Total syntheses of three copper (II) tetracarboranylphenylporphyrins containing 40 or 80 boron atoms and their biological properties in EMT-6 tumor-bearing mice

Article abstract of DOI:10.1016/j.bmc.2006.04.010

Three carboranyltetraphenylporphyrins containing 40 or 80 boron atoms were synthesized and evaluated for their biodistribution and toxicity in EMT-6 tumor-bearing mice. Copper (II) meso-5,10,15,20-tetrakis[3-methoxy-4-(o-carboranylmethoxy)phenyl]porphyrin

Full text of DOI:10.1016/j.bmc.2006.04.010

Bioorganic & Medicinal Chemistry 14 (2006) 5083–5092
Total syntheses of three copper (II) tetracarboranylphenylporphyrins
containing 40 or 80 boron atoms and their biological properties
in EMT-6 tumor-bearing mice
Haitao Wu, Peggy L. Micca, Michael S. Makar and Michiko Miura*
Medical Department, Building 490, Brookhaven National Laboratory, Upton, NY 11973-5000, USA
Received 28 December 2005; revised 31 March 2006; accepted 6 April 2006
Available online 2 May 2006
Abstract—Three carboranyltetraphenylporphyrins containing 40 or 80 boron atoms were synthesized and evaluated for their biodis-
tribution and toxicity in EMT-6 tumor-bearing mice. Copper (II) meso-5,10,15,20-tetrakis[3-methoxy-4-(o-carboranylmethoxy)phen-
yl]porphyrin, 6, and copper (II) meso-5,10,15,20-tetrakis[3-hydroxy-4-(o-carboranylmethoxy)phenyl]porphyrin, 8, are B40 congeners
with different lipophilicities, each less than their B80 congener, copper (II) meso-5,10,15,20-tetrakis[m-(3,5-di-o-carboranylmethoxyb-
enzyloxy)phenyl]porphyrin, 18. Two days after the last of a series of ip injections in BALB/c mice bearing EMT-6 mammary tumors, a
dose of 185 mg/kg 6 (54 mg/kg B) delivered over 3.5 times the concentration of boron to tumor (169 lg/g B) than did 118 mg/kg 8
(36 mg/kg B), which delivered 35 lg/g B, or 87 mg/kg 18 (30 mg/kg B), which delivered 46 lg/g B. The tumor-to-blood and tumor-
to-brain boron concentration ratios at that time for all three porphyrins exceeded 80:1. Two days after the last injection, there resulted
moderate thrombocytopenia that essentially disappeared two days later from 6 and 18, and mild leukocytosis from 6, 8, and 18, all of
which were clinically inconsequential. Thus, 6 may rank among the most clinically promising carboranyl porphyrins ever made to deliv-
er 10B to tumors for boron neutron-capture therapy (BNCT) that has also been tested for its toxicity in vivo.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
phenylalanine (BPA).7,8 However, BSH has only moder-
ate selectivity for tumor cells and both BSH and BPA
have low retention times in tumors. At least 15–30 lg/
Boron neutron-capture therapy (BNCT) is an experi-
mental binary radiotherapy1,2 currently used for high-
grade gliomas, brain metastases, melanomas, and head
and neck cancers.3,4 BNCT is based on the nuclear reac-
tion, 10B(n,a)7Li, whereby 10B captures low-energy neu-
trons and produces high linear-energy-transfer (LET)
charged particles with short range in tissues (approxi-
mately one cell diameter, 5–10 lm). Even one such par-
ticle traversing any part of the nucleus of a normal or
neoplastic stem cell may disable that cell’s clonogenicity.
Hence, effective preferential destruction of neoplastic
cells in the presence of normal cells relies heavily on
the tumor selectivity of the boron-containing drug with-
in the irradiated target volume.
g
10B is required for effective BNCT assuming homoge-
neous distribution of boron in cells.9 Improved
compounds should have higher selectivity (ideally,
tumor-to-blood and tumor-to-normal tissues ratios > 5)
and inconsequential toxicities.9,10 During the past 15
years various candidate BNCT agents have been
synthesized and tested, including boronated nucleosides,
amino acids, peptides, phospholipids, liposomes,
monoclonal antibodies, porphyrins, and more recently,
nanotubes.11–14 Among those, several boron-containing
porphyrins appear to be particularly attractive on
account of their high boron content, tumor selectivities,
and long retention times in tumors.15–18
Currently, two boron agents are undergoing Phase I/II
BNCT clinical trials for BNCT; sodium sulfhydryl
boron hydride, Na2B12H11SH(BSH),5,6 and 4-borono-
Many carboranylporphyrins have been reported, with
both hematoporphyrin or meso-tetraphenylporphyrin
structure and ester, amide, ether or carbon–carbon link-
ages to carborane clusters.13,17,19 Porphyrins in the TCP
class have shown promising biodistribution and toxico-
logical properties at BNCT-relevant doses; CuTCPH, in
particular, has enabled ablation of some murine leg
tumors in vivo.15 Although the low toxicity and high
Keywords: BNCT; Porphyrins; EMT-6 tumors; Mice.
*
Corresponding author. Tel.: +1 631 344 3618; fax: +1 631 344
5311; e-mail: Miura@bnl.gov
0968-0896/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2006.04.010

5084
H. Wu et al. / Bioorg. Med. Chem. 14 (2006) 5083–5092
selectivity of CuTCPH and its analogs in the irradiated
target volume make them worthwhile candidates for
BNCT, the high lipophilicity of CuTCPH necessitated
large amounts of excipient for its parenteral administra-
tion into animals. In our endeavor to improve CuTCPH
we sought two avenues: one was to construct a porphy-
rin that is somewhat more polar than CuTCPH but not
water-soluble and the other was to increase the percent-
age of boron in the porphyrin. To increase polarity, a
porphyrin bearing hydroxyl moieties directly attached
to the phenyl group bearing the o-carborane cage was syn-
thesized via the methoxy derivative. Syntheses of porphy-
rins that contain eight rather than two or four carborane
cages have been described previously, but to our knowl-
edge, their properties in vivo have not yet been report-
ed.20,21 Herein we report the total synthesis of copper
(II) meso-5,10,15,20-tetrakis[3-methoxy-4-(o-carboranyl-
methoxy)phenyl]porphyrin, 6, copper (II) meso-5,10,15,20-
tetrakis[3-hydroxy-4-(o-carboranylmethoxy)phenyl]por-
phyrin, 8, and copper (II) meso-5,10,15,20-tetrakis[m-
(3,5-di-o-carboranylmethoxybenzyloxy)phenyl]porphy-
rin, 18. Some biodistribution and toxicological proper-
ties of 6, 8, and 18 in EMT-6 tumor-bearing mice are
also presented.
direct precursor to hydroxyporphyrin 7. The synthetic
route used to synthesize porphyrin, 5, shown in Scheme
1, is similar to that used to synthesize CuTCPH,22 but re-
quired 4-hydroxy-3-methoxybenzyl alcohol, 1 as the
starting material instead of 3-hydroxybenzyl alcohol used
for CuTCPH. All the reactions were straightforward ex-
cept the alcohol oxidation to form aldehyde 4. The reac-
tion was often sluggish and required a stronger
oxidizing agent than pyridinium chlorochromate (PCC),
such as di-chlorodicyanobenzoquinone (DDQ).23 The
methoxy groups were O-demethylated to form hydrox-
yporphyrin 7 using BBr3.24 Both copper porphyrins 6
and 8 were then evaluated in tumor-bearing mice.
