Pinacol-Pinacolone Rearrangements in vic-Dihydroxychlorins and Bacteriochlorins: Effect of Substituents at the Peripheral Positions

Article abstract of DOI:10.1021/jo960720h

Upon reaction with osmium tetraoxide a series of porphyrins and chlorins were converted into the corresponding vic-dihydroxychlorins and bacteriochlorins. The presence of an electron-withdrawing substituent at a peripheral position on the porphyrins or chlorins deactivated that particular pyrrole unit toward oxidation, and also directed the oxidation regioselectively to the pyrrole ring opposite to the one bearing the electronegative group. The vic-dihydroxychlorins and bacteriochlorins were converted into the corresponding oxochlorins and dioxobacteriochlorins under pinacol-pinacolone reaction conditions. The migratory behavior of the various substituents were found to be quite complex, since distant conjugated peripheral substituents were able to affect the stability of the carbocation intermediates during the process; the ability to rearrange was affected not only by the intrinsic nature of the migratory group but also by steric and electronic factors operative elsewhere on the porphyrin and chlorin macrocycles. Preferential migration of the propionic ester over the methyl substituent in dioxobacteriochlorins obtained from 2,3,12,13-tetrahydroxycoproporphyrin II tetramethyl ester (IUPAC nomenclature) under pinacol-pinacolone conditions was confirmed by a single crystal X-ray study. The dioxobacteriochlorins obtained from mesoporphyrin III dimethyl ester and coproporphyrin II tetramethyl ester were converted into the corresponding dithio-analogues using Lawesson's reagent; this caused a red shift of 62 nm (compared with the dioxo compounds) affording long wavelength absorption at λ_max 746 nm.

Full text of DOI:10.1021/jo960720h

J . Org. Chem. 1997, 62, 1463-1472
1463
P in a col-P in a colon e Rea r r a n gem en ts in vic-Dih yd r oxych lor in s
a n d Ba cter ioch lor in s: Effect of Su bstitu en ts a t th e P er ip h er a l
P osition s
Ravindra K. Pandey,*,†,‡ Meden Isaac,† Ian MacDonald,‡ Craig J . Medforth,†
Mathias O. Senge,†,§ Thomas J . Dougherty,‡ and Kevin M. Smith*,†
Department of Chemistry, University of California, Davis, California 95616, and Chemistry Division,
Department of Radiation Biology, Division of Radiation Medicine, Roswell Park Cancer Institute,
Buffalo, New York 14263
Received April 19, 1996X
Upon reaction with osmium tetraoxide a series of porphyrins and chlorins were converted into the
corresponding vic-dihydroxychlorins and bacteriochlorins. The presence of an electron-withdrawing
substituent at a peripheral position on the porphyrins or chlorins deactivated that particular pyrrole
unit toward oxidation, and also directed the oxidation regioselectively to the pyrrole ring opposite
to the one bearing the electronegative group. The vic-dihydroxychlorins and bacteriochlorins were
converted into the corresponding oxochlorins and dioxobacteriochlorins under pinacol-pinacolone
reaction conditions. The migratory behavior of the various substituents were found to be quite
complex, since distant conjugated peripheral substituents were able to affect the stability of the
carbocation intermediates during the process; the ability to rearrange was affected not only by the
intrinsic nature of the migratory group but also by steric and electronic factors operative elsewhere
on the porphyrin and chlorin macrocycles. Preferential migration of the propionic ester over the
methyl substituent in dioxobacteriochlorins obtained from 2,3,12,13-tetrahydroxycoproporphyrin
II tetramethyl ester (IUPAC nomenclature) under pinacol-pinacolone conditions was confirmed
by a single crystal X-ray study. The dioxobacteriochlorins obtained from mesoporphyrin III dimethyl
ester and coproporphyrin II tetramethyl ester were converted into the corresponding dithio-
analogues using Lawesson’s reagent; this caused a red shift of 62 nm (compared with the dioxo
compounds) affording long wavelength absorption at λmax 746 nm.
In tr od u ction
The formation of gem-dialkyl-â-oxoporphyrins with
hydrogen peroxide in acidic media from alkylated por-
phyrins was reported by Fisher et al. in 1940.1 Later,
Bonnett et al.2 and Inhoffen and Nolte3 synthesized vic-
dihydroxyoctaethylchlorin 2 by reacting octaethylpor-
phyrin 1 with OsO4; upon acid catalyzed pinacol-
pinacolone rearrangement the oxochlorin 3 was obtained.
Chang and co-workers4 later reacted a variety of unsym-
metrical porphyrins such as deuteroporphyrin IX di-
methyl ester 4 with OsO4 and, as expected, four possible
vicinal dihydroxychlorins 4a , 4b, 4c, and 4d were ob-
tained in almost equal quantity. Similar results were
obtained with other unsymmetrical porphyrins such as
mesoporphyrin IX dimethyl ester 5 and 3,8-(2-chloro-
ethyl)deuteroporphyrin dimethyl ester 6.5 Treatment of
vic-diols 4, 5, 6 (a , b, c, and d ) under acidic conditions
gave the ketones. The isomeric structure of the oxochlo-
rins was confirmed by nuclear Overhauser enhancements
(NOE) studies.5
* Address correspondence to these authors.
† University of California.
‡ Roswell Park Cancer Institute.
Studies on the migratory aptitude in generic pinacol
rearrangements have been reported since 1950 in various
systems.6 Reaction rates are well documented for various
alkyl and aryl groups with electron-donating and electron-
withdrawing groups. It is generally accepted that the
relative tendency of migration follows as aryl > alkenyl
> alkyl. The reaction has been believed to proceed
stepwise via a carbocation intermediate, similar to Wag-
ner-Meerwein rearrangement.7 According to this mech-
anism, pinacol rearrangement proceeds to the formation
§ Permanent address: Fachbereich Chemie, Institut fu¨r Organische
Chemie (WE 02), Freie Universita¨t Berlin, Takustrasse 3, 14195 Berlin
Dahlem, Germany.
X Abstract published in Advance ACS Abstracts, February 15, 1997.
(1) (a) Fischer, H.; Orth, H. Die Chemie des Pyrrols; Akademische
Verlag: Leipzig, 1937; Vol. 2, part 1, p 269. (b) Fischer, H.; Pfeiffer,
H. Liebigs Ann. Chem. 1944, 556, 131.
(2) (a) Bonnett, R.; Dolphin, D.; J ohnson, A. W.; Oldfield, D.;
Stephenson, G. F. Proc. Chem. Soc., London 1964, 371. (b) Bonnett,
R.; Dimsdale, M. J .; Stephenson, C. F. J . Chem. Soc.(C) 1969, 564.
(3) Inhoffen, H. H.; Nolte, W. Liebigs Ann. Chem. 1969, 725, 167.
(4) Chang, C. K.; Sotiriou, C. J . Heterocycl. Chem. 1985, 22, 1739.
(5) (a) Sotiriou, C.; Chang, C. K. J . Am. Chem. Soc. 1988, 110, 2264.
(b) Chang, C. K.; Sotiriou, C.; Wu, W. J . Chem. Soc., Chem. Commun.
1986, 1213.
(6) Stiles, M.; Mayer, R. P. J . Am. Chem. Soc. 1959, 81, 1497.
S0022-3263(96)00720-7 CCC: $14.00 © 1997 American Chemical Society

1464 J . Org. Chem., Vol. 62, No. 5, 1997
Pandey et al.
substituents during acid-catalyzed rearrangement of the
vicinal diol to ketone.
Resu lts a n d Discu ssion
For our study, a series of porphyrins and chlorins with
and without electron-withdrawing substituents were
used as substrates. Etioporphyrin II 7 was prepared by
following the literature procedure.10 Mesoporphyrin III
dimethyl ester (40%) 8 and coproporphyrin II tetramethyl
ester (42%) 9 were prepared by reacting the diformyl-
dipyrromethane 1010 with dipyrromethane dicarboxylic
acids 1111 and 12, respectively, under McDonald12 condi-
tions. 3-Acetyl- 13 and 8-acetyl-deuteroporphyrin IX
of a carbonyl compound via a 1,2-shift of the R group in
the intermediate â-hydroxycarbocation. Recently, how-
ever, on the basis of molecular orbital calculations,
Nakamura and Osamura8 reported the possibility of a
concerted mechanism without a carbocation intermediate
in the pinacol rearrangement. The migratory aptitude
of the hydride, methyl, vinyl, and cyclopropyl groups were
calculated theoretically. The energy barriers for methyl
migration and hydrogen migration were found to be 27.1
and 23.1 kcal/mol, respectively, indicating that hydrogen
migration is preferred over methyl migration.
