Multigram synthesis of a water-soluble porphyrazine and derived seco-porphyrazine labeling agents

Article abstract of DOI:10.1021/ol702481x

(Chemical Equation Presented) Porphyrazine III has been synthesized on a large scale (18.4 g), with minimal chromatographic purification by employing a novel one-pot, 3-step sequence. Two dinitrile precursors I and II, the latter of which consisted of a m

Full text of DOI:10.1021/ol702481x

ORGANIC
LETTERS
2007
Vol. 9, No. 25
5291-5294
Multigram Synthesis of a Water-Soluble
Porphyrazine and Derived
seco-Porphyrazine Labeling Agents
Xavier Guinchard,† Matthew J. Fuchter,† Andrea Ruggiero,† Brian J. Duckworth,†
Anthony G. M. Barrett,*†, and Brian M. Hoffman*,‡
Department of Chemistry, Imperial College London, London SW7 2AZ, England, and
Department of Chemistry, Northwestern UniVersity, EVanston, Illinois 60208
agm.barrett@imperial.ac.uk
Received October 11, 2007
ABSTRACT
Porphyrazine III has been synthesized on a large scale (18.4 g), with minimal chromatographic purification by employing a novel one-pot,
3-step sequence. Two dinitrile precursors I and II, the latter of which consisted of a mixture of geometric isomers, were transformed, via the
corresponding pyrroline diimines, into a mixture of III and the octa-Ar1-porphyrazine. Isolated macrocycle III was subsequently transformed
into IV, a water-soluble seco-porphyrazine suitable for the labeling of biological vectors.
Photodynamic therapy1 (PDT) is a noninvasive cancer
treatment that uses a combination of visible light and a
photosensitizing drug.2 Following internalization of the
photosensitizer in tumor cells, irradiation generates localized
singlet oxygen, which may destroy the cancer.3,4 Suitable
photosensitizers for PDT include both porphyrins5 and
tetraazaporphyrins; the former class incorporates Photofrin,
the first approved photochemical drug used for cancer
therapy.3 Porphyrins and tetraazaporphyrins are topologically
related and differ by only the presence of meso-nitrogen
atoms within the ligand framework. Tetraazaporphyrins can
be further divided into phthalocyanines6 and porphyrazines7
(Pz). Vicinal diaminoporphyrazines readily undergo oxidative
ring scission of the R2NCdCNR2 unit to provide the
corresponding seco-porphyrazines. These macrocyclic com-
pounds, as well as porphyrazines in general, may be of use
† Imperial College London.
‡ Northwestern University.
(1) For general literature on PDT, see: Dougherty, T. J.; Levy, J. G. In
CRC Handbook of Organic Photochemistry and Photobiology, 2nd ed.;
Horspool, W., Lenci, F., Eds.; CRC Press: Boca Raton, FL, 2004; pp 147/
117-147/141.
(2) For general applications of optical agents in detection of tumors,
see: (a) Jiang, H.; Iftimia, N. V.; Xu, Y.; Eggert, J. A.; Fajardo, L. L.;
Klove, K. L. Acad. Radiol. 2002, 9, 186. (b) Weissleder, R.; Ntziachristos,
V. Nat. Med. 2003, 9, 123. (c) Sevick-Muraca, E. M.; Godavarty, A.;
Houston, J. P.; Thompson, A. B.; Roy, R. In Handbook of Biomedical
Fluorescence; Pogue, B.W., Mycek, M., Eds.; Marcel Dekker:New York,
2003; pp 445-527.
(3) For general applications of optical agents on treatment of tumors,
see: (a) Kessel, D.; Dougherty, T. J. ReV. Contemp. Pharmacother. 1999,
10, 19. (b) Bonnett, R. ReV. Contemp. Pharmacother. 1999, 10, 1. (c)
Dolmans, D. E. J. G. J.; Fukumura, D.; Jain, R. K. Nat. ReV. Cancer 2003,
3, 380. (d) Jori, G. In CRC Handbook of Organic Photochemistry and
Photobiology, 2nd ed.; Horspool, W., Lenci, F., Eds.; CRC Press: Boca
Raton, FL, 2004; pp 146/110-146/141.
