Synthetic approaches to mixed ligand chelators on tert-butylphenol- formaldehyde oligomer (PFO) platforms

Article abstract of DOI:10.1016/j.tet.2012.09.032

Synthetic approaches to mixed ligand chelators on readily available tert-butylphenol-formaldehyde oligomer, PFO, scaffolds were examined. In a promising approach, tris and tetraphenol oligomers were selectively mono or di protected using tert-butyldiphenyl silyl chloride. The utility of these protected intermediates to prepare representative mixed PFO chelators, carrying ligands such as hydroxamic acid, 3,2-hydroxypyridinones, and others was then demonstrated. The introduction of the ligand tethers onto the phenolic scaffold can be done sequentially under relatively mild conditions that tolerate the presence of other sensitive ligand groups. The differential reactivity of the disilyl derivative 20b, allowed stepwise introduction of two different ligands on the internal phenolic positions. This enabled the introduction of three different ligand groups of choice onto the tetraphenol platform.

Full text of DOI:10.1016/j.tet.2012.09.032

Tetrahedron 68 (2012) 10030e10039
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthetic approaches to mixed ligand chelators on tert-butylphenole
formaldehyde oligomer (PFO) platforms
*
*
Jennifer A. Young, Sukhen Karmakar, Hollie K. Jacobs , Aravamudan S. Gopalan
Department of Chemistry and Biochemistry, MSC 3C, 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 1 August 2012
Received in revised form 4 September 2012
Accepted 5 September 2012
Available online 13 September 2012
Synthetic approaches to mixed ligand chelators on readily available tert-butylphenoleformaldehyde
oligomer, PFO, scaffolds were examined. In a promising approach, tris and tetraphenol oligomers were
selectively mono or di protected using tert-butyldiphenyl silyl chloride. The utility of these protected
intermediates to prepare representative mixed PFO chelators, carrying ligands such as hydroxamic acid,
3,2-hydroxypyridinones, and others was then demonstrated. The introduction of the ligand tethers onto
the phenolic scaffold can be done sequentially under relatively mild conditions that tolerate the presence
of other sensitive ligand groups. The differential reactivity of the disilyl derivative 20b, allowed stepwise
introduction of two different ligands on the internal phenolic positions. This enabled the introduction of
three different ligand groups of choice onto the tetraphenol platform.
Keywords:
tert-Butylphenoleformaldehyde oligomers
Metal ion chelators
Hydroxypyridinone
Ó 2012 Elsevier Ltd. All rights reserved.
Hydroxamic acid
1. Introduction
arenes has been recently reported. Some members of this library
were shown to be host molecules for guest peptides in aqueous
The development of selective chelators for a variety of metal
ions has been an area of high interest. Metal ion chelators have
been shown to have numerous applications that range from
therapeutics and diagnostics to separation technology and envi-
ronmental remediation.1 A major challenge in this area is to
design and synthesize chelators capable of specifically binding
the target cation in the desired manner.2 This requires an un-
derstanding of the coordination chemistry, geometry, and ligand
preferences that complement the target metal ion. In many ap-
plications the resultant complex must also address stability,
solubility, and toxicity concerns.3 The specific attributes of the
metalechelator complexes need to be varied to meet the pro-
posed application. In many cases selective binding of the target
cation in the presence of competing cations is desired and the
strength of the metal binding (e.g., high binding constant) may
be less critical.
media.7,8
Some time ago, we disclosed the syntheses of the 4-tert-butyl-
calix[4]arene derived tetrahydroxamate,9 1, and the 3-hydroxy-2-
pyridinone (3,2-HOPO)10 2, metal ion extractants designed for the
separation of hard cations such as actinide(IV) using liquideliquid
extractions. In order to ascertain the importance of the calix[4]
arene backbone in the selectivity and efficiency of metal ion
binding, and to develop a more systematic understanding of the
actinide chelation/extraction properties of this class of ligands, we
also prepared the corresponding acyclic (phenoleformaldehyde
oligomers, PFOs) trihydroxamate 3, and tetrahydroxamate 4, and
the tetraHOPO 5. Just like the parent calixarenes 1 and 2, the PFO
extractants 3, 4, and 5 were excellent extractants of cations such as
iron(III) and thorium(IV) into chloroform from acidic aqueous so-
lutions.11,12 Our results strongly supported the hypothesis that the
rigidity of the calixarene backbone is not imperative to achieve
strong metal ion binding and may not offer increased metal ion
binding selectivity. Hence, both calixarenes and the corresponding
ligand functionalized PFOs are useful templates for separation ap-
plications.13 Compared to calixarenes, development of PFO-based
chelators has received minimum attention. Some phenolic oligo-
mers have been functionalized with various ligand groups to pre-
pare receptors for cations14 and anions.15 It is also interesting to
note that the unfunctionalized PFOs have been shown to form
a variety of hosteguest complexes with various organic com-
pounds.16
A number of reports have appeared on the properties and ap-
plications of calix[n]arenes, a unique class of macromolecules.4
Recent reviews document the potential uses of the calixarene
scaffold in the development of new drugs5 and as hosts for a variety
of metal ions.6 A solid phase synthesis of a library of peptidocalix[4]
* Corresponding authors. Tel.: þ1 575 646 2589; fax: þ1 575 646 2649; e-mail
address: agopalan@nmsu.edu (A.S. Gopalan).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.09.032

J.A. Young et al. / Tetrahedron 68 (2012) 10030e10039
10031
provide the starting material III. Lithiation of III and subsequent
coupling with an aldehyde, IV,18 carrying L2 should proceed to
give benzylic alcohol, V, which could be reduced with trie-
thylsilane and trifluoroacetic acid to give VI. The challenge is
how to repeat this sequence to add the third phenolic moiety.
One might anticipate that selective monoformylation of in-
termediate VI would not be possible since it is not as reactive as
the corresponding phenol. Also the highly basic phenol orga-
nolithium coupling conditions would only be compatible with
the most stable ligands.
In spite of the potential hurdles, it was decided to examine the
viability of the key aldehyde coupling step in this approach to PFO
platforms by the synthesis of a trimeric host carrying stable poly-
ether ligands. Polyether-type ligands have been prepared and
shown to be extractants of alkali metal cations.19 The arylbromide 6
was prepared by alkylation of 2-bromophenol with 2-(2-
methoxyethoxy)ethyl methanesulfonate using Cs2CO3 in refluxing
acetonitrile (Scheme 1). Formylation of bisphenol 720 was accom-
plished using paraformaldehyde, MgCl2, and triethylamine in
refluxing THF for 3 d.21 The authors of this paper have proposed
that the initially formed salicyl alcohol undergoes a redox reaction
with a second equivalent of formaldehyde, to give the corre-
sponding aldehyde and methanol. Two major products, the mon-
oaldehyde 8 and the dialdehyde 9 were isolated in 46 and 20%
yields, respectively, after chromatographic purification. Our at-
tempts to selectively obtain the monoaldehyde, 8, in higher yields
were not successful. It is interesting to note that when the for-
mylation reaction of 7 was conducted in a microwave reactor in
acetonitrile under pressure at elevated temperature, the dia-
ldehyde 9 was obtained in 95% yield. This is a useful finding as the
dialdehyde, 9, is potentially a useful intermediate for the synthesis
of other polyphenol metal binding hosts. The monoaldehyde 8 was
then alkylated with 2-(2-methoxyethoxy)ethyl methanesulfonate
under similar conditions to give the polyether aldehyde 10 in 52%
yield.