Scheme 2 outlines the original plan for producing octa-
carboranylporphyrin 13. Although the route to the alde-
hyde 12 was fairly straightforward, the cyclization with
pyrrole gave a complex mixture yielding only very small
amounts of porphyrin 13.
Since more sterically hindered porphyrins have been
synthesized using the Lindsey cyclization method, the
low yield of 13 is probably due to electronic effects.
An alternative method for forming an octa-
carboranylporphyrin is outlined in Scheme 3. In this
route, the dicarboranylphenyl group is further removed
from the porphyrin macrocycle by a benzylether linkage.
The dicarboranylbenzyl alcohol 11, used in Scheme 2,
was brominated in 92% yield (shown in Scheme 3) using
CBr4 with triphenylphosphine25 and then coupled to 3-
hydroxybenzyl alcohol in the presence of base to form
15 in 96% yield. After PCC oxidation, the resulting alde-
hyde 16 was treated with pyrrole under Lindsey condi-
2. Results
2.1. Porphyrin syntheses
Because a free hydroxyl group will react with decaborane
and because of potential solubility difficulties of the inter-
mediates, the methoxyporphyrin 5 was targeted as the
OH
O
O
c
CH O
3
CH O
3
a, b
CH O
3
Cl
X
+
OH
OAc
OAc
2
1
3
d,e
OR
O
CH O
3
f, g (h)
RO
N
N
M
X
X
N
N
OR
CHO
4
X =
O
RO
X
5
6
7
8
R = CH3 M = 2H
R = CH3 M = Cu
i
R = H
R = H
M = 2H
M = Cu
Scheme 1. (a) K2CO3, KI, acetone, reflux 2d (94%); (b) AcCl, pyridine, 5 h (85%); (c) decaborane/CH3CN/toluene 3 h prior to addition of 2, after 2
added, 80–90 ꢁC 3d (80%); (d) HCl/MeOH reflux 3 h, 98%; (e) PCC, CH2Cl2, 2 h (94%); (f) pyrrole, TFA, CH2Cl2; (g) DDQ, reflux 1 h (31%); (h)
Cu(OAc)2, MeOH, CH2Cl2 (98%). (i) BBr3, CH2Cl2, 25 ꢁC, 30 min.

H. Wu et al. / Bioorg. Med. Chem. 14 (2006) 5083–5092
5085
HO
OH
O
O
O
O
c
a, b
OH
OAc
OAc
9
10
Y
d, e
N
NH
N
Y
Y
HN
O
O
f, g
X
Y
O
Y =
O
11 X = CH2OH
12 X = CHO
13
Scheme 2. (a) Propargyl chloride, K2CO3, KI, acetone, reflux for 24 h (97%); (b) Ac2O, H2SO4, 95 ꢁC for 3 h (96%); (c) decaborane, CH3CN, in
toluene, 25 ꢁC for 3 h; followed by 10, 90 ꢁC for 48 h (81%); (d) HCl, MeOH, reflux for 2 h (93%); (e) PCC, CH2Cl2, 2 h; (b, f) pyrrole, BF3 Æetherate,
CH2Cl2, 25 ꢁC for 2 h; (g) DDQ, reflux, 1 h.
OR
O
RO
c, d, e (f)
O
O
N
N
a, b
N
N
O
M
Y
X
O
OR
15 Y = CH2OH
16 Y = CHO
11 X = OH
14 X = Br
RO
O
R =
O
17 M = 2H
18 M = Cu
Scheme 3. (a) CBr4, Ph3P, THF, 25 ꢁC, 30 min (92%); (b) m-hydroxybenzyl alcohol, K2CO3, KI, acetone, reflux for 24 h (96%); (c) PCC, CH2Cl2,
25 ꢁC, 3 h; (99%); (d) pyrrole, BF3 Æether, CH2Cl2, 25 ꢁC for 1 h; (e) DDQ, reflux, 1 h (22%); (f) Cu(OAc)2 Æ H2O, MeOH/CH2Cl2, 25 ꢁC for 20 min
(92%).
tions26 to form porphyrin 17 in 22% yield and copper
was inserted to form 18 in 92% yield. As with porphyrin
13, porphyrins 17 and 18 also bear eight carborane
groups but were isolated in good yield. The percentage
of boron by weight of 17 and 18 are 36% and 35%,
respectively.
2.2. Biodistribution study
For in vivo studies, the porphyrins were first solubilized
in a 9% Cremophor EL/18% propylene glycol/saline
emulsion.27,28
The biodistribution data from mice given either porphy-
rin 6, 8, 18, or the reference porphyrin CuTCPH, are
shown in Table 1. Because the doses of boron delivered
as 6, 8, and 18 were not identical (Table 1), the tumor
boron concentrations were arithmetically normalized
to the dose of boron delivered as CuTCPH, 58 lg/g in
Figure 1. As with other lipophilic tetraphenylporphy-
In order to determine relative polarities of the porphy-
rins, they were analyzed by reverse-phase HPLC using
an acetonitrile/methanol gradient. Based on retention
times, the order of decreasing polarities (increasing
retention times) was:
(37.3 min), 6 (40.1 min), and 18 (>120 min).
8
(13.4 min), CuTCPH

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H. Wu et al. / Bioorg. Med. Chem. 14 (2006) 5083–5092
Table 1. Median boron concentrations (and range) in various tissues of mice given porphyrins 6, 8, 18, or CuTCPH by serial ip injections at 2 or 4
days after the last injection
Porphyrin
Time after last
injection (days)
No. of mice
Porphyrin dose
(B dose) (mg/kg)
EMT-6 tumor
(lg/g B)
Blood
(lg/g B)
Brain
(lg/g B)
Liver
(lg/g B)
6
2
2
2
2
4
4
4
4
5
5
5
7
5
5
5
7
185 (54)
118 (36)
87 (30)
169 (137–200)
35.3 (28.8–42.2)
46.4 (30.4–53.1)
59.5 (49.8–89.0)
142 (133–257)
22.2 (20.4–36.8)
26.4 (21.6–40.5)
68.3 (43.6–111)
0.4 (0.2–2.8)
0.3 (0.2–0.5)
0.5 (0.2–0.7)
0.0 (0–0)
0.1 (0.1–0.3)
0.3 (0.1–0.6)
0.2 (0.1–0.2)
0.1 (0–0.4)
537 (443–839)
475 (445–559)
353 (284–429)
550 (492–707)
414 (388–515)
448 (366–516)
230 (189–370)
492 (439–801)
8
18
CuTCPH16
190 (58)
185 (54)
118 (36)
87 (30)
6
0.1 (0.1–0.2)
0.2 (0–0.3)
0.0 (0–0.2)
0.0 (0–0.1)
8
18
0.2 (0.1–0.2)
0.3 (0.2–0.4)
0.3 (0.2–0.4)
0.7 (0.3–1.0)
CuTCPH16
190 (58)
300
250
200
150
100
50
from 6) at 4 days. Figure 1 shows that the normalized
boron concentrations in the EMT-6 carcinoma from 6
are more than three times greater than those from 8.
