The synthesis of azacrown ethers with quinoline-based sidearms as potential zinc(II) fluorophores

Article abstract of DOI:10.1016/S0040-4020(02)00451-9

Two novel fluorophores, 12 and 13, composed of diaza-18-crown-6 ligands containing two quinoline-based sidearms which are structurally similar to Zn(II) fluorophores TSQ (1) and Zinquin (2) were synthesized as potential Zn(II) fluorophores by reductive amination of 8-benzenesulfonamido-2-quinoline carboxaldehyde 6 and 8-benzenesulfonamido-6-quinolyloxyacetate-2-carboxaldehyde 11 with diaza-18-crown-6 using sodium triacetoxyborohydride (NaBH(OAc)₃) as the reducing agent. Preliminary photophysical properties of ligands 12 and 13 show that they possess the properties necessary to be effective chemosensors for Zn²⁺. The solid state structure of 12 is also reported.

Full text of DOI:10.1016/S0040-4020(02)00451-9

TETRAHEDRON
Pergamon
Tetrahedron 58 52002) 4809±4815
The synthesis of azacrown ethers with quinoline-based sidearms
as potential zincꢀII) ¯uorophores
Guoping Xue,a Jerald S. Bradshaw,a,p N. Kent Dalley,a Paul B. Savage,a Reed M. Izatt,a
Luca Prodi,b Marco Montaltib and Nelsi Zaccheronib
aDepartment of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602-4678, USA
bDipartimento di Chimica ªG. Ciamicianº, Universita di Bologna, Via Selmi 2, I-40126 Bologna, Italy
Received 18 February 2002; revised 19 April 2002; accepted 22 April 2002
AbstractÐTwo novel ¯uorophores, 12 and 13, composed of diaza-18-crown-6 ligands containing two quinoline-based sidearms which are
structurally similar to Zn5II) ¯uorophores TSQ 51) and Zinquin 52) were synthesized as potential Zn5II) ¯uorophores by reductive amination
of 8-benzenesulfonamido-2-quinoline carboxaldehyde 6 and 8-benzenesulfonamido-6-quinolyloxyacetate-2-carboxaldehyde 11 with diaza-
18-crown-6 using sodium triacetoxyborohydride 5NaBH5OAc)3) as the reducing agent. Preliminary photophysical properties of ligands 12
and 13 show that they possess the properties necessary to be effective chemosensors for Zn21. The solid state structure of 12 is also reported.
q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
Zinc is an essential element for humans and plays an impor-
tant role in biochemical and nutritional processes.1 Approxi-
mately 300 enzymes contain zinc5II) as an essential
component, either for structural purposes or as part of a
catalytic site.2 Furthermore, zinc is a global excess burden
on the environment due to human activities. Increased levels
of zinc are the result of smelting, re®ning, and manufactur-
ing processes, but domestic waste waters also can contain
high local zinc concentrations especially in aquatic eco-
systems.3 The level of zinc in seawater3,4 is of importance
Figure 1. Structure of zinc-active ¯uorophores.
since this metal meets the needs of many species for
survival, and for the productivity of plankton.5 Therefore,
there is a need for reliable, fast, and low-cost methods for
because they are not selective for Zn21 but form complexes
the quantitative analysis and monitoring of zinc levels in
with many metal ions with varying ¯uorescence
environmental and biological systems.