(4) Brown, S. B.; Brown, E. A.; Walker, I. Lancet Oncol. 2004, 5, 497.
(5) The Porphyrins; Dolphin, D., Ed.; Academic Press: New York,
1978-1979; Vols. 1-7.
(6) Phthalocyanines: Properties and Applications; Leznoff, C. C., Lever,
A. B. P., Eds.; VCH Publishers: Weinheim, Germany, 1989-1996; Vols.
1-4.
(7) (a) Michel, S. L. J.; Hoffman, B. M.; Baum, S. V.; Barrett, A. G. M.
Peripherally-Functionalized Porphyrazines: Novel Metallomacrocycles with
Broad, Untapped Potential. In Progress in Inorganic Chemistry; Karlin, K.
D., Ed.; J. Wiley and Sons: New York, 2001; p 473. (b) Montalban, A.
G.; Baum, S. M.; Barrett, A. G. M.; Hoffman, B. M. J. Chem. Soc., Dalton
Trans. 2003, 2093.
10.1021/ol702481x CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/15/2007

for PDT and biomedical optical imaging8 due to their intense
Q-band in the UV-vis spectrum and, in many cases, excel-
lent singlet oxygen quantum yield9 on photosensitization.
While a number of procedures have been developed
recently for the synthesis of metalated and free-base por-
phyrazines,10 the magnesium ion-templated Linstead mac-
rocyclization11 of acyclic maleonitriles is still the most widely
used method for the preparation of these macrocycles. For
the synthesis of unsymmetrical porphyrazines, the statistical
co-macrocyclization of two different (Z)-dinitriles (repre-
sented by A and B) is currently the only viable method for
their synthesis. This procedure results in the formation of a
mixture of porphyrazines A4Pz, A3BPz, both cis- and trans-
A2B2Pz, AB3Pz, and B4Pz, the ratios of which depend on
the ratios of the precursor dinitriles A and B. Such reactions
are frequently plagued with poor yields and difficulties with
purification. Previously, we have used a ROM-polymeriza-
tion-capture release strategy to tackle this shortcoming.12 In
this paper, we wish to describe the multigram scale synthesis
of an A3B porphyrazine 15 and its application to the synthesis
of the seco-porphyrazine 1 (Figure 1), a current candidate
internalization of dye in cells, (ii) a carboxylic acid moiety,
used for bioconjugation,13 and (iii) the seco functionality,
which provides high singlet oxygen quantum yields.9 We
now report an efficient, concise chromatography-minimized
synthesis via Linstead macrocyclization of pyrroline diimines.
Utilizing the protocol of Sheppard and co-workers, ma-
leonitrile 5 was prepared in three steps from commercially
available diaminomaleonitrile 2 (Scheme 1).14 Heating ma-
Scheme 1
leonitrile 2 in ethanol in the presence of methyl 4-formyl-
benzoate yielded the imine 3, which was reduced with
sodium borohydride in THF and methanol to give the amine
4 in 73% yield over the two steps. Subsequent methylation
with dimethyl sulfate gave maleonitrile 5 in 95% yield.
Maleonitrile 10 was prepared from phenol 6 by alkylation
with chloride 7 to give the alcohol 8 in quantitative yield
(Scheme 2). Following protection of 8 by dihydropyran to
Scheme 2
Figure 1. seco-Porphyrazine photosensitizer.
for PDT studies. Photosensitizer 1 possesses (i) polyethylene
glycol chains, to enhance water solubility and facilitate the
(8) Hammer, N. D.; Lee, S.; Vesper, B. J.; Elseth, K. M.; Hoffman, B.
M.; Barrett, A. G. M.; Radosevich, J. A. J. Med. Chem. 2005, 48, 8125.
(9) (a) Andersen, K.; Anderson, M.; Anderson, O. P.; Baum, S.;
Baumann, T. F.; Beall, L. S.; Broderick, W. E.; Cook, A. S.; Eichhorn, D.
