Preparation of 3-benzyloxy-2-pyridinone functional linkers: Tools for the synthesis of 3,2-hydroxypyridinone (HOPO) and HOPO/hydroxamic acid chelators

Article abstract of DOI:10.1016/j.tet.2015.10.031

In contrast to 2,3-dihydroxypyridine, the 3-benzyloxy protected derivative, 2, undergoes facile alkylation at ambient temperatures with a variety of functionalized alkyl halides in good yields. This alkylation has been used to prepare a number of linkers that permit the attachment of 3,2-HOPO moieties onto various scaffolds using a wide range of coupling methods. The Mitsunobu reaction of 2 with representative alcohols was found to be of limited value due to competing O-alkylation that led to product mixtures. The phthalimide 3j can be converted in two steps to HOPO isocyanate 6 in excellent yields. Isocyanate 6 can be coupled to amines at room temperature or to alcohols in refluxing dichloroethane to obtain the corresponding urea or carbamate linked ligand systems. The coupling of isocyanate 6 with TREN followed by deprotection gave the tris-HOPO 10, an interesting target as it has both cationic and anionic binding sites. The HOPO hydroxylamine linker 11 was shown to be especially valuable as its coupling with carboxylic acids proceeds with the concomitant generation of an additional hydroxamate ligand moiety in the framework. The utility of this linker was shown by the preparation of two mixed HOPO-hydroxamate chelators, 16 and 19, based on the structure of desferrioxamine, a well-known trihydroxamate siderophore.

Full text of DOI:10.1016/j.tet.2015.10.031

Tetrahedron 71 (2015) 9271e9281
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Preparation of 3-benzyloxy-2-pyridinone functional linkers: tools
for the synthesis of 3,2-hydroxypyridinone (HOPO) and
HOPO/hydroxamic acid chelators
*
Sarah Gibson, Rasika Fernando, Hollie K. Jacobs, Aravamudan S. Gopalan
Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, NM 88003-8001, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 August 2015
Received in revised form 9 October 2015
Accepted 12 October 2015
Available online 22 October 2015
In contrast to 2,3-dihydroxypyridine, the 3-benzyloxy protected derivative, 2, undergoes facile alkylation
at ambient temperatures with a variety of functionalized alkyl halides in good yields. This alkylation has
been used to prepare a number of linkers that permit the attachment of 3,2-HOPO moieties onto various
scaffolds using a wide range of coupling methods. The Mitsunobu reaction of 2 with representative al-
cohols was found to be of limited value due to competing O-alkylation that led to product mixtures. The
phthalimide 3j can be converted in two steps to HOPO isocyanate 6 in excellent yields. Isocyanate 6 can
be coupled to amines at room temperature or to alcohols in refluxing dichloroethane to obtain the
corresponding urea or carbamate linked ligand systems. The coupling of isocyanate 6 with TREN fol-
lowed by deprotection gave the tris-HOPO 10, an interesting target as it has both cationic and anionic
binding sites. The HOPO hydroxylamine linker 11 was shown to be especially valuable as its coupling
with carboxylic acids proceeds with the concomitant generation of an additional hydroxamate ligand
moiety in the framework. The utility of this linker was shown by the preparation of two mixed HOPO-
hydroxamate chelators, 16 and 19, based on the structure of desferrioxamine, a well-known trihydrox-
amate siderophore.
Keywords:
Hydroxypyridinone
Mixed ligand chelators
Desferrioxamine analogs
Alkylation
Synthetic siderophore
Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction
NH
3
R
O
N
O
O
R =
O
O
Siderophores are low molecular weight molecules with high
affinity for iron (III) that are produced by bacteria and fungi to se-
quester iron from their environment. Structures of natural side-
rophores can be quite diverse and the ligand groups involved in the
complexation of iron vary. Desferrioxamine, DFO is a trihydrox-
amate that was first isolated from Streptomyces pilosus in 1950 and
is probably the most widely studied siderophore in terms of ther-
apeutic potential. DFO is used for the treatment of iron overload in
NH
HN
O
HO
O
3
HO
O
R
O
O
O
O
Enterobactin OH
N
N OH
OH
R
NH
NH2
O
R =
Desferrioxamine B
DFO
N
HO
3,2-Hopobactin
O
patients with b
-thalassemia.1 It is one of the rare siderophores to
Fig. 1. Structures of desferrioxamine, enterobactin and 3,2-hopobactin.
have a functional group (amine) available for subsequent modifi-
cation.2 This fact has facilitated the preparation of a number of DFO-
conjugates for various biochemical studies.3 Enterobactin is a side-
rophore of enterobacteria in which three catecholate groups an-
chored to a cyclic serine trimer backbone are used to bind the ferric
iron in an hexadentate manner.4 Many analogs of both DFO and
enterobactin have been synthesized and examined for iron co-
ordination and potential biomedical applications (Fig. 1).5
Hydroxypyridinones, HOPOs, are powerful chelating groups for
hard metal ions (Fig. 2). As chelating groups, one could view HOPOs
as monobasic pyridine analogs of catechols in which bidentate
coordination occurs through both oxygens. There has been much
interest in the incorporation of this ligand onto various platforms to
prepare new generations of synthetic siderophores. The use of
hydroxypyridinones as ‘privileged’ structures for the design of
medicinal drugs has been recently reviewed.6 As therapeutic
agents, the 3,4-HOPO, deferiprone, is used for in vivo iron clearance
* Corresponding author. E-mail address: agopalan@nmsu.edu (A.S. Gopalan).
http://dx.doi.org/10.1016/j.tet.2015.10.031
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

9272
S. Gibson et al. / Tetrahedron 71 (2015) 9271e9281
Our group has published methods for the attachment of the 3,2-
HOPO ligand onto scaffolds without concomitant formation of an
amide bond. The goal has been to prepare less structurally rigid
ligands with greater water solubility. In one method, ester D was
converted into electrophilic imidate salt, F, which reacts readily
with secondary amines and phenols. For example, salt F, was
reacted with 1,4,7-triazacyclononane, to give tris HOPO ligand,
TACN-3,2-HOPO, after deprotection.19
Given the interest in siderophores for various applications,
synthetic methods that would allow the introduction/tethering of
3,2-HOPO onto a variety of scaffolds are of value. However, as dis-
cussed, current methods to introduce 3,2-HOPO ligands to prepare
a variety of targets are limited. There is a need for functional 3,2-
HOPO linkers, 3, that can be readily conjugated/tethered to poly-
mers, biomolecules and antibacterial drugs (Scheme 2). Further,
functional linkers, 3, could be used to prepare new classes of
siderophores including those that have mixed ligands and analogs
essential for structure activity relationships. It is important that the
functional groups, Z, on the HOPO linker can be varied to accom-
modate the proposed coupling method to the substrate of interest.
Fig. 2. Hydroxypyridinone chelators for Fe(III).16
(Fig. 2).7 HOPO compounds have also been evaluated for cancer
treatment8 and as novel antibacterial compounds.9,10 HOPO side-
rophores have been studied in a variety of diagnostic applications
including as MRI contrast agents11,12 and in positron emission to-
mography (PET).13,14 It is important to mention that hydroxypyr-
idinones for selective actinide binding and remediation of
transuranic waste is an active area of interest.15
Methods to introduce hydroxypyridinones onto scaffolds and
for its conjugation into biomolecules are limited both in terms of
number and flexibility. One popular approach to introduce the 3,2-
HOPO ligand, developed by Raymond and co-workers, involves
acylation of an activated HOPO carboxylic acid substrate (C, Scheme
1) with various amines. Reagent C is available in four steps from
commercially available 2,3-dihydroxypyridine, DHP, 1. The key step
in this sequence involves carboxylation at the 4 position of the
pyridinone ring of A using KolbeeSchmitt conditions to get B. This
reaction is limited in terms of substrate tolerance and works best
when there is either a methyl or ethyl group on the nitrogen of the
pyridinone ring. The activated ester C is prepared in two steps from
B and can be coupled to a polyamine such as tris(2-amino)ethyl-
amine, TREN (Scheme 1) to obtain the hexadentate siderophore,
TRENHOPO, after deprotection.17 The method developed by Hider
and co-workers for tethering HOPO to amine backbones involves
the use of an activated acyl derivative introduced on the nitrogen of
the pyridinone ring. The sequence begins with the alkylation of 1
with excess ethyl bromoacetate at refluxing temperature to give D.
The workup for the reaction involves removing the excess ethyl
bromoacetate, a potent lachrymator, by distillation. Subsequently,
ester D is converted in two steps to NHS ester, E, for acylation with
amines. Coupling with an amine, for example, TREN, followed by
deprotection gives CP-130.18 The serious drawback to this approach
is that the alkylation of 1 is a poor reaction with most electrophiles.
Both of the protocols described above, involve attachment of the
HOPO moiety via an amide linkage.
OBn
OBn
O
BnBr, NaOH, MeOH,
40° C, 2h, 53%
RX
Z = CO2H, CO2R, alkyne,
alkene, NH2, NHOBn
1
N
O
Z
N
H
2
3
Scheme 2.
The major impediment to prepare 3,2-HOPO linkers has been
limitations on the alkylation of 2,3-dihydroxypyridine, 1. In this
paper, we report that O-benzyl protected HOPO, 2, is a good nu-
cleophile and can be readily alkylated to give access to a variety of
functional HOPO linkers, 3. The synthetic utility of the linkers
prepared in this study has been demonstrated by the preparation of
a urea linked tris-3,2-HOPO attached to a TREN backbone. It is also
noteworthy that this study gives access to a new class of HOPO
linkers that can be coupled to acids with concomitant generation of
a hydroxamate bond. To demonstrate the value of this class of
linkers, two new mixed ligand hydroxamate-HOPO siderophores,
which are modeled on DFO, have been prepared.
We began with a systematic study of the alkylation of 3-
benzyloxy-2-pyridinone, 2, which is readily prepared by O-benzy-
lation of 1 (Scheme 2).20 There have been some isolated examples
in the literature of N-alkylation of protected 3-alkoxy-2-
Scheme 1.

