Design and stereoselective synthesis of a C-aryl furanoside as a conformationally constrained CHIR-090 analogue

Article abstract of DOI:10.1016/j.carres.2012.06.006

The UDP-3-O-[(R)-3-hydroxymyristoyl]-N-acetylglucosamine deacetylase (LpxC) is a promising target for the development of novel antibiotic substances against multidrug-resistant Gram-negative bacteria. The C-aryl glycoside 3 was designed as conformationally constrained analogue of the potent LpxC-inhibitor CHIR-090. The chiral pool synthesis of 3 started with d-mannose. The C-aryl glycoside 8 was synthesized stereoselectively by nucleophilic attack of 4-iodine-substituted phenyllithium and subsequent reduction with Et ₃SiH. The ester 10 was obtained in a one-pot diol cleavage, CrO ₃ oxidation, and esterification. A Sonogashira reaction of the aryl iodide 11 led to the alkyne 17 which was transformed with H₂NOH into the hydroxamic acid 3.

Full text of DOI:10.1016/j.carres.2012.06.006

Carbohydrate Research 359 (2012) 59–64
Contents lists available at SciVerse ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Design and stereoselective synthesis of a C-aryl furanoside as a
conformationally constrained CHIR-090 analogue
⇑
Alberto Oddo, Ralph Holl
Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Hittorfstraße 58-62, D-48149 Münster, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 April 2012
Received in revised form 10 June 2012
Accepted 11 June 2012
Available online 18 June 2012
The UDP-3-O-[(R)-3-hydroxymyristoyl]-N-acetylglucosamine deacetylase (LpxC) is a promising target for
the development of novel antibiotic substances against multidrug-resistant Gram-negative bacteria.
The C-aryl glycoside 3 was designed as conformationally constrained analogue of the potent LpxC-
inhibitor CHIR-090.
The chiral pool synthesis of 3 started with D-mannose. The C-aryl glycoside 8 was synthesized stereose-
lectively by nucleophilic attack of 4-iodine-substituted phenyllithium and subsequent reduction with
Et3SiH. The ester 10 was obtained in a one-pot diol cleavage, CrO3 oxidation, and esterification. A Sono-
gashira reaction of the aryl iodide 11 led to the alkyne 17 which was transformed with H2NOH into the
hydroxamic acid 3.
Keywords:
LpxC inhibitors
CHIR-090 analogue
C-Glycosides
Ó 2012 Elsevier Ltd. All rights reserved.
Diphenylacetylenes
1. Introduction
tors share common structural features including a Zn2+-coordinat-
ing hydroxamate group as well as a hydrophobic moiety which
Despite the large number of antibiotics being available today,
there is an urgent need for novel antibiotic substances as an increas-
ing number of bacterial pathogens develops resistance mechanisms
against the major classes of commercial antibacterials.1,2
mimics the natural substrate’s fatty acid chain and therefore occu-
pies the enzyme’s hydrophobic substrate binding tunnel.16
In disc diffusion assays, CHIR-090, which is one of the most
extensively studied LpxC inhibitors, shows an antibacterial activity
against E. coli and Pseudomonas aeruginosa comparable to that of
ciprofloxacin.15 Therefore, this substance was chosen as lead com-
pound for the design of the C-glycosidic CHIR-090 analogue 3. In
this conformationally constrained derivative the pharmacophoric
hydroxamate moiety and the diphenylacetylene side chain of
CHIR-090 are fixed in a defined spatial orientation. The conforma-
tional restriction should lead to a reduced loss of degrees of free-
dom when binding to the enzyme, leading to a higher affinity.
The central C-glycosidic scaffold was inspired by the sugar moiety
of LpxC’s natural substrate 1. In compound 3, the amide group of
CHIR-090 and the hydroxyethyl moiety of its threonyl group are
replaced by a 3,4-dihydroxytetrahydrofuran ring. Although the
hydrogen-bond donating NH group of CHIR-090’s amide moiety
is exchanged by an ether oxygen, the affinity of oxazoline deriva-
tive L-161,240 toward the enzyme indicates that also a hydro-
gen-bond acceptor is tolerated in that position.
In order to combat infections caused by multiresistant Gram-
negative bacteria, the inhibition of the biosynthesis of lipid A
was identified as an attractive strategy which is so far unexploited
by commercially available drugs.3,4 Lipid A is a hexaacylated gluco-
samine disaccharide and represents the hydrophobic membrane
anchor of lipopolysaccharide (LPS), constituting the main compo-
nent of the outer leaflet of the outer membrane of Gram-negative
bacteria.5 While bacteria with a defective lipid A biosynthesis show
an increased sensitivity to a range of anti-infective drugs as well as
a decreased viability, the inhibition of the biosynthesis of lipid A is
lethal to Gram-negative bacteria.6–10
LpxC is a Zn2+-dependent enzyme catalyzing the irreversible
deacetylation of UDP-3-O-[(R)-3-hydroxymyristoyl]-N-acetylglu-
cosamine (1) which is the first committed step in the biosynthesis
of lipid A (Fig. 1).11,12 As the inhibition of LpxC is lethal to Esche-
richia coli and other Gram-negative bacteria, inhibitors of this key
enzyme are promising new antibiotics.13
Some inhibitors of LpxC have been described in the literature:
the hydroxamate-containing substrate-analogue TU-514,14 the aryl
oxazoline derivative L-161,240,9 the sulfonamide BB-78485,10 and
the diphenylacetylene derivative CHIR-090 (Fig. 2).15 These inhibi-
In this paper we wish to report the synthesis of C-glycoside 3
which will serve as starting point for the preparation of a new class
of potential LpxC inhibitors.
2. Synthesis
⇑
In the first step of the chiral pool synthesis, the tetrahydrofuran
scaffold of the designed LpxC inhibitors had to be established
Corresponding author. Tel.: +49 251 8333372; fax: +49 251 8332144.
E-mail address: hollr@uni-muenster.de (R. Holl).
