Toward a general synthesis of chlorins

Article abstract of DOI:10.1021/ja0780075

Recently, we described a new synthesis of C,D-ring symmetric chlorins 11, involving 2 + 2 condensation of bis-formyl-dihydrodipyrrins 9 with symmetrically substituted dipyrromethane diacids 10 (Method I). However, while versatile in many aspects, Method I

Full text of DOI:10.1021/ja0780075

Published on Web 01/01/2008
Toward a General Synthesis of Chlorins
William G. O’Neal and Peter A. Jacobi*
Burke Chemical Laboratory, Dartmouth College, HanoVer, New Hampshire 03755
Received October 26, 2007; E-mail: peter.a.jacobi@dartmouth.edu
Abstract: Recently, we described a new synthesis of C,D-ring symmetric chlorins 11, involving 2 + 2
condensation of bis-formyl-dihydrodipyrrins 9 with symmetrically substituted dipyrromethane diacids 10
(Method I). However, while versatile in many aspects, Method I was unsuited to the broader goal of
synthesizing fully non-symmetric chlorins of general structure 15, which requires regioselective control over
the reacting centers in the A,B- and C,D-ring components. In this paper, we describe four new 2 + 2
strategies that accomplish this differentiation (Methods II-V). Of these, Method V, which combines
operational simplicity with moderate to high product yields, proved to be the most effective route, exploiting
reactivity differences between the two formyl groups of A,B-rings 9 to impart excellent regioselectivity.
Methods II-IV are also useful alternatives to Method V, although in some cases, the appropriately
functionalized precursors are less readily available. All four approaches generate single regioisomers of
diversely substituted chlorins, and in every case, the 2 + 2 condensation is accomplished in a simple,
one-flask procedure without need for additives such as oxidizing agents or metals. Taken together, these
methodologies provide expanded access to an array of chlorins for SAR studies that may advance the
effectiveness of PDT and other applications.
an alternative fuel;4e,6 and (4) the generation of electricity with
chlorin-based solar cells.7 Synthetic chlorins are also being
Introduction
The chlorins are a class of 18π-electron aromatic tetrapyrroles,
formally derived by saturation of the C2-C3 bond in ring A of
porphyrins (see below). The most ubiquitous members of this
class belong to the chlorophyll a (1) group of chromophores,
the primary photoreceptors in photosynthesis in higher plants,
algae, cyanobacteria, and other microorganisms.1 Although far
less abundant than 1, other chlorins play crucial roles in both
terrestrial and marine organisms. Among these, bonellin (2) is
the hormone responsible for sexual differentiation in larvae of
the echiuran worm Bonella Viridis,2 and cyclopheophorbide (3)
is representative of several closely related chlorins believed to
inhibit oxidative damage in certain marine invertebrates.3 Other
pheophorbides show promising anti-tumor activity.3c
studied for applications in materials science8 and medical
imaging.9 Finally, in the medical field, chlorins are emerging
as more effective “second generation” photosensitizers in
photodynamic therapy (PDT), a treatment method that employs
visible light to trigger phototoxic reactions that eradicate
malignant tissue or infections.10 While PDT is an established
and effective means of treating certain cancers, there are many
lesser known but increasingly important applications.11 Of
(4) (a) Wasielewski, M. R. Chem. ReV. 1992, 92, 435. (b) Kay, A.; Gra¨tzel,
M. J. Phys. Chem. 1993, 97, 6272. (c) Kay, A.; Humphry-Baker, R.; Gra¨tzel,
M. J. Phys. Chem. 1994, 98, 952. (d) Wasielewski, M. R.; Wiederrecht,
G. P.; Svec, W. A.; Niemczyk, M. P. Sol. Energy Mater. Sol. Cells 1995,
38, 127. (e) Itoh, T.; Asada, H.; Tobioka, K.; Kodera, Y.; Matsushima, A.;
Hiroto, M.; Nishimura, H.; Kamachi, T.; Okura, I.; Inada, Y. Bioconjugate
Chem. 2000, 11, 8. (f) Ro¨ger, C.; Mu¨ller, M. G.; Lysetska, Y.; Holzwarth,
A. R.; Wu¨rthner, F. J. Am. Chem. Soc. 2006, 128, 6542.
(5) (a) Taniguchi, M.; Ra, D.; Kirmaier, C.; Hindin, E.; Schwartz, J. K.; Diers,
J. R.; Knox, R. S.; Bocian, D. F.; Lindsey, J. S.; Holten, D. J. Am. Chem.
Soc. 2003, 125, 13461. (b) Tamiaki, H.; Miyatake, T.; Tanikaga, R.;
Holzwarth, A. R.; Schaffner, K. Angew. Chem., Int. Ed. Engl. 1996, 35,
772. (c) Balaban, T. S. Acc. Chem. Res. 2005, 38, 612.