S. Gibson et al. / Tetrahedron 71 (2015) 9271e9281
9273
pyridinones, such as 2.21 However, the reaction has not been well
studied. Further, the relative reactivity of the O-protected derivative
of 2,3-dihydroxypyridine, 2, relative to the parent, 1, in alkylation
reactions has not been evaluated. It is known that protection of the
3-hydroxy group of both 3,2 and 3,4-HOPOs has a large impact on
the observed regioselectivity of aminomethylation (Mannich re-
action) compared to the corresponding unprotected parents.22
Hence, a potential concern was the possibility of competing O-al-
kylation with the desired N-alkylation of the substrate and how
that might impact the utility of this reaction.
were higher when sodium hydride in DMF was used instead of KF/
alumina. In a few cases, some of the corresponding O-alkylated
product, 4, was also formed (Table 2, entries 2, 4, 8, 9, 11). The O-
alkylation products were much less polar than the desired product
of N-alkylation and were easily removed by chromatography.
2.2. Alkylation of 2 with alcohols
Because functionalized alcohols are readily available starting
materials, the Mitsunobu reaction of 2 using allyl alcohol as a model
was investigated. Reaction of HOPO 2 with allyl alcohol in the
2. Results and discussion
2.1. Alkylation of 2
Table 2
Alkylation of 3-benzyloxy-2-pyridinone, 2, with alkyl halides
It is known that the alkylation of 1 with ethyl bromoacetate can
be carried out using large excess of the alkylating agent under
reflux conditions. To determine the effect of protecting the 3-
hydroxy group, the alkylation of 2 with ethyl bromoacetate
(1 equiv) using sodium hydride in DMF was investigated. The re-
action was facile and the desired N-alkylated product was isolated
in 93% yield after only 2 h (Table 1, entry 1). The ease of this reaction
compared to the direct alkylation of 1 was remarkable. Further, the
product from O-alkylation was not observed.
Entry
R-X
Product, 3
Conditions Yield
3 (%)
1
A
B
88
90
The positive results from this initial reaction led us to study the
alkylation of 2 with tert-butyl bromoacetate (Table 1, entry 2) under
a variety of conditions. Treatment of 2 with sodium hydride
(1.1 equiv) in DMF followed by addition of tert-butyl bromoacetate
(1.1 equiv), gave the desired product in 80% yield after chromato-
graphic purification. The reaction could be carried out in either
DMF or THF though the reaction was much faster in DMF as ex-
pected. When the alkylation was carried out using potassium
fluoride on alumina as the base in acetonitrile solvent, the product
was isolated in 73% yield after purification. Although the KF/alu-
mina is somewhat expensive, the simple filtration work-up and
avoiding DMF (easier for workup) is an advantage. The product
from O-alkylation was not observed in either the sodium hydride or
KF/alumina reactions. The reaction was also investigated using ei-
ther DBU or K2CO3 as the base in DMF. In both cases, the product
formation was very slow, making it an unattractive reaction.
The alkylation study was then expanded to include a variety of
functionalized alkyl halides (Table 2). In the case of reactive allyl
bromide (Table 2, entry 1), excellent yields of the desired N-alky-
lated product could be obtained using either sodium hydride in
DMF or KF/alumina. In general, the yields of the alkylation reaction
2
3
A
79a
A
B
81
63
4
5
A
B
75a
49
A
75
Table 1
Alkylation of 3-benzyloxy-2-pyridinone, 2, with a-bromoesters
6
7
8
A
A
A
77
Entry
1
R-X
Product, 3
Conditions
Yield 3 (%)
93
80
A
82a
A
B
80
73
2
Conditions: A. NaH, DMF, 0 ꢀC to rt, N2, 2 h.
B. KF/alumina, CH3CN, rt, 24 h.
(continued on next page)

9274
S. Gibson et al. / Tetrahedron 71 (2015) 9271e9281
Table 2 (continued )
improve the reaction yield, the reaction was performed using tri-
phenylphosphine in place of PS-PPh3 (Table 3, entry 3). In this case,
the product of O-alkylation, 4d, was the major product and was
isolated in 51% yield. While it is interesting to note that alkylation of
2 directly with alcohols is feasible under Mitsunobu conditions,
there is significant and undesirable competition with O-alkylation.
Entry
R-X
Product, 3
Conditions Yield
3 (%)
9
A
69a
2.3. Applications of functional HOPO linkers
2.3.1. Tethering of 3,2-HOPO via carbamate and urea linkages. The
N-alkylation of 2 provides easy access to a variety of HOPO linkers
differing in functional groups. The phthalimide products, 3j and 3k,
are precursors to the corresponding amines, 5. This was demon-
strated by the conversion of phthalimide, 3j, to amine, 5, using
aqueous methylamine in 90% yield (Scheme 4). Amine 5 has been
prepared by an alternate route and successfully coupled with acid
chlorides and sulfonyl chlorides.23
10
11
A
A
86
81a
The conversion of the HOPO amine 5 to the corresponding iso-
cyanate provides a reactive linker for coupling with amines and
alcohols. Treatment of amine 5 with a solution of phosgene in
toluene in the presence of proton sponge in dichloromethane gave
the corresponding isocyanate 6 in 82% yield. The isocyanate was of
sufficient purity to use without further purification. The reaction of
HOPO isocyanate was then examined with alcohols and amines. As
an example, reaction of isocyanate, 6, with 1-octanol proceeded
cleanly in dichloroethane at 80 ꢀC to give carbamate linked HOPO,
7. As expected, the reaction of 1-octylamine with isocyanate, 6, in
dichloromethane at 0 ꢀC was faster and gave excellent yield of the
corresponding HOPO urea, 8, after chromatographic purification.
Conditions: A. NaH, DMF, 0 ꢀC to rt, N2, 24 h.
B. KF/Al2O3, CH3CN, rt, 24 h.
a
10e15 % yield of the corresponding O-alkylated product 4 was isolated.
presence of diisopropyl azodicarboxylate (DIAD) and polystyrene-
supported triphenylphosphine in THF gave predominantly the
product of N-alkylation, 3c, along with 20% of the product from O-
alkylation, 4c (Table 3, entry 1) (Scheme 3). It is noteworthy that the
O-allyl product, 4c, can be easily rearranged to the N-allyl product,
3c, in xylene at 80 ꢀC in the presence of a catalytic amount of PdCl2
(see 4.6). When the Mitsunobu reaction of 2 was carried out with
11-decen-1-ol under the same conditions, the desired product of N-
alkylation, 3d, was obtained in only 27% yield along with 20% yield
of the corresponding O-alkylated product, 4d (Table 3, entry 2). To
2.3.2. Synthesis of urea-linked tris-HOPO chelator, 10. Ion pair rec-
ognition is an emerging area in supramolecular chemistry.24 There
has been much interest in the design of ditopic chelators capable of
simultaneous complexation of both anions and cations in their
scaffolds. It has been hypothesized that the binding of the cation
could preorganize the receptor for enhanced binding of the anion.25
TREN based urea receptors have been shown to be effective for the
binding of oxyanions and to facilitate their encapsulation.26 TREN
has been a highly used tripodal platform to prepare hydroxamates
and hydroxypyridinones that show strong binding to iron.27
A TREN tris-urea HOPO ditopic chelator was a tempting target to
demonstrate the utility of the new HOPO isocyanate linker 6. Re-
action of TREN with a slight excess of isocyanate 6, in dichloro-
methane at 0 ꢀC gave the protected HOPO, 9, in 67% yield after
chromatographic purification (Scheme 5). Debenzylation of 9 using
a hydrogen balloon and 5% Pd on carbon gave the desired urea-
linked tris-HOPO chelator, 10, in quantitative yield.
For R = allyl (4c)
PdCl2 (cat.), xylene
80°C, 82%
O
O
OR
alcohol (1 eq),
DIAD, reagent,
THF, rt, N2, 24h
BnO
BnO
R
BnO
NH
N
N
+
2
3
4
Scheme 3.
Table 3
Reaction of 2 with alcohols under Mitsunobu conditions
2.3.3. Synthesis of mixed HOPO/hydroxamate analogs of desferriox-
amine, DFO. In DFO and enterobactin, iron complexation is ach-
ieved by three hydroxamate or three catecholate ligands,
respectively. There are also many natural siderophores where the
ferric ion is complexed by a mixed ligand system. For example,
Mycobacterium tuberculosis produces a suite of siderophores called
Entry
ROH
Reagent
Product, yield %
Product, yield %
1
2
3
Allyl alcohol
11-Undecen-1-ol
11-Undecen-1-ol
PS-PPh3
PS-PPh3
PPh3
3c, 47
3d, 27
3d, 26
4c, 20
4d, 20
4d, 51
O
O
COCl2 (2 eq),
proton sponge (2 eq),
O
O
CH3NH2 (aq),
rt, 2 d, 88%
BnO
BnO
BnO
NCO
N
O
N
N
NH2
CH2Cl2, 0°C,15 min, 82%
N
6
5
3j
1-octylamine, CH2Cl2,
0°C, 10 min, 90%
1-octanol, dichloroethane,
80°C, 24 h, 87%
O
O
O
O
C8H17
C8H17
BnO
BnO
N
N
N
O
N
N
H
H
H
7
8
Scheme 4.