0008-6215/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.carres.2012.06.006

60
A. Oddo, R. Holl / Carbohydrate Research 359 (2012) 59–64
OH
OH
desired furanose system. Lactol 5 was transformed into lactone 6
by a Swern oxidation.18
LpxC
O
O
HO
HO
O
O
In the next step of the synthesis an aromatic moiety bearing a
good leaving group for a Sonogashira cross-coupling reaction
should be introduced to the tetrahydrofuran scaffold. Therefore
4-iodine-substituted phenyllithium was generated by treating
1,4-diiodobenzene with n-butyllithium in THF at ꢀ78 °C. In order
to avoid a double halogen-metal exchange, a fourfold excess of
1,4-diiodobenzene over n-butyllithium was employed. The nucleo-
philic attack of the generated aryllithium species to lactone 6
yielded hemiketal 7.19 In its 1H NMR spectrum only one anomer
could be observed.
O
HN
O
H2N
UDP
CH3
UDP
acetate
O
HO
HO
( )10
( )10
H3C
H3C
1
2
Figure 1. LpxC catalyzed deacetylation of UDP-3-O-[(R)-3-hydroxymyristoyl]-N-
acetylglucosamine (1).
OH
Subsequent reduction with Et3SiH and BF3ꢁOEt2 led to the stereo-
controlled transformation of hemiketal 7 into C-glycoside 8. This SN1
type reaction proceeded via an oxocarbenium ion generated by
BF3ꢁOEt2. The hydride of triethylsilane was then transferred to this
O
HO
O
TU-514
Ki ~ 650 nM
O
O
OH
N
H
carbocation from the less hindered Re-face yielding the C-aryl b-
D-
H3C
HO
mannofuranoside 8. Due to the presence of the Lewis acid BF3
a
partial cleavage of the side chain acetonide occurred additionally.
Therefore, the crude product of the reduction was dissolved in meth-
anol and catalytic amounts of p-toluenesulfonic acid were added to
completely convert the remaining bisacetonide 8 into the desired diol
9. The stereochemistry of the tetrahydrofuran scaffold of 9 was con-
firmed by 1H NMR spectroscopy. The doublet caused by the newly
introduced proton in 5-position shows a coupling constant of 3.6 Hz
indicating its cis-orientation relative to the proton in 4-position of
the tetrahydrofuran ring. The obtained 1H NMR data of 9 are in agree-
OCH3
OCH3
O
L-161,240
N
N
H
Ki ~ 50 nM
O
CH3
O
H
N
HO
BB-78485
Ki ~ 20 nM
N
S
O
H
O
ment with the already described C-phenyl b-D
-mannofuranoside.19
In order to transform the 1,2-diol 9 into the ester 10, an oxidant
solution composed of periodic acid and catalytic amounts of CrO3
in wet acetonitrile was used.20 First, the periodic acid led to a gly-
col cleavage, then the CrO3-mediated oxidation of the resulting
aldehyde yielded the corresponding carboxylic acid. After work-
up and extraction, the acid was transformed into methyl ester 10
by heating the crude product in methanol in the presence of p-tol-
uenesulfonic acid. These acidic reaction conditions led to partial
cleavage of the acetonide affording a mixture of acetonide 10
and diol 11. Heating ester 10 in methanol containing catalytic
amounts of p-toluenesulfonic acid led to the cleavage of the isopro-
pylidene protecting group to give diol 11.
N
O
O
H
N
CHIR-090
HO
HO
N
H
Ki ~ 2 nM
O
HO
CH3
N
O
O
O
3
N
H
HO
OH
The side chain of CHIR-09021 was synthesized in three reaction
steps (Scheme 2). First, 4-bromobenzyl bromide (12) was reacted
with morpholine (13) affording the tertiary amine 14. Subsequent
Sonogashira coupling of 14 with trimethylsilylacetylene gave the
silyl protected phenylacetylene 15. Finally, the fluoride-mediated
removal of the silyl protective group yielded the phenylacetylene
16.
Figure 2. Structures and Ki values versus E. coli LpxC of several LpxC inhibitors15
compared with the structure of the newly designed hydroxamic acid 3.
(Scheme 1). Therefore,
D-mannose (4) was reacted with
acetone using iodine as catalyst.17 The reaction led to the
thermodynamically most stable bisacetonide 5, possessing the
O
O
O
OH
H3C
H3C
H3C
H3C
H3C
H3C
O
5
O
O
OH
O
O
OH
OH
HO
HO
O
O
O
(a)
(b)
(c)
(d)
O
O
O
O
O
O
I
OH
4
H3C
CH3
H3C
CH3
H3C
CH3
6
7
O
O
HO
HO
I
I
I
H3C
H3C
O
O
9
O
O
I
O
H3CO
O
(e)
(f)
H3CO
+
O
O
O
O
O
O
HO
OH
H3C
CH3
H3C
CH3
H3C
CH3
8
10
11
(g)
Scheme 1. Reagents and conditions: (a) acetone, I2, rt, 2 h, 51%; (b) oxalyl chloride, DMSO, CH2Cl2, ꢀ78 °C, 10 min, then 5, 30 min, then NEt3, rt, 91%; (c) 1,4-diiodobenzene, n-
BuLi, THF, ꢀ78 °C, 15 min, then 6, 30 min, 71%; (d) BF3ꢁOEt2, Et3SiH, H3CCN, ꢀ40 °C, 1 h; (e) p-TsOH, MeOH, rt, 16 h, 56% (over two steps); (f) (1) CrO3/H5IO6, H3CCN, rt, 3 h; (2)
p-TsOH, MeOH,
D, 16 h, 40% (10) and 37% (11); (g) p-TsOH, MeOH, D, 16 h, 39%.

A. Oddo, R. Holl / Carbohydrate Research 359 (2012) 59–64
61
N
(a)
(b)
O
Br
HN
N
+
H3C
Si
O
O
Br
Br
H3C
CH3
12
13
14
15
N
11
(d)
O
N
(c)
(e)
O
O
O
H3CO
HC
HO
OH
16
17
N
O
O
O
HO
N
H
HO
OH
3
Scheme 2. Reagents and conditions: (a) H3CCN,
D, 4 h, 98%; (b) (H3C)3SiC„CH, Pd(PPh3)4, CuI, NEt3, D, 16 h, 71%; (c) Bu4NF, THF, 0 °C, 30 min, 99%; (d) Pd(PPh3)4, CuI, NEt3,
H3CCN, rt, 2 h, 26%; (e) H2NOHꢁHCl, NaOMe, MeOH, rt, 16 h, 29%.