The primary goal of this study was to develop and demonstrate
the utility of a flexible synthetic approach to access sets of mixed
ligand chelators17 built on lipophilic PFO platforms that could be
screened for the binding of cations of interest. Having access to
a related set of metal binding hosts built on PFO platforms, would
also provide useful information on the impact of ligand variation on
metal ion complexation. This class of chelators has the potential to
be useful as diagnostic agents and in selective metal sequestration.
More specifically, our goal was to develop synthetic methodology
for the preparation of a broad range of trimeric and tetrameric
polyphenol chelators, exemplified by I and II (Fig. 1). The proposed
synthetic methodology would allow one to specifically install the
ligand of choice (some examples are shown in Fig. 1) on each of the
phenol monomer units, leading to a diverse array of unique cation
binding hosts.
Fig. 1. Potential polyphenol extractants.
2. Results and discussion
Arylbromide 6 was lithiated with s-butyl lithium at ꢀ78 ꢁC in
THF and then transferred via cannula to a solution of the aldehyde
10 at ꢀ78 ꢁC in THF (Scheme 2).18 The crude benzylic alcohol ob-
tained from the reaction was reduced with trifluoroacetic acid and
triethylsilane22 to give the tris polyether chelator 11 in 45% yield
(two steps) after purification. A significant byproduct was the re-
duced monomeric phenol ether. This suggests that nucleophilic
A straightforward approach, to build PFO hosts of the types I
and II, would involve a stepwise linking of functionalized phe-
nolic monomer units carrying the desired ligands. This approach
is illustrated in Fig. 2. Bromination of 4-tert-butylphenol fol-
lowed by its alkylation with the desired first ligand L1 should
Fig. 2. Proposed synthetic route for synthesis of mixed ligand PFOs.

10032
J.A. Young et al. / Tetrahedron 68 (2012) 10030e10039
differing ligand moieties. Further, addition of another phenolic
monomer to obtain a tetra PFO chelator is not possible due to the
lack of a viable procedure to achieve selective bromination or for-
mylation of 11.
CH3(OCH2CH2)2OMs (2 eq),
Cs2CO3 (5 eq), CH3CN,
reflux, 48h, 76%
Br
O
Br
O
OH
Given the questionable stability of the ligands being considered
for this study, it was decided to explore a strategy to prepare dif-
ferentially protected PFO moieties by phenol coupling reactions.
The synthetic approach is depicted by the attempted synthesis of 12
(Scheme 3). The monoprotected tert-butyldiphenyl silyl (TBDPS)
phenol 13 was prepared in 39% yield by treatment of bisphenol 7
with TBDPSCl (1 equiv) and imidazole (1 equiv) in DMF. As ex-
pected, in addition to the desired product 13, unreacted starting
material (25%) and disilylated product (10%) were obtained after
purification. The silylphenol 13 was then treated with MgCl2 and
formaldehyde in the presence of triethylamine in refluxing aceto-
nitrile to give the differentially monoprotected bisphenol aldehyde
14 in excellent yield.21 Alkylation with benzyl bromide using
standard conditions gave aldehyde 15.
6
O
MgCl2 (4 eq)
Et3N (4 eq)
CH2O (6 eq),
THF, reflux,
3 days
CHO
CHO
OHC
OH
OH
OH
OH
8 (46%)
OH
OH
9 (20%)
7
CH3(OCH2CH2)2OMs (3 eq),
Cs2CO3 (3 eq), CH3CN,
reflux, 48 h, 52 %
The methoxymethyl (MOM) protected arylbromide 16 (2 equiv)
was treated with s-BuLi (2 equiv) in anhydrous THF at ꢀ78 ꢁC for
3 h. A solution of aldehyde 15 in anhydrous THF was then added to
the aryllithium and the reaction mixture stirred at ꢀ78 ꢁC for 1 h.18
After workup and purification, none of the desired coupling prod-
uct was obtained. The aldehyde 15 was recovered in near quanti-
tative yield along with the debrominated MOM protected phenyl
ether, 17. This indicated that the desired lithiation of 16 had oc-
curred but the coupling with the aldehyde 15 did not proceed.
These aldehydes are not particularly good electrophiles presumably
because of electron donation from the alkoxy moiety (vinylogous
esters). Proton abstraction successfully competes with the nucleo-
philic addition of the aryllithium to the aldehyde. Given these ob-
servations, this approach was abandoned.
CHO
O
O
O
O
10
O
O
Scheme 1. Preparation of bromide 6 and aldehyde 10.
1) secBuLi (2eq) , THF,
N2, -78oC, 3 h
6
2.1. Selective protection of PFOs
(2eq)
2) 10 (1eq), 1 h
O
O
O
O
3) TFA (4eq), Et3SiH (8eq),
DCM, 20 min
The sequential assembly of substituted phenolic units to
prepare the PFO targets, although highly attractive, proved to be
experimentally fraught with problems. Although our goal
remained to develop methodology for mixed chelators of the
types I and II, it became clear that further studies were required
before we could achieve the synthesis of such complex targets.
Hence, we decided to explore an alternate approach to the target
hosts.
O
O
O
O
O
O
O
O
38%
11 (45%)
Scheme 2. Synthesis of tris polyether extractant 11.
In this approach we begin with the desired PFO template. The
key to this approach is the preparation of an intermediate such as
IX with three orthogonal protecting groups (Fig. 3). The nature of
the protecting groups needs to allow selective deprotection at the
desired phenolic unit. Subsequently the desired ligand group could
be attached to the phenol using standard alkylation conditions.
addition to the aldehyde competes with proton exchange. It is
highly unlikely that such a coupling could proceed in the presence
of sensitive ligands or the aldehyde 10. Although we were suc-
cessful in the preparation of 11, this approach does not allow the
systematic introduction of phenolic monomer units carrying
MgCl2 (4 eq),
TBDPSCl (1 eq)
Benzyl Bromide,
K2CO3, CH3CN
reflux, 24 h, 67%
CH2O (6 eq),
imidazole (1 eq),
Et3N (4 eq),
CH3CN, reflux,
24 h, 91%
7
rt, 24h, 39 %
CHO
CHO
O
OH
O
OH
O
O
TBDPS
13
TBDPS
14
TBDPS
15
Bn
1) secBuLi (2eq),
THF,-78 oC, N2, 3 h
15
Br
MOM
2) 15, THF, -78°C, 1h
O
O
MOM
17
OTBDPS OBn
12
OMOM
16
(2 eq)
Scheme 3. Attempted synthesis of an orthogonally protected PFO 12.

