
catalytic activities of other metal compounds such as Na2MoO4 and
ReO2 were very low (entries 4, 5, 8–14). When the MoO3-catalyzed
dehydrative cyclization was conducted in polar solvents such as
nitroethane, propionitrile, and 1,4-dioxane, the yields of 2a signif-
icantly decreased (<3% yields).
b
Determined by HPLC analysis.
Yield of 3a or 3b in parentheses.
c
The reaction was conducted in toluene under azeotropic reflux
conditions with the removal of water. As a result, the ammonium
salts and acetylacetonate complex of molybdenum(VI) oxide such
as (NH4)6Mo7O24$4H2O, (NH4)2MoO4, and MoO2(acac)2 were found
to have good catalytic activities (entries 3–5). The reaction of 1a
was conducted under high-dilution conditions (0.01 M), since
a small amount of dimer 3a was obtained as a byproduct. When the
reaction of 1a was carried out using (NH4)2MoO4 at a higher con-
centration (0.05 M), the yield of 3a increased to 27% and the yield of
2a decreased to 53%. In contrast, the reaction of 1b did not produce
dimer 3b even at a higher concentration (0.05 M). Interestingly, the
Next, we examined the catalytic activities of commercially
available molybdenum oxides for the dehydrative cyclization of 1a
and N-(3-phenylpropionyl)-L-threonine methyl ester (1b) (Table 2).
Table 1
Initial screening for catalytic activities of metal compounds for the dehydrative
cyclization of 1aa,b
reaction of 1b proceeded with a retention of configuration at the b-
HO
catalyst
position of the threonine residue (biomimetic mechanism).
CoMoO4 and FeMoO4 also effectively promoted the reaction of 1b,
but the catalytic activities were slightly lower than those of
(NH4)6Mo7O24$4H2O, (NH4)2MoO4 and MoO2(acac)2 (entries 6 and
7). 3-Nitrophenylboronic acid [3-(NO2)C6H4B(OH)2]3 was almost
inert for the present reaction (entry 8).
O
O
(10 mol %)
toluene
Ph
CO2Me
Ph
N
H
CO2Me
N
reflux, 2 h
1a
2a
Entry
Catalyst
Yieldc (%)
1
2
3
4
5
6
7
8
(NH4)6Mo7O24$4H2O
MoO2
MoO3
MoO2Cl2
Na2MoO4
HOReO3
TMSOReO3
ReO2
68
53
51
30
13
49
49
0
We then examined the dehydrative cyclization of more complex
dipeptide substrates Cbz-L-Ala-L-Ser-OMe (4a) and Cbz-L-Ala-L-Thr-
OMe (4b) (Table 3). The ammonium salts of molybdenum(VI) ox-
ides, (NH4)6Mo7O24$4H2O and (NH4)2MoO4, showed excellent
catalytic activities, and gave the corresponding oxazolines 5a and
5b in a short reaction time, along with small amounts of 6a and 6b,
which are epimers at the C2-exomethine position of the alanine
residue (entries 3 and 4). In contrast to molybdenum(VI) oxides, the
dehydrative cyclization of 4b catalyzed by TsOH8 gave a 1:1 mixture
of 5b and 6b, probably due to the strong acidity of TsOH.
Hennoxazole A (Fig. 1), which displays potency against herpes
simplex virus type 1 and peripheral analgesic activity comparable
to that of indomethacin, has a bisoxazole structure, in which two
oxazole rings are directly connected.17 We synthesized a key syn-
thetic intermediate 14 of hennoxazole A,18 which includes the
9
V2O4
VCl3
WO3
TiCl4
TiO2
SnO2
14
4
0
22
0
0
10
11
12
13
14
a
The reaction of 1a (0.05 mmol) was conducted in the presence of catalyst
(10 mol %) in toluene (2.5 mL) under reflux conditions for 2 h.
b
The amounts of catalysts were calculated based on the metal.
Estimated by HPLC analysis.
c

2104
A. Sakakura et al. / Tetrahedron 65 (2009) 2102–2109
HO
Table 3
HO
MoO2(acac)2
(20 mol %)
Synthesis of oxazolines 5a
O
O
H
H
N
N
HO
R
toluene, 2 h
Cbz
N
H
N
H
CO2Me
O
H
azeotropic reflux
catalyst (10 mol %)
O
N
15
toluene
Cbz
N
H
CO2Me
azeotropic reflux
4a: R = H
O
O
H
H
4b: R = Me
N
N
Cbz
CO2Me
N
N
R
R
O
O
O
16 (95%)
H
N
H
+
N
Cbz
CO2Me
Cbz
CO2Me
Scheme 3. Dehydrative cyclization of tetrapeptide 15.
N
N
5a: R = H
5b: R = Me
6a: R = H
6b: R = Me
elimination product 9 as a major product (47%) and the desired
product 8 was not obtained.19 It is conceivable that the dehydrative
double-cyclization of N-serylserine derivatives was very difficult. In
fact, the reaction of 7 conducted with Burgess reagent (2.4 equiv)
also gave 9 as a major product. In contrast, the dehydrative double-
cyclization of tetrapeptide 15, in which two threonine residues
were separated by a alanine residue, proceeded rapidly to give the
corresponding bis(oxazoline) 16 in 95% yield, although 16 was
obtained as a diastereomeric mixture (Scheme 3).20
Entry
Catalyst
4a/5a
4b/5b
Time (h)
Yieldb,c (%)
Time (h)
Yieldb,c (%)
1
2
3
4
5
MoO2
MoO3
(NH4)6Mo7O24$4H2O
(NH4)2MoO4
8
8
2.5
1
1
80 (4)
83 (2)
90 (0)
93 (0)
68 (0)
2.5
3
2
1.5
1
80 (5)
82 (6)
86 (5)
84 (8)
82 (11)
MoO2(acac)2
a
The reaction of
4 (0.5 mmol) was conducted in the presence of catalyst
(10 mol %) in toluene (50 mL for 4a and 10 mL for 4b) under azeotropic reflux with
We next tried to construct two oxazole rings in a stepwise
manner. Dehydrative cyclization of 10 using (NH4)2MoO4 (10 mol %)
gave oxazoline 11 in 81% yield. Oxidation of oxazoline 11 to oxa-
the removal of water.
b
Determined by HPLC analysis.