(6) (a) Saiki, Y.; Amao, Y. Bioconjugate Chem. 2002, 13, 898. (b) Takeuchi,
Y.; Amao, Y. Bioconjugate Chem. 2003, 14, 268. (c) Himeshima, N.; Amao,
Y. Green Chem. 2005, 7, 742.
(7) (a) Amao, Y.; Yamada, Y.; Aoki, K. J. Photochem. Photobiol., A 2004,
47. (b) Takeuchi, Y.; Amao, Y. J. Jpn. Pet. Inst. 2004, 47, 355. (c) Amao,
Y.; Yamada, Y. J. Jpn. Pet. Inst. 2004, 47, 406. (d) Amao, Y.; Yamada,
Y. Biosens. Bioelectron. 2007, 22, 1561. (e) Stromberg, J. R.; Marton, A.;
Kee, H. L.; Kirmaier, C.; Diers, J. R.; Muthiah, C.; Taniguchi, M.; Lindsey,
J. S.; Bocian, D. F.; Meyer, G. J.; Holten, D. J. Phys. Chem., C 2007, 111,
15464.
“Non-natural” chlorins are also of considerable chemical and
biological interest, in part because of their “tunable” photo-
physical properties. Owing to this capability they have come
under increasing scrutiny as key components in various light-
mediated applications, ranging from alternative energy sources
to medicine. Light-energy conversion techniques have received
particular attention, encompassing such topics as (1) the creation
of artificial photosynthetic systems;4 (2) the design of molecular
wires or antenna arrays;4f,5 (3) the production of hydrogen as
(1) Montforts, F.-P.; Glasenapp-Breiling, M. Progress in the Chemistry of
Organic Natural Products; Herz, W., Falk, H., Kirby, G.W., Eds.;
Springer: Wein, New York, 2002; Vol. 84, pp 1-51.
(2) Agius, L.; Ballantine, J. A.; Ferito, V.; Jaccarini, V.; Murray-Rust, P.; Pelter,
A.; Psaila, A. F.; Schembri, P. J. Pure Appl. Chem. 1979, 51, 1847.
(3) (a) Karuso, P.; Berguquist, P. R.; Buckleton, J. S.; Cambie, R. C.; Clark,
G. R.; Rickard, C. E. F. Tetrahedron Lett. 1986, 27, 2177. (b) Watanabe,
N.; Yamamoto, K.; Ihshikawa, H.; Yagi, A. J. Nat. Prod. 1993, 56, 305.
(c) Wongsinkongman, P.; Brossi, A.; Wang, H.-K.; Bastow, K. F.; Lee,
K.-H. Bioorg. Med. Chem. 2002, 10, 583.
(8) Milgrom, L. R. The Colours of Life; Oxford University: Oxford, U.K.,
1997; Chapter 7.
(9) Licha, K. Top. Curr. Chem. 2002, 222, 1.
(10) Bonnett, R. Chemical Aspects of Photodynamic Therapy; Gordon and
Breach: Amsterdam, The Netherlands, 2000; pp 177-289.
(11) (a) Wickens, J.; Blinder, K. J. Drug Safety, 2006, 29, 189. (b) Gold, M. H.
Dermatol. Clin. 2007, 25, 1. (c) Kereiakes, D. J.; et al. Circulation, 2003,
108, 1310.
9
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J. AM. CHEM. SOC. 2008, 130, 1102-1108
10.1021/ja0780075 CCC: $40.75 © 2008 American Chemical Society

General Synthesis of Chlorins
A R T I C L E S
Chart 1. Chlorin Skeleton and Some Natural Chlorins
Scheme 1. Chlorin Syntheses by Battersby, Montforts, and
Lindsey
step (∼20-72% yields).15,17 In addition, the photochemical
process is only practical on very small scales. In a noteworthy
variant of this approach, Lindsey et al. have shown that
condensation of fragments 6 and 7, followed by oxidative
cyclization employing Zn as a template, provides Zn-chlorins
8 in 7-45% yields (often this sequence can be performed in a
single reaction vessel with only slightly lower yields).13a,14,18
As in the Battersby/Montforts strategies, though, a limiting factor
in this approach is the availability of precursors of type 6 and
7, in particular with respect to synthesizing more highly
substituted derivatives.13a,14,19 Finally, while numerous other
strategies for synthesizing chlorins have been devised, a truly
general approach remains elusive.20
particular note, PDT shows great promise in combating infec-
tious disease, including antibiotic-resistant strains of bacteria.12
Most naturally occurring chlorins bear a full complement of
substituents on the pyrrolic rings and have an asymmetric
substitution pattern.1 The nature and position of these substit-
uents can have a dramatic effect on the spectral properties of
the chromophore and can affect the functions of biologically
active chlorins.13 Furthermore, the ability to control substituent
placement may be crucial to the successful use of synthetic
chlorins in many applications, including multi-chlorin arrays.14
Despite this importance, the selective assembly of fully sub-
stituted, unsymmetrical chlorins remains a significant challenge.