J.A. Young et al. / Tetrahedron 68 (2012) 10030e10039
10033
selective
deprotection
repeat
VIII
alkylation
OH
OH
18a
OH
L
OP1
OP2
OP3
X
IX
Fig. 3. Selective protection approach to preparation of chelators of type VIII.
Repetition of the sequence would allow the synthesis of chelators
such as VIII using relatively simple chemistry.
tetraphenol, 18b, treatment with 1 equiv of TBDPSCl using the
conditions described earlier, gave the desired monosilylated
product, 19b, in 42% yield accompanied by the symmetrical dis-
ilylated product, 20b, and unreacted starting material. In com-
parison to the trisphenol, the tetraphenol could be disilylated in
high yield and selectivity with only 2 equiv of TBDPSCl. The
symmetry of the disilyl derivatives made structural assignments
by 1H NMR and 13C NMR straightforward. The subtle difference in
reactivity of the trisphenol and tetraphenol is not readily
explained.
In order to develop a method for differential protection of
phenols, it was necessary to understand the relative reactivity of
the phenols in the PFO structure (internal vs external). It was first
decided to study the silylation of the tri and tetraphenols 18a and
18b with tert-butyldiphenyl silyl chloride, TBDPSCl. This group was
chosen because it was stable to the alkylation conditions used to
attach the ligand arms. The steric bulk of this group was also ex-
pected to affect the relative reactivity of the internal and external
phenols of the oligomeric chain.
The results of this study are shown in Table 1. Treatment of
trisphenol 18a with TBDPSCl (1 equiv) and imidazole (1 equiv) in
DMF gave the monoprotected product 19a in 53% yield. The re-
sult may not be surprising and can be ascribed to favorable steric
factors and simple statistics. When the trisphenol was treated
with 2 equiv of TBDPSCl under similar conditions, the major
product was the symmetric disilylated product, 20a, along with
some mono product, 19a. The preferred method for preparing the
disilyl derivative involved heating the trisphenol 18a with
3 equiv of TBDPSCl. Under these conditions, the desired the dis-
ilylated phenol 20a was isolated in 65% yield. It is interesting to
note that no significant formation of the trisilylated product was
observed under these reaction conditions. In the case of the
2.2. Synthesis of mixed chelators on the trisphenol scaffold
With the mono and disilyl protected intermediates of the tri-
sphenol (19a and 20a) and the tetraphenol (19b and 20b) in hand,
the goal was to demonstrate their usefulness in the synthesis of
sets of mixed ligand chelators that would permit structur-
eeactivity comparisons. Our group has been actively involved in
the synthesis of hydroxamates23 and hydroxypyridinones
(HOPO),24 well-known ligands for iron(III) and actinides. Hence,
these ligand systems were chosen for incorporation onto the PFO
platform in our studies.
The disilyl derivative 20a was used to prepare the diHOPO-
mono hydroxamate 25 as shown in Scheme 4. Treatment of the
Table 1
Protection of phenoleformaldehyde oligomers, 18
TBDPSCl,
imidazole,
starting
DMF
material
OH
OH
OH
OH
OTBDPS
OH
OH
OTBDPS
OTBDPS
n
n
n
18a n=1
18b n=2
19a n=1
19b n=2
20a n=1
20b n=2
Entry
1
Phenoleformaldehyde oligomer
n
Conditions
Starting material 18 (%)
MonoTBDPS 19 (%)
DiTBDPS 20 (%)
18a
1
1 equiv TBDPSCl
1 equiv imidazole
rt 14 h
19
53
11
51
65
14
96
a
a
2
3
4
18a
18a
18b
18b
1
1
2
2
2 equiv TBPSCl
4 equiv imidazole
rt 24 h
23
3 equiv TBDPSCl
3 equiv imidazole
rt 1 d, 50 ꢁC 1 d
Trace
1 equiv TBDPSCl
1.5 equiv imidazole
6 h rt
35
42
a
a
5
2 equiv TBDPSCl
3 equiv imidazole
16 h rt
a
In these runs, only the major products were isolated.

10034
J.A. Young et al. / Tetrahedron 68 (2012) 10030e10039
I
4
Scheme 4. Synthesis of symmetrical mixed HOPO/hydroxamic acid chelator, 25.
disilyl phenol 20a with an excess of ethyl-5-iodovalerate in the
presence of Cs2CO3 in DMF for 3 d at rt gave the desired ethyl
ester 22, in 80% yield after purification. The TBDPS groups were
then removed by treatment with TBAF in THF and the resultant
product was alkylated with the known iodo-HOPO derivative10 21
to obtain the diHOPO ester 23. The ethyl ester 23 was saponified
with lithium hydroxide in aqueous ethanol and after an acidic
workup the corresponding carboxylic acid was isolated in
sufficient purity to be used in the next step directly. Treatment of
the carboxylic acid with oxalyl chloride gave the corresponding
acid chloride, which was then coupled with an excess of O-ben-
zylhydroxylamine hydrochloride in the presence of triethylamine
in dichloromethane at rt to obtain the amide 24 in 66% (three
steps) after purification. Hydrogenolysis of the benzyl protecting
groups using 10% Pd/C in ethanol gave the desired target
extractant 25 in 98% yield.
I(CH2)4CO2Et,
Cs2CO3, CH3CN,
reflux, 74%
19a
O
O
OTBDPS
26
CO2Et
CO2Et
1. TBAF, THF,
rt, 10 h, 83%
2. 21, Cs2CO3,
CH3CN, reflux, 65%
1. LiOH, 95% EtOH, rt
2. (COCl)2, C6H6, rt,
3.BnONH2.HCl, Et3N, CH2Cl2
O
O
O
O
O
O
0 oC -rt, 58% (3 Steps)
O
O
O
O
CO2Et
CO2Et
N
O
NHOR
NHOR
N
O
OR
OBn
27
28, R = Bn
29, R = H
10% Pd/C, H2
EtOH, 97%
Scheme 5. Synthesis of unsymmetrical dihydroxamic acid/HOPO, 29.

J.A. Young et al. / Tetrahedron 68 (2012) 10030e10039
10035
3.
.
Scheme 6. Synthesis of symmetrical HOPO/hydroxamic acid extractant, 33.