Yield of 6a or 6b in parentheses.
c
zole,15a hydrolysis of methyl ester, and condensation with
L-serine
ethyl ester gave 12 in 59% overall yield. Since 12 was less reactive in
the Mo(VI)]O-catalyzed dehydrative cyclization, the reaction of 12
was conducted in chlorobenzene (bp 132 ꢀC) and gave oxazoline 13
(75%) along with recovered 12 (8%). Oxidation of the oxazoline
ring15a and reduction of the ethyl ester of 13 gave 14 in 58% yield.
Bis(oxazoline)s are a very useful class of chiral ligands for
asymmetric catalysis21 and are generally synthesized from the
corresponding bis(amide)s via sulfonylation or chlorination of the
two hydroxyl groups. Bis(oxazoline)s 18 could be easily synthesized
bis(oxazole) structure, using the present Mo(VI)]O-catalyzed
dehydrative cyclization as a key step (Scheme 2). We first tried to
construct the bis(oxazoline) structure via the dehydrative double-
cyclization of dipeptide 7. Unfortunately, however, the MoO2(a-
cac)2-catalyzed dehydrative cyclization of 7 gave the dehydrative
OH
OMe
(NH4)2MoO4
(2–20 mol%)
toluene, 3 h
azeotropic
reflux
O
O
O
O
O
N
HO
R'
OH
R'
R'
R'
O
MeO
H
NH HN
N
N
N
O
R
R
R
R
18a: R = i-Pr, R' = H
17a: R = i-Pr, R' = H
17b: R = Ph, R' = H
18b: R = Ph, R' = H
18c: R = CO2Me, R' = Me
Figure 1. Hennoxazole A.
17c: R = CO2Me, R' = Me
Scheme 4. Synthesis of bis(oxazoline)s 18, chiral ligands for asymmetric catalysis.
HO
O
O
O
H
N
MoO2(acac)2 (20 mol %)
N
N
CO2Me
TBDPSO
CO2Me
+
TBDPSO
CO2Me
TBDPSO
N
H
N
H
N
toluene (0.01 M)
3
3
3
azeotropic reflux, 7.5 h
O
O
O
HO
7
8 (0%)
9 (47%)
1. BrCCl3, DBU, CH2Cl2
2. LiOH, THF–MeOH–H2O (10:1:1)
HO
O
O
(NH4)2MoO4 (10 mol %)
TBDPSO
TBDPSO
TBDPSO
CO2Me
toluene (0.01 M)
3. H-L-Ser-OEt•HCl, DPPA, Et3N, DMF
(59%, 3 steps)
N
N
H
CO2Me
3
3
azeotropic reflux, 3 h
10
11
(81%)
1. BrCCl3
O
(NH4)2MoO4
(10 mol %)
DBU
O
O
H
N
CH2Cl2
CO2Et
N
N
TBDPSO
CO2Et
TBDPSO
CHO
N
3
N
N
chlorobenzene
3
3
2. DIBAL
CH2Cl2
O
azeotropic reflux, 20 h
(75%)
O
O
HO
12
13
14
(58%, 2 steps)
Scheme 2. Synthesis of 14, a key synthetic intermediate of hennoxazole A.

A. Sakakura et al. / Tetrahedron 65 (2009) 2102–2109
2105
Table 4
HO
(NH4)2MoO4
(10 mol %)
toluene (0.1 M)
azeotropic reflux
4 h
Synthesis of oxazolines 20aa
MeO
O
MeO
O
HO
CO2Me
N
H
CO2Me
N
HO
HO
O
O
Mo(VI)=O cat.
additive
21
22 (75%)
N
H
CO2Me
CO2Me
N
toluene
azeotropic reflux
Scheme 5. Dehydrative cyclization of N-(o-methoxybenzoyl)-L-threonine methyl
ester 21.
19a
20a
Entry
Mo(VI)]O cat.
Additive, mol %
Yieldb (%)
bis(trifluoromethyl)benzoic acid [3,5-(CF3)2C6H3CO2H], and 4-
nitrobenzoic acid [4-(NO2)C6H4CO2H] gave good results (entries 5,
8–11). The optimal amount of C6F5CO2H was 1 mol equiv per
molybdenum(VI) oxide (entries 5–7). Since these benzoic acids
themselves showed no catalytic activities (entries 13 and 14), they
primarily promoted the activities of molybdenum(VI) oxides. These
benzoic acids might promote decomposition of the stable and
inactivated complexes of molybdenum(VI) oxide and 20a to re-
generate the active catalyst. The experimental finding that the iso-
lated yield of 20a was decreased without an aqueous work-up also
supported the formation of a stable complex of molybdenum(VI)
oxides with 20a.
1
2
3
4
5
6
7
8
(NH4)2MoO4
MoO2(acac)2
(NH4)2MoO4
(NH4)2MoO4
(NH4)2MoO4
(NH4)2MoO4
(NH4)2MoO4
(NH4)2MoO4
(NH4)2MoO4
MoO2(acac)2
MoO2(acac)2
d
d
17
5
d
TsOH, 10
C6H5CO2H, 10
C6F5CO2H, 10
C6F5CO2H, 2
C6F5CO2H, 20
3,5-(CF3)2C6H3CO2H, 10
4-(NO2)C6H4CO2H, 10
C6F5CO2H, 10
19
57
76
47
76
76
67
76
79
19
1
9
10
11
12
13
14
3,5-(CF3)2C6H3CO2H, 10
TsOH, 10
C6F5CO2H, 10
d
d
3,5-(CF3)2C6H3CO2H, 10
0
a
In contrast to the dehydrative cyclization of 19a, the reaction of
m- and p-hydroxy derivatives 19b and 19c proceeded smoothly
even in the absence of C6F5CO2H to give 20b and 20c in respective
yields of 91 and 87% (Table 5, entries 2 and 3). The reaction was
conducted in toluene–DMF (9:1, v/v), since 19b and 19c did not
dissolve in toluene. Since 20a was obtained in only 18% yield when
the reaction of 19a catalyzed by (NH4)2MoO4 and C6F5CO2H was
conducted in toluene–DMF (9:1, v/v) (entry 1), DMF did not pro-
mote the reaction of 19b and 19c. The dehydrative cyclization of
19d and 19e, bearing m-alkyl substituents, showed very low re-
activity even in the presence of C6F5CO2H (59 and 3%, entries 4 and
5). These poor results might be attributed to the greater stabilities
of complexes of molybdenum(VI) oxide with 20d and 20e.
