Studies in chlorin chemistry. 3. A practical synthesis of C,D-ring symmetric chlorins of potential utility in photodynamic therapy

Article abstract of DOI:10.1021/jo060041z

C,D-ring symmetric chlorins 8 were prepared in 47-85% yield, on scales up to several hundred milligrams, by condensation of appropriately substituted bis-formyldihydrodipyrrins 6 and dipyrromethane biscarboxylic acids 7 in 5% TFA/CH₂Cl₂

Full text of DOI:10.1021/jo060041z

Studies in Chlorin Chemistry. 3. A Practical Synthesis of C,D-Ring
Symmetric Chlorins of Potential Utility in Photodynamic Therapy
William G. O’Neal, William P. Roberts, Indranath Ghosh, Hui Wang, and Peter A. Jacobi*
Burke Chemical Laboratory, Dartmouth College, HanoVer, New Hampshire 03755
peter.a.jacobi@dartmouth.edu
ReceiVed January 7, 2006
C,D-ring symmetric chlorins 8 were prepared in 47-85% yield, on scales up to several hundred milligrams,
by condensation of appropriately substituted bis-formyldihydrodipyrrins 6 and dipyrromethane bis-
carboxylic acids 7 in 5% TFA/CH2Cl2 (25 examples). Target chlorins were chosen to systematically
probe the effect of lipophilic and hydrophilic substituents on tissue partitioning and cellular membrane
penetration in photodynamic therapy (PDT).
Introduction
The chlorins are a class of 18π-electron aromatic tetrapyrroles
formally derived from porphyrins by saturation of a peripheral
double bond (cf. ring A, Figure 1). Chlorophyll a (1, R ) phytyl)
is the most ubiquitous example, serving as a light-harvesting
chromophore in photosynthetic plants, algae, and cyanobacteria
(certain bacteriochlorophylls perform a similar function in
phototrophic bacteria).1 However, a number of lesser known
chlorins also play important biological roles. Cyclopheophorbide
(2) and related species are thought to inhibit damaging oxidative
processes in certain marine species, including Darwinella oxeata
(a sponge), the short-necked clam Ruditapes philippinarum, and
the scallop Patinopecten yessoensis.2 Also, the structurally
unique chlorin bonellin (3) is a hormone responsible for sexual
differentiation in the marine worm Bonella Viridis.3 Finally, in
addition to their natural functions, synthetically derived chlorins
have attracted significant attention in both medical and materials
(1) Montforts, F.-P.; Glasenapp-Breiling, M. In Progress in the Chemistry
of Organic Natural Products; Herz, W., Falk, H., Kirby, G. W., Eds.;
Springer: Wien, New York, 2002; Vol. 84, pp 1-51.
(2) (a) Karuso, P.; Berguquist, P. R.; Buckleton, J. S.; Cambie, R. C.;
Clark, G. R.; Rickard, C. E. F. Tetrahedron Lett. 1986, 27, 2177-2178.
(b) Watanabe, N.; Yamamoto, K.; Ihshikawa, H.; Yagi, A. J. Nat. Prod.
1993, 56, 305-317.
(3) Agius, L.; Ballantine, J. A.; Ferrito, V.; Jaccarini, V.; Murray-Rust,
P.; Pelter, A.; Psaila, A. F.; Schembri, P. J. Pure Appl. Chem. 1979, 51,
1847.
FIGURE 1. Some naturally occurring chlorins.
sciences. Due to their favorable photophysical properties,
chlorins show promise in tumor photodynamic therapy (PDT),
a technique that employs photostimulated production of singlet
oxygen to selectively eradicate malignant tissue.4 In a relatively
new area of exploration, materials engineers have studied this
ring system as a chromophore in artificial photosynthesis.5
10.1021/jo060041z CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/29/2006
3472
J. Org. Chem. 2006, 71, 3472-3480

Studies in Chlorin Chemistry
SCHEME 1. Battersby-Montforts Synthesis of Chlorins
SCHEME 2. Chlorin Synthesis by the 2+2 Method
Most de novo syntheses of chlorins are modeled on the
methodology of Battersby6a and Montforts,6b involving either
photochemical or alkali-induced ring closure of properly
substituted linear tetrapyrroles 4 (Scheme 1; X ) OMe, Br,
etc.).7 Tetrapyrroles 4 are derived from simpler ring systems
employing techniques such as sulfide contraction,6b,8 thio-Wittig
reaction,9 and reductive cyclization of pyrrole-substituted
nitroketones.10 While elegant in concept, the cyclization of 4
to 5 can be problematic and is typically carried out on small
scales, employing metal templates, and affording 5 in modest
to good yields.6,8
SCHEME 3. First-Generation Synthesis of A,B-Ring
Precursors 6
In 2001, we described in communication form a new synthesis
of chlorins based upon a variant of the MacDonald porphyrin
synthesis11 and involving condensation of bis-formyldi-
hydrodipyrrins 6 with symmetrical dipyrromethanes 7 (Scheme
2).12 Simple dissolution of 6 and 7 in neat TFA was found to
afford chlorins 8 in 35-45% yield with no special precautions
against air or light and without metal complexation. A key
feature of this approach is that the chlorin chromophore is
obtained directly in the proper oxidation state and with no need
for subsequent isomerization. We believe this characteristic
accounts in large part for the simplicity of the experimental
conditions.
Since dipyrromethanes of type 7 are readily available,13
a
formyldihydrodipyrrins 6 built upon the ready availability of
enelactones 11, prepared in 70-96% yield from alkyne acids 9
and iodopyrroles 10 (Scheme 3).12 Lactones 11 were then
converted to E,Z-mixtures of thioimidates 12 by a three-step
sequence consisting of (1) aminolysis, (2) thiolactam formation,
and (3) concomitant decarboxylative formylation/S-methylation
employing trimethylorthoformate (TMOF) in neat TFA.9b We
intended to convert both isomers of 12 to the corresponding
dihydrodipyrrins 13 by transition-metal-catalyzed methylation.
