Tunable meso -tetraphenyl-alkyloxazolo-chlorins and -bacteriochlorins

Article abstract of DOI:10.1021/ol2006264

Chemical equations presented. Alkyl-Grignard addition to meso-tetraphenylporpholactone generates monoalkyl- and gem-bis- alkyloxazolochlorins. Together with compounds made by further synthetic manipulations of these derivatives, a series of chlorin-type c

Full text of DOI:10.1021/ol2006264

ORGANIC
LETTERS
2011
Vol. 13, No. 9
2380–2383
Tunable meso-Tetraphenyl-alkyloxazolo-
chlorins and -bacteriochlorins†
€
Junichi Ogikubo and Christian Bruckner*
Department of Chemistry, University of Connecticut, Storrs, Connecticut 06269-3060,
United States
c.bruckner@uconn.edu
Received March 9, 2011
ABSTRACT
Alkyl-Grignard addition to meso-tetraphenylporpholactone generates monoalkyl- and gem-bis-alkyloxazolochlorins. Together with
compounds made by further synthetic manipulations of these derivatives, a series of chlorin-type chromophores with modulated optical
properties is generated. Furthermore, their OsO4-mediated dihydroxylations and subsequent functional group transformations generate a
family of bacteriochlorins that possess substituent-dependent optical properties. Thus, the formal replacement of a pyrrolidine moiety in
chlorins and bacteriochlorins by variously substituted oxazoles is a flexible methodology to generate novel and stable chromophores that
are tunable over a considerable range of the optical spectrum.
For porphyrinoid chromophores to find utility as, for
instance, photosensitizers, imaging agents in tissue, or in
light-harvesting systems, their optical properties need to be
tuned to the particular application. This frequently means
shifting the maximum wavelength of absorbance (λmax) of
the prototypical porphyrin meso-tetraphenylporphyrin from
bacteriochlorins (2,3,12,13-tetrahydroporphyrins) fullfill these
optical requirements.3
Many principal approaches can be taken to achieve the
synthesis of red-absorbing porphyrinoids. Among them
are the synthesis of ring expanded systems4 and annulated
porphyrins5,6 as well as the development of methods
to convert porphyrins to chlorins and bacteriochlorins.7
Representative of the latter approach is the addition of
648 nm bathochromically into the ‘optical window’ of tissue,
1
while preferably also increasing the absorbance at λmax
.
In addition, a considerable portion of sun light is in the
region above 650 nm. Chromophores absorbing strongly in
these regions can potentially increase their light harvest
efficiency.2 In nature, chlorins (2,3-dihydroporphyrins) and
(3) Chlorophylls; Scheer, H., Ed.; CRC: Boca Raton, FL, 1991.
(4) (a) Sessler, J. L.; Weghorn, S. Expanded, Contracted & Isomeric
Porphyrins; Pergamon Press: New York, NY, 1997. (b) The Porphyrin
Handbook, Vol. 2 - Heteroporphyrins, Expanded Porphyrins and Related
Macrocycles; Kadish, K. M., Smith, K. M., Guilard, R., Eds.; Academic
Press: San Diego, 2000; Vol. 2.
† Oxazolochlorins 4. Oxazolochlorins 3: Khalil, G. E.; Daddario, P.; Lau,
K. S. F.; Imtiaz, S.; King, M.; Gouterman, M.; Sidelev, A.; Ghandehari, M.;
Br€uckner, C. Analyst 2010, 135, 2125À2131.
(5) Fox, S.; Boyle, R. W. Tetrahedron 2006, 62, 10039–10054.
(6) For recent examples, see: (a) Jiao, C. J.; Huang, K. W.; Guan,
Z. P.; Xu, Q. H.; Wu, J. S. Org. Lett. 2010, 12, 4046–4049. (b) Diev, V. V.;
Hanson, K.; Zimmerman, J. D.; Forrest, S. R.; Thompson, M. E.
Angew. Chem., Int. Ed. 2010, 49, 5523–5526. (c) Davis, N. K. S.;
Thompson, A. L.; Anderson, H. L. J. Am. Chem. Soc. 2011, 133, 30–
(1) The ‘optical window’ is between 600 and 1300 nm; the wavelength
of maximum penetration of breast tissue is ∼725 nm: Cerussi, A. E.;
Berger, A. J.; Bevilacqua, F.; Shah, N.; Jakubowski, D.; Butler, J.;
Holcombe, R. F.; Tromberg, B. J. Acad. Radiol. 2001, 8, 211–218.
(2) For example, see: Artificial Photosynthesis & Solar Fuels thematic
issue of Acc. Chem. Res. 2009, 42, 1859À2029.
€
31. (d) Akhigbe, J.; Zeller, M.; Bruckner, C. Org. Lett. 2011, 13, 1322–
1325.
(7) Flitsch, W. Adv. Heterocycl. Chem. 1988, 43, 73–126.
r
10.1021/ol2006264
Published on Web 04/01/2011
2011 American Chemical Society