intensities.10
While development of ¯uorescent chemosensors has been
made for other biologically important divalent metal ions, in
A new type of selective and ef®cient Zn21 ¯uorophore, a
particular Ca21 and Mg21 with several selective ¯uoro-
dansylamide-substituted macrocyclic tetraamine 5dansyl-
phores,6 there are few Zn21 selective ¯uorophores. Several
amidoethylcyclen), has been developed by Kimura and
co-workers.11 Recently, we reported an ef®cient and
convenient one-step method to introduce the dansyl
quinoline-based compounds, such as 6-methoxy-8-p-
toluenesulfonamido)-quinoline 1 5TSQ)7,8 and its ester
chromophone onto macrocyclic polyamines.12 The success
ether derivative 2 5Zinquin)9 5Fig. 1), are currently the
of the dansylamidoethylcyclen ¯uorophore is due to a high
most widely used zinc-activated ¯uorophores. However,
af®nity of the aza macrocycle for Zn21, a strong af®nity for
for quantitative analysis of Zn21 either in living cells or in
aromatic sulfonamides by the Zn21±cyclen complex, and
other environments, TSQ and Zinquin are not satisfactory
the strong luminescence property of the dansyl chromo-
phore. Herein, we report the synthesis of two diaza-18-
crown-6 ligands containing two quinoline-based sidearms
which are structurally similar to TSQ 1 and Zinquin 2.
We expected that attachment of TSQ or Zinquin analogues
Keywords: chemosensors; ¯uorophores; crown ethers; quinoline; reductive
amination.
p
Corresponding author. Tel.: 11-801-422-2415; fax: 11-801-422-0153;
e-mail: jerald_bradshaw@byu.edu
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020502)00451-9

4810
G. Xue et al. / Tetrahedron 58 12002) 4809±4815
Scheme 1. 5a) H2/Pd-C/EtOH; 5b) Benzenesulfonyl chloride/pyridine/0±58C; 5c) SeO2/1,4-dioxane.
Scheme 2. 5a) BrCH2CO2Et/5i-Pr)2NEt; 5b) H2/Pd-C/EtOH; 5c) Benzenesulfonyl chloride/pyridine/0±58C; 5d) SeO2/1,4-dioxane.
Scheme 3. 5a) 6/NaBH5OAc)3/DCE; 5b) 11/NaBH5OAc)3/DCE.
to crown ethers to form 12 and 13 would improve af®nities
of the ligands for Zn21 or other heavy metal ions. An X-ray
crystal structure of ligand 12 is also described. Preliminary
photophysical studies show that these two ligands can be
2. Results and discussion
The synthesis of ligands 12 and 13, employing reductive
amination,13 is outlined in Scheme 3. The preparation of
quinolinecarboxaldehyde precursor 6 5Scheme 1) began
effective chemosensors for Zn21
.

G. Xue et al. / Tetrahedron 58 12002) 4809±4815
4811
Figure 2. The solid state structure of 12 with hydrogen atoms omitted except for those that are involved in hydrogen bonding.
with commercially available 8-nitroquinaldine 53).
Reduction of 3 to amino compound 4 was accomplished
in 95% yield by hydrogenation using Pd±C as the catalyst.
Treatment of 4 with benzenesulfonyl chloride in pyridine at
0±58C gave 5 in 97% yield. Oxidation of 5 was accom-
plished with SeO2 in 1,4-dioxane to provide aldehyde 6 in
a 90% yield. Key quinolinecarboxaldehyde precursor 11
5Scheme 2) was prepared from commercially available
6-hydroxy-8-nitroquinaldine 57). Intermediates 8 and 9
were prepared by reported methods.9a Reaction of 9 with
benzensulfonyl chloride in pyridine at 0±58C gave Zinquin
analogue 10 in 90% yield. Oxidation of 10 with SeO2 in 1,4-
dioxane gave aldehyde 11 in 88% yield. Finally, diaza-18-
crown-6 was treated with aldehydes 6 and 11 in the presence
of NaBH5OAc)3 in DCE to give ligands 12 and 13 in 85 and
78% yields, respectively.
water is hydrogen bonded to an oxygen atom and a nitrogen
atom of the macrocycle and the amide hydrogen atom of the
sidearm. This suggests the possibility that this ligand could
bind to two cations such as Zn21 with each interacting with a
combination of donor atoms of the macrocycle and the side-
arms.