In practice, this transformation worked well with Z-thioimidates
12-Z employing the reagent system Pd(0)/MeZnI. The resulting
Z-dihydrodipyrrins 13-Z were then oxidized in good yield to
the desired diformyl derivatives 6. Surprisingly, however, the
corresponding E-thioimidates 12-E were unreactive toward
methylation using Pd(0)/MeZnI and most other commonly
employed cross-coupling techniques (trace quantities of 13 were
produced with Ni(II) catalysts). Eventually, this difference was
traced to a selective activating effect of Zn, which serves to
polarize the thioimidate C-S bond in 12-Z by chelation.14 This
reactivity pattern had far reaching consequences because the
ratio of 12-Z:12-E decreased dramatically with increasing size
practical synthesis of A,B-ring dialdehydes 6 is an essential
component of this 2+2 approach. Our original route to bis-
(4) Bonnett, R. Chemical Aspects of Photodynamic Therapy; Gordon and
Breach: Amsterdam, 2000.
(5) (a) Wasielewski, M. R.; Wiederrecht, G. P.; Svec, W. A.; Niemczyk,
M. P. Sol. Energy Mater. Sol. Cells 1995, 38, 127-134. (b) Tamiaki, H.;
Yagai, S. J. Photosci. 2002, 9, 66-69.
(6) (a) Battersby, A. R.; Dutton, C. J.; Fookes C. J. R.; Turner, S. P. D.
J. Chem. Soc., Perkin Trans. 1 1988, 1557-1567. (b) Montforts, F.-P.
Angew. Chem., Int. Ed. Engl. 1981, 20, 778-779. (c) Montforts, F.-P.;
Gerlach, B.; Ho¨per, F. Chem. ReV. 1994, 94, 327-347. (d) Montforts, F.-
P.; Glasenapp-Breiling, M. Prog. Heterocycl. Chem. 1998, 10, 1-24.
(7) For other representative synthetic approaches to the chlorin macro-
cycle, see: (a) Burns, D. H.; Li, Y. H.; Shi, D. C.; Caldwell T. M. J. Org.
Chem. 2002, 67, 4536. (b) Gryko, D. T.; Galeˆzowski, M. Org. Lett. 2005,
7, 1749-1752.
(8) Montforts, F.-P.; Schwartz, U. M. Liebigs Ann. Chem. 1991, 609.
(9) (a) Battersby, A. R.; Turner, S. P. D.; Block, M. H.; Sheng, Z.-C.;
Zimmerman, S. C. J Chem. Soc. Perkin Trans. 1 1988, 1577. (b) Arnott,
D. M.; Harrison, P. J.; Henderson, G. B.; Sheng, Z.-C.; Leeper, F. J.;
Battersby, A. R. J. Chem. Soc., Perkin Trans. 1 1989, 265.
(10) (a) Harrison, P. J.; Sheng, Z.-C. Fookes, C. J. R.; Battersby, A. R.
J. Chem. Soc. Perkin Trans. 1 1987, 1667. (b) Battersby, A. R.; Dutton, C.
J.; Fookes, C. J. R. J. Chem. Soc., Perkin Trans. 1 1988, 1569. (c) Strachan,
J.-P.; O’Shea, D. F.; Balasubramanian, T.; Lindsey, J. S. J. Org. Chem.
2000, 65, 3160. (d) Balasubramanian, T.; Strachan, J.-P.; Boyle, P. D.;
Lindsey, J. S. J. Org. Chem. 2000, 65, 7919. (e) Taniguchi, M.; Ra, D.;
Mo, G.; Balasubramanian, T.; Lindsey, J. S. J. Org. Chem. 2001, 66, 7342.
(f) Ptaszek, M.; Bhaumik, J.; Kim, H.-J.; Taniguchi, M.; Lindsey, J. S.
Org. Process Res. DeV. 2005, 9, 651-659.
(13) (a) For an overview, see: Smith, K. M. In The Porphyrin Handbook;
Kadish, K. M., Smith, K. M., Guilard, R., Eds.; Academic Press: San Diego,
2000; Vol. 1, p 4. (b) Jackson A. H.; Pandey R. K.; Smith K. M. J. Chem.
Soc., Perkin Trans. 1 1987, 299-305. (c) Fischer, H.; Orth, H. Die Chemie
des Pyrrols; Akademische Verlagsgesellschaft: Leipzig, 1934; Vol. 1, p
333. (d) Mironov, A. F.; Ovsepyan, T. R.; Evstigneeva, R. P.; Preobrazen-
skii, N. A. Zh. Obshch. Khim. 1965, 35, 324. (e) Freeman B. A.; Smith, K.
M. Synth. Commun. 1999, 29, 1843-1855.
(11) Arsenault, G. P.; Bullock, E.; MacDonald, S. F. J. Am. Chem. Soc.
1960, 82, 4384.
(12) Jacobi, P. A.; Lanz, S.; Ghosh, I.; Leung, S. H.; Lower, F.; Pippin,
D. Org. Lett. 2001, 3, 831.
(14) Ghosh, I.; Jacobi, P. A. J. Org. Chem. 2002, 67, 9304.
J. Org. Chem, Vol. 71, No. 9, 2006 3473

O’Neal et al.
SCHEME 4. Synthesis of 13 by Method A (Conditions i)
synthesis of dihydrodipyrrins 13 in which R ) small- to
medium-sized alkyl group. Other derivatives of 13 are best
prepared by method A, utilizing the appropriate decarboxylative
formylation procedure (conditions i for R ) H, conditions ii
for R ) Ph or alkyl).
