Molybdenum oxides as highly effective dehydrative cyclization catalysts for the synthesis of oxazolines and thiazolines

Article abstract of DOI:10.1021/ol050543j

(Chemical Equation Presented) In the presence of molybdenum oxide the dehydrative cyclization of N-acylserines, N-acylthreonines, and N-acylcysteines can be carried out under Dean-Stark conditions in toluene to give oxazolines and thiazolines. The ammoniu

Full text of DOI:10.1021/ol050543j

ORGANIC
LETTERS
2005
Vol. 7, No. 10
1971-1974
Molybdenum Oxides as Highly Effective
Dehydrative Cyclization Catalysts for the
Synthesis of Oxazolines and Thiazolines
Akira Sakakura, Rei Kondo, and Kazuaki Ishihara*
Graduate School of Engineering, Nagoya UniVersity,
Chikusa, Nagoya, 464-8603 Japan
ishihara@cc.nagoya-u.ac.jp
Received March 12, 2005
ABSTRACT
In the presence of molybdenum oxide the dehydrative cyclization of N-acylserines, N-acylthreonines, and N-acylcysteines can be carried out
under Dean Stark conditions in toluene to give oxazolines and thiazolines. The ammonium salts (NH4)6Mo7O24 4H2O and (NH4)2MoO4 have
−
‚
excellent catalytic activities for the dehydrative cyclization of serine and threonine derivatives, and the acetylacetonate complex MoO2(acac)2
has a remarkable catalytic activity for the dehydrative cyclization of cysteine derivatives. In addition, polyaniline-supported MoO2(acac)2 can
easily be recovered and reused.
Oxazoline, oxazole, thiazoline, and thiazole rings are im-
portant constituents of numerous bioactive natural products
and pharmaceuticals.1 The biosynthesis of many naturally
occurring oxazolines and thiazolines appears to involve the
dehydrative cyclization of serine, threonine, and cysteine
residues.1c Oxazoles and thiazoles are synthesized by the
oxidation of oxazolines and thiazolines, respectively
(Scheme 1).
that do not have any other functional groups. In this
communication, we describe a biomimetic synthesis of
Scheme 1. Proposed Biosynthesis of Oxazolines, Thiazolines,
Oxazoles, and Thiazoles
Although several stoichiometric reagents are known to be
effective for the dehydrative cyclization of N-(â-hydroxy-
ethyl)amides or N-(â-mercaptoethyl)amides to oxazolines or
thiazolines,2 few successful examples of dehydrating catalysts
have been reported: 3-nitrophenylboronic acid,3 a lanthanide
chloride,4 a zeolite,5 TiCl4,6 TsOH,7 etc. In these catalytic
reactions, the addition of an excess amount of substrate or
heating to a high reaction temperature is required because
of their low catalytic activities. In addition, these catalytic
methods are limited to simple acid- or base-tolerant substrates
(1) (a) Jin, Z. Nat. Prod. Rep. 2003, 20, 584 and references therein.
(b) Lewis, J. R. Nat. Prod. Rep. 2002, 19, 223 and references therein.
(c) Roy, R. S.; Gehring, A. M.; Milne, J. C.; Belshaw, P. J.; Walsh, C. T.
Nat. Prod. Rep. 1999, 16, 249.
oxazolines and thiazolines catalyzed by molybdenum (IV or
VI) oxides.8 To the best of our knowledge, this is the first
10.1021/ol050543j CCC: $30.25
© 2005 American Chemical Society
Published on Web 04/16/2005

