Total synthesis of vulnibactin: A natural product iron chelator

Article abstract of DOI:10.1055/s-2007-965960

A short, high-yield, flexible synthesis is described for accessing vulnibactin and related siderophores, e.g., vibriobactin analogues and homologues. The spectral properties of the synthetic vulnibactin are identical with those reported for the natural pr

Full text of DOI:10.1055/s-2007-965960

PAPER
1033
Total Synthesis of Vulnibactin: A Natural Product Iron Chelator
Total
Synthesis
o
a
f
V
ulnibact
y
in mond J. Bergeron,* Neelam Bharti, Shailendra Singh
Department of Medicinal Chemistry, University of Florida, Gainesville, FL 32610-0485, USA
Fax +1(352)3928406; E-mail: rayb@ufl.edu
Received 15 November 2006; revised 20 December 2006
yl)spermidine (parabactin) (Figure 1). We described
the synthesis of this ligand and a number of other
polyamine-based catecholamide ligands that followed,
e.g., N4-[2-(2,3-dihydroxyphenyl)-(4S,5R)-trans-5-meth-
yl-2-oxazoline-4-carboxamido]-N1,N8-bis(2,3-dihydroxy-
benzoyl)spermidine (agrobactin),4 N4-[2-(2,3-dihydroxy-
phenyl)-(4S,5R)-trans-5-methyl-2-oxazoline-4-carbox-
amido]-N1,N7-bis(2,3-dihydroxybenzoyl)norspermidine
(fluviabactin),4 and N-[3-(2,3-dihydroxybenzamido)pro-
pyl]-1,3-bis[2-(2,3-dihydroxyphenyl)-trans-5-methyl-2-
oxazoline-4-carboxamido]propane (vibriobactin).5 This
current study focuses on the assembly of a new sidero-
Abstract: A short, high-yield, flexible synthesis is described for ac-
cessing vulnibactin and related siderophores, e.g., vibriobactin ana-
logues and homologues. The spectral properties of the synthetic
vulnibactin are identical with those reported for the natural product,
thus confirming the proposed structure of vulnibactin.
Key words: chelates, iron, medicinal chemistry, natural products,
receptors
The concentration of ferric ion required to support the
growth of most microorganisms lies in the range of
5 × 10–8 to 1 × 10–6 mol/L. However, because of the ex-
treme insolubility of ferric hydroxide at physiological pH,
about 10–18 mol/L,1 microorganisms have developed a
means of solubilizing and transporting this metal. Many
microbes excrete large quantities of low molecular weight
chelators, siderophores, which preferentially bind ferric
iron, rendering the metal accessible to the organism.2
In 1975, Tait3 isolated the first hexacoordinate catechola-
mide iron chelator predicated on a polyamine backbone,
N4-[2-(2-hydroxyphenyl)-(4S,5R)-trans-5-methyl-2-ox-
azoline-4-carboxamido]-N1,N8-bis(2,3-dihydroxybenzo-
phore,
N-[3-(2,3-dihydroxybenzamido)propyl]-1,3-
bis[2-(2-hydroxyphenyl)-trans-5-methyl-2-oxazoline-4-
carboxamido]propane (vulnibactin), isolated from vibrio
vulnificus.6
Since the time of parabactin’s isolation, considerable in-
terest has been focused on the biological and physical
properties of these catecholamide-based siderophores and
their ferric chelates.3,7 The coordination chemistry of a
number of catecholamide iron complexes has been thor-
oughly investigated. It has been determined that the for-
OH
OH
OH
HO
HO
OH
OH
N
O
N
O
HO
HO
OH
OH
O
O
O
O
O
O
N
HN
N
HN
N
N
H
H
parabactin
agrobactin
OH
OH
OH
OH
OH
OH
OH
OH
OH
HO
HO
HO
HO
HO
N
O
N
O
N
O
N
O
N
O
OH
O
HO
O
O
O
O
O
O
O
O
N
NH
N
NH
HN
HN
N
NH
HN
fluviabactin
vulnibactin
vibriobactin
Figure 1 Hexacoordinate catecholamide iron chelators predicated on a polyamine backbone
SYNTHESIS 2007, No. 7, pp 1033–1037
x
x
.
