Convergent total syntheses of fluvibactin and vibriobactin using molybdenum(vi) oxide-catalyzed dehydrative cyclization as a key step

Article abstract of DOI:10.1039/b805880f

Efficient total syntheses of fluvibactin and vibriobactin have been achieved via molybdenum(vi) oxide-catalyzed dehydrative cyclization, Sb(OEt)₃-catalyzed ester-amide transformation, and WSCI and HOAt-promoted dehydrative amide formation. The Royal Society of Chemistry.

Full text of DOI:10.1039/b805880f

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Convergent total syntheses of fluvibactin and vibriobactin using
molybdenum(VI) oxide-catalyzed dehydrative cyclization as a key stepw
Akira Sakakura,b Shuhei Umemuraa and Kazuaki Ishihara*a
Received (in Cambridge, UK) 7th April 2008, Accepted 28th April 2008
First published as an Advance Article on the web 6th June 2008
DOI: 10.1039/b805880f
Efficient total syntheses of fluvibactin and vibriobactin have been
achieved via molybdenum(VI) oxide-catalyzed dehydrative cycli-
zation, Sb(OEt)3-catalyzed ester–amide transformation, and
WSCI and HOAt-promoted dehydrative amide formation.
Many oxazoline-containing natural products have been isolated
from marine organisms.1 The biosynthesis of these oxazolines
appears to involve the dehydrative cyclization of serine and
threonine residues.1c Fluvibactin (1)2 and vibriobactin (2)3 are
representative catecholate siderophores that have been isolated
from low-iron cultures of Vibrio fluvialis and Vibrio cholerae,
respectively. These compounds consist of a norspermidine back-
bone with 2-(o,m-dihydroxyphenyl)oxazoline-4-carboxylate and
2,3-dihydroxybenzoate moieties. They serve as Fe(III) ion-speci-
fic chelators and facilitate Fe(III) ion uptake.4 These sidero-
phores have been attracting much attention from researchers,
and several reports concerning their chemical syntheses, bio-
syntheses and biological activities have been published.5
Scheme 1 Bergeron’s first total syntheses of fluvibactin (1) and
vibriobactin (2).
(o-hydroxyphenyl)oxazolines, and we achieved the first syn-
thesis of BE-70016, an antitumor substance, using the
Mo(VI)QO-catalyzed method as a key step.11 Since the
Mo(VI)QO-catalyzed method was expected to work for the
synthesis of 2-(o,m-dihydroxyphenyl)oxazoline structures, we
investigated the total syntheses of 1 and 2 using Mo(VI)Q
O-catalyzed dehydrative cyclization as a key step.
The first total syntheses of 16 and 27 were reported by
Bergeron et al.8 According to their reports, synthesis of the
2-(o,m-dihydroxyphenyl)oxazoline structure is one of the most
problematic steps. They synthesized the 2-(o,m-dihydroxyphe-
nyl)oxazoline moieties by reacting L-threonine amides with
2,3-dihydroxybenzimidate at the last stage of the total synth-
esis (Scheme 1). However, the yields of the products were
moderate (65 and 58%), despite the use of large amounts (4
and 6.6 equivalents) of 2,3-dihydroxybenzimidate. It is con-
ceivable that steric hindrance of the L-threonine amides de-
creased the yields of 1 and 2. Moreover, the synthesis of 2,3-
dihydroxybenzimidate requires 6 steps (48% overall yield).8b,9
For more efficient total syntheses of 1 and 2, construction of
the 2-(o,m-dihydroxyphenyl)oxazoline moiety at an early
stage, if possible, would be more desirable.
Our plan for the convergent synthesis of fluvibactin (1) and
vibriobactin (2) is illustrated in Scheme 2. We planned to
synthesize 2-(o,m-dialkoxyphenyl)oxazoline 3 at an early
stage from N-(o,m-dialkoxybenzoyl)-L-threonine 6 via the
Mo(VI)QO-catalyzed method. Compounds 1 and 2 would be
synthesized by the assembly of 3, 2,3-dialkoxybenzoate 4 and
norspermidine (5).
First, we investigated the molybdenum(VI) oxide-catalyzed
dehydrative cyclization of 6 (Table 1). Recently, we reported
that the dehydrative cyclization of N-(o-hydroxybenzoyl)-
L-threonine methyl ester could proceed using the combination
of (NH4)2MoO4 and pentafluorobenzoic acid (C6F5CO2H),
even without protection of the o-hydroxyl group, to give the
Recently, we reported that molybdenum(VI) oxides were
highly effective dehydrative cyclization catalysts for the synth-
esis of oxazolines and thiazolines.10 As in biosynthesis, the
molybdenum(VI) oxide-catalyzed dehydrative cyclization of
L-threonine derivatives proceeds with retention of configura-
tion at the b-position of the threonine residue. Therefore, this
catalytic method is quite useful for the synthesis of naturally
occurring oxazolines derived from an L-threonine residue. This
Mo(VI)QO-catalyzed method was effective for the synthesis of
a Graduate School of Engineering, Nagoya University, Chikusa,
Nagoya, 464-8603, Japan. E-mail: ishihara@cc.nagoya-u.ac.jp;
Fax: þ81 52 789 3222; Tel: þ81 52 789 3331
b EcoTopia Science Institute, Nagoya University, Japan
w Electronic supplementary information (ESI) available: Experimental
details; 1H and 13C NMR spectra for all products. See DOI: 10.1039/
b805880f
Scheme 2 Plan for the synthesis of 1 and 2.