The aromatic substituent of CHIR-090 was introduced into the
C-glycosidic scaffold of 11 by a Sonogashira coupling.22 Reaction
of aryl iodide 11 with phenylacetylene 16 gave access to the
diphenylacetylene 17.
z (% of basis peak). HPLC methods for the determination of product
purity: Method 1: Merck Hitachi Equipment; UV detector: L-7400;
autosampler: L-7200; pump: L-7100; degasser: L-7614; column:
LiChrospherÒ 60 RP-select B (5
l
m); LiCroCARTÒ 250-4 mm car-
In the last step the hydroxamate group was established. Treat-
ment of ester 17 with hydroxylamine hydrochloride and sodium
methoxide in dry methanol yielded the desired hydroxamic acid 3.23
tridge; flow rate: 1.00 mL/min; injection volume: 5.0 lL; detection
at k = 210 nm for 30 min; solvents: A: water with 0.05% (V/V) triflu-
oroacetic acid; B: acetonitrile with 0.05% (V/V) trifluoroacetic acid:
gradient elution: (A%): 0–4 min: 90% , 4–29 min: gradient from 90%
to 0%, 29–31 min: 0%, 31–31.5 min: gradient from 0% to 90%, 31.5–
40 min: 90%. Method 2: Merck Hitachi Equipment; UV detector:
3. Conclusion
L-7400; pump: L-6200A; column: phenomenex GeminiÒ
5
l
m C6-
Phenyl 110 Å; LC Column 250 ꢃ 4.6 mm; flow rate: 1.00 mL/min;
injection volume: 5.0 L; detection at k = 254 nm for 20 min; sol-
A convergent synthesis was established giving access to the
conformationally constrained CHIR-090 analogue 3. This hydroxa-
mic acid possesses a C-glycosidic scaffold, which replaces the thre-
onine amide substructure of CHIR-090, and displays the first
representative of a novel class of LpxC inhibitors.
l
vents: A: acetonitrile:10 mM ammonium formate = 10:90 with
0.1% formic acid; B: acetonitrile:10 mM ammonium formate =
90:10 with 0.1% formic acid; gradient elution: (A%): 0–5 min:
100%, 5–15 min: gradient from 100% to 0%, 15–20 min: 0%, 20–
22 min: gradient from 0% to 100%, 22–30 min: 100%.
4. Experimental section
4.1. Chemistry, general
4.2. Synthetic procedures
4.2.1. (3aS,4S,6R,6aS)-6-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-
2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-ol (5)
Unless otherwise mentioned, THF was dried with sodium/benzo-
phenone and was freshly distilled before use. Thin layer chromatog-
raphy (TLC): Silica gel 60 F254 plates (Merck). Flash
Iodine (1.42 g, 5.6 mmol) was added to a suspension of D-man-
nose (5.0 g, 27.8 mmol) in acetone (250 mL) and the mixture was
stirred for 2 h at ambient temperature. Then the reaction mixture
was cooled down to 0 °C quenched with aqueous sodium bicarbon-
ate and sodium thiosulfate. The mixture was extracted with CH2Cl2
(3ꢃ). The combined organic layers were dried (Na2SO4), filtered,
and the solvent was removed in vacuo. The crude product was
crystallized from an acetone/n-hexane mixture to give 5 as color-
chromatography (fc): Silica Gel 60, 40–64 lm (Macherey-Nagel);
parentheses include: diameter of the column, fraction size, eluent,
Rf value. Melting point (mp): Melting point apparatus SMP 3 (Stuart
Scientific), uncorrected. Optical rotation
a [°] was determined with
a Polarimeter 341 (Perkin Elmer); path length 1 dm, wavelength
589 nm (sodium D line); the unit of the specific rotation ½a D20
ꢂ
[° mL dmꢀ1 gꢀ1] is omitted; the concentration of the sample c
[mg mLꢀ1] and the solvent used are given in brackets. 1H NMR
(400 MHz), 13C NMR (100 MHz): Mercury plus 400 spectrometer
(Varian); d in ppm related to tetramethylsilane; coupling constants
are given with 0.5 Hz resolution. Where necessary, the assignment
of the signals in the 1H NMR and 13C NMR spectra was performed
using 1H–1H and 1H–13C COSEY NMR spectra as well as NOE (nuclear
Overhauser effect) difference spectroscopy. IR: IR Prestige-21 (Shi-
madzu). MS: HRMS: MicrOTOF-QII (Bruker); ESI: LCQ Finnigan
MAT mass spectrometer (Thermo Finnigan), peaks are given in m/
less solid (3.66 g, 14.1 mmol, 51%). Mp: 125 °C; ½a D20
ꢂ
+16.1 (8.1;
CH2Cl2); 1H NMR (CDCl3): d (ppm) = 1.32 (s, 3H, CH3), 1.38 (s, 3H,
CH3), 1.45 (s, 3H, CH3), 1.46 (s, 3H, CH3), 2.92 (d, J = 2.4 Hz, OH),
4.02–4.11 (m, 2H, OCHCH2O), 4.18 (dd, J = 7.2/3.7 Hz, 1H, 6-H),
4.37–4.43 (m, 1H, OCHCH2O), 4.62 (d, J = 5.9 Hz, 1H, 3a-H), 4.81
(dd, J = 5.9/3.7 Hz, 1H, 6a-H), 5.38 (d, J = 2.4 Hz, 4-H); 13C NMR
(CDCl3): d (ppm) = 24.5 (1C, C(CH3)2), 25.3 (1C, C(CH3)2), 25.9 (1C,
C(CH3)2), 27.1 (1C, C(CH3)2), 66.7 (1C, OCHCH2O), 73.4 (1C, OCH-
CH2O), 79.7 (1C, C-6a), 80.3 (1C, C-6), 85.5 (1C, C-3a), 101.3 (1C,

62
A. Oddo, R. Holl / Carbohydrate Research 359 (2012) 59–64
C-4), 109.2 (1C, C(CH3)2), 112.8 (1C, C(CH3)2); IR (neat):
m
(cmꢀ1) =
4.2.4. (R)-1-[(3aS,4R,6S,6aR)-6-(4-Iodophenyl)-2,2-dimethyl-
3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]ethane-1,2-diol
(9)
3436, 2978, 2948, 2899, 1372, 1201, 1060, 975, 838; HRMS (m/z):
[M+Na]+ calcd for C12H20O6Na, 283.1152; found, 283.1152.