x
x
.2
0
0
7
Advanced online publication: 28.02.2007
DOI: 10.1055/s-2007-965960; Art ID: M06806SS
© Georg Thieme Verlag Stuttgart · New York

1034
R. J. Bergeron et al.
PAPER
mation constants for the 1:1 iron(III) complexes of many therapeutic design strategies, e.g., assembly of competi-
of these ligands at alkaline pH are in the range of 1048. The tive inhibitors and/or of irreversible covalent inhibitors of
biological studies of these ligands revolved around two transport.9 However, a high-yield, flexible synthetic
different issues: understanding the details of how micro- method providing facile access to the vulnibactin platform
organisms assembled and utilized these chelators for iron is first required.
assimilation and their application as deferration agents in
various iron overload diseases.
In fact, parabactin was shown to be nearly 300% more ef- sessed on the basis of NMR and mass spectral data.8 The
fective at removing iron from a rodent model than desfer- current synthesis provides facile access to large quantities
Vulnibactin was first isolated from cultures of Vibrio
vulnificus in a very small quantity and its structure as-
rioxamine,
a
clinically accepted agent for iron of the siderophore in addition to confirming the structural
decorporation. Unfortunately, as with desferrioxamine, assignment. As with vibriobactin (Figure 1), the position-
catecholamides do not work well orally, and require sub- al asymmetry of donor groups of vulnibactin sets the strat-
cutaneous administration.
egy for the synthesis. The primary difference between
vibriobactin and vulnibactin is that vulnibactin has 2-hy-
droxybenzoyl groups fixed to the oxazoline, while vibrio-
bactin has 2,3-dihydroxybenzoyl in this position. Briefly,
the synthesis of vibriobactin began with N5-benzyl-N1-
(tert-butoxycarbonyl)spermidine. This reagent was acy-
lated with 2,3-dimethoxybenzoyl chloride. The resulting
amide was debenzylated, the Boc group removed, and the
free nitrogens acylated with L-N-tert-butoxycarbonylthre-
onine. The threonyl Boc groups were removed and the
threonyl fragment condensed with the ethyl imidate of
2,3-dihydroxybenzoic acid to yield vibriobactin in an
overall yield of 31%. However, the initial reagent,
N4-benzoyl-N1-(tert-butoxycarbonyl)norspermidine,
although accessible in 63% overall yield, requires a six-
step synthesis. This of course reduces the overall yield to
20% making the assembly procedure cumbersome when
large quantities of vibriobactin are needed.
There are three notable structural features of the
polyamine catecholamide ligands: the nature of the
polyamine backbones, the ligand donor groups, and the
symmetry of the donor groups (Figure 1). The first two
catecholamides, parabactin and agrobactin, utilize sper-
midine, an unsymmetrical polyamine, as a backbone; each
presents with a 2,3-dihydroxybenzoyl donor at the termi-
nal nitrogens. Parabactin has a 2-(2-hydroxyphenyl)-
(4S,5R)-trans-5-methyl-2-oxazoline-4-carboxamide frag-
ment fixed to the central nitrogen, while agrobactin has
a 2-(2,3-dihydroxyphenyl)-(4S,5R)-trans-5-methyl-2-ox-
azoline-4-carboxamide fixed to the central nitrogen. The
latter three ligands, vibriobactin, fluviabactin, and vulni-
bactin employ the symmetrical polyamine norspermidine
with a 3,3-methylene backbone as a platform. Fluviabac-
tin, like parabactin and agrobactin, is symmetrical with re-
gards to the N-terminal 2,3-dihydroxybenzoyl donors. It
presents with the same central nitrogen donor as agrobac- The current synthesis of vulnibactin (Scheme 1) begins
tin.