In this paper we report our studies on: (i) the synthesis
of a series of porphyrins and chlorins with and without
electron-withdrawing groups attached at peripheral posi-
tions, (ii) their conversion into vic-dihydroxychlorins, vic-
dihydroxybacteriochlorins (in the case of oxidation of
natural chlorins), and vic-tetrahydroxybacteriochlorins,5b,9
and (iii) the competitive migratory reactions of the
dimethyl ester 14 (IUPAC nomenclature) were prepared
as a mixture from deuteroporphyrin IX dimethyl ester4
by following the standard methodology reported in the
literature.13 The mixture was separated, in gram quanti-
ties, into the individual isomers either by preparative
HPLC or by Chromatotron chromatography. 3,8-Di-
acetyldeuteroporphyrin IX dimethyl ester 15 was ob-
tained in excellent yield by oxidation of hematoporphyrin
IX dimethyl ester 16 (commercially available as the
dicarboxylic acid) with tetrapropylammonium perruth-
enate/N-methylmorpholine N-oxide.14
It has been shown that octaethylporphyrin 1 can be
converted into the tetrahydroxy bacteriochlorin 17 by
reaction with OsO4/H2S; under acidic reaction condi-
tions,15 a mixture of two isomers 18 and 19 was obtained.
(10) Hudson , M. F.; Smith, K. M. Tetrahedron 1975, 31, 3077.
(11) Clezy, P. S.; Fookes, C. J . R.; Liepa, A. J . Aust. J . Chem. 1972,
25, 1979.
(12) Arsenault, G. P.; Bullock, E.; MacDonald, S. F. J . Am. Chem.
Soc. 1960, 82, 4384.
(13) Smith, K. M.; Fujinari, E. M.; Langry, K. C.; Parish, D. W.;
Tabba, H. D. J . Am. Chem. Soc. 1983, 105, 6638.
(14) Pandey, R. K.; Smith, K. M.; Dougherty, T. J . J . Med. Chem.
1990, 33, 2032.
(15) Arasasingham, R. D.; Balch, A. L.; Olmstead, M. M. Heterocycles
1988, 27, 2111.
(7) (a) Saunders, M.; Chandrasekhar, J .; Schleyer, P. v. R. In
Rearrangement in Ground and Excited States; de Mayo, P., Ed.;
Academic Press: New York, 1980; Vol. 1, pp 1-53. (b) Isaacs, N. S.
Reactive Intermediates in Organic Chemistry; Wiley: New York, 1974;
pp 147, 167.
(8) (a) Nakamura, K.; Osamura, Y. J . Phys. Org. Chem. 1990, 3,
737. (b) Nakamura, K.; Osamura, Y. Tetrahedron Lett. 1990, 31, 251.
(9) Kozyrev, A. N.; Dougherty, T. J .; Pandey, R. K. Tetrahedron Lett.
1996, 37, 3781.

Pinacol-Pinacolone Rearrangements
J . Org. Chem., Vol. 62, No. 5, 1997 1465
In order to understand the migratory behavior of various
substituents, tetrahydroxybacteriochlorin 20 (a cis/trans
F igu r e 1. Nuclear Overhauser enhancement connectivities
determined for A: compound 21; B: compound 27; C: com-
pound 28a ; D: compound 30a .
mixture of cis-diols), obtained from etioporphyrin II 7,
was treated with H2SO4, and the isomeric dioxobacterio-
chlorins 21 were isolated as the predominant product.
Splitting of the saturated ring CH3CH2 group resonances
in the proton NMR spectrum indicated the presence of
isomeric forms in 21, but carbon-13 NMR spectra failed
to show evidence of cis/ trans isomerism; NOE experi-
ments (Figure 1A) indicated that the methyl group had
migrated to give 21 as the only regioisomer. Reaction of
porphyrin 8 with OsO4 produced chlorin 22 as a major
product in which a pyrrolic ring substituted with alkyl
substituents (Me, Et) was transformed into the vic-
dihydroxy derivative. Reaction of 8 with excess OsO4
(then H2S) gave bacteriochlorin 24 in 65% yield, along
with a small amount of vic-dihydroxychlorin 22. Follow-
ing similar reaction conditions, coproporphyrin II tet-
ramethyl ester 9 gave chlorin 23 and bacteriochlorin 25,
respectively. Reaction of vic-dihydroxychlorins 22, 23
and bacteriochlorins 24, 25 with H2SO4 under pinacol-
pinacolone conditions produced oxochlorins 26 and 27,
and dioxobacteriochlorins 28a and 30a as major products,
along with 28b and 30b as minor products. The isomeric
structures of all the pinacolone products were confirmed
by 1H NMR spectroscopy. For example, due to symmetry
in bacteriochlorin 30a , the resonance for the meso
protons were observed at 9.69 and 9.10 ppm, each
integrating for two protons, and in dioxobacteriochlorin
30b due to asymmetry associated with the molecule (ring
“B” propionate ester group migrated over the methyl
substituent, and in ring “D” the methyl group migrated
over the propionic ester side chain), the meso protons
were observed at 9.70, 9.60, 8.92, and 8.82 ppm, respec-
tively. Similar results were obtained with bacteriochlorin
24. The preferential migration of the ethyl (to give 26
and 28a ) and the 2-(methoxycarbonyl)ethyl groups (to
give 27 and 30a , respectively) over methyl substituents
was initially confirmed by NOE studies; typical NOE
connectivities for compounds 27, 28a , and 30a are shown
in Figure 1B,C,D, respectively. Unambiguous proof of
the structure of one crystalline isomer and its specific
regiochemistry was obtained from a single crystal X-ray
analysis. Figure 2 shows a view of the molecular
structure of bacteriochlorin 30a .16a The structure shows
the typical geometrical characteristics of a bacterio-
chlorin.16b The C(3)-O(5) bond length, at 1.238(9) Å, is
typical for the oxo-form. However, a slight inequivalency
is found between the bond lengths of C(1)-C(2) at
1.525(10) Å and C(3)-C(4) at 1.471(10) Å, indicating
some degree of participation by the carbonyl group in the
conjugation via the latter bond. As is typical for hydro-
porphyrins, the compound shows an enlarged core with
different center-nitrogen distances of 2.10 Å for the
nitrogen in the reduced (oxo-modified) ring and 2.07 Å
for the pyrrole nitrogen. The macrocycle shows slight
deviations from planarity, the macrocyclic atoms deviat-
ing on average by 0.053 Å from their least-squares
planes. Individual displacements of up to 0.2 Å are
observed for some Câ-positions.
Bacteriochlorin 30b had a strong long wavelength
absorption at 684 nm (ꢀ 90000). Conversion of oxo-(CdO)
(16) (a) The authors have deposited atomic coordinates and a full
structure description for 30a with the Cambridge Crystallographic
Data Center. The structure can be obtained, on request, from the
Director, Cambridge Crystallographic Data Center, 12 Union Road,
Cambridge CB2 1EZ, UK. (b) Barkigia, K. M.; Fajer, J .; Chang, C. K.;
Young, R. J . Am. Chem. Soc. 1984, 106, 6457. Barkigia, K. M.;
Gottfried, D. S.; Boxer, S. G.; Fajer, J . J . Am. Chem. Soc. 1989, 111,
6444.
(17) Cava, M. P.; Levinson, M. I. Tetrahedron 1985, 41, 5061.

1466 J . Org. Chem., Vol. 62, No. 5, 1997
Pandey et al.
F igu r e 2. Crystal structure determination of dioxobacterio-
chlorin 30a . Hydrogen atoms have been omitted for clarity.