Method A. After our initial communication,12 we found that
lactones 11 undergo clean reaction with the Petasis reagent
(TiCp2Me2), affording high yields of enol ethers 14 incorporating
a wide range of meso-substituents R (Scheme 4).16 This
discovery provided the basis for a very streamlined synthesis
of dihydrodipyrrins 15, which were formed in “one pot” by
hydrolysis of 14 to the corresponding diketones, followed by
condensation with an appropriate ammonia source. Importantly,
the Petasis reagent was compatible with commonly occurring
functional groups such as propionate esters (D ) CH2CH2CO2-
Me), as well as regioisomeric substitution patterns in ring A
(A,B ) di-Me, di-H).
Conditions i. With esters 15 in hand, we first attempted
decarboxylative formylation under standard conditions.17 Un-
fortunately, pretreatment of 15 with TFA followed shortly
thereafter with trimethylorthoformate (TMOF) proved to be
highly capricious, affording 13 in yields ranging from 8% to
69%, depending partly upon the nature of meso-substituents R.
Only with R ) H were we able to obtain reproducible yields in
the range of ∼70%. These difficulties were not entirely
unexpected since Battersby et al. experienced similar problems
with a closely related ring system during the course of a
synthesis of bonellin (3).10b
It is well-known that pyrroles bearing electron-withdrawing
groups exhibit decreased reactivity toward electrophilic substitu-
tion and decarboxylation.18 As illustrated in Scheme 4, we
suspect that rapid protonation of the pyrroline ring under the
reaction conditions leads to intermediates such as 16-H+, which
are analogous to monopyrroles bearing electron-withdrawing
groups. Furthermore, decarboxylation via a dication of type 16-
2H+ would be highly unlikely. Thus, the poor behavior of
dihydrodipyrrins under conditions i may be due in part to the
inhibition of decarboxylation and/or formylation (i.e., 16-H+
f 17-H+ f 13) by competitive protonation at the basic
pyrroline ring nitrogen in 16.
We explored many approaches for improving the conversion
of 15 to 13, initially employing meso-phenyl substrate 15a in
combination with variants of conditions i (Scheme 5). As above,
these experiments gave erratic yields of the desired formylated
compound 13a, accompanied by significant decomposition. In
most cases, the only identifiable byproduct was the trifluoro-
methyl ketone 18a (13-18%). Battersby et al. also observed
trifluoromethyl ketone formation in their studies cited above,10b
but the origin of this compound was not investigated.
Interestingly, we could find no trace of the presumed
intermediates 16a and 17a in the crude reaction mixtures, and
it remains an open question whether formylation precedes or
follows decarboxylation. In the case of ketone 18a, two
observations provided insight into the question of origin: First,
15a gave essentially identical yields of 18a upon treatment with
TFA alone, seemingly eliminating any mechanistic role for
of R (i.e., H > Me . Ph), making it impractical to incorporate
larger meso-substituents (C5 in 8). Because of this complication,
we were able to prepare only a few chlorin precursors 6 by this
method.
The properties of meso-substituents R can significantly
influence tissue partitioning of chlorins in PDT,15 but introduc-
tion of these groups by existing methodology has typically been
challenging. We have devoted much effort since our original
paper to developing improved synthetic routes to A,B-ring
dialdehydes 6, incorporating diverse substituents A-D and in
particular meso-groups R. Because dihydrodipyrrins 13 had
proven to be useful precursors to dialdehydes 6, we focused
primarily on the conversion of lactones 11 to intermediates 13.
In this paper, we describe two new syntheses of these materials,
each of which is best suited for the incorporation of particular
meso-substituents (Section I). In addition, we report greatly
improved conditions for the oxidation of 13 to 6 (Section II)
and the condensation of 6 and 7 to afford C,D-ring symmetric
chlorins 8 (Section III).
Results and Discussion
I. Synthesis of Formyldihydrodipyrrins 13. Summary. We
have developed two new syntheses of 13 from 11: Method A
involves conversion of lactones 11 to dihydrodipyrrins 15
(Scheme 4), which are transformed to 13 by decarboxylative
formylation using one of two procedures (conditions i or ii).
Method B is based on the decarboxylative formylation of
lactones 11. Subsequent conversion to 13 is accomplished by
lactone ring opening, followed by aminolysis of the intermediate
diketones 24 (Scheme 9). Method B is most useful for the
(16) O’Neal, W. G.; Roberts, W. P.; Ghosh, I.; Jacobi, P. A. J. Org.
Chem. 2005, 70, 7243-7251.
(17) Clezy, P. S.; Fookes, C. J. R.; Liepa, A. J. Aust. J. Chem. 1972, 25,
1979-1990.
(15) Pandey, R. K.; Zheng G. In The Porphyrin Handbook; Kadish, K.
M., Smith, K. M., Guilard, R., Eds.; Academic Press: San Diego, 2000;
Vol. 6, pp 157-230.
(18) Jackson, A. H. In Pyrroles; Jones, R. A., Ed.; The Chemistry of
Heterocyclic Compounds; John Wiley & Sons: New York, 1990; Vol. 48,
Part 1, pp 301, 315.
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Studies in Chlorin Chemistry
SCHEME 5. Formation of Side Product 18a
SCHEME 6. Reversed Order of Oxidation and
Decarboxylative Formylation
Conditions ii. In contrast to the reaction with TFA, meth-
ylpyrroline 15a underwent clean decarboxylation with HBr/
HOAc, affording a 96% yield of the R-free pyrrole 17a as a
mixture of Z- and E-isomers (Table 1). With decarboxylation
no longer an issue, we examined a number of milder reagents
for effecting the desired formylation of 17a to 13a. Of these,
only the Vilsmeier reagent (POCl3/DMF)20 exhibited modest
promise, affording a 43% yield of 13a (Z-isomer only).