Preliminary photophysical properties of ligands 12 and 13
and their complexes with Zn21, Cd21, and the alkaline earth
metal ions have been investigated. All the complexation
experiments were carried out in dioxane/water mixtures
51/1, v/v) because of the low solubilities of both compounds
in water. Dioxane was preferred to acetonitrile since during
some preliminary titrations in MeCN/water, precipitation of
the metal complexes was observed. The solutions were
buffered at pH 7.4 with 3-5N-morpholino)-2-hydroxypro-
panesulfonic acid 5MOPSO).
The solid state structure of 12 is shown in Fig. 2. The struc-
ture lies on a center of inversion and contains two water
molecules of hydration, each interacting with 12 through
three hydrogen bonds. It is interesting to note that each
The two bis58-benzenesulfonamido)quinoline-containing
ligands 512 and 13) present quite different absorption
spectra; the introduction of an ethereal oxygen on the
quinoline moiety resulting in 13 causes a red shift of the
two bands 5242 and 307 nm) typical of this chromophore
5Fig. 3 and Table 1). Both compounds show only a very
weak ¯uorescence originating from a short-lived excited
state 5Table 1).
The responses of the two ligands to the addition of metal
ions are very similar. As can be seen from Figs. 4 and 5,
addition of Zn21 to a solution of 12 or 13 leads to strong
changes of the absorption spectra until 1 equiv. of metal ion
has been added. No further changes were observed for Zn21
concentrations greater than 1 equiv. A different pattern is
observed from the ¯uorescence spectra as can be seen from
Figs. 5 and 6. The ¯uorescence intensity increases in an
almost linear manner up to the addition of 2 equiv. of
Zn21. All these ®ndings can be rationalized in terms of
the formation in solution of two different complexes with
1:1 and 1:2 5ligand/metal) stoichiometries, respectively; a
possibility that was also suggested, as discussed above, from
the analysis of X-ray data. Qualitatively, the changes
Figure 3. Absorption spectra of ligands 12 5- - -) and 13 5Ð) in dioxane/
water 51/1, v/v).

4812
G. Xue et al. / Tetrahedron 58 12002) 4809±4815
Table 1. Absorption and luminescence data relative to compounds 12 and 13 and their metal ion complexes in dioxane/water 51/1, v/v) buffered at pH 7.4 with
MOPSO
Absorption
Luminescence
l
max 5nm)
1
max 5M21cm21
)
l
max 5nm)
420
F
t 5ns)
,0.4
15
log ba
12
242
307
261
357
260
365
261
358
244
258
310
69,000
9400
65,800
7400
58,600
6900
64,300
8100
0.003
0.17
0.33
0.15
0.08
12 Zn
12 Zn2
12 Cd
12 Ba
503
8.3^0.3
12.9^0.3
8.3^0.5
4.7^0.1
514
21
499
13
51,700
36,100
7500
490
17
13
246
336
264
360
264
362
264
360
251
259
346
73,700
7900
70,300
8080
64,800
7600
68,000
9000
420
495
500
489
480
0.004
0.19
0.37
0.19
0.13
,0.4
16
13 Zn
13 Zn2
13 Cd
13 Ba
8.8^0.1
14.6^0.2
8.6^0.6
4.9^0.1
24
16
48,400
46,000
7500
15
a
Apparent global association constant.
observed in the absorption and luminescence spectra are
very similar to those reported for TSQ and Zinquin at the
same pH. For these two ligands at neutral pH, the complexa-
tion process was associated with the deprotonation of the
sulfonamido group,7±9 leading to the observed large spectral
changes. From the changes in the absorption spectra, it is
evident that inclusion of the ®rst metal ion leads to depro-
tonation of both of the chromophoric groups, while the
formation of the bimetallic complex causes only minor
changes in the spectra. The increased charge density close
to the two chromophoric groups could be suf®cient to
further increase the luminescence band that, having charge
transfer character, is very sensitive to the polarity of the
environment. The increase in the observed excited state life-
time on going from the mononuclear to the binuclear
complex is consistent with this hypothesis.