Chem. Commun., 2008, 3561–3563 | 3561
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corresponding oxazoline in good yield.11 However, the combi-
nation of (NH4)2MoO4 and C6F5CO2H did not work for the
dehydrative cyclization of N-(o,m-dihydroxybenzoyl)-L-threo-
nine methyl ester (6a) (entries 1 and 2), probably due to rapid
oxidation of the unprotected catechol moiety of 6a. The present
Mo(VI)QO-catalyzed reaction required protection of the cate-
chol moiety. In fact, N-(o,m-dimethoxybenzoyl)threonine
methyl ester (6b) showed good reactivity for (NH4)2MoO4-
catalyzed dehydrative cyclization under azeotropic reflux condi-
tions in toluene, to give the corresponding oxazoline 3b in 88%
yield (entry 3). Methyl protection of the hydroxyl groups
completely suppressed decomposition of the catechol moiety.
Unfortunately, such methyl protection was difficult to remove at
the last stage of our synthesis of 1 and 2. Therefore, we
investigated other protecting groups that could be more easily
removed at the last step. Benzyl-protected substrate 6c showed
lower reactivity than 6b, giving oxazoline 3c in 46% yield (entry
4). The bulkiness of the benzyl group might decrease the
reactivity of 6c. In contrast to methyl protection, the benzyl
groups in 3c could be easily removed by conventional hydro-
genolysis (H2, Pd/C). Therefore, we examined other Mo(VI)QO
catalysts for the dehydrative cyclization of 6c. As a result,
commercially available MoO2(acac)2 and MoO2(TMHD)2 were
found to have good catalytic activities, and gave 3c in respective
yields of 77 and 91% (entries 5 and 6). Corey et al. reported the
dehydrative cyclization of p-methoxybenzoyl-L-threonine methyl
ester using TsOH as a catalyst.12 However, the catalytic activity
of TsOH was lower than that of MoO2(TMHD)2 for the
reaction of 6c (entry 7).
Further investigation of the protecting groups for the
hydroxyl groups of the catechol moiety revealed that com-
pound 6d protected by a cyclic o-xylylene group (o-Xyl)13
showed excellent reactivity. When the reaction of 6d was
conducted with 10 mol% of (NH4)2MoO4, oxazoline 3d was
obtained in 96% yield (entry 8). Very interestingly, only
0.5 mol% of MoO2(TMHD)2 efficiently promoted the reaction
of 6d to give 3d in 94% yield (entry 9). The high reactivity of 6d
might be attributed to the lower steric hindrance of the
o-xylylene group. Furthermore, the o-xylylene group in 3d
could be easily removed by conventional hydrogenolysis
(H2, Pd/C). Recently, we reported that cis-bis(2-phenyl-8-
quinolinolato-N,O)-dioxomolybdenum(VI) [MoO2(Ph-quinoli-
nolato)2] showed good catalytic activity for the dehydrative
cyclization of N-acyl-L-threonines to oxazolines.10b However,
the activity of MoO2(Ph-quinolinolato)2 was lower than that
of MoO2(TMHD)2 for the dehydrative cyclization of 6d (entry
10). Compound 6d could be easily prepared from commer-
cially available 2,3-dihydroxybenzoic acid by a five-step trans-
formation via compound 7 (72% overall yield) (eqn (1)).