The resulting % injected dose per gram tumor tissue of
ꢀ19% from 6 is the highest ever observed in the EMT-
6 carcinoma in our laboratory. In general water-soluble
porphyrins appear to show lower liver and higher kid-
ney uptake than their lipophilic counterparts, most
likely due to greater excretion through the kidneys. It
is hypothesized that the more polar a porphyrin, the less
affinity for the liver, however, the more polar 8 appears
to effect 47% higher average boron concentrations in liv-
er than 6 when porphyrin doses were normalized. In any
event, the microlocalization properties of porphyrin 8
are likely to be somewhat different from those of por-
phyrin 6.
2-Day Tumor Boron
4-Day Tumor Boron
0
6
8
18
CuTCPH
Unlike porphyrins 6, 8, and CuTCPH, 18 was adminis-
tered to tumor-bearing mice by a series of three ip injec-
tions over 8 h rather than six ip injections over 32 h,
totaling a lower dose of 30 mg/kg boron. No visible
abnormalities were noted either physically or behavior-
ally in mice during and after administration of any of
the porphyrins. At necropsy, all tissues appeared nor-
mal. Table 2 shows the weight changes and hematologic
parameters in BALB/c mice given porphyrins 6, 8, 18, or
solvent only. Two days after the last injection, weight
losses in mice from 6 were slightly greater than those
from the other porphyrins but two days later, those
weight losses were no different from solvent-only con-
trols. The significant transient weight loss from porphy-
rin 6 is likely due to the higher dose of 6 relative to 8
Porphyrin
Figure 1. Tumor boron concentrations from porphyrins 6, 8, 18, and
CuTCPH (from Table 1) arithmetically normalized to a mean boron
dose of 58 mg/g at either 2 or 4 days after the last injection.
rins, the boron in blood and in brain was negligible by 2
days after the last injection of any of the four porphyrins
yielding very high tumor-to-blood and tumor-to-brain
boron ratios. Although the differences in boron from
blood and brain between the porphyrins were negligible,
the differences in normalized liver boron concentrations
were significant. Porphyrin 8 delivered the highest nor-
malized concentration to liver by ꢀ40% (vs the lowest
from CuTCPH) at 2 days and by ꢀ50% (vs the lowest
Table 2. Weight changes and hematologic parameters in mice given porphyrins 6, 8, 18 or solvent only at 2 or 4 days after the last injection
Porphyrin
Porphyrin dose Time after last injection No. of mice % weight change
(days)
Platelets (103/mm3) Leukocytes (103/mm3)
(mg/kg)
Solvent only
6
—
2
2
2
2
4
4
4
4
4
5
5
5
4
5
5
5
À1.3 (À4.5–1.1)
640 (568–730)
4.86 (2.52–5.62)
185
118
87
À4.7 (À9.3–0.9)*** 181 (105–248)*
10.81 (9.41–13.21)**
7.56 (6.82–10.50)**
11.24 (9.56–15.08)**
4.26 (3.63–6.87)
8
18
À0.1 (À2.0–1.4)
0.2 (À4.9–2.5)
À0.7 (À2.2–2.1)
5.2 (1.5–7.4)
617 (441–781)
193 (51–432)*
527 (500–618)
429 (346–481)**
633 (561–824)
917 (670–1128)**
Solvent only
6
—
185
118
87
9.03 (8.29–10.66)**
8
18
2.4 (0.9–3.9)
0 (À4.7–1.5)
7.26 (5.50–9.20)
6.09 (4.04–6.41)
Values are reported as median (range).
The Wilcoxon two-sample test with the corresponding solvent-only group shows the following differences:
* P < 0.01.
** P < 0.02.
*** P < 0.05.

H. Wu et al. / Bioorg. Med. Chem. 14 (2006) 5083–5092
5087
(57% higher) and 18 (113% higher), respectively. Rela-
tive to controls, blood platelet counts were decreased
(thrombocytopenia) 2 days after the last injection of 6
and 18 and although they had not fully recovered after
two more days, platelet counts from 6 were closer to
those of the controls by that time. The thrombocytope-
nia from 18 had been completely reversed by then; plate-
let counts were higher than control values—a common
overshooting during compensatory hyperplasia follow-
ing transient depletion of platelets.
boranes as the boron moiety. In comparing the lipophil-
icity of CuTCPH with the porphyrins in this report,
porphyrin 6 appears to be as lipophilic, while porphyrin
18 is more lipophilic and the hydroxyporphyrin 8 is
much less lipophilic. Although the lipophilic porphyrins
have the disadvantage of requiring excipients for in vivo
administration and generally higher liver boron concen-
trations, the advantages are that the tumor boron con-
centrations often reach 100 ppm levels from 200 mg/kg
doses, the kidney boron is lower, and the blood boron
decreases to levels less than 1 ppm, which are 10-fold
lower than those from the water-soluble porphyrins.
Furthermore, serious thrombocytopenia and high mor-
tality have been reported after some water-soluble por-
phyrins have been administered at doses relevant to
BNCT.16
3. Discussion
The failure of the BNCT clinical trials in the 1950s and
1960s was attributed to the lack of selectivity of the bor-
on carriers and the poor quality of the thermal neutron
irradiation.2 The quality of the reactor components has
since been greatly improved by the use of a more pene-
trating epithermal beam and sophisticated moderators
and filters, thus providing a neutron beam of greater
purity. Although the boron carriers BPA and BSH are
a considerable improvement over those used in earlier
clinical trials, the next breakthrough in BNCT will come
from further improvement in the boron carrier. This is
because the maximum allowable dose to tumor is deter-
mined by normal tissue tolerance dose thresholds, which
are, in turn, determined by the biodistribution proper-
ties of the boron carrier.
