Preparation of bifunctional isocyanate hydroxamate linkers: Synthesis of carbamate and urea tethered polyhydroxamic acid chelators

Article abstract of DOI:10.1016/j.tetlet.2012.09.025

Two novel bifunctional N-methylhydroxamate-isocyanate linkers 20 and 21 were prepared in good yield and high purity from the corresponding amine salts using a biphasic reaction with phosgene. The facile ring opening reaction of N-Boc lactams using the anion of O-benzylhydroxylamine gave the protected amino hydroxamates 6a and 6c in good yields. The selective methylation of the hydroxamate nitrogen in the presence of the N-Boc group in these intermediates could be readily accomplished. The utility of the linkers was clearly demonstrated by the synthesis of the carbamate-tethered trishydroxamic acid 27 and the urea-tethered 29.

Full text of DOI:10.1016/j.tetlet.2012.09.025

Tetrahedron Letters 53 (2012) 6367–6371
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Preparation of bifunctional isocyanate hydroxamate linkers: synthesis of
carbamate and urea tethered polyhydroxamic acid chelators
⇑
Rasika Fernando, Jonathan M. Shirley, Emilio Torres, 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:
Two novel bifunctional N-methylhydroxamate–isocyanate linkers 20 and 21 were prepared in good yield
and high purity from the corresponding amine salts using a biphasic reaction with phosgene. The facile
ring opening reaction of N-Boc lactams using the anion of O-benzylhydroxylamine gave the protected
amino hydroxamates 6a and 6c in good yields. The selective methylation of the hydroxamate nitrogen
in the presence of the N-Boc group in these intermediates could be readily accomplished. The utility of
the linkers was clearly demonstrated by the synthesis of the carbamate-tethered trishydroxamic acid
27 and the urea-tethered 29.
Received 27 August 2012
Revised 5 September 2012
Accepted 6 September 2012
Available online 21 September 2012
Keywords:
Polyhydroxamate chelators
Isocyanate
Ó 2012 Elsevier Ltd. All rights reserved.
Carbamate
Urea
The monobasic hydroxamate ligand is well-known for its ability
to complex hard metal ions such as Fe(III) and the actinides(IV). In
fact, many natural siderophores used by bacteria and fungi to pro-
cure iron essential for their growth are polyhydroxamates.1 In
many synthetic hydroxamate siderophores that have been re-
ported, a tripodal platform is employed to attach three hydroxa-
platform. The most common linkage seen in synthetic and natural
hydroxamate siderophores is amides. Our interest in developing
methodology for the attachment of hydroxamates on various scaf-
folds using urea and carbamate linkages was stimulated by two
reasons. The first was, of course, to create a new class of com-
pounds for biological and metal complexation studies. But another
important reason is that ureas and carbamates have been incorpo-
rated into scaffolds to generate ditopic chelators where an anion
and cation are bound simultaneously.8 Polyhydroxamates an-
chored on ureas and carbamates could provide binding sites for
various anions in addition to the cation of interest (ditopic chela-
tors) as well as changing H-bonding, geometry, and lipophilicity/
hydrophobicity of the chelator.9 Carbamate (polyurethanes) link-
ages have been shown to be useful to manipulate properties of
dendrimers in order to meet specific application needs.10 In this
communication, we report the preparation of new bifunctional
hydroxamate–isocyanate linkers and their successful coupling
chemistry to prepare polyhydroxamates with urea and carbamate
tethers.
The key to our approach was the preparation of bifunctional
hydroxamate–isocyanate linkers that can be coupled to amines
and alcohols (Fig. 1). The isocyanate linkers should be available
from the corresponding protected amines. The question was the
best way to prepare the protected amine hydroxamate intermedi-
ates. Two alternate routes were envisioned for this purpose, one
that used the corresponding linear amine ester and the other that
begins with protected N-Boc lactams.
mates and obtain
a chelator that can achieve hexadentate
coordination of the ferric ion.2 One popular tripodal platform for
the tethering of three ligand arms is tris(2-amino)ethylamine,
TREN.3
In addition to their role as iron chelators, hydroxamic acids have
received much attention due to their potential therapeutic applica-
tions.4 The trihydroxamate siderophore Desferrioxamine, is used
for the treatment of iron overload in patients with b-thalassemia.5
Many hydroxamic acids have been shown to inhibit enzymes such
as matrix metalloproteinases and histone deacetylases.6 The recent
approval of suberoylanilide hydroxamic acid (SAHA) for the treat-
ment of cutaneous T-cell lymphoma along with the other potential
pharmaceutical uses of hydroxamic acids, clearly demonstrates the
need to develop new methods to incorporate hydroxamic acids
into a variety of structures.