Under N2 atmosphere Et3SiH (0.63 mL, 452 mg, 3.9 mmol) was
added to a solution of 7 (1.5 g, 3.2 mmol) and BF3ꢁEt2O (0.41 mL,
460 mg, 3.2 mmol) in acetonitrile (30 mL) at ꢀ40 °C. The mixture
was stirred at ꢀ40 °C for 1 h, then a saturated aqueous solution
of K2CO3 (3 mL) was added and the mixture was stirred for 1 h at
ambient temperature. Then water was added and the mixture
was extracted with ethyl acetate (3ꢃ). The combined organic lay-
ers were dried (Na2SO4), filtered, and the solvent was removed in
vacuo. The residue was dissolved in methanol (30 mL) and p-tolu-
enesulfonic acid monohydrate (123 mg, 0.65 mmol) was added.
The mixture was stirred at ambient temperature for 16 h. Then a
saturated aqueous solution of NaHCO3 was added and the mixture
was extracted with ethyl acetate (3ꢃ). The combined organic lay-
ers were dried (Na2SO4), filtered, and the solvent was removed in
vacuo. The residue was purified by flash column chromatography
(4 cm, 30 mL, n-hexane/ethyl acetate = 1/1, Rf = 0.11) to give 9 as
4.2.2. (3aS,6R,6aS)-6-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-2,2-
dimethyl-6,6a-dihydrofuro[3,4-d][1,3]dioxol-4(3aH)-one (6)
Under N2 atmosphere a solution of oxalyl chloride (1.75 mL,
2.34 g, 18.4 mmol) in CH2Cl2 (50 mL) was cooled down to ꢀ78 °C.
Then a solution of DMSO (2.91 mL, 3.2 g, 41.0 mmol) in CH2Cl2
(10 mL) was added dropwise and the mixture was stirred for
10 min at ꢀ78 °C. Then a solution of 5 (4.42 g, 17.0 mmol) in
CH2Cl2 (25 mL) was added dropwise and the solution was stirred
for another 30 min at ꢀ78 °C. Afterward, triethylamine (12 mL,
8.7 g, 86.3 mmol) was added and the mixture was allowed to warm
to ambient temperature. Then n-hexane was added, the mixture
was filtered, and the precipitate was washed with Et2O. The
organic layer was concentrated in vacuo and the residue was puri-
fied by flash column chromatography (8 cm, 60 mL, n-hexane/ethyl
acetate = 8/2, Rf = 0.19) to give
6
as colorless solid (4.0 g,
colorless solid (744 mg, 1.8 mmol, 56%). Mp: 181 °C; ½a D20
ꢂ
+66.1
15.5 mmol, 91%). Mp: 126 °C; ½a D20
ꢂ
+56.5 (4.6; CH2Cl2); 1H NMR
(1.6; CH2Cl2); 1H NMR (CDCl3): d (ppm) = 1.29 (s, 3H, CH3), 1.45
(s, 3H, CH3), 3.71 (dd, J = 7.8/3.8 Hz, 1H, H-4), 3.80 (dd, J = 11.6/
5.6 Hz, 1H, HOCHCH2OH), 3.93 (dd, J = 11.6/3.4 Hz, 1H, HOCH-
CH2OH), 4.12–4.20 (m, 1H, HOCHCH2OH), 4.57 (d, J = 3.6 Hz, 1H,
6-H), 4.80 (dd, J = 5.9/3.6 Hz, 1H, 6a-H), 4.93 (dd, J = 5.9/3.8 Hz,
1H, 3a-H), 7.09–7.14 (m, 2H, 20-H4-iodophenyl, 60-H4-iodophenyl), 7.65–
7.70 (m, 2H, 30-H4-iodophenyl, 50-H4-iodophenyl); 13C NMR (CDCl3): d
(ppm) = 24.5 (1C, C(CH3)2), 25.8 (1C, C(CH3)2), 64.8 (1C, HOCH-
CH2OH), 70.4 (1C, HOCHCH2OH), 81.0 (1C, C-4), 81.5 (1C, C-3a),
82.1 (1C, C-6a), 83.2 (1C, C-6), 93.9 (1C, C-404-iodophenyl), 112.9
(1C, C(CH3)2), 129.4 (2C, C-204-iodophenyl, C-604-iodophenyl), 135.2 (1C,
C-104-iodophenyl), 137.2 (2C, C-304-iodophenyl, C-504-iodophenyl); IR (neat):
(CDCl3): d (ppm) = 1.39 (s, 3H, CH3), 1.42 (s, 3H, CH3), 1.47 (s, 3H,
CH3), 1.48 (s, 3H, CH3), 4.07 (dd, J = 9.3/3.7 Hz, 1 H, OCHCH2O),
4.15 (dd, J = 9.2/5.8 Hz, 1H, OCHCH2O), 4.37 (dd, J = 8.2/3.3 Hz,
1H, 6-H), 4.43 (ddd, J = 8.2/5.9/3.7 Hz, 1H, OCHCH2O), 4.84 (d,
J = 5.3 Hz, 1H, 3a-H), 4.88 (dd, J = 5.3/3.4 Hz, 1H, 6a-H); 13C NMR
(CDCl3): d (ppm) = 25.2 (1C, C(CH3)2), 26.1 (1C, C(CH3)2), 26.9 (1C,
C(CH3)2), 27.1 (1C, C(CH3)2), 66.6 (1C, OCHCH2O), 72.7 (1C,
OCHCH2O), 75.9 (1C, C-6a), 76.2 (1C, C-3a), 78.2 (1C, C-6), 110.0
(1C, C(CH3)2), 114.7 (1C, C(CH3)2), 173.6 (1C, C-4); IR (neat):
m
(cmꢀ1) = 2987, 2891, 1769, 1381, 1194, 1082, 1039, 976, 851;
HRMS (m/z): [M+Na]+ calcd for C12H18O6Na, 281.0996; found,
281.0993.
m
(cmꢀ1) = 3456, 2978, 2919, 2862, 1482, 1381, 1207, 1161, 1009,
857, 745; MS (ESI): m/z = 429 (M+Na+, 100); HRMS (m/z):
[M+Na]+ calcd for C15H19IO5Na, 429.0169; found, 429.0173; HPLC
(method 1): tR = 17.3 min, purity 97.3%.