with a starting material accessible in one step in 80%
yield, N-(tert-butoxycarbonyl)norspermidine (1).10 This
protected triamine is terminally N-acylated with 2,3-
dimethoxybenzoic acid in the presence of carbonyl diimi-
dazole to produce the diamide 2 in 99% yield. The t-Boc
protecting group is next removed with trifluoroacetic acid,
providing monamide 3 in 97% yield. This monamide di-
amine is acylated with N-Boc-threonine providing the tri-
amide 4 in 99% yield. The methyl and t-Boc protecting
group of 4 are removed simultaneously with BBr3 to gen-
erate catechol 5 in 90% yield. Finally, the ethyl imidate11
of salicylic acid is condensed with the triamide 5 to pro-
vide the final product in 90% yield. It is this step which al-
lows for access to a variety of different and potentially
useful tools. The aromatic imidates are easily accessible
and can be functionalized with any number of useful elec-
trophiles, e.g., halides, aldehydes, or photochemically ac-
tivatable groups, e.g., azides. The 1H NMR spectra and the
optical rotations were essentially identical with the report-
ed data, thus confirming the structure of vulnibactin. The
overall yield of the five-step synthesis beginning with
amide 1 is 76%, over twice that of our previous seven-step
vibriobactin synthesis. As described above, factoring the
starting material problem in the initial vibriobactin syn-
thesis, vibriobactin was generated in 20% yield. The same
consideration for the vulnibactin leads to a 60% yield. The
vulnibactin approach could also be used for assembly of
Both vibriobactin and vulnibactin are unsymmetrical with
respect to the ligating groups. Both have a single 2,3-di-
hydroxybenzoyl donor fixed to a terminal nitrogen on nor-
spermidine. The remaining two nitrogens in vibriobactin
are coupled to 2-(2,3-dihydroxyphenyl)-(4S,5R)-trans-5-
methyl-2-oxazoline-4-carboxamide groups, while vulni-
bactin utilizes a 2-(2-hydroxyphenyl)-(4S,5R)-trans-5-
methyl-2-oxazoline-4-carboxamide fragment on the re-
maining two nitrogens.
The first two ligands are derived from soil microorgan-
isms, parabactin from Paracoccus dentrificans and agro-
bactin from Agrobacterium tumefaciens. The last three
ligands are derived from human pathogens, vibriobactin
from Vibrio cholera, fluviabactin from Vibrio fluvialis
and vulnibactin from Vibrio vulnificus. Both Vibrio fluvi-
alis and Vibrio vulnificus are halophilic opportunistic
pathogens.
Recent studies with a CRP mutant of Vibrio vulnificus
showed that transcriptional suppression of genes respon-
sible for vulnibactin synthesis and vulnibactin receptor
proteins, vis and vuuA, resulted in less pathogenic organ-
isms. The CRP mutant was unable to utilize transferrin-
bound iron and its growth was severely retarded on both
transferrin-bound iron and cirrhotic ascites.8 This finding
makes the vulnibactin transporter an attractive target in
Synthesis 2007, No. 7, 1033–1037 © Thieme Stuttgart · New York

PAPER
Total Synthesis of Vulnibactin
1035
O
O
O
O
O
O
O
O
b
a
H
O
O
H
N
H
N
NH2
HN
NH
HN
N
HN
NH2
3
1
2
c
OH
O
OH
O
O
O
O
HO
HO
O
O
HO
HO
OH
H2N
H2N
O
OH
N
O
N
O
OH
HN
HN
OH
e
d
O
O
O
O
O
O
O
N
NH
HN
N
NH
N
NH
HN
HN
⋅2HBr
5
4
6
Scheme 1 Synthesis of vulnibactin (6). Reagents and conditions: (a) 2,3-dimethoxybenzoic acid, CDI, CH2Cl2 (99%); (b) TFA, CH2Cl2, 0 °C
(97%); (c) N-Boc-threonate, DMF, 72 h (99%); (d) BBr3, CH2Cl2, –78 °C (90%); (e) ethyl 2-hydroxybenzimidate, EtOH, 70 °C, 36 h (90%).
vibriobactin and lends itself nicely to scale-up. Assembly In conclusion, a short, high-yield, flexible synthesis is
of the D-threonyl analogues is currently underway.
available for accessing vulnibactin and related sidero-
phores, e.g., vibriobactin analogues and homologues. The
spectral properties of the synthetic vulnibactin are identi-
cal with those reported for the natural product, thus con-
firming the proposed structure of vulnibactin.