Our group has been interested in the design and synthesis of
chelators for the specific binding of ferric ion and actinides, for
therapeutic and environmental remediation applications.7 While
numerous synthetic siderophores have been studied, to our knowl-
edge, none of them has carbamate and urea linkages generated in
the process of attaching the hydroxamic acid ligand moiety to the
Several methods exist for the preparation of hydroxamic acids
(both protected and unprotected) but one of the more common
routes involves coupling of activated acid derivatives with hydrox-
⇑
Corrresponding author. Tel.: +1 575 646 2589; fax: 1 575 646 2649.
E-mail address: agopalan@nmsu.edu (A.S. Gopalan).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.09.025

6368
R. Fernando et al. / Tetrahedron Letters 53 (2012) 6367–6371
with the anion of O-benzylhydroxylamine to prepare protected
amino hydroxamates, 6, of different chain lengths was attractive.
It was thought that these substrates would undergo facile ring
opening upon nucleophilic attack on the lactam carbonyl with ben-
zyloxyamine anion, as the N-Boc should be a good leaving group.
It was gratifying to observe that lactam 5a readily reacted with
the anion of benzyloxyamine under conditions similar to those de-
scribed before (Scheme 2). The desired product 6a was obtained in
77% yield after chromatographic purification. The seven membered
lactam 5c, also underwent facile ring opening to give 6c in high
yield. Surprisingly, the same conversion with d-lactam 5b pro-
ceeded in only modest yields (36%). Many attempts to improve
the yield of this reaction were not successful and the reason for this
unique behavior is not understood. The ring opening reaction also
worked well with Vince lactam, 7, though in this example, it was
necessary to conduct the reaction at À42 °C in order to make it
go to completion. Vince lactam has been shown to be an important
synthon for the preparation of a variety of pharmaceutically active
molecules including carbocyclic nucleoside analogs.15
In order to access N-methyl analogs of the bifunctional
hydroxamate isocyanate linkers, the ring opening reaction of 5a
using the anion of N-methyl O-benzylhydroxylamine was also
studied. Despite examining a variety of reaction conditions, only
the starting lactam was recovered from the reaction. This forced
us to examine the direct alkylation of the hydroxamate nitrogen
as a route to N-methyl hydroxamates. The benzyloxy hydroxamate
2 was treated with excess methyl iodide and K2CO3 in acetonitrile
between 40–45 °C. Alkylation of the hydroxamate was found to be
much more facile than alkylation of the N-Boc moiety. The crude
product was purified using column chromatography to give 3 in
75% yield. The selective methylation of the hydroxamate nitrogen
also occurred readily on other substrates (Table 1).
Figure 1. Proposed synthetic scheme.
ylamines or protected hydroxylamines.11,12 The direct reaction of
esters with hydroxylamine under basic conditions is a useful reac-
tion but the products are difficult to purify particularly when they
are polyhydroxamic acids. A recent publication that described the
preparation of O-benzyl hydroxamates by the reaction of methyl
esters and lactones with O-benzyl hydroxylamine in the presence
of excess lithium hexamethyldisilylamide (LHMDS)13 is an attrac-
tive direct route. Although not reported or known, we envisioned
that protected amino hydroxamates could be prepared by an anal-
ogous reaction of benzylhydroxylamine with N-Boc protected
lactams.
