Effect of meso-substituents on the osmium tetraoxide reaction and pinacol-pinacolone rearrangement of the corresponding vic-dihydroxyporphyrins

Article abstract of DOI:10.1021/jo0100143

To investigate the effects of electron-donating and electron-withdrawing substituents upon the reaction of porphyrins with osmium tetraoxide, and the pinacol-pinacolone rearrangement of the resulting diols, a series of meso-substituted porphyrins were prepared by total synthesis. Porphyrins with electron-donating substitutents at the meso-positions gave vic-dihydroxychlorins in which the adjacent pyrrole subunit was predominantly oxidized. No such selectivity was observed in a porphyrin containing a methoxycarbonyl as the electron-withdrawing group, whereas a formyl substituent again resulted in oxidation at the pyrrole unit adjacent to the meso-substituent. Under pinacol-pinacolone conditions, vic-dihydroxy chlorins containing 4-methoxyphenyl or 3,5-dimethoxyphenyl groups at the meso-position showed preferential migration of the ethyl group over the methyl group to give 8-ketochlorins, whereas the diol with an n-heptyl substituent under similar reaction conditions gave both 7- and 8-ketochlorins. In contrast, the diol containing a meso-formyl substituent produced the corresponding 7-ketochlorin exclusively. These results indicate that it is not possible to predict the reactivity of meso-substituted porphyrins in the osmium tetraoxide reaction nor the general substituent migratory aptitudes in the pinacol-pinacolone rearrangement based on simple electronic arguments, most likely because many parameters (e.g., meso-β-pyrrolic steric crowding and long-range electronic effects) ultimately determine the reactivity. The structural assignments of the porphyrin diols and the keto-analogues were confirmed by extensive ¹H NMR studies; some of the dihydroxychlorins and ketochlorins were found to display unusual features in their ¹H NMR spectra.

Full text of DOI:10.1021/jo0100143

3930
J . Org. Chem. 2001, 66, 3930-3939
Effect of Meso-Su bstitu en ts on th e Osm iu m Tetr a oxid e Rea ction
a n d P in a col-P in a colon e Rea r r a n gem en t of th e Cor r esp on d in g
vic-Dih yd r oxyp or p h yr in s
Yihui Chen,† Craig J . Medforth,‡ Kevin M. Smith,‡ J ames Alderfer,§
Thomas J . Dougherty,† and Ravindra K. Pandey*,†,|
Chemistry Division, Photodynamic Therapy Center, NMR Facility, Molecular and Cellular Biophysics,
and Department of Nuclear Medicine/ Radiology, Roswell Park Cancer Institute,
Buffalo, New York 14263, and Department of Chemistry,University of California, Davis, CA95616
ravindra.pandey@roswellpark.org
Received J anuary 4, 2001
To investigate the effects of electron-donating and electron-withdrawing substituents upon the
reaction of porphyrins with osmium tetraoxide, and the pinacol-pinacolone rearrangement of the
resulting diols, a series of meso-substituted porphyrins were prepared by total synthesis. Porphyrins
with electron-donating substitutents at the meso-positions gave vic-dihydroxychlorins in which the
adjacent pyrrole subunit was predominantly oxidized. No such selectivity was observed in a
porphyrin containing a methoxycarbonyl as the electron-withdrawing group, whereas a formyl
substituent again resulted in oxidation at the pyrrole unit adjacent to the meso-substituent. Under
pinacol-pinacolone conditions, vic-dihydroxy chlorins containing 4-methoxyphenyl or 3,5-dimethox-
yphenyl groups at the meso-position showed preferential migration of the ethyl group over the
methyl group to give 8-ketochlorins, whereas the diol with an n-heptyl substituent under similar
reaction conditions gave both 7- and 8-ketochlorins. In contrast, the diol containing a meso-formyl
substituent produced the corresponding 7-ketochlorin exclusively. These results indicate that it is
not possible to predict the reactivity of meso-substituted porphyrins in the osmium tetraoxide
reaction nor the general substituent migratory aptitudes in the pinacol-pinacolone rearrangement
based on simple electronic arguments, most likely because many parameters (e.g., meso-â-pyrrolic
steric crowding and long-range electronic effects) ultimately determine the reactivity. The structural
1
assignments of the porphyrin diols and the keto-analogues were confirmed by extensive H NMR
studies; some of the dihydroxychlorins and ketochlorins were found to display unusual features in
1
their H NMR spectra.
In tr od u ction
aerogenes was later reinvestigated by Timkovich et al.4
who showed that heme d is in fact a derivative of 5,6-
dihydroxyprotochlorin IX. It has also been reported by
Sotiriou and Chang5 that heme d1 obtained from Pseu-
domonas aeruginosa and Paracocis denitrificans is a
dioxoisobacteriochlorin. In recent years, some of the
oxochlorins, oxobacteriochlorins, dioxobacteriochlorins,
and their vic-dihydroxy precursors have been investi-
gated as potential photosensitizers for the treatment of
cancer using photodynamic therapy (PDT).6 Thus, due
to their biological and medicinal importance, the oxo- and
their corresponding vic-dihydroxy derivatives have gen-
erated considerable interest.
In their studies with a variety of unsymmetrical
porphyrins, Chang and Sotiriou7 showed that unsym-
metrical porphyrins (e.g., deuterioporphyrin IX dimethyl
ester 1, mesoporphyrin IX dimethyl ester 2) upon reaction
with OsO4 gave all the possible four (ring A, B, C, and
D) vic-dihydroxychlorins 3, 4 without any pyrrole subunit
selectivity (see Scheme 1). Acid-catalyzed pinacol-pina-
colone rearrangement of the vic-dihydroxy compounds
gave the corresponding ketones, and migratory aptitudes
of hydrogen, ethyl, or alkyl groups (including the propi-
In continuation of our ongoing studies, the present
work describes the results of an investigation to deter-
mine the effect of substituents placed regioselectively at
the meso-positions of the porphyrin macrocycle to gener-
ate the vic-dihydoxy- and the corresponding oxochlorins
under appropriate reaction conditions. The oxo-deriva-
tives of chlorins, isobacteriochlorins, and bacteriochlorins
have been known for some time,1 but their biological
significance was not recognized until recently.2 For
example, the dihydroxyporphyrin structure originally
proposed3 by Barrett for heme d isolated from Aerobacter
* Corresponding author: Phone: (716) 845-3203, Fax: (716) 845-
8920.
† Chemistry Division, Photodynamic Therapy Center, Roswell Park
Cancer Institute.
‡ University of California.
§ NMR Facility, Molecular and Cellular Biophysics, Roswell Park
Cancer Institute.
| Department of Nuclear Medicine/Radiology, Roswell Park Cancer
Institute.
(1) (a) Bonnett, R.; Dimsdale, M. J .; Stephenson, C. F. J . Chem. Soc.
(C) 1969, 564. (b) Inhoffen, H. H.; Nolte, W. Liebigs Ann. Chem. 1969,
725, 167. (c) Chang, C. K.; Sotiriou, C.; Wu, W. J . Chem. Soc., Chem.
Commun. 1986, 1213.
(4) Timkovich, R.; Cork, M. S.; Gennis, R. B.; J ohnson, P. Y. J . Am.
Chem. Soc. 1985, 107, 6069.
(2) Pandey, R. K.; Zheng, G. Porphyrins as photosensitizers in
Photodynamic Therapy. In The Porphyrin Handbook; Kadish, Smith,
and Guilard, Eds.; Academic Press: New York, 2000; Vol. 6.
(3) Barrett, J . Biochem. J . 1956, 64, 626.
(5) Sotiriou, C.; Chang, C. K. J . Am. Chem. Soc. 1988, 110, 2264.
(6) Kessel, D.; Smith, K. M.; Pandey, R. K.; Shiau, F.-Y.; Henderson,
B. W. Photochem. Photobiol. 1993, 58, 200.
(7) Chang, C. K.; Sotiriou, C. J . Heterocycl. Chem. 1985, 22, 1739.