Employing TMOF/TFA as a formylating agent, the yields of
13a were actually lower than those obtained by direct decar-
boxylative formylation of 15a to 13a (Scheme 5). This was
mainly because 17a was unstable to prolonged exposure to TFA.
In experiments designed to minimize this problem, we found
that 13a-Z,E was obtained in 73% yield when a solution of crude
17a in CH2Cl2/triethylorthoformate (TEOF) was added to
precooled TFA (Conditions ii). These conditions provided
reproducible results and were also satisfactory for preparing
formyl derivatives 15d (R ) C5H11, 57%) and 15e (R ) C10H21,
61%). However, for substrates bearing small meso-substituents
even these conditions proved to be too harsh (15b,c).
TABLE 1. Isolated Yields of 13 Prepared by Method A
(Conditions ii)
Method B. In parallel studies, we were exploring a second
strategy for synthesizing 13 that provided additional flexibility.
Based on the mechanistic considerations described above, we
expected that enelactones 11 would be better substrates for
decarboxylative formylation since these compounds do not
contain a pyrroline nitrogen to compete for protonation (Scheme
7). Satisfyingly, 11 routinely afforded 75-95% yields of formyl
derivatives 22 upon treatment with TEOF/TFA (E-isomers only).
We further hoped that 22 might undergo a selective Petasis
reaction at the lactone carbonyl group, as previously observed
with ester lactones 11 (cf. Scheme 4). However, all attempts at
effecting this conversion produced complex mixtures.
We had previously examined the ring opening of ester-
lactones 11 with alkyllithium species Li-Nu, but we were
unable to prevent multiple addition of sterically unhindered
nucleophiles such MeLi.16 Nevertheless, we attempted the same
transformation with formyl lactones 22 and were pleased to find
that these species underwent selective ring opening with a
variety of nucleophiles Li-Nu (22 f 23 f 24). Even Li-Me
(Li-A), possessing little if any steric hindrance, showed excellent
chemoselectivity, affording 74-80% yields of 24aA-eA upon
slow addition at -78 °C. At present, we have no rigorous
explanation for this selectivity, although it is likely that the acidic
15
R
overall yield of 13-Z,E
a
b
c
d
e
Ph
Me
Z (64%), E (9%)
25% combined
<15% combined
Z only (57%)
H
C5H11
C10H21
Z only (61%)
TMOF in the formation of this compound. Second, 17a prepared
independently (Table 1) reacted only very slowly with TFA
under conditions that led to rapid conversion of 15a to 18a.
Together, these results suggest that a likely intermediate in the
conversion of 15a to 18a is the mixed anhydride 19a, which
might be transformed to 18a in either inter- or intramolecular
fashion. In any event, it was clear that decarboxylation of 15a
with TFA would inevitably lead to substantial loss of starting
material to this side reaction.
In an effort to circumvent this problem, we briefly explored
the possibility of reversing the order of decarboxylative formy-
lation and oxidation (Scheme 6). Our thought was that the
electron-withdrawing formyl group in 20a would decrease the
basicity of the pyrroline ring, thereby facilitating protonation
of the pyrrole ring. Although we obtained reasonable yields in
the conversion of 15a to 20a (∼65%), all attempts at decar-
boxylative formylation produced only the carboxylic acid 21a
along with decomposition products. Decarboxylation also failed
with very strong acid combinations such as HBr/HOAc.19
(19) Neya, S.; Ohyama, K.; Funasaki, N. Tetrahedron Lett. 1997, 38,
4113-4116.
(20) Silverstein, R. M.; Ryskiewicz, E. E.; Willard, C. Organic Syntheses;
Wiley & Sons: New York, 1963; Collect. Vol. 4, p 831.
J. Org. Chem, Vol. 71, No. 9, 2006 3475

O’Neal et al.
SCHEME 9. Method B: Pyrroline Ring Closure of
SCHEME 7. Method B: Ring Opening of Lactones 22 by
Various Nucleophiles
Diketones 24
Even simple diketone derivatives 24a-e presented a number
of hurdles to cyclization, partly because of the presence of the
very sensitive formyl group (Scheme 9). Formylpyrroles as a
class are generally unstable to acids,22 a property that was
especially pronounced with 24a-e. These substrates underwent
rapid decomposition with even weakly acidic ammonium salts.
In contrast, basic or neutral sources of ammonia cleanly afforded
mixtures of hemiaminal intermediates 26, but these species were
resistant to dehydration and easily reverted to diketones 24.
Working with substrate 24b (R ) Me), we eventually found
that the combination of (NH4)2CO3/basic Al2O3 in CH3CN at
75 °C gave ∼75% yields of the corresponding dihydrodipyrrin
13b, a significant improvement over method A (cf. Table 1).
In analogous fashion, diketone 24d (R ) n-pentyl) afforded 13d
in much improved yield (77%). However, the relatively
unhindered substrate 24c (R ) H) required special care. This
material was susceptible to competing aldol condensation and
upon aminolysis at 75 °C gave predominantly the aldol product
27c (51%) along with only 18% of dihydrodipyrrin 13c. After
further experimentation, we found that the aldol pathway was
greatly reduced by effecting aminolysis at rt for 24 h before
briefly heating to 75 °C, affording 13c in 58% yield along with
17% of 27c. Finally, we were surprised to find that the meso-
Ph diketone 24a underwent significant decomposition upon
attempted aminolysis, since in related examples the Ph-
substituent appeared to have a stabilizing influence.16
Summary. Because of the unpredictable effect of meso-
substituents R on substrate reactivity/stability, a truly general
synthesis of formyl derivatives 13 remains elusive. However,
this investigation culminated in two complementary routes to
these key intermediates that together are far more efficient than
our original approach.12 The utility of each route is summarized
in Scheme 10. Three general conclusions can be drawn: (1)
Synthesis of meso-H derivative 13c was accomplished in best
overall yield using method A, conditions i. (2) Derivatives of
13 bearing larger meso-substituents (R ) Ph or C10H21) were
best prepared using method A, conditions ii. (3) Derivatives of
13 bearing small- to medium-sized meso-alkyl groups (R ) Me
or C5H11) were best prepared using method B.
