Swallowtail bacteriochlorins. Lipophilic absorbers for the near-infrared

Article abstract of DOI:10.1021/ol800436u

Bacteriochlorins absorb strongly in the near-infrared spectral region and hence are ideally suited for diverse photomedical applications, yet naturally occurring bacteriochlorins have limited stability and synthetic malleability. A de novo route has been

Full text of DOI:10.1021/ol800436u

ORGANIC
LETTERS
2008
Vol. 10, No. 10
1931-1934
Swallowtail Bacteriochlorins. Lipophilic
Absorbers for the Near-Infrared
K. Eszter Borbas, Christian Ruzié, and Jonathan S. Lindsey*
Department of Chemistry, North Carolina State UniVersity;
Raleigh, North Carolina 27695-8204
jlindsey@ncsu.edu
Received February 26, 2008
ABSTRACT
Bacteriochlorins absorb strongly in the near-infrared spectral region and hence are ideally suited for diverse photomedical applications, yet
naturally occurring bacteriochlorins have limited stability and synthetic malleability. A de novo route has been exploited to prepare synthetic
bacteriochlorins that bear a geminal dimethyl group in each pyrroline ring for stability and a symmetrically branched 1,5-dimethoxypentyl
group attached to each pyrrole ring for solubility in lipophilic media.
The ability to tailor photoactive molecules that absorb near-
infrared (NIR) light is expected to open a number of
diagnostic and therapeutic opportunities in photomedicine,
namely, optical imaging1 and photodynamic therapy (PDT),2
respectively.3 The benefit of NIR light, particularly in the
700-900 nm region, stems from the deep penetration of soft
tissue afforded by light of this frequency.4 Bacteriochloro-
phylls have been regarded as ideal for PDT given their strong
absorption in this spectral region; indeed, the palladium
chelate of a derivative of bacteriochlorophyll a (Tookad, or
WST09) has been used in a variety of studies (Figure 1).5 A
taurine conjugate of a bacteriochlorophyll a derivative also
(1) Licha, K. Top. Curr. Chem. 2002, 222, 1–29.
(2) Juzeniene, A.; Peng, Q.; Moan, J. Photochem. Photobiol. Sci. 2007,
6, 1234–1245.
Figure 1. Naturally derived versus synthetic bacteriochlorins.
(3) Taniguchi, M.; Cramer, D. L.; Bhise, A. D.; Kee, H. L.; Bocian,
D. F.; Holten, D.; Lindsey, J. S. New J. Chem. Published online. DOI:
10.1039/b717803d.
has been prepared upon opening of the isocyclic ring.6
However, more extensive modifications of naturally occur-
ring bacteriochlorophylls have proven difficult given their
susceptibility toward adventitious dehydrogenation (giving
the chlorin or porphyrin)7 and the nearly full complement
of substituents about the perimeter of the macrocycle.8 We
recently developed a de novo synthesis of bacteriochlorins
(4) Dawson, J. B.; Barker, D. J.; Ellis, D. J.; Grassam, E.; Cotterill,
J. A.; Fisher, G. W.; Feather, J. W. Phys. Med. Biol. 1980, 25, 695–709.
(5) (a) Chen, Q.; Huang, Z.; Luck, D.; Beckers, J.; Bru´n, P.-H.; Wilson,
B. C.; Scherz, A.; Salomon, Y.; Hetzel, F. W. Photochem. Photobiol. 2002,
76, 438–445. (b) Weersink, R. A.; Forbes, J.; Bisland, S.; Trachtenberg, J.;
Elhilali, M.; Bru´n, P. H.; Wilson, B. C. Photochem. Photobiol. 2005, 81,
106–113.
10.1021/ol800436u CCC: $40.75
Published on Web 04/18/2008
2008 American Chemical Society