10.1021/jo0100143 CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/02/2001

Pinacol-Pinacolone Rearrangement of vic-Dihydroxyporphyrins
J . Org. Chem., Vol. 66, No. 11, 2001 3931
Sch em e 1
Sch em e 2
onate side chain) over the methyl group were estab-
lished.7,8 We later extended this study to porphyrin and
chlorin systems in which electron-withdrawing groups
were present at peripheral positions of the macrocycle;
it was shown that the regiospecificity of pyrrole subunits
to OsO4 oxidation in porphyrins is affected significantly
by the presence of electron-withdrawing groups, and the
pyrrole unit containing the electron-withdrawing group-
(s) did not undergo to oxidation.9Migratory aptitudes in
subsequent pinacol-pinacolone rearrangements of por-
phyrin and pheophorbide vic-diol systems were likewise
dependent upon the stability of the intermediate car-
bocation which was affected by the number of electron-
withdrawing functionalities in the tetrapyrrolic ring
system.10
In general, the syntheses of vic-dihydroxyporphyrins
and chlorins are achieved by reacting porphyrins or
chlorins with osmium tetraoxide (OsO4). The intermedi-
ate osmate ester is then hydrolyzed reductively to give
insoluble osmium salts or oxidatively to regenerate the
osmium tetraoxide reagent. In either case the corre-
sponding vicinal cis-diol is formed selectively in good
yield. There exist several methods to hydrolyze the
osmate ester,11 but in porphyrins the reductive cleavage
with hydrogen sulfide appears to give the best results.
As in other alicyclic systems,12 addition of pyridine to
hydroxylation reactions led to a marked increase in the
rate of formation of the intermediate osmate ester
complexes. The dihydroxy derivatives, under acidic con-
ditions, can then be converted into the corresponding
keto-analogues via pinacol-pinacolone rearrangement.
A notable observation is that the migratory aptitudes of
side chains at the peripheral position(s) of the macrocycle
generally appear to be dictated by the stability of the
intermediate carbocation.
substrates (Scheme 2). In porphyrins 5 and 7, the
electron-donating groups were regioselectively introduced
at the meso-positions (position-5) of the macrocycle,
whereas in porphyrins 6, 8, and 10 electron-withdrawing
groups were incorporated. The basic idea for selecting
these porphyrins as substrates was to address the
following questions: (a) can we achieve any selectivity
for the formation of the vic-dihydroxy analogues on
reacting with osmium tetraoxide, (b) is it possible to
dictate the formation of the intermediate carbocation(s)
and thus the regioselective formation of 7- or 8-ketochlo-
rins under pinacol-pinacolone conditions using electronic
effects? Information derived from this study will help to
establish the effect of various groups upon the regiospeci-
ficity of the oxidation reaction, and upon subsequent
pinacol-pinacolone rearrangements of the intermediate
diol(s) in porphyrin systems.
Porphyrins 5-7 were prepared in a sequence of reac-
tions in which 2-ethoxycarbonyl-3-ethyl-4-methylpyr-
role12 was converted into dipyrromethanes 15, 16, and
17 in excellent yields13 (Scheme 3). These pyrromethanes
were then individually condensed with the diformyl
dipyrromethane 20 under acidic conditions and the
desired porphyrins obtained in 35 to 40% yield, respec-
tively. Porphyrin 8 containing a methoxycarbonyl group
at the meso-position was obtained by condensing the 1,9-
diformyldipyrromethane 20 with dipyrromethane-1,9-
dicarboxylic acid 27 under MacDonald reaction condi-
tions14 and was isolated in 32% yield (Scheme 3). Reaction
of Ni(II) octaethylporphyrin (OEP) with Vilsmeier re-
agent (POCl3/DMF) produced the corresponding formyl
analogue in 70% yield.15 Removal of nickel under strongly
acidic conditions gave the free base porphyrin 10 in
quantitative yield.
Resu lts a n d Discu ssion
In our earlier studies, we showed that in the porphyrin
system, the presence of an electron-withdrawing sub-
stituent on the pyrrole subunit deactivated that particu-
lar pyrrole unit toward the OsO4 reaction; oxidation was
achieved at the diagonally opposite pyrrole subunit which
is presumably more electron-rich than the others.9 For
our present study, porphyrins 5-8 and 10 were used as
(8) Sotiriou, C. J .; Chang, C. K. J . Am. Chem. Soc. 1988, 110, 2264
and the references therein.
Our interest in chlorin compounds is related in part
to their use in photodynamic therapy (PDT).16,17 Chlorins
in general are suitable candidates for such treatment due
(9) Pandey, R. K.; Shiau, F.-Y.; Isaac, M.; Ramaprasad, S.; Dough-
erty, T. J .; Smith, K. M. Tetrahedron Lett. 1992, 33, 7815.
(10) Pandey, R. K.; Isaac, M.; McDonald, I.; Senge, M. O.; Dougherty,
T. J .; Smith, K. M. J . Org. Chem. 1997, 62, 1463.
(11) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976,
1973.
(12) (a) Lee, D. A.; Brisson, J . M.; Smith, K. M. Heterocycles 40, 131,
1995. (b) Lee, D. A.; Smith, K. M. J . Chem. Soc., Perkin Trans. 1 1215,
1997.
(13) Walker; M.; Forsyth, T. P.; Smith, K. M. Unpublished results.
(14) Arsenault, G. P.; Bullock, E.; MacDonald, S. F. J . Am. Chem.
Soc. 1960, 82, 4384.
(15) Bushell, M. J .; Evans, B.; Kenner, G. W.; Smith, K. M.
Heterocycles 1977, 7, 67.

3932 J . Org. Chem., Vol. 66, No. 11, 2001
Chen et al.
Sch em e 3
to (a) their strong absorptions in the red region of the
electronic absorption spectra, (b) their strong fluores-
cence, enabling them to be easily detected, and (c) their
high singlet oxygen yield, an essential requirement for
killing the tumor cells. We have recently synthesized and
evaluated a series of vic-dihydroxy- and oxo-bacteriochlo-
rins prepared from methyl 9-deoxy-meso-pyropheophor-
bide.19 Among such analogues, the oxo-bacteriochlorins
were found to be more effective than the corresponding
vic-dihydroxy analogues from which they were derived.19
In another study, among the alkyl ether analogues of
various methylpheophorbides,20 pyropheophorbides,21 and
purpurinimides,22 we showed that altering the length of
the carbon chain yielded a remarkable difference in pho-
tosensitizing efficacy. Thus, to investigate the effect(s)
of the alkoxyalkyl substituents at the meso-position of
the macrocycle on PDT efficacy, p-methoxyphenylporphy-
rin 5 was also converted into the corresponding alkyl
ether derivatives with variable carbon units 29-31 as
precursors because of interest in testing the efficacy of
the corresponding dihydroxychlorins as photodynamic
agents.
(20) Pandey, R. K.; Bellnier, D. A.; Smith, K. M.; Dougherty, T. J .
Photochem. Photobiol. 1991, 53, 65.
(21) (a) Henderson, B. W.; Bellnier, D. A.; Graco, W. R.; Sharma,
A.; Pandey, R. K.; Vaughan, L.; Weishaupt, K. R.; Dougherty, T. J .,
Cancer Res., 1997, 57, 4000. (b) Pandey, R. K.; Sumlin, A.; Constantine,
S.; Bellnier, D. A.; Henderson, B. W.; Rodgers, M. A. J .; Smith, K. M.;
Dougherty, T. J . Photochem. Photobiol. 1996, 63, 194. (c) D. A. Bellnier,
B. W. Henderson, R. K. Pandey, W. R. Potter; Dougherty, T. J . J .
Photochem. Photobiol. 1993, 20, 55. 2. (d) Pandey, R. K.; Constantine,
S.; Goff, D. A.; Kozyrev, A.; Dougherty, T. J .; Smith, K. M. Bioorg.
Med. Chem. Lett. 1996, 6, 105. (e) Dougherty, T. J .; Pandey, R. K.;
Nava, H. R.; Smith, J . A.; Douglass, H. O.; Edge, S. B.; Bellnier, D. A.;
O’Malley, L.; Cooper, M. Proc. SPIE 2000, 3909, 25.
(22) (a) Rungta, A.; Zheng, G.; Missert, J . R.; Potter, W. R.;
Dougherty, T. J .; Pandey, R. K. Bioorg. Med. Chem. Lett. 2000, 10,
1463. (b) Zheng, G.; Potter, W. R.; Sumlin, A.; Dougherty, T. J .; Pandey,
R. K.. Bioorg. Med. Chem. Lett. 2000, 10, 123. (c) Zheng, G., Ph.D.
Thesis, Roswell Park Graduate Division, SUNY, Buffalo, December
1998.