It is worth noting that the luminescence quantum yields 5w),
as shown in Table 1, increase about a hundred-fold upon
complexation, while the increase in the luminescence inten-
sity upon excitation in the 350±400 nm region, where the
absorbance of the free ligand is negligible, can be more than
a thousand-fold. For this reason, the two ligands are both
good OFF/ON luminescent chemosensors for zinc ions
since they are almost non-luminescent when uncomplexed
and give strongly luminescent complexes with this metal
ion.
These ligands also form luminescent complexes with Cd21
.
With this ion, no evidence of a 1:2 5ligand/metal) was
found. Both the absorption and luminescence data recorded
during the titration could be ®tted simply for formation of a
complex with a 1:1 stoichiometry.
Figure 5. Changes in the absorbance 5246 nm, X, and 361 nm, B) and in
the ¯uorescence spectra 5lexˆ330 nm; lexˆ500 nm, O) upon addition of
increasing amounts of Zn5ClO4)2 to 13.
Figure 4. Absorption spectra of a 1.27£1025 M solution of 13 and upon
addition of increasing amounts of Zn5ClO4)2.

G. Xue et al. / Tetrahedron 58 12002) 4809±4815
4813
Preliminary photophysical properties of 12 and 13 show that
.
they are effective chemosensors for Zn21
3. Experimental
Melting points were taken on a Thomas±Hoover melting
1
point apparatus and are uncorrected. The H and 13C NMR
spectra were recorded at 200 or 300 MHzand 50 or 75 MHz
in CDCl3 unless otherwise indicated. IR spectra were
recorded on a Perkin±Elmer paragon 500 Ft-IR spectro-
meter. HRMS spectra were obtained on a Finnegan 8430
high-resolution mass spectrometer using fast atom bom-
bardent 5FAB) and chemical ionization 5CI) methods.
Elemental analyses were performed by MHW Laboratories,
Phoenix, AZ. Solvents and starting materials were
purchased from commercial sources where available.
Compounds 4,14 8,9a and 99a were prepared by the reported
methods. The solvent for photophysical measurements was
dioxane/water 51/1, v/v). Absorption spectra were recorded
on a Perkin±Elmer lambda 40 spectrophotometer. Uncor-
rected emission and corrected excitation spectra were
obtained on a Fluorolog spectro¯uorimeter equipped with
a R928 phototube. In order to allow comparison of emission
intensities, corrections for instrumental response, inner ®lter
effects,15 and phototube sensitivity were performed. A
correction for differences in the refraction index was
introduced when necessary.
Figure 6. Luminescence spectra 5lexˆ330 nm) of a 1.27£1025 M solution
of 13 and upon addition of increasing amounts of Zn5ClO4)2.
Table 2. Crystal data and experimental details for 12
Formula
C44H50N6O8S2´2H2O
891.05
Monoclinic
P21/n
11.267 54)
11.757 52)
16.743 54)
93.02 52)
2214.7 59)
2
Formula weight
Crystal system
Space group
Ê
a 5A)
Ê
b 5A)
Ê
c 5A)
Ê
b 5A)
V 5A )
Ê 3
3.1. Synthesis of new ligands
Z
F5000)
Dx 5g cm23
944
1.336
3.1.1. 8-Benzenesulfonamidoquinaldine ꢀ5). Benzene-
sulfonyl chloride 52.48 g, 14 mmol) was added dropwise
to a cooled, stirred solution of 8-aminoquinaldine 54)
51.85 g, 11.7 mmol) in 10 mL of pyridine and the mixture
was stirred in an ice bath for 3 h. Ice water was then added
and the resulting precipitate was ®ltered, washed well with