SCHEME 8. Method B: Failed Pyrroline Ring Closures of
“Oxidized Diketones” 24
pyrrole N-H group plays a role both in protecting the formyl
group and in preventing multiple addition (two equivalents of
Li-Nu are required for complete reaction). As a working
hypothesis, we suggest that the C-4 ketone deriving from 22 is
stabilized in a chelated structure of type 23, maintaining the
enolate tautomer until acid workup.
Of particular interest, reaction of 22c with lithiodithiane
(Li-B) cleanly produced the protected glyoxaldehyde derivative
24cB (74%), while (phenylthio)methyllithium (Li-C) gave a
78% yield of ring-opened species 24bC. Both 24cB and 24bC
held out the possibility of directly attaining the desired oxidation
state of 6 after pyrroline formation.21 Unfortunately, we were
unable to effect the desired ring closure of diketones 24cB or
24bC despite intensive efforts over a period of many months
(Scheme 8). Dithiane 24cB was typically recovered intact
following aminolysis, most likely due to steric hindrance at the
C-1 carbonyl group (X-ray analysis subsequently confirmed this
suspicion; cf. Scheme 8 and Supporting Information). In
contrast, thioanisole derivative 24bC underwent rapid aldol
condensation to cyclopentenone 25 under mildly basic condi-
tions (83%), reflecting the increased acidity of the C-20
methylene protons (chlorin numbering).
II. Oxidation of Pyrrolines 13 to Bis-formyldihydrodipyr-
rins 6. In our original studies, we carried out the conversion of
(21) (a) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis; John Wiley & Sons: New York, 1999; pp 333-340. (b) Bakuzis
P.; Bakuzis M. L. F.; Fortes C. C.; Santos R. J. Org. Chem. 1976, 41,
2769-2770.
(22) Jackson, A. H. In Pyrroles; Jones R. A., Ed.; The Chemistry of
Heterocyclic Compounds; John Wiley & Sons: New York, 1990; Vol. 48,
Part 1. p 316
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Studies in Chlorin Chemistry
SCHEME 10. Summary of Two New Syntheses of 13a
SCHEME 11. Oxidation of Dihydrodipyrrin 13
called “wet” solvents described in the literature as having
beneficial effects (in our case even trace amounts of water
accelerated decomposition).27 We did, however, observe very
clean reactions using dry CH2Cl2 as solvent with 1-2 equiv of
pyridine as additive (the rate-accelerating effect of pyridine is
well documented).27 Employing 13b (R ) Me) as a substrate,
we consistently obtained yields of 6b in the range of 65-70%
following this protocol. While these results were promising, ICP-
MS analysis indicated that the product was still contaminated
with up to 0.61 wt % (2 mol %) of selenium. While these
experiments were underway, we became aware of a report
describing the removal of colloidal selenium by brief heating
in DMF. This produces a black metallic allotrope that can be
easily removed by filtration.28 When this step was applied to
the crude oxidation product prepared as above, the resultant
precipitate was easily removed, the overall yield remained
essentially the same, and 6b was obtained in a high state of
purity. In analogous fashion, diformyl derivatives 6a-e were
prepared in 60-70% yield without further optimization.
III. Chlorin Formation. The experiments described above
provided a convenient and versatile synthesis of A,B-ring
dialdehydes 6. To further enhance the practicality of the 2+2
methodology, we next endeavored to optimize the final con-
densation of precursors 6 and 7 to afford C,D-ring symmetric
chlorins. Our original conditions for this reaction called for
dissolution of 6 and 7 in neat TFA, which was deemed necessary
to initiate decarboxylation of 7 to the presumably more reactive
R-unsubstituted derivatives (Scheme 12).12 This protocol af-
forded 35-45% yields of a limited number of chlorins 8. With
greater quantities of 6 available, we began more detailed studies,
which revealed that our assumption pertaining to decarboxyla-
tion was not valid.
We first examined the stability of representative substrates
6b and 7b in neat TFA, now aware of the potential side reactions
that this solvent might induce (Scheme 12). Under these
conditions, dihydrodipyrrin 6b decomposed within minutes at
ambient temperature. Dipyrromethane 7b afforded moderate
yields of the bis-decarboxylated product 29b along with
significant quantities of trifluoroacylated derivative 28b,29
mirroring our experience with dihydrodipyrrins 15 outlined in
Scheme 5. When reacted with 6b under otherwise identical
conditions, isolated and purified dipyrromethane 29b (for which
we expected trifluoroacylation to be minimized; cf. Scheme 5)
gave lower yields of chlorin 8bb than did dicarboxylic acid 7b
(33% vs 42%). To explore this result further, we screened
a Key: (a) conditions i: (1) neat TFA, (2) TMOF, 25 °C; (b) conditions
ii: (1) HBr/HOAc, (2) TEOF/CH2Cl2, (3) TFA, 0 °C; (c) method B: (1) 2
equiv of MeLi, (2) (NH4)2CO3/CH3CN, 75 °C.
formyldihydrodipyrrins 13a-c to dialdehydes 6a-c by oxida-
tion with selenium dioxide (cf. Scheme 3).12 While this
procedure generally gave satisfactory yields of 6a-c, the final
products were invariably contaminated with selenium metal that
was very difficult to separate. Among other consequences, this
made obtaining accurate analytical data difficult and no doubt
also impacted subsequent steps. We therefore spent considerable
time exploring other means of accomplishing the desired
oxidation, eventually resorting to a simple modification of the
original procedure. A brief account of our findings is presented
here.