groups to thiono-(CdS) 31b by reaction with Lawesson’s
reagent17 gave a red shift of 62 nm, affording a strong
absorption maximum at 746 nm. By following a similar
approach, dithono derivative 29a was prepared from the
corresponding dioxo analogue 28a . Osmium tetraoxide
reactions with porphyrins 13, 14 (in which the electron-
withdrawing groups are present at position-3 or -8 of the
macrocycle) under similar reaction conditions produced
as major products the vic-dihydroxychlorin 32 and 34,
respectively, in which the hydroxylation occurred at the
pyrrole rings opposite to the electron-withdrawing sub-
stituted pyrroles. These results suggest that in porphy-
rins, the electron-withdrawing groups deactivate both the
pyrrole units to which they are attached and those
immediately adjacent, and a regioselective synthesis of
dihydroxy chlorins can therefore be achieved. Similarly
3,8-diacetyldeuteroporphyrin IX dimethyl ester 15 pro-
duced a mixture of dihydroxychlorins 37 and 38 which
were separated into the individual isomers by preparative
chromatography on silica gel. Pinacol-pinacolone rear-
rangement of vic-dihydroxychlorin 32 produced mainly
the oxochlorin 33 in which the (2-(methoxycarbonyl)ethyl)
group had migrated in preference to the methyl substitu-
ent. Surprisingly, vic-dihydroxychlorin 34 under pina-
col-pinacolone conditions afforded a mixture of oxochlo-
rins 35 and 36. Chlorin 38 (structure was confirmed by
NOE studies), upon treatment with acid, also gave a
mixture of oxochlorins 39 and 40. These compounds were
not studied as their individual isomers. The structures
of chlorins 32 and 34 were confirmed by NOE studies,18
and also by preparation of the respective spirolactones
41 and 43, following the methodology of Sotiriou and
Chang.5 The intramolecular lactonization was found to
be a general base-catalyzed reaction. The formation of
cis-lactones 41 and 43 were accomplished easily by
refluxing the respective diol with methanolic sodium
acetate, while the trans-lactones 42 and 44 were obtained
by epimerization of the corresponding cis- lactones with
1
silica gel. The most obvious feature exhibited by the H
NMR spectra of the lactones is the disappearence of one
methyl singlet due to the formation of the spirolactone
from the OH group and the pyrroline propionic ester side
chain. No methylene protons appear below 3.06 ppm in
1
the 1H NMR spectra. Almost the same pattern of H
NMR peaks was observed for the lactone 41 derived from
8-acetyl-17,18-dihydroxydeuterochlorin IX dimethyl es-
ter, 32, as well as lactones 43 obtained from 3-acetylpor-
phyrin 34. The spirolactone methylene proton signals
overlapped with methyl peaks making further analysis
difficult.
The procedure of Sotiriou and Chang5 was followed in
the conversion of the cis-isomer to the trans-isomer. The
lactones 41 and 43 were loaded separately onto silica gel
plates and then left inside the developing tank overnight
(eluting with 3% methanol/dichloromethane); this gave
compounds 42 and 44, respectively, as the sole products.
Stirring the lactones 41 and 43 with silica gel G overnight
produced the same result; there were no significant
changes in the Rf values before and after exposure to
(18) Pandey, R. K.; Shiau, F.-Y.; Isaac, M.; Ramaprasad, S.; Dough-
erty, T. J .; Smith, K. M. Tetrahedron Lett. 1992, 33, 7815.
1
silica gel. The only difference observed in the H NMR

Pinacol-Pinacolone Rearrangements
J . Org. Chem., Vol. 62, No. 5, 1997 1467
methyl pyropheophorbide-a 45 and chlorin e6 trimethyl
ester 51 with OsO4/NaIO4.
Reaction of methyl mesopyropheophorbide-a 47 with
OsO4/pyridine gave the dihydroxy bacteriochlorin 54 with
cis-vicinal hydroxyl pairs either up or down (relative to
ring D). When subjected to acid treatment, diol 54 gave
the oxobacteriochlorin 61 in which the migrating group
was ethyl (NOE studies). By following a similar ap-
proach, mesochlorin e6 trimethyl ester 52 was converted
into vic-dihydroxy bacteriochlorins 59, which, under
pinacol-pinacolone reaction conditions gave oxochlorin
isomers 65. Similarly 57, obtained by OsO4 oxidation of
methyl 3-de(1-hydroxyethyl)-3-acetylbacteriopheophor-
bide-d 50 (prepared from bacteriopheophorbide-d 49 by
oxidation with tetra-n-propylammonium perruthenate/
spectra (for example of compounds 43 and 44) is the
chemical shift pattern of the methyl resonances. Over-
lapping peaks in the region where the methylene signals
appear make other assignments difficult. Currently,
efforts are being made to grow good crystals for confir-
matory X-ray studies.
In order to understand the effect of electron-withdraw-
ing substituents upon the migratory behavior of alkyl
substituents in the chlorin series, methyl mesopy-
ropheophorbide-a 47, methyl 3-formylpyropheophorbide-a
46, methyl 3-de(1-hydroxyethyl)-3-acetylbacteriopheophor-
bide-d 50 [obtained from 49 by oxidation of the 3-sub-
stituent with tetra-n-propylammonium perruthenate/N-
methylmorpholine N-oxide (NMO)], mesochlorin e6
trimethyl ester 52, and 3-formylchlorin e6 trimethyl ester
53 were used as substrates. Methyl mesopyropheophor-
bide-a 47 and mesochlorin e6 trimethyl ester 52 were
obtained in quantitative yield by catalytic hydrogenation
of methyl pyropheophorbide-a 45 and chlorin e6 trimethyl
ester 51, respectively. Formyl derivatives 46 and 53 were
prepared (in 80 and 75% yields, respectively) by reacting
F igu r e 3. Nuclear Overhauser enhancement connectivities
determined for compound 64.

1468 J . Org. Chem., Vol. 62, No. 5, 1997
Pandey et al.
Exp er im en ta l Section
General details are as previously described.19 Carbon-13
NMR spectra were measured on a GE QE 300 spectrometer,
at 75 MHz. Mass spectra were measured at the Mass
Spectrometry Facility, University of California, San Francisco.
Cr ysta l Str u ctu r e An a lysis of 30a . Crystals suitable for
X-ray analysis could only be grown with difficulty due to the
presence of a mixture of cis/trans isomers. Very small black
parallelpipeds were finally obtained by slow evaporation of a
solution of the compound in dichloromethane/methanol. Crys-
tal data at 130 K (Cu KR radiation, λ ) 1.54178, 2Θmax
)
108.5°), monoclinic, space group P21/n, a ) 12.248(6) Å, b )
6.2720(10) Å, c ) 24.113(5) Å, â ) 90.62(3)°, V ) 1852.3(10)
Å3, Z ) 2, R ) 0.092, Rw ) 0.124 for 1517 reflections with F >
3.0σ(F) and 244 parameters.
NMO) gave cis/ trans oxobacteriochlorins 64 as the sole
regioisomer after reaction with H2SO4. Figure 3 shows
the NOE connectivities observed in the proton NMR
spectrum of 64. Interestingly, under similar pinacol-
pinacolone reaction conditions, the vic-dihydroxy bacte-
riochlorin 55 and 60 (obtained from methyl 3-devinyl-3-
formylpyropheophorbide-a 46 and formylchlorin e6
trimethyl ester 53, respectively) produced a mixture of
oxobacteriochlorins isomeric pairs 62, 63 (from 55) and
66, 67 (from 60).
Meth yl 3-Devin yl-3-for m ylp yr op h eop h or bid e-a (46).
Methyl pyropheophorbide-a 45 (250 mg) [in tetrahydrofuran
(60 mL)], sodium periodate (600 mg) [in water (15 mL) and
dioxane (25 mL)], and osmium tetraoxide (45 mg) [in carbon
tetrachloride (2 mL)] were mixed and then stirred at room
temperature for 2 h. Progress of the reaction was monitored
by spectrophotometry. The mixture was diluted with dichlo-
romethane (200 mL) and washed with 2% aqueous sodium
acetate, and again with water until pH 7. The organic layer
was dried over anhydrous sodium sulfate. Evaporation of the
solvent gave a residue which was chromatographed on alumina
(elution with dichloromethane). The major band was collected,
and after evaporating the solvent the title compound was
crystallized from CH2Cl2/hexane to give 200 mg (80% yield),
mp 188-191 °C. λmax: 386 nm (ꢀ 61 000), 428 (69 500), 521
Our study reveals that in porphyrin and chlorin
systems the regioselective oxidation of pyrrole subunits
in porphyrins by OsO4 is significantly affected by the
presence of electron-withdrawing groups at various points
on the macrocycles. Migratory behavior of the substit-
uents in subsequent pinacol-pinacolone rearrangements
also depends upon the position and the number of the
electron-withdrawing substituents present.
(19) Wallace, D. M.; Leung, S. H.; Senge, M. O.; Smith, K. M. J .
Org. Chem. 1993, 58, 7245.

Pinacol-Pinacolone Rearrangements
J . Org. Chem., Vol. 62, No. 5, 1997 1469
(16 500), 554 (17 000), 632 (13 000), 695 (56 000). 1H NMR
(δ): 11.42 (s, 1H), 10.13, 9.43, 8.76 (each s, 1H), 5.16-5.29 (q,
2H), 4.53 (m, 1H), 4.33 (m, 1H), 3.74 (q, 2H), 3.70 (s, 3H), 3.69,
3.59, 3.20 (each s, 3H), 2.66 (m, 1H), 2.33 (m, 1H), 2.56 (m,
1H), 2.29 (m, 1H), 1.83 (d, 3H), 1.64 (t, 3H), -2.20 (br s, 2H).
HRMS: Calcd for C33H34N4O4: 550.2580. Found: 550.2578.
Anal. Calcd for C33H34N4O4: C, 71.98; H, 6.22; N, 10.17.