ð1Þ
Table 1 Mo(VI)QO-catalyzed dehydrative cyclization of 6a
Next, we investigated the synthesis of fluvibactin (1) using 3d
as a key building block (Scheme 3). Sb(III) alkoxide-catalyzed
ester–amide transformation14 worked well for the selective synth-
esis of diamide 8, although the reaction required an equimolar
amount of Sb(III) alkoxide. When the reaction of a 2 : 1 mixture
of 7 and norspermidine (5) was conducted in the presence of
Sb(OEt)3 (1.0 equiv) under solvent-free conditions at 80 1C, the
desired diamide 8 was obtained in 86% yield along with mono-
amide 9 (13%). Interestingly, the present ester–amide transfor-
mation gave the best results under solvent-free conditions,
although Sb(III)-templated macrolactamization was conducted
in benzene or toluene under azeotropic reflux conditions.14 The
ester–amide transformation between 7 and 5 in toluene under
azeotropic reflux conditions resulted in 6% yield.z
Entry
R (6)
Mo(VI)QO cat. (mol%)b
Yield (%)c
With the key synthetic intermediate 8 in hand, the stage was
set for amide formation at the secondary amine in 8. In contrast
to the primary amines, the amide formation at the secondary
amine in 8 was extremely difficult to promote. In fact, attempts
with Sb(III)-catalyzed ester–amide transformation between 3d
and 8 failed under several reaction conditions, and resulted in
decomposition of the oxazoline moiety of 3d to give a mixture of
byproducts.y Therefore, we investigated the dehydrative con-
densation of 8 with carboxylic acid 10 which was prepared from
3d in 97% yield [CsOH (2 equiv), acetone–MeOH–H2O (2 : 1 :
1 v/v/v), 0 1C, 1 h]. Through the intensive examination of
dehydrative condensation of 8 with 10, we found that WSCIꢁ
HCl and HOAt (1.5 equiv) showed high activity for the con-
densation of 8 with 10 (1.1 equiv) and gave the desired triamide
11 in 98% yield. Finally, the three o-xylylene groups in 11 were
1
H, H (6a)
H, H (6a)
(NH4)2MoO4, 10
(NH4)2MoO4, 10
(NH4)2MoO4, 10
(NH4)2MoO4, 10
MoO2(acac)2, 10
MoO2(TMHD)2, 10
TsOH, 10
(NH4)2MoO4, 10
MoO2(TMHD)2, 0.5
MoO2(Ph-quinolinolato)2, 1
0
10
88
46
77
91
44
96
2d
3
Me, Me (6b)
Bn, Bn (6c)
Bn, Bn (6c)
Bn, Bn (6c)
Bn, Bn (6c)
o-Xyl (6d)
o-Xyl (6d)
o-Xyl (6d)
4
5
6
7e
8
9
10
94 [90]f
83
a
The reaction of 6 (1 mmol) was conducted with molybdenum(VI)
oxide (10 mol%) in toluene (100 mL) under azeotropic reflux condi-
b
tions for 5 h. The amount of catalyst was calculated based on the
c
d
metal. Determined by 1H NMR analysis. The reaction was con-
ducted in the presence of C6F5CO2H (10 mol%) in mesitylene–DMF
e
1 v/v) for 12 h. The reaction was conducted in toluene
(9
(3 mL). The reaction was conducted for 3 h.
:
f
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longest linear sequence required 9 steps from 2,3-dihydroxyben-
zoic acid, with an overall yield of 50%.
In conclusion, we have convergently synthesized fluvibactin (1)
and vibriobactin (2) in respective overall yields of 65 and 50%.
Our MoO2(TMHD)2-catalyzed dehydrative cyclization was found
to be a powerful protocol for constructing the 2-(o,m-dihydrox-
yphenyl)oxazoline core at an early stage in the total synthesis. A
cyclic o-xylylene group was very effective for protecting the
catechol moieties. This compact protecting group helped the
dehydrative cyclization of 6d to proceed rapidly. Sb(OEt)3-cata-
lyzed ester–amide transformation of the primary amines was
conducted under solvent-free conditions, and diamide 8 and
monoamide 9 could be selectively synthesized just by appropri-
ately setting the ratio of 5 and 7. Furthermore, WSCIꢁHCl and
HOAt successfully promoted amide formation at the secondary
amines in 8 and 12 with carboxylic acid 10. These successes
significantly increased the overall yields of 1 and 2.
This project was supported by JSPS.KAKENHI (Grant
20245022), the Toray Science Foundation, the G-COE in
Chemistry, Nagoya and JSPS Research Fellowships for
Young Scientists (S.U.).
Scheme 3 Synthesis of fluvibactin (1). WSCIꢁHCl = 1-ethyl-3-(3-
dimethylaminopropyl)carbodiimide hydrochloride; HOAt = 1-hydro-
xy-7-azobenzotriazole.
easily removed by hydrogenolysis using 10% Pd/C to give 1 in
1
Notes and references
99% yield. Synthetic 1 showed H and 13C NMR spectra and
z Compound 7 was recovered in 50% yield. Monoamide 9 was
HRMS dataw that were identical to those reported for natural
fluvibactin.2 The longest linear sequence required 9 steps from
2,3-dihydroxybenzoic acid, with an overall yield of 65%.
obtained in 14% yield.
y The structures of the byproducts were not determined.
z Attempts at triamide formation between 12 and 3d using Sb(OEt)3
failed, and led to decomposition of the oxazoline moiety of 3d.
Vibriobactin (2) could be synthesized from 9, 3d and 10 via a
strategy similar to that for fluvibactin (1) (Scheme 4). Selective
monoamide formation between 5 and 7 could also be performed
using Sb(OEt)3. When the reaction of a 1 : 2 mixture of 7 and 5
was conducted in the presence of Sb(OEt)3 (1.0 equiv) under
solvent-free conditions at 80 1C, monoamide 9 was obtained in
88% yield along with diamide 8 (6%). Monoamide 9 was then
subjected to the second ester–amide transformation with an
equimolar amount of 3d using Sb(OEt)3 (1.0 equiv), and gave
diamide 12 in 90% yield. As in the case of fluvibactin, con-
densation of 12 with 10 (1.5 equiv) using WSCIꢁHCl and HOAt
(1.5 equiv) successfully gave triamide 13 in 82% yield.z The final
removal of the o-xylylene groups in 13 gave 2 in 99% yield.w The
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Scheme 4 Synthesis of vibriobactin (2).
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