Next, we investigated the dehydrative cyclization of N-(o,m-
The reaction of 19a (1 mmol) was conducted with Mo(VI)]O (10 mol %) in tol-
uene (10 mL) under azeotropic reflux conditions for 10–12 h.
b
Determined by 1H NMR analysis.
by the molybdenum(VI) oxide-catalyzed dehydrative double-cy-
clization of bis(amide)s 17 (Scheme 4). Bis(amide)s 17a and 17b
were reacted with (NH4)2MoO4 (20 mol %) under azeotropic reflux
with the removal of water for 3 h. After purification by silica gel
chromatography, bis(oxazoline)s 18a and 18b were obtained in
respective yields of 84 and 83%. Furthermore, bis(oxazoline) 18c
was synthesized in the presence of (NH4)2MoO4 (2 mol %) in 69%
yield with a retention of configuration at the
b-position.
dihydroxybenzoyl)-L
-threonine methyl ester (23a) (Table 6).12d
2.2. Dehydrative cyclization of N-(o-hydroxybenzoyl)-
L-
threonine derivatives and N-(o,m-dihydroxybenzoyl)-L-
However, the combination of (NH4)2MoO4 and C6F5CO2H did not
threonine derivatives
work for the reaction of 23a (entries 1 and 2). These poor results
Among oxazoline-containing natural compounds, 2-(o-hydroxy-
phenyl)oxazoline structures and 2-(o,m-dihydroxyphenyl)oxazo-
line structures are common. The biosynthesis of these natural
products appears to involve the dehydrative cyclization of N-(o-
Table 5
Synthesis of oxazolines 20a
(NH4)2MoO4 (10 mol %)
C6F5CO2H (10 mol %)
HO
O
hydroxybenzoyl)-
L
-threonines or N-(o,m-dihydroxybenzoyl)-
L-
O
threonines with a retention of configuration at the
b
-position. For
toluene–DMF (9:1 v/v)
Ar
N
H
CO2Me
Ar
CO2Me
N
azeotropic reflux
the chemical synthesis of these bioactive compounds, oxazolines
20 and 24 are useful building blocks.22 Therefore, we investigated
19
20
the dehydrative cyclization of N-(o-hydroxybenzoyl)-
L
-threonines
Entry
1
Ar
Time (h)
10
Yieldb (%)
and N-(o,m-dihydroxybenzoyl)-L-threonines using molybde-
19a: o-OH
18
num(VI) oxide catalysts.
2c
3c
19b: m-OH
19c: p-OH
1
4
91
87
We initially examined the catalytic activities of molybdenum(VI)
HO
Me
oxides for the dehydrative cyclization of N-(o-hydroxybenzoyl)-L-
threonine methyl ester (19a) to oxazoline 20a (Table 4).12b Un-
fortunately, the catalytic activities of (NH4)2MoO4 and MoO2(acac)2
were very low (entries 1 and 2). One of the reasons for the low ac-
tivities of these molybdenum(VI) oxides is their tight complexation
OH
OH
4d
19d
19e
12
12
59
with 20a. Actually, the reaction of N-(o-methoxybenzoyl)-L-threo-
nine methylester21 proceeded welltogive oxazoline 22 in 75%yield
(Scheme 5). To increase the reactivity of 19a, we examined several
Brønsted acids as additives. p-Toluenesulfonic acid (TsOH) did not
promote the reaction of 19a at all (entry 3). The catalytic activity of
TsOH itself was also very low (entry 12), although it shows good
catalytic activity for the dehydrative cyclization of N-(p-methoxy-
t-Bu
5d
3
t-Bu
a
The reaction of 19 (1 mmol) was conducted in toluene–DMF (9:1 v/v, 10 mL)
benzoyl)-L
-threonine methyl ester.8 Very interestingly, some
benzoic acids bearing electron-withdrawing substituents efficiently
promoted the molybdenum(VI) oxide-catalyzed dehydrative cycli-
zation of 19a. In particular, pentafluorobenzoic acid (C6F5CO2H), 3,5-
under azeotropic reflux conditions.
b
Determined by 1H NMR analysis.
c
The reaction was conducted with (NH4)2MoO4 (2 mol %) in the absence of
C6F5CO2H.
d
The reaction was conducted in toluene (10 mL).

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A. Sakakura et al. / Tetrahedron 65 (2009) 2102–2109
Table 6
Table 7
Synthesis of oxazolines 24a
Dehydrative cyclization of N-(3-phenylpropionyl)-
L
-cysteine methyl ester (25)a
HO
catalyst
(10 mol %)
HS
OR
O
OR
O
Mo(VI)=O
cat.