The literature contains many examples of related oxidations
employing a wide variety of reagents. Of these, we screened
15-20 procedures that appeared to offer the most promise (see
ref 23 for a complete listing).23-25 Generally speaking, these
fell into three categories: (1) direct oxidation using powerful
reagents of the Cr(VI), Co(II), Cu(II), and Pb(IV) families;24
(2) oxidation initiated by bis-halogenation (NCS, NBS, SOCl2,
etc.) followed by hydrolysis;25 and (3) methyl anion generation
followed by in situ capture with oxidants including diselenides,
disulfides, NBS, etc.25b In several cases, we examined both
stoichiometric and catalytic variants of the literature procedures.
The results were uniformly discouraging, with some reagents
exhibiting little reactivity and others causing rapid decomposi-
tion (Scheme 11).
Ultimately, we returned to the SeO2 procedure, exploring the
effect of reagent purity, additives, and co-oxidants. Freshly
sublimed SeO2 provided no apparent advantage,26 nor did so-
(23) (a) Reagents that were screened include: PCC, PDC, CAN, DDQ,
MnO2, CrO3, Pb(OAc)4, Co(OAc)2, CuI/TBHP, CuCl2/TBHP, Pd/TBHP,
Pd(OAc)2/ PhI(OAc)2, (SePh)2/PhIO2, t-BuI/FeCl2/DMSO, CuCl2/LiCl,
NCS/NBS, SO2Cl2. Leading references are included for certain reagents.
(24) (a) Co(II): Salvador, J. A. R.; Clark J. H. Chem. Commun. 2001,
33-34. (b) Cu(I): Salvador, J. A. R.; Melo, M. L. Sa´ e; Neves, A. S. C.
Tetrahedron Lett. 1997, 38, 119-122. (c) Cu(I): Arsenou, E. S.; Koutsourea,
A. I.; Fousteris, M. A.; Nikolaropoulos, S. S. Steroids 2003, 68, 407-414.
(d) Cu(II): Rothenburg, G.; Feldberg, L.; Wiener, H.; Sasson, Y. J. Chem.
Soc., Perkin Trans. 2 1998, 2429-2434. (e) Pd/TBHP: Yu, J.-Q.; Corey,
E. J. Org. Lett. 2002, 4, 2727-2730. (f) Pd(OAc)2/PhI(OAc)2: Dick, A.
R.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004, 126, 2300-2301.
(g) (SePh)2/PhIO2: Barton, D. H. R.; Crich, D. Tetrahedron 1985, 41, 4359.
(h) t-BuI/FeCl2/DMSO: Vismara, E.; Fontana F.; Minisci, F. Gazz. Chim.
Ital. 1987, 117, 135-136.
(27) Trachtenberg, E. N. In Oxidation; Augustine, R. L., Ed.; Marcel
Dekker: New York, 1969; pp 19-187.
(28) Milstein, S. R.; Coats, E. A. Aldrichim. Acta 1978, 11, 10.
(29) Xie, H.; Lee, D. A.; Wallace, D. M.; Senge, M. O.; Smith, K. M.
J. Org. Chem. 1996, 61, 8508-8517.
(25) (a) CuCl2/LiCl: Nobrega, J. A.; Gonc¸alves, S. M. C.; Peppe, C.
Synth. Commun. 2002, 32, 3711-3717. (b) NCS/NBS/SO2Cl2: Tehrani,
K. A.; Borremans, D.; De Kimpe, N. Tetrahedron 1999, 55, 4133-4152.
(26) Kaplan, H. J. Am. Chem. Soc. 1941, 63, 2654-2655.
J. Org. Chem, Vol. 71, No. 9, 2006 3477

O’Neal et al.
SCHEME 12. Optimization of Chlorin Formation by the
2+2 Method
FIGURE 2. Schematic representation of the effect of tether length
-(CH2)n- on cellular membrane penetration. The hydrophilic car-
boxylate groups “anchor” at the aqueous interface.
Conclusion
An important component of these studies was preparation of
C,D-ring symmetric chlorins 8 bearing a substitution pattern
that could be useful in probing structure-activity relationships
in photodynamic therapy (PDT, vide supra). It has been known
for many years that lipophilic substituents can exert a strong
influence on such critical parameters as drug uptake, intracellular
location, and photosensitizing efficacy.15 Moreover, as recently
shown by Ehrenberg et al.,33 carboxylate “anchors” of the type
incorporated in rings C and D in 8 might be tailored in length
to either minimize or maximize cellular membrane penetration
1
and, thus, overall exposure to photogenerated O2 (Figure 2).
Chlorins 8aa-ee in Table 2, incorporating both a lipophilic
“head” and a hydrophilic “tail”, provide an attractive starting
point for testing this hypothesis.
numerous solvent and acid combinations with 29b, including
such Lewis acids as TiCl4, BF3, and Sc(OTf)3 that have been
successfully employed in similar condensations.30 In the present
case, these catalysts caused significant decomposition, and little
or no chlorin 8bb could be detected by TLC and/or UV analysis.
More promising results were obtained with Bronsted acids,
especially TsOH in MeOH/CH2Cl2.31 Unfortunately, these
conditions proved unreliable for larger scale syntheses of 8bb.
On the basis of these experiments, it appeared that decarboxy-
lation was at the least not a prerequisite to chlorin formation,
raising the possibility that dicarboxylic acid 7b might be a
superior condensation partner under more refined conditions.
Finally, the described methodology should also be suitable
for preparing chlorins of potential interest in materials science.
It is worth noting, though, that with C,D-ring symmetric chlorins
8 our synthetic objectives were simplified by the fact that it
was not necessary to differentiate either the formyl groups in 6
or the R-pyrrole positions in dipyrromethanes 7. The application
of this 2 + 2 strategy to the synthesis of unsymmetrical chlorins
presents additional challenges that will be the subject of a
forthcoming paper.