The preparation of protected aminohydroxamate 2 from ester 1
following a published protocol was investigated (Scheme 1). A
solution of LHMDS (4 equiv) in THF was added to a suspension of
O-benzyl hydroxylamine hydrochloride in THF at À78 °C. After stir-
ring for 15 min, a solution of the methyl ester 1 in THF was added
dropwise to the benzyloxyamine solution in THF at À78 °C. The
reaction was stirred at this temperature for 2 h, quenched with sat-
urated NH4Cl and the product extracted into ethyl acetate. Using
this method, pure O-benzyloxy hydroxamate 2 could be prepared
in multigram quantities after recrystallization from ethyl acetate.
It was of interest to examine whether we could extend this
reaction and its value by preparation of protected N-methyl
hydroxamate 3 in one step by using N-methyl O-benzylhydroxyl-
amine in the coupling reaction. Using a similar experimental pro-
cedure, 1 was reacted with the anion of N-methyl O-benzyl
hydroxylamine (Scheme 1). This led to the formation of the desired
product 3 in moderate yields (the best yield was 52%) after careful
chromatographic purification. Unfortunately, a significant quantity
Having established convenient methods to prepare the pro-
tected amino hydroxamates needed for our study, we proceeded
forward on the synthesis of the desired bifunctional isocyanate
linkers. Deprotection of the Boc group in hydroxamate 2 with
TFA in dichloromethane gave the corresponding trifluoroacetate
salt 13. The excess TFA was removed in vacuo and trituration of
the crude solid with ether gave the desired product in high yield
and purity. Using a similar protocol, the N-methyl hydroxamate
derivatives 3 and 9 could also be readily deprotected to obtain
the desired salts in high purities and yield. The salts were directly
used in the next step, the conversion of the amine to the desired
isocyanates.
of the amide by-product 4, was also formed in this reaction.14
A
number of experimental conditions (reaction time and tempera-
ture, and number of equivalents of LHMDS) were examined to sup-
press the unwanted amide formation and obtain high yields of the
desired product 3. Due to difficulties in the separation of 3 and 4, it
was not possible to scale up the reaction to obtain multigram
quantities of 3.
The conversion of amines to isocyanates is a well-known reac-
tion but can be tricky due to competitive formation of urea formed
by reaction of the unreacted amine with the reactive isocyanate
product. A procedure for preparing peptidyl isocyanates in high
Given the fact that N-Boc lactams are readily accessible, a sec-
ond approach involving ring opening of this class of substrates
.
BnONH2 HCl (1.5 eq)
Boc-protected
lactam
protected
aminohydroxamate
LHMDS (3 eq)
THF, -78°C, N2
O
n
Conditions/
Yield
BnO
NHBoc
.
O
BnONH2 HCl (1 eq)
LHMDS (4 eq)
O
N
O
N
H
n
Boc
MeO
NHBoc
THF, -78°C, N2, 86%
BnOHN
NHBoc
1
5a (n = 1)
5b (n = 2)
5c (n = 3)
6a (n = 1)
6b (n = 2)
6c (n = 3)
2 h, 77%
1 h, 36%
5 h, 76%
2
BnONHCH3
LHMDS
THF, -78°C, N2
NHOBn
O
O
NHBoc
O
O
1.5 h, -42°
76%
H
+
N
BnON
NHBoc
N
NHBoc
Boc
H3C
CH3
(R)-
7
3
4
8
Scheme 1.
Scheme 2.

R. Fernando et al. / Tetrahedron Letters 53 (2012) 6367–6371
6369
Table 1
Methylation of representative hydroxamates and their deprotection
CH3I (3 eq)
protected
amino-
hydroxamate
K2CO3 (1 eq)
CH3CN, 40°C
2-3 days
methylated
aminohydroxamate
TFA, DCM, rt
TFA salt
O
Yield
75%
Yield
3
Scheme 5.
+
2
quant
BnON
CH3
NH3
CF3CO2
-
11
O
N
O
BnO
NHBoc
+
94%
80%
6a
BnO
NH3
CF3CO2
-
N
CH3
CH3
9
12
CH3
N
OBn
NHBoc
O
84%
8
10
purities and yield by the reaction of amines with phosgene under
biphasic reaction conditions was attractive for our system.16
The first reaction to be investigated was the conversion of
amine salt 13 to the corresponding isocyanate. Saturated sodium
bicarbonate was added to a solution of amine TFA salt 13 in
DCM. After stirring for 30 s, the layers were allowed to separate
and a 20% solution of phosgene (2 equiv) in toluene was added
to the organic layer at room temperature (Scheme 3). The major
product that was isolated was the cyclic benzyloxyhydrouracil 15
and not the desired isocyanate 14. The hydrouracil 15 presumably
is formed by the intramolecular cyclization of the initially formed
isocyanate 14 with the hydroxamic acid nitrogen.