S. Gibson et al. / Tetrahedron 71 (2015) 9271e9281
9275
O
O
6 (3.3 eq), CH2Cl2,
0°C, 2 h, 67%
N
OR
N(CH2CH2NH2)3
N
N
N
H
H
3
9, R = Bn
10, R = H, TREN-UREA-3,2-HOPO
H2, 5% Pd/C
MeOH, 5 d, quant
Scheme 5.
carboxymycobactins to sequester iron to support its growth.29 The
coordination of iron is accomplished by a cyclic hydroxamic acid,
a hydroxamic acid and a phenolate oxazoline. In aerobactin, one of
the siderophores of pathogenic Escherichia coli, the complexation of
iron is achieved by two hydroxamic acids and a citrate moiety.28
While mixed ligand chelators occur widely in natural side-
rophores,29 synthetic analogs have not been as widely studied
perhaps due to greater difficulty in their syntheses. An interesting
example of the use of mixed ligands is the recent publication of
a biscatecholateemonohydroxamate conjugated to an antibiotic to
generate a new drug candidate that is selective against A. bau-
mannii.30 A recent review on sequestering agents for actinides
documents several synthetic mixed ligand 3,2-HOPO chelators.15
Our own group has published the synthesis of mixed ligand 3,2-
HOPO/hydroxamic acid and 3,2-HOPO/carboxylic acid and 3,2-
HOPO mixed chelators on polyphenol platforms.31
that the chain lengths of both linkers 11 and 12 can be readily
varied. Also, a variety of acid chlorides can substitute for acetyl
chloride in the preparation of 15, making this synthetic approach
highly flexible.
The next target to be prepared was the diHOPO/hydroxamate
mixed ligand, 19, in which two hydroxamic acids of DFO are
replaced with 3,2-HOPO ligands (Scheme 7). It is interesting to note
that the chemistry uses two HOPO linkers produced from this work
to create the mixed ligand siderophore. Hydrolysis of t-butyl ester,
3g, using TFA in dichloromethane gave the HOPO acid, 17, in 95%
yield. HATU mediated coupling of HOPO acid, 17, with HOPO hy-
droxylamine, 11, generated the fully protected mixed ligand, 18, in
83% yield after purification. Global deprotection of the benzyl
groups was accomplished using 5% Pd/C in ethanol to give the
diHOPO/hydroxamate mixed ligand DFO analog, 19, in 87% yield.
The HOPO linkers developed in this study are convenient in-
termediates for the synthesis of HOPO mixed ligand systems that
have not been hitherto examined. We envisioned using the bi-
functional linkers to prepare mixed HOPO/hydroxamic acid ligands
inspired by the structure of the siderophore, desferrioxamine, DFO.
The protected HOPO-hydroxylamine linker 11 is a useful tool as it
provides a novel advantage. After deprotection of 3m to the cor-
responding hydroxylamine 11, it can be coupled to a carboxylic acid.
This coupling reaction generates a hydroxamic acid linkage,
resulting in a mixed hydroxamate-HOPO mixed ligand system.
The first DFO analog to be prepared was the HOPO/dihydrox-
amate mixed ligand, 15, in which one hydroxamic acid of DFO is
replaced with a 3,2-HOPO ligand (Scheme 6). The protected hy-
droxylamine HOPO, 11, was coupled to the functionalized carbox-
ylic acid, 12, using HATU in the presence of triethylamine in
dichloromethane to give 13. It is pleasing to note that this key step,
in which the hydroxamic acid bond is formed, proceeded in good
yield. Removal of the Boc protecting group of 13 using TFA gave the
free hydroxylamine 14, in 77% yield after chromatographic purifi-
cation. Hydroxylamine, 14, was coupled with acetyl chloride in the
presence of triethylamine in dichloromethane to generate the fully
protected mixed ligand 15. Global deprotection of the benzyl pro-
tecting groups using 5% Pd on carbon gave the mixed dihydroxamic
acid/HOPO ligand, 16, in excellent yield. It is important to point out
Scheme 7.
3. Conclusions
The hydroxypyridinone ligand has become an integral part in
the design of new classes of synthetic siderophores targeted to-
wards therapeutic and diagnostic applications. In particular,
HOPO and HOPO/terephthalamide (mixed ligand) chelators have
been widely studied as MRI contrast agents.11 Hence, synthetic
methods that give access to new generations of HOPO chelators
as well as those that allow the conjugation of this ligand to
existing platforms are important. The functional HOPO linkers
reported in this study allow its attachment to various platforms
O
1.
OBn
N
OBn
OBn
Boc
O
H
O
N
N
R
N
HO
BnO
BnO
BnO
OBn
4
12
N
N
N
4
4
4
HATU, Et3N, CH2Cl2,
rt, 3h, 76%
11
O
13 R = Boc
14 R = H
TFA, CH2Cl2,
98%
2. TFA, CH2Cl2, 77%
CH3COCl, Et3N, CH2Cl2, 80%
Boc
OR
N
OR
N
O
O
N
OBn
RO
4
N
4
4
O
O
3m
15, R = Bn
16, R = H
5% Pd/C, H2,
EtOH, 24h, 97%
Scheme 6.

9276
S. Gibson et al. / Tetrahedron 71 (2015) 9271e9281
via a number of coupling protocols. For instance, the HOPO al-
kynes from this study are potential partners for both click
chemistry with azides32 and Sonogashira coupling33 with aryl
halides. The ability to alkylate 3-benzyloxy-2-pyridinone, 2, with
a variety of functionalized alkylating agents in good yields and
under mild conditions (sodium hydride in DMF at room tem-
perature) removes a serious hurdle faced by researchers in this
area by greatly improving the availability of HOPO coupling
agents. In the case of more active alkylating agents, such as allyl
bromide, the alkylation can be performed using potassium fluo-
ride on alumina. This protocol offers simplicity in the product
isolation. In most cases, O-alkylation of 2 was a minor pathway
and posed no problems.
It is interesting to note that 2 can function as a partner in Mit-
sunobu reactions with primary alcohols. To our knowledge, this
reaction has not been studied before.34 Unfortunately, under the
reaction conditions both O and N-alkylated products of 2 are
formed with low selectivity, limiting the usefulness of this
approach.
Particularly useful HOPO linkers to emerge from this work are
the isocyanate 6 and the HOPO-hydroxylamine, 11. HOPO iso-
cyanate, 6, should be a highly desirable partner for bioconjugation
where an amine is available for coupling. This reagent also allows
the preparation of new classes of potential ditopic receptors as
demonstrated by the preparation of TREN-UREA-3,2-HOPO, 10.
The syntheses of mixed HOPO/hydroxamate ligands, 16 and 19,
exemplifies the special advantages of linkers such as 11. The teth-
ering of an HOPO moiety with concomitant generation of
a hydroxamate binding site in the skeleton is novel. In addition,
ligands 16 and 19 are the first examples of mixed hydroxamate/
HOPO analogs of DFO in which the HOPO moiety is part of the
backbone and not just appended to the terminal amine of DFO. This
new coupling protocol should greatly enhance the ability to syn-
thesize mixed HOPO-hydroxamate mixed ligands for therapeutic
and diagnostic studies.
1.09 mmol). The mixture was warmed to rt and stirred for
30 min. After cooling back to 0 ꢀC, ethyl bromoacetate (0.12 mL,
1.09 mmol) was added and the mixture stirred at rt for 2 h. The
reaction was quenched with saturated NH4Cl (10 mL) and the
product extracted into ethyl acetate (3ꢁ30 mL). The combined
organic extract was dried (Na2SO4) and the solvent removed in
vacuo. Excess DMF was removed by Kugelrohr distillation. The
crude product was purified by radial chromatography (hexane/
ethyl acetate gradient) to give ester 3a (0.26 g, 93%) as a white
solid: mp 114e115 ꢀC; IR (neat) 2986, 1751 (C]O), 1654 (HOPO
C]O), 1598 cmꢂ1; 1H NMR (300 MHz, CDCl3)
d 7.43e7.36 (m, 2H),
7.34e7.21 (m, 3H), 6.87 (dd, J¼6.9, 1.6 Hz, 1H), 6.64 (dd, J¼7.4,
1.6 Hz, 1H), 5.99 (dd, J¼7.4, 6.9 Hz, 1H), 5.04 (s, 2H), 4.62 (s, 2H),
4.18 (q, J¼7.1 Hz, 2H), 1.23 (t, J¼7.1 Hz, 3H); 13C NMR (75 MHz,
CDCl3)
d 167.7, 158.1, 148.6, 136.2, 129.6, 128.4, 127.9, 127.3, 116.1,
104.8, 70.6, 61.6, 50.6, 14.1. HRMS [MþHþ] m/z calcd for
C
16H18NO4 288.1236, found 288.1230.
4.3. Representative procedure B for the alkylation of 2 using
KF/Al2O3
4.3.1. Synthesis of tert-butyl 2-(3-(benzyloxy)-2-oxopyridin-1(2H)-
yl)acetate (3b). To a suspension of 2 (0.20 g, 0.994 mmol) in CH3CN
(17 mL) was added tert-butyl bromoacetate (0.22 mL, 1.49 mmol)
and KF/Al2O3 (1.73 g, 11.9 mmol) and the mixture was stirred at rt
for 24 h. The solids were filtered off and rinsed with ethyl acetate.
The solvent was removed in vacuo and the crude product was
purified by radial chromatography (hexane/ethyl acetate gradient)
to give ester 3b (0.23 g, 73%) as a white solid. Using representative
procedure A, 3b was isolated in 80% yield: mp 130e131 ꢀC; IR (neat)
2975, 1743 (C]O), 1655 (HOPO C]O), 1602 cmꢂ1
;
1H NMR
(400 MHz, CDCl3) 7.44e7.37 (m, 2H), 7.36e7.23 (m, 3H), 6.84 (dd,
d
J¼7.2, 1.7 Hz, 1H), 6.64 (dd, J¼7.2, 1.7 Hz, 1H), 6.02 (t, J¼7.2 Hz, 1H),
5.09 (s, 2H), 4.57 (s, 2H), 1.47 (s, 9H); 13C NMR (50 MHz, CDCl3)
d
166.8, 158.1, 148.8, 136.3, 129.5, 128.5, 127.9, 127.3, 115.9, 104.6,
82.6, 70.7, 51.0, 28.0. HRMS [MþHþ] m/z calcd for C18H22NO4
4. Experimental
316.1549, found 316.1537.