The synthesis of unsymmetrical HOPO/dihydroxamic acid,
shown in Scheme 5, demonstrates the usefulness of the monosilyl
derivative. Alkylation of the monosilylated trisphenol 19a with
excess ethyl iodovalerate in refluxing acetonitrile using cesium
carbonate as base gave the diester 26 in 74% yield after purification.
The silyl protecting group was removed using TBAF and the phenol
alkylated with HOPO iodide 21 to give 27. Conversion of the ethyl
esters to the corresponding protected hydroxamic acid by the
three-step procedure established previously gave the fully pro-
tected chelator 28 in 58% yield for three steps. Removal of the
benzyl protecting groups was accomplished using hydrogenolysis
to give the unsymmetrical dihydroxamic acid/HOPO chelator 29 in
97% yield.
subsequent alkylation, possibly due to steric factors. This finding
enabled the incorporation of two different ligand groups on the
internal phenols of 20b. The unreacted phenol group of 34 was
alkylated with diethyl 5-iodopentylphosphonate to give 35 in
moderate yield. Deprotection of the silyl groups followed by al-
kylation with the HOPO iodide, 21, gave 36 in good yield after pu-
rification. The final transformation of the ester to the desired benzyl
protected hydroxamic acid was accomplished using a one-pot
procedure. Treatment of O-benzylhydroxylamine hydrochloride
(5 equiv) with LHMDS (1 M in THF, 10 equiv) at ꢀ78 ꢁC for 15 min
followed by addition of the ester 36, gave the benzyl protected
hydroxamate derivative 37 in 53% yield after workup and purifi-
cation.25 Finally, the benzyl protecting groups were removed by
hydrogenolysis to give the chelator 38, having three different ligand
moieties in its scaffold. This route is straightforward and flexible
and clearly holds much promise for the incorporation of three
different ligand groups onto the tetraphenol backbone.
2.3. Synthesis of mixed chelators on the tetraphenol platform
The symmetric disilylated tetraphenol, 20b, is a useful scaffold
for attachment of one set of ligands on the internal phenols and
a different ligand system on the external phenol rings. This was
demonstrated by the synthesis of chelator 33, Scheme 6. The two
internal phenols of 20b were alkylated with ethyl iodovalerate
(3 equiv) using cesium carbonate in DMF to give the diester 30 in
81% yield after purification. Subsequent removal of the silyl pro-
tecting groups and alkylation of the external phenols with HOPO
iodide, 21, gave the diester diHOPO 31 in 66% yield. The ethyl esters
were converted to the protected hydroxamic acid, 32, in three steps
and in moderate yield. Finally, cleavage of the benzyl protecting
groups gave the organic soluble (chloroform) mixed diHOPO
dihydroxamic acid chelator, 33, in excellent yield. It is pertinent to
mention that tetrahydroxamate and tetraHOPO derivatives of cal-
ixarenes as well as the corresponding open chain phenol oligomers
have been shown to be efficient extractants of actinide(IV) ions.
Substrates prepared in this study would be valuable analogs for
complexation studies.
3. Conclusions
The goal of developing a practical route to mixed ligand systems
of types I and II built on PFO platforms, although conceptually
simple and easily stated, has presented an interesting synthetic
challenge. The first approach was to develop methodology that
would allow the sequential addition of phenolic units carrying the
desired ligands, to build the oligomeric chain. To some extent this
approach was successful as demonstrated by the synthesis of the
polyether ligand 11. However, this approach has limited scope.
Further, the extension of this methodology to yield potentially
useful orthogonally protected PFOs, such as 12, was not possible.
The coupling of the organolithium derived from 16 with aldehyde
15 did not yield the desired product. Better strategies to achieve the
desired coupling reaction need to be developed to make this a vi-
able approach.
In our attempts to dialkylate the disilyl protected tetraphenol
20b with ethyl iodovalerate, an interesting finding was made. We
realized that it was possible to obtain the monoalkylated product
34 in 72% yield by using 1 equiv of ethyl iodovalerate (and potas-
sium carbonate) in this reaction (Scheme 7). This suggests that the
initially formed monoalkylated phenol, 34, is more resistant to
The second approach to mixed PFO ligands system uses existing
PFO oligomers, which are readily available. The availability of or-
thogonally protected tris and tetraphenols would allow selective
deprotection and introduction of a desired ligand group at a specific
site, providing positional control on the ligand being introduced.
Once again the challenge is the preparation of these intermediates.

10036
J.A. Young et al. / Tetrahedron 68 (2012) 10030e10039
I(CH2)4CO2Et,
K2CO3, CH3CN,
reflux, 75 %
I(CH2)5PO(OEt)2,
Cs2CO3, CH3CN,
reflux, 58%
20b
O
O
O
OH
OTBDPS
OTBDPS
OTBDPS
OTBDPS
34
CO2Et
CO2Et
35
OEt
OEt
P
O
1. TBAF, THF, rt, 90%
2. 21, Cs2CO3,
CH3CN, reflux, 60%
BnONH2.HCl
LHMDS, THF, -78°C
then add 36 in THF,
-78°C, 53%
O
O
O
O
O
O
O
O
O
O
O
O
NHOR
OEt
OEt
OEt
OEt
OEt
N
O
P
N
O
P
O
N
O
O
N
O
O
O
OR
OBn
OBn
OR
36
37, R = Bn
38, R = H
10% Pd/C, H2
EtOH, 94%
Scheme 7. Synthesis of mixed ligand extractant, 38.
We have made significant progress to demonstrate the simplicity
and viability of this approach. The phenolic moieties of the tris and
tetra PFOs can be differentiated by selective silylation with TBDPS
chloride. Using this strategy, we have prepared the monosilyl de-
rivatives 19a and 19b and the disilyl derivatives 20a and 20b. The
value of these protected intermediates has been demonstrated by
the preparation of some mixed ligand systems, the most complex
being the synthesis of 38, which has three different ligands (two
HOPO, a phosphonate, and a hydroxamate) on the tetraphenol
backbone. It is noteworthy that the disilyl derivative of the tetra-
phenol 20b can be monoalkylated in good yields. This allows the
introduction of a two different ligands in the middle of the oligo-
meric chain. Symmetric and asymmetric mixed hydroxamate/
HOPO ligand systems such as 25, 29, and 33 were readily prepared
using this methodology. The introduction of the ligand tethers onto
the phenolic scaffold can be done sequentially under mild condi-
tions that tolerate the presence of other sensitive ligand groups.
The alkylating agent is not limited to ligand arms but can be tuned
to the application in mind such as development of catalysts and
sensors.
Our studies have shown that the selective protection of the
phenolic groups in PFOs and subsequent chemistry will provide an
attractive pathway for the preparation of sets of mixed ligand
chelators. While significant progress has been made, much remains
to be done in realizing the goal of developing a convenient route to
mixed ligand chelators of types I and II. It is important to point out
that the results of this study are also relevant to the search to in-
crease ligand diversity in other phenolic host systems such as
calixarenes.