Recently, we described a new synthetic approach to C,D-
symmetric chlorins of general structure 11, involving acid-
catalyzed condensation of A,B-ring dialdehydes 9 and C,D-ring
dipyrromethanes 10 (Method I, Scheme 2).21 An attractive
feature of this approach is that the cyclodehydration of 9 and
10 leads directly to the thermodynamically stable, aromatic
chlorin nucleus 11, with no need for oxidation state adjustment18
or double bond isomerization(s).20a Consequently, the experi-
mental conditions are straightforward, requiring no metal
template and only routine precautions against air and light. Also,
there is considerable flexibility in setting substituents about the
The majority of de novo chlorin syntheses build upon the
pioneering work of Battersby and Montforts, involving either
photochemical or base-induced cyclization of tetrapyrroles 4
to afford chlorins of general structure 5 (Scheme 1).15 This
strategy has been employed in the syntheses of numerous
naturally occurring and “non-natural” chlorins, and it played a
prominent role in early studies on vitamin B12 biosynthesis.16
It is not without shortcomings, however. Principally, these relate
to the limited choice of methodology for preparing tetrapyrroles
4 and the generally inefficient nature of the macrocyclization
(12) (a) Wainwright, M. J. Antimicrob. Chemother. 1998, 42, 13. (b) Soukos,
N. S.; Ximeniz-Fyvie, L. A.; Hamblin, M. R.; Socransky, S. S.; Hasan, T.
Antimicrob. Agents Chemother. 1998, 42, 2595. (c) Jori, G.; Brown, S. B.
Photochem. Photobiol. Sci. 2004, 3, 403. (d) Ferro, S.; Ricchelli, F.;
Mancini, G.; Tognon, G.; Jori, G. J. Photochem. Photobiol., B 2006, 83,
98.
(17) (a) Battersby, A. R.; Dutton, C. J.; Fookes, C. J. R. J. Chem. Soc., Perkin
Trans. 1 1988, 1569. (b) Battersby, A. R.; Turner, S. P. D; Block, M. H.;
Sheng, Z.-C.; Zimmerman, S. C. J. Chem. Soc., Perkin Trans. 1 1988,
1577.
(18) (a) Strachan, J.-P.; O’Shea, D. F.; Balasubramanian, T.; Lindsey, J. S. J.
Org. Chem. 2000, 65, 3160. (b) Taniguchi, M.; Ra, D.; Mo, G.;
Balasubramanian, T.; Lindsey, J. S. J. Org. Chem. 2001, 66, 7342. (c)
Ptaszek, M.; McDowell, B. E.; Taniguchi, M.; Kim, H.-J.; Lindsey, J. S.
Tetrahedron 2007, 63, 3826.
(19) Taniguchi, M.; Kim, M. N.; Ra, D.; Lindsey, J. S. J. Org. Chem. 2005, 70,
275.
(20) For other representative synthetic approaches to chlorins, see: (a) Burns,
D. H.; Li, Y. H.; Shi, D. C.; Caldwell, T. M. J. Org. Chem. 2002, 67,
4536. (b) Gałezowski, M.; Gryko, D. T. J. Org. Chem. 2006, 71, 5942.
(21) (a) Jacobi, P. A.; Lanz, S.; Ghosh, I.; Leung, S. H.; Lower, F.; Pippin, D.
Org. Lett. 2001, 3, 831. (b) O’Neal, W. G.; Roberts, W. P.; Ghosh, I.;
Wang, H.; Jacobi, P. A. J. Org. Chem. 2006, 71, 3472.
(13) (a) Laha, J. K.; Muthiah, C.; Taniguchi, M.; McDowell, B. E.; Ptaszek,
M.; Lindsey, J. S. J. Org. Chem. 2006, 71, 4092, and references cited
therein. (b) Taniguchi, M.; Ptaszek, M.; McDowell, B. E.; Boyle, P. D.;
Lindsey, J. S. Tetrahedron 2007, 63, 3850. (c) Montforts, F.-P.; Gerlach,
B.; Ho¨per, F. Chem. ReV. 1994, 94, 327. (d) Milgrom, L. R. The Colours
of Life; Oxford University: Oxford, 1997; Chapter 1.
(14) Balasubramanian, T.; Strachan, J.-P.; Boyle, P. D.; Lindsey, J. S. J. Org.
Chem. 2000, 65, 7919.
(15) (a) Battersby, A. R.; Dutton, C. J.; Fookes, C. J. R.; Turner, S. P. D. J.
Chem. Soc., Perkin Trans. 1 1988, 1557. (b) Montforts, F.-P. Angew. Chem.,
Int. Ed. Engl. 1981, 20, 778.
(16) For an overview see: Battersby, A. R. Acc. Chem. Res. 1986, 19, 147.
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A R T I C L E S
O’Neal and Jacobi
Scheme 4. Synthesis of A,B-ring Precursors 12a-c
Scheme 2. Synthesis of C,D-ring Symmetric Chlorins (Method I)a
a f ) Me, (CH2)2CO2Me, (CH2)3CO2Me, (CH2)4CO2Me, (CH2)10CO2Me;
R ) H, Me, Ph, (CH2)4Me, (CH2)9Me.