4.1. General methods
4.4. Synthesis of functional HOPO linkers, 3
Melting points were measured in capillary tubes and are un-
corrected. Infrared spectra were recorded on an FT-IR Spectrometer.
NMR spectral samples were prepared using CDCl3 unless otherwise
indicated. All chemical shifts are reported in parts per million
(ppm) relative to the deuterated solvent or an internal tetrame-
thylsilane (TMS) reference. High resolution mass spectral analyses
were obtained using electrospray ionization with the samples
dissolved in either chloroform or methanol. Analytical thin layer
chromatography was performed on silica 60/F254 plastic plates.
Column chromatography was done using silica gel (60e200 mesh
or 200e400 mesh) unless otherwise indicated. Radial chromatog-
raphy was conducted using a centrifugal thin-layer chromatograph
and plates were prepared using silica gel 60 containing gypsum.
Polystyrene-triphenylphosphine (PS-PPh3) had a loading capacity
of 1.88 mmol/g. Sodium hydride (NaH) was obtained as a 57e63%
mineral oil dispersion. Potassium fluoride on alumina (KF/Al2O3)
was 40% by weight KF. Phosgene was obtained as a 20% solution in
toluene. 3-(Benzyloxy)pyridin-2(1H)-one, 2, was prepared accord-
ing to literature procedure.20
4.4.1. 1-Allyl-3-(benzyloxy)pyridin-2(1H)-one (3c). Representative
procedure A was followed using allyl bromide in place of ethyl
bromoacetate and the reaction mixture was stirred 24 h to give
alkene 3c as a yellow solid in 88% yield. Using representative pro-
cedure B, 3c was isolated in 90% yield. mp 51e52 ꢀC; IR (neat) 3033,
1652 (HOPO C]O), 1602 cmꢂ1
;
1H NMR (300 MHz, CDCl3)
d
7.47e7.40 (m, 2H), 7.40e7.24 (m, 3H), 6.88 (dd, J¼6.9, 1.7 Hz, 1H),
6.64 (dd, J¼7.4, 1.7 Hz, 1H), 6.03 (dd, J¼7.4, 6.9 Hz, 1H), 5.99e5.87
(m, 1H), 5.27e5.15 (m, 2H), 5.12 (s, 2H), 4.61 (dt, J¼5.9, 1.5 Hz, 2H);
13C NMR (50 MHz, CDCl3)
d 157.9, 148.8, 136.3, 132.5, 128.5, 128.5,
127.9, 127.2, 118.3, 115.6, 104.7, 70.6, 51.0. HRMS [MþHþ] m/z calcd
for C15H16NO2 242.1181, found 242.1172.
4.4.2. 3-(Benzyloxy)-1-(undec-10-enyl)pyridin-2(1H)-one
(3d). Representative procedure
A was followed using 11-
bromoundec-1-ene in place of ethyl bromoacetate and the re-
action mixture was stirred 24 h to give alkene 3d as a yellow oil in
79% yield. The corresponding O-alkylated product 4d was also
isolated in 12% yield. 3d: IR (film) 2926, 1655 (HOPO C]O),
1606 cmꢂ1 1H NMR (300 MHz, CDCl3)
; d 7.46e7.38 (m, 2H),
4.2. Representative procedure A for the alkylation of 3-(ben-
zyloxy)pyridin-2(1H)-one, 2, using sodium hydride
7.36e7.22 (m, 3H), 6.87 (dd, J¼7.1, 1.7 Hz, 1H), 6.62 (dd, J¼7.1, 1.7 Hz,
1H), 5.97 (t, J¼7.1 Hz,1H), 5.87e5.70 (m,1H), 5.08 (s, 2H), 5.04e4.86
(m, 2H), 3.92 (t, J¼7.4 Hz, 2H), 2.03 (q, J¼6.8 Hz, 2H), 1.81e1.65 (m,
4.2.1. Synthesis of ethyl 2-(3-(benzyloxy)-2-oxopyridin-1(2H)-yl)ac-
etate (3a). To a solution of 2 (0.20 g, 0.99 mmol) in anhydrous
DMF (3 mL) under N2 at 0 ꢀC was added NaH (0.044 g,
2H), 1.43e1.19 (m, 12H); 13C NMR (75 MHz, CDCl3)
d 158.01, 148.83,
139.04, 136.43, 129.06, 128.42, 127.81, 127.25, 115.52, 114.13, 104.34,
70.63, 49.80, 33.76, 29.37, 29.34, 29.19, 29.10, 29.04, 28.86, 26.61.

S. Gibson et al. / Tetrahedron 71 (2015) 9271e9281
9277
HRMS [MþHþ] m/z calcd for C23H32NO2 354.2433, found 354.2430.
(d, JPC¼15.7 Hz), 22.9 (d, JPC¼141.9 Hz), 22.0 (d, JPC¼5.1 Hz). HRMS
[MþHþ] m/z calcd for C29H31NO5P 504.1940, found 504.1927.
4d: IR (film) 2926, 1595, 1449, 1201 cmꢂ1 1H NMR (300 MHz,
;
CDCl3)
d
7.73 (dd, J¼5.0, 1.6 Hz, 1H), 7.46e7.23 (m, 5H), 7.04 (dd,
J¼7.7,1.6 Hz,1H), 6.74 (dd, J¼7.7, 5.0 Hz,1H), 5.90e5.70 (m,1H), 5.14
(s, 2H), 5.04e4.86 (m, 2H), 4.38 (t, J¼6.9 Hz, 2H), 2.04 (q, J¼6.8 Hz,
2H), 1.85 (quintet, J¼7.2 Hz, 2H), 1.57e1.18 (m, 12H); 13C NMR
4.4.7. Diethyl
3-(3-(benzyloxy)-2-oxopyridin-1(2H)-yl)propyl-
phosphonate (3i). Representative procedure A was followed using
diethyl 3-bromopropylphosphonate in place of ethyl bromoacetate
to give 3i as a yellow oil in 80% yield: IR (film) 2983, 1654 (HOPO
(75 MHz, CDCl3) d 155.3,143.1,139.2,138.0,136.8,128.6,127.9,127.2,
120.9, 116.4, 114.1, 71.0, 66.3, 33.8, 29.6, 29.5, 29.4, 29.2, 29.1, 29.0,
26.1. HRMS [MþHþ] m/z calcd for C23H32NO2 354.2433, found
354.2433.
C]O), 1604 cmꢂ1; 1H NMR (300 MHz, CDCl3)
d 7.48e7.23 (m, 5H),
6.95 (dd, J¼7.2, 1.8 Hz, 1H), 6.65 (dd, J¼7.2, 1.8 Hz, 1H), 6.0 (t,
J¼7.2 Hz, 1H), 5.11 (s, 2H), 4.20e3.95 (m, 6H), 2.21e1.98 (m, 2H),
1.88e1.64 (m, 2H), 1.32 (t, J¼7.0 Hz, 6H); 13C NMR (75 MHz, CDCl3)
4.4.3. 3-(Benzyloxy)-1-(prop-2-ynyl)pyridin-2(1H)-one
(3e). Representative procedure A was followed using propargyl
bromide in place of ethyl bromoacetate and the reaction mixture
was stirred for 24 h to give alkyne 3e as a light yellow oil in 81%
yield. Using representative procedure B, 3e was isolated in 63%
yield: IR (neat) 3217, 2121 (C^C),1652 (HOPO C]O),1602 cmꢂ1; 1H
d 158.1, 148.9, 136.3, 129.0, 128.5, 128.0, 127.3, 115.5, 104.8, 70.7, 61.7
(d, JPC¼6.5 Hz), 49.6 (d, JPC¼16.8 Hz), 22.6 (d, JPC¼142.4 Hz), 22.2 (d,
JPC¼4.6 Hz), 16.5 (d, JPC¼6.1 Hz). HRMS [MþHþ] m/z calcd for
C19H27NO5P 380.1627, found 380.1628.
4.4.8. 2-(3-(3-(Benzyloxy)-2-oxopyridin-1(2H)-yl)propyl)isoindo-
line-1,3-dione (3j). Representative procedure A was followed using
N-(3-bromopropyl)phthalimide in place of ethyl bromoacetate and
the reaction mixture was stirred for 24 h to give phthalimide 3j as
a light yellow solid in 82% yield. The corresponding O-alkylated
product 4j was also isolated in 10% yield. 3j: mp 102e103 ꢀC; IR
NMR (300 MHz, CDCl3) d 7.45e7.38 (m, 2H), 7.37e7.25 (m, 3H), 7.21
(dd, J¼7.2, 1.7 Hz, 1H), 6.63 (dd, J¼7.2, 1.7 Hz, 1H), 6.05 (t, J¼7.2 Hz,
1H), 5.09 (s, 2H), 4.77 (d, J¼2.6 Hz, 2H), 2.47 (t, J¼2.6 Hz, 1H); 13C
NMR (75 MHz, CDCl3) d 157.6, 148.5, 136.2, 128.5, 127.9, 127.3, 127.2,
115.6, 105.0, 77.1, 75.0, 70.7, 37.5. HRMS [MþHþ] m/z calcd for
C
15H14NO2 240.1025, found 240.1022.
(neat) 2937, 1702 (C]O), 1650 (HOPO C]O), 1595 cmꢂ1
;
1H NMR
(300 MHz, CDCl3) 7.87e7.77 (m, 2H), 7.76e7.64 (m, 2H), 7.46e7.39
d
4.4.4. 3-(Benzyloxy)-1-(hex-5-ynyl)pyridin-2(1H)-one
(3f). Representative procedure A was followed using 6-iodo-1-
hexyne in place of ethyl bromoacetate and the reaction was stir-
red for 24 h to give alkyne 3f as a light brown solid in 75% yield. The
corresponding O-alkylated product 4f was isolated in 10% yield.