M.; Goldberg, D.; Hope, H.; Jarrell, W.; Lange, S. J.; McCubbin, Q. J.;
Mani, N. S.; Miller, T.; Montalban, A. G.; Rodriguez-Morgade, M. S.; Lee,
S.; Nie, H.; Olmstead, M. M.; Sabat, M.; Sibert, J. W.; Stern, C.; White,
A. J. P.; Williams, D. B. G.; Williams, D. J.; Barrett, A. G. M.; Hoffmann,
B. M. J. Heterocycl. Chem. 1998, 35, 1013. (b) Mani, N. S.; Beall, L. S.;
White, A. J. P.; Williams, D. J.; Barrett, A. G. M.; Hoffman, B. M. J.
Chem. Soc., Chem. Commun. 1994, 1943. (c) Montalban, A. G.; Lange, S.
J.; Beall, L. S.; Mani, N. S.; Williams, D. J.; White, A. J. P.; Barrett, A. G.
M.; Hoffman, B. M. J. Org. Chem. 1997, 62, 9284. (d) Sakellariou, E. G.;
Montalban, A. G.; Meunier, H. G.; Ostler, R. B.; Rumbles, G.; Barrett, A.
G. M.; Hoffman, B. M. J. Photochem. Photobiol. A: Chem. 2000, 136, 185.
(10) (a) Giribabu, L.; Chandrasekharam, M.; Mohan, S. M.; Rao, C. S.;
Kantam, M. L.; Reddy, M. R.; Reddy, P. Y.; Toru, T. Synlett 2006, 1604.
(b) Chandrasekharam, M.; Srinivasa Rao, C.; Surya, P. S.; Lakshmi Kantam,
M.; Ramesh Reddy, M.; Yella Reddy, P.; Toru, T. Tetrahedron Lett. 2007,
48, 2627. (c) Donzello, M. P.; Dini, D.; D’Arcangelo, G.; Ercolani, C.;
Zhan, R.; Ou, Z.; Stuzhin, P. A.; Kadish, K. M. J. Am. Chem. Soc. 2003,
125, 14190.
give 9, oxidative coupling with carbon tetrachloride under
basic conditions15 gave a mixture of maleonitrile Z-10 and
(11) Linstead, R. P.; Whalley, M. J. Chem Soc. 1952, 4839.
(12) (a) Fuchter, M. J.; Vesper, B. J.; Murphy, K. A.; Collins, H. A.;
Philips, D.; Hoffman, B. M.; Barrett, A. G. M. J. Org. Chem. 2005, 70,
2793. (b) Fuchter, M. J.; Hoffman, B. M.; Barrett, A. G. M. J. Org. Chem.
2005, 70, 5086.
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Org. Lett., Vol. 9, No. 25, 2007

fumaronitrile E-10 isolated in 36% and 38% yields, respec-
tively, by chromatography on silica gel. In our hands,
however, this separation could not be easily performed on
more than a 5 g scale since larger scale separations resulted
in partial THP-deprotection and/or degradation. These dif-
ficulties were avoided by using the mixture of geometric
isomers directly in the next step without separation. It is
noteworthy that this three-step sequence could be performed
on a 100 g scale of the starting phenol 6 to provide the
mixture of dinitriles E,Z-10 in 83% (150 g) overall yield.
Scheme 3
As an initial approach to the A3B porphyrazine, dinitriles
5 and Z-10 (1:6 ratio) were co-macrocyclized under Linstead
conditions11 by reflux in n-butanol in the presence of freshly
prepared magnesium butoxide to give the desired transes-
terified A3BPz 14, along with the symmetrical A4Pz 12.
Chromatography on silica gel gave pure A3B 14 in 36%
isolated yield. This method of purification on quantities larger
than 500 mg, however, is prohibitively time-consuming due
to the high polarity and strong aggregation of the macro-
cycles. We consequently sought to develop another strategy
to allow the scale-up of this synthesis. Importantly, any such
procedure would ideally utilize both E- and Z-10 as their
separation is an obvious bottleneck in the synthetic sequence.