(200 MHz) and 13C NMR (50 MHz) were obtained on a Varian
Gemini 200. 1H NMR (400 MHz) and 13C NMR (100 MHz) were
obtained on a Varian Unity 400 spectrometer. 1H NMR (300 MHz)
and 13C NMR (75 MHz) were obtained on a 300 MHz Varian NMR
system. NMR spectral samples were prepared in CDCl3. All chemical
shifts are given in parts per million (ppm) relative to tetrame-
thylsilane (TMS) reference. Elemental analyses were performed by
Desert Analytics, Tucson, Arizona. HRMS analyses were performed
by the University of California Riverside Mass Spectrometry Facility.
Flash chromatography was performed on an Isco CombiFlash sys-
tem using prepackaged columns. Radial chromatography was per-
formed on a Chromatotron using plates prepared from silica gel 60
containing gypsum. Reagents were normally obtained from Sig-
maeAldrich or Alfa Aesar and were used as received unless oth-
erwise noted. Tetrahydrofuran was freshly collected from
a GlassContourÔ solvent purification system. Other anhydrous
solvents (DMF, methylene chloride, acetonitrile, etc.) were obtained
from SigmaeAldrich. Solvents used for chromatography were re-
agent grade. Tetrabutylammonium fluoride was obtained as a 1 M
solution in THF. The bisphenol (7), trisphenol (18a), tetraphenol
(18b),20 and iodo-HOPO (21)10 were prepared according to litera-
ture procedures.
4.2. Representative procedure for TBDPS protection of tert-
butylphenoleformaldehyde oligomers
4.2.1. 2-(5-tert-Butyl-2-(tert-butyldiphenylsilyloxy)benzyl)-4-tert-
butylphenol (13). Imidazole (108 mg, 1.59 mmol) and TBDPSCl
(413 mL, 1.59 mmol) were added to a solution of bisphenol (7)
(500 mg, 1.59 mmol) in DMF (3 mL) under N2. After stirring at rt for
24 h, the solvent was removed in vacuo. The residue was dissolved
in ethyl acetate (150 mL), washed with 1 N HCl (25 mL), saturated
NaHCO3 (25 mL), brine (25 mL), and dried (Na2SO4). The solvent
was removed in vacuo. Purification of the crude product by Com-
biflash on silica gel gave 13 (0.345 g, 39%) as a clear oil. IR (neat)
3437, 3072, 3051, 2962, 2903, 2860, 1607 cmꢀ1; 1H NMR (300 MHz,
4. Experimental
4.1. General methods
Melting points were obtained on an ElectrothermalÒ melting
point apparatus and are uncorrected. Infrared spectra were recor-
ded on a Perkin Elmer Spectrum One FT-IR Spectrometer. 1H NMR
CDCl3)
d 7.76e7.69 (m, 4H), 7.47e7.32 (m, 6H), 7.22e7.09 (m, 3H),

J.A. Young et al. / Tetrahedron 68 (2012) 10030e10039
10037
6.81e6.72 (m, 2H), 6.40 (d, J¼8.5 Hz, 1H), 5.84 (s, 1H), 4.12 (s, 2H),
CDCl3) d 150.1, 148.9, 144.0, 142.9, 135.5, 132.6, 129.9, 128.9, 127.8,
1.29 (s, 9H), 1.14 (s, 9H), 1.08 (s, 9H); 13C NMR (75 MHz, CDCl3)
126.9, 126.6, 125.5, 125.2, 123.7, 118.3, 34.0, 31.6, 31.4, 26.5, 19.4.
Anal. Calcd for C75H92O4Si2: C, 80.88; H, 8.33. Found: C, 80.48; H,
8.47.
d
151.9, 149.9, 144.2, 143.2, 135.5, 132.5, 130.0, 128.3, 127.8, 127.4,
127.3, 126.0, 124.4,123.9, 118.5,115.2, 34.0, 31.6, 31.3, 31.2, 26.7, 19.5.
Analysis Calcd for C37H46O2Si$0.5H2O: C, 79.38; H, 8.46. Found: C,
79.08; H, 8.29.
4.3. Ethyl 5-(4-tert-butyl-2-(5-tert-butyl-2-(tert-butyldiphe-
nylsilyloxy)benzyl)-6-(5-tert-butyl-3-(5-tert-butyl-2-(tert-bu-
tyldiphenylsilyloxy)benzyl)-2-hydroxybenzyl)phenoxy)penta-
noate (34)
4.2.2. 4-tert-Butyl-2-(5-tert-butyl-2-(tert-butyldiphenylsilyloxy)ben-
zyl)-6-(5-tert-butyl-2-hydroxybenzyl)phenol (19a). The representa-
tive procedure for TBDPS protection was followed using 18a
(100 mg, 0.21 mmol) to give 19a (79 mg, 53%) along with 20a
(22 mg, 11%) and 18a (19 mg, 19%). Compound 19a: oil; IR (neat)
A
mixture of 20b (0.80 g, 0.76 mmol), ethyl iodovalerate
(0.224 g, 0.86 mmol), and K2CO3 (0.16 g, 1.1 mmol) in anhydrous
CH3CN (15 mL) was heated at reflux for 9 h. The reaction mixture
was cooled and the solvent removed in vacuo. The residue was
dissolved in ethyl acetate (50 mL) and washed with water (10 mL),
dried (Na2SO4), and concentrated. The crude product was purified
by radial chromatography to yield 34 (0.701 g, 75%) as an oil. IR
3368, 2960, 1600 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d 7.73e7.69 (m,
6H), 7.44e7.35 (m, 2H), 7.27 (d, J¼2.3 Hz, 1H), 7.19 (d, J¼2.3 Hz, 1H),
7.09e7.09 (m, 4H), 6.81 (s, 1H), 6.75 (d, J¼1.8 Hz, 1H), 6.73 (d,
J¼1.8 Hz, 1H), 6.40 (d, J¼8.51 Hz, 1H), 4.06 (s, 2H), 3.88 (s, 2H), 1.27
(s, 9H), 1.26 (s, 9H), 1.12 (s, 9H), 1.06 (s, 9H); 13C NMR (75 MHz,
CDCl3)
d
151.3, 149.6, 148.3, 144.5, 143.7, 143.2, 135.5, 132.3, 130.0,
(neat) 3420, 2960, 2860, 1655 cmꢀ1 1H NMR (300 MHz, CDCl3)
;
128.1, 127.9, 127.4, 126.6, 126.4, 125.7, 125.5, 124.5, 124.1, 118.7, 116.0,
34.0, 31.6, 31.5, 31.5, 26.6, 19.5. Anal. Calcd for C62H84O7Si$CHCl3: C,
69.50; H, 7.87. Found: C, 69.88; H, 7.67.