S
O
RO
RO
N
H
CO2Me
CO2Me
toluene, 8 h
CO2Me
N
Ph
CO2Me
Ph
N
H
N
toluene
azeotropic
reflux
azeotropic reflux
23
24
25
26
Yieldb (%)
Entry
Catalyst
Yieldb (%)
Entry
23 [R, R]
Mo(VI)]O cat.,
Time (h)
mol %
1
2
3
4
5
6
MoO2
MoO3
(NH4)6Mo7O24$4H2O
(NH4)2MoO4
MoO2(acac)2
No catalyst
29
18
96
99
81
9
1c
2d
3c
4
23a [H, H]
23a [H, H]
23b [Me, Me]
23b [Me, Me]
23c [Bn, Bn]
(NH4)2MoO4, 10
(NH4)2MoO4, 10
(NH4)2MoO4, 10
(NH4)2MoO4, 10
(NH4)2MoO4, 10
MoO2(acac)2, 10
MoO2(TMHD)2, 10
(NH4)2MoO4, 10
MoO2(TMHD)2, 0.5
12
12
8
10
5
5
5
5
5
0
10
72
96
46
77
91
5
6
23c [Bn, Bn]
a
The reaction of 25 (0.5 mmol) was conducted with catalyst (10 mol %) in toluene
7
23c [Bn, Bn]
(50 mL) under azeotropic reflux conditions for 8 h.
8
9
23d [o-xylylene]
23d [o-xylylene]
96
Determined by 1H NMR analysis.
b
94 [90]e
a
The reaction of 23 (1 mmol) was conducted with Mo(VI)]O cat. in toluene
(100 mL) under azeotropic reflux conditions.
The reactivity of a more complex dipeptide substrate, Cbz-
-Cys-OMe (27a), was much lower than that of 25, and MoO3,
L-Ala-
b
Determined by 1H NMR analysis.
L
c
The reaction was conducted in toluene (10 mL).
The reaction was conducted in mesitylene–DMF (9:1 v/v, 10 mL).
The reaction was conducted for 3 h.
d
(NH4)6Mo7O24$4H2O, and (NH4)2MoO4 gave poor results (Table 8,
entries 1–3). In contrast, MoO2(acac)2 showed good catalytic ac-
tivity to give the corresponding thiazoline in 85% yield, although
the obtained product was a 82:18 mixture of the desired thiazoline
28a and epimer 29a (entry 4). The dehydrative cyclization of 27a
was conducted under high-dilution conditions (0.01 M of 27a).
When the reaction of 27a was conducted at a higher substrate
concentration (0.05 M), the yield of thiazoline 28a was decreased
(62%).
e
were probably attributed to rapid oxidation of the unprotected
catechol moiety of 23a. Therefore, the dehydrative cyclization of 23
required protection of the catechol moiety. Actually, the reaction of
N-(o,m-dimethoxybenzoyl)-L-threonine methyl ester (23b) gave
the corresponding oxazoline 24b in 72% yield even in the absence of
C6F5CO2H (entry 3). Methyl protection of the hydroxyl groups
completely suppressed decomposition of the catechol moiety and
the complexation of molybdenum(VI) oxide with 23b. Further-
more, when the reaction of 23b was conducted under high-dilution
conditions (0.01 M of 23b), the yield of 24b significantly increased
(entry 4). Since it was difficult to remove the methyl protection
without decomposition of the oxazoline moiety, we next examined
the benzyl group, which could be easily removed under conven-
tional hydrogenolysis (H2, 10% Pd/C, rt, EtOH), for protection of the
catechol moiety. However, benzyl-protected substrate 23c showed
lower reactivity than 23b (46% yield, entry 5). The bulkiness of the
benzyl group might decrease the reactivity of 23c. By screening the
catalytic activities of several molybdenum(VI) oxides, we found
that commercially available MoO2(acac)2 and MoO2(TMHD)2
showed good catalytic activities and gave 24c in respective yields of
77 and 91% (entries 6 and 7).
Further investigation of the protecting groups for the catechol
moiety revealed that compound 23d protected by a cyclic o-xyly-
lene [o-C6H4(CH2)2]23 showed excellent reactivity. Very in-
terestingly, only 0.5 mol % of MoO2(TMHD)2 efficiently catalyzed
the reaction of 23d to give 24d in 94% yield (entry 9). The high
reactivity of 23d might be attributed to the lower steric hindrance
of the o-xylylene group. Since the o-xylylene group in 24d could be
easily removed by conventional hydrogenolysis (H2, 10% Pd/C, rt,
EtOH) without any decomposition of the oxazoline moiety, the o-
xylylene is suitable for protection of the catechol moiety.
It is conceivable that the generation of epimer 29a could be
attributed to the relatively high acidity of MoO2(acac)2. In general,
thiazolines are more susceptible to epimerization than oxazolines
under both acidic and basic conditions.7a,9 To decrease the epime-
rization of thiazolines, it might be important to control the Lewis
acidities and Brønsted basicities of molybdenum catalysts by
more suitable ligands. Furthermore, homogeneous monomeric
Table 8
Catalytic activities of molybdenum(VI) oxides for the dehydrative cyclization of di-
peptide 27aa
HS
O
Mo(VI)=O cat.
H
N
toluene
N
H
Cbz
CO2Me
azeotropic reflux
27a
S
S
H
N
H
N
+
Cbz
CO2Me
Cbz
CO2Me
N
N
28a
29a
Entry
Mo(VI)]O cat.,
Time (h)
Yieldb (%)
drc (28a/29a)
mol %
1
2
3
4
5
6
7
8
MoO3, 10
8
8
8
8
5
5
5
2
5
5
2
8
9
16
26
85
80
40
93
96
80
96
94
0
ND
ND
ND
(NH4)6Mo7O24$4H2O, 10
(NH4)2MoO4, 10
MoO2(acac)2, 10
30a, 10
30a, 1
30b, 1
30c, 1
30d, 1
30e, 1
30f, 1
82:18
96:4
89:11
95:5
97:3
85:15
96:4
86:14
ND
2.3. Dehydrative cyclization of cysteine derivatives
9
We first examined the dehydrative cyclization of N-(3-phe-
nylpropionyl)-L-cysteine methyl ester (25) using molybdenum
10
11
12
oxides as catalysts (Table 7). As a result, (NH4)6Mo7O24$4H2O,
(NH4)2MoO4, and MoO2(acac)2 showed good catalytic activities
(respective yields of 96, 99, and 81%, entries 3–5), whereas the
catalytic activities of MoO2 and MoO3 were very low (entries 1
and 2).