Found: C, 71.84; N, 6.18; N, 10.12.
3-Devin yl-3-for m ylch lor in e6 Tr im eth yl Ester (53).
Chlorin e6 trimethyl ester 51 (225 mg) was reacted with OsO4
(50 mg) and NaIO4 (900 mg) by following the procedure
discussed for the foregoing compound; the title product was
isolated in 80% yield (180 mg), mp 257-260 °C. λmax: 417 nm
(ꢀ 49 000), 513 (4800), 546 (5200), 633 (2800), 690 (26 900).
1H NMR (δ): 11.52 (s, 1H), 10.26, 9.62, 8.88 (each s, 1H), 5.25-
5.48 (q, 2H), 4.5 (q, 1H), 4.32 (m, 1H), 3.80 (q, 2H), 4.25, 3.75,
3.72, 3.65, 3.60, 3.40 (each s, 3H), 2.66 and 2.29 (m, each 2H),
1.80 (t, 6H), -1.60 and -1.80 (each s, 1H). Anal. Calcd for:
C35H40N4O7: C, 66.86; H, 6.41; N, 8.91. Found: C, 66.89; H,
6.28; N, 8.53.
Mesop or p h yr in II Dim eth yl Ester (8). Dipyrromethane-
1,9-dicarboxylic acid 11 (1.1 g) and 1,9-diformyldipyrromethane
10 (1.26 g) were dissolved in dichloromethane (250 mL).
p-Toluenesulfonic acid (4.0 g) dissolved in methanol (50 mL)
was added, and the reaction mixture was stirred overnight
under a nitrogen atmosphere. Zinc(II) acetate (4.0 g) dissolved
in methanol (100 mL) was added, and the reaction mixture
was stirred further for 12 h while a slow stream of air was
bubbled through the solution. The dichloromethane layer was
washed with water, aqueous sodium bicarbonate and again
with water. The organic layer was separated and dried over
anhydrous sodium sulfate, and the residue obtained after
evaporating the solvent was treated with TFA (20 mL) for 1 h
under an inert atmosphere. After the standard workup the
residue was chromatographed on alumina (elution with dichlo-
romethane). The major band was collected, and the solvent
was evaporated. The title compound was crystallized from
CH2Cl2/hexane, to give 620 mg (33%), mp 233 °C (lit.20 233
°C). 1H NMR (δ): 10.08 and 10.06 (each s, 2H), 4.40 (t, 4H),
4.07 (q, 4H) ; 3.66 (s, 6H), 3.65, 3.62 (each s, 6H), 3.32 (t, 4H),
1.89 (t, 6H), -3.77 (s, 2H).
flask. The reaction was monitored by analytical TLC and
spectrophotometry. H2S gas was then bubbled through the
solution for 2-3 min, and the mixture was diluted with
dichloromethane. It was then filtered, the black precipitate
was washed several times with dichloromethane, and the
combined eluates were evaporated. The residue was chro-
matographed on a silica gel column (elution with 5% methanol/
dichloromethane). The major band was collected. After
evaporating the solvent the product was crystallized.
3-Acetyl-12,13-d ih yd r oxyd eu ter och lor in IX Dim eth yl
Ester (34). 3-Acetyldeuteroporphyrin IX dimethyl ester 13
(100 mg) was dissolved in dichloromethane (300 mL), reacted
with OsO4 (98 mg, 0.385 mmol) in ether (2 mL) and 15 drops
of pyridine, and stirred ovenight. The mixture was worked
up by following the general method discussed above. The
major brownish green band was collected from the column and
crystallized from dichloromethane/n-hexane to give 71 mg
(68%) of the title compound and 12 mg of starting porphyrin.
Compound 34 had mp 109-110 °C. λmax, 410 nm (ꢀ 158 600),
508 (12 300), 542 (10 700), 580 (8300), 632 (26 700). 1H-NMR
(δ): 10.00 (s, 1H), 9.41 (s, 1H), 8.90 (s, 2H), 8.52 (s, 1H), 4.52
(br s, 2H), 4.05 (t, 2H), 3.71 (s, 3H), 3.52 (s, 3H), 3.40, 3.34
(each s, 6H), 3.27 (s, 3H), 3.01 (t, 2H), 2.89 (s, 3H), 2.75 (m,
2H), 2.61 (m. 2H), 2.12 (s, 3H), -2.51 (br s, 2H). HRMS: Calcd
for C34H38N4O7‚H2O: 596.2629. Found: 596.2648 (38%, M -
H2O) and 520.2489 (100%). Anal. Calcd for C34H38N4O7: C,
66.44; H, 6.23; N, 9.11. Found: C, 66.23; H, 6.18; N, 9.19.
8-Acetyl-17,18-d ih yd r oxyd eu ter och lor in -IX Dim eth yl
Ester (32). The same procedure as above was followed for
cis-hydroxylation of 8-acetyldeuteroporphyrin-IX dimethyl
ester 14 to give the desired dihydroxychlorin in 60% yield along
with 10% of recovered starting compound. Mp 208-209 °C.
λmax
: 412 nm (ꢀ 141 700), 508 (12 600), 546 (12 200), 582
(10 000), 634 (28 400). 1H-NMR (δ): 10.33 (s, 1H,), 9.69 (s,
1H), 9.02, 8.98 (each s, 1H), 8.89 (1H, s), 4.39 (br s, 2H), 4.11
(t, 2H), 3.69, 3.61, 3.40 (each s, 3H), 3.55, 3.50 (each s, 3H),
3.12 (t, 2H), 3.12 (s, 3H), 2.82 (m, 2H), 2.621 (m, 2H), 2.24
(3H, s), -2.16, -2.42 (each br s, 1H). HRMS: Calcd for
C
34H38N4O7‚H2O: 596.2629. Found: 596.2613 (100%, M -
H2O), 520.245782 (82%). Anal. Calcd for C34H38N4O7: C,
66.44; H, 6.23; N, 9.11. Found: C, 66.61; H, 6.18; N, 8.91.
Cop r op or p h yr in II Tetr a m eth yl Ester (9). 1,9-Di-
formyldipyrromethane 10 (1.20 g) was condensed with dipyr-
romethane-1,9-dicarboxylic acid 12 (1.30 g) following the
method discussed above for the foregoing porphyrin; the title
porphyrin was obtained in 30% yield (630 mg), mp 285 °C (lit.21
286-289 °C). 1H NMR (δ): 10.08 and 10.06 (each s, 2H), 4.46
(t, 8H), 3.70-3.75 (s, 24 H), 3.25 (t, 8H), -3.85 (s, 2H).
Meth yl 3-De(1-h ydr oxyeth yl)-3-acetyl-12-eth yl-8-isobu -
tylbacter ioph eoph or bide-d (50). 12-Ethylbacteriopheophor-
bide-d 49 (200 mg) was dissolved in dichloromethane (200 mL),
before addition of tetrapropylammonium perruthenate (20 mg)
and N-methylmorpholine N-oxide (450 mg). The reaction
mixture was stirred for 20 min (monitored by TLC). It was
then diluted with dichloromethane and washed with water,
and the organic layer was separated, dried over anhydrous
sodium sulfate, and evaporated to give a residue, which was
chromatographed on a short column of alumina (elution with
dichloromethane). The major band was collected. Evaporation
of the solvent gave a residue which was crystallized from
CH2Cl2/hexane to give the title compound (180 mg, 90%), mp
174-176 °C. 1H NMR (δ): 9.98, 9.60, 8.76 (each s, 1H), 5.21
(q, 2H), 4.56 (q, 1H), 4.35 (m, 1H), 4.17 (q, 2H), 3.65, 3.62 (each
s, 3H), 3.56 (d, 2H), 3.29, 3.28 (each s, 3H), 2.70-2.20 (m, 5H),
1.96 (t, 3H), 1.81 (d, 3H), 1.21 (d, 6H); 0.00 and -1.97 (each s,
1H). Anal. Calcd for C37H42N4O4: C, 73.24; H, 6.97; N, 9.23.
Found: C, 73.04; H, 7.13; N, 9.29.