4.2.3. (3aS,6R,6aS)-6-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-4-(4-
iodophenyl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-
d][1,3]dioxol-4-ol (7)
Under N2 atmosphere a 1.6 M solution of n-butyllithium in hex-
anes (2.0 mL, 3.2 mmol) was added to a solution of 1,4-diiodoben-
zene (2.97 g, 9 mmol) in THF (40 mL). After stirring at ꢀ78 °C for
15 min, a solution of 6 (775 mg, 3 mmol) in THF (20 mL) was added
dropwise and the mixture was stirred for additional 30 min at
ꢀ78 °C. Then the mixture was allowed to warm to room tempera-
ture and a saturated aqueous solution of NaHCO3 was added. The
mixture was extracted with CH2Cl2 (3ꢃ), the combined organic
layers were dried (Na2SO4), filtered, and the solvent was removed
in vacuo. The residue was purified by flash column chromatogra-
phy (4 cm, 30 mL, n-hexane/ethyl acetate = 8/2, Rf = 0.25) to give
4.2.5. Methyl (3aR,4S,6S,6aR)-6-(4-iodophenyl)-2,2-dimethyl-
3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxole-4-carboxylate (10)
and methyl (2S,3R,4S,5S)-3,4-dihydroxy-5-(4-iodophenyl)-
2,3,4,5-tetrahydrofuran-2-carboxylate (11)
An oxidant solution (17 mL), which was prepared by dissolving
H5IO6 (11.4 g, 50 mmol) and CrO3 (23 mg, 0.23 mmol) in wet aceto-
nitrile (114 mL, 0.75% water V/V), was added to a solution of 9
(1.23 g, 3.0 mmol) in acetonitrile (20 mL). The mixture was stirred
at ambient temperature for 3 h. The reaction was quenched by the
addition of ethylene glycol. Then hydrochloric acid (1 M) was added
and the mixture was extracted with ethyl acetate (3ꢃ). The com-
bined organic layers were dried (Na2SO4), filtered, and the solvent
was removed in vacuo. The residue was dissolved in methanol
(30 mL) and p-toluenesulfonic acid monohydrate (57 mg,
0.30 mmol) was added. The mixture was heated to reflux for 16 h.
Then the solvent was removed in vacuo and the residue was purified
by flash column chromatography (4 cm, 30 mL, n-hexane/ethyl ace-
tate = 8/2?1/1) to give 10 (n-hexane/ethyl acetate = 8/2, Rf = 0.13)
as colorless solid (490 mg, 1.2 mmol, 40%) and 11 (n-hexane/ethyl
acetate = 1/1, Rf = 0.20) as colorless solid (400 mg, 1.1 mmol, 37%).
Analytical data of 10: mp: 167.6 °C; TLC (n-hexane/ethyl acetate,
7 as colorless solid (990 mg, 2.14 mmol, 71%). Mp: 80 °C; ½a D20
ꢂ
+66.7 (0.6; CH2Cl2); 1H NMR (DMSO-d6): d (ppm) = 1.15 (s, 3H,
CH3), 1.24 (s, 3H, CH3), 1.29 (s, 3H, CH3), 1.35 (s, 3H, CH3), 3.96
(dd, J = 8.3/6.0 Hz, 1H, OCHCH2O), 4.05 (dd, J = 8.3/6.5 Hz, 1H, OCH-
CH2O), 4.21 (dd, J = 5.8/3.9 Hz, 1H, 6-H), 4.38 (q, J = 6.1 Hz, 1H,
OCHCH2O), 4.45 (d, J = 5.8 Hz, 1H, 3a-H), 4.85 (dd, J = 5.8/3.9 Hz,
1H, 6a-H), 6.75 (s, 1H, OH), 7.20–7.25 (m, 2H, 20-H4-iodophenyl, 60-
H
4-iodophenyl), 7.66–7.72 (m, 2H, 30-H4-iodophenyl, 50-H4-iodophenyl);
13C NMR (DMSO-d6): d (ppm) = 24.0 (1C, C(CH3)2), 25.3 (1C,
C(CH3)2), 25.4 (1C, C(CH3)2), 26.6 (1C, C(CH3)2), 65.7 (1C,
OCHCH2O), 73.1 (1C, OCHCH2O), 78.0 (1C, C-6), 79.9 (1C, C-6a),
86.1 (1C, C-3a), 94.3 (1C, C-404-iodophenyl), 104.9 (1C, C-4), 107.8
8:2 V/V): RF = 0.13; ½a D20
ꢂ
+34.4 (1.9; CH2Cl2); 1H NMR (CDCl3): d
(ppm) = 1.26 (s, 3H, CH3), 1.41 (s, 3H, CH3), 3.85 (s, 3H, OCH3),
4.39 (d, J = 4.6 Hz, 1H, 4-H), 4.62 (d, J = 3.5 Hz, 1H, 6-H), 4.80
(dd, J = 5.9/3.5 Hz, 1H, 6a-H), 5.08 (dd, J = 5.9/4.6 Hz, 1H, 3a-H),
7.19–7.24 (m, 2H, 20-H4-iodophenyl, 60-H4-iodophenyl), 7.67–7.72 (m,
(1C, C(CH3)2), 111.5 (1C, C(CH3)2), 129.4 (2C, C-204-iodophenyl
,
C-604-iodophenyl), 136.0 (2C, C-304-iodophenyl, C-504-iodophenyl), 140.2
(1C, C-104-iodophenyl); IR (neat):
m
(cmꢀ1) = 3374, 2985, 2937, 1372,
1208, 1039, 1002, 821; MS (ESI): m/z = 485 (M+Na+, 100); HRMS
(m/z): [M+Na]+ calcd for C18H23IO6Na, 485.0432; found,
485.0422; HPLC (method 1): tR = 20.4 min, purity 97.4%.