Scheme 3. Method II for Synthesizing Unsymmetrical Chlorins
seco-chlorins 14 would afford chlorins 15 upon decarboxylative
formylation, with the stipulation that mono-formylation is
followed by rapid cyclodehydration as opposed to oligomer-
ization. As precedent for this approach, porphyrins have been
prepared by a similar method in fair yields (30-35%),23
although in these examples post-cyclization oxidation was
required to give the aromatic macrocycles. In the analogous
cyclization of 14, the aromatic chlorin would be obtained
directly upon cyclodehydration (cf. 16 f 15), with the same
advantages as described above for Method I. In particular,
aromatization would drive forward any equilibrium processes.
To explore this route, we prepared a group of three A,B-ring
substrates 12a-c, employing methodology closely analogous
to that earlier developed for synthesizing diformyl-dihydrodipyr-
rins 9 (Scheme 4). As described previously,24 dihydrodipyrrins
21 were derived in three steps, on scales ranging up to several
grams, by (1) Pd(0)-mediate coupling-cyclization of alkyne acids
17 with iodopyrrole 18 to afford enelactones 19 (74-98%); (2)
methylenation of the lactone carbonyl group with Petasis’s
reagent (19 f 20; 86-92%); and (3) in situ enol-ether
hydrolysis/amination (20 f 21; 71-82%). The desired A,B-
ring aldehydes 12a-c were then obtained directly from 21 by
selenium dioxide oxidation of the C-20 methyl group (65-81%).
Our initial investigations using Method II were conducted
with the A,B-ring substrate 12a and unsymmetrical C,D-ring
substrate 13a, and provided encouraging results. Thus, decar-
boxylation of 13a with p-toluenesulfonic acid (TsOH) in CH2-
Cl2/MeOH afforded an 84% yield of the C-19 unsubstituted
dipyrromethane 22, which on coupling with 12a in the presence
of TiCl4 gave a 66% yield of the moderately stable tetrapyrrole
14a (path a, Scheme 5). Next, dissolution of 14a in neat TFA,
periphery of the macrocycle. In one investigation, for example,
Method I was employed in the synthesis of a diversely
substituted series of 25 chlorins 11 designed to probe substituent
effects on depth of cell membrane penetration in PDT (38-
85% yields).21b However, while versatile in many aspects, in
its present form, Method I is unsuited to the broader goal of
synthesizing unsymmetrical chlorins, which requires regiose-
lective control over the four reacting carbon atoms in 9 and 10.
To address this limitation we have been exploring variations of
this “2 + 2” condensation strategy that incorporate the desired
level of selectivity, four of which are described below (Methods
II-V).
Results and Discussion
Syntheses of Unsymmetrical Chlorins via a “2 + 2”
Strategy. Method II. Any “2 + 2” approach to unsymmetrical
chlorins requires that the reactive sites of the A,B- and C,D-
rings be differentiated, such that a single regioisomer is
generated. The first strategy we tested for meeting this criterion
is outlined in Scheme 3, in which the differentiating step
involves mild acid-catalyzed condensation of C-9 protected A,B-
ring precursors of type 12 with readily available22 C-11 protected
C,D-ring precursors 13 (Method II). Our supposition was that
(23) (a) Li, W.; Lash, T. D. Tetrahedron Lett. 1998, 39, 8571. (b) Zhang, B.;
Lash, T. D. Tetrahedron Lett. 2003, 44, 7253.
(24) O’Neal, W. G.; Roberts, W. P.; Ghosh, I.; Jacobi, P. A. J. Org. Chem.
2005, 70, 7243.
(22) For example, see: Jackson, A. H.; Pandey, R. K.; Rao, K. R. N.; Roberts,
E. Tetrahedron Lett. 1985, 26, 793 and ref. 23b.
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General Synthesis of Chlorins
A R T I C L E S
Scheme 5. Three Variations of Method II; paths a-c
Table 1. Chlorins Prepared by Method II
Method I
yield (%)b
15
substituentsa
yield (%)
a
b
c
d
e
f
f ) Me; R ) Me
f ) Me; R ) Ph
f ) Me; R ) H
f ) PMe; R ) Me
f ) PMe; R ) Ph
f ) PMe; R ) H
38
59
11
37
38
12
73
60
63
a PMe ) CH2CH2CO2Me. b See ref 21b.
followed shortly thereafter by dilution with CH2Cl2 and excess
triethyl orthoformate (TEOF), gave a 50% yield of the desired
chlorin 15a as a single regioisomer. The substitution pattern of
15a was unequivocally established by NOE studies (see
Supporting Information), as well as by direct comparison with
its subsequently prepared regioisomer 26 (vide infra).
and in no case was evidence found for formation of regioiso-
meric chlorin products.26
To test the generality and effectiveness of Method II, we
synthesized two additional unsymmetrical chlorins 15b,c, and
for comparison, three C,D-ring symmetric chlorins 15d-f
previously prepared by Method I (Table 1; cf. also Scheme 2).