R ea ct ion of 3,8-Dia cet yld eu t er op or p h yr in IX Di-
m eth yl Ester w ith OsO4. 3,8-Diacetyldeuteroporphyrin IX
dimethyl ester 15 (250 mg) was reacted with OsO4 (250 mg)
by following the general procedure. After the standard workup
two separate bands were isolated by preparative chromatog-
raphy. Band A: 3,8-Diacetyl-17,18-dihydroxydeuterochlorin-
IX dimethyl ester 37, mp 205-208 °C. λmax: 368 nm (ꢀ 31 300),
420 (106 800), 514 (13 200), 548 (7800), 596 (8100), 650
(28 300). 1H-NMR (δ): 10.04, 9.63 (each s, 1H), 9.43, 8.92 (each
s, 1H), 4.82 (br s, 2H), 4.12 (m, 2H), 3.75, 3.49, 3.26 (each s,
3H), 3.43 (s, 6H), 3.13 (t, 2H), 3.03, 2.92 (each s, 3H), 2.80 (m,
2H), 2.40 (m, 2H), 2.34 (s, 3H), -1.84 (br s, 2H). HRMS: Calcd
for C36H40N4O8: 656.2846. Found: 656.2870. Anal. Calcd for
C36H40N4O8: C, 65.02; H, 6.14; N, 8.53. Found: C, 65.26; H,
6.43; N, 8.13. Band B: 3,8-Diacetyl-12,13-dihydroxydeutero-
chlorin-IX dimethyl ester 38, mp 105-106 °C. λmax: 354 nm
(ꢀ 29 100), 422 (125 100), 516 (14 000), 552 (10 200), 600 (9300),
652 (31 000). 1H-NMR (δ): 10.15 (s, 2H), 9.00, 8.96 (each s,
1H), 4.50 (br s, 2H), 4.25 (m, 2H), 3.69, 3.54, 3.35 (each s, 3H),
3.50, 3.45 (each s, 3H), 3.10 (t, 2H), 3.06 (s, 6H), 2.75 (m, 2H),
2.60 (m, 2H), 2.24 (s, 3H), -2.25 (br s, 2H). HRMS: Calcd for
C
36H40N4O8: 656.2846. Found: 656.2814.
Meth yl cis-7,8-Dih ydr oxym esopyr oph eoph or bide-a (54)
(Isom er ic P a ir ). Methyl mesopyropheophorbide-a 47 was
dihydroxylated in 60% yield following the same procedure as
for 3-acetyldeuteroporphyrin-IX dimethyl ester. The title
product had mp 145-146 °C. λmax: 358 nm (ꢀ 96 000), 371
(69 900), 484 (13 400), 514 (30 800), 636 (16 800), 694 (28 900).
1H-NMR (δ): 8.31, 8.27, 7.90 (each s, 1H), 4.86-4.56 (q, 2H,),
4.03 (q, 1H), 3.82 (m, 1H), 3.61 (s, 3H), 3.53 (q, 2H), 3.18 (s,
3H), 3.04 (s, 3H), 2.47-2.19 (m, 4H), 1.86 (s, 3H), 1.80 (d, 3H),
1.59 (m, 2H), 1.33 (t, 3H), 1.22 (t, 3H), 0.21, 0.11 (each s, 1H).
Anal. Calcd for C34H40N4O5: C, 69.84; H, 6.90; N, 9.59.
Found: C, 69.94; H, 6.93; N, 9.32.
Gen er a l P r oced u r e for OsO4 Rea ction . The porphyrin
or chlorin substrate was dissolved in dichloromethane. A few
drops of pyridine were added, and OsO4 dissolved in ether was
added. The reaction mixture was stirred overnight in a sealed
(20) Fischer, H.; Orth, H. Die Chemie des Pyrrols; Akademische
Verlag: Leipzig, 1937; Vol. 2, part 1, p 436.
(21) Fischer, H.; Orth, H. Die Chemie des Pyrrols; Akademische
Verlag: Leipzig, 1937; Vol. 2, part 1, p 489.

1470 J . Org. Chem., Vol. 62, No. 5, 1997
Pandey et al.
Meth yl 3-Devin yl-3-for m yl-7,8-d ih yd r oxyba cter iop y-
r op h eop h or bid e-a (55) (1:1 Dia ster eom er ic Mixtu r e of
cis-Diols). Methyl 3-formylpyropheophorbide-a 46 (100 mg)
was reacted with OsO4 by following the general procedure, and
the vic-dihydroxybacteriochlorin 55 was isolated in 74% yield
(70 mg), mp 215-217 °C. λmax: 368 nm (ꢀ 76 600), 506 (9200),
542 (32 400), 688 (10 600), 754 (70 500). 1H NMR (δ): 11.42
(s, 2H,), 8.74, 8.73, 8.94, 8.91, 8.67, 8.66 (each s, 1H), 5.0-
5.20 (q, 4H), 4.41 (q, 2H), 4.23 (m, 2H), 3.65, 3.64 (each s, 6H),
3.53, 3.51 (each s, 3H), 2.40-2.67 (m, 8H), 2.36, 2.27 (s, 3H),
1.84, 1.80 (each d, 3H), 1.16, 1.01 (each t, 3H), 0.10 and 0.00
(each s, 1H), -1.22 (s, 2H). Anal. Calcd for C33H36N4O6: C,
67.79; H, 6.21; N, 9.58. Found: C, 67.92; H, 5.91, H, 9.73.
7,8-Dih yd r oxy-m esoba cter ioch lor in e6 Tr im eth yl Es-
ter (59) (Alm ost 1:1 Dia ster eom er ic Mixtu r e of cis-Diols).
Mesochlorin e6 trimethyl ester 52 (120 mg) was reacted with
OsO4 by following the general method, and after the chro-
matographic purification the title compound was isolated in
63% yield (80 mg), mp 155-158 °C. λmax: 358 nm (ꢀ 86 000),
448 (7500), 478 (9600), 508 (26 500), 652 (11 300), 718 (38 500).
1H NMR (δ): 8.66, 8.47, 8.29 (each s, 1H, major isomer), 5.02
(q, 2H), 4.05-4.30 (m, 2H), 4.17, 3.72, 3.62, 3.30, 3.18 (each s,
3H), 3.70 (q, 2H), 2.1-2.5 (m, 4H), 2.06 (s, 3H), 1.66 (d, 3H),
1.65 (q, 2H), 0.98, 0.82 (each t, 3H) 0.66 and -0.38 (each s,
1H). Anal. Calcd for C37H46N4O8: C, 65.86; H, 6.87; N, 8.30.
Found: C, 65.74; H, 6.92, H, 8.16. HRMS: Calcd for
C37H46N4O8‚H2O: 674.3315. Found: 674.3323.
3-Devin yl-3-for m yl-7,8-d ih yd r oxych lor in e6 Tr im eth yl
Ester (60) (3:2 Dia ster eom er ic Mixtu r e of cis-Diols).
3-Formylchlorin e6 trimethyl ester 53 (100 mg) was converted
into the title compound in 62% yield upon reaction with OsO4
by following the general method. The product had mp 143-
146 °C. λmax: 369 nm (ꢀ 82 300), 528 (31 400), 690 (11 600),
750 (70 100). 1H NMR (δ): 11.06 (s, 1H, major isomer), 10.91
(s, 1H, minor isomer), 9.32, 8.82, 8.53 (each s, 1H, major), 9.38,
8.56 and 8.48 (each s, 1H, minor), 5.25 (q, 4H), 4.22, 3.75, 3.67,
3.52, 3.43 (each s, 3H, major), 1.60-1.70 (m, 4H, minor and
major), 4.22, 3.77, 3.64, 3.36, 3.25 (each s, 3H, minor), 1.98-
2.70 (m, 8H), 2.25 (s, 3H, major), 2.20 (s, 3H, minor), 1.70 (d,
3H, major), 1.60 (d, 3H, minor), 0.70 (t, 3H, minor), 0.42 (t,
3H, major), -0.70, -0.85, -0.90 and -1.00 (each s, 1H).
HRMS: Calcd for C36H42N4O9: 674.2945. Found: 674.2930.
Rea ction of Meth yl 3-De(2-h yd r oxyeth yl)-3-a cetyl-12-
eth yl-8-isobu tylp h eop h or bid e-d w ith OsO4 (1:1 Dia ster -
eom er ic Mixtu r e of cis-Diols). Methyl 3-de(1-hydroxyethyl)-
3-acetyl-12-ethyl-8-isobutylpheophorbide-d 50 (80 mg) was
treated with OsO4 (50 mg) as discussed for the preparation of
other cis-dihydroxybacteriopheophorbides, and the title com-
pound was obtained in 59% yield (50 mg), mp: 224-227 °C.
cally 50 mg) were treated with concd H2SO4 (typically 10 mL)
for 30 min at rt and under a nitrogen atmosphere. The
reaction mixture was poured into ice cold water and extracted
with dichloromethane, and the organic layer was washed with
aqueous sodium bicarbonate and then with water. It was then
dried over anhydrous sodium sulfate, evaporated to dryness,
and the crude residue was purified using preparative silica
gel plates (elution with 2% methanol in dichloromethane), or
by column chromatography (silica gel or alumina; typically
eluted with up to 2% methanol in dichloromethane). Most of
the oxochlorins or dioxobacteriochlorins were crystallized from
dichloromethane/hexane.