The octacarboranylporphyrin 18 is considered more lipo-
philic than CuTCPH judging by its longer HPLC reten-
tion time. It appears that no advantage was gained by
the addition of four more carborane moieties in terms
of boron delivery or toxicity per mass of porphyrin. In
fact, mild thrombocytopenia was observed at a dose less
than 100 mg/kg, whereas neither CuTCPH nor CuT-
CPBr had levels of platelets different from solvent-only
controls at double this dose.27 Porphyrin 6 shows tremen-
dous ability in delivering large concentrations of boron to
the EMT-6 carcinoma. Although the weight loss and de-
crease in platelets were significantly different from sol-
vent-only controls at 2 days after administration, their
robust rebound after two more days indicates it was a
mild and reversible toxicity. Porphyrin 8 delivered the
lowest boron concentration to tumor but the differences
between 8, 18, and CuTCPH were not as large as those
between 6 and the remaining three porphyrins (Fig. 1).
Because of the greater polarity of the hydroxyporphyrin
8, its microlocalization in tumor tissue may be consider-
ably different from that of CuTCPH. If distributed more
homogeneously, it could prove more efficacious in BNCT
even at a lower average concentration of boron in tumor.
Since neither mouse body weights nor the platelets were
affected at 118 mg/kg, dose escalation may be possible,
which would enable higher tumor boron concentrations
without serious thrombocytopenia.
The requirements that minimum average boron concen-
tration be >30 lg/g B in tumor tissue and that
tumor:normal tissue boron concentration ratios >5:1
with acceptable toxicity have been met by only a small
fraction of the boron agents synthesized to date. Agents
that are able to deliver tumor boron levels greater than
100 lg/g B are even fewer but, allowing for intra-tumor-
al administration techniques into intracranial gliomas,
such agents include monoclonal antibodies conjugated
with boronated dendrimers29 and water-soluble porphy-
rins.30 Porphyrin 6, described herein, as well as other
lipophilic porphyrins27 and BPA31 have also delivered
boron concentrations >100 lg/g B to various tumors
but serial ip injections or iv infusions were used rather
than intra-tumoral injection. However, of the latter,
only BPA could deliver such high concentrations to
intracranial gliomas as it appears to be difficult for com-
pounds greater than 500 Da such as porphyrins to accu-
mulate in malignancies within brain tissues even with
their blood–brain barriers disrupted.
4. Conclusions
Three new carboranylporphyrins have been synthesized
as potential 10B carriers for BNCT. Of the three, por-
phyrins 6 and 8 are the most promising as possibly supe-
rior to CuTCPH given their robust tumor boron
delivery, their equally low toxicity, and their similarly
thorough blood clearances.
Nevertheless, among the various categories of boron
carriers, porphyrins remain as one of the more promis-
ing due primarily to their long retention time, high affin-
ity for a variety of types of tumors, and substantial
clearance from the blood. Within the porphyrin catego-
ry, a number of porphyrins have been synthesized with
variable polarities, although most porphyrins synthe-
sized for BNCT are water-soluble.13,18,19 On one end
are lipophilic porphyrins such as CuTCPH15 and CuT-
CPBr27 and on the other end are highly polar, water-sol-
uble porphyrins such as VCDP32 and DCPK,33,34 which
use anionic nido-carboranes instead of neutral closo-car-
5. Experimental
5.1. Animals
All in vivo experiments were approved by the Brookha-
ven National Laboratory Institutional Animal Care and
Use Committee. Food and water were provided ad libi-

5088
H. Wu et al. / Bioorg. Med. Chem. 14 (2006) 5083–5092
tum. Subcutaneous (sc) EMT-6 tumors were initiated on
the dorsal thorax of 18–22 g BALB/c mice (Taconic
Farms, Germantown, NY) using single-cell suspensions
of 2.5 · 105 cells in 0.05–0.10 mL culture medium.
EMT-6 tumor cells were grown in vivo and in vitro in
succession.35 Single-cell monolayers were prepared from
mouse-grown tumors by trypsinization, expanded in al-
pha MEM with 10% FBS (Gibco BRL Products, Grand
Island, NY) for several passages. Aliquots of the cells in
10% DMSO were frozen in liquid nitrogen for storage
and were thawed and regrown in tissue culture medium
prior to implantation. Porphyrin injections were initiat-
ed 11 days after tumor cell implantation.
silica gel (precoated sheets, 2.5 · 7.5 cm, J. T. Baker
Inc., Phillipsburg, NJ). Reactions were monitored by
TLC and by optical absorption spectroscopy (CARY
50 CONC UV–vis spectrophotometer, Varian Inc., Palo
Alto, CA). 1H NMR spectra were obtained on a Bruker
400 MHz/50 mm UltrashieldTM spectrometer (Rheinstet-
ter, Germany) with tetramethylsilane (TMS) as the
reference and all 13C NMR are proton-decoupled.
Fast-atom bombardment mass spectra (FAB MS) were
obtained at the Mass Spectrometry Facility, State
University of New York at Stony Brook, NY. All
reagents were purchased from Aldrich Chemical Co.
(Milwaukee, WI) unless otherwise stated and used
without further purification. Decaborane was purchased
from Strem Chemicals (Newburyport, MA).
5.2. Porphyrin administration
Tumor-bearing mice were given porphyrins 6 and 8 in
six ip injections at 3/day (within 8 h) over a period of
2 days using a volume of 0.01 mL/g body weight per
injection. Those given porphyrin 18 were given three
ip injections within 8 h. Mice given any of the three por-
phyrins were euthanized 2 or 4 days after the last
injection.
Standard work-up of a reaction product consisted of
dilution of the reaction mixture or evaporated residue
with dichloromethane (DCM), washing of the organic
layer with water three times, drying over anhydrous
Na2SO4, MgSO4, or K2CO3, and rotary evaporation
of solvents.
HPLC column: Phenomenex Prodigy 5l, ODS3, 100A,
150 · 4.6 mm, 5 lm particle size.
5.3. Euthanasia and necropsy
Under deep Halothane inhalation anesthesia leading to
euthanasia, right ventricular blood (0.2–0.5 mL total)
was put into a MicrotainerTM (Becton–Dickinson, Ruth-
erford, NJ) tube containing EDTA for hematological
analyses, which was subsequently used for boron analy-
ses. Tumor, brain, muscle, and liver were sampled at
necropsy for boron analyses.
HPLC system: Hewlett Packard HP 1050; software: LC
ChemStation revision A.06.04.
Detector: diode array detector; wavelength: 463 nm;
4 nm bandwidth (reference: 599 nm, 2 nm bandwidth).
Solvent flow rate: 1 mL/min. Solvent system: acetoni-
trile/methanol gradient 50:50–0:100 in 15–35 min to
50:50 in 40 min.
5.4. Boron analyses
5.7. Preparation of Cremophor EL/propylene glycol
emulsion
Direct current plasma-atomic emission spectroscopy
(DCP-AES) (ARL/Fisons Model SS-7) was used to as-
say boron (detection limit: 0.1 lg B/mL). Samples from
individual mice (50–130 mg) were digested at 60 ꢁC with
sulfuric acid/nitric acid (1:1). Triton X-100 and water
were added to give final concentrations of ꢀ50 mg tis-
sue/mL, 15% total acid v/v, and 5% Triton X-100 v/v.