(16) (a) Pandey, R. K.; Herman, C. Chem. Ind. (London) 1998, 379.
(b) Pandey, R. K. Recent advances in photodynamic therapy J .
Porphyrins Phthalocyanines 2000, 4, 185. (c) Dougherty, T. J .; Gomer,
V.; Henderson, B. W.; J ori, G.; Kessel, D.; Kprbelik, M.; Moan, J .; Pang,
Q. J . Natl. Cancer Inst. 1998, 90, 889.
(17) (a) Ali, H.; van Lier, J . E. Metal Complexes as Photo- and
Radiosensitizers. Chem. Rev. 1999, 99, 2379. (b) Sharman, W. M.;
Allen, C. M.; van Lier, J . E. Photodynamic therapeutics: basic
principles and clinical applications. Current Trends, Drug Discovery
Today; Elsevier Sci.: London, 1999; Vol. 4, p 507.
(18) Sharman, W. M.; Allen, C. M.; van Lier, J . E., Role of activated
oxygen species in photodynamic therapy. Methods Enzymol. 2000, 319,
376.
(19) Pandey, R. K.; Tsuchida, T.; Constantine, S.; Zheng, G.;
Medforth, C.; Kozyrev, A.; Mohammad, A.; Rodgers, M. A. J .; Smith,
K. M.; Dougherty, T. J . J . Med. Chem. 1997, 40, 3770.

Pinacol-Pinacolone Rearrangement of vic-Dihydroxyporphyrins
J . Org. Chem., Vol. 66, No. 11, 2001 3933
Sch em e 4
the methyl substituent. In contrast, the 5-heptyldihy-
droxychlorin 37 afforded a mixture of ketochlorins 45
(ethyl migrated instead of methyl) and 46 (methyl
migrated instead of ethyl) in almost equal ratio with a
combined yield of 60%, and the 5-meso-formyldihydroxy-
chlorin 42 produced the 7-ketochlorin 47 as a single
isomer. The main objective for the synthesis of chlorins
34-36 was to determine the effect of variable length of
alkyl ether carbon chains in PDT efficacy in the presence
of hydrophilic hydroxy substituents, so they were not
subjected to pinacol-pinacole conditions. On the basis
of these results (Scheme 7), it seems that similar to the
non-meso-substituted porphyrin-diols, the migratory ap-
titude of the alkyl substituents in the corresponding
meso-dihydroxychlorins depends in large part on the
stability of the intermediate carbocation(s) formed under
acidic conditions.
As mentioned earlier, Chang and Sotiriou5 showed that
reaction of unsymmetrical porphyrins (e.g., deuteriopor-
phyrin IX dimethyl ester 1 and mesoporphyrin IX dim-
ethyl eser 2) with OsO4 produced a mixture of all four
possible vic-dihydroxy analogues 3 and 4 (a ,b,c,d ), and
no selectivity was observed. Under similar conditions,
reaction of porphyrins 5 and 6 with 1.5 equiv of OsO4
gave predominantly one isomer in >75% yield, along with
unreacted starting material (5%). These compounds were
assigned as vic-dihydroxyporphyrins 32 and 33 (see
Scheme 5) by NMR spectroscopy. If an excess of OsO4 is
used in the reaction, the same porphyrins (e.g., 5)
produced mainly the corresponding tetrahydroxybacte-
riochlorins (e.g., 38) as an isomeric mixture in which the
pyrrole rings diagonal to each other were oxidized. The
other diols containing O-hexyl- 34, O-heptyl- 35, and
O-decyl- 36, and n-heptyl group 37 were obtained from
their respective porphyrins in similar yields and with
similar selectivities.
The structure of the vic-dihydroxychlorin 42 and the
migration patterns of the ketochlorins 43, 45, 46, and
47 were determined either by NOE or ROESY 1H NMR
studies (Figure 1). Of particular interest was the fact that
no interaction between the 5-formyl and the 3-ethyl
protons was observed in ketochlorin 47. This might be
due to hydrogen bonding of the 5-formyl proton with the
adjacent keto-group substituted at position-7 of the
macrocycle, which would orient the formyl proton away
from the 3-ethyl group. Other unusual features were
1
observed in the H NMR spectra of porphyrins 42 and
45. In the case of the vic-dihydroxychlorin 42, there was
a signal at δ 8.20, which could be assigned to an OH
group of the diol based on its exchange characteristics
with D2O. This signal was shifted substantially downfield
of its expected position (Figure 2). We attribute this to
hydrogen bonding with the adjacent 5-formyl (CHO)
group as shown in Figure 2. Furthermore, the resonances
of 7-ketochlorin 46 were sharp, while those of 8-ketochlo-
rin 45 showed substantial broadening. Addition of pyri-
dine-d5 to the samples was ineffective in sharpening the
lines and ruled out the possibility of aggregation. How-
ever, variable temperature 1H NMR 1D spectra indicated
A porphyrin 8 containing a methoxycarbonyl group at
5-position, however, did not show any selectivity, the
product being identified as the mixture of 7,8-dihydroxy-
(39) and 17,18-dihydroxychlorin (40) in almost equal ratio
and could not be separated. However, replacing the
methoxy carbonyl group with a formyl group at the meso-
position (10) produced a remarkable selectivity, and the
7,8-dihydroxyporphyrin 42 in which the pyrrole unit
adjacent to the substituent had oxidized was isolated as
a sole product. We had envisioned that porphyrins
containing electron-withdrawing substituents at the
meso-position should decrease the electron density of the
adjacent pyrrole units, and thus these pyrroles should
be less susceptible to oxidation than those away from
such substituent. However, the experimental results were
in contrast to those we had hypothesized and suggested
that in porphyrin system, the site of oxidation by osmium
tetraoxide does not follow the electron-withdrawing/
donating ability of the meso-substituents. The oxidation
always seems to occur at the ring adjacent to the
substituent, except in the porphyrin with a meso-meth-
oxycarbonyl group, where ring C was also oxidized. These
results tend to suggest that the relief of strain between
the meso- and â-substituents is a dominant factor in the
osmium tetraoxide oxidation.
the presence of a dynamic process (∆G ) 68 + 2 kJ mol-1
)
with two species being observed at lower temperature
(Figure 3). At low temperature, the meso-hydrogen
signals indicated a ratio of 55:45. The dynamic process
being observed in this system is probably due to rotation
of the meso-alkyl group, something which has been seen
in other porphyrin systems.23 A similar effect might be
present for the 7-keto isomer 46, but not being seen
because one rotamer is highly favored, the rotational
barrier is lower, or the chemical shift differences are too
small. The electronic absorption spectra of chlorindiols
and ketochlorins in dichloromethane also showed some
interesting characteristics. The diols and the related keto-
analogues have similar spectra. However, compared to
diols containing an electron-donating group, diols with
electron-withdrawing groups (e.g., 42) exhibited a red
shift in their long wavelength absorptions (Figure 4).
Among 8-keto- and 7-ketochlorins (45 and 46, respec-
tively), the 8-keto isomer 45 exhibited a red shift of about
7 nm in its long wavelength absorption (Figure 5).
Rea r r a n gem en t of th e Alk yl Gr ou p s u n d er P in a -
col-P in a colon e Con d ition s. On treating with acid
under pinacol-pinacole conditions, the vic-dihydroxy
chlorins 32 and 33 containing a p-methoxyphenyl or 3,5-
dimethoxy phenyl group at the meso-position (position-
5) produced keto-chlorins 43 and 44, respectively. In both
chlorins, the ethyl group had migrated in preference to
(23) For a recent review of 1H NMR studies of dynamic process in
porphyrins, see: Medforth, C. J . In The Porphyrin Handbook; Kadish,
K. M.; Smith, K. M.; Guilard, R., Eds.; Academic Press: Boston, MA,
2000; Vol. 5, pp 60-74.

3934 J . Org. Chem., Vol. 66, No. 11, 2001
Chen et al.
Sch em e 5
Sch em e 6
Francisco Mass Spectrometry Laboratory. Elemental analyses
were obtained from Midwest Microlabs, Indianapolis, IN.
Electronic absorption spectra were measured in dichlo-
romethane using a Hewlett-Packard 8450A.