8,18-Dioxo Der ivative of Etiopor ph yr in II (21). Etiopor-
phyrin II 7 (200 mg) was reacted with OsO4 (400 mg) in
pyridine (0.5 mL); the 7,8,17,18-tetrahydroxybacteriochlorin
20 so obtained was not characterized, and was immediately
treated with concd H2SO4 as described above. After the
standard workup the title compound was purified by prepara-
tive plates, to give 75 mg (43%), mp 336-338 °C. λmax: 400
nm (ꢀ 178 500), 408 (197 700), 484 (9000), 510 (11 400), 552
(14 700), 622 (10 500), 622 (10 500), 650 (12 000), 684 (104 300).
1H NMR (δ): 9.72, 9.05 (each s, 2H), 3.95 (q, 4H), 3.51 (s, 6H),
2.72 (q, 4H), 2.00 (s, 6H), 1.77 (t, 6H), 0.45 (t, 6H), -2.71 (s,
2H). 13C NMR:(no evidence of cis/trans isomerism) δ, ppm,
210.4, 163.3, 146.1, 138.4, 135.9, 135.5, 132.8, 93.9, 93.7, 54.7,
32.0, 23.1, 19.5, 17.3, 11.1, 8.8. HRMS: Calcd for
C32H38N4O2: 510.2994. Found: 510.3012. Anal. Calcd for
C32H38N4O2: C, 72.26; H, 7.50, N, 10.97. Found: C, 72.05, H,
7.48, N, 10.86.
3,8-Die t h yl-7,17-d ioxo-13,18-b is[2-(m e t h oxyca r b on -
yl)eth yl]-2,8,12,18-tetr am eth ylbacter ioch lor in (28a) (Mix-
tu r e of cis a n d tr a n s Isom er s). Mesoporphyrin II dimethyl
ester 8 (120 mg) was reacted with OsO4 (240 mg). After the
standard workup, the tetrahydroxy analogue 24 was purified
by silica gel column chromatography (elution with 10% metha-
nol/dichloromethane). After evaporating the solvent, the
product was crystallized from dichloromethane/hexane in 60%
yield (150 mg). It was not characterized, but was treated
immediately with H2SO4 as described in the general procedure
to give the title compound in 62% yield (125 mg), mp 188-
190 °C. λmax: 410 nm (ꢀ 180 000), 480 (10 000), 510 (12 000),
550 (17 000), 586 (13 000), 640 (35 000). 1H NMR (δ): 9.71,
9.67, 9.07 and 9.06 (each s, 1H), 4.31 (t, 2H), 3.98 (q, 2H), 3.76,
3.52, 3.49 and 3.33 (each s, 3H), 3.22 (t, 2H), 3.03 (t, 2H), 2.72
(q, 2H), 2.08, 1.52 (each m, 1H), 2.03, 2.00 (each s, 3H), 1.77
(t, 3H), 0.46 (t, 3H), -2.73 and -2.79 (each s, 1H). 13C NMR:
(no evidence of cis/trans isomerism) δ, ppm, 210.2, 173.1, 173.0,
163.5, 162.4, 146.7, 145.6, 140.1, 137.0, 136.4, 135.6, 135.1,
134.2, 132.5, 131.9, 94.5, 94.0, 93.6, 93.6, 54.6, 53.1, 51.8, 51.3,
36.6, 33.1, 32.0, 28.9, 23.2, 23.2, 21.4, 19.3, 17.2, 11.3, 11.2,
8.8. HRMS: Calcd for C36H42N4O6: 626.3096. Found:
626.3092.
3,8-D ie t h y l-13,18-b is [2-(m e t h o x y c a r b o n y l)e t h y l]-
2,8,12,18-tetr a m eth yl-7,17-d ith ion oba cter ioch lor in (29a ).
The foregoing dioxobacteriochlorin 28a (30 mg) was dissolved
in dry toluene (50 mL), and Lawesson’s reagent (120 mg) was
added in portions. The reaction mixture was refluxed under
nitrogen for 1 h while being monitored by spectrophotometry.
The solvent was evaporated, and the product was chromato-
graphed on alumina (elution with dichloromethane). The
major band was collected, and evaporation of the solvent gave
a residue which was crystallized from dichloromethane/hexane
to give the title compound in 65% yield (20 mg), mp 231-232
°C. λmax: 373 nm (ꢀ 22 200), 430 (84 500), 446 (68 400), 476
(98 200), 652 (22 100), 680 (26 200), 712 (23 000), 746 (87 000).
1H NMR (δ): 10.03 and 9.91 (each s, 1H), 8.91 (s, 2H), 4.28 (t,
2H), 3.91 (q, 2H), 3.73, 3.46, 3.42, 3.01 (each s, 3H), 3.20 (t,
2H), 2.12-2.95 (m, 4H), 2.12 (q, 2H), 2.03, 2.00 (each s, 3H),
1.73 (t, 3H), 0.90 (t, 3H), -2.80 and -2.90 (each s, 1H).
HRMS: Calcd for C36H42N4O4: 658.2647. Found: 658.2631.
Anal. Calcd for C36H36N4O4S2: C, 65.62; H, 6.43; N, 8.50.
Found: C, 65.26; H, 6.57, N, 8.14.
λmax
: 363 nm (ꢀ 97 400), 536 (31 800), 652 (12 600), 746
(56 300). 1H NMR (δ): 9.18, 9.15, 8.78, 8.72, 8.46, 8.44 (each
s, 1H), 4.99 (q, 4H), 4.14 (m, 2H), 4.30 (m, 2H), 3.84 (q, 4H),
3.63, 3.62, 3.47, 3.46, 3.15, 3.13 (each s, 3H,), 2.00-2.52 (m,
10H); 1.86 [d, 2H], 1.83 (t merged, 6H), 1.56 (s, 6H), 1.02, 0.93,
0.88 and 0.70 (each d, 3H); 0.39, 0.25, -0.96 and -1.06 (each
s, 1H). HRMS Calcd for C37H44N4O6: 596.2629. Found:
596.2620.
Met h yl 3-(1-H exyloxyet h yl)-vic-7,8-d ih yd r oxyb a ct e-
r iop h eop h or bid e-a (56). Methyl 3-devinyl-3-[1-(hexyloxy)-
ethyl]pyropheophorbide-a 48 (200 mg) was reacted with OsO4
(200 mg) by following the general procedure discussed above,
and the title compound was isolated in 70% yield (147 mg),
mp 119-122 °C.
λmax: 359 nm (ꢀ 94 000), 458 (9000), 486
(13 300), 518 (31 700), 644 (16 900), 704 (32 400). 1H NMR:
Due to the presence of four isomers the NMR spectrum was
complicated, and it was difficult to assign all peaks. However,
1
the meso region was well resolved; the meso H assignments
and CH(O-hexyl)CH3 were as follows: 8.72, 8.42, and 8.06
(each s, 2H), 8.70, 8.68, 8.39, 8.38, 8.04, 8.02 (each s, 1H), 5.65
(m, 4H). Other assignments: 4.80 (m, 8H), 4.15 (m, 4H), 3.95
(m, 4H), 3.0-3.65 (several s, 3H); 2.48, 2.18 (each m, 8H), 1.1-
2.00 (multiple peaks); 0.80 (m, 12H), -0.08 to -0.23 (m, 8H).
Anal. Calcd for C40H52N4O6: C, 70.15; H, 7.65; N, 8.18.
Found: 70.43; H, 7.75; N, 7.93.
3,8,13,17-Tetr akis[2-(m eth oxycar bon yl)eth yl]-2,8,12,18-
tetr a m eth yl-7-oxoch lor in (27). Coproporphyrin II tetram-
ethyl ester 9 (150 mg) was reacted with OsO4 (300 mg) as
described above. The resulting diol 23 was not characterized
P in a col-P in a colon e Rea r r a n gem en t: Gen er a l P r o-
ced u r e. The cis-dihydroxychlorins or bacteriochlorins (typi-

Pinacol-Pinacolone Rearrangements
J . Org. Chem., Vol. 62, No. 5, 1997 1471
but was subjected to pinacol-pinacolone rearrangement fol-
lowing the general procedure to afford the title compound in
68% yield (104 mg), mp 172-175 °C. λmax: 404 nm (ꢀ 183 400),
508 (15 500), 546 (17 800), 584 (12 300), 640 (37 000). 1H NMR
(δ): 9.87, 9.85, 9.77, 9.13 (each s, 1H), 4.38, 4.33, 4.20 (each t,
2H), 3.73, 3.66, 3.65, 3.57, 3.57, 3.43, 3.29, (each s, 3H), 3.25-
3.04 (m, 8H), 2.09 (s, 3H), 2.10, 1.48 (each m, 1H), -2.96, -3.02
(each s, 1H). HRMS: Calcd for C40H46N4O9: 726.3258.