substituent was located at a meso position. Here we describe
the synthesis of bacteriochlorins bearing lipophilic swallow-
tail motifs at the 2,12- or 3,13-positions.19 Such bacterio-
chlorins are of interest for PDT studies, the results of which
will be described elsewhere.
The de novo bacteriochlorin synthesis relies on a dihy-
drodipyrrin that can undergo self-condensation by virtue of
a free R-pyrrole position and an acetal at the R-position of
the pyrroline ring.3,9,20 Introduction of ꢀ-pyrrole substituents
can be achieved via precursors to the pyrrole or by bromi-
nation of the pyrrole employed to prepare the dihydrodipyr-
rin. The route to the swallowtail-substituted dihydrodipyrrin
is modeled on the reported synthesis of p-tolyl-substituted
dihydrodipyrrins, which accordingly required the synthesis
of a swallowtail pyrrole.
Figure 2. Newman projection showing the swallowtail alkyl chains
above and below the plane of a tetrapyrrole macrocycle.
that are stable by virtue of the presence of a geminal dimethyl
group in each reduced ring.9 The bacteriochlorins prepared
previously also contained p-tolyl groups at the 2- and 12-
positions,9,10 or bromo groups at the 3- and 13-positions.3
The latter provided a versatile scaffold for the introduction
of auxochromes (e.g., acetyl, ethynyl, vinyl) at the 3- and
13-positions via a variety of Pd-mediated coupling reactions.
For applications in photomedicine, the ability to tailor the
bacteriochlorin with groups ranging in polarity from lipo-
philic to hydrophilic is desirable for selectively targeting
biological organisms, organelles, or molecules. For lipophilic
architectures, we were drawn to the use of branched alkyl
(i.e., “swallowtail”)11 groups attached directly to the bacte-
riochlorin macrocycle. Swallowtail groups adopt a conforma-
tion wherein alkyl moieties project above and below the face
of the macrocycle (Figure 2), thereby suppressing aggregation
of the macrocycles. The suppression of aggregation is
important for retaining photochemical activity (i.e., fluores-
cence for optical imaging, intersystem crossing, and energy
transfer to oxygen for PDT). Swallowtail groups have been
employed with porphyrins,12–16 chlorins,17 and multipor-
phyrin arrays.18 The swallowtail groups include all-hydro-
carbon units (pent-3-yl,12 tridec-7-yl13,18 ) that afford in-
creased solubility in organic media, and polar-terminated
analogues (e.g., 1,5-diphosphonopent-3-yl) that afford solu-
bility in aqueous media.14–17 In each case, the swallowtail
A swallowtail-substituted pyrrole was prepared via the van
Leusen method,21 which employed swallowtail aldehyde 1
as a precursor. Two aldehydes, bearing methoxy or benzyl-
oxy termini were investigated. The benzyl ether proved
unstable to the final Ti(III)-mediated reductive cyclization
(Supporting Information). Methyl ether-substituted swallow-
tail aldehyde 1 was synthesized from commercially available
bromoethyl methyl ether via one of the two routes shown in
Scheme 1. Aldehyde 1 is a known compound,22 but the only
reported procedure requires five steps and a 20-fold excess
of the costly bromoethyl methyl ether. Route A follows
reported procedures for the synthesis of symmetrically
branched aldehydes23 and entails deprotonation of acetonitrile
with LDA followed by dialkylation with bromoethyl methyl
ether. The product after column chromatography contained
small amounts of monoalkylated and trialkylated nitriles;
reduction of this material with DIBALH followed by
chromatography afforded 1 in pure form. Route B employs
commercially available 4-methoxybutanol as the starting
material. Swern oxidation24 followed by treatment of the
crude product with cyclohexylamine and subsequent Kugel-
rohr distillation gave imine 3 in 89% yield. The procedure
to give 3 was readily carried out at >10 g scale. Deproto-
nation of the imine with LDA followed by alkylation with
bromoethyl methyl ether yielded 1 in 63% yield from 3, and
56% overall yield from 4-methoxybutanol. Route B was
superior owing to cleanliness, avoidance of aluminum salts,
and low cost of the starting materials.
(6) Brandis, A.; Mazor, O.; Neumark, E.; Rosenbach-Belkin, V.;
Salomon, Y.; Scherz, A. Photochem. Photobiol. 2005, 81, 983–993.
(7) (a) Limantara, L.; Koehler, P.; Wilhelm, B.; Porra, R. J.; Scheer, H.
Photochem. Photobiol. 2006, 82, 770–780. (b) Vakrat-Haglili, Y.; Weiner,
L.; Brumfeld, V.; Brandis, A.; Salomon, Y.; McIlroy, B.; Wilson, B. C.;
Pawlak, A.; Rozanowska, M.; Sarna, T.; Scherz, A. J. Am. Chem. Soc. 2005,
127, 6487–6497.
Reaction of
1
with (carbethoxymethylene)triphe-
nylphosphorane yielded unsaturated ester 4 in excellent yield.
Van Leusen reaction of 4 with TosMIC in Et2O/DMSO (2:
1) in the presence of NaH furnished swallowtail carbethoxy-
(8) Kozyrev, A. N.; Chen, Y.; Goswami, L. N.; Tabaczynski, W. A.;
Pandey, R. K. J. Org. Chem. 2006, 71, 1949–1960.
(9) Kim, H.-J. Lindsey, J. S. J. Org. Chem. 2005, 70, 5475–5486.
(10) Fan, D.; Taniguchi, M.; Lindsey, J. S. J. Org. Chem. 2007, 72,
5350–5357.
(17) Borbas, K. E.; Chandrashaker, V.; Muthiah, C.; Kee, H. L.; Holten,
D.; Lindsey, J. S. J. Org. Chem. 2008, 73, 3145– 3158.
(18) Thamyongkit, P.; Lindsey, J. S. J. Org. Chem. 2004, 69, 5796–
5799.
(11) (a) Demmig, S.; Langhals, H. Chem. Ber. 1988, 121, 225–230. (b)
Langhals, H.; Demmig, S.; Potrawa, T. J. Prakt. Chem. 1991, 333, 733–
748.
(12) Wiehe, A.; Stollberg, H.; Runge, S.; Paul, A.; Senge, M. O.; Ro¨der,
(19) Preliminary studies concerning the 2,12-disubstituted bacteriochlo-
rins have been described in a patent application: Lindsey, J. S.; Laha, J. K.;
Muthiah, C.; Borbas, K. E. WO 2007/064842 A2.
B. J. Porphyrins Phthalocyanines 2001, 5, 853–860
.
(13) Thamyongkit, P.; Speckbacher, M.; Diers, J. R.; Kee, H. L.;
Kirmaier, C.; Holten, D.; Bocian, D. F.; Lindsey, J. S. J. Org. Chem. 2004,
(20) Kim, H.-J.; Dogutan, D. K.; Ptaszek, M.; Lindsey, J. S. Tetrahedron
69, 3700–3710
.
2007, 63, 37–55.
(14) Borbas, K. E.; Mroz, P.; Hamblin, M. R.; Lindsey, J. S. Biocon-
jugate Chem. 2006, 17, 638–653
(21) van Leusen, A. M.; Siderius, H.; Hoogenboom, B. E.; van Leusen,
D. Tetrahedron Lett. 1972, 13, 5337–5340.
.
(15) Yao, Z.; Borbas, K. E.; Lindsey, J. S. New J. Chem. 2008, 32,
(22) Cheeseman, E. N. Org. Prep. Proc. Int. 1990, 22, 519–521.
(23) Vader, J.; Sengers, H.; de Groot, A. Tetrahedron 1989, 45, 2131–
2142.
436–451
.
(16) Borbas, K. E.; Kee, H. L.; Holten, D.; Lindsey, J. S. Org. Biomol.
Chem. 2008, 6, 187–194
.
(24) Mancuso, A. J.; Swern, D. Synthesis 1981, 165–185.
1932
Org. Lett., Vol. 10, No. 10, 2008