Exp er im en ta l Section
Melting points were uncorrected and were measured on a
Thomas/Bristoline microscopic hot stage apparatus. Silica gel
60 (70-230 and 230-400 mesh, Merck) or neutral alumina
(Merck; usually Brockmann Grade III, i.e., deactivated with
6% water) were used for column chromatography. Preparative
scale thin-layer chromatography was carried out on 20 × 20
cm glass plates coated with Merck G 254 silica gel (2 mm
thick). Reactions were monitored by thin-layer chromatogra-
phy and spectrophotometry, and were carried out under
nitrogen and in the dark. Proton NMR spectra and NOE
difference spectra were measured at 300 MHz using a General
Electric QE300 or Brucker 400 MHz spectrometer. Deuterio-
chloroform was used as the solvent, and the chemical shifts
were referenced to the residual chloroform signal at 7.258 ppm.
Mass spectra were obtained at the Mass Spectrometry Facility,
Michigan State University, East Lansing, and the UC San
3,9-Dieth yl-6-h ep tyl-4,8-d im eth yl-2,10-d ieth oxyca r bo-
n yld ip yr r om eth a n e (14). Pyrrole 11 (5.0 g) and octyl alde-
hyde (1.77 g) were dissolved in ethanol (50 mL), and p-tolue-
nesulfonic acid (100 mg) was added. The reaction was refluxed
overnight under nitrogen and was monitored by analytical
TLC. It was then diluted with dichloromethane (200 mL) and
washed with aqueous sodium bicarbonate and finally with
water. The organic layer was then dried over anhydrous
sodium sulfate. Evaporation of the solvent gave a residue
which was chromatographed over silica column eluted with
1% methanol/dichloromethane. Appropriate eluates were col-
lected and combined. Evaporation of the solvent gave the title
1
compound as a yellow colored viscous oil. H NMR (400 MHz,

Pinacol-Pinacolone Rearrangement of vic-Dihydroxyporphyrins
J . Org. Chem., Vol. 66, No. 11, 2001 3935
Sch em e 7
1
F igu r e 1. Interactions observed by NOE and 2D ROESY H NMR studies.
CDCl3): δ 9.30 (s, 2H, 2 NH); 4.25 (m, 5H, 2 × CO2CH2 CH3
and bridge CH); 2.75 (m, 4H, 2 × CH2 CH3); 2.10 (m, 2H, CH2-
(CH2 )5 CH3); 1.90 (s, 6H, 2 × CH3); 1.25 (m, 10H, CH2(CH2
)
5
CH3); 1.12 (t, 6H, 2 × CH2 CH3 ); 0.80 (t, 3H, (CH2)5CH3. HRMS
for C28H44N2O4: 472.3297. Found: 472.3290.
3,9-Die t h yl-6-h e p t yl-4,8-d im e t h yl-2,10-d ip yr r om e -
th a n e (17). The foregoing diethoxycarbonyl dipyrromethane
(1.0 g) was dissolved in ethylene glycol. Sodium hydroxide (1.0
g) was added, and the reaction mixture was refluxed for 1 h.
It was then cooled, diluted with dichloromethane (300 mL),
and washed with water (3 × 250 mL). The dichloromethane
layer was dried over anhydrous sodium sulfate. The residue
obtained after evaporating the solvent was chromatographed
over silica column eluted with chloroform. The appropriate
eluates were combined, the solvent was evaporated, and the
desired dipyrromethane was obtained in 50% yield (347 mg)
1
F igu r e 2. Partial 400 MHz H NMR spectrum (in CDCl3) of
chlorin 42, showing downfield shift of the 7-OH proton.
as a light yellow viscous oil. 1H NMR (400 MHz, CDCl3): δ
9.35 (s, 2H, 2 × NH); 6.50 (d, 2H, R-pyrrolic H); 4.00 (br s,
1H, bridge CH); 2.40 (m, 4H, 2 × CH2CH3); 2.00 (s merged

3936 J . Org. Chem., Vol. 66, No. 11, 2001
Chen et al.
Toluenesulfonic acid (3.0 g) dissolved in methanol (50 mL) was
added, and the reaction mixture was stirred at room-temper-
ature overnight under nitrogen atmosphere. A saturated
solution of zinc acetate/methanol (100 mL) was added, and the
reaction was stirred for a further 12 h. It was then diluted
with dichloromethane and washed with water, and the organic
layer was dried over anhydrous sodium sulfate. Evaporation
of the solvent gave a residue, which was treated with trifluo-
roacetic acid (30 mL) for 1 h. The zinc-free porphyrin thus
obtained after the standard workup was chromatographed over
a
short Grade III Alumina column, eluted with dichlo-
romethane. The major band was collected, and the solvent
evaporated. The residue was crystallized from dichloromethane/
hexane in 42% yield (750 mg), mp >300 °C. UV/vis (λ max, ꢀ):
403 (140 000); 500 (20 000); 536 (16 000); 569 (14 000); 620
(12 000). 1H NMR (400 MHz, CDCl3): δ 10.20 (s, 2H, 2 × meso
H); 9.90 (s, 1H, meso H); 7.88 and 7.25 [each d, 2H, C6H4
(OCH3)]; 4.40 (t, 4H, 2 × CH2 CH2 CO2CH3); 4.12 (s, 3H,
OCH3); 4.02 (q, 4H, 2 × CH2CH3); 3.62 (s, 12H, 2 × CH2CH2
CO2CH3, and 2 × ring CH3); 3.25 (t, 4H, 2 × CH2CH2 CO2-
CH3); 2.52 (s, 6H, 2 × ring CH3); 1.75 (t, 6H, 2 × CH2CH3 );
-3.22 and -3.27 (each s, 1H, 2 × NH). Anal. Calcd for
F igu r e 3. 400 MHz H NMR spectra of 5-heptyl-8-ketochlorin
45 at 323 K (A); 303 K (B); 293 K (C); and 278 K (D). At low
temperature, one meso-hydrogen shows the presence of two
forms with an equilibrium distribution of 55:45 (∆G ) 0.4 kJ
mol-1).
C
43H48N4O5: C, 73.69; H, 6.90; N, 7.99. Found: C, 73.45; H,
6.93; N, 7.95.
2,8-Dieth yl-13,17-bis(2-m eth oxyca r bon yleth yl)-5-(3′,5′-
d im eth oxyp h en yl)-3,7,12,18-tetr a m eth ylp or p h yr in (6).
Diformyl dipyrromethane 20 was reacted with pyrromethane
16 (937 mg) by following the method discussed for the
preparation of porphyrin 5 and was obtained in 30% yield (560
mg), mp 300 °C. UV/vis [CH2Cl2, λmax, (ꢀ)]: 403 (136 000); 500
(20 700); 536 (15 000); 569 (15 000); 623 (12 000). 1H NMR (400
MHz, CDCl3): δ 10.18 (s, 2H, 2 × meso H); 9.97 (s, 1H, meso
H); 7. 39 (s, 2H, 2 × H of C6H3(OCH3)2 and 7.08 [s, 1H, C6H3-
(OCH3)2]; 4.41 (t, 4H, 2 × CH2 CH2 CO2CH3); 4.12 (s, 6H, 2 ×
OCH3); 4.02 (q, 4H, 2 × CH2CH3); 3.66 (s, 12H, 2 × CH2CH2
CO2CH3, and 2 × ring CH3); 3.31 (t, 4H, 2 × CH2CH2 CO2-
CH3); 2.54 (s, 6H, 2 × ring 3, 7- CH3); 1.80 (t, 6H, 2 × CH2CH3
); -3.22 and -3.24 (each s, 1H, 2 × NH). Anal. Calcd for
C
44H50N4O6: C, 72.31; H, 6.90; N, 7.67. Found: C, 71.78; H,
6.87; N, 7.47.
2,8-Dieth yl-5-h eptyl-13,17-bis(2-m eth oxycar bon yleth yl)-
3,7,12,18-tetr a m eth ylp or p h yr in (7). Dipyrromethane 17
(260 mg) was condensed with diformyl dipyrromethane 20 (460
mg) following the procedure discussed for the preparation of
porphyrin 5. After purification, the residue was crystallized
from CH2Cl2/hexane. Yield: 108 mg (20%), mp 155-158 °C,
F igu r e 4. Electronic absorption spectra (CH2Cl2) of compound
37 (- - -) and 42 (___) at the same concentration (17.0 µM).