water, dried and dissolved in CH2Cl2. The resulting solution
was washed with 1 M HCl and the aqueous phase was
extracted with CH2Cl2. The resulting solution was washed
with 1 M HCl and the aqueous phase was extracted with
CH2Cl2 53£15 mL). The organic layers were combined,
washed with a saturated solution of Na2CO3, dried
5MgSO4) and the solvent was removed under reduced
pressure. Crystallization of the residue from EtOH gave
)
Crystal size 5mm3)
0.4£0.4£0.2
m 5mm21
)
0.185
293
Temperature 5K)
2umax58)
Total data
Independent data
Total parameters
Goodness of ®t on F2
R[I.2s5I)]
50.0
4503
3866 5Rintˆ0.0352)
284
1.065
0.0609
0.1020
0.350
20.265
R 5all data)
Largest diff. peak 5e A
Ê 23
Ê 23
)
Largest diff. hole 5e A
)
Considering alkaline earth metal ions, only barium ions
gave stable complexes 5see Table 1). Addition of up to
5 equiv. of Mg21, Ca21, and Sr21 caused only a very
small increase in the luminescence band. From excited
state lifetime measurements, it was possible to verify that
in all three cases, the new emission was due to a very small
amount of a quite strongly emitting species 5tˆ16 ns). This
could imply that complexes with Mg21, Ca21, and Sr21 are
luminescent but have a low stability 5log b,3) or that at
this pH only a small amount of the complex is present in a
form having the two 8-benzenesulfonamidoquinoline
groups deprotonated. Some preliminary competition experi-
ments con®rmed that the presence of these three metal ions
1
3.38 g 597%) of 5 as white crystals; mp 158±1598C; H
NMR: d 9.23 5s, 1H), 7.98±7.74 5m, 4H), 7.44±7.25 5m,
6H), 2.69 5s, 3H); 13C NMR d 159.7, 145.1, 141.0, 139.7,
138.8, 133.8, 129.0, 128.6, 128.0, 126.9, 125.2, 123.2,
122.8, 25.4; IR 5KBr) 3065, 1605, 1439, 1370, 1173,
1068, 795 cm21; HRMS m/z: calcd for C16H15N2O2S
5M11)1: 299.0856, found: 299.0836. Anal. calcd for
C16H14N2O2S: C, 64.41; H, 4.73. Found: C, 64.49; H, 4.59.
3.1.2.
8-Benzenesulfonamido-2-quinolinecarboxalde-
hyde ꢀ6). To a stirred suspension of freshly sublimed
SeO2 53.33 g, 30 mmol) in 150 mL of dioxane at 50±558C
was added a solution of 5 54.89 g, 16.4 mmol) in 50 mL of
dioxane during the course of 1.5 h. The mixture was heated
to 90±958C overnight, ®ltered, and the dioxane was
removed under reduced pressure. The residue was puri®ed
by column chromatography on silica gel with CH2Cl2 as
eluent to give 4.61 g 590%) of 6 as white needles; mp
does not cause interference with the determination of Zn21
.
In conclusion, we have attached Zn5II) ¯uorophores TSQ
and Zinquin to diaza-18-crown-6. The synthetic procedure
presented here is ef®cient and convenient, which should
make it useful for the synthesis of other new ¯uorophores.

4814
G. Xue et al. / Tetrahedron 58 12002) 4809±4815
194±1958C; 1H NMR: d 10.13 5s, 1H), 9.11 5s, 1H), 8.22 5d,
Jˆ8.4 Hz, 1H), 8.05 5d, Jˆ8.4 Hz, 1H), 7.95±7.87 5m, 3H),
7.61±7.33 5m, 5H); 13C NMR d 192.6, 150.9, 139.3, 138.2,
137.9, 134.7, 133.3, 130.3, 129.9, 129.2, 127.3, 122.3,
118.2, 116.2; IR 5KBr) 2842, 1710, 1503, 1468, 1157,
841, 744 cm21; HRMS m/z: calcd for C16H12N2O3S 5M1):
312.0569, found: 312.0562. Anal. calcd for C16H12N2O3S:
C, 61.52; H, 3.87. Found: C, 61.34; H, 3.91.