Our results although disappointing are not surprising. It has
been reported that the isocyanate 14, prepared from the Curtius
reaction of the corresponding acid azide undergoes in situ cycliza-
tion albeit at higher temperatures to benzyloxyhydrouracil 15.17
Cleavage of the benzyl protecting group of 15 occurred readily
using standard catalytic hydrogenolysis conditions to give the
known 3-hydroxydihydrouracil 16.18
Scheme 6.
O
O
20 (4.5 eq),
N
OR
DCE, N2, reflux,
2.5 d, 72%
O
N
N
N(CH2CH2OH)3
H
3
CH3
26, R = Bn
H2, 5% Pd/C,
MeOH/DCM,
4d, quant
27, R = H
O
O
N
20 (3.4 eq),
DCM, N2, 0°C,
25 min, 87%
We then examined the conversion of the amine TFA salt 17 to
its corresponding isocyanate. In this case, it was thought that the
isocyanate 17 would be more stable and hence isolable because
the undesired intramolecular cyclization to give the corresponding
seven membered ring urea 19 would be much less favorable. In
fact, treatment of 17 with phosgene under biphasic conditions gave
N
OR
N
H
N
N(CH2CH2NH2)3
H
3
CH3
28, R = Bn
H2, 5% Pd/C,
MeOH,2 d, quant
29, R = H
Scheme 7.
O
O
a 2:1 mixture of isocyanate 18 to cyclized product 19, based on
proton NMR analysis of the crude product (Scheme 4). The pres-
ence of isocyanate, 18, in the product mixture could be easily ob-
served by the characteristic absorption in the IR (2278 cmÀ1).
However, it was not possible to isolate pure isocyanate 18 due to
its instability. Our results clearly showed that the desired pro-
tected primary hydroxamate–isocyanate linkers were too labile
for isolation and hence not useful for our purpose.
20% COCl2 in toluene (2 eq)
DCM, satd NaHCO3, 86%
BnO
BnO
+
N
H
NH3
N
H
NCO
-
CF3CO2
13
14
O
O
BnO
O
H2, Pd/C (5%)
MeOH, 1 h,
rt, quant.
HO
N
N
N
H
O
N
H
It was thought that the isocyanates derived from the secondary
hydroxamates would be more stable and less prone to the intramo-
lecular cyclization observed with the primary hydroxamates. The
15
16
Scheme 3.
20% COCl in
2
O
toluene (5 eq)
DCM, satd
O
O
BnO
O
+
N
BnO
NH
3
BnO
NCO +
NaHCO , 15 min
3
N
H
N
H
-
CF CO2
3
17
18
HN
19
Scheme 4.

6370
R. Fernando et al. / Tetrahedron Letters 53 (2012) 6367–6371
amine TFA salt 11 was treated with phosgene using the procedure
described (Scheme 5).16 After workup, the isocyanate 20 was iso-
lated in good yields and in sufficient purity, as judged by TLC anal-
ysis and IH NMR spectra, to use in coupling reactions.19 Reaction of
amine TFA salt 12 with phosgene under similar conditions gave the
corresponding isocyanate 21.20 Both isocyanates were stable when
stored in the refrigerator but it was preferable to use them soon
after their preparation.
Acknowledgments
This research was supported by grants from the National Insti-
tutes of Health under Grant nos. 1SC3GM084809 and GM07667-35
(fellowship to ET).
References and notes
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With the bifunctional N-methylhydroxamate–isocyanates 20
and 21 in hand, their reactions with simple alcohols and amines
were examined, to determine optimum coupling conditions. No
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3-aminopropanol gave the corresponding urea 25 in good yield.