UV/vis [CH2Cl2, λ
(ꢀ)]: 404 (161 000); 502 (15 000); 535
max
1
(6 000); 574 (6 000); 620 (3 000). H NMR (400 MHz, CDCl3):
δ 10.07 (s, 2H, 2 × meso H); 9.81 (s, 1H, meso H); 4.36 (t, 4H,
2 × CH2CH2CO2CH3); 4.11 (br q, 4H, 2 × CH2CH3); 3.60-3.67
(merged signals, 18H, 2 × CH2CH2CO2CH3 and 4 × ring CH3);
3.27 (t, 4H, 2 × CH2CH2 CO2CH3); 1.81 (t, 6H, 2 × CH2CH3 ),
5.15, 2.07. 1.38, 1.31 [m, 12H, (CH2)6 CH3]; 0.88 [t, 3H, (CH2)6
CH3 ]; -2.88 and -2.96 (each s, 1H, 2 × NH). MS for
C
43H56N4O4: 692.43. Found (FAB): m/e 693.50 (M + 1).
3,7-Diet h yl-5-m et h oxyca r b on yl-13,17-b is(2-m et h oxy-
car bon yleth yl)-2,8,12,18-tetr am eth ylpor ph yr in (8). Dipyr-
romethane dicarboxylic acid 27 (210 mg) was condensed with
diformyl dipyrromethane 20 (225 mg) following the method
discussed for porphyrin 5 and was isolated in 55% (200 mg)
yield as a fluffy deep red solid, mp > 300 °C. UV/vis [CH2Cl2,
λ
max, (ꢀ)]: 399 (115 600); 499 (15 200); 535 (11 400); 571
(9 700), 675 (8 200). 1H NMR (400 MHz, CDCl3): δ 10.15 (s,
2H, 2 × meso H); 9.97 (s. 1H, meso H); 4.51 (s, 3H, meso CO2-
CH3); 4.36 (t, 4H, 2 × CH2CH2CO2CH3); 3.77 (q, 4H, 2 × CH2-
CH3); 3.62 and 3.52 (s merged, 18 H, 2 × CH2CH2CO2CH3 and
4 × ring CH3); 3.26 (t, 4H, 2 × CH2CH2 CO2CH3); 1.67 (t, 6H,
2 × CH2CH3); -3.50 and -3.54 (each s, 1H,2 × NH). Anal.
Calcd for C38H44N4O6: C, 69.92; H, 6.79; N, 8.58. Found: C,
69.02; H, 6 69; N, 8.42.
5-F or m yl-2,3,7,8,12,13,18,19-oct a et h ylp or p h yr in (10).
Octaethylporphyrin (500 mg) was dissolved in o-xylene (200
mL), and nickel acetylacetonate (500 mg) was added. The
reaction mixture was refluxed for 30 min, and after the
standard workup the corresponding Ni(II) complex was ob-
F igu r e 5. Electronic absorption spectra (CH2Cl2) of compound
45 (- - -) and 46 (___) at the same concentration (8.6 µM).
with m, 2 × CH3, 4 × CH2 of (CH2)5 CH3; 1.25 (m, 10H, 2 ×
(CH2)5 CH3);1.20 (t, 6H, 2 × CH2CH3); 0.80 (3H, t, (CH2)6CH3.
Mass calcd for C22H36N2: 328.2875. Found (FAB): m/e 329 (M
+ 1).
2,8-Diet h yl-13,17-b is(2-m et h oxyca r b on ylet h yl)-5-(4′-
m eth oxyp h en yl)-3,7,12,18-tetr a m eth ylp or p h yr in (5). Di-
formyl dipyrromethane 20 (1.03 g) and dipyrromethane 15
(1.14 g) were dissolved in dichloromethane (250 mL). p-

Pinacol-Pinacolone Rearrangement of vic-Dihydroxyporphyrins
J . Org. Chem., Vol. 66, No. 11, 2001 3937
tained in 100% (553 mg) yield. It was then reacted with
Vilsmeier reagent prepared from POCl3 (3.5 mL) and DMF (5
mL) for 1 h at 0 °C. The reaction was monitored by analytical
TLC. The intermediate iminium salt was hydrolyzed overnight
with aqueous sodium carbonate (pH > 10). After the standard
workup, the Ni(II) formyloctaethylporphyrin that was isolated
in quantitative yield on treating with concentrated H2SO4
ylp or p h yr in (32) a n d 2,8-Dieth yl-7,8,17,18-tetr a h yd r oxy-
13,17-bis(2-m eth oxycar bon yleth yl)-5-(4′-m eth oxyph en yl)-
3,7,12,18-tetramethylporphyrin (38).Themethoxyphenylporphyrin
5 (100 mg) was dissolved in dichloromethane, and a few drops
of pyridine were added. OsO4 (100 mg) dissolved in ether (2
mL) was added, and the reaction mixture was stirred at room-
temperature overnight. The reaction was diluted with dichlo-
romethane (50 mL), and hydrogen sulfide gas was bubbled
through the solution. It was then filtered, and the solvent was
evaporated. The crude product was purified by preparative
plates, using 5% methanol/dichloromethane as a solvent; three
bands were separated and identified as follows: (a) the faster
moving band (minor amount) was characterized as the starting
porphyrin, the middle band [major product, 50 mg (48%)] was
identified as dihydoxychlorin 32. UV/vis [CH2Cl2, λ max (ꢀ): 399
1
produced the title compound in 93% (489 mg) yield. H NMR
(400 MHz, CDCl3): δ 12.77(s, 1H, CHO); 10.06 (2H, 2 × meso
H); 9.94 (1H, meso H), 4.1-3.8(m, 16 H 8 × CH2CH3), 1.95-
1.47 (m, 24H 8 × CH2CH3). mp 254-255 °C, reported: 255
°C.15
2,8-Dieth yl-5-(4′-h yd r oxyp h en yl)-13,17-bis(2-m eth oxy-
ca r bon yleth yl)-3,7,12,18-tetr a m eth ylp or p h yr in (28). The
4-methoxyphenylporphyrin 5 (200 mg) was dissolved in dry
dichloromethane (25 mL) and placed in a round-bottom flask
equipped with a nitrogen inlet. The solution was cooled to -40
°C with CH3CN-dry ice slush bath. Boron tribromide (1 mL)
was added, and the solution was then allowed to warm to room
temperature. The reaction mixture was diluted with dichlo-
romethane (100 mL). The excess of BBr3 was quenched by
cautious dropwise addition of methanol (Caution! Violently
exothermic!). An aqueous solution (10% w/v) of sodium bicar-
bonate (50 mL) was then added and the solution stirred for
30 min. The organic layer was separated and dried under high
vacuum. The solid so obtained was redissolved in 5% methanol/
CH3Cl (10 mL) and passed through a 1 cm × 25 cm silica
column using 5% MeOH/CHCl3 eluent. The slow major band
was collected and evaporated to yield the title compound in
77% (150 mg) yield, mp 300 °C. UV/Vis [CH2Cl2, λ max (ꢀ)]: 405
(177, 800), 503 (14, 000), 537 (4, 500), 571 (5, 200); 623 (1,
1
(100 300); 499 (31 000); 592 (26 000); 646 (40 000)]. H NMR
(400 MHz, CDCl3): δ 9.90, 9.62, 9.22 (each s, 1H, 3 × meso
H); 7.90, 7.70 (each d, H, phenyl H) and 7.20 (m, 2H, phenyl
H); 4.30 and 4.25 (each t, 2H, 2 × CH2 CH2CO2CH3), 4.10 (s,
3H, OCH3); 4.00 (q, 2H, ring A CH2 CH3); 3.69, 3.68 (each s,
3H, CH2CH2CO2CH3); 3.46, 3.48 (each s, 3H, 2 × ring CH3);
3.20 (m, 4H, 2 × CH2CH2 CO2CH3); 2.40 (q merged with s, 5H,
ring B CHCH and 3-CH3); 1.70 (t, 3H, ring A CH2CH3 ); 1.50
(s, 3H, ring B CH3); 0.50 (t, 3H, 8-CH2CH3); -2.38 (s, 2H,
2NH). HRMS calcd for C43H50N4O7: 734. 3679; Found: 734.
3670. Anal. Calcd for C43H50N4O7: C, 70.28, H, 6.86, N, 7.62.
Found: C, 69.71, H, 6.80, N, 7.99.