3.1.6. 7,16-Bis[ꢀ8-benzenesulfonamido-6-oxyacetate)-2-
quinolinylmethyl]diaza-18-crown-6ꢀ13). Macrocycle 13
was prepared as above for 12 from diaza-18-crown-6
5393 mg, 1.5 mmol) and 11 51.37 g, 3.3 mmol). Crude 13
was puri®ed by column chromatography on silica gel with
acetone/CH2Cl2 53:1) as eluent to give a 78% yield of the
1
pure product: mp ,358C; H NMR: d 7.97±7.84 5m, 8H),
7.62±7.39 5m, 10H), 6.64 5s, 1H), 6.63 5s, 1H), 4.68 5s, 4H),
4.29 5q, Jˆ7.2 Hz, 4H), 3.95 5s, 4H), 3.67 5t, Jˆ5.5 Hz, 8H),
3.63 5s, 8H), 2.89 5t, Jˆ5.5 Hz, 8H), 1.31 5t, Jˆ7.2 Hz, 6H);
13C NMR: d 168.4, 157.7, 155.9, 139.6, 135.4, 134.7, 134.2,
132.9, 128.9, 127.9, 127.2, 122.7, 107.4, 101.7, 70.8, 70.0,
65.7, 61.8, 61.5, 54.4, 14.1; IR 5KBr) 3260, 3236, 2875,
1605, 1570, 1510, 1470, 1471, 1351, 1165, 1123, 1090,
848, 750, 685, 581 cm21 HRMS: m/z calcd for
3.1.3. 2-Methyl-8-ꢀbenzenesulfonamido)-6-quinolyloxy-
acetate ꢀ10). Compound 10 was prepared as above for 5
from 9. Crude compound 10 was puri®ed by column chro-
matography on silica gel with CH2Cl2/hexane 53:1) as eluent
followed by recrystallization 5CH2Cl2/hexane) to give a
1
90% yield of 10 as a white solid: mp 136±1378C; H
NMR: d 9.25 5br, 1H), 7.95±7.83 5m, 3H), 7.53±7.22 5m,
5H), 6.62 5d, Jˆ2.7 Hz, 1H), 4.65 5s, 2H), 4.27 5q,
Jˆ7.2 Hz, 2H), 2.63 5s, 3H), 1.29 5t, Jˆ7.2 Hz, 3H); 13C
NMR d 168.5, 155.5, 155.4, 143.7, 136.3, 135.2, 134.4,
134.3, 129.5, 127.1, 126.7, 123.3, 106.7, 101.0, 65.5, 61.5,
24.7, 14.1; IR 5KBr) 3252, 2984, 1767, 1607, 1505, 1374,
1341, 1204, 1175, 1160, 1092, 840, 665, 544 cm21; HRMS
m/z: calcd for C20H21N2O5S 5M11)1: 401.1172, found:
401.1161. Anal. calcd for C20H20N2O5S: C, 59.98; H,
5.03. Found: C, 59.79; H, 5.23.
C52H62N6O14S2Na
5M1Na)1:
1081.3667,
found:
1081.3678. Anal. calcd for C52H62N6O14S2: C, 58.96; H,
5.90. Found: C, 58.75; H, 5.77.
3.2. X-Ray crystallography data
Crystal data and experimental details are listed in Table 2.
Single crystal data were collected using a Bruker P4 auto-
mated diffractometer which utilized graphite mono-
chromated Mo Ka radiation. The structure was solved
using direct methods and re®ned on F2 using a full-matrix,
least-squares procedure. All non-hydrogen atoms were
re®ned anisotropically. Positions for hydrogen atoms with
the exception of those bonded to C9, N21 5the amide nitro-
gen) and the water oxygen were calculated. The positions
for the other hydrogens were obtained from a difference
map. All hydrogen atoms were allowed to ride on their
neighboring heavy atoms during the re®nement. The struc-
ture was solved, re®ned and displayed using SHELXTL
PC16 computer program package.
3.1.4.