Tissue samples were analyzed from individual mice.
Boron concentrations of injection solutions were
determined by prompt c-ray spectroscopy,36 which
was carried out at the Massachusetts Institute of
Technology Reactor Prompt-Gamma Neutron Activa-
tion Facility.
To prepare a solution of ꢀ2.9 mg/mL porphyrin in 9%
Cremophor EL (CRM) and 18% propylene glycol
(PRG), the porphyrin was dissolved in tetrahydrofuran
(THF) (1.5% of the total volume) and then heated at
40 ꢁC for 15 min.28 CRM (9% of total volume) was then
added and the mixture was heated to 60 ꢁC for 2 h
removing most if not all the THF. After cooling to room
temperature, PRG (18% of total volume) was added,
followed by slow dropwise addition of saline (71.5% of
total volume) with rapid stirring. The solution was de-
gassed by stirring under vacuum (ꢀ30 mmHg) for 30–
60 min and then filtered (Millipore, 8 lm).
5.5. Blood analyses
5.8. 3-Methoxy-4-propargyloxybenzyl alcohol
Hematologic assays were carried out at BNL using a
VetScan HMT Hematology Analyzer (Abaxis, Sunny-
vale, CA). Mice were weighed daily and necropsies were
carried out promptly after euthanasia.
Finely powdered K2CO3 (10.4 g, 0.075 mol), KI (9.1 g,
0.060 mol), and acetone (150 mL) were stirred at room
temperature as 3-methoxy-4-hydroxybenzyl alcohol, 1
(7.71 g, 0.050 mol) and propargyl chloride (4.10 g,
0.055 mol) were added. The mixture was stirred at reflux
for approximately 2 days. The reaction was monitored
by TLC, which showed no starting material at this time.
The solution was first filtered and then worked up using
standard method. The organic layer was purified using a
2-cm silica pad eluting with DCM. The solvents were
5.6. Chemicals and procedures
Melting points were measured on a Mel-Temp II appa-
ratus and are uncorrected. Silica gel (200–400 mesh) was
used for chromatography. Analytical thin-layer chroma-
tography (TLC) was performed using Baker-flex F254

H. Wu et al. / Bioorg. Med. Chem. 14 (2006) 5083–5092
5089
1
removed leaving a colorless liquid (9 g, 94% yield). H
NMR (CDCl3) d ppm: 2.49 (t, 1H, C„CH); 2.57 (s,
1H, OH); 3.81 (s, 3H, OCH3); 4.55 (d, 2H, CH2C„C);
6.83 (m, 1H, ArH); 6.89 (m, 1H, ArH); 6.94 (m, 1H,
ArH). 13C NMR (CDCl3) d ppm: 55.8 (ArOCH2); 56.8
(CH3); 64.8 (ArCH2); 75.8 (C„CH); 78.5 (C„CH);
110.2 (ArC); 114.3 (ArC); 119.0 (ArC); 135.2 (ArC);
146.0 (ArC); 149.7 (ArC). C11H12O3 requires 192.20
MS (FAB) m/e 192.1 (M+).
solvents, the residue was worked up leaving a yellow oil,
which was purified using a silica pad with DCM as eluent,
and yielded a clear oil, which crystallized upon standing
(3.5 g, 99% yield). 1H NMR (CDCl3) d ppm: 1.5–3.0 (br
m, 10H, BH); 3.39 (s, 3H, OCH3); 3.85 (s, 2H, CH2-carbo-
rane); 4.33 (s, 1H, CH); 4.39 (s, 2H, ArCH2OH); 6.85 (m,
2H, ArH); 6.92 (m, 1H, ArH). 13C NMR (CDCl3) d ppm:
55.9 (ArOCH3); 58.0 (OCH3); 58.3 (ArCH2); 71.7
(–CCHB10H10); 74.4 (–CCHB10H10); 112.0 (ArC); 117.0
(ArC); 120.3 (ArC); 134.5 (ArC); 146.4 (ArC); 150.5
(ArC).
5.9. 3-Methoxy-4-propargyloxybenzyl acetate (2)
Acetyl chloride (5.0 g, 0.064 mol) and pyridine37
(20 mL) were cooled in an ice-water bath while stirring
as a solution of 3-methoxy-4-propargyloxybenzylalco-
hol (9.5 g, 0.050 mol) in pyridine (20 mL) was added
dropwise. After the mixture was stirred for 5 h, the reac-
tion mixture was poured into conc. HCl/ice and worked
up extracting with DCM. The resulting oily residue was
crystallized using hot 95% ethanol, to yield a yellowish
5.12. 3-Methoxy-4-o-carboranylmethoxybenzaldehyde (4)
Pyridinium chlorochromate (PCC) (2.4 g, 11 mmol) was
stirred in DCM (25 mL) in an ice bath. A solution of 3-
methoxy-4-o-carboranylmethoxy benzyl alcohol (1.71 g,
5.5 mmol) in DCM (25 mL) was added dropwise to the
cooled PCC solution. The resulting mixture was stirred
for two hours, at which time TLC showed no starting
material. The black heterogeneous solution was fil-
tered/purified through a 2-cm silica pad, and gave an
off-white solid, which was recrystallized in 95% ethanol
to yield pale yellow solid (1.4 g, 85% yield). Mp: 146–
1
solid (9.2 g, 79%). Mp 69–71 ꢁC. H NMR (CDCl3) d
ppm: 2.09 (s, 3H, CH3); 2.50 (t, 1H, C„CH); 3.89 (s,
3H, CH3); 4.76 (d, 2H, CH2C„C); 5.05 (s, 2H, ArCH2);
6.92 (s, 1H, ArH); 6.93 (m, 1H, ArH); 7.01 (d, 1H,
ArH). 13C NMR (CDCl3) d ppm: 21.2 (CH3); 56.1 (Ar-
OCH2); 56.9 (OCH3); 66.6 (ArCH2); 76.0 (C„C); 78.6
(C„C); 112.4 (ArC); 114.3 (ArC); 121.1 (ArC); 130.0
(ArC); 147.0 (ArC); 149.8 (ArC); 171.0 (CO).
C13H14O4 requires 234.25 MS (FAB) m/e 234.6 (M+).
1
147 ꢁC. H NMR (CDCl3) d ppm: 1.5–3.0 (br m, 10H,
BH); 3.92 (s, 3H, OCH3); 4.28 (s, 1H, CH2CCHB10H10);
4.51 (s, 2H, CH2CCHB10H10); 6.92 (s, 1H, ArH); 7.44
(m, 2H, ArH); 9.88 (s, 1H, CHO). 13C NMR (CDCl3)
d
ppm: 56.2 (ArOCH2); 58.1 (OCH3); 70.6
(–CCHB10H10); 71.4 (–CCHB10H10); 110.3 (ArC);
114.4 (ArC); 126.0 (ArC); 132.3 (ArC); 150.6 (ArC);
190.9 (CO). C11H20O3B10 requires 308.4 MS (FAB) m/
e 309.7 (M+1)+.