The most polar band was isolated in minor amount (10 mg)
and was characterized as dihydroxybacteriochlorin 38 as an
isomeric mixture. UV/vis [CH2Cl2, λ max (ꢀ)]: 379 (121 000);
478 (11 000); 508 (24 000); 712 (55 000). HRMS calcd for
C43H52N4O9: 768.3628 - 18 (H2O) ) 750.3628; Found 750.3594.
Anal. Calcd for C43H52N4O9: C, 67.12; H, 6.82; N, 7.29.
Found: C, 67.32; H, 6.74, N, 7.39.
2,8-Dieth yl-7,8-vic-d ih yd r oxy-13,17-bis(2-m eth oxyca r -
bon yleth yl)-5-(3,5-d im eth oxyp h en yl)-3,7,12,18-tetr a m e-
th ylp or p h yr in (33). The dimethoxyphenylporphyrin 6 (100
mg) was dissolved in CH2Cl2 (20 mL) and pyridine (0.25 mL)
and reacted with OsO4 (90 mg) in ether (2 mL) for 6 h. The
major band was isolated after the standard workup described
for 32, and the desired product was isolated in 55% (57 mg)
yield as a green solid, mp 237-240 °C. UV/vis: [CH2Cl2, λmax
(ꢀ)] 396 (100, 300); 499 (31, 000); 592 (25, 000); 646 (39, 900)].
1H NMR (400 MHz, CDCl3): δ 9.87, 9.63, 9.23 (each s, 1H, 3
× meso H), 7.26, 6.98, 6.85 (each s, 1H, phenyl H); 4.28, 4.17
(each t, 2H, 2 × CH2 CH2CO2CH2); 4.00 (q, ring A CH2); 3.98,
3.89, 3.69, 3.66, 3.49, 3.45, 2.52 (each s, 3H, 2 × CH2CH2-
CO2CH3 and 2 × OCH3 and 3 × ring CH3); 3.17 (m, 4H, 2 ×
CH2CH2 CO2CH3); 2.38 (q, 2H, ring 8-CH2CH3 ); 1.60 (s, 3H,
ring B CH3); 0.55 (t, 3H, ring B CH2CH3 ); -2.33 (s, 2H, 2 ×
NH). Anal.Calcd. for C44H52N4O8: C, 69.09; H, 6.85; N, 7.32.
Found: C, 68.72; H, 6.79; H, 7.22.
1
500). H NMR (400 MHz, CDCl3): δ 10.07 (s, 2H, 2 meso H);
9.90 (s, 1H, meso H); 7.78 and 7.12 (each m, 2H, phenyl H);
4.20 (m, 4H, 2 × CH2 CH2CO2CH3); 4.00 (q, 2H, 2 × CH2CH3);
3.62 (m, 12H, 2 × CH2CH2CO2CH3 and 2 × ring CH3); 2.50 (s,
6H, 2 × ring CH3); 1.75 (m, 6H, 2 × CH2 CH3 ); -2.22 (br s,
2H, 2x NH). HRMS Calcd for C42H46N4O5: 686. 3468; Found:
686.3450. Anal. Calcd for C42H46N4O5: C, 73.45; H, 6.75; N,
8.16. Found: C, 73.26; H, 6.61; N, 7.85.
Gen er a l P r oced u r e for th e Syn th esis of P or p h yr in s
29, 30. Porphyrin 28 (100 mg) was dissolved in acetonitrile
(40 mL), and the related 1-bromoalkane (1-bromohexane for
29, 1-bromoheptane for 30) (1.5 mL) was added along with
anhydrous potassium carbonate (200 mg). The reaction mix-
ture was refluxed under nitrogen for 48 h. It was then diluted
with dichloromethane and washed with water, and the organic
layer separated and dried over anhydrous sulfate. Evaporation
of the solvent gave a residue which was chromatographed over
an alumina (Grade III) column eluted with dichloromethane.
The major band was collected, and the residue obtained after
evaporating the solvent was crystallized from CH2Cl2/hexane
as fluffy light red solid.
Compound 29 was isolated in 89% (100 mg) yield, mp 263-
266 °C. UV/vis [CH2Cl2, λ max (ꢀ): 402 (110 000); 502 (16 700),
535 (11 700); 625 (8 700)]; 1H NMR (400 MHz, CDCl3): δ 10.06
(s, 2H, 2 × meso H); 10.00 (s, 1H, meso H); 7.80 and 7.30 (each
d, 2H, phenyl); 4.40 (m. 4H, CH2 CH2CO2CH3); 4.30 (t, 2H,
OCH2); 4.10 (m, 4H, CH2 CH3); 3.70 (m, 12H, 2 × CH3 and 2
× CH2CH2CO2CH3); 3.25 (q, 4H, CH2CH2 CO2CH3); 2.52 (s,
6H, 2 × ring CH3); 0.78, 0.98-2.01 (several m, total 11H, (CH2
(CH2)4 CH3); 1.10 (t, 6H, 2 × CH2 CH3 ); -3.21 and -3.31 (each
s, 1H, 2 × NH). Anal. Calcd for C48H58N4O5: C, 74.78; H, 7.58;
N, 7.27. Found: C, 73.90; H, 7.76; N, 6.83.
2,8-Diet h yl-5-(4′-h exyloxylp h en yl)-7,8-d ih yd r oxy-13,-
17-bis(2-m eth oxycar bon yleth yl)-3,7,12,18-tetr am eth ylpor -
p h yr in (34). The title compound was prepared by reacting
porphyrin 29 (50 mg) with osmium tetraoxide (50 mg), follow-
ing the procedure discussed for the foregoing dihydroxy
analogue, and was obtained in 70% (36 mg) yield, mp 122-
124 °C. UV-vis [CH2Cl2, λmax (ꢀ)]: 398 (134 500); 500 (14 000);
646 (34 000). 1H NMR (400 MHz, CDCl3): δ 9.86, 9.63, 9.22
(each s, 1H, 3 × meso H); 7.90, 7.65, 7.25, 7.15 (each dd, 1H,
4 phenyl H); 4.32 (t, 2H, OCH2); 4.15 (m, 4H, 2 × CH2CH2-
COOCH3); 3.95 (m, 2H, 2-CH2CH3); 3.68 (s, 3H), 3.66 (s, 3H),
3.48 (3H), 3.44 (s, 3H) (2 × COOCH3, 2 × ring CH3); 3.17 (q,
4H, 2 × CH2CH2CO2CH3); 2.4 (s, 3H, ring-CH3); 2.36 (m, 2H,
8-CH2CH3); 1.48 (s, 3H, 7-CH3); 1.95, 1.68-1.25, 0.92 (several
m, 8H, OCH2(CH2)4CH3, 6H, 2 × CH2CH3); 0.55 (t, 3H,
O(CH)5CH3). HRMS calcd for C48H60N4O7: 804.4540. Found
(FAB): m/e 805.4554 (M + 1).
Compound 30: mp. 268-270. UV/vis (ꢀ): 402 (112 000); 502
(17 700), 535 (12 700); 625 (9 000)]; 1H NMR (400 MHz, CDCl3):
δ 10.15 (s, 2H, 2 × meso H); 9.95 (s, 1H, meso H); 7.90 and
7.26 (each d, 2H, phenyl); 4.40 (m. 4H, CH2 CH2CO2CH3); 4.26
(t, 2H, OCH2); 4.06 (m, 4H, CH2 CH3); 3.67 (12H, 2 × CH3 and
2 × CH2CH2CO2CH3); 3.30 (q, 4H, CH2CH2 CO2CH3); 2.52 (s,
6H, 2 × ring CH3); 0.72, 0.98-2.01 (several m, total 13H, (CH2
(CH2)5CH3); 1.08 (t, 6H, 2 × CH2 CH3 ); -3.21 and -3.31 (each
s, 1H, 2 × NH). HRMS calcd for C49H60N4O5: 784. 4557. Found
785. 4560 (M + 1).
2, 8-Dieth yl-5-(4′-h ep tyloxylp h en yl)-7,8-d ih yd r oxy-13,-
17-bis(2-m eth oxycar bon yleth yl)-3,7,12,18-tetr am eth ylpor -
p h yr in (35). Reaction of porphyrin 30 (40 mg) with osmium
tetraoxide (40 mg) afforded the title compound in 68% (28 mg)
yield, mp 132-134 °C. UV-vis [CH2Cl2, λmax (ꢀ)]: 398 (134 000);
500 (14 500); 646 (34 500). 1H NMR (400 MHz, CDCl3) δ 9.86,
2,8-Dieth yl-7,8-vic-d ih yd r oxy-13,17-bis(2-m eth oxyca r -
b on ylet h yl)-5-(4′-m et h oxyp h en yl)-3,7,12,18-t et r a m et h -

3938 J . Org. Chem., Vol. 66, No. 11, 2001
Chen et al.