azomethine ylide to meso-tetraarylporphyrin to pro-
duce a chlorin and bacteriochlorin 1.8 Multiple other
porphyrin-to-chlorin conversion reactions have become
known.7,9
Scheme 1. Literature-Known Syntheses of the meso-Tetraphe-
nylporpholactone 6 and meso-Tetraphenyloxazolochlorin 7
An alternative strategy toward the synthesis of novel
meso-aryl- and β-alkyl-chorins and bacteriochlorins of gen-
eral structures 3 and 4 is their total synthesis, as impressively
demonstrated by Lindsey and co-workers.10 Their studies
also delineated the structural requirements that result in
high extinction coefficients in these chromophores.10
À
5 using MnO4 leads to formation of porphyrin-like
porpholactone 6 (Scheme 1).13,16 This chromophore, pre-
viously discovered by others,17 could be reduced to the
chlorin-like hydroxy-/alkoxy-modified oxazolochlorin
7.18,19 However, hemiacetals of type 7 possess a relatively
low chemical stability and O-alkylation does not modulate
their optical properties.18,19
We report here the addition of alkyl-Grignard reagents
to the carbonyl group in porpholactone, generating a
family of alkyloxazolochlorins that can also be converted
to bacteriochlorins. Most significantly, their optical prop-
erties can be tuned.
We established the OsO4-mediated dihydroxylation of
meso-tetrarylporphyrins to generate dihydroxychlorin 5
and tetrahydroxybacteriochlorin 2.11,12 Functional group
manipulation of the diol functionality of chlorin 5 allowed
the synthesis of a range of chromophores carrying a
nonpyrrolic moiety.11,13À15 For instance, oxidation of diol
Thus, reaction of the zinc complex of porpholactone,
6Zn, with a 15-fold molar excess of i-PrMgCl in THF at
ambient temperature, followed by an acid workup proce-
dure that also removes the Zn(II), converts the green,
higher polarity (Rf = 0.38, silica/CH2Cl2) starting material
in good yield (∼80%, 0.72 mmol scale) to the purple lower
polarity (Rf = 0.5, silica/CH2Cl2) product 8 (Scheme 2)
that possesses a chlorin-like UVÀvis spectrum (Figure 1;
for a detailed discussion of the electronic spectra of the
chromophores prepared, see below). The use of the Zn(II)
‘protecting group’ in 6 prevents any NH deprotonation
and subsequent inactivation toward nucleophilic attack.
Reaction of hemiketal 8 with a stoichiometric excess of
(8) Silva, A. M. G.; Tome, A. C.; Neves, M. G. P. M. S.; Silva,
A. M. S.; Cavaleiro, J. A. S. J. Org. Chem. 2005, 70, 2306–2314.
€
(9) (a) Sternberg, E. D.; Dolphin, D.; Bruckner, C. Tetrahedron 1998,
54, 4151–4202. (b) Chen, Y.; Li, G.; Pandey, R. K. Curr. Org. Chem.
2004, 8, 1105–1134.
(10) For a cross section of their work, see: (a) Ptaszek, M.; Lahaye,
D.; Krayer, M.; Muthiah, C.; Lindsey, J. S. J. Org. Chem. 2010, 75,
1659–1673. (b) Ptaszek, M.; McDowell, B. E.; Taniguchi, M.; Kim, H.-
J.; Lindsey, J. S. Tetrahedron 2007, 63, 3826–3839. (c) Taniguchi, M.;
Cramer, D. L.; Bhise, A. D.; Kee, H. L.; Bocian, D. F.; Holten, D.;
Lindsey, J. S. New J. Chem. 2008, 32, 947–958. (d) Mass, O.; Ptaszek, M.;
Taniguchi, M.; Diers, J. R.; Kee, H. L.; Bocian, D. F.; Holten, D.;
Lindsey, J. S. J. Org. Chem. 2009, 74, 5276–5289. (e) Krayer, M.;
Ptaszek, M.; Kim, H.-J.; Meneely, K. R.; Fan, D.; Secor, K.; Lindsey,
J. S. J. Org. Chem. 2010, 75, 1016–1039.
Et3SiH under Lewis acid catalysis (BF3 OEt2) affects its
€
(11) Bruckner, C.; Rettig, S. J.; Dolphin, D. J. Org. Chem. 1998, 63,
2094–2098.
3
hydrodehydroxylation to isopropyloxazolochlorin 9 in ac-
ceptable yields (76%, 0.15 mmol scale). A diagnostic peak in
its 1H NMR is the oxazole proton signal (d, 6.9 ppm, 3J =
2.3 Hz, 1H) that is coupled to the isopropyl CHMe2 proton.
Unlike hemiacetal 7, hemiketal 8 and oxazolochlorin 9 are
chemically robust with respect to oxidation back to por-
pholactone 6, or other undesirable spontaneous oxidations.
Reaction of 6Zn with excess i-PrMgCl in the presence of
€
(12) Samankumara, L. P.; Zeller, M.; Krause, J. A.; Bruckner, C.
Org. Biomol. Chem. 2010, 8, 1951–1965.
€
(13) McCarthy, J. R.; Jenkins, H. A.; Bruckner, C. Org. Lett. 2003, 5,
19–22.
€
(14) (a) McCarthy, J. R.; Melfi, P. J.; Capetta, S. H.; Bruckner, C.
Tetrahedron 2003, 59, 9137–9146. (b) Akhigbe, J.; Ryppa, C.; Zeller, M.;
€
Bruckner, C. J. Org. Chem. 2009, 74, 4927–4933.
€
(15) (a) Daniell, H. W.; Bruckner, C. Angew. Chem., Int. Ed. 2004, 43,
€
1688–1691. (b) McCarthy, J. R.; Hyland, M. A.; Bruckner, C. Org.
Biomol. Chem. 2004, 2, 1484–1491. (c) Banerjee, S.; Hyland, M. A.;
€
Bruckner, C. Tetrahedron Lett. 2010, 51, 4505–4508.
(16) Khalil, G. E.; Daddario, P.; Lau, K. S. F.; Imtiaz, S.; King, M.;
BF3 OEt2 resulted in the formation of bis-adduct 10 as the
3
€
Gouterman, M.; Sidelev, A.; Puran, N.; Ghandehari, M.; Bruckner, C.
€
(18) Bruckner, C.; McCarthy, J. R.; Daniell, H. W.; Pendon, Z. D.;
Ilagan, R. P.; Francis, T. M.; Ren, L.; Birge, R. R.; Frank, H. A. Chem.
Analyst 2010, 135, 2125–2131.
(17) (a) Crossley, M. J.; King, L. G. J. Chem. Soc., Chem. Commun
1984, 920–922. (b) Gouterman, M.; Hall, R. J.; Khalil, G.-E.; Martin,
P. C.; Shankland, E. G.; Cerny, R. L. J. Am. Chem. Soc. 1989, 111, 3702–
3707.
Phys. 2003, 294, 285–303.
(19) McCarthy, J. R.; Perez, M. J.; Bruckner, C.; Weissleder, R. Nano
€
Lett. 2005, 5, 2552–2556.
Org. Lett., Vol. 13, No. 9, 2011
2381