5.10. 3-Methoxy-4-o-carboranylmethoxybenzyl acetate
(3)
Decaborane (2.07 g, 0.017 mol) was dissolved in toluene
(100 mL) under an argon atmosphere at room tempera-
ture as acetonitrile (2.1 mL, 0.040 mol) was added and
the mixture was allowed to stir for 3 h. Acetate (2)
(3.82 g, 0.0163 mol) was added and the mixture was
heated at 80–90 ꢁC for 3 days, after which TLC showed
no presence of starting material. The excess decaborane
was decomposed by the slow addition of methanol
(20 mL) while cooling in an ice-water bath. After the sol-
vents were removed by rotary evaporation, the resulting
residue was dissolved in DCM and worked up washing
first with saturated bicarbonate solution followed by
water. The resulting solid was recrystallized in DCM/
hexanes (1:1) yielding a white microcrystalline solid
Alternative method: Equimolar amounts of 3-methoxy-
4-o-carboranylmethoxy benzyl alcohol and 2,3-dichlo-
ro-5,6-dicyano-1,4-benzoquinone (DDQ)23 were stirred
in dioxane for 1 h. The solvent was then removed by
rotary evaporation. DCM was then added to selectively
extract the product. The insoluble DDQH2 side-product
was removed by filtration. Rotary evaporation of the
resulting filtrate yielded the final product.
5.13. meso-5,10,15,20-Tetrakis[3-methoxy-4-o-carbora-
nylmethoxyphenyl] porphyrin (5)
A solution of benzaldehyde (4) (50 mg, 0.162 mmol) and
freshly distilled pyrrole (11.3 lL, 0.162 mmol) in anhy-
drous DCM (40 mL) was purged with argon for
20 min. Trifluoroacetic acid (TFA) (5.4 lL, 0.045 mmol)
was added and the mixture was allowed to stir under ar-
gon overnight. DDQ (34 mg, 0.149 mmol) was then add-
ed, which immediately turned the solution very dark,
and the solution was stirred at reflux for 1 h. The prod-
uct was then purified by flash chromatography using
silica and 50% hexane/DCM yielding a purple solid
1
(3.48 g, 60% yield). Mp 84–85 ꢁC. H NMR (CDCl3) d
ppm: 1.5–3.0 (br m, 10H, BH); 2.00 (s, 3H, CH3); 3.76
(s, 3H, OCH3); 4.29 (s, 1H, CH); 4.54 (s, 2H,
OCH2CCHB10H10); 4.95 (s, 2H, ArCH2); 6.74 (m, 2H,
ArH); 7.17 (s, 1H, ArH). 13C NMR (decoupled, CDCl3)
d ppm: 21.1 (OCH3); 56.0 (ArOCH2); 58.0 (OCH3); 66.4
(ArCH2); 71.6 (–CCHB10H10); 72.1 (–CCHB10H10);
112.8 (ArC); 116.8 (ArC); 121.2 (ArC); 132.0 (ArC);
146.8 (ArC); 150.4 (ArC); 171.0 (CO). C13H24B10O4
requires 352.44 MS (FAB) m/e 352.8 (M+).
1
(15 mg, 31% yield). H NMR (CDCl3) d ppm: À2.77
(s, 2H, NH); 1.5–3.0 (br m, 40H, BH); 3.94 (s, 12H,
OCH3); 4.50 (s, 4H, CHB10H10); 4.74 (s, 8H,
CH2CCHB10H10); 7.21 (d, 4H, ArH); 7.72 (d, 4H,
ArH); 7.77 (s, 4H, ArH); 8.85 (s, 8H, pyrrole-H).
C60H86N4O8B40 requires 1423.8, MS (FAB) m/e 1424.7
(M+H)+. UV–vis (DCM) kmax (nm): 423, 517, 554,
5.11. 3-Methoxy-4-o-carboranylmethoxybenzyl alcohol
To a solution of acetate (3) (4.0 g, 11 mmol) in methanol
(50 mL) concentrated HCl (2 mL) was added and the mix-
ture was allowed to stir at reflux for 3 h. After removal of

5090
H. Wu et al. / Bioorg. Med. Chem. 14 (2006) 5083–5092
593, and 648. C60H86N4O8B40 requires 1423.8, MS
evaporated down to dryness, the residue was worked
up leaving a pale yellow oil, which solidified upon stand-
ing to give 5.7 g in 88% yield. Mp 79–80 ꢁC; H NMR
(CDCl3) d ppm: 2.52 (t, 2H, C„CH); 2.15 (br s, 1H,
hydroxyl); 4.65 (d, 4H, ArOCH2); 4.60 (s, 2H, ArH2);
6.52 (s, 1H, ArH); 6.60 (s, 2H, ArH). 13C NMR (CDCl3)
d ppm: 56.1 (ArOCH2); 65.1 (ArCH2); 75.9 (C„C); 78.6
(C„C); 101.6 (ArC); 106.4 (ArC); 143.8 (ArC); 159.0
(ArC). C13H12O3 requires 216.4, MS (FAB) m/e 217.5
(M+H)+.
(FAB) m/e 1424.7 (M+H)+.
1
5.14. Copper meso-5,10,15,20-tetrakis[3-methoxy-4-o-
carboranylmethoxyphenyl] porphyrin (6)
A solution of Cu(OAc)2ÆH2O (20 mg, 100 mmol) in
methanol (5 mL) was added to a solution of porphyrin
(5) (130 mg, 91 mmol) in DCM (10 mL) and the mixture
was stirred for 20 min, after which time TLC showed
completion of reaction. After the solvents were re-
moved, the resulting residue was worked up leaving a
red solid, which was then dissolved in DCM and purified
using a silica pad eluting with hexane/DCM (1:1). The
The above 3,5-dipropargyloxybenzyl alcohol (5.7 g,
0.026 mol) was stirred in acetic anhydride (5.4 g,
0.053 mol) as concentrated sulfuric acid (two drops)
was added and the solution was stirred for 3 h at
90 ꢁC. After cooling to room temperature, the solution
was poured into ice water, neutralized with a saturated
sodium carbonate solution and the product was worked
up, leaving a yellow oil, which was purified by recrystal-
lization in ethanol to give a pale yellow compound (5.2 g
solvents were removed leaving red porphyrin
6
(132 mg, 98% yield). C60H84N4O8B40Cu requires
1485.29, MS (FAB) m/e 1486.3 (M+H)+. UV–vis
(DCM) kmax (nm): 418, 542.