Found: 726.3251. Anal. Calcd for C40H46N4O9: C, 66.10; H,
6.38; N, 7.71. Found: C, 66.31; H, 6.28; N, 7.58.
3,8,13,18-Tetr akis[2-(m eth oxycar bon yl)eth yl]-2,8,12,18-
tetr a m eth yl-7,17-d ioxoba cter ioch lor in (30a ) (Mixtu r e of
cis a n d tr a n s Isom er s). Coproporphyrin II tetramethylester
9 (120 mg) was reacted with excess OsO4 (240 mg), and the
intermediate tetrahydroxybacteriochlorin was purified, but not
characterized, and was immediately reacted with H2SO4. After
the standard purification, the title compound was obtained in
62% yield (77 mg), mp 229-230 °C. λmax: 408 nm (ꢀ 189 800),
484 (9000), 510 (12 100), 552 (14 400), 620 (10 100), 650
(11 500), 684 (90 000). 1H NMR (δ): 9.69, 9.10 (each s, 2H),
4.31 (t, 4H), 3.77, 3.53, 3.33 (each s, 6H), 3.22, 3.04 (each t,
2H), 2.12, 1.54 (each m, 2H), 2.05 (s, 6H), - 2.78 (s, 2H).). 13C
NMR: (no evidence of cis/trans isomerism) δ, ppm, 209.0,
173.0, 172.9, 162.5, 146.0, 136.7, 136.0, 134.7, 133.1, 94.6, 93.7,
53.1, 51.8, 51.3, 36.6, 33.1, 28.9, 23.2, 21.4, 11.4. HRMS: Calcd
for C40H46N4O10: 742.3207. Found: 742.3222. Anal. Calcd
for C40H46N4O10: C, 64.68; H, 6.24; N, 7.46. Found: C, 64.44;
H, 6.19; N, 7.46.
3.32 (each s, 3H), 2.55-2.80 (m, 4H), 2.20-2.40 (m, 2H); 1.94
(t, 3H), 1.89, 1.87 (s, 3H total), 1.81 (d, 3H), 1.20-1.35 (m,
1H), 0.38-0.51 (four d, 6H total, cis/trans isomers), -0.62,
-2.00 (each s, 1H). 13C NMR (δ): 209.1, 199.0, 195.0, 173.3,
169.0, 163.0 (split, cis/trans isomers), 161.5, 148.1, 147.2 (split),
139.5, 137.2, 135.2 (split), 134.9, 133.7, 131.3, 108.7, 98.5, 97.0,
95.4, 53.1, 52.3, 51.7, 49.2, 48.1, 47.6 (split), 33.5, 30.8, 29.9,
26.3 (split), 25.7, 24.1, 24.0 (split), 23.4, 20.6, 16.7, 13.1.
HRMS Calcd for C37H42N4O5: 622.3149. Found: 622.3029.
3-(1-Hydr oxyeth yl)-7,8-cis-dih ydr oxybacter ioph eoph or -
b id e-d (58) (Mixt u r e of F ou r Isom er s). Acetylbacte-
riopheophorbide 57 (120 mg) was dissolved in dichloromethane
(25 mL) and stirred at <5 °C. Sodium borohydride (100 mg)
dissolved in cold methanol (10 mL) was added, and the reaction
mixture was stirred under a nitrogen atmosphere for 15 min
(monitored by TLC). After the standard workup, the crude
reaction chromatographed as three bands; the least polar band
(minor amount <5%) was identified as the starting material,
the middle band (major amount) was characterized as the title
compound, and the most polar band, which was in minor
quantity (not characterized) was possibly a diol mixture
obtained by reduction of both the acetyl group and the isocyclic
keto group. The major band was crystallized from CH2Cl2/
hexane in to afford 67 mg (70%), mp 170-172 °C. λmax: 363
nm (ꢀ 97 400), 536 (31 800), 652 (12 600), and 746 (56 300).
1H NMR (δ): Due to the presence of four isomers, the NMR
spectrum was complicated. The meso region was well resolved.
The meso 1H assignment and CH(OH)CH3 assignments were
as follows: 8.75, 8.65, 8.60, 8.55 (each s, 1H), 8.42, 8.38, 8.00,
7.95 (each s, 2H), 6.16 (m, 2H). Anal. Calcd for C37H46N4O6:
C, 69.14; H, 7.21; N, 8.72. Found: 69.24; H, 7.13 and N, 8.59.
cis-3-Acetyl-12-h yd r oxyd eu ter och lor in -IX Meth yl Es-
ter 13,13-γ-Sp ir ola cton e (43). 12,13-Dihydroxychlorin 34
(100 mg, 0.163 mmol) in dry methanol (25 mL) was refluxed
with anhydrous sodium acetate (1.2 g) for 30 min. The solution
after cooling was washed with water and then extracted with
dichloromethane. The product was then purified on silica gel
plates (elution with 5% methanol/dichloromethane) to yield the
lactone (60 mg, 64%) after crystallization from dichloromethane/
n-hexane. It had mp 246-248 °C. λmax: 410 nm (ꢀ 169 700),
506 (14 000), 540 (11 800), 578 (9100), 632 (28 900). 1H-NMR
(δ): 10.50 (s 1H), 9.66 (s, 1H), 9.05, 8.96 (each s, 1H), 8.66 (s,
1H), 4.05 (t, 2H), 3.99 (s, 1H), 3.69, 3.58, 3.28 (each s, 3H),
3.58 (s, 3H), 3.38-3.80 (m, 4H), 3.22 (3H, s), 3.06 (m, 2H), 1.87
(s, 3H), -2.37, -2.46 (each br s, 1H). HRMS: Calcd for
C33H34N4O6: 582.24781. Found: 582.249773 (39%, M+),
520.247587 (100%). IR: ν (KBr) 1777, 1716, 1639 cm-1. Anal.
Calcd for C33H34N4O6: C, 68.01; H, 5.89; N, 9.62. Found: C,
67.99; H, 5.85; N, 9.51.
cis-8-Acetyl-18-h yd r oxyd eu ter och lor in -IX Meth yl Es-
ter 17,17-γ-Sp ir ola cton e (41). The same procedure as above
was followed for the synthesis of the lactochlorin from 32, to
give the product in 64% yield, mp 250-252 °C. λmax: 412 nm
(ꢀ 166 000), 506 (12 400), 546 (11 800), 578 (9200), 634 (32 500).
1H-NMR (δ): 10.54 (s, 1H), 9.71 (s, 1H), 9.13, 9.06 (each s,
1H), 8.88 (s, 1H), 4.18 (t, 2H), 3.93 (s, 1H), 3.67 (s, 3H), 3.53
(s, 3H), 3.49 (s, 6H), 3.36-3.79 (m, 4H), 3.19 (s, 3H), 3.11 (m,
2H), 1.88 (s, 3H,), -2.50, -2.46 (each br s, 1H). HRMS: Calcd
for C33H34N4O6: 582.24781. Found: 582.244540 (30%, M+),
520.247072 (100%). Anal. Calcd for C33H34N4O6: C, 68.01;
H, 5.89; N, 9.62. Found: C, 67.86; H, 5.83; N, 9.55.
tr a n s-3-Acet yl-12-h yd r oxyd eu t er och lor in -IX Met h yl
Ester 13,13-γ-Sp ir ola cton e (44). A mixture of cis-lactone
43 (8 mg), chloroform (15 mL), methanol (1 mL), and silica
gel was stirred as a suspension overnight in the dark. The
silica gel was filtered off, and then the solvent was removed
from the eluates. The product was crystallized from dichlo-
romethane/n-hexane to yield the trans-lactone (6 mg, 75%),
mp 254-256 °C. λmax: 410 nm (ꢀ 169 700), 506 (14 000), 540
(11 800), 578 (9100), 632 (28 900). 1H-NMR (δ): 10.548 (s, 1H),
9.82 (s, 1H), 9.08, 9.02 (each s, 1H), 8.69 (s, 1H), 4.15 (t, 2H),
3.92 (s, 1H), 3.75, 3.57, 3.45 (each s, 3H), 3.61 (s, 3H), 3.40-
3.80 (m, 4H), 3.24 (s, 3H), 3.10 (m, 2H), 1.89 (s, 3H), -2.28 (br
s, 2H). HRMS Calcd for C33H34N4O6: 582.2478. Found:
582.2481. Anal. Calcd for C33H34N4O6: C, 68.01; H, 5.89; N,
9.62. Found: C, 67.63; H, 5.93; N, 9.29.
3,8,13,18-Tetr akis[2-(m eth oxycar bon yl)eth yl]-2,8,12,18-
tetr a m eth yl-7,17-d ith ion oba cter ioch lor in (31a ) (Mixtu r e
of cis a n d tr a n s Isom er s). The foregoing dioxobacteriochlo-
rin 30a (30 mg) was converted into the dithiono analogue by
following the method discussed for the preparation of related
bacteriochlorin 29a ; the title compound was isolated in 70%
yield (22 mg), mp 283-286 °C. λmax
: 428 (ꢀ 97 300), 446
(78 200), 476 (96 800), 656 (23 800), 680 (29 000), 713 (21 000),
746 (101 100). 1H NMR (δ): 9.97, 8.92 (each s, 2H), 4.22 (t,
4H,), 3.67, 3.38, 3.21 (each s, 6H), 3.00 (m, 4H), 3.18 (m, 4H),
3.21, 2.90 (m, 4H), 2.00 (m, 4H), 2.02 (s, 6H), -1.79 (s, 2H).