2H, 30-H4-iodophenyl
,
50-H4-iodophenyl); 13C NMR (CDCl3):
d
(ppm) = 25.0 (1C, C(CH3)2), 25.8 (1C, C(CH3)2), 52.3 (1C, OCH3),
80.8 (1C, C-4), 81.7 (1C, C-6a), 82.0 (1C, C-3a), 83.0 (1C, C-6),

A. Oddo, R. Holl / Carbohydrate Research 359 (2012) 59–64
63
94.1 (1C, C-404-iodophenyl), 113.6 (1C, C(CH3)2), 129.5 (2C,
(ppm) = 0.13 (3C, Si(CH3)3), 53.7 (2C, NCH2CH2O), 63.2 (1C,
NCH2Ar), 67.0 (2C, NCH2CH2O), 94.2 (1C, C„CSi(CH3)3), 105.1
(1C, C„CSi(CH3)3), 122.1 (1C, C-404-ethynylphenyl), 129.2 (2C,
C-204-ethynylphenyl, C-604-ethynylphenyl), 132.0 (2C, C-304-ethynylphenyl, C-
C-204-iodophenyl, C-604-iodophenyl), 134.6 (1C, C-104-iodophenyl), 137.2
(2C, C-304-iodophenyl, C-504-iodophenyl), 167.7 (1C, C@O); IR (neat):
m
(cmꢀ1) = 2984, 2934, 1752, 1486, 1436, 1382, 1207, 1099, 1038,
815, 742; MS (ESI): m/z = 427 (M+Na+, 100); HRMS (m/z): [M+Na]+
calcd for C15H17IO5Na, 427.0013; found, 427.0018; HPLC (method
1): tR = 19.8 min, purity 98.5%.
504-ethynylphenyl), 138.3 (1C, C-104-ethynylphenyl); IR (neat):
m
(cmꢀ1) =
2959, 2851, 2811, 2156, 1507, 1245, 1114, 1005, 851, 766; MS
(ESI): m/z = 274 (M+H+, 100); HRMS (m/z): [M+H]+ calcd for
C16H23NOSiH, 274.1622; found, 274.1614; HPLC (method 1):
4.2.6. Methyl (2S,3R,4S,5S)-3,4-dihydroxy-5-(4-iodophenyl)-
2,3,4,5-tetrahydrofuran-2-carboxylate (11)
tR = 18.5 min, purity 97.5%.
p-Toluenesulfonic acid monohydrate (43 mg, 0.23 mmol) was
added to a solution of 10 (460 mg, 1.14 mmol) in methanol
(30 mL). The mixture was heated to reflux for 16 h. Then the solvent
was removed in vacuo and the residue was purified by flash column
chromatography (3 cm, 20 mL, n-hexane/ethyl acetate = 1/1,
Rf = 0.20) to give 11 as colorless solid (162 mg, 0.44 mmol, 39%).
4.2.9. 4-(4-Ethynylbenzyl)morpholine (16)
A
1.0 M solution of tetrabutylammonium fluoride in THF
(2.35 mL, 2.35 mmol) was added dropwise to an ice-cooled solu-
tion of 15 (547 mg, 2.0 mmol) in THF (10 mL). The mixture was
stirred at 0 °C for 30 min. Then a saturated solution of ammonium
chloride (15 mL) was added and the mixture was extracted with
ethyl acetate (3ꢃ). The combined organic layers were washed with
water and brine, dried (Na2SO4), filtered, and the solvent was re-
moved in vacuo. The residue was purified by flash column chroma-
tography (4 cm, 30 mL, n-hexane/ethyl acetate = 2/1, Rf = 0.29) to
give 16 as colorless solid (397 mg, 1.97 mmol, 99%). Mp: 65 °C;
1H NMR (CDCl3): d (ppm) = 2.41–2.45 (m, 4H, NCH2CH2O), 3.49
(s, 2H, NCH2Ar), 3.69–3.72 (m, 4H, , NCH2CH2O), 7.27–7.31 (m,
2H, 20-H4-ethynylphenyl, 60-H4-ethynylphenyl), 7.43–7.46 (m, 2H, 30-
Mp: 125 °C;
½
a 2D0 +55.5 (1.3; CH2Cl2); 1H NMR (CDCl3):
d
ꢂ
(ppm) = 2.89 (s br, 1H, OH), 3.19 (s br, 1H, OH), 3.84 (s, 3H, OCH3),
4.21–4.25 (m, 1H, 4-H), 4.68–4.74 (m, 2H, 2-H, 3-H), 5.07 (d, J =
4.6 Hz, 1H, 5-H), 7.20–7.24 (m, 2H, 20-H4-iodophenyl, 60-H4-iodophenyl),
7.70–7.74 (m, 2H, 30-H4-iodophenyl, 50-H4-iodophenyl); 13C NMR (CDCl3):
d (ppm) = 52.8 (1C, OCH3), 73.7 (1C, C-4), 74.1 (1C, C-3), 78.9 (1C, C-
2), 83.2 (1C, C-5), 93.9 (1C, C-404-iodophenyl), 128.9 (2C, C-204-iodophenyl
C-604-iodophenyl), 135.8 (1C, C-104-iodophenyl), 137.6 (2C, C-304-iodophenyl
,
,
C-504-iodophenyl), 172.6 (1C, C@O); IR (neat):
m
(cmꢀ1) = 3453, 3386,
H
4-ethynylphenyl, 50-H4-ethynylphenyl); 13C NMR (CDCl3): d (ppm) = 53.7
2943, 2876, 1738, 1480, 1402, 1222, 1122, 1084, 1005, 976, 809,
743; MS (ESI): m/z = 387 (M+Na+, 100); HRMS (m/z): [M+Na]+ calcd
for C12H13IO5Na, 386.9700; found, 386.9705; HPLC (method 1):
tR = 15.4 min, purity 97.7%.
(2C, NCH2CH2O), 63.2 (1C, NCH2Ar), 67.1 (2C, NCH2CH2O),
77.2 (1C, C„CH), 83.7 (1C, C„CH), 121.0 (1C, C-404-ethynylphenyl),
129.2 (2C, C-204-ethynylphenyl
,
C-604-ethynylphenyl), 132.2 (2C,
C-304-ethynylphenyl, C-504-ethynylphenyl), 138.5 (1C, C-104-ethynylphenyl);
IR (neat):
m
(cmꢀ1) = 3223, 2926, 2824, 2036, 1454, 1351, 1110,
4.2.7. 4-(4-Bromobenzyl)morpholine (14)
1004, 855, 684; MS (ESI): m/z = 202 (M+H+, 100); HRMS (m/z):
[M+H]+ calcd for C13H15NOH, 202.1226; found, 202.1240; HPLC
(method 1): tR = 9.8 min, purity 97.5%.