9.64, 9.22 (each s, 1H, 3 × meso H); 7.92, 7.66, 7.25, 7.16 (each
dd, 1H, 4-phenyl H); 4.32 (t, 2H, OCH2); 4.20 (m, 4H, 2 × CH2-
CH2COOCH3); 3.95 (m, 2H, 2-CH2CH3); 3.68 (s, 3H), 3.66 (s,
3H), 3.48 (3H), 3.44 (s, 3H) (2 × COOCH3, 2 × ring CH3); 3.18
(q, 4H, 2 × CH2CH2COOCH3); 2.41 (s, 3H, 3-CH3); 2.36 (m,
2H, 8-CH2CH3); 1.50 (s, 3H, ring-CH3); 1.95, 1.70-1.27, 0.95
(several m, 10H, OCH2(CH2)5CH3, 6H, 2 × CH2CH3); 0.5 (t,
3H, O(CH2)5CH3). HRMS calcd for C49H62N4O7: 818.4611.
Found: 818.4622.
0.52 (t, 3H, CH2CH3). Anal. Calcd for C37H48N4O3: C, 74.46;
H, 8.10; N, 9.38. Found: C, 74.26; H, 8.36; N, 8.68.
2,7-Dieth yl-13,17-(2-m eth oxyca r bon yleth yl)-5-(4-m eth -
oxyp h en yl)-3,7,12,18-tetr a m eth yl-8-k etoch lor in (43). The
vic-dihydroxy porphyrin 32 (100 mg) was treated with con-
centrated H2SO4 (10 mL) for 30 min at room temperature
under a nitrogen atmosphere. The reaction mixture was
poured in ice-cold water and extracted with dichloromethane.
The dichloromethane layer was washed with aqueous sodium
bicarbonate and again with water. The organic layer was dried
over anhydrous sodium sulfate. The crude residue obtained
after evaporating the solvent was purified by preparative
plates using 5% methanol/dichloromethane as eluting solvents.
The title product was crystallized from dichloromethane/
hexane as a green powder. Yield: 40% (39 mg), mp 255-258
°C. UV/vis [CHCl2, λmax (ꢀ): 408 (180 000); 511 (17 500); 550
(16 600); 589 (13 200); 646 (33 900)]. 1H NMR (400 MHz,
CDCl3): δ 10.00, 9.98, and 9.80 (each s, 1H, 3 × meso H); 7.82,
7.12 (each m, 4H phenyl); 4.37 and 4.25 (each t, 2H, 2 × CH2-
CH2CO2CH3); 4.20 (s, 3H, OCH3); 4.12 (q, 2H, 2-CH2CH3); 3.75,
3.73, 3.67, 3.52, 2.40 (each s, 3H, 2 × CH2CH2CO2CH3 and 3
× ring CH3); 3.25 (m, 4 h, 2 × CH2CH2CO2CH3); 2.38 (q, 2H,
7-CH2CH3); 1.60 (s, 3H, 7-CH3); 0.50 (t, 3H, 7-CH2CH3); -2.17
2, 8-Dieth yl-5-(4′-d ecyloxylp h en yl)-7,8-d ih yd r oxy-13,-
17-bis(2-m eth oxycar bon yleth yl)-3,7,12,18-tetr am eth ylpor -
p h yr in (36). Porphyrin 31 (60 mg), prepared by reacting the
hydroxyphenylporphyrin (65 mg) 29 with 1-iododecane (1 mL),
was treated with osmium tetraoxide (60 mg) by following the
method discussed for the preparation of the related heptyl
analogue 35 and was obtained in 72% (63 mg) yield, mp 135-
137 °C. UV-vis [CH2Cl2, λmax (ꢀ)]: 398 (133 500); 500 (13 200);
646 (33 500). 1H NMR (400 MHz, CDCl3): δ 9.86, 9.64, 9.22
(each s, 1H, 3 × meso H); 7.92, 7.66, 7.25, 7.16 (each dd, 1H,
phenyl H); 4.30 (t, 2H, OCH2); 4.20 (m, 4H, 2 × CH2CH2-
COOCH3); 3.95 (m, 2H, 2-CH2CH3); 3.68 (s, 3H), 3.66 (s, 3H),
3.48(3H), 3.44 (s, 3H) (2 × COOCH3, 2 × ring CH3); 3.18 (q,
4H, 2 × CH2CH2COOCH3); 2.41 (s, 3H, 3-CH3); 2.36 (m, 2H,
8-CH2CH3); 2.18, 2,12, 2.0-0.84 (several m, 16H, OCH2(CH2)8-
CH3, 6H, 2 × CH2CH3, 3H, 7-CH3); 0.5 (t, 3H, O(CH)5CH3).
HRMS calcd for C52H68N4O7: 861.5166. Found: 861.5146
7,8-vic-Dih ydr oxy-3,8-dieth yl-5-h eptyl-17,18-bis(2-m eth -
oxyca r bon yleth yl)-3,7,12,18-tetr a m eth ylch lor in (37). Por-
phyrin 7 (200 mg) was reacted with OsO4 (150 mg) by following
the methodology discussed for the synthesis of the other diols.
The product obtained after the standard workup was purified
by silica column chromatography eluting with 5% methanol/
dichloromethane. The title compound was obtained in 65% (136
mg) yield, mp 155-159 °C. UV-vis [CH2Cl2, λmax (ꢀ)]: 402
(130 000); 504 (13 250); 648 (29 500). 1H NMR (400 MHz,
CDCl3): δ 9.75, 9.56, 0.9.00 (each s, 1H, 3 × meso H); 4.65
(m, 2H, CH2(CH2)5CH3); 4.25 (m, 2H, CH2CH2 COOCH3); 4.15
(m, 2H, CH2CH2CO2CH3); 4.02 (m, 2H, 3-CH2CH3); 3.68, 3.64,
3.52, 3.45, 3.41 (each s, 2 × COOCH3, 3 × ring CH3); 3.15 (m,
4H, 2 × CH2CH2COOCH3); 1.9-0.75 (several m, 3H, CH3, 6H,
2 × CH2CH3, 2H, CH2CH3, 13H, CH2(CH2)5CH3). HRMS Calcd
for C43H58N4O6: 726.4434 Found (FAB): m/e 727.4458 (M +
1).
and -2.75 (each s, 1H,
43H48N4O6: 716.3573; Found: 716. 3555.
2,7-Die t h yl-13,17-(2-m e t h oxyca r b on yle t h yl)-5-(3,5-
2
×
NH). HRMS Calcd for
C
d im et h oxyp h en yl)-3,7,12,18-t et r a m et h yl-8-k et och lor in
(44). The vic-dihydroxy porphyrin 33 (100 mg) was treated
with concentrated H2SO4 by following the methodology de-
scribed for ketochlorin 43, and the title compound was obtained
in 42% (41 mg) yield. mp 245-250 °C. UV/vis [CHCl2, λmax (ꢀ):
410 (185 000); 510 (17 000); 550 (16 500); 590 (13 000); 645
1
(34 000)]. H NMR (400 MHz, CDCl3): δ 9.99, 9.98, and 9.86
(each s, 1H, 3 × meso H); 7.16, 7.12, and 6.87 (each s, 1H,
phenyl); 4.37 and 4.23 (each t, 2H, 2 × CH2CH2CO2CH3); 4.03
(q, 2H, 2-CH2CH3); 3.92 (s, 6H, 2 × OCH3); 3.67, 3.66, 3.61,
3.49, 2.56 (each s, 3H, 2 × CH2CH2 CO2CH3 and 3 × ring CH3);
3.25 (m, 4H, 2 × CH2CH2 CO2CH3); 2.40 (q, 2H, 7-CH2CH3);
1.76 (s, 3H, 7-CH3); 0.30 (t, 3H, 7-CH2CH3); -2.18 and -2.78
(each s, 1H, 2 × NH). HRMS calcd for C44H50N4O7: 746.3673;
Found: 746.3565.