d
7.71e7.65 (m, 8H), 7.43e7.31 (m, 12H), 7.19 (d, J¼2.6 Hz, 1H), 7.15
(d, J¼2.6 Hz, 1H), 7.12 (d, J¼2.6 Hz, 1H), 7.01 (d, J¼2.3 Hz, 2H), 6.91
(d, J¼2.3 Hz, 1H), 6.86 (d, J¼2.3 Hz, 1H), 6.81e6.70 (m, 2H), 6.38 (d,
J¼8.5 Hz, 1H), 6.30 (d, J¼8.5 Hz, 1H), 4.21 (s, 2H), 4.13 (s, 2H), 4.08
(q, J¼7.3 Hz, 2H), 3.98e3.94 (m, 4H), 2.31 (t, J¼7.3 Hz, 2H),
1.98e1.91 (m, 2H), 1.86e1.78 (m, 2H), 1.21 (t, J¼7.0 Hz, 3H), 1.20 (s,
9H), 1.15 (s, 18H), 1.30 (s, 9H), 0.97 (s, 9H), 0.84 (s, 9H); 13C NMR
4.2.3. 2-(3-(5-tert-Butyl-2-(tert-butyldiphenylsilyloxy)benzyl)-5-
tert-butyl-2-hydroxybenzyl)-6-(5-tert-butyl-2-hydroxybenzyl)-4-
tert-butylphenol (19b). The representative procedure for TBDPS
protection was followed using 18b (0.500 g, 0.785 mmol), imidaz-
ole (0.080 g, 1.17 mmol) and TBDPSCl (0.204 mL, 0.785 mmol) to
give 19b (0.289 g, 42.1%) along with 20b (0.127 g, 14.5%) and 18b
(0.174 g, 34.8%). Compound 19b: white solid. Mp 133e136 ꢁC; IR
(75 MHz, CDCl3) d 173.2, 151.4, 151.0, 150.7, 150.0, 147.3, 143.3, 143.1,
142.0, 135.5, 135.4, 133.1, 133.0, 132.9, 132.4, 129.8, 129.6, 129.6,
129.2, 128.2, 127.7, 127.6, 127.5, 126.2, 126.1, 125.5, 124.9, 124.7,
123.4, 123.1, 117.8, 74.3, 60.2, 34.2, 34.0, 33.9, 32.0, 31.6, 31.4, 31.4,
31.3, 31.0, 30.0, 29.5, 26.4, 26.4, 21.5, 19.4, 19.3, 19.2. Anal. Calcd for
C82H104O6Si2: C, 79.31; H, 8.44. Found: C, 79.61; H, 8.31.
(KBr) 3271, 2961, 1503 cmꢀ1 1H NMR (300 MHz, CDCl3)
; d 8.34 (s,
1H), 7.76e7.69 (m, 3H), 7.60 (s, 1H), 7.48e7.35 (m, 5H), 7.31e7.27
(m, 2H), 7.21e7.02 (m, 5H), 6.76 (dd, J¼2.3, 8.5 Hz, 1H), 6.70 (d,
J¼8.2 Hz,1H), 6.46 (d, J¼8.5 Hz,1H), 4.06 (s, 2H), 3.86 (s, 4H),1.26 (s,
9H), 1.26 (s, 9H), 1.24 (s, 9H), 1.13 (s, 9H), 1.10 (s, 9H); 13C NMR
4.4. Ethyl 5-(4-tert-butyl-2-(5-tert-butyl-2-(tert-butyldiphe-
nylsilyloxy)benzyl)-6-(5-tert-butyl-3-(5-tert-butyl-2-(tert-bu-
tyldiphenylsilyloxy)benzyl)-2-(5-(diethoxyphosphoryl)penty-
loxy)benzyl)phenoxy)pentanoate (35)
(75 MHz, CDCl3) d 151.4, 149.5, 147.9, 147.4, 144.7, 144.1, 144.0, 143.1,
135.5, 132.2, 130.1, 128.2,127.9, 127.5, 127.4,127.3,127.2, 126.8, 126.7,
126.5, 125.8, 125.7, 125.6, 124.5, 124.2, 118.8, 116.0, 34.0, 33.98,
33.96, 33.95, 31.9, 31.6, 31.5, 31.4, 31.3, 26.7, 19.5. Anal. Calcd for
C59H74O4Si$2CH2Cl2: C, 71.10; H, 7.52. Found: C, 69.71; H, 7.48.
A
mixture of 34 (0.80 g, 0.65 mmol), diethyl 5-
iodopentylphosphonate (0.54 g, 1.6 mmol), and Cs2CO3 (0.31 mg,
1.6 mmol) in anhydrous CH3CN (14 mL) was heated at reflux for
48 h. The reaction mixture was cooled and the solvent removed in
vacuo. The residue was dissolved in ethyl acetate (50 mL) and
washed with water (10 mL), dried (Na2SO4), and concentrated. The
crude product was purified by radial chromatography to yield 35
(540 mg, 58%). IR (neat) 2962, 2868, 1649 cmꢀ1; 1H NMR (300 MHz,
4.2.4. 2,6-Bis(5-tert-butyl-2-(tert-butyldiphenylsilyloxy)benzyl)-4-
tert-butylphenol (20a). The representative procedure for TBDPS
protection was followed using 18a (1.0 g, 2.1 mmol), imidazole
(0.48 g, 7.0 mmol), and TBDPSCl (1.86 g, 6.8 mmol). The reaction
mixture was stirred at rt for 24 h and then heated at 50 ꢁC for 24 h
to give 20a (1.3 g, 65%). White solid. Mp 106e110 ꢁC; IR (KBr) 3431,
CDCl3)
d 7.74e7.70 (m, 8H), 7.42e7.32 (m, 12H), 7.04 (m, 2H),
2960, 2860, 1606, 1502 cmꢀ1
;
1H NMR (300 MHz, CDCl3)
6.94e6.93 (m, 4H), 6.78 (dd, J¼2.3, 8.5 Hz, 2H), 6.36 (d, J¼8.5 Hz,
2H), 4.25 (s, 4H), 4.14e4.01 (m, 8H), 3.73e3.84 (m, 4H), 2.31e2.21
(m, 2H), 1.76e1.48 (m, 12H), 1.27 (t, J¼7.0 Hz, 6H), 1.19 (t, J¼7.0 Hz,
3H),1.14 (s,18H),1.13 (s, 9H),1.13 (s, 9H),1.30 (s, 9H),1.02 (s, 9H); 13C
d
7.75e7.67 (m, 8H), 7.45e7.27 (m, 12H), 7.12 (d, J¼2.6 Hz, 2H), 7.03
(s, 2H), 6.73 (dd, J¼2.6, 8.5 Hz, 2H), 6.45 (s, 1H), 6.34 (d, J¼8.5 Hz,
2H), 4.15 (s, 4H), 1.24 (s, 9H), 1.10 (s, 18H), 0.99 (s, 18H); 13C NMR
(75 MHz, CDCl3)
d
150.1, 143.7, 142.2, 135.5, 132.7, 129.8, 129.1, 127.8,
NMR (75 MHz, CDCl3) d 173.3, 153.73, 153.66, 151.0, 145.97, 145.93,
127.7, 126.3, 125.0, 123.5, 118.2, 34.0, 33.9, 31.6, 31.6, 31.4, 31.2, 26.5,
22.6, 19.4, 14.1. Anal. Calcd for C64H78O3Si2: C, 80.79; H, 8.26. Found:
C, 80.47; H, 8.03.