The focus now was to demonstrate the use of the bifunctional
linkers to prepare new classes of trishydroxamic acid chelators
with carbamate and urea linkages. To avoid purification problems,
it was important to ensure that their reactions with polyols and
polyamines go to completion to minimize products of partial cou-
pling. As mentioned earlier, TREN has been a highly used platform
for synthetic siderophores. So it was decided to synthesize the tris-
hydroxamato derivatives of TREN and triethanolamine using our
linkers. These targets would be structurally similar and would
facilitate the comparison of urea vs carbamates in metal ion bind-
ing and biological properties.
Triethanolamine was refluxed with excess isocyanate 20 in
dichloroethane (Scheme 7). Progress of the reaction was monitored
by TLC analysis and stepwise formation of mono, di, and tri prod-
ucts was observed. The crude product was purified using column
chromatography to give carbamate 26 in 72% yield. Deprotection
of carbamate 26, which had limited solubility in methanol, was
done by catalytic hydrogenolysis (5% Pd on carbon) in 1:1 DCM/
MeOH. This reaction was carefully monitored by TLC analysis to
ensure completion. The crude product after filtration was tritu-
rated with hot ethyl acetate to give pure tris hydroxamic acid 27.21
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dichloromethane gave the protected trishydroxamic acid with urea
linkages 28 in 87% yield after chromatographic purification
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In conclusion, bifunctional N-methylhydroxamate-isocyanate
linkers 20 and 21 were prepared in good yields and high purity
from the corresponding amine salts using biphasic reaction condi-
tions with phosgene and sodium bicarbonate. Our studies showed
that the corresponding primary hydroxamate–isocyanate analogs
cannot be isolated as they underwent intramolecular cyclization
to give cyclic N-benzyloxyheterocycles. A key finding is that the
facile ring opening reaction of N-Boc lactams using the anion of
O-benzylhydroxylamine can be exploited to prepare protected
amino hydroxamates. These intermediates can be selectively
methylated on the hydroxamate nitrogen in good yields and then
readily deprotected. The utility of the bifunctional linkers was
clearly demonstrated by the synthesis of the carbamate tethered
trishydroxamic acid 27 and the urea tethered 29. The methodology
described in this Letter will provide access to new classes of carba-
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17. Klötzer, W. Monatsh. Chem. 1964, 95(6), 1729.
18. (a) Buess, C. M.; Bauer, L. J. Org. Chem. 1955, 20, 33; (b) Hurd, C. D.; Buess, C. M.;
Bauer, L. J. Org. Chem. 1954, 19, 1140.
19. Synthesis of isocyanate 20. Saturated NaHCO3 (5 mL) was added to a solution of
TFA salt, 11, (0.160 g, 0.476 mmol) in DCM (5 mL) and the mixture stirred for
30 s. The layers were allowed to separate and a solution of phosgene (1.25 mL,
2.5 mmol, 20% in toluene) was added via syringe to the DCM layer. The reaction
was then stirred for 20 min until the evolution of gas had ceased. The organic
layer was separated and the aqueous layer again extracted with DCM (5 mL).
The combined organic layers were washed with saturated NaCl (5 mL) and

R. Fernando et al. / Tetrahedron Letters 53 (2012) 6367–6371
6371
dried (MgSO4). The isocyanate 20 (0.095 g, 80.5%) was obtained as an oil and
22. Synthesis of urea 28. A solution of isocyanate 20 (0.10 g, 0.41 mmol) in DCM
(3 mL) was added to tris(2-aminoethylamine) (0.02 g, 0.12 mmol) at 0 °C and
the reaction stirred for 20 min. The solvents were removed in vacuo and the
resultant residue was washed with ether (3 Â 10 mL). The crude product was
purified by silica gel chromatography (Ethyl acetate/MeOH, 7:3) to give the tris
was used without purification. IR (Neat) 3032, 2941, 2879, 2274, 1659 cmÀ1
;
1H NMR (300 MHz, CDCl3) d 2.6 (t, J = 6.6 Hz, 2H), 3.22 (s, 3H), 3.52 (t, J = 6.6 Hz,
2H), 4.84 (s, 2H), 7.37–7.41 (m, 5H); 13C NMR (75 MHz, CDCl3) 32.1, 33.5, 38.4,
76.3, 128.8, 129.2, 129.4, 134.2, 153.7, 171.8.