Representative procedure B was followed using 6-iodo-1-hexyne in
place of tert-butyl bromoacetate to give 3f in 49% yield. 3f: mp
41e43 ꢀC; IR (neat) 3232, 2952, 2111 (C^C), 1651 (HOPO C]O),
(m, 2H), 7.38e7.22 (m, 3H), 7.03 (dd, J¼7.1, 1.6 Hz, 1H), 6.64 (dd,
J¼7.1, 1.6 Hz, 1H), 6.03 (t, J¼7.1 Hz, 1H), 5.09 (s, 2H), 4.02 (t, J¼6.9 Hz,
2H), 3,75 (t, J¼6.9 Hz, 2H), 2.17 (quintet, J¼6.9 Hz, 2H); 13C NMR
(75 MHz, CDCl3)
d 168.2, 157.9, 148.8, 136.3, 134.0, 131.9, 129.2,
128.4, 127.9, 127.3, 123.2, 115.5, 104.7, 70.6, 47.5, 35.3, 28.2. HRMS
[MþHþ] m/z calcd for C23H21N2O4 389.1501, found 389.1490.
4.4.9. 2-(5-(3-(Benzyloxy)-2-oxopyridin-1(2H)-yl)pentyl)isoindo-
line-1,3-dione (3k). Representative procedure A was followed using
N-(5-bromopentyl)phthalimide in place of ethyl bromoacetate and
the reaction mixture was stirred for 24 h to give phthalimide 3k as
a yellow solid in 69% yield. The corresponding O-alkylated product
4k was also isolated in 12% yield. 3k: mp 123e124 ꢀC; IR (neat)
1592 cmꢂ1 1H NMR (400 MHz, CDCl3)
; d 7.46e7.38 (m, 2H),
7.38e7.22 (m, 3H), 6.89 (dd, J¼6.9, 1.7 Hz, 1H), 6.63 (dd, J¼7.4,
1.7 Hz, 1H), 6.01 (dd, J¼7.4, 6.9 Hz, 1H), 5.10 (s, 2H), 3.98 (t, J¼7.2 Hz,
2H), 2.24 (td, J¼7.0, 2.7 Hz, 2H), 1.96 (t, J¼2.7 Hz, 1H), 1.91e1.83 (m,
2H), 1.62e1.50 (m, 2H); 13C NMR (50 MHz, CDCl3)
d 158.1, 148.9,
136.4, 128.9, 128.5, 127.9, 127.3, 115.5, 104.6, 83.7, 70.7, 68.9, 49.1,
28.2, 25.4, 18.1. HRMS [MþHþ] m/z calcd for C18H20NO2 282.1494,
found 282.1484.
2938, 1704 (C]O), 1651 (HOPO C]O), 1595 cmꢂ1
;
1H NMR
(300 MHz, CDCl3) 7.85e7.75 (m, 2H), 7.73e7.62 (m, 2H), 7.46e7.38
d
(m, 2H), 7.37e7.21 (m, 3H), 6.89 (dd, J¼7.1, 1.7 Hz, 1H), 6.63 (dd,
J¼7.1, 1.7 Hz, 1H), 5.98 (t, J¼7.1 Hz, 1H), 5.08 (s, 2H), 3.94 (t, J¼7.4 Hz,
2H), 3.67 (t, J¼7.2 Hz, 2H), 1.81 (quintet, J¼7.4 Hz, 2H), 1.17 (quintet,
4.4.5. tert-Butyl 6-(3-(benzyloxy)-2-oxopyridin-1(2H)-yl)hexanoate
(3g). Representative procedure A was followed using tert-butyl
6-iodohexanoate in place of ethyl bromoacetate and the reaction
mixture was stirred for 24 h to give ester 3g as a light brown oil
in 75% yield: IR (film) 2935, 1729 (C]O), 1652 (HOPO C]O),
J¼7.2 Hz, 2H), 1.47e1.30 (m, 2H); 13C NMR (75 MHz, CDCl3)
d 168.3,
158.0, 148.8, 136.4, 133.9, 132.0, 129.0, 128.4, 127.8, 127.3, 123.1,
115.5, 104.5, 70.6, 49.5, 37.6, 28.5, 28.1, 23.8. HRMS [MþHþ] m/z
calcd for C25H25N2O4 417.1814, found 417.1816.
1606 cmꢂ1 1H NMR (300 MHz, CDCl3)
; d 7.46e7.36 (m, 2H),
7.36e7.20 (m, 3H), 6.88 (dd, J¼7.1, 1.7 Hz, 1H), 6.63 (dd, J¼7.1,
1.7 Hz, 1H), 5.98 (t, J¼7.1 Hz, 1H), 5.08 (s, 2H), 3.93 (t, J¼7.3 Hz,
2H), 2.20 (t, J¼7.4 Hz, 2H), 1.75 (quintet, J¼7.5 Hz, 2H), 1.61
(quintet, J¼7.5 Hz, 2H), 1.42 (s, 9H), 1.38e1.29 (m, 2H); 13C NMR
4.4.10. tert-Butyl benzyloxy(3-(3-(benzyloxy)-2-oxopyridin-1(2H)-
yl)propyl)carbamate (3l). Representative procedure A was followed
using tert-butyl benzyloxy(3-bromopropyl)carbamate35 in place of
ethyl bromoacetate and the reaction mixture was stirred for 24 h to
give 3l as a light brown oil in 86% yield: IR (film) 2980, 1695 (C]O),
(75 MHz, CDCl3)
d 172.8, 158.0, 148.8, 136.4, 129.1, 128.4, 127.8,
127.2, 115.5, 104.4, 79.9, 70.6, 49.5, 35.2, 28.7, 28.1, 26.0, 24.6.
HRMS [MþHþ] m/z calcd for C22H30NO4 372.2175, found
372.2166.
1652 (HOPO C]O), 1606 cmꢂ1 1H NMR (300 MHz, CDCl3)
;
d
7.45e7.37 (m, 4H), 7.37e7.22 (m, 6H), 6.85 (dd, J¼6.9, 1.7 Hz, 1H),
6.61 (dd, J¼7.3, 1.7 Hz, 1H), 5.95 (dd, J¼7.3, 6.9 Hz, 1H), 5.06 (s, 2H),
4.85 (s, 2H), 3.96 (t, J¼6.8 Hz, 2H), 3.48 (t, J¼6.8 Hz, 2H), 2.05
(quintet, J¼6.8 Hz, 2H), 1.49 (s, 9H); 13C NMR (75 MHz, CDCl3)
4.4.6. Dibenzyl
phosphonate (3h). Representative procedure
3-(3-(benzyloxy)-2-oxopyridin-1(2H)-yl)propyl-
was followed
A
d 158.0, 156.4, 148.8, 136.4, 135.4, 129.4, 129.3, 128.5, 128.5, 128.4,
using dibenzyl 3-iodopropylphosphonate in place of ethyl bro-
127.9, 127.3, 115.5, 104.5, 81.5, 77.0, 70.7, 47.7, 47.0, 28.3, 26.8. HRMS
moacetate to give 3h as a yellow oil in 77% yield IR (film) 3033, 1656
(MþNaþ) m/z calcd for C27H32N2NaO5 487.2209, found 487.2207.
(HOPO C]O), 1606 cmꢂ1 1H NMR (300 MHz, CDCl3)
; d 7.48e7.21
(m,15H), 6.77 (dd, J¼7.2,1.6 Hz,1H), 6.60 (dd, J¼7.2,1.6 Hz,1H), 5.93
(t, J¼7.2 Hz, 1H), 5.07 (s, 2H), 5.06e4.90 (m, 4H), 3.96 (t, J¼7.0 Hz,
2H), 2.10e1.94 (m, 2H), 1.80e1.68 (m, 2H); 13C NMR (75 MHz,
4.4.11. tert-Butyl benzyloxy(5-(3-(benzyloxy)-2-oxopyridin-1(2H)-
yl)pentyl)carbamate (3m). Representative procedure A was fol-
lowed using tert-butyl benzyloxy(5-iodopentyl)carbamate35 in
place of ethyl bromoacetate and the reaction mixture was stirred
for 24 h to give 3m as a yellow oil in 81% yield. The corresponding
CDCl3)
d
158.0,148.8,136.4,136.2 (d, JPC¼5.6 Hz),129.0,128.6,128.5,
128.5, 128.0, 127.9, 127.3, 115.4, 104.6, 70.7, 67.3 (d, JPC¼6.7 Hz), 49.4

9278
S. Gibson et al. / Tetrahedron 71 (2015) 9271e9281
O-alkylated product 4m was also isolated in 12% yield. 3m: IR (film)
2938, 1694 (C]O), 1652 (HOPO C]O), 1606 cmꢂ1 1H NMR
(300 MHz, CDCl3)
were removed in vacuo and the residue was dissolved in CH2Cl2
(15 mL) and washed with 1M HCl (15 mL). The aqueous layer was
again extracted with CH2Cl2 (15 mLꢁ2) and the combined organic
layers were dried (Na2SO4) and the solvent was removed in vacuo.
The product was further dried under high vacuum to give the iso-
cyanate 6 as a pale yellow oil (0.18 g, 82%), which was used without
further purification: IR (neat) 2952, 2278 (NCO), 1652 (HOPO C]O),
;
d
7.45e7.19 (m, 10H), 6.81 (dd, J¼7.1, 1.7 Hz, 1H),
6.60 (dd, J¼7.1, 1.7 Hz, 1H), 5.94 (t, J¼7.1 Hz, 1H), 5.05 (s, 2H), 4.80 (s,
2H), 3.89 (t, J¼7.3 Hz, 2H), 3.40 (t, J¼7.1 Hz, 2H), 1.72 (quintet,
J¼7.5 Hz, 2H), 1.61 (quintet, J¼7.4 Hz, 2H), 1.49 (s, 9H), 1.38e1.23 (m,
2H); 13C NMR (75 MHz, CDCl3)
d 157.9, 156.4, 148.7, 136.4, 135.6,
129.3, 129.0, 128.4, 128.3, 127.8, 127.2, 115.5, 104.4, 81.0, 76.7, 70.5,
1606 cmꢂ1; 1H NMR (300 MHz, CDCl3)
d 7.18e7.45 (m, 5H), 6.89 (dd,
49.5, 49.2, 28.7, 28.3, 26.6, 23.7. HRMS (MþNaþ) m/z calcd for
J¼6.8, 1.5 Hz, 1H), 6.65 (dd, J¼7.4, 1.4 Hz, 1H), 6.05 (t, J¼7.1 Hz, 1H),
C
29H36N2NaO5 515.2516, found 515.2521.