It has been reported that Linstead macrocyclization can be
performed with not only Z-dinitriles but also pyrroline
diimines. These latter compounds may be considered as
analogues of the initial intermediates in Linstead macrocy-
clization, and can be obtained by reaction of a dinitrile with
ammonia in the presence of a catalytic amount of sodium in
ethylene glycol.16 Under these reaction conditions, isomer-
ization of either the dinitrile or a subsequent reaction
intermediate occurs meaning both Z and E dinitriles yield
the corresponding, geometrically locked, pyrroline diimine.
Indeed, the reaction of the mixture of dinitriles E,Z-10 with
ammonia in n-butanol or ethylene glycol, at 100 °C, afforded
the corresponding pyrroline diimine 11 (Scheme 3). This
compound, however, is highly polar and although it can be
purified by chromatography, its poor stability renders the
process difficult and subject to low yields. Instead, a one-
pot reaction was developed. The pyrrolidine diimine was
generated in situ, and used directly without isolation in the
crossed Linstead macrocyclization reaction.11,17 The crude
pyrroline 11 was prepared by reaction of dinitriles E,Z-10
with ammonia in anhydrous n-butanol, and the resulting
solution of 11 was directly added to a freshly prepared
solution of magnesium butoxide in n-butanol.
Reflux for 16 h gave the desired symmetrical (A4) Pz 12
(31%). This protocol was applied to the synthesis of the
unsymmetrical A3B porphyrazine 14. Dinitriles E,Z-10 and
5 (7:1 ratio) were heated for 16 h in n-butanol at 95 °C with
a catalytic amount of sodium, under a constant flow of
gaseous ammonia (Scheme 4).16 The mixture of crude
pyrrolines 11 and 13 in butanol was immediately added to a
preformed solution of magnesium butoxide in n-butanol.
After 48 h at reflux, the crude mixture of A4Pz 12 and A3-
BPz 14 was saponified to give a mixture of A3BPz 15,18
A4Pz 12, and minor impurities. Macrocycle 15 could be
purified by chromatography on amberlyst A21 or more
conveniently silica gel, which afforded the acid 15 in 33%
overall yield from dinitrile 5 for the three steps of the
synthesis. This process could be successfully applied to 120
g of starting dinitriles E,Z-10 and 5, providing 18.4 g of
A3BPz 15 after three steps and a single chromatographic
purification. Such a scale is unusual for unsymmetrical
porphyrazines, and these compounds are usually prepared
on a small scale (<500 mg) due to low yields and difficulties
in purification. To complete the synthesis of the potential
PDT photosensitizer 1, the acid 15 was esterified by
n-butanol under Yamaguchi conditions,19 giving ester 14 in
(13) Hudson, R.; Carcenac, M.; Smith, K.; Madden, L.; Clarke, O. J.;
Pelegrin, A.; Greenman, J.; Boyle, R. W. Br. J. Cancer 2005, 92, 1442.
(14) Begland, R. W.; Hartter, D. R.; Jones, F. N.; Sam, D. J.; Sheppard,
W. A.; Webster, O. W.; Weigert, F. J. J. Org. Chem. 1974, 39, 2341.
(15) Irie, M.; Mohri, M. J. Org. Chem. 1988, 53, 803.
(16) For the use of di-iminopyrrolines in the synthesis of unsymmetrical
porphyrazines see: (a) Baumann, T. F.; Barrett, A. G. M.; Hoffman, B. M.
Inorg. Chem. 1997, 36, 5661. (b) Nie, H.; Stern, C. L.; Hoffman, B. M.;
Barrett, A. G. M. Chem. Commun. 1999, 703. (c) Nie, H.; Barrett, A. G.
M.; Hoffman, B. M. J. Org. Chem. 1999, 64, 6791. (d) Vasil’ev, S. I.;
Kulinich, V. P.; Shaposhnikov, G. P.; Smirnov, R. P. Russ. J. Gen. Chem.