Morpholine (13, 1.4 mL, 1.39 g, 16 mmol) was added to a solu-
tion of 4-bromobenzyl bromide (12, 1.0 g, 4 mmol) in acetonitrile
(50 mL) and the mixture was heated to reflux for 4 h. Then water
was added and the mixture was extracted with CH2Cl2 (3ꢃ). The
combined organic layers were dried (Na2SO4), filtered, and the sol-
vent was removed in vacuo. The residue was purified by flash col-
umn chromatography (6 cm, 50 mL, n-hexane/ethyl acetate = 8/2,
Rf = 0.19) to give 14 as colorless solid (1.0 g, 3.9 mmol, 98%). Mp:
85 °C; 1H NMR (CDCl3): d (ppm) = 2.41–2.45 (m, 4H, NCH2CH2O),
3.45 (s, 2H, NCH2Ar), 3.69–3.72 (m, 4H, NCH2CH2O), 7.19–7.23
4.2.10. Methyl (2S,3R,4S,5S)-3,4-dihydroxy-5-(4-{2-[4-(morpholi
nomethyl)phenyl]ethynyl}phenyl)-2,3,4,5-tetrahydrofuran-2-
carboxylate (17)
Under N2 atmosphere triethylamine (0.21 mL, 1.54 mmol), cop-
per(I) iodide (8.4 mg, 0.044 mmol), and tetrakis(triphenylphos-
phine)palladium(0) (24 mg, 0.022 mmol) were added to
a
solution of 11 (80 mg, 0.22 mmol) in acetonitrile (5 mL). Then a
solution of 16 (358 mg, 1.76 mmol) in acetonitrile (3 mL) was
added dropwise over a period of 2 h. After evaporation of the sol-
vent the residue was purified by flash column chromatography
(2 cm, 10 mL, ethyl acetate, Rf = 0.14) to give 17 as colorless solid
(m, 2H, 20-H4-bromophenyl
,
60-H4-bromophenyl), 7.42–7.46 (m, 2H,
30-H4-bromophenyl 50-H4-bromophenyl); 13C NMR (CDCl3):
,
d
(ppm) = 53.7 (2C, NCH2CH2O), 62.8 (1C, NCH2Ar), 67.1
(2C, NCH2CH2O), 121.1 (1C, C-404-bromophenyl), 131.0 (2C,
C-204-bromophenyl
,
C-604-bromophenyl), 131.5 (2C, C-304-bromophenyl
,
(25 mg, 0.06 mmol, 26%). Mp: 165 °C; ½a D20
ꢂ
+60.0 (0.7; CH2Cl2);
C-504-bromophenyl), 136.7 (1C, C-104-bromophenyl); IR (neat):
m
(cm
1H NMR (CDCl3): d (ppm) = 2.43–2.48 (m, 4H, NCH2CH2O), 3.51
(s, 2H, NCH2Ar), 3.69–3.73 (m, 4H, NCH2CH2O), 3.85 (s, 3H,
OCH3), 4.25–4.28 (m, 1H, 4-H), 4.70–4.75 (m, 2H, 2-H, 3-H), 5.14
(d, J = 3.9 Hz, 1H, 5-H), 7.30–7.34 (m, 2H, Harom.), 7.45–7.50 (m,
ꢀ1) = 2966, 2927, 2862, 2815, 1487, 1449, 1351, 1110, 1065,
1007, 910, 863, 848, 789; MS (ESI): m/z = 256 (M(79Br)+H+, 100),
258 (M(81Br)+Na+, 94); HRMS (m/z): [M+H]+ calcd for
C11H14BrNOH, 256.0332; found, 256.0327; HPLC (method 1):
4H, H d
arom.), 7.53–7.57 (m, 2H, Harom.); 13C NMR (CDCl3):
tR = 11.4 min, purity 99.9%.
(ppm) = 52.8 (1C, OCH3), 53.7 (2C, NCH2CH2O), 63.2 (1C, NCH2Ar),
67.0 (2C, NCH2CH2O), 73.8 (1C, C-4), 74.1 (1C, C-2), 79.0 (1C, C-
3), 83.4 (1C, C-5), 89.3 (1C, C„C), 89.6 (1C, C„C), 122.2 (1C, Carom.),
123.2 (1C, Carom.), 127.0 (2C, Carom.), 129.3 (2C, Carom.), 131.6 (2C,
4.2.8. 4-[4-(2-(Trimethylsilyl)ethynyl)benzyl]morpholine (15)
Under N2 atmosphere copper(I) iodide (65 mg, 0.34 mmol),
tetrakis(triphenylphosphine)palladium(0) (197 mg, 0.17 mmol),
and trimethylsilylacetylene (2.4 mL, 1.66 g, 16.9 mmol) were
added to a solution of 14 (2.93 g, 11.4 mmol) in triethylamine
(70 mL). The mixture was heated to reflux for 16 h. After evaporation
of the solvent the residue was purified by flash column chromatog-
raphy (6 cm, 50 mL, n-hexane/ethyl acetate = 8/2, Rf = 0.21) to give
15 as colorless solid (2.2 g, 8.0 mmol, 71%). Mp: 62 °C; 1H NMR
(CDCl3): d (ppm) = 0.24 (s, 9H, Si(CH3)3), 2.41–2.45 (m, 4H,
NCH2CH2O), 3.49 (s, 2H, NCH2Ar), 3.69–3.72 (m, 4H, NCH2CH2O),
7.25–7.29 (m, 2H, 20-H4-ethynylphenyl, 60-H4-ethynylphenyl), 7.40–7.43
(m, 2H, 30-H4-ethynylphenyl, 50-H4-ethynylphenyl); 13C NMR (CDCl3): d
C
arom.), 131.7 (2C, Carom.), 136.2 (1C, Carom.), 138.1 (1C, Carom.),
172.5 (1C, C@O); IR (neat):
m
(cmꢀ1) = 3368, 2952, 2852, 2805,
1712, 1519, 1231, 1113, 1086, 1007, 865, 781; HRMS (m/z):
[M+H]+ calcd for C25H28NO6, 438.1911; found, 438.1912; HPLC
(method 1): tR = 14.8 min, purity 95.4%.
4.2.11. (2S,3R,4S,5S)-N,3,4-Trihydroxy-5-(4-(2-(4-
(morpholinomethyl)phenyl)ethynyl)phenyl)-tetrahydrofuran-
2-carboxamide (3)
A 2.0 M solution of sodium methoxide in methanol (0.55 mL,
1.1 mmol) was added to a solution of 17 (200 mg, 0.46 mmol)

64
A. Oddo, R. Holl / Carbohydrate Research 359 (2012) 59–64
3. Raetz, C. R. H. Prog. Clin. Biol. Res. 1998, 397, 1–14.
4. Raetz, C. R. H.; Reynolds, C. M.; Trent, M. S.; Bishop, R. E. Annu. Rev. Biochem.
2007, 76, 295–329.
and hydroxylamine hydrochloride (69 mg, 1.0 mmol) in methanol
(30 mL) and the mixture was stirred at ambient temperature for
16 h. Then the solvent was evaporated. Then water was added
and the mixture was extracted with ethyl acetate (3ꢃ). Then the
aqueous phase was extracted with CH2Cl2/methanol (8:2, 3ꢃ).