3,7-Dieth yl-5-h ep tyl-8-k eto-13,17-bis(2-m eth oxyca r bo-
n yleth yl)-3,7,12,18-tetr a m eth ylch lor in (45) a n d 2,8-Di-
eth yl-5-h eptyl-7-keto-13,17-bis(2-m eth oxycar bon yleth yl)-
3,8,12,18-tetr am eth ylch lor in (46).Thevic-dihydroxyporphyrin
37 (40 mg) was treated with 93% H2SO4 (10.0 mL) for 50 min
at room temperature and under nitrogen atmosphere. The two
isomers 45 and 46 were isolated in 46% (18.0 mg) and 36%
(14.0 mg) yields, respectively.
3,7-Dieth yl-7,8-d ih yd r oxy- (39), 3,7-d ieth yl-17,18-d ih y-
d r oxy- (40), a n d 7,8,17,18-tetr a h yd r oxy-5-m eth oxyca r -
bon yl-13,17-(2-m eth oxyca r bon yleth yl)-2,8,12,18-tetr a m -
eth ylch lor in (41). Porphyrin 8 (100 mg) was reacted with
OsO4 (100 mg) by following the procedure as discussed above.
Two major bands were isolated: the less polar band was found
to be a mixture of dihydroxychlorins 39 and 40 and could not
Com p ou n d 45. mp 133-136 °C. UV-vis [CH2Cl2, λmax (ꢀ)]:
1
1
be purified to individual isomer. The H NMR spectrum of the
413 (154 600); 516 (14 500); 650 (26 000). H NMR (400 MHz,
mixture was quite complex, and it was difficult to assign the
CDCl3): δ 9.93 (s, 1H, 20-meso H); 9.88 (s, 1H, 10-meso H);
9.76 (s, 1H, 15-meso H); 4.92 (m, 2H, CH2(CH2)5CH3); 4.36 (t,
2H, CH2CH2CO2CH3), 4.22 (t, 2H, CH2CH2COOCH3), 4.12 (m,
2H, CH2CH3); 3.67, 3.65, 3.60, 3.58, 3.48 (each s, 3H, 3 × CH3,
2 × CH2CH2 CO2CH3); 3.22 (m, 4H, 2 × CH2CH2COOCH3);
2.76 (m, 2H, CH2CH3); 2.25-0.80, 0.3 (several m, 16 H, 7-CH3,
3H, 2-CH2CH3, CH2(CH2)5CH3); 0.92 (t, 3H, 7-CH2CH3); -2.2,
-2.7 (each s, 1H, 2 × NH). Anal .Calcd for C43H56N4O5: C,
72.85; H, 7.96; N, 7.90. Found: C, 72.39; H, 8.44; N, 7.75.
Com p ou n d 46. mp 123-126 °C. UV-vis [CH2Cl2, λmax (ꢀ)]:
412 (176 000); 515 (14 500); 642 (26 400). 1H NMR (400 MHz,
CDCl3): δ 9.92 (s, 1H, 10- H); 9.57 (s, 1H, 15- H); 8.98 (s, 1H,
20-H); 5.48 (m, 1H, CH2 (CH2)5CH3); 4.56 (m, 1H, CH2(CH2)5-
CH3); 4.32 and 4.18 (t, 2H each, CH2CH2COOCH3); 4.08 (m,
2H, 2-CH2CH3); 3.72 (s, 6H, 2 × CH2CH2CO2CH3); 3.60, 3.52,
3.46 (each s, 3H, 3 ring CH3); 3.24, 3.19 (each t, 2H, 2 ×
CH2CH2CO2CH3); 2.70 (2H, 8-CH2CH3); 1.77 (t, 3H, 8-CH2CH3);
1.54, 1.38 (two m, 13H, CH2(CH2)5CH3 and 8-CH3); 0.92 (t, 3H,
8-CH2CH3); 0.35 (t, 3H, CH2(CH2)5CH3); -2.00, -2.32 (each s,
1H, 2 × NH). Anal. Calcd for C43H56N4O5: C, 72.85; H, 7.96;
N, 7.90. Found: C, 72.95; H, 8.54; N, 8.15.
resonances of all the protons. HRMS calcd for C38H46N4O7
-
H2O ) C38H44N4O6 ) 668.3210. Found 668.3194. The most
polar band was characterized as one of the possible isomers
of tetrahydroxybacteriochlorin 41, mp > 300 nm. 1H NMR (400
MHz, CDCl3): δ 8.91. 8.10, 8.09 (each s, 1H, 3 × meso-H); 3.80
(t, 2H, ring C, CH2CH2CO2CH3); 4.28 (s, 3H, CO2CH3); 3.66,
3.48, 3.30, 3.01 (each s, 3H, 2 × CH2CH2CO2CH3 and 2 × ring
CH3); 2.90 (t, 2H, ring C, CH2CH2 CO2CH3); 3.60 (q, 2H, ring
A CH2CH3); 2.40-2.60 (4 h, ring D CH2CH2CO2CH3); 2.38 (q,
2H, ring B CH2CH3); 2.34 and 2.13 (each s, 3H, ring B and
ring D CH3); 1.51 (t, 3H, ring A CH2CH3 ); -0.40 (t, 3H, ring
B CH2CH3); -2.27 and -2.32 (each s, 1H, 2 × NH). Anal. Calcd
for C38H48N4O10: C, 63.30, H, 6.71; N, 7.77. Found: C, 63.94;
H, 6.64; N, 7.92.
7,8-vic-Dih yd r oxy-5-for m yl-2,3,7,8,12,13,17,18-octa eth -
ylch lor in (42). 5-Formyloctaethylporphyrin 10 (200 mg) was
reacted with OsO4 (150 mg) for 16 h, and the title compound
was isolated in 63% (134 mg) yield, mp 255-258 °C. UV-vis,
[CH2Cl2, λmax, (ꢀ)]: 403 (114 700); 501 (12 000); 550 (10 000);
663 (33 000); 693 (18 000). 1H NMR (400 MHz, CDCl3): δ 11.65
(s, 1H, CHO); 9.45, 9.32, 8.70 (each s, 1H, 3 × meso H); 8.13
(s, 1H, OH); 3.96-3.62 (m, 12H, CH2CH3); 2.68-2.32 (m, 4H,
CH2CH3); 1.82-1.68 (m, 18H, CH2CH3); 1.15 (t, 3H, CH2CH3);
5-F or m yl-7-k etoocta eth ylch lor in (47). The vic-dihydroxy
porphyrin 42 (40 mg) was treated with 93% H2SO4 (10 mL)
for 50 min at room temperature under a nitrogen atmosphere.

Pinacol-Pinacolone Rearrangement of vic-Dihydroxyporphyrins
J . Org. Chem., Vol. 66, No. 11, 2001 3939
After the standard workup, the title compound was obtained
in quantitative yield (39 mg), mp 257-259 °C. UV-vis [CH2-
Cl2, λmax (ꢀ)]: 412 (211 800); 515 (17 100); 553 (18 500); 590
(13 300); 644 (41 000). 1H NMR (400 MHz, CDCl3): δ 12.56
(s, 1H CHO); 10.04, 9.84 (each s, 1H, 15, 20-meso H); 9.16 (s,
1H, 10-H); 4.07-3.82 (m, 10H, 5 × CH2CH3); 3.76 (q, 2H, CH2-
CH3); 2.72 (q, 4H, 2 × CH2CH3); 1.9-1.79 (m, 15H, 5 ×
CH2CH3); 1.65 (t, 3H, CH2CH3); 0.42 (t, 6H, 2 × CH2CH3).
Anal. Calcd for C37H46N4O2: C, 76.78; H, 8.01; N, 9.68.
Found: C, 76.56; H, 8.21; N, 9.47.
05577), and the Oncologic Foundation of Buffalo. Partial
support by shared resources of the Roswell Park Cancer
Support Grant (P30CA16056) is also acknowledged.
Mass spectrometry analyses were performed by the
Mass Spectrometry Facility, Michigan State University,
East Lansing, and UCSF Mass Spectrometry Facility,
supported by the Biomedical Research Technology
Program of the National Center for Research Resources,
NIH NCRR BRTP01614. C.J .M. gratefully acknowl-
edges financial support from Prof. J . A. Shelnutt (Sandia
National Laboratories, University of New Mexico).
Ack n ow led gm en t. This work was supported by
grants from the National Institutes of Health (CA
55791), the National Science Foundation (CHE-93-
J O0100143