No catalyst
a
The reaction of 27a (0.1 mmol) was conducted with Mo(VI)]O cat. (1–10 mol %)
in toluene (10 mL) under azeotropic reflux conditions.
b
Determined by 1H NMR analysis.
Determined by HPLC analysis.
c

A. Sakakura et al. / Tetrahedron 65 (2009) 2102–2109
2107
molybdenum complexes were expected to exhibit higher catalytic
activities even under lower catalyst loading conditions. In an in-
tensive examination of the catalytic activities of molybdenum
complexes for the dehydrative cyclization of 27a, we found that
bis(quinolinolato)dioxomolybdenum(VI) complexes 30, which
were easily prepared from MoO2(acac)2 and known 8-quinolinols
(Scheme 6), showed good catalytic activities.12c The reaction was
conducted with a molybdenum(VI) complex 30 in toluene under
azeotropic reflux conditions with the removal of water. Molybde-
num(VI) complexes 30 dissolved well in toluene and appeared to be
stable under the reaction conditions. 8-Quinolinolato complex 30a
(10 mol %) showed good catalytic activity (80% yield), and epime-
rization at the C2-exomethine position of 28a was effectively sup-
pressed, as expected (28a/29a¼96:4) (entry 5). Unfortunately,
however, the use of 1 mol % of 30a decreased the reactivity (40%
yield, entry 6). Further investigation of the design of 8-quinolino-
lato complexes 30 revealed that the introduction of an alkyl group
to the 2-position of the 8-quinolinol significantly increased the
catalytic activities of the quinolinolato complexes. In particular, 2-
ethyl-8-quinolinolato complex 30c and 2,4-dimethyl-8-quinolino-
lato complex 30e exhibited remarkably higher catalytic activities
than 30a and MoO2(acac)2, to give 28a in 96% yield despite the
lower catalyst loading (1 mol %) (entries 8 and 10). The use of
complexes 30c and 30e significantly suppressed the yield of 29a to
less than 4%. Although 2,4-dimethyl-5,7-dibromo-8-quinolinolato
complex 30f showed high catalytic activity (94% yield), epimeri-
zation increased to 86:14 dr (entry 11). It is conceivable that the
stronger Lewis acidity of complex 30f due to two electronegative
bromine atoms promoted epimerization of the C2-exomethine
position. In contrast, the introduction of an alkyl group to the 2-
position increased the basicity of the quinolinolato-nitrogen to
suppress epimerization.
We then examined the dehydrative cyclization of other
cysteine-containing dipeptides Cbz-L-Phe-L-Cys-OMe (27b), Boc-L-
Ala- -Cys-OMe (27c), and Fmoc- -Ala-L
L
L
-Cys-OMe (27d) (Table 9).
Dipeptides 27b–d could be converted to the corresponding thia-
zolines 28b–d in good isolated yields (82–91%). tert-Butoxy-
carbonyl (Boc) and 9-fluorenylmethoxycarbonyl (Fmoc) groups,
which are useful protecting groups for the synthesis of peptides
and peptide-containing natural products, were also compatible
with the reaction conditions (entries 2 and 3). In all cases, epime-
rization of the C2-exomethine position of the products was sup-
pressed to less than 6%.24
3. Conclusion
In summary, we have developed an efficient dehydrative cycli-
zation of serine, threonine, and cysteine residues catalyzed by
molybdenum(VI) oxo compounds. Commercially available molyb-
denum(VI) oxides efficiently catalyzed the dehydrative cyclization
of a variety of serine and threonine derivatives to give oxazolines in
good yields. For the dehydrative cyclization of cysteine derivatives,
the use of bis(quinolinolato)dioxomolybdenum(VI) complexes
significantly suppressed the loss of stereochemical integrity at the
C2-exomethine position and gave thiazolines in excellent yields.
The present reaction is useful for the synthesis of common in-
termediates for oxazoline- and/or thiazoline-containing bioactive
natural products.
R1
N
R1
N
R2
R3
R2
R3
MoO2(acac)2
EtOH, rt
MoO2
OH
O
4. Experimental
4.1. General
R3
R3
2
30
R2
R1
H
R2
R3
R1
30d Ph
30e Me Me
30f
R3
IR spectra were recorded on a JASCO FT/IR-460 plus spectrom-
eter. 1H spectra were measured on a Varian Gemini-2000 spec-
trometer (300 MHz) or a JEOL ESC400 spectrometer (400 MHz) at
ambient temperature. Data were recorded as follows: chemical
shift in parts per million from internal tetramethylsilane on the
30a
H
H
H
H
H
H
H
H
H
30b Me
30c Et
Me Me Br
d
scale,
multiplicity
(s¼singlet;
d¼doublet;
t¼triplet;
Scheme 6. Preparation of bis(quinolinolato)dioxomolybdenum(VI) complexes 30.
m¼multiplet), coupling constant (Hz), and integration. 13C NMR
spectra were measured on a Varian Gemini-2000 spectrometer
(75 MHz) or a JEOL ESC400 spectrometer (100 MHz). Chemical
shifts were recorded in parts per million from the solvent reso-
nance used as the internal standard (CDCl3 at 77.0 ppm). Analytical
HPLC was performed on a Shimadzu Model LC-6A instrument using
a column of Nomura Chemical Develosil 30-5 (4.6ꢁ250 mm) or
Daicel CHIRALPAK OD-H (4.6ꢁ250 mm). All experiments were
carried out under an atmosphere of dry nitrogen. For TLC analysis,
Merck precoated TLC plates (silica gel 60 F254 0.25 mm) were used.