example of the catalytic dehydrative cyclization of dipeptide
substrates that include serine, threonine, and cysteine resi-
dues.
complex of molybdenum(VI) oxide such as (NH4)6Mo7O24‚
4H2O, (NH4)2MoO4, and MoO2(acac)2, as well as MoO2 and
In the course of screening various metal oxides as catalysts
for the dehydrative cyclization of N-(3-phenylpropionyl)-L-
serine methyl ester (1a) to oxazoline 2a, we found that
molybdenum oxides (MoO2, MoO3) had good catalytic
activities (entries 1 and 2, Table 1). Hence, we investigated
Table 2. Synthesis of Oxazolines 5a
Table 1. Synthesis of Oxazolines 2a
4a f 5a
4b f 5b
time
(h)
yield
(%)b,c
time
(h)
yield
(%)b,c
entry
catalyst
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
1a f 2a
1b f 2b
a Reactions were carried out with 0.5 mmol of substrate and 10 mol %
of catalyst in toluene (50 mL for serine derivatives and 10 mL for threonine
derivatives) at azeotropic reflux with the removal of water. b Determined
by HPLC analysis. c Yield of 6a or 6b in parentheses.
time
yield
(%)b,c
time
yield
(%)b,c
entry
catalyst
(h)
(h)
1
2
3
4
5
6
7
MoO2
MoO3
(NH4)6Mo7O24‚4H2O
(NH4)2MoO4
MoO2(acac)2
3-(NO2)C6H4B(OH)2
no catalyst
8
8
4
4
1
8
8
86 (10)
78 (5)
87 (11)
89 (11)
87 (7)
3 (0)
8
8
2
2
1
8
8
97 (0)
99 (0)
97 (0)
95 (0)
90 (0)
4 (0)
MoO3, were also found to have good catalytic activities.
3-Nitrophenylboronic acid3 showed lower catalytic activity
than molybdenum oxides under the same conditions (entry
6). In the reaction of 1a, a small amount of dimer 3 was
obtained as a byproduct. The yield of dimer 3 could be
reduced by conducting the reactions under high-dilution
conditions (10 mM). When the reaction of 1a was carried
out using (NH4)2MoO4 at a higher concentration (50 mM),
2a was obtained in 53% yield along with 3 in 27% yield.
We then examined the dehydrative cyclization of more
complex dipeptide substrates, Cbz-L-Ala-L-Ser-OCH3 (4a)
and Cbz-L-Ala-L-Thr-OCH3 (4b). Surprisingly, the am-
monium salts of molybdenum(VI) oxides, (NH4)6Mo7O24‚
4H2O and (NH4)2MoO4, exhibited remarkable catalytic
activities and gave oxazolines 5a and 5b in a short reaction
time, along with small amounts of 6a and 6b, which are
epimers at the R-position of the alanine residue (Table 2).9
Next, we examined the dehydrative cyclization of
cysteine derivatives to thiazolines using molybdenum oxides
as catalysts (Table 3). In the case of N-(3-phenylpro-
pionyl)-L-cysteine methyl ester (7a), (NH4)6Mo7O24‚4H2O,
(NH4)2MoO4, and MoO2(acac)2 showed excellent catalytic
0 (0)
0 (0)
a Reactions were carried out with 0.5 mmol of substrate and 10 mol %
of catalyst in toluene (50 mL for serine derivatives and 10 mL for threonine
derivatives) at azeotropic reflux with the removal of water. b Determined
by HPLC analysis. c Yield of 3a or 3b in parentheses.
the catalytic activities of several commercially available
molybdenum oxides. In the presence of 10 mol % of
molybdenum oxide, a solution of serine derivative 1a and
threonine derivative 1b in toluene was heated at reflux with
the azeotropic removal of water for several hours. After
removal of the solvent, the resulting crude products were
analyzed by HPLC. The ammonium salts and acetylacetonate
(2) (a) Martin’s sulfrane: Yokokawa, F.; Shioiri, T. Tetrahedron Lett.
2002, 43, 8679. (b) DAST: Phillips, A. J.; Uto, Y.; Wipf, P.; Reno, M. J.;
Williams, D. R. Org. Lett. 2000, 2, 1165. (c) Burgess reagent: Wipf, P.;
Miller, C. P. Tetrahedron Lett. 1992, 33, 907. (d) Mitsunobu reagent:
Gale´otti, N.; Montagne, C.; Poncet, J.; Jouin, P. Tetrahedron Lett. 1992,
33, 2807. (e) Mitsunobu reagent: Wipf, P.; Miller, C. P. Tetrahedron Lett.
1992, 33, 6267. (f) Ph2SO-Tf2O: Yokokawa, F.; Hamada, Y.; Shioiri, T.
Synlett 1992, 153. (g) DAST: Burrell, G.; Evans, J. M.; Jones, G. E.; Stemp,
G. Tetrahedron Lett. 1990, 31, 3649. (h) PPh3-CCl4: Meyers, A. I.; Denton,
H. Tetrahedron Lett. 1985, 26, 4687. (i) PPh3-CCl4: Vorbru¨ggen, H.;
Krolikiewicz, K. Tetrahedron Lett. 1981, 22, 4471. (j) Ph3PO-Tf2O: You,
S.-L.; Razavi, H.; Kelly, J. W. Angew. Chem., Int. Ed. 2003, 42, 83.
(3) Wipf, P.; Wang, X. J. Comb. Chem. 2002, 4, 656.
(5) Cwik, A.; Hell, Z.; Hegedu¨s, A.; Finta, Z.; Horva´th, Z. Tetrahedron
Lett. 2002, 43, 3985.
(6) (a) Raman, P.; Razavi, H.; Kelly, J. K. 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.
(7) Reddy, L. R.; Saravanan, P.; Corey, E. J. J. Am. Chem. Soc. 2004,
126, 6230.
(4) Zhou, P.; Blubaum, J. E.; Burns, C. T.; Natale, N. R. Tetrahedron
Lett. 1997, 38, 7019.
1972
Org. Lett., Vol. 7, No. 10, 2005