1999, 69, 314. (e) Bellec, N.; Montalban, A. G.; Williams, D. B. G.; Cook,
A. S.; Anderson, M. E.; Feng, X.; Barrett, A. G. M.; Hoffman, B. M. J.
Org. Chem. 2000, 65, 1774. (f) Vasil’ev, S. I.; Kulinich, V. P.; Shaposh-
nikov, G. P.; Smirnov, R. P. Russ. J. Gen. Chem. 2000, 70, 304. (g)
Montalban, A. G.; Sakellariou, E. G.; Riguet, E.; McCubbin, Q. J.; Barrett,
A. G. M.; Hoffman, B. M. Inorg. Chim. Acta 2001, 317, 143. (h) Kulinich,
V. P.; Shaposhnikov, G. P. Russ. J. Gen. Chem. 2001, 71, 1632. (i) Zhao,
M.; Zhong, C.; Stern, C.; Barrett, A. G. M.; Hoffman, B. M. Inorg. Chem.
2004, 43, 3377. (j) Khelevina, O. G.; Ferro, V. R.; Islyaikin, M. K.;
Veselkova, E. A.; Stryapan, M. G.; De la Vega, J. M.; Garcia, J. Phys.
Org. Chem. 2005, 18, 329. (k) Cheng, K. F.; Thai, N. A.; Teague, L. C.;
Grohmann, K.; Drain, C. M. Chem. Commun. 2005, 4678. (l) Goslinski,
T.; Zhong, C.; Fuchter, M. J.; Stern, C. L.; White, A. J. P.; Barrett, A. G.
M.; Hoffman, B. M. Inorg. Chem. 2006, 45, 3686. (m) Gan, Q.; Xiong, F.;
Li, S.; Wang, S.; Shen, S.; Xu, H.; Yang, G. Inorg. Chem. Commun. 2005,
8, 285. For an example of the use of di-iminoisoindolines in the synthesis
of unsymmetrical phthalocyanines see: Kobayashi, N.; Higashi, Y.; Osa,
T. J. Chem. Soc., Chem. Commun. 1994, 1785.
(17) It is possible that the macrocyclization reaction involves a sodium
template and late transmetalation; see ref 10c.
(18) A3BPz 15 was obtained in 72% yield when the reaction was
performed with chromatographically purified 14.
(19) (a) Inanaga, J.; Hirata, K.; Katsuki, T.; Yamaguchi, M. A. Bull.
Chem. Soc. Jpn. 1972, 52, 1989. (b) Haslam, E. Tetrahedron 1980, 36,
2409.
Org. Lett., Vol. 9, No. 25, 2007
5293

Scheme 4
89% yield. Subsequent treatment with acetic acid yielded
Acknowledgment. We thank the Royal Society and the
Wolfson Foundation for a Royal Society Wolfson Research
Merit Award (to A.G.M.B.), the Wolfson Foundation for
establishing the Wolfson Center for Organic Chemistry in
Medical Sciences at Imperial College, the EPSRC for
generous support of our research, and Anna M. A. Gonc¸alves
de Oliveira and Sergei Bolshakov (Imperial College London)
for assistance with back-up synthesis.
pure demetalated Pz 16, which was remetalated with zinc
acetate in DMF to give the zinc Pz 17 in 68% global yield.
Exposure to air and light at room temperature in CH2Cl2
gave the seco-Pz 18 (97%).8 Finally, saponification with
NaOH in n-propanol and acidic deprotection of the THP
protecting groups gave the target Pz 1, which could be
purified on lipophilic Sephadex to give 1 (55%).
In conclusion, a large-scale synthesis of a new highly
functionalized, water-soluble seco-porphyrazine has been
achieved. This is a suitable compound for the labeling of
biomolecules for imaging and PDT studies. This synthetic
procedure has allowed the preparation several grams of the
desired Pz 15 in one single reaction sequence in good overall
yield.
Supporting Information Available: Experimental pro-
1
cedures and characterization data for all products and H
NMR and/or 13C NMR spectra of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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Org. Lett., Vol. 9, No. 25, 2007