For preparative column chromatography, Merck silica gel 60
(0.040–0.063 mm) was used. High resolution mass spectral analysis
(HRMS) was performed at the Chemical Instrumentation Facility,
Nagoya University. Oxazolines 2a, 2b, 5a–e, 11, 12, 13, 14, 18a, 18b,
20a–c, 22, 24a–d, thiazolines 26, 28a–d, and bis(quinolinolato)-
Table 9
Synthesis of thiazoline 28a
HS
O
H
30c (1 mol %)
N
toluene, 1 h
PG
N
H
CO2Me
azeotropic reflux
R
27
S
S
H
H
N
+
N
PG
CO2Me
PG
CO2Me
N
N
R
R
29
28
dioxomolybdenum(VI)
complexes
30a–f
were
reported
previously.12
Entry
Dipeptide 27 [PG, R]
Yieldb (%)
drc (28:/29)
1
2
3
27b [Cbz, Bn]
27c [Boc, Me]
27d [Fmoc, Me]
85
82
91
98:2
94:6
96:4
4.2. General procedure for the dehydrative cyclization of
dipeptides 4 and 27
a
The reaction of dipeptide 27 (0.1 mmol) was conducted with 30c (1 mol %) in
Single-necked, round-bottomed flask equipped with a Teflon-
coated magnetic stirring bar and a 5-mL pressure-equalized ad-
dition funnel [containing a cotton plug and ca. 0.4 g of CaH2]
toluene (10 mL) under azeotropic reflux conditions for 1 h.
b
Isolated yields of 28 and 29.
c
Determined by HPLC analysis.

2108
A. Sakakura et al. / Tetrahedron 65 (2009) 2102–2109
surmounted by a reflux condenser was charged with a dipeptide 4
or 27 (0.50 mmol) and an oxomolybdenum(VI) catalyst (1–
10 mol %) in toluene (50 mL for 1a and 27, 10 mL for 1b). The
mixture was heated for several hours under azeotropic reflux
conditions with the removal of water. The reaction mixture was
cooled to ambient temperature, washed with saturated aqueous
solution of NaHCO3 and brine, and the organic solvent was then
removed to give a crude product. The obtained crude product was
purified by column chromatography on silica gel using hexane–
EtOAc (for 5) or toluene–acetone (for 28), to give the corre-
sponding oxazoline 5 or thiazoline 28.
122.4, 128.6, 136.6, 140.1, 157.1, 167.9, 171.1; HRMS (FAB) calcd for
C
20H30NO4 [(MþH)þ] 348.2175. Found: 348.2183.
Acknowledgements
This project was supported by JSPS.KAKENHI (Grant 20245022),
the Toray Science Foundation, and the G-COE in Chemistry, Nagoya
University.
References and notes
1. (a) Jin, Z. Nat. Prod. Rep. 2006, 23, 464; (b) Lewis, J. R. Nat. Prod. Rep. 2002, 19,
223; (c) Roy, R. S.; Gehring, A. M.; Milne, J. C.; Belshaw, P. J.; Walsh, C. T. Nat.
Prod. Rep. 1999, 16, 249.
2. (a) You, S.-L.; Razavi, H.; Kelly, J. W. Angew. Chem., Int. Ed. 2003, 42, 83; (b)
Yokokawa, F.; Shioiri, T. Tetrahedron Lett. 2002, 43, 8679; (c) Philips, A. J.; Uto, Y.;
Wipf, P.; Reno, M. J.; Williams, D. R. Org. Lett. 2000, 2, 1165; (d) Wipf, P.; Fritch,
P. C. Tetrahedron Lett. 1994, 35, 5397; (e) Wipf, P.; Miller, C. P. Tetrahedron Lett.
4.2.1. Dehydrative cyclization of dipeptide 7
The reaction of 7 (0.6 mmol) was conducted with MoO2(acac)2
(20 mol %) in toluene (60 mL) according to the procedure shown
in Section 4.2 to give dehydrative elimination product 9 (47%
yield). IR (neat) 3390, 1746, 1698, 1608, 1513 cmꢂ1 1H NMR
;
´
1992, 33, 6267; (f) Galeotti, N.; Montagne, C.; Poncet, J.; Jouin, P. Tetrahedron
(300 MHz, CDCl3)
d
7.88 (br s, 1H), 7.65 (d, J¼6.9 Hz, 4H), 7.54–
Lett. 1992, 33, 2807; (g) Wipf, P.; Miller, C. P. Tetrahedron Lett. 1992, 33, 907; (h)
Yokokawa, F.; Hamada, Y.; Shioiri, T. Synlett 1992, 153; (i) Burrell, G.; Evans, J.
M.; Jones, G. E.; Stemp, G. Tetrahedron Lett. 1990, 31, 3649; (j) Meyers, A. I.;
Hoyer, D. Tetrahedron Lett. 1985, 26, 4687; (k) Vorbru¨ggen, H.; Krolikiewicz, K.
Tetrahedron Lett. 1981, 22, 4471.
7.34 (m, 6H), 6.52 (s, 1H), 5.61 (s, 1H), 4.83 (dd, J¼7.8, 10.5 Hz, 1H),
4.65 (dd, J¼7.8, 9.0 Hz, 1H), 4.56 (dd, J¼9.0, 10.5 Hz, 1H), 3.80 (s,
3H), 3.70 (t, J¼6.3 Hz, 2H), 2.46 (t, J¼7.2, Hz, 2H), 1.92 (tt, J¼6.3,
7.2 Hz, 2H), 1.04 (s, 9H); 13C NMR (75 MHz, CDCl3)
d 171.8, 170.8,
3. Wipf, P.; Wang, X. J. Comb. Chem. 2002, 4, 656.
4. Oshima, T.; Iwasaki, T.; Mashima, K. Chem. Commun. 2006, 2711.
5. Zhou, P.; Blubaum, J. E.; Burns, C. T.; Natale, N. R. Tetrahedron Lett. 1997, 38, 7019.
6. Cwik, A.;Hell, Z.;Hegedu¨s, A.;Finta,Z.;Horva´th,Z. TetrahedronLett. 2002, 43, 3985.
7. (a) Raman, P.; Razavi, H.; Kelly, J. W. Org. Lett. 2000, 2, 3289; (b) Kuriyama, N.;
Akaji, K.; Kiso, Y. Tetrahedron 1997, 53, 8323; (c) Walker, M. A.; Heathcock, C. H.