143.1,135.4,133.09,133.05,133.02,132.6,129.91,129.87,129.7,127.7,
127.54, 127.51, 125.8, 125.7, 125.43, 125.37, 123.14, 123.10, 117.7, 72.9,
72.7, 61.3(d, JPC¼6 Hz), 60.1, 34.2, 34.0, 33.9, 31.41, 31.37, 30.43,
30.36, 30.1, 29.9, 29.4, 27.5, 27.2, 26.6, 25.6 (d, JPC¼132 Hz) , 22.6,
22.5, 21.7, 19.5, 16.4(d, JPC¼6 Hz), 14.2. Anal. Calcd for
C91H123O9PSi2: C, 75.48; H, 8.56. Found: C, 75.34; H, 8.81.
4.2.5. 2-(3-(5-tert-butyl-2-(tert-butyldiphenylsilyloxy)benzyl)-5-
tert-butyl-2-hydroxybenzyl)-6-(5-tert-butyl-2-(tert-butyldiphenylsi-
lyloxy)benzyl)-4-tert-butylphenol (20b). The representative pro-
cedure for TBDPS protection was followed using 18b (1.0 g,
1.7 mmol), imidazole (0.34 g, 5.0 mmol), and TBDPSCl (0.94 g,
4.5. Ethyl 5-(2-(2-(2-(2-(3-(benzyloxy)-2-oxopyridin-1(2H)-yl)
ethoxy)ethoxy)-5-tert-butylbenzyl)-6-(3-(2-(2-(2-(3-(benzy-
loxy)-2-oxopyridin-1(2H)-yl)ethoxy)ethoxy)-5-tert-butylben-
zyl)-5-tert-butyl-2-(5-(diethoxyphosphoryl)pentyloxy)ben-
zyl)-4-tert-butylphenoxy)pentanoate (36)
3.4 mmol) to give 20b (1.7 g, 96.9%) as
a
white solid. Mp
110e114 ꢁC; IR (KBr) 3401, 2961, 1501 cmꢀ1
;
1H NMR (300 MHz,
CDCl3)
d 7.73e7.68 (m, 8H), 7.42e7.33 (m, 10H), 7.33e7.30 (m, 2H),
7.18 (d, J¼2.3 Hz, 2H), 7.13 (d, J¼2.4 Hz, 2H), 6.97 (d, J¼2.9 Hz, 2H),
6.75 (dd, J¼2.7, 8.5 Hz, 2H), 6.37 (d, J¼8.5 Hz, 2H), 4.10 (s, 4H), 3.92
(s, 2H), 1.23 (s, 18H), 1.13 (s, 18H), 0.97 (s, 18H); 13C NMR (75 MHz,
To a solution of 35 (122 mg, 0.084 mmol) in anhydrous THF
(10 mL) was added TBAF (130 mg, 0.5 mmol) and stirred at rt for

10038
J.A. Young et al. / Tetrahedron 68 (2012) 10030e10039
12 h. Water (20 mL) was added to the reaction mixture and the
crude product extracted into ethyl acetate (3ꢂ40 mL). The com-
bined organic layers were dried (Na2SO4) and concentrated. The
silyl byproducts were removed by radial chromatography to pro-
vide the phenol (80 mg, 99%) as an oil. IR (neat) 3366, 2962, 1736,
C96H124N3O15P: C, 72.47; H, 7.86; N, 2.64. Found: C, 72.13; H, 7.53;
N, 2.55.
4.7. Diethyl 5-(4-tert-butyl-2-(5-tert-butyl-2-(2-(2-(3-
hydroxy-2-oxopyridin-1(2H)-yl)ethoxy)ethoxy)benzyl)-6-(5-
tert-butyl-3-(5-tert-butyl-2-(2-(2-(3-hydroxy-2-oxopyridin-
1(2H)-yl)ethoxy)ethoxy)benzyl)-2-(5-(hydroxyamino)-5-ox-
opentyloxy)benzyl)phenoxy)pentylphosphonate (38)
1609 cmꢀ1 1H NMR (300 MHz, CDCl3)
; d 7.72 (s, 1H), 7.47 (s, 1H),
7.15 (d, J¼2.3 Hz, 1H), 7.10 (m, 2H), 7.07 (d, J¼2.3 Hz, 1H), 7.01 (m,
2H), 6.85 (d, J¼2.6 Hz, 1H), 6.80 (d, J¼2.6 Hz, 1H), 6.66 (dd, J¼2.0,
8.2 Hz, 2H), 4.09e3.99 (m, 6H), 3.96 (s, 2H), 3.83e3.78 (m, 6H), 3.67
(t, J¼7.0 Hz, 2H), 2.27 (t, J¼7.0 Hz, 2H), 1.85e1.38 (m, 12H), 1.24 (t,
J¼7.0 Hz, 6H), 1.21 (s, 9H), 1.19 (s, 9H), 1.17 (t, J¼7.0 Hz, 3H), 1.11 (s,
9H), 1.08 (s, 9H). A mixture of the phenol (72 mg, 0.072 mmol),
HOPO iodide 21 (86 mg, 0.21 mmol), and Cs2CO3 (41 mg,
0.21 mmol) in anhydrous CH3CN (5 mL) was heated at reflux for 3 d.