5.11 (s, 2H), 4.07 (t, J¼6.8 Hz, 2H), 3.40 (t, J¼6.3 Hz, 2H), 2.04e2.13
(quintet, J¼6.6 Hz, 2H); 13C NMR (75 MHz, CDCl3)
d 158.3, 149.2,
4.5. Representative procedure for the Mitsunobu reaction of
2 with alcohols
136.4, 128.7, 128.6, 128.2, 127.5, 122.0, 115.7, 105.2, 70.9, 47.5, 40.4,
30.2. Anal. Calcd C16H16N2O3: C, 67.59; H, 5.67; N, 9.85; Found: C,
67.81, H, 5.84, N, 9.86.
4.5.1. Synthesis of 3c. To a suspension of 2 (0.20 g, 0.994 mmol) in
anhydrous THF (9 mL) under N2 was added PS-PPh3 (1.06 g,
1.99 mmol) followed by DIAD (0.39 mL, 1.99 mmol). After 5 min,
allyl alcohol (0.068 mL, 0.994 mmol) was added and the mixture
stirred at rt for 24 h. The PS-PPh3 was filtered off and the solvent
removed in vacuo. The crude product was purified by radial chro-
matography (hexane/ethyl acetate gradient) to give 3c (0.11 g, 47%)
(see 4.4.1) and 4c (0.047 g, 20%) as a light yellow oil. 4c: IR (film)
4.9. Octyl-3-(3-(benzyloxy)-2-oxopyridin-1(2H)-yl)pro-
pylcarbamate (7)
A solution of 6 (0.34 g, 0.18 mmol) and 1-octanol (0.043 mL,
0.27 mmol) in anhydrous 1,2-dichloroethane (2.5 mL) was heated
at reflux for 1 day under N2. After cooling, the reaction mixture was
diluted with CH2Cl2 (5 mL) and washed with saturated NH4Cl
(15 mL), saturated NaCl (15 mL), dried (Na2SO4) and the solvents
removed in vacuo. Excess octanol was removed by Kugelrohr dis-
tillation to give the carbamate 7 as a pale yellow oil (0.065 g, 87%):
IR (neat) 3317 (NH), 2928, 2856, 1714 (C]O), 1652 (HOPO C]O),
3066, 2933, 1595 cmꢂ1; 1H NMR (300 MHz, CDCl3)
d
7.72 (dd, J¼5.0,
1.5 Hz, 1H), 7.45e7.23 (m, 5H), 7.05 (dd, J¼7.8, 1.5 Hz, 1H), 6.75 (dd,
J¼7.8, 5.0 Hz, 1H), 6.23e6.07 (m, 1H), 5.42 (dq, J¼17.2, 1.5 Hz, 1H),
5.25 (dq, J¼10.4, 1.5 Hz, 1H), 5.14 (s, 2H), 4.95 (dt, J¼5.4, 1.5 Hz, 2H);
13C NMR (75 MHz, CDCl3)
d
154.4, 143.0, 137.7, 136.6, 133.6, 128.6,
1601 cmꢂ1 1H NMR (300 MHz, CDCl3)
; d 7.30e7.44 (m, 5H), 6.89
128.0, 127.2, 120.7, 117.3, 116.8, 70.9, 66.6. HRMS [MþHþ] m/z calcd
(dd, J¼6.8, 1.2 Hz, 1H), 6.67(dd, J¼7.5, 1.6 Hz, 1H), 6.07 (t, J¼7.1 Hz,
1H), 5.76 (br s, 1H), 5.12 (s, 2H), 4.00e4.09 (m, 4H), 3.13 (dt, J¼6.4,
5.7 Hz, 2H), 1.86e1.95 (m, 2H), 1.52e1.65 (m, 2H), 1.27 (br s, 10H),
for C15H16NO2 242.1181, found 242.1180.
4.5.2. Synthesis of 3d. Using representative procedure for the
Mitsunobu alkylation, the N-alkylated product 3d was obtained in
27% yield and the O-alkylated product 4d was obtained in 20% yield.
When triphenylphosphine was used in place of PS-PPh3, and the
crude reaction mixture purified by column chromatography on
neutral alumina (hexane/ethyl acetate gradient), 3d was obtained
in 26% yield and 4d was obtained in 51% yield.
0.88 (t, J¼6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 158.9,157.4,149.0,
136.4, 128.9, 128.8, 128.3, 127.6, 115.7, 105.7, 71.1, 65.1, 46.4, 37.2,
32.1, 30.2, 29.46, 29.3, 26.1, 22.9, 14.4.
4.10. 1-(3-(3-(Benzyloxy)-2-oxopyridin-1(2H)-yl)propyl)-3-
octylurea (8)
A solution of 1-octylamine (0.03 mL, 0.21 mmol) in CH2Cl2
(2 mL) was added to isocyanate 6 (0.04 g, 0.141 mmol) at 0 ꢀC and
stirred for 10 min. The reaction mixture was diluted with CH2Cl2
(5 mL) and washed with saturated NH4Cl (15 mL), saturated NaCl
(15 mL), dried (Na2SO4) and the solvents removed in vacuo. The
crude product was purified using radial chromatography (ethyl
acetate) to give urea 8 as a pure white solid (0.05 g, 90%): mp
93e94 ꢀC; IR (KBr) 3335 (NH), 2925, 2854, 1656 (HOPO C]O),
4.6. Synthesis of 3c via rearrangement of 4c
To a solution of 4c (0.039 g, 0.162 mmol) in xylene (1 mL) under
N2 was added PdCl2 (0.0028 g, 0.0162 mmol) and the mixture was
heated at 80 ꢀC for 3 h. After cooling, the catalyst was removed by
filtration through a short silica gel column rinsing with CHCl3. The
solvent was removed in vacuo and the crude product was purified
by radial chromatography to give 3c (0.032 g, 82%) (see 4.4.1).
1621 cmꢂ1; 1H NMR (300 MHz, CDCl3)
d 7.33e7.43 (m, 5H), 6.90 (dd,
J¼6.7, 1.7 Hz, 1H), 6.67 (dd, J¼7.5, 1.6 Hz, 1H), 6.11 (t, J¼7.2 Hz, 1H),
5.76 (t, J¼5.7 Hz,1H), 5.13 (s, 2H), 4.37 (m,1H), 4.09 (t, J¼6.1 Hz, 2H),
3.12e3.20 (m, 4H), 1.85e1.93 (m, 2H), 1.43e1.49 (m, 2H), 1.27 (br s,
4.7. 1-(3-Aminopropyl)-3-(benzyloxy)pyridin-2(1H)-one (5)
The phthalimide 3j (1.83 g, 4.71 mmol) was suspended in 40%
aqueous methylamine (23 mL, 0.30 mol) and the mixture stirred
for 2 days until all of the phthalimide had dissolved. The reaction
mixture was diluted with water (20 mL) and the product
extracted into CHCl3 (3ꢁ30 mL), dried (MgSO4) and the solvent
removed in vacuo to give the known HOPO amine 5.31b (1.07 g,
10H), 0.88 (t, J¼6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 158.9,149.0,
136.3, 129.1, 128.9, 128.4, 127.6, 115.9, 106.0, 71.1, 46.7, 40.8, 36.4,
32.1, 30.6, 30.5, 29.7, 27.2, 23.0, 14.4.
4.11. 1,10,100-(2,20,200-Nitrilotris(ethane-2,1-diyl))tris(3-(3-(3-
(benzyloxy)-2-oxopyridin-1(2H)-yl)propyl)urea) (9)
87.7%). 1H NMR (300 MHz, CDCl3)
d 7.45e7.33 (m, 5H), 6.92 (dd,
J¼6.9, 1.8 Hz, 1H), 6.63 (dd, J¼6.9, 1.8 Hz, 1H), 6.03 (t, J¼7.3 Hz,
1H), 5.12 (s, 2H), 4.09 (t, J¼6.9 Hz, 2H), 2.72 (t, J¼6.5 Hz, 2H), 1.89
(quintet, J¼6.8 Hz, 2H).
A solution of tris-(2-aminoethyl)amine (0.040 g, 0.24 mmol) in
CH2Cl2 (2 mL) was added to isocyanate 6 (0.21 g, 0.80 mmol) at 0 ꢀC
and stirred for 2 h at 0 ꢀC. The solvent was removed in vacuo and
the crude product was purified using silica gel chromatography
(methanol) to give urea 9 as a white solid (0.16 g, 67%): mp
65e67 ꢀC; IR (KBr) 3366 (NH), 3063, 2922, 2852,1651 (HOPO C]O),
4.8. 3-(Benzyloxy)-1-(3-isocyanatopropyl)pyridin-2(1H)-one (6)
A solution of 5 (0.20 g, 0.77 mmol) and 1,8-bis(dimethyl)ami-
nonaphthalene (0.36 g, 1.54 mmol) in CH2Cl2 (5 mL) was added
dropwise to a solution of phosgene (0.79 mL, 1.54 mmol) in toluene
at 0 ꢀC and the reaction mixture was stirred for 15 min. The solvents
1598 cmꢂ1 1H NMR (300 MHz, CDCl3)
; d 7.29e7.39 (m, 15H), 6.94
(dd, J¼6.9, 1.6 Hz, 3H), 6.64 (dd, J¼7.4, 1.4 Hz, 3H), 6.16 (br s, 3H),
6.04 (t, J¼7.1 Hz, 3H), 5.95e6.05 (m, 3H), 5.02 (s, 6H), 3.99 (t,
J¼6.5 Hz, 6H), 3.06e3.14 (m, 12H), 2.49e2.52 (m, 6H), 1.79e1.88 (m,

S. Gibson et al. / Tetrahedron 71 (2015) 9271e9281
9279
6H); 13C NMR (75 MHz, CDCl3)
128.8, 128.4, 127.7, 115.7, 105.6, 71.0, 55.8, 47.1, 39.0, 36.8, 30.3;
HRMS [MþHþ] m/z calcd for C54H67N10O9 999.5087, found
999.5105.
d
159.6, 158.5, 148.8, 136.3, 129.5,
4.15. tert-Butyl benzyloxy(6-(benzyloxy(5-(3-(benzyloxy)-2-
oxopyridin-1(2H)-yl)pentyl)amino)-6-oxohexyl)carbamate
(13)
To a solution of acid 12 (0.134 g, 0.398 mmol) in anhydrous
CH2Cl2 (1.5 mL) under N2 at 0 ꢀC was added triethylamine
(0.076 mL, 0.543 mmol) followed by HATU (0.151 g, 0.398 mmol)
and 11 (0.142 g, 0.362 mmol). The mixture was stirred at rt for 3 h.