J. Org. Chem. 1992, 57, 5566.
8. Reddy, L. R.; Saravanan, P.; Corey, E. J. J. Am. Chem. Soc. 2004, 126, 6230.
9. Yonetani, K.; Hirotsu, Y.; Shiba, T. Bull. Chem. Soc. Jpn. 1975, 48, 3302.
10. For recent studies on the synthesis of bioactive macrocyclic peptide derivatives,
see: (a) You, S.-L.; Kelly, J. W. Tetrahedron 2005, 61, 241; (b) You, S.-L.; Kelly, J. W.
Chem.dEur. J. 2004, 10, 71; (c) Yokokawa, F.; Sameshima, H.; In, Y.; Minoura, K.;
Ishida, T.; Shioiri, T. Tetrahedron 2002, 58, 8127; (d) Kutsumura, N.; Sata, N. U.;
Nishiyama, S. Bull. Chem. Soc. Jpn. 2002, 75, 847; (e) Yokokawa, F.; Sameshima,
H.; Shioiri, T. Synlett 2001, 986.
11. Wipf reported the conversion of cis-oxazolines to trans-oxazolines; (a) Wipf, P.;
Miller, C. P. J. Am. Chem. Soc. 1992, 114, 10975; (b) Wipf, P.; Miller, C. P. J. Org.
Chem. 1993, 58, 1575; (c) Wipf, P.; Fritch, P. C. J. Am. Chem. Soc. 1996, 118, 12358;
(d) Downing, S. V.; Aguilar, E.; Meyers, A. I. J. Org. Chem. 1999, 64, 826.
12. (a) Sakakura, A.; Kondo, R.; Ishihara, K. Org. Lett. 2005, 7, 1971; (b) Sakakura, A.;
Umemura, S.; Kondo, R.; Ishihara, K. Adv. Synth. Catal. 2007, 349, 551; (c) Sa-
kakura, A.; Kondo, R.; Umemura, S.; Ishihara, K. Adv. Synth. Catal. 2007, 349,
1641; (d) Sakakura, A.; Umemura, S.; Ishihara, K. Chem. Commun. 2008, 3561.
13. Ishihara, K.; Sakakura, A.; Hatano, M. Synlett 2007, 686.
163.7, 135.5, 133.7, 129.6, 128.5, 127.6, 106.8, 70.5, 67.8, 62.8, 52.8,
34.0, 27.9, 26.8, 19.2; HRMS (FAB) calcd for C27H35N2O5Si
[(MþH)þ] 495.2315. Found: 495.2317.
4.2.2. Dehydrative cyclization of tetrapeptide 15
The reaction of 15 (0.1 mmol) was conducted with MoO2(acac)2
(20 mol %) in toluene (10 mL) according to the procedure shown in
Section 4.2 to give bis(oxazoline) 16 (95% yield) as a diastereomeric
mixture. IR (neat) 1718, 1657, 1522, 1453, 1260, 1216, 1058 cmꢂ1; 1H
NMR (300 MHz, CD3OD)
d 7.41–7.18 (m, 5H), 5.20–5.05 (m, 2H),
4.98–4.78 (m, 1H), 4.78–4.69 (m, 1H), 4.69–4.56 (m, 1H), 4.47–4.35
(m, 1H), 4.36–4.25 (m, 1H), 4.23–4.14 (m, 1H), 3.75 (s, 2.1H), 3.73 (s,
0.9H), 1.52–1.30 (m, 12H); 13C NMR (75 MHz, CDCl3)
d 18.1, 18.4,
20.9, 21.4, 48.6, 48.8, 49.6, 67.6, 74.8, 75.6, 81.5, 82.0, 128.8, 129.0,
129.4, 138.2, 158.1, 171.7, 172.2, 172.5, 173.0.
4.2.3. Dehydrative cyclization of 17c
The reaction of 17c (11.9 mmol) was conducted with
(NH4)2MoO4 (2 mol %) in toluene (30 mL) for 12 h according to the
procedure shown in Section 4.2 to give bis(oxazoline) 18c (69%
yield) along with monocyclized product (22% yield). IR (KBr) 1740,
14. The present method should also be applicable to the synthesis of oxazole- and
thiazole-containing natural products, since oxazoles and thiazoles could be
prepared from oxazolines and thiazolines by oxidation.15 (a) Tera, M.; Ishizuka,
H.; Takagi, M.; Suganuma, M.; Shin-ya, K.; Nagasawa, K. Angew. Chem., Int. Ed.
2008, 47, 5557; (b) Doi, T.; Yoshida, M.; Shin-ya, K.; Takahashi, T. Org. Lett. 2006,
8, 4165; (c) Chattopadhyay, S. K.; Biswas, S.; Pal, B. K. Synthesis 2006, 1289; (d)
Nakamura, Y.; Takeuchi, S. QSAR Comb. Sci. 2006, 25, 703; (e) Nicolaou, K. C.;
Chen, D. Y.-K.; Huang, X.; Ling, T.; Bella, M.; Snyder, S. A. J. Am. Chem. Soc. 2004,
126, 12888; (f) Plant, A.; Stieber, F.; Scherkenbeck, J.; Lo¨sel, P.; Dyker, H. Org. Lett.
2001, 3, 3427; (g) Xia, Z.; Smith, C. D. J. Org. Chem. 2001, 66, 3459; (h) Somogyi,
L.; Haberhauer, G.; Rebek, J., Jr. Tetrahedron 2001, 57, 1699; (i) Yokokawa, F.;
Asano, T.; Shioiri, T. Org. Lett. 2000, 2, 4169.
1649 cmꢂ1; 1H NMR (300 MHz, CDCl3)
d
4.84 (dq, J¼6.3, 6.9 Hz, 2H),
4.29 (d, J¼6.6 Hz, 2H), 3.77 (s, 6H), 1.55 (s, 6H), 1.38 (d, J¼6.3 Hz,
6H); 13C NMR (75 MHz, CDCl3)
d 171.3, 170.9, 79.1, 74.3, 52.5, 38.7,
23.9, 20.8; HRMS (FAB) calcd for C15H23N2O6 [(MþH)þ] 327.1556.