The stoichiometry of the ferric complex of vulnibactin
was determined at lmax 558nm. The Job’s plot of the com-
plex is in keeping with a 1:1 ligand-to-metal stoichiome-
try (Figure 2).
Reagents were purchased from Aldrich Chemical Co. (Milwaukee,
WI), and Fisher Optima-grade solvents were routinely used. Organ-
ic extracts were dried with Na2SO4 and filtered. DMF was distilled
under an inert atmosphere. Distilled solvents and glassware that had
been presoaked in 3 N HCl for 15 min were employed in reactions
involving chelators. Silica gel 70–230 from Fisher Scientific was
utilized for column chromatography, and silica gel 32–63 from Se-
lecto Scientific, Inc. (Suwanee, GA) was used for flash column
chromatography. Sephadex LH-20 was obtained from Amersham
Biosciences (Piscataway, NJ). Melting points are uncorrected. Op-
tical rotation was run at 589 nm (sodium D line) utilizing a Perki-
nElmer 341 polarimeter with c as g of compound/100 mL of
solution. NMR spectra were obtained at 400 MHz (1H) or 100 MHz
(13C) on a Varian Mercury-400BB spectrometer. Chemical shifts
(d) for 1H spectra are given in parts per million downfield from tet-
ramethylsilane for organic solvents (CDCl3 not indicated). Chemi-
cal shifts (d) for 13C spectra are given in parts per million referenced
to the residual solvent resonance in CDCl3 (d = 77.16) or CD3OD
(d = 49.00). Coupling constants (J) are in Hertz. The base peaks are
reported for the ESI-FTICR mass spectra.
N1-(tert-Butoxycarbonyl)norspermidine (1) was prepared as previ-
ously described.10
N1-(tert-Butoxycarbonyl)-N8-(2,3-dimethoxybenzoyl)norsper-
midine (2)
Figure 2 Job’s plot of the iron(III) complex of vulnibactin. Briefly,
solutions containing different ligand/Fe (III) ratios were prepared
such that [ligand] + [Fe(III)] = 1.0 mM. The data points were fitted to
the mole fraction (1) from 0 to 0.5 and (2) from 0.5 to 1.00,
r2 = 0.9996 and 0.9987, respectively. The theoretical mole fraction
for a 1:1 ligand-to-iron complex is 0.5. A linear intercept maximum
of 0.55 was found at 558 nm.
1,1¢-Carbonyldiimidazole (2.80 g, 17.29 mmol) was added to a so-
lution of 2,3-dimethoxybenzoic acid (3.15 g, 17.29 mmol) in
CH2Cl2 (25 mL). After stirring for 1 h, the mixture was added to a
solution of N1-(tert-butoxycarbonyl)norspermidine (1; 4.0 g, 17.29
mmol) in CH2Cl2 (20 mL) at 0 °C. The solution was stirred for 16 h
(0 °C to r.t.), and was washed with aq 2 N NaOH (25 mL) and evap-
Synthesis 2007, No. 7, 1033–1037 © Thieme Stuttgart · New York

1036
R. J. Bergeron et al.
PAPER
orated in vacuo. Chromatography on silica gel eluting with 0.5%
NH4OH–MeOH gave 6.70 g (99%) of 2 as a viscous oil.
1H NMR (CD3OD): d = 1.25–1.33 (m, 6 H), 1.79–2.02 (m, 4 H),
3.29–4.32 (m, 12 H), 6.70–6.76 (m, 1 H), 6.92–6.95 (m, 1 H), 7.21–
7.26 (m, 1 H).