We observed little effect of non-meso-C,D-ring substituents f
on the course of these syntheses. However, the nature of the
A,B-ring meso-substituents R had a significant influence on
reaction efficiency, with dihydrodipyrrins 12a (R ) Me) and
12b (R ) Ph) affording considerably higher yields of the
corresponding chlorins 15a,d and 15b,e than the case with
unsubstituted substrate 12c (R ) H). These results are consistent
with a reaction pathway involving cationic intermediates
stabilized by electron donating substituents at C-5. Interestingly,
Method II proved to be less efficient than Method I for
synthesizing C,D-ring symmetric chlorins of type 15d-f, yields
in each case being significantly lower. However, even with these
limitations, Method II does provide access to unsymmetrical
chlorins via the readily available precursors 12 and 13.
Most of our efforts at optimizing Method II centered on the
decarboxylative formylation process leading from tetrapyrroles
14 to presumed chlorin intermediates 16 (cf. Scheme 3), which
we had reason to believe might be problematic. In particular,
the initial step in such transformations involves ipso-protonation
(or formylation) on the carboxyl-bearing pyrrole ring, followed
by re-aromatization with loss of CO2.27 Consequently, acid-
catalyzed decarboxylation (or decarboxylative formylation) of
electron deficient pyrroles is typically very slow.28 In the present
case, tetrapyrrole 14 is a vinylogous amidine presumably
favoring N-protonation in ring A or D, either of which lowers
Having established proof-of-concept, we were hopeful that
the transformation of 13a to 15a could be streamlined to a
“single pot” procedure, bypassing the isolation of the R-unsub-
stituted dipyrromethane 22 and seco-chlorin 14a. There was
precedent for this possibility in our original studies on C,D-
symmetric chlorins (cf. Scheme 2), where we found that
dipyrromethane dicarboxylic acids 10 and dialdehydes 9 un-
derwent acid-catalyzed condensation under conditions where
t-butyl ester cleavage is exceedingly slow (5% TFA/CH2Cl2).
The initial step of this goal, avoiding isolation of 22, was readily
accomplished by treating a solution of dipyrromethane 13a and
aldehyde-ester 12a in CH2Cl2 with sufficient neat TFA to bring
the final concentration to 5% (path b, Scheme 5). After being
stirred for ∼1 h at rt under Ar, the anticipated seco-chlorin 14a
was isolated in 68% yield. Cyclization of 14a as before then
provided a route to chlorins that circumvented the separate
TiCl4-catalyzed condensation of 22 and 12a. Next, a second
simplification was realized by effecting the TFA-initiated
condensation and cyclization steps in a single flask without
isolation of intermediate 14a (path c). In this modification, a
solution of 13a and 12a in 5% TFA/CH2Cl2 was stirred at rt
under Ar for a period of 5 h, when it appeared that formation
of 14a was complete.25 The resulting deep purple reaction was
then adjusted to a concentration of 20% TFA/CH2Cl2 by addition
of neat TFA and then treated with excess trimethyl orthoformate.
After stirring an additional 16 h at rt, chlorin 15a was isolated
in 34% yield by straightforward concentration and chromatog-
raphy. This yield compares favorably with the overall yields of
28% and 34% obtained following paths a and b respectively,
(26) These yields are considered optimized with respect to temperature effects,
reaction time, concentration, reagent quantity, and the presence of various
metal templates, which had no beneficial effect.
(27) Jackson, A. H. Pyrroles. In The Chemistry of Heterocyclic Compounds;
Jones, R. A., Ed.; John Wiley & Sons: New York, 1990; Vol. 48, Part 1,
p 315.
(28) Jackson, A. H. Pyrroles. In The Chemistry of Heterocyclic Compounds;
Jones, R. A., Ed.; John Wiley & Sons: New York, 1990; Vol. 48, Part 1,
pp 297-301.
(25) Shorter reaction periods were found to be less effective since the final
reaction mixtures were invariably contaminated with unidentified pigments
that complicated isolation of chlorin. The 5 h reaction time for this step
eliminated these pigments.
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A R T I C L E S
O’Neal and Jacobi
Scheme 6. Design and Testing of Methods III-V
Scheme 7. Synthesis of C,D-rings 23 and 25 for Methods III and
IV
routine) followed by benzyl ester hydrogenolysis (Scheme 7).