20. Isocyanate 21. IR (Neat) 3032, 2941, 2879, 2274, 1659 cmÀ1
;
1H NMR (300 MHz,
urea 28 as a viscous oil (0.088 g, 87%): IR (KBr) 3380, 2927, 1651, 1558 cmÀ1
;
CDCl3) d 1.85 (p, J = 6.6 Hz, 2H), 2.44 (t, J = 7.2 Hz, 2H), 3.22 (s, 3H), 3.34 (t,
J = 6.6 Hz, 2H), 4.84 (s, 2H), 7.40 (br s, 5H); 13C NMR (75 MHz, CDCl3) 25.9, 28.8,
33.5, 42.5, 76.2, 122.0, 128.8, 129.1, 129.4, 134.4, 174.0.
1H NMR (300 MHz, CDCl3) d 2.50 (unres t, 6H), 2.65 (unres t, 6H), 3.10–3.20 (m,
6H), 3.17 (s, 9H), 3.45 (q, J = 5.6 Hz, 6H), 4.82 (s, 6H), 5.66 (br s, 3H), 5.83 (br s,
6H), 7.37 (s, 15H); 13C NMR (75 MHz, CDCl3) d 33.2, 33.4, 35.7, 38.5, 55.1, 76.3,
128.7, 128.9, 129.2, 134.4, 159.1, 174.3. HRMS (m/z) [MH]+ calculated for
21. Carbamate 26. IR (Neat) 3333, 2939, 1715, 1651 cmÀ1 1H NMR (300 MHz,
;
CDCl3) d 2.6 (unres t, 6H), 2.79 (t, J = 5.8 Hz, 6H), 3.20 (s, 9H), 3.39–3.44 (m, 6H),
4.07 (t, J= 5.7 Hz, 6H), 4.81 (s, 6H), 5.52 (br s, 3H), 7.38 (s, 15H); 13C NMR
(75 MHz, CDCl3) d 32.8, 33.7, 36.6, 54.1, 63.3, 76.6, 129.0, 129.4, 129.6, 134.6,
156.8, 174.1; HRMS (m/z) [MH]+ calculated for C42H60N10O9 849.4618, found
849.4631.
C42H61N10O9 849.4618, found 849.4631.
Synthesis of trishydroxamic acid 29. A suspension of urea 28 (0.09 g, 0.10 mmol)
and 5% Pd/C (0.01 g) in MeOH (3 mL) was stirred under H2 (balloon) for 2 days.
The catalyst was removed through a 0.45 lm nylon filter rinsing with MeOH. The
solvent was removed in vacuo. The resultant crude was washed with ether and
Trishydroxamic acid 27. IR (Neat) 3317, 2936, 1704, 1633 cmÀ1
;
1H NMR
EtOAc to give trishydroxamic acid 29 as a yellow oil (0.061 g, quant): IR (Neat)
(300 MHz, CD3OD) d 2.65–2.71 (m, 6H), 2.81–2.85 (m, 6H), 3.19 (s, 9H), 3.36 (t,
J = 6 Hz, 6H), 4.08 (q, J = 5.6 Hz, 6H); 13C NMR (75 MHz, CD3OD) d 34.3, 37.1,
38.5, 55.8, 65.1, 159.6, 174.7; HRMS (m/z) [MH]+ calculated for C21H40N7O12
582.2729, found 582.2737.
3322, 2923, 1634, 1568 cmÀ1 1H NMR (300 MHz, D2O) d 2.55–2.63 (m, 3H), 2.71
;
(t, J = 6.5 Hz, 6H), 3.13 (s, 9H), 3.31–3.26 (m, 9H), 3.41–3.37 (t, J = 5.6 Hz, 6H); 13
C
NMR (75 MHz, D2O) d 33.0, 35.9, 36.5, 49.5, 55.4, 161.0, 174.1; HRMS (m/z) [MH]+
calculated for C21H43N10O9 579.3209, found 579.3226.