Bis(oxazoline)s are a very useful class of chiral ligands
for asymmetric catalysis11 and are generally synthesized from
the corresponding bis(amide)s via sulfonylation or chlorina-
tion of the two hydroxyl groups. The present method was
applied to the synthesis of bis(oxazoline)s (Scheme 2). Bis-
Table 3. Synthesis of Thiazolines 8a
Scheme 2. Synthesis of Bis(oxazoline)s 10, Chiral Ligands
for Asymmetric Catalysis
7a f 8a
yield (%)b
7b f 8b
yield (%)b
entry
catalyst
1
2
3
4
5
6
MoO2
MoO3
(NH4)6Mo7O24‚4H2O
(NH4)2MoO4
MoO2(acac)2
no catalyst
29c
6c
18c
9c
96c
99c
16c
26c
70 (15)e,f
0c
81 (98.7% ee)d
9c
(amide)s 9a and 9b were reacted with 20 mol % of
(NH4)2MoO4 at azeotropic reflux with the removal of water
for 3 h. After purification by silica gel chromatography, bis-
(oxazoline)s 10a and 10b were obtained in respective yields
of 84% and 83%.
We next tried to synthesize a key synthetic intermediate
16 of a natural bioactive compound, hennoxazole A12
(Scheme 3). Dehydrative cyclization of serine derivative 11
a Reactions were carried out with 0.5 mmol of substrate and 10 mol %
of catalyst in toluene (50 mL) at azeotropic reflux with the removal of
water for 8 h. b Determined by 1H NMR analysis. c Enantiomeric exess or
diastereomeric ratio of the product was not determined. d Determined by
HPLC analysis on Chiralcel OD-H. e 5 h. f Yield of 8c in parentheses.
Determined by HPLC analysis on Develosil 30-5.
activities, giving thiazoline 8a (respective yields of 96%,
99%, and 81%, entries 3-5) without any byproducts,
whereas MoO2 and MoO3 showed lower activities (entries
1 and 2). The optical purity of 8a obtained by the reaction
using MoO2(acac)2 was 98.7% ee. MoO2(acac)2 could
catalyze the dehydrative cyclization of a more complex
dipeptide substrate, Cbz-L-Ala-L-Cys-OCH3 (7b), to give
thiazoline 8b in 70% yield along with diastereomer 8c in
15% yield (entry 5).10 Other molybdenum oxides exhibited
poor catalytic activities in the dehydrative cyclization of 7b
(entries 1-4). The dehydrative cyclization of cysteine
derivatives 7a and 7b was conducted under high-dilution
conditions (10 mM of substrates). When the dehydrative
cyclization reaction of 7b was conducted at a higher substrate
concentration (50 mM), lower yields of thiazolines 8b (62%)
were obtained.
Scheme 3. Synthesis of 16, a Key Intermediate of
Hennoxazole A
(8) For the chemical synthesis of oxazolines/thiazolines, there are two
methodoligies: one is the retentive cyclization of N-(â-hydroxyethyl)amides/
N-(â-mercaptoethyl)amides (biomimetic synthesis) at the â-position, the
other is its invertive cyclization.
(9) Corey et al. reported the dehydrative cyclization of a threonine
derivative using TsOH as a catalyst (ref 7). Dehydrative cyclization of 4b
using TsOH gave 5b in 48% yield along with 6b in 50% yield, probably
due to its strong acidity.
(10) Kelly et al. reported that the deprotection-cyclodehydration of Cbz-
L-Phe-L-Cys(Tr)-OCH3 using TiCl4 at 0 °C afforded a 1: 1 mixture of the
corresponding diastereomeric thiazoline (60% yield, ref 6a). Although the
dehydrative cyclization of 7b using MoO2(acac)2 was conducted at high
reaction temperature (toluene reflux), the loss of stereochemical integrity
was less than with the reaction using TiCl4, which was mainly because the
molybdenum oxide is a nearly neutral compound.
using 10 mol % of (NH4)2MoO4 gave oxazoline 12 in 81%
yield. The oxidation of oxazoline 12 to oxazole 13 by the
(11) (a) Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325.
(b) Ghosh, A. K.; Mathivanan, P.; Cappiello, J. Tetrahedron: Asymmetry
1998, 9, 1.
Org. Lett., Vol. 7, No. 10, 2005
1973