The reaction mixture was diluted with CH2Cl2 (30 mL) and washed
with 2 N HCl (2ꢁ15 mL), saturated NaHCO3 (2ꢁ15 mL), saturated
NaCl (15 mL) and dried (Na2SO4). The solvent was removed in vacuo
and the crude product was purified by radial chromatography
(hexane/ethyl acetate gradient) to give 13 (0.195 g, 76%) as a color-
less oil: IR (film) 2937, 1698, 1655 (HOPO C]O), 1607 cmꢂ1; 1H NMR
4.12. 1,10,100-(2,20,200-nitrilotris(ethane-2,1-diyl))tris(3-(3-(3-
hydroxy-2-oxopyridin-1(2H)-yl)propyl)urea (10)
A suspension of 9 (0.07 g, 0.07 mmol) and 5% Pd/C (0.08 g) in
methanol was stirred under H2 balloon for four days. The catalyst
was removed by the filtration through a 0.45 mm nylon filter rinsing
with methanol. The solvents were removed in vacuo and the
product was dried under high vacuum to give urea 10 as a viscous
brown oil (0.059 g, quant.): IR (neat) 3334 (NH), 1646 (br) (C]O)
cmꢂ1
;
1H NMR (300 MHz, CDCl3)
d
7.09e7.11 (d, J¼5.13 Hz, 3H),
(300 MHz, CDCl3)
d
7.47e7.25 (m, 15H), 6.84 (dd, J¼7.1, 1.4 Hz, 1H),
6.79e6.82 (d, J¼7.2 Hz, 3H), 6.20e6.25 (m, 3H), 4.04 (unres t, 6H),
6.62 (dd, J¼7.1, 1.4 Hz, 1H), 5.97 (t, J¼7.1 Hz, 1H), 5.08 (s, 2H), 4.81 (s,
2H), 4.76 (s, 2H), 3.92 (t, J¼7.3 Hz, 2H), 3.62 (t, J¼6.8 Hz, 2H), 3.40 (t,
J¼7.2 Hz, 2H), 2.36 (t, J¼7.5 Hz, 2H), 1.83e1.69 (m, 2H), 1.69e1.53
(m, 6H), 1.49 (s, 9H), 1.40e1.23 (m, 4H); 13C NMR (75 MHz, CDCl3)
3.17 (unres t,12H), 2.61 (t, J¼5 MHz, 6H),1.89 (unres t, 6H); 13C NMR
(75 MHz, CD3OD) d 161.3, 160.1, 148.4, 129.2, 117.0, 108.5, 56.1, 48.5,
39.6, 38.2, 31.3; HRMS [MþHþ] m/z calcd for C33H49N10O9 729.3679,
found 729.3709.
d 174.6, 158.0, 156.5, 148.9, 136.4, 135.6, 134.5, 129.3, 129.1, 129.0,
128.9, 128.7, 128.5, 128.4, 128.4, 127.8, 127.3, 115.5, 104.5, 81.0, 76.8,
76.3, 70.7, 49.6, 49.4, 45.0, 32.2, 28.6, 28.3, 26.9, 26.6, 26.4, 24.3,
23.7. HRMS [MþHþ] m/z cald for C42H54N3O7 712.3962, found
712.3965.
4.13. Representative procedure for hydrolysis of Boc protect-
ing group
Synthesis of 3-(benzyloxy)-1-(5-(benzyloxyamino)pentyl)pyridin-
2(1H)-one (11). A solution of 3m (0.695 g, 1.41 mmol) in 1:1 TFA/
CH2Cl2 (12 mL) was stirred at rt for 2.5 h. The solvent was removed
in vacuo and the residue was adjusted to pH 10 using 1 N NaOH. The
product was extracted into CH2Cl2 (3ꢁ50 mL) and the extract was
dried (Na2SO4). The solvent was removed in vacuo to give 11
(0.442 g, 98%) as a brown oil, which was used without purification:
4.16. N-(Benzyloxy)-N-(5-(3-(benzyloxy)-2-oxopyridin-1(2H)-
yl)pentyl)-6-(benzyloxyamino)hexanamide (14)
Following the representative procedure for hydrolysis of Boc
group, and substituting 13 for 3m, the protected hydroxylamine 14
was obtained in 77% yield as a yellow oil after radial chromatog-
raphy (hexane/ethyl acetate gradient then 10% methanol/ethyl ac-
etate). IR (film) 3436 (NH), 2939, 1653 (HOPO C]O), 1605 cmꢂ1; 1H
IR (neat) 3249, 2937, 1652 (HOPO C]O), 1606 cmꢂ1
;
1H NMR
(300 MHz, CDCl3) 7.46e7.37 (m, 2H), 7.37e7.19 (m, 8H), 6.82 (dd,
d
J¼7.1, 1.3 Hz, 1H), 6.60 (dd, J¼7.1, 1.3 Hz, 1H), 5.96 (t, J¼7.1 Hz, 1H),
5.52 (br s,1H), 5.06 (s, 2H), 4.66 (s, 2H), 3.90 (t, J¼7.3 Hz, 2H), 2.88 (t,
J¼7.0 Hz, 2H), 1.73 (quintet, J¼7.5 Hz, 2H), 1.52 (quintet, J¼7.3 Hz,
NMR (300 MHz, CDCl3) d 7.46e7.38 (m, 2H), 7.38e7.20 (m, 13H),
6.82 (dd, J¼6.9, 1.6 Hz, 1H), 6.60 (dd, J¼7.4, 1.6 Hz, 1H), 6.01e5.91
(m, 1H), 5.09 (s, 2H), 4.76 (s, 2H), 4.68 (s, 2H), 3.90 (t, J¼7.3 Hz, 2H),
3.69e3.55 (m, 2H), 2.90 (t, J¼7.0 Hz, 2H), 2.36 (t, J¼7.4 Hz, 2H),
1.79e1.70 (m, 2H), 1.68e1.55 (m, 4H), 1.55e1.44 (m, 2H), 1.37e1.25
2H), 1.40e1.25 (m, 2H); 13C NMR (75 MHz, CDCl3)
d 158.0, 148.8,
138.0, 136.4, 129.0, 128.4, 128.3, 128.3, 127.8, 127.7, 127.2, 115.4,
104.4, 76.1, 70.6, 51.8, 49.6, 28.9, 27.0, 24.2.
(m, 4H); 13C NMR (75 MHz, CDCl3)
d 174.7, 158.0, 148.8, 138.0, 136.4,
134.5,129.1,129.0,128.8,128.7,128.4,128.3,127.8,127.7,127.2,115.6,
104.6, 76.2, 76.1, 70.7, 51.9, 49.6, 45.0, 32.2, 28.5, 27.1, 26.9, 26.4,
24.4, 23.7. HRMS [MþHþ] m/z calcd for C37H46N3O 612.3437, found
612.3443.
4.14. 6-(Benzyloxy(tert-butoxycarbonyl)amino)hexanoic acid
(12)
To
a solution of tert-butyl benzyloxycarbamate (4.02 g,
18.0 mmol) in anhydrous DMF (60 mL) under N2 at 0 ꢀC was added
NaH (1.51 g, 37.8 mmol). The mixture was warmed to rt and stirred
for 30 min. After cooling back to 0 ꢀC, 6-bromohexanoic acid
(3.86 g, 19.8 mmol) was added and the mixture was stirred at rt for
1 h and then heated at 70 ꢀC for 18 h. The reaction mixture was
cooled and quenched with saturated NH4Cl (50 mL) and the
aqueous layer acidified to pH 2 with conc. HCl. The product was
extracted into ethyl acetate (3ꢁ50 mL), dried (Na2SO4) and the
solvent was removed in vacuo. The crude product was dissolved in
1M NaOH and impurities removed by extraction with ethyl acetate
(2ꢁ20 mL). The aqueous later was then acidified with conc. HCl,
and the product extracted into ethyl acetate (3ꢁ30 mL), dried
(Na2SO4) and the solvent removed in vacuo to give acid 12 (4.27 g,
70%) as an oil, which was used in the next step without further
purification. A portion of 12 was purified by preparative chroma-
tography for characterization: IR (film) 2937, 1705 (C]O) cmꢂ1; 1H
4.17. N-(Benzyloxy)-N-(5-(3-(benzyloxy)-2-oxopyridin-1(2H)-
yl)pentyl)-6-(N-(benzyloxy)acetamido)hexanamide (15)
To a solution of 14 (0.305 g, 0.499 mmol) in anhydrous CH2Cl2
(2 mL) under N2 at 0 ꢀC was added triethylamine (0.10 mL,
0.748 mmol) followed by acetyl chloride (0.039 mL, 0.548 mmol).