The reaction mixture was cooled and the solvent was removed in
vacuo. The residue was dissolved in ethyl acetate (40 mL) and
washed with water (20 mL), dried (Na2SO4), and concentrated. The
crude product was purified by radial chromatography to yield 36
(66 mg, 60%). IR (neat) 2955, 2868, 1733, 1655, 1608, cmꢀ1; 1H NMR
Palladium on carbon (10%, 10 mg) was added to a solution of 37
(60 mg, 0.038 mmol) in absolute ethanol (3 mL) and the reaction
mixture stirred under H2 balloon at rt for 24 h. The reaction mixture
was diluted with ethanol (20 mL) and filtered through a pad of celite
on a sintered glass filter. The solvent was removed in vacuo to afford
chelator 38 as thick oil (47 mg, 94%). IR (neat) 3226, 2960, 1652,
1600 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d 7.10e7.05 (m, 3H), 7.01e6.95
(m, 2H), 6.91e6.89 (m, 2H), 6.88e6.78 (m, 4H), 6.70 (m, 3H), 5.99e5.92
(m, 2H), 4.08e3.90 (m, 16H), 3.78e3.72 (m, 4H), 3.69e3.60 (m, 8H),
3.46 (m, 2H), 2.01 (m, 2H),1.70e1.50(m, 9H),1.46e1.36 (m, 3H), 1.21 (t,
J¼7.0 Hz, 6H), 1.13 (s, 9H), 1.14 (s, 18H), 1.04 (s, 9H); 13C NMR (75 MHz,
(300 MHz, CDCl3)
d 7.36e7.32 (m, 4H), 7.29e7.18 (m, 6H), 7.05 (dd,
J¼2.6, 8.5 Hz, 2H), 6.95e6.84 (m, 8H), 6.70 (d, J¼8.5 Hz, 2H), 6.52
(dd, J¼1.5, 7.3 Hz, 2H), 5.80 (t, J¼7.0, 2H), 4.98 (s, 4H), 4.09e4.05 (m,
4H), 4.00e3.94 (m, 12H), 3.92 (s, 4H), 3.80e3.72 (m, 4H), 3.72e3.64
(m, 4H), 3.64e3.54 (m, 4H), 2.17e2.10 (m, 2H), 1.69e1.57 (m, 8H),
1.43e1.32 (m, 4H), 1.20 (t, J¼7.0 Hz, 6H), 1.11 (s, 18H), 1.11 (t,
J¼7.0 Hz, 3H), 1.06 (s, 9H), 1.04 (s, 9H); 13C NMR (75 MHz, CDCl3)
CDCl3)d169.9,158.6,154.4,154.2,153.5,153.2,146.4,145.9,143.3,143.2,
133.0, 132.4, 132.4, 129.9, 129.0, 128.4, 127.6, 127.2, 126.2, 126.1, 125.7,
125.3,123.4,123.3,114.6,114.4,111.0,110.9,106.3, 73.0, 72.5, 69.9, 69.2,
69.2, 68.1, 68.0, 61.7, 61.6, 49.8, 49.7, 34.2, 34.2, 34.0, 34.0, 32.6, 31.5,
31.4, 31.4, 31.3, 29.9, 29.8, 29.6, 29.5, 27.2, 27.0, 25.3 (d, JPC¼140 Hz),
22.4, 22.3, 16.4, 16.3. Anal. Calcd for C75H106N3O15P$2H2O: C, 66.40; H,
8.17; N, 3.10. Found: C, 66.21; H, 7.90; N, 2.96.
d
173.2, 158.1, 154.37, 154.35, 153.7, 153.67, 148.6, 145.88, 145.84,
143.15, 143.12, 136.3, 133.01, 132.95, 132.37, 132.32, 130.52, 130.51,
129.41, 129.37, 128.48, 128.43, 127.89, 127.83, 127.4, 127.3, 127.2,
126.08, 125.96, 125.7, 123.2, 115.7, 110.93, 110.89, 104.1, 103.9, 73.0,
72.7, 72.3, 70.6, 69.8, 69.1, 67.6, 67.5, 61.6, 61.3 (d, JPC¼7 Hz), 60.0,
49.6, 34.1, 34.0, 33.9, 31.41, 31.35, 30.0, 29.8, 29.6, 29.5, 27.3, 27.1,
25.6 (d, JPC¼140 Hz), 22.5, 22.4, 21.5, 16.4 (d, JPC¼6 Hz), 14.2. Anal.
Calcd for C91H121N2O15P: C, 72.20; H, 8.06; N, 1.85. Found: C, 72.57;
H, 7.79; N, 1.94.
Acknowledgements
This work was supported in part by the National Institutes of
Health under PHS Grant nos. S06 GM08136 and SC3 GM084809. We
also thank WERC/DOE, New Mexico for their support.
Supplementary data
Full experimental details for compounds 6e12, 14, 15, and
22e33. Supplementary data associated with this article can be
found in the online version, at http://dx.doi.org/10.1016/
j.tet.2012.09.032. These data include MOL files and InChiKeys of the
most important compounds described in this article.
4.6. Diethyl 5-(2-(2-(2-(2-(3-(benzyloxy)-2-oxopyridin-1(2H)-
yl)ethoxy)ethoxy)-5-tert-butylbenzyl)-6-(3-(2-(2-(2-(3-(ben-
zyloxy)-2-oxopyridin-1(2H)-yl)ethoxy)ethoxy)-5-tert-bu-
tylbenzyl)-2-(5-(benzyloxyamino)-5-oxopentyloxy)-5-tert-bu-
tylbenzyl)-4-tert-butylphenoxy)pentylphosphonate (37)
References and notes
Lithium bis(trimethylsilylamide) (1 M in THF, 0.8 mL, 0.8 mmol)
was added to a suspension of O-benzylhydroxylamine hydrochlo-
ride (66 mg, 0.41 mmol) in anhydrous THF (5 mL) at ꢀ78 ꢁC under
N2. After 15 min, a solution of the ester 36 (125 mg, 0.083 mmol) in
anhydrous THF (2 mL) was added and reaction mixture was stirred
for 30 min. The reaction was quenched with saturated NH4Cl
(10 mL) at ꢀ78 ꢁC. The product was extracted into ethyl acetate
(3ꢂ25 mL) and dried (Na2SO4). The crude product was purified by
radial chromatography to give 37 (69 mg, 53%) as an oil. IR (neat)
3428, 3196, 3034, 2959, 2868, 1651, 1605 cmꢀ1; 1H NMR (300 MHz,
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5. de Fatima, A.; Fernandes, S. A.; Sabino, A. A. Cur. Drug Discov. Technol. 2009, 6,
CDCl3)
d 10.1 (s, 1H, NH), 7.42e7.23 (m, 15H), 7.13(m, 2H), 7.05 (d,
151e170.
J¼2.6 Hz, 1H), 6.99e6.90 (m, 7H), 6.74 (t, J¼7.2 Hz, 2H),
6.60e6.57(m, 2H), 5.90 (m, 2H), 5.04 (s, 4H), 5.01 (s, 2H), 4.83 (s,
2H), 4.11e3.86 (m,16H), 3.79e3.47 (m,10H), 2.03 (m, 2H),1.76e1.61
(m, 10H), 1.49e1.39 (m, 2H), 1.26 (t, J¼7.0 Hz, 6H), 1.20 (s, 9H), 1.18
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d 158.1,
154.4, 154.3, 153.6, 153.3, 148.59, 148.56, 145.9, 143.3, 143.2, 136.31,
136.27, 133.0, 132.7, 132.5, 132.3, 130.5, 129.3, 129.2, 129.0, 128.5,
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