13C NMR (CD3OD): d = 20.2, 20.4, 28.2, 29.6, 37.9, 38.1, 44.8,
46.9, 56.8, 60.4, 67.4, 67.8, 116.7, 118.8, 119.6, 119.7, 147.3,
150.1, 168.6, 168.8, 171.6.
1H NMR: d = 1.43 (s, 9 H), 1.65 (quint, J = 6.6 Hz, 2 H), 1.79 (quint,
J = 6.6 Hz, 2 H), 2.63–2.72 (m, 4 H), 3.20 (q, J = 6.0 Hz, 2 H), 3.55
(q, J = 6.4, 2 H), 3.88 (s, 3 H), 3.89 (s, 3 H), 5.37 (br s, 1 H), 7.03
(dd, J = 8.0, 1.6 Hz, 1 H), 7.14 (t, J = 8.0 Hz, 1 H), 7.66 (dd, J = 7.6,
1.6 Hz, 1 H), 8.15 (br s, 1 H).
13C NMR: d = 28.5, 29.8, 29.9, 37.7, 39.0, 47.3, 47.6, 56.1, 61.3,
78.8, 115.2, 122.7, 124.5, 127.1, 147.4, 152.6, 156.2, 165.3.
HRMS: m/z calcd for C21H35N5O7: 470.2609 (M + H, free amine);
found: 470.2600.
N-[3-(2,3-Dihydroxybenzamido)propyl]-1,3-bis[2-(2-hydroxy-
phenyl)-trans-5-methyl-2-oxazoline-4-carboxamido]propane
(Vulnibactin) (6)
HRMS: m/z calcd for C20H33N3O5: 396.2493 (M + H); found:
396.2482.
Ethyl 2-hydroxybenzimidate11 (0.85 g, 5.12 mmol) was added to a
solution of 5 (1.01 g, 1.60 mmol) in anhyd EtOH (25 mL). The mix-
ture was heated at reflux under N2 for 36 h and then concentrated in
vacuo. Column chromatography on LH-20 (eluting with 10%
EtOH–toluene) afforded 0.97 g (90%) of 6 as a grey solid. The spec-
tral characteristics were identical with those reported in the litera-
ture;6 mp 94–97 °C (Lit.6 mp 93–97 °C); [a]25 +92.5 (c = 0.80,
CH3OH).
1H NMR (CD3OD): d = 1.40 (2 d, J = 6.4, 3 H), 1.51 (2 d, J = 6.4
Hz, 3 H), 1.76–1.88 (m, 2 H), 1.91–2.09 (m, 2 H), 3.12–3.85 (m, 8
H), 4.42 (2 d, J = 7.2 Hz, 1 H), 4.77 (2 d, J = 6.4 Hz, 1 H), 4.91 (2
quint, J = 6.4 Hz, 1 H), 5.24 (2 quint, J = 6.4 Hz, 1 H), 6.65 (2 t,
J = 8.0 Hz, 1 H), 6.78–6.94 (m, 5 H), 7.17–7.21 (m, 1 H), 7.28–7.40
(m, 2 H), 7.57–7.65 (m, 2 H).
N1-(2,3-Dimethoxybenzoyl)norspermidine (3)
Freshly distilled trifluoroacetic acid (48 mL) in CH2Cl2 (10 mL)
was added dropwise to a flask containing 2 (6.30 g, 16.10 mmol) in
CH2Cl2 (30 mL) under N2 with ice-bath cooling and the mixture was
stirred at 0 °C for 1 h and at r.t. for 1 h. Solvents were removed un-
der vacuum to give a light brown oil. The oil was taken up in CH2Cl2
(100 mL) and extracted with aq sat. K2CO3 (2 × 25 mL). The com-
bined organic layers were evaporated in vacuo to give 4.61 g (97%)
of 3.