Working from this premise, we eventually identified the
combination of 5% TFA in CH2Cl2 as a particularly effective
medium for condensation,32 affording chlorin 8bb in a remark-
ably high state of purity after washing with either 3M NH4OH
or saturated KHCO3. Final purification by chromatography
consistently afforded 65-75% yields of 8bb on scales up to
several hundred milligrams (typically, however, reactions were
run on 25-50 mg scale for convenience). In analogous fashion,
we prepared chlorin derivatives 8aa-ee bearing lipophilic
substituents ranging up to n-decyl at C5, along with aliphatic
esters of chain length 2-10 at C13 and C17 (Table 2; the potential
usefulness of a carboxylate functionality is described below).
Yields employing the optimized conditions ranged from 47 to
85% and are shown in bold. Where applicable, yields employing
other conditions are also included.
Experimental Section
Representative procedures for the synthesis of chlorins 8:
5-[1-(4,4-Dimethyl-5-oxodihydrofuran-2-ylidene)ethyl]-3,4-di-
methyl-1H-pyrrole-2-carbaldehyde (22b). TFA (8.80 mL, 118
mmol) was added to 11b (1.0 g, 3.0 mmol) under a nitrogen
atmosphere, and the solution was stirred vigorously for 5 min. The
reaction was cooled to 0 °C for 10 min and then treated with triethyl
orthoformate (2.7 mL, 16.4 mmol). After 20 min, the reaction was
poured into 10% aq KH2PO4 (40 mL) at 0 °C and extracted with
CH2Cl2 (3 × 15 mL). The combined organic extracts were washed
sequentially with water and saturated aq NaHCO3, dried over
Na2SO4, filtered, and concentrated. The residue was purified by
flash chromatography (silica gel, EtOAc/hexanes ) 3:7) to give
22b (695 mg, 89%) as a colorless crystalline solid: mp 172.5-
174 °C; Rf (4:6 EtOAc/hexanes) 0.41; IR (thin film) 3253, 1799,
1700, 1628, 1079 cm-1; H NMR (500 MHz, CDCl3) δ 1.27 (s,
1
6H), 1.91 (s, 3H), 2.01 (t, J ) 1.71, 3H), 2.27 (s, 3H), 2.58 (q, J
) 1.71, 2H), 9.54 (s, 1H), 9.74 (br s, 1H); 13C NMR (500 MHz,
CDCl3) δ 9.2, 9.7, 16.1, 25.0, 40.5, 40.5, 104.9, 119.2, 129.2, 132.5,
(30) Geier, G. R., III; Callinan, J. B.; Rao, P. D.; Lindsey, J. S. J.
Porphyrins Phthalocyanines 2001, 5, 810-823.
(31) (a) Burns, D. H.; Li Y. H.; Shi, D. C.; Caldwell, T. M. J. Org.
Chem. 2002, 67, 4536-4546. (b) Nguyen, L. T.; Senge, M. O.; Smith, K.
M. J. Org. Chem. 1996, 61, 998-1003.
(33) (a) Lavi, A.; Weitman, H.; Holmes, R. T.; Smith, K. M.; Ehrenberg,
B. Biophys. J. 2002, 82, 2101-2110. (b) Bronshtein, I.; Afri, M.; Weitman,
H.; Frimer, A. A.; Smith, K. M.; Ehrenberg, B. Biophys. J. 2004, 87, 1155-
1164.
(32) For use of TFA/CH2Cl2 in a related context, see: (a) Lash, T. D. J.
Porphyrins Phthalocyanines 1997, 1, 29-44. (b) Lash, T. D. Chem. Eur.
J. 1996, 2, 1197-1200.
3478 J. Org. Chem., Vol. 71, No. 9, 2006

Studies in Chlorin Chemistry
TABLE 2. Isolated Yields of Chlorins Prepared by the 2+2 Methoda
a Conditions: (a) neat TFA; (b) TsOH/MeOH/CH2Cl2; (c) 5% TFA in CH2Cl2.
1
136.3, 146.7, 177.0, 180.0. Anal. Calcd for C15H19NO3: C, 68.94;
H, 7.33; N, 5.36; O, 18.37. Found: C, 68.54; H, 7.28; N, 5.33.
3,4-Dimethyl-5-(1,4,4-trimethyl-2,5-dioxohexyl)-1H-pyrrole-
2-carbaldehyde (24b). A solution of 22b (1.77 g, 6.77 mmol) in
THF (130 mL) was cooled to -78 °C and treated dropwise with
1.6 M MeLi in Et2O (8.40 mL, 13.5 mmol) over 20 min. The
reaction was then quenched by addition to 200 mL of saturated aq
NH4Cl. After the mixture was allowed to warm to room temper-
ature, Et2O (50 mL) was added, and the layers were separated. The
organic layer was washed sequentially with water and brine, dried
over Na2SO4, filtered, and concentrated. The resulting yellow oil
was purified by flash chromatography (silica gel, EtOAc/hexanes
) 3:7) to give 24b (1.50 g, 80%) as a colorless crystalline solid:
mp 103-104 °C; Rf (2:3 EtOAc/hexanes) 0.25; IR (thin film) 3253,
1706, 1628 cm-1; H NMR (500 MHz, CDCl3) 1.12 (s, 3H), 1.13
(s, 3H), 1.36 (d, J ) 7.3, 3H), 1.93 (s, 3H), 2.16 (s, 3H), 2.25 (s,
3H), 2.59 (d, J ) 17.9, 1H), 2.87 (d, J ) 17.9, 1H), 3.89 (q, J )
7.1, 1H), 9.53 (s, 1H), 9.74 (br s, 1H); 13C NMR (500 MHz, CDCl3)
δ 8.6, 9.0, 15.7, 25.1, 25.5, 25.7, 44.5, 45.9, 51.2, 118.5, 128.9,
132.4, 136.1, 176.8, 207.5, 213.3; HRMS (EI) calcd for C16H23-
NO3 277.1678, found 277.1678. Anal. Calcd for C16H23NO3: C,
69.29; H, 8.36; N, 5.05; O, 17.31. Found: C, 69.44; H, 8.35; N,
4.96.