The combined CH2Cl2 phases were dried (Na2SO4), filtered, and
evaporated to give 3 as colorless solid (58 mg, 0.13 mmol, 29%).
5. Raetz, C. R. H.; Whitfield, C. Annu. Rev. Biochem. 2002, 71, 635–700.
6. Vaara, M. Antimicrob. Agents Chemother. 1993, 37, 354–356.
7. Vuorio, R.; Vaara, M. Antimicrob. Agents Chemother. 1992, 36, 826–829.
8. Ritter, T. K.; Wong, C. Angew. Chem., Int. Ed. 2001, 40, 3508–3533.
9. Onishi, H. R.; Pelak, B. A.; Gerckens, L. S.; Silver, L. L.; Kahan, F. M.; Chen, M. H.;
Patchett, A. A.; Galloway, S. M.; Hyland, S. A.; Anderson, M. S.; Raetz, C. R.
Science 1996, 274, 980–982.
10. Clements, J. M.; Coignard, F.; Johnson, I.; Chandler, S.; Palan, S.; Waller, A.;
Wijkmans, J.; Hunter, M. G. Antimicrob. Agents Chemother. 2002, 46,
1793–1799.
11. Young, K.; Silver, L. L.; Bramhill, D.; Cameron, P.; Eveland, S. S.; Raetz, C. R. H.;
Hyland, S. A.; Anderson, M. S. J. Biol. Chem. 1995, 270, 30384–30391.
12. Barb, A. W.; Zhou, P. Curr. Pharm. Biotechnol. 2008, 9, 9–15.
13. Jackman, J. E.; Fierke, C. A.; Tumey, L. N.; Pirrung, M.; Uchiyama, T.; Tahir, S. H.;
Hindsgaul, O.; Raetz, C. R. H. J. Biol. Chem. 2000, 275, 11002–11009.
14. Li, X.; Uchiyama, T.; Raetz, C. R. H.; Hindsgaul, O. Org. Lett. 2003, 5, 539–541.
15. McClerren, A. L.; Endsley, S.; Bowman, J. L.; Andersen, N. H.; Guan, Z.; Rudolph,
J.; Raetz, C. R. H. Biochemistry 2005, 44, 16574–16583.
16. Barb, A. W.; Jiang, L.; Raetz, C. R. H.; Zhou, P. Proc. Natl. Acad. Sci. U.S.A. 2007,
104, 18433–18438. S18433/1–S18433/6.
17. Kartha, K. P. R. Tetrahedron Lett. 1986, 27, 3415–3416.
18. Mancuso, A. J.; Swern, D. Synthesis 1981, 165–185.
19. Shing, T. K. M.; Gillhouley, J. G. Tetrahedron 1994, 50, 8685–8698.
20. Ferlin, N.; Grassi, D.; Ojeda, C.; Castro, M. J. L.; Grand, E.; Cirelli, A. F.; Kovensky,
J. Carbohydr. Res. 2008, 343, 839–847.
21. Moser, H.; Lu, Q.; Patten, P. A.; Wang, D.; Kasar, R.; Kaldor, S.; Patterson, B. D.
Preparation of Antibacterial Agents; Achaogen, Inc.: USA, 2008. p 510.
22. Chinchilla, R.; Najera, C. Chem. Rev. (Washington, DC, US) 2007, 107,
874–922.
Mp: 155 °C; TLC (CH2Cl2/methanol, 9:1 V/V): Rf = 0.31; ½a D20
ꢂ
+68.4
(1.9; methanol); 1H NMR (D3COD): d (ppm) = 2.45–2.51 (m, 4H,
NCH2CH2O), 3.55 (s, 2H, NCH2Ar), 3.68–3.72 (m, 4H, NCH2CH2O),
4.21 (t, J = 4.4 Hz, 1H,4-H), 4.48 (d, J = 7.1 Hz, 1H, 2-H), 4.71 (dd,
J = 7.1/4.8 Hz, 1H, 3-H), 5.06 (d, J = 4.1 Hz, 1H, 5-H), 7.35–7.39
(m, 2H, Harom.), 7.45–7.51 (m, 6H, Harom.); 13C NMR (D3COD): d
(ppm) = 54.6 (2C, NCH2CH2O), 63.9 (1C, NCH2Ar), 67.7 (2C,
NCH2CH2O), 7.43 (1C, C-3), 74.8 (1C, C-4), 80.2 (1C, C-2), 85.2
(1C, C-5), 89.8 (1C, C„C), 90.3 (1C, C„C), 123.6 (1C, Carom.),
123.8 (1C, Carom.), 128.8 (2C, Carom.), 130.8 (2C, Carom.), 132.0 (2C,
C
arom.), 132.5 (2C, Carom.), 138.7 (1C, Carom.), 139.2 (1C, Carom.),
169.3 (1C, C@O); IR (neat):
m
(cmꢀ1) = 3175, 2920, 1655, 1516,
1454, 1296, 1107, 1026, 856, 833, 779; HRMS (m/z): [M+H]+ calcd
for C24H27N2O6, 439.1864; found, 439.1870; HPLC (method 2):
tR = 10.8 min, purity 96.2%.
References
23. Remiszewski, S. W.; Sambucetti, L. C.; Atadja, P.; Bair, K. W.; Cornell, W. D.;
Green, M. A.; Howell, K. L.; Jung, M.; Kwon, P.; Trogani, N.; Walker, H. J. Med.
Chem. 2002, 45, 753–757.
1. Boucher, H. W.; Talbot, G. H.; Bradley, J. S.; Edwards, J. E.; Gilbert, D.; Rice, L. B.;
Scheld, M.; Spellberg, B.; Bartlett, J. Clin. Infect. Dis. 2009, 48, 1–12.
2. Cooper, M. A.; Shlaes, D. Nature (London, UK) 2011, 472, 32.