8-Benzenesulfonamido-6-quinolyloxyacetate-2-
carboxaldehyde ꢀ11). Compound 11 was prepared as that
for 6 from 10. Crude compound 11 was puri®ed by column
chromatography on silica gel with CH2Cl2 as eluent to give
1
an 88% yield of 11; mp 154±1558C, H NMR: d 10.13 5s,
1H), 9.15 5s, 1H), 8.12±7.95 5m, 4H), 7.65±7.40 5m, 4H),
6.73 5d, Jˆ2.6 Hz, 1H), 4.68 5s, 2H), 4.30 5q, Jˆ7.2 Hz,
2H), 1.30 5t, Jˆ7.2 Hz, 3H); 13C NMR d 192.6, 168.0,
151.0, 139.5, 138.3, 138.0, 134.8, 133.5, 130.4, 130.0,
129.3, 127.6, 122.4, 118.5, 116.4, 65.8, 61.7, 14.1; IR
5KBr) 3260, 3085, 1720, 1630, 1590, 1361, 1138, 872,
3.3. Experimental data for UV±Vis and ¯uorescence
titration experiments
782 cm21
;
HRMS m/z calcd for C20H18N2O6SNa
5M1Na)1: 437.0784, found: 437.0781. Anal. calcd for
C20H18N2O6S: C, 57.96; H, 4.38. Found: C, 57.71; H, 4.38.
In a typical experiment, a solution of ligand 5concentration
2£1025 M) in dioxane/water 51/1, v/v) was titrated by
increasing amounts of a solution of the perchlorate salt of
the cation of interest 5concentration 5£1023 M) at room
temperature. After each addition of aliquots, the UV±Vis
and ¯uorescence spectra of the solution were recorded.
When the titration was completed, the spectra were imple-
mented into the Speci®t software.17
3.1.5.
7,16-Bis[ꢀ8-benzenesulfonamido)-2-quinolinyl-
methyl]diaza-18-crown-6ꢀ12). A mixture of diaza-18-
crown-6 5393 mg, 1.5 mmol) and 6 51.03 g, 3.3 mmol) in
25 mL of dichloroethane was stirred with NaBH5OAc)3
5848 mg, 4.0 mmol) under nitrogen at room temperature
for 5 h. The reaction was then quenched with saturated
Na2CO3 515 mL) and the mixture was extracted with
CH2Cl2 53£10 mL). The combined CH2Cl2 extracts were
dried 5Na2SO4), ®ltered, and concentrated under reduced
pressure. The residue was puri®ed by column chromato-
graphy on silica gel with acetone as eluent to give 1.09 g
585%) of 12 as white crystals; mp 184±1858C; 1H NMR: d
9.15 5br, 2H), 8.03±7.70 5m, 10H), 7.41±7.32 5m, 10H), 4.0
5s, 4H), 3.69 5t, Jˆ5.5 Hz, 8H), 3.65 5s, 8H), 2.92 5t,
Jˆ5.5 Hz, 8H); 13C NMR: d 160.1, 139.7, 137.7, 136.4,
133.4, 132.8, 128.8, 127.2, 126.2, 122.1, 122.0, 115.5,
70.9, 70.0, 62.1, 54.5; IR 5KBr) 3235, 2871, 1600, 1571,
1505, 1472, 1353, 1167, 1124, 1090, 930, 845, 754, 686,
Acknowledgements
Financial support from the Of®ce of Naval Research 5J. S.
B., P. B. S., and R. M. I.) and the Italian Ministry of
Research and Technology 5L. P., M. M., and N. Z.) is
gratefully acknowledged.
References
583 cm21
;
HRMS m/z calcd for C44H48N6O8S2Na3
1. For general reviews see: 5a) Frausto da Silva, J. J. R.;
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5M22H13Na)1: 921.2671, found: 921.2667. Anal. calcd
for C44H50N6O8S2: C, 61.80; H, 5.89. Found: C, 61.96; H,
5.81.

G. Xue et al. / Tetrahedron 58 12002) 4809±4815
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