The next step called for mild acid-catalyzed condensation of
23 with the A,B-ring precursor 12a, followed by t-butyl ester
hydrolysis and cyclodehydration. Each of these steps had close
precedent in path c of Method II (cf. Scheme 5), although self-
condensation of 23 was a potential complication. Blank experi-
ments, however, indicated that side reactions of this nature could
be controlled. In the event, condensation of 12a and 23 in 5%
TFA/CH2Cl2, followed by adjustment to 25% TFA/CH2Cl2,
afforded chlorin 15a in 28% yield, with no evidence for
byproducts arising from self-condensation (Scheme 6). During
this sequence, a polar intermediate was observable by TLC,
whose crude NMR spectrum was consistent with the anticipated
tetrapyrrole condensation product of 12a and 23. However,
several attempts at isolating and fully characterizing this
compound were unsuccessful, making further optimization
difficult. Thus, while clearly a viable means of synthesizing
unsymmetrical chlorins, Method III had no advantages over
Method II in terms of simplicity or effectiveness.
Method IV. Method IV constituted a relatively minor
variation on Method III, substituting a t-butyl ester in C,D-ring
precursor 25 for the carboxylic acid blocking group employed
in 23 (Scheme 6). We were also interested in preparing the
regioisomeric chlorin 26 to compare directly with the chlorin
15a synthesized previously using both Methods II and III. The
synthesis of 25 was simplified by the fact that it could be
prepared from the same dipyrromethane precursor 24 previously
employed in the synthesis of C,D-ring precursor 23 (Scheme
7). In the case of 25, benzyl ester hydrogenolysis and decar-
boxylation of 24 were effected first, followed by formylation
under very mild Vilsmeier-Haack conditions to ensure that the
t-butyl ester remained intact.30
As in the analogous step in Method III, self-condensation of
C,D-ring precursor 25 was a potential complication in Method
IV, in particular under the more strongly acidic conditions
required for t-butyl ester cleavage (25% TFA/CH2Cl2). However,
we were again confident that the far more electrophilic C-20
formyl group in ring A of 12a would react preferentially. A
second point worth noting pertains to the t-butyl ester group at
C-9 in ring B. Although we fully expected this group to undergo
concomitant ester cleavage, we had previously found that
decarboxylation in such ring systems is sluggish, due to the
the likelihood of ipso-electrophilic attack on rings B or C.
Indeed, in earlier mechanistic studies we observed the same
phenomenon with dihydrodipyrrins having a basic pyrroline ring
nitrogen.21b Since this step in Method II could not be optimized
further, we examined three additional approaches to unsym-
metrical chlorins that avoided decarboxylative formylation on
basic ring systems (Methods III-V, Scheme 6). Methods III
and IV achieve regioselectivity in similar fashion to Method II,
except that in both cases a formyl group is incorporated in the
C,D-ring fragment. In contrast, Method V employs the same
bis-formyl A,B-ring precursor 9 previously utilized in our
syntheses of C,D-ring symmetric chlorins (Method I, cf. Scheme
2), regioselectivity being dictated by the far greater reactivity
of the formyl group in ring A.
Method III. Our synthetic design for Method III is similar
in concept to Method II (cf. Schemes 3 and 5), except the
aldehyde destined to become C-10 is incorporated early on
(Scheme 6). To test this approach, model aldehyde-acid 23 was
synthesized from the known dipyrromethane 24,29 by a two step
sequence consisting of decarboxylative formylation (in this case
(29) Pandey, R. K.; Rezzano, I. N.; Smith, K. M. J. Chem. Res., Miniprint 1987,
8, 2171.
(30) Chong, R.; Clezy, P. S.; Liepa, A. J.; Nichol, A. W. Aust. J. Chem. 1969,
22, 229.
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General Synthesis of Chlorins
A R T I C L E S
electron withdrawing effect of the protonated pyrroline ring A.21b
This argument formed the basis for regiochemical control in
the condensation of 12a and 25 and for avoiding self-
condensation of A,B-ring precursor 12a. Thus, we expected that
relatively rapid deprotection of C-19, followed by condensation
with the highly reactive C-20 aldehyde, would afford a bilin
intermediate that is properly disposed for ring closure to the
corresponding chlorin. This turned out to be the case, as stirring
of 12a and 25 in 25% TFA/CH2Cl2 for 24 h provided chlorin
26 in 39% yield (Method IV, Scheme 6). Direct comparison of
chlorins 26 and 15a then demonstrated conclusively that there
had been no crossover in regiochemical control in Methods II-
IV. While this result was satisfying, evidence was accumulating
that an even more straightforward approach to unsymmetrical
chlorins was feasible employing diformyl ring-A,B precursors
9 (Method V).