reported procedure,12 hydrolysis of the methyl ester of 13,
and subsequent amide condensation with L-serine ethyl ester
gave 14 in 59% overall yield from 12. Dehydrative cycliz-
ation of 14 using 10 mol % of (NH4)2MoO4 in chlorobenzene
gave oxazoline 15 (75%) along with recovered 14 (8%).
Oxidation of the oxazoline ring13 and reduction of the ethyl
ester of 15 gave 16 in 58% yield.
cyclization of 1b. The immobilized catalyst was recovered
by filtration and reused more than five times for the
dehydrative cyclization of 1b (Scheme 4).
In conclusion, we have developed an efficient molybde-
num oxide catalyzed dehydrative cyclization of serine,
threonine, and cysteine derivatives, which gives oxazolines
and thiazolines in good yield. In particular, (NH4)6Mo7O24‚
4H2O and (NH4)2MoO4 showed excellent catalytic activities
for the dehydrative cyclization of serine and threonine
derivatives, and MoO2(acac)2 had a remarkable catalytic
activity for the dehydrative cyclization of cysteine deriva-
tives. The present method can be applied to a wide range of
complex substrates because the reaction proceeds under
neutral conditions. Mechanistic studies and the application
of this method to the synthesis of more complex natural
products are in progress.
Scheme 4. Dehydrative Cyclization Using
Polyaniline-Supported MoO2(acac)2 as a Recyclable Catalyst
Acknowledgment. Financial support for this project was
provided by the JSPS.KAKENHI (15205021), the Tatematsu
Foundation, and the 21st Century COE program “the
Creation of Nature-Guided Materials Processing” of MEXT.
Next, we examined polymer-supported molybdenum ox-
ides as recyclable catalysts. Polyaniline-supported
MoO2(acac)2 also catalyzed efficiently the dehydrative
14
Supporting Information Available: Experimental details
and spectroscopic data. This material is available free of
charge via the Internet at http://pubs.acs.org.
(12) Williams, D. R.; Brooks, D. A.; Berliner, M. A. J. Am. Chem. Soc.
1999, 121, 4924.
(13) Williams, D. R.; Lowder, P. D.; Gu, Y.-G.; Brooks, D. A.
Tetrahedron Lett. 1997, 38, 331.
(14) Velusamy, S.; Ahamed, M.; Punniyamurthy, T. Org. Lett. 2004, 6,
4821.
OL050543J
1974
Org. Lett., Vol. 7, No. 10, 2005