Scheme 2. Synthesis of the meso-Tetraphenylalkyl-oxazolochlorins and -bacteriochlorins
alkylation and dehydroxylation modulate λmax of the spec-
tra significantly (Figure 1). The optical spectra of the parent
hemiacetal 7 (not shown) and its alkylated analogue 8 are
essentially identical. Removal of the hydroxy group, how-
ever, results in an ∼20 nm bathochromic shift. We noted the
strong influence of the β-hydroxy groups on the porphyrinic
chromophore before,12 but this shift is unusually pro-
nounced. gem-Alkylation of the oxazolochlorins results in
an ∼30% reduction of the extinction coefficients but other-
wise only in a minor (>5 nm) hypochromic shift of λmax
.
Because of their absorbance at wavelengths above 700 nm,
bacteriochlorin-type chromophores are particularly
appealing. An OsO4-mediated dihydroxylation of oxazo-
lochlorin 8, followed by a reductive workup, produced
triol 11 as an inseparable mixture of two diasteromers (all
hydroxy group on the same side of the plane defined by the
macrocycle, or cis-diol and quaternary alcohol function-
alities on opposite sides).20 Surprisingly, the corresponding
oxidation of alkyloxazolochlorin 9 also generates triol 11,
albeit in lower yields. This unintended oxidation of the
oxazole moiety defines the limits of the stability of these
oxaolochlorins in the presence of strong oxidants.
Figure 1. UVÀvis (solid traces) spectra and fluorescence emission
(broken traces) spectra (CH2Cl2) of the novel oxazolochlorins 8
(blue trace), 9 (red trace), and 10 (light blue trace). Florescence
spectra were recorded by excitation at the respective λSoret
.
sole low-polarity product in ∼30% yield. This unopti-
mized reaction is accompanied by extensive side reactions.
The double alkylation is confirmed by NMR spectroscopy
and mass spectrometry. Importantly, bis-isopropyl-sub-
stituted oxazolochlorin 10 is, unlike monoadduct 8, devoid
of stereoisomers that complicate further manipulations.
Oxazolochlorins 8, 9, and 10 all possess chlorin-type
UVÀvis absorption and fluorescence emission spectra, but
Triol 11 possesses a typical bacteriochlorin-like optical
spectrum (Figure 2). The spectrum is significantly red-shifted
(20) Each diastereomer is chiral; thus they are each expected to exist
as a racemic pair.
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Org. Lett., Vol. 13, No. 9, 2011