The reaction mixture was stirred at rt for 24 h. The reaction mixture
was diluted with CH2Cl2 (30 mL) and washed with 2 N HCl
(2ꢁ15 mL), saturated NaHCO3 (2ꢁ15 mL), saturated NaCl (15 mL)
and dried (Na2SO4). The solvent was removed in vacuo and the
crude product was purified by radial chromatography (hexane/
ethyl acetate gradient then 10% methanol/ethyl acetate) to give 15
(0.279 g, 86%) as a yellow oil: IR (film) 2939, 1651 (HOPO C]O),
1606 cmꢂ1 1H NMR (300 MHz, CDCl3)
; d 7.46e7.22 (m, 15H), 6.85
(dd, J¼7.2, 1.7 Hz, 1H), 6.62 (dd, J¼7.2, 1.7 Hz, 1H), 5.97 (t, J¼7.2 Hz,
1H), 5.07 (s, 2H), 4.78 (s, 2H), 4.76 (s, 2H), 3.91 (t, J¼7.3 Hz, 2H), 3.61
(t, J¼6.8 Hz, 4H), 2.36 (t, J¼7.4 Hz, 2H), 2.07 (s, 3H), 1.75 (quintet,
J¼7.5 Hz, 2H), 1.69e1.54 (m, 6H), 1.39e1.22 (m, 4H); 13C NMR
NMR (300 MHz, CDCl3)
d 11.2e10.85 (br s, 1H), 7.46e7.28 (m, 5H),
4.82 (s, 2H), 3.40 (t, J¼7.1 Hz, 2H), 2.32 (t, J¼7.5 Hz, 2H), 1.73e1.54
(m, 4H), 1.50 (s, 9H), 1.40e1.23 (m, 2H); 13C NMR (75 MHz, CDCl3)
(75 MHz, CDCl3) d 174.6,172.0,158.0,148.8,136.4,134.5,129.1,128.8,
d
179.7, 156.6, 135.7, 129.4, 128.5, 128.4, 81.3, 76.9, 49.4, 34.0, 28.3,
128.6,128.4,127.8, 127.2,115.5,104.4, 76.2, 76.1, 70.6, 49.5, 45.1, 32.1,
26.7, 26.2, 24.4. HRMS (MþNaþ) m/z calcd for C18H27NO5Na
28.6, 26.7, 26.5, 26.4, 24.2, 23.7, 20.5. HRMS [MþHþ] m/z calcd for
360.1781, found 360.1777.
C39H48N3O6 654.3543, found 654.3553.

9280
S. Gibson et al. / Tetrahedron 71 (2015) 9271e9281
4.18. N-Hydroxy-N-(5-(3-hydroxy-2-oxopyridin-1(2H)-yl)pen-
tyl)-6-(N-hydroxyacetamido)hexanamide (16)
J¼6.8 Hz, 2H), 4.86 (br s, 3H), 4.00 (t, J¼7.0 Hz, 4H), 3.60 (t, J¼6.7 Hz,
2H), 2.47 (d, J¼7.2 Hz, 2H), 1.82e1.70 (m, 4H), 1.70e1.56 (m, 4H),
1.44e1.26 (m, 4H); 13C NMR (75 MHz, CD3OD)
d 175.8, 160.0, 159.9,
To a solution of 15 (0.377 g, 0.577 mmol) in EtOH (5 mL) was
added 5% Pd on carbon (0.123 g, 0.0577 mmol) and the mixture was
stirred at rt under a H2 balloon for 24 h. The catalyst was removed
by centrifugation followed by filtration. The filtrate was concen-
trated in vacuo to give 16 (0.215 g, 97%) as a light brown oil: IR
148.3, 129.3, 129.2, 116.9, 116.9, 108.3, 108.3, 50.9, 50.7, 48.7, 33.1,
30.1, 30.0, 27.4, 27.3, 25.6, 24.6. HRMS [MþHþ] m/z calcd for
C21H30N3O6 420.2135, found 420.2133.
Acknowledgements
(neat) 3176, 2937, 1600 cmꢂ1; 1H NMR (300 MHz, CD3OD)
d 7.10 (d,
J¼6.8 Hz, 1H), 6.83 (d, J¼6.8 Hz, 1H), 6.24 (d, J¼6.8 Hz, 1H), 4.96 (br
s, 3H), 4.00 (t, J¼7.0 Hz, 2H), 3.64e3.56 (m, 4H), 2.47 (t, J¼7.2 Hz,
2H), 2.09 (s, 3H),1.82e1.72 (m, 2H),1.71e1.55 (m, 6H),1.40e1.27 (m,
This research was supported in part by a grant from the National
Institutes of Health under PHS Grant no. 5SC3GM084809.
4H); 13C NMR (75 MHz, CD3OD)
d 175.8, 173.4, 159.8, 148.2, 129.2,
Supplementary data
117.1, 108.4, 50.7, 48.8, 48.7, 33.2, 29.9, 27.5, 27.2, 25.6, 24.5, 20.4.
HRMS [MþHþ] m/z calcd for C18H30N3O6 354.2129, found 384.2138.
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2015.10.028.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
4.19. 6-(3-(Benzyloxy)-2-oxopyridin-1(2H)-yl)hexanoic acid
(17)
Following the representative procedure for hydrolysis of Boc
group, 3g was hydrolyzed to give acid 17 in 95% yield as a light
brown solid: mp 104e105 ꢀC; IR (neat) 2943, 1723 (C]O), 1639
References and notes
1. (a) Tam, T. F.; Leung-Toung, R.; Li, W.; Wang, Y.; Kariman, K.; Spino, M. Curr.
Med. Chem. 2003, 10, 938e995; (b) Kalinowski, D. S.; Richardson, D. R. Phar-
macol. Rev. 2005, 57, 547e583.
(HOPO C]O), 1579 cm-1; 1H NMR (300 MHz, CDCl3)
d 7.46e7.39
(m, 2H), 7.39e7.24 (m, 3H), 6.89 (dd, J¼7.2, 1.6 Hz, 1H), 6.67 (dd,
J¼7.2,1.6 Hz,1H), 6.50 (t, J¼7.2 Hz,1H), 5.06 (s, 2H), 3.95 (t, J¼7.3 Hz,
2H), 2.28 (t, J¼7.3 Hz, 2H), 1.75 (quintet, J¼7.5 Hz, 2H), 1.62 (quintet,
2. (a) Ji, C.; Miller, M. J. Bioorg. Med. Chem. 2012, 20, 3828e3836; (b) Poreddy, A.
R.; Schall, O. F.; Osiek, T. A.; Wheatley, J. R.; Beusen, D. D.; Marshall, G. R.;
Slomczynska, U. J. Comb. Chem. 2004, 6, 239e254.
J¼7.5 Hz, 2H), 1.45e1.28 (m, 2H); 13C NMR (75 MHz, CDCl3)
d 177.6,
€
€
3. (a) Mollmann, U.; Heinisch, L.; Bauernfeind, A.; Kohler, T.; Ankel-Fuchs, D. Bi-
ometals 2009, 22, 615e624; (b) Girijavallabhan, V.; Miller, M. J. “Therapeutic
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pp 413e433.
158.2, 148.8, 136.2, 128.9, 128.5, 127.9, 127.4, 115.6, 105.3, 70.7, 49.8,
33.9, 28.7, 26.0, 24.3. HRMS [MþHþ] m/z calcd for C18H22NO4
316.1549, found 316.1540.
4. Budzikiewicz, H. Mini-Reviews Org. Chem. 2004, 1, 163e168.
5. (a) Weizman, H.; Shanzer, A. Chem. Commun. 2000, 2013e2014; (b) Meyer, M.;
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4.20. N-(Benzyloxy)-6-(3-(benzyloxy)-2-oxopyridin-1(2H)-yl)-
N-(5-(3-(benzyloxy)-2-oxopyridin-1(2H)-yl)pentyl)hex-
anamide (18)
To a solution of acid 17 (0.127 g, 0.404 mmol) in anhydrous
CH2Cl2 (1.5 mL) under N2 at 0 ꢀC was added triethylamine
(0.077 mL, 0.550 mmol) followed by HATU (0.153 g, 0.404 mmol)
and 11 (0.144 g, 0.367 mmol). The reaction mixture was stirred at rt
for 4 h. The reaction mixture was diluted with CH2Cl2 (30 mL) and
washed with 2 N HCl (2ꢁ15 mL), saturated NaHCO3 (2ꢁ15 mL),
saturated NaCl (15 mL) and dried (Na2SO4). The solvent was re-
moved in vacuo and the crude product was purified by radial
chromatography (hexane/ethyl acetate gradient then 10% metha-
nol/ethyl acetate) to give 18 (0.209 g, 83%) as a yellow oil: IR (film)
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2942, 1660, 1652 (HOPO C]O), 1606 cmꢂ1
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CDCl3) 7.45e7.40 (m, 4H), 7.37e7.23 (m, 11H), 6.89e6.82 (m, 2H),
d
6.63 (d, J¼7.5 Hz, 1H), 6.62 (d, J¼7.5 Hz, 1H), 5.98 (t, J¼7.1 Hz, 1H),
5.97 (t, J¼7.1 Hz, 1H), 5.08 (s, 4H), 4.78 (s, 2H), 3.93 (t, J¼7.3 Hz, 2H),
3.92 (t, J¼7.3 Hz, 2H), 3.61 (br t, J¼6.8 Hz, 2H), 2.36 (t, J¼7.4 Hz, 2H),
1.85e1.70 (m, 4H), 1.69e1.54 (m, 4H), 1.41e1.23 (m, 4H); 13C NMR
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(75 MHz, CDCl3) d 174.5,158.0,148.9,136.4,134.5,129.1, 129.1, 128.9,
128.7, 128.5,127.9, 127.3, 115.49, 115.48, 104.5, 104.4, 76.3, 70.7, 49.6,
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(del); IR (neat) 3130, 2932, 1647, 1585 cmꢂ1
;
1H NMR (300 MHz,
7.08 (d, J¼6.8 Hz, 2H), 6.82 (d, J¼6.8 Hz, 2H), 6.22 (d,
CD3OD)
d

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