Table 2. Chlorins Prepared by Method V
Method I
yield (%)b
15
substituentsa
yield (%)
a
b
c
d
e
f
g
h
i
e,f ) Me; g ) PMe; R ) Me
e,f ) Me; g ) PMe; R ) Ph
e,f ) Me; g ) PMe; R ) H
e ) Me; f,g ) PMe; R ) Me
e ) Me; f,g ) PMe; R ) Ph
e ) Me; f,g ) PMe; R ) H
e ) PMe; f,g ) Me; R ) Me
e ) PMe; f,g ) Me; R ) Ph
e ) PMe; f,g ) Me; R ) H
74
87
39
78
73
38
38
77
22
73
60
63
Method V. In our previous chlorin studies, we demonstrated
that diformyl derivatives 9 are excellent A,B-ring precursors
for synthesizing C,D-symmetric chlorins 11 (cf. Scheme 2).21
We had assumed, though, that these materials lacked the
unambiguous differentiation at C-10 and C-20 necessary to
impart regioisomeric selectivity. The validity of this assumption
was now called into question, based upon the substantial
reactivity differences we had uncovered between pyrrole- and
pyrroline-type formyl groups (vide supra). Thus, it now seemed
clear that electron rich pyrroles would undergo selective
condensation with the more reactive pyrroline aldehyde found
on ring A in 9, as opposed to the vinylogous amide-like formyl
group present in ring B. This approach was first tested with
dialdehyde 9a and dipyrromethane 13a, which were stirred
together for 5 h at rt in 5% TFA/CH2Cl2 to effect decarboxy-
lation at C-19 and initial condensation. After stirring an
additional 16 h in 25% TFA/CH2Cl2. chlorin 15a was isolated
in 74% yield without any effort at optimization.31 Furthermore,
this methodology proved to be quite general. Both C,D-ring
symmetric and unsymmetrically substituted chlorins were ac-
cessible by this route, with yields ranging from 22 to 87% (Table
2). As can be seen, the C-5 meso-substituent still exerted some
influence on the reaction efficiency, with the trend mirroring
that previously noted for Method II. That is, meso-H derivatives
15c,f,i were consistently formed in lower yields than the
corresponding meso-Me or meso-Ph chlorins, again suggesting
the intermediacy of cationic species. Importantly, however, the
yields of all chlorins were significantly improved over those
obtained by Method II, including the meso-H series which were
brought into a preparatively useful range (note that the 22%
yield for 15i is atypically low, even for meso-H substituted
derivatives). Finally, direct comparison of Methods I and V was
possible for the series of C,D-ring symmetric chlorins 15d-f.
In these examples, the yields for meso-Me and meso-phenyl
chlorins 15d,e were somewhat higher employing Method V
(78% and 73%, respectively; vs 73% and 60% for Method I),
presumably due to better control over competing oligomeriza-
tion. Interestingly, though, meso-H chlorin 15f did not follow
this trend, and was better prepared using Method I (38% vs
63%).
a PMe ) CH2CH2CO2Me. b See ref 21b.
Conclusions
In summary, we have built upon our 2 + 2 synthesis of C,D-
ring symmetric chlorins to develop four new strategies for the
preparation of chlorins that are fully asymmetric in their
substitution pattern. Method V, which combines operational
simplicity with moderate to high product yields, proved to be
the most effective route, with reactivity differences between the
two formyl groups of A,B-rings 9 imparting excellent regiose-
lectivity. Methods II-IV are also useful alternatives to Method
V if the appropriately functionalized precursors are readily
available. All four approaches generate single regioisomers of
diversely substituted chlorins, and in every case the 2 + 2
condensation is accomplished in a simple, one-flask procedure
without need for additives such as oxidizing agents or metals.
Taken together, these methodologies provide expanded access
to an array of chlorins for SAR studies that may advance the
effectiveness of PDT and other applications.
Experimental Section
Representative procedures for the syntheses of chlorins by Methods
II-V:
2,2,5,7,8,12, 13,18-Octamethylchlorin-17-propionic Acid Methyl
Ester (15a). Method II. A solution of 12a (10.1 mg, 29 µmol) and
13a (12.2 mg, 29 µmol) in CH2Cl2 (2.6 mL) was treated with TFA
(130µL) and stirred at RT in the dark for 5 h. TFA (520 µL) and TMOF
(63 µL, 578 µmol) were then added, and the solution was stirred for
an additional 16 h. The solvent was removed by rotary evaporation.
The residue was redissolved in CH2Cl2 and washed with cold, saturated
aq KHCO3, dried over Na2SO4, filtered, and concentrated. The oil was
purified by flash chromatography (silica gel, EtOAc:hexanes ) 1:4,
1% NEt3) to give 15a (5.1 mg, 34%) as a green film; Rf (1:4 EtOAc/
hexanes) 0.30; IR(thin film) 3325, 1730 cm-1; H NMR (500 MHz,
1
CDCl3) δ -2.52 (br s, 1H), -2.05 (br s, 1H), 2.07 (s, 6H), 3.22 (t, J
) 8.1, 2H), 3.41 (s, 3H), 3.42 (s, 3H), 3.43 (s, 3H), 3.48 (s, 3H), 3.53
(s, 3H), 3.74 (s, 3H), 3.80 (s, 3H), 4.33 (t, J ) 7.9, 2H), 4.44 (s, 2H),
8.85 (s, 1H), 9.62 (s, 1H), 9.72 (s, 1H); 13C NMR (500 MHz, CDCl3)
δ 11.6, 12.00, 12.02, 16.6, 21.4, 21.9, 32.1, 37.1, 46.0, 52.1, 52.4, 91.1,
97.5, 98.8, 105.3, 128.6, 129.5, 131.5, 133.4, 135.1, 135.3, 136.4, 137.2,
(31) Trace amounts of an isomeric chlorin could be detected by UV analysis,
but the structure of this compound was not conclusively identified.