5.15. meso-5,10,15,20-Tetrakis[3-hydroxy-4-o-carbora-
nylmethoxyphenyl] porphyrin (7)
1
in 76% yield). Mp 65–66 ꢁC. H NMR (CDCl3) d ppm:
2.11 (s, 3H, CH3); 2.54 (t, 2H, C„CH); 4.67 (d, 4H, Ar-
OCH2); 5.05 (s, 2H, ArCH2); 6.58 (s, 1H, ArH); 6.61 (s,
2H, ArH). 13C NMR (CDCl3) d ppm: 21.3 (CH3); 56.0
(ArOCH2); 66.2 (ArCH2); 76.2 (C„C); 78.6 (C„C);
102.3 (ArC); 108.0 (ArC); 138.8 (ArC); 159.0 (ArC);
171.1 (CO). C15H14O4 requires 258.3, MS (FAB) m/e
259.5 (M+H)+.
Porphyrin 5 (44 mg, 0.031 mmol) was stirred in dry
DCM (15 mL) under argon at room temperature while
BBr3 (1.0 mmol of a 1 M solution in DCM) was added
and the solution was allowed to stir for 30 min.24 At this
time an ice-cold saturated aqueous sodium bicarbonate
or dilute ammonium hydroxide solution (ꢀ10 mL) was
added to hydrolyze the porphyrin borate and to destroy
excess BBr3. The product was worked up and the result-
ing green solution was purified with a silica pad eluting
with acetone/methanol (5:1 v/v) solvent mixture. A red-
5.18. 3,5-Di-o-carboranylmethoxybenzyl acetate (10)
Decaborane (2.70 g, 0.022 mol) was dissolved in dry tol-
uene (80 mL) and stirred at room temperature under a
nitrogen atmosphere. Acetonitrile (12 mL, 0.22 mol)
was added and the solution was allowed to stir for 3 h.
1
dish brown solid was obtained in 91% yield (38 mg). H
NMR (CDCl3) d ppm: À2.88 (s, 2H, NH); 1.5–3.0 (br
m, 40H, BH); 4.04 (s, 4H, CHB10H10); 4.71 (s, 8H,
CH2CCHB10H10); 5.64 (s, 4H, ArOH); 7.10 (s, 4H,
ArH); 7.63 (s, 4H, ArH); 7.77 (s, 4H, ArH); 8.82 (s,
8H, pyrrole-H). UV–vis (acetone) kmax (nm): 420, 513,
549, 591, 648. C56H78N4O8B40 requires 1367.7, MS
(FAB) m/e 1368.0 (M+).
A
solution comprised of compound
9
(2.84 g,
0.011 mol) in toluene (80 mL) was added to the decabo-
rane solution. The rest of the procedure was similar to
that for compound 3. The resulting yellow oil solidified
upon standing yielding 4.40 g in 81% yield. Mp 122–
1
123 ꢁC. H NMR (CDCl3) d ppm: 1.5–3.0 (br m, 20H,
5.16. Copper meso-5,10,15,20-tetrakis[3-hydroxy-4-o-
carboranylmethoxyphenyl] porphyrin (8)
BH); 2.12 (s, 3H, CH3); 4.06 (s, 2H, CCHB10H10); 4.39
(s, 4H, ArOCH2); 5.01 (s, 2H, ArCH2); 6.32 (s, 1H,
ArH); 6.52 (s, 2H, ArH). 13C NMR (CDCl3) d ppm:
21.4 (CH3); 58.3 (ArOCH2); 65.8 (ArCH2); 69.6
(–CCHB10H10); 71.5 (–CCHB10H10); 102.3 (ArC);
108.5 (ArC); 139.8 (ArC); 158.6 (ArC); 171.0 (CO).
C15H34O4B20 requires 494.6, MS (FAB) m/e 496.0
(M+H)+.
Porphyrin 7 (50 mg, 36 mmol) and Cu(OAc)2ÆH2O
(8 mg, 40 mmol) were dissolved in methanol (10 mL)
and stirred for 20 min during which time the color
turned red. After the solvent was removed, the resulting
residue was worked up, leaving a red compound, which
was purified using a silica pad eluting with a solvent
mixture of hexane/DCM/acetone (3:1:1, v/v/v). The por-
phyrin (36 mg) was isolated in 70% yield. UV–vis (ace-
tone) kmax (nm): 417, 534. C56H78N4O8B40Cu requires
1429.2, MS (FAB) m/e 1428.0 (MÀ1)+.
5.19. 3,5-Di-o-carboranylmethoxybenzyl alcohol (11)
The hydrolysis conditions using methanol and HCl were
carried out in a procedure similar to that used to hydro-
lyze compound 3. A white solid was obtained (3.4 g) in
1
5.17. 3,5-Dipropargyloxybenzyl acetate (9)
93% yield. Mp 267–269 ꢁC. H NMR (CDCl3) d ppm:
1.5–3.0 (br m, 20H, BH); 2.54 (br s, 1H, OH); 4.04 (s,
2H, CCHB10H10); 4.40 (s, 4H, ArOCH2); 4.65 (s, 2H,
ArCH2); 6.28 (s, 1H, ArH); 6.54 (s, 2H, ArH). 13C
NMR (CDCl3) d ppm: 58.0 (ArOCH2); 64.7 (ArCH2);
69.4 (–CCHB10H10); 71.3 (–CCHB10H10); 101.5 (ArC);
106.6 (ArC); 144.7 (ArC); 158.5 (ArC). C13H32O3B20
requires 452.6, MS (FAB) m/e 453.0 (M+).
Finely powdered K2CO3 (14 g, 0.10 mol) and KI (17 g,
0.10 mol) were stirred in acetone (200 mL) under a
nitrogen atmosphere. 3,5-Dihydroxybenzyl alcohol
(4.2 g, 0.030 mol) and propargyl chloride (5.3 g,
0.070 mol) were added and mixture was allowed to stir
at reflux overnight. After the solution was filtered and

H. Wu et al. / Bioorg. Med. Chem. 14 (2006) 5083–5092
5091
5.20. 3,5-Di-o-carboranylmethoxybenzaldehyde (12)
(s, 2H, CCHB10H10); 4.42 (s, 4H, ArOCH2); 5.00 (s, 2H,
ArCH2O); 6.33 (s, 1H, ArH); 6.61 (s, 2H, ArH); 7.23 (s,
1H, ArH); 7.44 (m, 1H, ArH); 7.50 (m, 2H, ArH); 9.98
(s, 1H, CHO). 13C NMR (CDCl3) d ppm: 58.0
(CH2CCHB10H10); 69.5 (–CCHB10H10); 69.7 (ArCH2-
OAr); 71.2 (–CCHB10H10); 102.0 (ArC); 107.4 (ArC);
112.8 (ArC); 122.4 (ArC); 124.8 (ArC); 130.6 (ArC);
138.1 (ArC); 138.4 (ArC); 140.3 (ArC); 158.6 (ArC);
192.1 (CHO). C20H36O4B20 requires 556.7, MS (FAB)
m/e 558.0 (M+H)+.