1H NMR: d = 1.66 (quint, J = 6.8 Hz, 2 H), 1.81 (quint, J = 6.8 Hz,
2 H), 2.70–2.81 (m, 6 H), 3.55 (q, J = 6.4 Hz, 2 H), 3.89 (s, 3 H),
3.90 (s, 3 H), 7.03 (dd, J = 8.0, 1.6 Hz, 1 H), 7.15 (t, J = 8.0 Hz, 1
H), 7.66 (dd, J = 8.0, 1.6 Hz, 1 H), 8.12 (br s, 1 H).
13C NMR: d = 29.2, 30.5, 37.2, 40.8, 46.6, 48.4, 56.1, 61.4, 115.4,
122.6, 124.5, 152.6, 161.9, 162.6, 165.9.
13C NMR (CD3OD): d = 20.2, 21.4, 28.3, 30.1, 37.6, 37.8, 44.6,
46.6, 72.9, 75.7, 79.7, 80.6, 111.5, 111.6, 116.7, 117.6, 117.7,
118.5, 119.6, 119.7, 119.9, 120.0, 129.4, 129.6, 135.0, 135.1, 147.4,
150.3, 160.9, 161.1, 167.4, 167.9, 171.1, 171.6, 173.2.
HRMS: m/z calcd for C15H25N3O3: 296.1969 (M + H); found:
296.1965.
HRMS: m/z calcd for C35H39N5O9: 675.2891 (M + 2 H); found:
675.2871.
N1,N4-Bis[(L)-N-tert-butoxycarbonylthreonyl]-N7-(2,3-dimeth-
oxybenzoyl)norspermidine (4)
A solution of freshly prepared (L)-N-hydroxysuccinimido-N-(tert-
butoxycarbonyl)threonate)12 (3.48 g, 11.0 mmol) in DMF (25 mL)
was added to a solution of 3 (1.48g, 5.0 mmol) in anhyd DMF (25
mL). After stirring for 72 h, the solvent was removed under vacuum
and the residue was taken up in CH2Cl2 (100 mL). The CH2Cl2 layer
was washed with aq 5% K2CO3 (3 × 50 mL), distilled H2O (50 mL),
brine, and concentrated in vacuo. Flash chromatography eluting
with 10% EtOH–EtOAc afforded 3.45 g (99%) of 4 as a white foam.
1H NMR: d = 1.15–1.24 (m, 6 H), 1.45 (s, 18 H), 1.62–2.01 (m, 4
H), 3.20–3.74 (m, 8 H), 3.89 (s, 3 H), 3.91 (s, 3 H), 3.96–4.59 (m, 6
H), 5.60 (d, J = 9.2 Hz, 2 H), 7.03–7.06 (m, 1 H), 7.11–7.17 (m, 1
H), 7.62–7.66 (m, 1 H), 8.35 (br, 1 H).
Determination of Stoichiometry of Ligand–Fe(III) Complex
(Job’s Plot)
The stoichiometry of ligand–Fe(III) complex of vulnibactin was de-
termined spectrophotometrically from Job’s plot. Solutions were
monitored at the visible lmax (558 nm). A 25 mM MOPS buffer with
50% MeOH (v/v) was used to maintain pH at 7.4. Solutions contain-
ing different ligand/Fe(III) ratios were prepared by mixing appro-
priate volumes of 0.9 mM ligand solution (pH 7.4) and 0.9 mM
Fe(III) nitriloacetate (NTA) in MOPS–MeOH solution (pH 7.4).
The 0.9 mM Fe(III)-NTA solution was prepared immediately prior
to use by dilution of a 45 mM Fe(III)-NTA stock solution with
MOPS–MeOH (50:50) mixture. The Fe(III)-NTA stock solution
was prepared by mixing equal volumes of 90 mM of FeCl2 and 180
mM trisodium NTA. The iron content was verified by ICP-MS.
13C NMR: d = 18.9, 19.3, 27.8, 28.3, 28.4, 28.8, 36.3, 37.3, 42.9,
45.2, 53.5, 56.1, 59.0, 61.4, 67.3, 68.6, 80.1, 80.5, 115.4, 122.6,
124.4, 126.7, 147.6, 152.6, 156.4, 165.6, 171.3, 172.1, 173.0.