Scheme 1
.
Swallowtail Pyrrole Synthesis
Scheme 2.
Swallowtail Dihydrodipyrrin Synthesesa
pyrrole 5. Saponification and decarboxylation was achieved
with NaOH in hot ethylene glycol, affording the swallowtail-
pyrrole 6.
Vilsmeier formylation of 6 in CH2Cl2 yielded two regio-
1
isomeric formylpyrroles (2:1 by H NMR analysis of the
a R ) same as in Scheme 1.
crude product), which were not separable by column chro-
matography. Carrying out the reaction in DMF reversed the
1
regioselectivity (0.65:1 by H NMR analysis of the crude
product). Unlike the previous 2-formyl-3-p-tolylpyrrole,9
7a/b is an oil and thus not purifiable through crystallization.
The mixture 7a/b was carried forward (Scheme 2).
by the first method, the second method is preferred because
of its operational simplicity and better reproducibility. The
structures of the pure compounds were confirmed by NMR
experiments. The identity of regioisomer 8a was confirmed
by 1H-1H gCOSY, 1H-13C HSQC, and 1H-13C gHMBC
experiments, as well as by 1H NMR spectroscopy following
deuterium exchange of the pyrrolic NH proton. The sequence
4 f 8 could be performed with only simple aqueous-organic
workup of each reaction, without the need to obtain the
intermediates in an analytically pure form.
Two methods were explored for the synthesis of nitro-
ethylpyrroles 8a and 8b: (i) the reaction of 7a/b in a
methanolic solution of nitromethane containing propylamine
i
and acetic acid, followed by NaBH4 in PrOH/CHCl3/silica
gel,10 gave readily separable isomeric nitroethylpyrroles 8a
and 8b upon silica column chromatography in 38% and 29%
yield, respectively (67% overall); (ii) the reaction of 7a/b in
neat nitromethane containing methylamine hydrochloride and
potassium acetate, followed by reduction with NaBH4 in
MeOH/THF,9 gave 8a and 8b in 16% and 24% yield,
respectively (40% overall). Despite the higher yields obtained
Treatment of 8a or 8b with the dimethyl acetal derivative
of mesityl oxide9,25 (9, 3 equiv) in the presence of DBU (5
equiv) under solventless conditions20 yielded hexanone 10a
or 10b as a yellow oil. Ti(III)-mediated reductive cyclization
Org. Lett., Vol. 10, No. 10, 2008
1933