9
J. AM. CHEM. SOC. VOL. 130, NO. 3, 2008 1107

A R T I C L E S
O’Neal and Jacobi
137.4, 138.3, 149.8, 151.8, 162.0, 171.8, 173.9; UV-vis (CHCl3): λmax
-
dark for 24 h, then cooled to 0 °C and quenched with NEt3 (1.5 mL).
The solution was washed sequentially with water (3 × 5 mL) and brine,
dried over Na2SO4, filtered, and concentrated. The residue was purified
by chromatography (silica gel, EtOAc:hexanes ) 1:4, 1% NEt3) to give
26 (7.2 mg, 39%) as a green solid, decomp. > 240 °C. Rf (3:7 EtOAc/
hexanes) 0.49; IR (thin film) 3311, 1731, 1150, 917 cm-1; UV-vis
(12% CH2Cl2 in MeOH): λmax (ꢀ L mol-1 cm-1) ) 642 (13000), 591,
501, 358 nm; 1H NMR (500 MHz, CDCl3) δ -2.43 (br s, 1H), -2.05
(br s, 1H), 2.05 (s, 6H), 3.18 (t, J ) 8.09, 2H), 3.44 (s, 3H), 3.46 (s,
3H), 2.49 (s, 3H), 3.50 (s, 3H), 3.53 (s, 3H), 3.74 (s, 3H), 3.86 (s, 3H),
4.19 (t, J ) 8.09, 2H), 4.46 (s, 2H), 8.78 (s, 1H), 9.54 (s, 1H), 9.75 (s,
1H); 13C NMR (500 MHz, CDCl3) δ 11.6, 11.7, 11.9, 12.0, 16.6, 21.5,
22.2, 32.0, 37.5, 46.1, 51.9, 52.3, 90.7, 97.3, 99.3, 105.1, 128.3, 129.6,
131.1, 133.3, 134.9, 135.3, 137.8, 138.29, 138.34, 138.5, 148.9, 150.4,
161.8, 172.3, 174.3. HRMS (EI) Calcd for C32H38N4O2: 510.2995;
found: 510.2993.
(ꢀ, mol-1 cm-1) ) 399(151,000), 501(12,000), 651(42,000) nm; HRMS
(EI) Calcd for C32H38N4O2: 510.2995; found: 510.3002.
Method III. A solution of 12a (20.3 mg, 58 µmol) and 23 (20.3
mg, 58 µmol) in CH2Cl2 (5.5 mL) was cooled to 0 °C and treated with
TFA (280 µL, 5 v/v%). After stirring for 1h, an additional 1.1 mL (20
v/v%) of TFA was added, the ice bath was removed, and the reaction
was stirred at RT for 1.5 h. The solution was cooled to 0 °C and
quenched with NEt3 (2.6 mL). The mixture was washed sequentially
with water (3 × 5 mL) and brine, dried over Na2SO4, filtered, and
concentrated. The residue was purified by chromatography (silica gel,
EtOAc:hexanes ) 1:4, 1% NEt3) to give 15a (8.3 mg, 28%) as a green
solid that was identical to the material prepared by Method II.
Method V. A solution of 9a (16.9 mg, 62 µmol) and 13a (26.0 mg,
62 µmol) in CH2Cl2 (5.7 mL) was treated with TFA (280µL, 5 v/v %)
and stirred at RT in the dark for 5 h. More TFA (1.1 mL, 20 v/v %)
was then added, and the solution was stirred for an additional 16 h.
The solvent was removed by rotary evaporation. The residue was
redissolved in CH2Cl2 and washed with cold, saturated aq KHCO3, dried
over Na2SO4, filtered, and concentrated. The product was purified by
flash chromatography (silica gel, EtOAc:hexanes ) 1:4, 1% NEt3) to
give 15a (23.5 mg, 74%) as a green film that was identical to the
material prepared by Method II.
Acknowledgment. Financial support of this work by the
National Institutes of Health, NIGMS Grant No. GM38913 is
gratefully acknowledged. We thank Dr. William P. Roberts for
his work during the initial development of Method II.
Supporting Information Available: Complete ref 11c, ex-
perimental 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.
2,2,5,7,8,12, 17,18-Octamethylchlorin-13-propionic Acid Methyl
Ester (26). Method IV. A solution of 12a (12.4 mg, 36 µmol) and 25
(15 mg, 36 µmol) in CH2Cl2 (3.3 mL) was cooled to 0 °C and treated
with TFA (820 µL, 15 v/v%). The mixture was stirred at RT in the
JA0780075
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1108 J. AM. CHEM. SOC. VOL. 130, NO. 3, 2008