HRMS: m/z calcd for C35H55N5O11 698.3971 (M + H); found:
698.3960.
Acknowledgment
Funding was provided by the National Institutes of Health Grant
No. R37-DK49108. We acknowledge the spectroscopy services in
the Chemistry Department, University of Florida, for the mass spec-
trometry analyses.
N1,N4-Bis[(L)-threonyl]-N7-(2,3-dimethoxybenzoyl)norspermi-
dine Dihydrobromide (5)
A 1 M solution of BBr3 (62.3 mL, 62.3 mmol) was added dropwise
at –78 °C to a solution of 4 (2.90 g, 4.16 mmol) in CH2Cl2 (50 mL).
After complete addition of BBr3, the mixture was allowed to warm
to r.t. and stirred for an additional 20 h. The mixture was cooled to
0 °C and cautiously treated dropwise with H2O (75 mL). After 3 h
of vigorous stirring, the aqueous layer was removed and evaporated
in vacuo at 25 °C to give a light brown solid. This residue was taken
up in EtOH (25 mL) and concentrated several times. The resulting
brown solid was easily purified on Sephadex LH-20 eluting with
20% EtOH–toluene to give 2.35 g (90%) of 5 as a brown solid.
References
(1) Raymond, K. N.; Carrano, C. J. Acc. Chem. Res. 1979, 12,
183.
(2) (a) Winkelmann, G. Biochem. Soc. Trans. 2002, 30, 691.
(b) Albrecht-Gary, A. M.; Crumbliss, A. L. In Metal Ions in
Biological Systems, Vol. 35; Sigel, A.; Sigel, H.; Sigel, K.,
Eds.; Taylor & Francis: New York, 1998, 239.
(c) Neilands, J. B. Annu. Rev. Biochem. 1981, 50, 715.
(3) Tait, G. H. Biochem. J. 1975, 146, 191.
Synthesis 2007, No. 7, 1033–1037 © Thieme Stuttgart · New York

PAPER
(4) Bergeron, R. J.; Xin, M. G.; Weimar, W. R.; Smith, R. E.;
Wiegand, J. J. Med. Chem. 2001, 44, 2469.
(5) Bergeron, R. J.; Garlich, J. R.; McManis, J. S. Tetrahedron
1985, 41, 507.
Total Synthesis of Vulnibactin
1037
(9) Diarra, M. S.; Lavoie, M. C.; Jacques, M.; Darwish, I.;
Dolence, E. K.; Dolence, J. A.; Ghosh, A.; Ghosh, M.;
Miller, M. J.; Malouin, F. Antimicrob. Agents Chemother.
1996, 40, 2610.
(6) Okujo, N.; Saito, M.; Yamamoto, S.; Yoshida, T.; Miyoshi,
S.; Shinoda, S. BioMetals 1994, 7, 109.
(10) Krapcho, A. P.; Kuell, C. S. Synth. Commun. 1990, 20, 2559.
(11) Loughlin, W. A.; Knevitt, S. A.; Hosking, R. E.; Marshall,
R. L. Aust. J. Chem. 2000, 53, 457.
(12) Bergeron, R. J.; Kline, S. J. J. Am. Chem. Soc. 1984, 106,
3089.
(7) (a) Peterson, T.; Neilands, J. B. Tetrahedron Lett. 1979, 20,
4805. (b) Peterson, T.; Falk, K.-E.; Leong, S. A.; Klein, M.
P.; Neilands, J. B. J. Am. Chem. Soc. 1980, 102, 7715.
(8) Choi, M.-H.; Sun, H.-Y.; Park, R.-Y.; Kim, C.-M.; Bai, Y.-
H.; Kim, Y.-R.; Rhee, J.-H.; Shin, S.-H. FEMS Microbiol.
Lett. 2006, 257, 285.
Synthesis 2007, No. 7, 1033–1037 © Thieme Stuttgart · New York