of the nitronate anion obtained from 10a or 10b upon
treatment with NaOMe yielded swallowtail dihydrodipyrrin
11a or 11b in 44% or 46% yield, respectively. Yields
throughout were comparable to those reported for p-tolyl
substituted analogues.
The synthesis of swallowtail bacteriochlorins was exam-
ined with both 11a and 11b (Scheme 3). Employing the
Figure 3. Absorption spectrum of swallowtail bacteriochlorin 12a
in CH2Cl2 at room temperature.
Scheme 3. Swallowtail Bacteriochlorin Syntheses
lower yields than that of 12a, likely because of steric
hindrance of the swallowtail substituent on the reactive
R-pyrrolic position. The 5-methoxy-substituted bacterio-
chlorin MeO-12b was observed upon LD-MS analysis of
the reaction mixture. The product distributions (12a/12a-
MeO and 12b/12b-MeO) were comparable to that reported
for the p-tolylbacteriochlorins, but the isolated yields were
lower. The lower yield may be due to diminished stability
of the dihydrodipyrrins 11a and 11b under the reaction
conditions versus that of the p-tolyl-substituted dihydrodipyr-
rin. Carrying out the condensation of 11b with lower acid
concentration (12.7 mM, 70% of that reported as optimal
for the p-tolylbacteriochlorin) or longer duration (43 h vs
24 h) did not increase the yield.
The 2,12- and 3,13-substituted bacteriochlorins 12a and
12b have absorption spectra that are almost identical to each
other (λmax, ratio of B and Q bands). The spectrum of 12a is
shown in Figure 3. Both 12a and 12b display strong
absorption bands in the UV (343 and 368 nm), weak bands
at 491 and 685 nm, and a strong band at 721 nm (12a) or
720 nm (12b). The ratio of the intensities of the 368 and
721 (or 720) nm bands was 1.05 for 12a, and 1.11 for 12b.
The solubility of bacteriochlorin 12a was examined in
solvents at room temperature without heating and without
sonication. The solubility decreased in the following order:
CHCl3 ≈ CH2Cl2 ≈ tetrahydrofuran (BHT free) ≈ N,N-
dimethylacetamide ≈ N,N-dimethylformamide > acetone >
acetonitrile > dimethyl sulfoxide > ethanol. The good
solubility in a range of organic solvents, including several
that are miscible with water, augurs well for use in optical
imaging, PDT, and other biomedical studies.
conditions developed for the synthesis of 2,12-di-p-tolyl-
bacteriochlorins,9 self-condensation of dihydrodipyrrin 11a
in CH3CN in the presence of BF3·OEt2 yielded two bacter-
iochlorins: 12a (major) and the 5-methoxy-substituted ana-
logue 12a-MeO (trace). Bacteriochlorin 12a was isolated in
13% yield, while 12a-MeO was observed upon LD-MS
analysis of the reaction mixture (m/z 660.7).
Acknowledgment. This work was supported by the NIH
(GM36238).
The self-condensation of 11b proceeded to afford bacter-
iochlorin 12b as the major product, albeit in significantly
Supporting Information Available: Experimental section
and spectral data for selected compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(25) Tiecco, M.; Testaferri, L.; Tingoli, M.; Bartoli, D. J. Org. Chem.
1990, 55, 4523–4528.
OL800436U
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Org. Lett., Vol. 10, No. 10, 2008