Found: 327.1566.
15. (a) Williams, D. R.; Lowder, P. D.; Gu, Y.-G.; Brooks, D. A. Tetrahedron Lett. 1997,
38, 331; (b) Meyers, A. I.; Tavares, F. X. J. Org. Chem. 1996, 61, 8207; (c) Tavares,
F.; Meyers, A. I. Tetrahedron Lett. 1994, 35, 6803; (d) Barrish, J. C.; Singh, J.;
Spergel, S. H.; Han, W.-C.; Kissick, T. P.; Kronenthal, D. R.; Mueller, R. H. J. Org.
Chem. 1993, 58, 4494; (e) Evans, D. L.; Minster, D. K.; Jordis, U.; Hecht, S. M.;
Mazzu, A. L., Jr.; Meyers, A. I. J. Org. Chem. 1979, 44, 497.
16. (a) Barroso, S.; Blay, G.; Cardona, L.; Pedro, J. R. Synlett 2007, 2659; (b) Pem-
berton, N.; Pinkner, J. S.; Edvinsson, S.; Hultgren, S. J.; Almqvist, F. Tetrahedron
2008, 64, 9368.
4.2.4. Dehydrative cyclization of 19d and 19e
The reaction of 19d or 19e (1 mmol) was conducted with
(NH4)2MoO4 (10 mol %) and C6F5CO2H (10 mol %) in toluene (10 mL)
according to the procedure shown in Section 4.2 to give oxazoline
20d (59% yield) or 20e (3% yield). Compound 20d: IR (neat) 2953,
1744, 1633, 1437, 1303, 1261, 1205, 1146, 1041 cmꢂ1 1H NMR
;
(400 MHz, CDCl3)
d
12.0 (br s, 1H), 7.51 (d, J¼7.8 Hz, 1H), 7.25 (d,
17. Ichiba, T.; Yoshida, W. Y.; Scheuer, P. J.; Higa, T.; Gravalos, D. G. J. Am. Chem. Soc.
1991, 113, 3173.
J¼7.4 Hz, 1H), 6.77 (dd, J¼7.4, 7.8 Hz, 1H), 4.97 (qd, J¼6.4, 6.8 Hz,
18. Williams, D. R.; Brooks, D. A.; Berliner, M. A. J. Am. Chem. Soc. 1999, 121, 4924.
19. In general, (NH4)2MnO4 is slightly more active than MoO2(acac)2 for the de-
hydrative cyclization of serine residue, as shown in Table 3. However,
MoO2(acac)2 showed slightly higher catalytic activity than (NH4)2MoO4 for the
dehydrative cyclization of 7 and 15. For example, when the reaction of 7 was
conducted with (NH4)2MoO4, 9 was obtained in 28% yield.
1H), 4.49 (d, J¼6.8 Hz, 1H), 3.78 (s, 3H), 2.28 (s, 3H), 1.53 (s, 3H); 13C
NMR (100 MHz, CDCl3)
d 15.8, 20.7, 52.6, 73.5, 78.3, 109.4, 118.1,
125.8, 125.9, 134.7, 158.3, 167.2, 170.9; HRMS (FAB) calcd for
C13H16NO4 [(MþH)þ] 250.1079. Found: 250.1096. Compound 20e:
IR (neat) 2957, 1744, 1631, 1439, 1362, 1278, 1254, 1218, 1203 cmꢂ1
;
20. The diastereomeric ratio of 16 could not be determined.
1H NMR (400 MHz, CDCl3)
d
12.2 (s, 1H), 7.53 (d, J¼2.3 Hz, 1H), 7.46
21. For recent reviews, see: (a) Rasappan, R.; Laventine, D.; Reiser, O. Coord. Chem.
Rev. 2008, 252, 702; (b) Desimoni, G.; Faita, G.; Jørgensen, K. A. Chem. Rev. 2006,
106, 3561.
22. (a) Kikkeri, R.; Traboulsi, H.; Humbert, N.; Gumienna-Kontecka, E.; Arad-Yellin,
R.; Melman, G.; Elhabiri, M.; Albrecht-Gary, A.-M.; Shanzer, A. Inorg. Chem.
(d, J¼2.7 Hz, 1H), 4.95 (qd, J¼6.4, 7.3 1H), 4.49 (d, J¼7.3 Hz, 1H), 3.80
(s, 3H), 1.54 (d, J¼6.4 Hz, 3H), 1.43 (s, 9H), 1.30 (s, 9H); 13C NMR
(100 MHz, CDCl3) d 20.8, 29.4, 31.5, 34.3, 35.2, 52.7, 73.7, 78.2, 109.4,

A. Sakakura et al. / Tetrahedron 65 (2009) 2102–2109
2109
2007, 46, 2485; (b) Nagao, Y.; Miyasaka, T.; Hagiwara, Y.; Fujita, E. J. Chem. Soc.,
Perkin Trans. 1 1984, 183.
23. (a) Poss, A. J.; Smyth, M. S. Synth. Commun.1989,19, 3363; (b) Balbuena, P.; Rubio, E. M.;
24. 8-Quinolinolato complexes 30d (1 mol %) showed excellent catalytic activity for
the dehydrative cyclization of 4b, Cbz- -Phe- -Thr-OMe (4c), Boc- -Ala- -Thr-
OMe (4d), and Fmoc- -Ala- -Thr-OMe (4e) to give the corresponding oxazolines
5b–e in 85–92% yields.12c The reaction also proceeded with a complete re-
tention of configuration at the -position.
L
L
L
L
L
L
´
´
Oritz Mellet, C.; Garcıa Fernandez, J. M. Chem. Commun. 2006, 2610; (c) Garcıa-Mor-
eno, M. I.; Aguilar, M.; Oritz Mellet, C.; Garcı´a Fernandez, J. M. Org. Lett. 2006, 8, 297.
b