HRMS: Calcd for C40H46N4O8S2: 774.2757. Found: 774.2753.
Met h yl 7-E t h yl-8-oxom esop yr op h eop h or b id e-a (61)
(Isom er ic P a ir ). Methyl dihydroxymesopyropheophorbide-a
54 (60 mg) was treated with concentrated H2SO4 following the
general procedure. The crude product was purified on silica
gel plates and was crystallized from CH2Cl2/hexane to give 40
mg (69%), mp >300 °C. λmax: 416 nm (ꢀ 43 500), 506 (10 600),
536 (9800), 604 (9700), 658 (19 600), 712 (9500). 1H-NMR
(δ): 9.19, 8.78, 8.50 (each s, 1H), 5.30 (m, 2H), 4.40, 4.25 (each
m, 1H), 3.83 (q 2H), 3.66, 3.60 (s, 6H), 3.28 (s, 3H, 2-Me), 2.60
(q, 2H), 2.60 and 2.23 (each m, 2H), 1.91 (d, 3H), 1.71 (d, 3H),
1.69 (t, 3H), 0.47 (t, 3H), -0.10, -1.68 (each s, 1H). HRMS
Calcd for C34H38N4O4: 566.2888. Found: 566.2890.
Meth yl 8-Deeth yl-3-devin yl-7-eth yl-3-for m yl-8-oxoch lo-
r in e6 Tr im et h yl E st er (66) a n d Met h yl 7-Dem et h yl-3-
d evin yl-8-m eth yl-3-for m yl-7-oxoch lor in e6 Tr im eth yl Es-
t er (67). The formyl-cis-7,8-dihydroxybacteriochlorin e6 60
was stirred with H2SO4, and after the standard workup the
oxo derivative was isolated as a 3:2 mixture of 66 and 67 in a
combined yield of 64%. This mixture was not separated. Mp
240-246 °C. λmax
: 365 nm (ꢀ 78 600), 538 (29 700), 758
(56 700). 1H NMR (δ): 11.27 (s, 2H), 9.47, 8.91, 8.60 (each s,
1H, minor isomer), 9.47, 8.84 and 8.65 (each s, 1H, major
isomer), 5.18 (q, 4H), 4.26 (m, 4H) 4.40 (m, 2H), 4.20 (m, 2H),
4.22, 3.75, 3.68, 3.77, 3.55 (each s, 3H, minor), 4.22, 3.76, 3.67,
3.59 and 3.72 (each s, 3H, major), 2.00-2.58 (m, 8H), 2.34 (s,
3H, major), 2.22 (s, 3H, minor), 1.57-1.62 (m, 12H), 0.69 (t,
3H, minor), 0.52 (t, 3H, major), -0.64, -0.78 (each s, 1H,
major), -0.89, -1.01 (each s, 1H, minor). HRMS Calcd for
C36H40N4O8: 656.2840. Found: 656.2856.
3-Acetyl-7-isobu tyl-8-oxoba cter iop h eop h or bid e-d (64)
(Mixtu r e of cis a n d tr a n s Isom er s). cis-Diol 57 [60 mg,
obtained by reacting 50 (100 mg) with OsO4 (100 mg)] was
converted into the title compounds in 68% yield (53 mg) upon
stirring with H2SO4 as described in the general procedure. Mp
182-185 °C. 1H NMR (δ): 9.84, 8.93, 8.82 (each s, 1H), 5.24
(m, 2H), 4.52 (q, 1H), 4.34 (d, 1H), 4.08 (q, 2H), 3.64, 3.61,

1472 J . Org. Chem., Vol. 62, No. 5, 1997
Pandey et al.
tr a n s-8-Acet yl-18-h yd r oxyd eu t er och lor in -IX Met h yl
Ester 17,17-γ-Sp ir ola cton e (42). The same procedure as
above was followed for the synthesis of trans-spirolactone from
mL). The general procedure was followed to give, after
crystallization from dichloromethane/n-hexane, 32 mg (36%)
of the title compound, mp 172-174 °C. λmax
: 414 nm (ꢀ
41. The product had mp 242-244 °C. λmax
:
412 nm (ꢀ
182 400), 516 (12 100), 564 (19 200), 582 (16 200), 638 (24 500).
1H-NMR (δ): 10.72, 9.94, 9.73, 9.14 (each s, 1H), 9.08 (s 1H),
4.33 (t, 2H), 3.79 (s, 3H), 3.74, 3.29 (each s, 3H), 3.64, 3.62
(each s, 3H), 3.25 (s, 3H), 3.06 (t, 2H), 1.26 (t, 2H), 0.88 (t,
2H,), -2.81, -2.91 (each s, 1H). HRMS: Calcd for
C34H36N4O6: 596.26346. Found: 596.262705 (100%, M+).
Anal. Calcd for C34H36N4O6: C, 68.44; H, 6.08; N, 9.39.
Found: C, 68.33; H, 6.20; N, 9.29.
166 700), 506 (12 500), 546 (12 100), 582 (9500), 634 (32 900).
1H-NMR (δ): 10.57 (s, 1H), 9.75 (s, 1H), 9.14, 9.07 (each s,
1H), 8.92 (s, 1H), 4.23 (t, 2H), 3.90 (s, 1H), 3.70 (s, 3H), 3.52
(s, 3H), 3.51 (s, 6H), 3.39-3.80 (m, 4H), 3.20 (s, 3H), 3.10 (m,
2H), 1.88 (s, 3H, s), -2.41 (br s, 2H). HRMS: Calcd for
C33H34N4O6: 582.2478. Found: 582.2468. Anal. Calcd for
C33H34N4O6: C, 68.01; H, 5.89; N, 9.62. Found: C, 68.04; H,
5.93; N, 9.21.
3,8-Dia cetyl-12-d em eth yl-13-m eth yl-12-oxodeu ter op or -
p h yr in IX Dim eth yl Ester (39) a n d 3,8-Dia cetyl-13-d e[2-
(m eth oxycar bon yl)eth yl]-12-[2-(m eth oxycar bon yl)eth yl]-
13-oxod eu ter op or p h yr in IX Mon om eth yl Ester (40). 3,8-
Diacetyl-12,13-cis-dihydroxydeuteroporphyrin IX dimethyl ester
38 (50 mg) was treated with H2SO4 (10 mL), and after the
standard workup the title compounds were isolated as a
mixture and were not separated. 1H NMR (δ): 10.80, 9.92,
9.90, 9.60 (each s, 1H, major isomer), 9.75, 10.18, 9.68, 9.12
(each s, 1H, minor isomer); other peaks for major and minor
isomers were difficult to distinguish. HRMS: Calcd for
C34H38N4O7: 614.2735. Found: 614.2825.
Ack n ow led gm en t. This work was supported by
grants from National Institutes of Health (CA 55791),
the National Science Foundation (CHE 93-05577),
Oncologic Foundation of Buffalo, and the Deutsche
Forschungsgemeinschaft (Se543/2-1 and /2-2). We thank
Dr. F.-Y. Shiau (UC Davis) for the initial preparation
of some bacteriochlorins. Mass spectrometric analyses
were performed by the UCSF Mass Spectrometry Facil-
ity (A. L. Burlingame, Director) supported by the
Biomedical Research Technology Program of the Na-
tional Center for Research Resources, NIH NCRR BRTP
01614, and by the Mass Spectrometry Facility, Michigan
State University.
8-Acetyl-17-d e[2-(m eth oxyca r bon yl)eth yl]-18-[2-(m eth -
oxyca r b on yl)et h yl]-17-oxod eu t er och lor in -IX
Mon o-
m eth yl Ester (33). To 8-acetyl-17,18-dihydroxydeuterochlo-
rin IX dimethyl ester 32 (90 mg) was added concd H2SO4 (25
J O960720H