chlorin 8. Thus, the lactone moiety exhibits here a
significant influence on the electronic structure of these
chromophores.
The fluorescence quantum yields φ of the chlorins (8,
φ = 0.35; 9 φ = 0.26; 10, φ = 0.31; 13, φ = 0.29) were
relatively high but those of the two most red-shifted
bacteriochlorins 11 and 12 were lower (φ = 0.14 and 0.07
respectively). These findings are in line with earlier reports
of the ground state photophysical properties of chlorins
and bacteriochlorins.12
In conclusion, we have shown that alkyl-Grignard addi-
tions to porpholactone and functional group manipula-
tions of the resulting oxazolochlorins result in the
formation of chemically stable chlorin and bacteriochlorin
analogues. Significantly, the substituents of the oxazolo-
chlorins and bacteriochlorins can be chosen to allow a
tuning of λmax in the range from 650 to 750 nm, in 20À
30 nm increments. This synthetic methodology offers a novel
tool for the synthetic manipulation of the porphyrinic
chromophore. The conversion of meso-tetraphenylpor-
phyrin into oxazolo-chlorins and -bacteriochlorins pre-
sents an alternative to the total synthesis of chlorins and
bacteriochlorins.10 Our method does not allow the exqui-
site control of the β-substituents and resulting electronic
properties of the chromophores the total synthesis meth-
ods offer. However, only a few steps from readily available
starting materials are required to generate intriguing chro-
mophores. Detailed structural and spectroscopic studies
and investigations of the biological activity of the alkylo-
zazolochlorins as photosensitizers in photodynamic ther-
apy are ongoing.
Figure 2. UVÀvis (solid traces) spectra and fluorescence emis-
sion (broken traces) spectra (CH2Cl2) of the novel oxazolobac-
teriochlorins 11 (purple trace) and 12 (dark green trace), and
bisoxazolochlorin 13 (lime-green trace). Florescence spectra
were recorded by excitation at the respective λSoret
.
compared to the spectrum of the corresponding tetrahy-
droxybacteriochlorin isomers.12 This is unexpected since
the optical spectra of parent oxazolochlorin 8 are not
shifted compared to those of dihydroxychlorin 5.18
The dihydroxylation reaction is also applicable to gem-
dialkyloxazolochlorin 10, generating dihydroxyoxazolo-
bacteriochlorin12, withtheaddedbenefitthatthisreaction
does not form a diasteromeric mixture (alas, it forms as a
racemic mixture of the enantiomers differentiated by the
vic-diol moiety pointing up or down). Parallel to the
observations made for their parent chlorins (8 and 10),
the bacteriochlorin-type absorbance and emission spectra
of 12 are also red-shifted compared to those of triol 11.
Application of the MnO4À-mediated diol oxidation
reaction to triol 11 converts it to the bisoxazolochlorin
13, the first porphyrin analogue containing two oxazole
moieties. The optical spectra of bisoxazolochlorin 13 are
chlorin-like; i.e., the lactone moiety acts spectroscopically
akin to a β,β-double bond, albeit the spectra are sig-
nificantly red-shifted compared to those of the parent
Acknowledgment. This work was supported by the U.S.
National Science Foundation under Grant Number
CHEM-0517782.
Supporting Information Available. Experimental pro-
cedures and characterization data of new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Org. Lett., Vol. 13, No. 9, 2011
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