3,4-Dimethyl-5-[1-(4,4,5-trimethyl-3,4-dihydropyrrol-2-yli-
dene)ethyl]-1H-pyrrole-2-carbaldehyde (13b). A solution of 24b
(1.35 g, 4.9 mmol) in CH3CN (53 mL) was treated with (NH4)2-
CO3 (4.6 g, 49 mmol) and basic alumina (6.7 g, grade I), flushed
with nitrogen, and heated to 75 °C in a sealed flask for 8 h. At the
J. Org. Chem, Vol. 71, No. 9, 2006 3479

O’Neal et al.
end of this period, the mixture was cooled to room temperature,
filtered, and concentrated. The residue was dissolved in CH2Cl2,
washed with water, dried over Na2SO4, filtered, and concentrated.
The resulting oil was purified by flash chromatography (silica gel,
EtOAc/hexanes ) 1:2) to give 13b (940 mg, 75%) as a crystalline
solid: mp 156-157 °C; Rf (1:2 EtOAc/hexanes) 0.27; IR (thin film)
3252, 1635, 1589 cm-1; 1H NMR (500 MHz, CDCl3) 1.20 (s, 6H),
2.11 (s, 3H), 2.16 (s, 3H), 2.17 (s, 3H), 2.26 (s, 3H), 2.58 (s, 2H),
9.58 (s, 1H), 11.77 (s, 1H); 13C NMR (500 MHz, CDCl3) δ 8.8,
11.2, 15.7, 17.9, 26.0, 43.8, 47.8, 113.3, 118.9, 128.3, 131.4, 136.9,
151.6, 176.0, 187.2; HRMS (EI) calcd for C16H22N2O 258.1732,
found 258.1726. Anal. Calcd for C16H22N2O: C, 74.38; H, 8.58;
N, 10.84; O, 6.19. Found: C, 74.41; H, 8.72; N, 10.78.12
5-[1-(5-Formyl-4,4-dimethyl-3,4-dihydropyrrol-2-ylidene)-
ethyl]-3,4-dimethyl-1H-pyrrole-2-carbaldehyde (6b). A solution
of 13b (0.80 g, 3.1 mmol) in CH2Cl2 (62 mL) and pyridine (0.37
mL, 3.7 mmol) was treated with SeO2 (0.41 g, 3.7 mmol) and stirred
at rt for 2 h. The solvent was then removed by rotary evaporation,
and the residue was redissolved in DMF (30 mL) and heated to 80
°C for 15 min. The reaction mixture was cooled to room
temperature, filtered, and poured into water (100 mL). The solution
was extracted with CH2Cl2 (4 × 30 mL), and the combined organic
extracts washed sequentially with saturated aq NaHCO3 and brine,
dried over Na2SO4, filtered, and concentrated. The resulting oil was
purified by flash chromatography (silica gel, EtOAc/hexanes ) 2:3)
to give 6b (599 mg, 71%) as a yellow crystalline solid: mp 135-
137 °C; Rf (1:2 EtOAc/hexanes) 0.34; IR (thin film) 3302, 1687,
1635 cm-1; 1H NMR (500 MHz, CDCl3) 1.37 (s, 6H), 2.20 (s, 3H),
2.22 (s, 3H), 2.28 (s, 3H), 2.73 (s, 2H), 9.66 (s, 1H), 9.94 (s, 1H),
11.32 (br s, 1H); 13C NMR (500 MHz, CDCl3) δ 8.9, 11.8, 19.3,
26.1, 46.0, 46.3, 122.0, 125.3, 130.0, 131.2, 135.3, 152.0, 177.4,
177.5, 190.5; HRMS (EI) calcd for C16H19N2O2 271.1447, found
271.1450. Anal. Calcd for C16H20N2O2: C, 70.56; H, 7.40; N, 10.29;
O, 11.75. Found: C, 70.45; H, 7.42; N, 10.12.12
3-[18-(2-Methoxycarbonyl-ethyl)-3,7,8,10,13,13,17-heptamethyl-
12,13,22,24-tetrahydroporphin-2-yl]propionic Acid Methyl Ester
(8bb). Nitrogen was bubbled through a suspension of 6b (201 mg,
0.74 mmol) and 7b (321 mg, 0.74 mmol) in CH2Cl2 (67 mL) for
10 min. The mixture was treated with TFA (3.36 mL) and stirred
at room temperature in the dark for 24 h. The reaction was then
poured into 3 M aqueous NH4OH (30 mL). The layers were
separated, and the aqueous layer was extracted with CH2Cl2 (30
mL). The combined organic layers were washed sequentially with
water and brine, dried over Na2SO4, filtered, and concentrated. The
residue was purified by flash chromatography (silica gel, EtOAc/
hexanes ) 1:5) to give 8bb (313 mg, 70%) as a green crystalline
solid that was identical to the literature compound.12
Acknowledgment. Financial support of this work by the
National Institutes of Health (NIGMS Grant No. GM38913) is
gratefully acknowledged. We are grateful to Victor G. Young,
Jr. and the X-ray Crystallographic Laboratory, Department of
Chemistry, University of Minnesota, for X-ray analysis of 24cB.
William G. O’Neal is the recipient of an NSF predoctoral
fellowship.
Supporting Information Available: Experimental details,
characterization data, and NMR spectra for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO060041Z
3480 J. Org. Chem., Vol. 71, No. 9, 2006