The oxidation of alcohol 11 was carried out in a proce-
dure similar to that used to synthesize 5. Aldehyde 12
was obtained in 70% yield (0.70 g). H NMR (CDCl3)
1
d ppm: 1.5–3.0 (br m, 20H, BH); 4.0 (s, 2H, carborane
CH); 4.5 (s, 4H, OCH2); 6.7 (s, 1H, p-ArH); 7.0 (s,
2H, o-ArH); 9.9 (s, 1H, CHO).
5.21. 3,5-Di-o-carboranylmethoxylbenzyl bromide (14)
Carboranylbenzyl alcohol 11 (0.45 g, 1.0 mmol) and
CBr4 (0.40 g, 1.2 mmol) were dissolved in dry THF
(2 mL) under an argon atmosphere. Triphenylphosphine
(0.31 g, 1.2 mmol) was added and the resulting mixture
was allowed to stir for 20 min.24 The mixture was then
poured into water, worked up, and purified using a silica
pad and DCM/hexane (1:1) as eluent. After solvent
evaporation, a white solid (0.48 g) was obtained in
5.24. meso-5,10,15,20-Tetrakis[m-(3,5-di-o-carboranyl-
methoxybenzyloxy)phenyl] porphyrin (17)
Compound 16 (337 mg, 0.60 mmol), anhydrous DCM
(100 mL), and freshly distilled pyrrole (420 lL,
0.60 mmol) were sequentially transferred to a dry
300 mL round-bottomed flask. The solution was purged
with nitrogen for 15–20 min. BF3ÆEt2O (76 lL,
0.060 mmol) was then added and the solution was al-
lowed to stir overnight. DDQ (150 mg, 0.60 mmol)
was added and the solution was stirred at reflux for
one hour. The major product was then purified using a
silica pad followed by column chromatography using
DCM/petroleum ether (1:1) as eluent, yielding a dark
1
92% yield. Mp 230–232 ꢁC. H NMR (CDCl3) d ppm:
1.5–3.0 (br m, 20H, BH); 4.02 (s, 2H, CCHB10H10);
4.37 (s, 2H, CH2Br); 4.39 (s, 4H, ArOCH2); 6.26 (s,
1H, ArH); 6.55 (s, 2H, ArH). 13C NMR (CDCl3) d
ppm:
32.4
(CH2Br);
58.0
(ArOCH2);
69.5
(–CCHB10H10); 71.1 (–CCHB10H10); 102.3 (ArC);
109.2 (ArC); 141.2 (ArC); 158.4 (ArC). C13H31O2B20Br
requires 515.5, MS (FAB) m/e 516.9 (M+H)+.
1
purple solid (78 mg) in 22% yield. H NMR (CDCl3) d
ppm: À2.84 (s, 2H, NH); 1.5–3.0 (br m, 80H, BH);
3.97 (s, 8H, CCHB10H10); 4.35 (s, 16H, ArOCH2); 5.19
(s, 8H, ArCH2); 6.31 (s, 4H, ArH); 6.65 (s, 8H, ArH);
7.40 (s, 4H, ArH); 7.70 (m, 4H, ArH); 7.79 (m, 4H,
ArH); 7.86 (m, 4H, ArH); 8.84 (s, 8H, pyrrole-H).
UV–vis (DCM) kmax (nm): 420, 516, 550, 589, and
645. C96H150N4O12B80 requires 2417.1, MS (FAB) m/e
2418.2 (M+H)+.
5.22. 3-(3,5-Di-o-carboranylmethoxybenzyloxy)benzyl
alcohol (15)
K2CO3 (1.0 g, 7.2 mmol), KI (1.0 g, 6.0 mmol), com-
pound 14 (0.41 g, 0.80 mmol), and 3-hydroxybenzylal-
cohol (0.10 g, 0.81 mmol) were stirred in acetone
(20 mL) and allowed to stir at reflux for 1 day under
an argon atmosphere. After cooling, the solvent was re-
moved and the residue was worked up. The residue was
purified on a silica pad eluting with DCM/hexane (1:1)
and a white solid was obtained (0.59 g) in 79% yield.
5.25. Copper meso-5,10,15,20-tetrakis[m-(3,5-di-o-carb-
oranylmethoxybenzyloxy)phenyl] porphyrin (18)
A solution of Cu(OAc)2ÆH2O (6 mg, 0.030 mmol) in
methanol (5 mL) was added to a solution of porphyrin
17 (60 mg, 0.025 mmol) in DCM (20 mL) and allowed
to stir for 20 min. After work-up, the resulting residue
was purified by a silica column using DCM/petroleum
ether (1:1, v/v) as eluent, to yield a red porphyrin
(57 mg, 92% yield). UV–vis (DCM) kmax (nm): 416,
539. C96H148N4O12B80Cu requires 2478.6, MS (FAB)
m/e 2479.9 (M+H)+.
1
Mp 259–261 ꢁC. H NMR (CDCl3) d ppm: 1.5–3.0 (br
m, 20H, BH); 1.70 (s, 1H, OH); 4.04 (s, 2H,
CCHB10H10); 4.40 (s, 4H, CH2CCHB10H10); 4.67 (s,
2H, ArCH2OH); 5.00 (s, 2H, ArCH2OAr); 6.31 (s, 1H,
Ar); 6.60 (s, 2H, ArH); 6.87 (m, 1H, ArH); 7.00 (m,
2H, ArH); 7.26 (m, 1H, ArH). 13C NMR (CDCl3) d
ppm: 58.2 (CH2CCHB10H10); 65.5 (ArCH2OH); 69.6
(–CCHB10H10); 71.4 (–CCHB10H10); 102.0 (ArC);
107.4 (ArC); 113.6 (ArC); 114.3 (ArC); 120.2 (ArC);
130.2 (ArC); 141.2 (ArC); 143.1 (ArC); 158.7 (ArC);
158.8 (ArC). C20H38O4B20 requires 558.7, MS (FAB)
m/e 559.0 (M+).
Acknowledgments
The authors thank Daniel Slatkin for useful comments.
The work described was supported by the U.S. Depart-
ment of Energy Office of Biological and Environmental
Research (Contract No. DE-AC02-98CH10886).
5.23. 3-(3,5-Di-o-carboranylmethoxybenzyloxy)benzalde-
hyde (16)
Pyridinum chlorochromate (PCC) (0.172 g, 0.80 mmol)
in DCM (10 mL) was cooled in an ice water bath. To
this a solution of 15 (0.223 g. 0.40 mmol) in DCM
(10 mL) was added dropwise and the mixture was al-
lowed to stir for 2 h. The major product was purified
using a silica pad. After the removal of solvents, a white
solid was obtained, 0.220 g, 99% yield. Mp 263–265 ꢁC.
1H NMR (CDCl3) d ppm: 1.5–3.0 (br m, 20H, BH); 4.04
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