A new synthesis of chlorins

Article abstract of DOI:10.1021/ol006983m

matrix presented A new synthesis of chlorins has been developed, based upon the acid-catalyzed condensation of dialdehydes AB with dipyrromethanes CD.

Full text of DOI:10.1021/ol006983m

ORGANIC
LETTERS
2001
Vol. 3, No. 6
831-834
A New Synthesis of Chlorins
Peter A. Jacobi,* Sandra Lanz, Indranath Ghosh, Sam H. Leung,
Franziska Lo1wer, and Douglas Pippin
Burke Chemical Laboratory, Dartmouth College, HanoVer, New Hampshire 03755
peter.a.jacobi@dartmouth.edu
Received December 8, 2000
ABSTRACT
A new synthesis of chlorins has been developed, based upon the acid-catalyzed condensation of dialdehydes AB with dipyrromethanes CD.
In Nature, aromatic tetrapyrroles can be divided formally
into two classes: (1) those that are fully oxidized, the most
common of which are the 22 π-electron porphyrins, and (2)
those that are partially reduced (hydroporphyrins) but still
contain the required 18 π-electrons for aromaticity (Figure
1).1 The porphyrin ring is ubiquitous, in part due to its
droporphyrins include members of the chlorin and bacterio-
chlorin families, corresponding to the H2- and H4-oxidation
level, respectively. In general, these ring systems are less
stable than the porphyrins.
Both porphyrins and hydroporphyrins serve diverse bio-
logical functions. The porphyrin Heme is the most important
biological carrier of oxygen and chlorophyll (a chlorin) is
the principal light gathering chromophore of photosynthesis
(bacteriochlorophyll, a bacteriochlorin, plays a similar role
in bacteria).1 Various hydroporphyrins have also been
identified as cofactors for redox enzymes.1e In addition to
their biological importance, many naturally occurring and
synthetic hydroporphyrins are of interest in both materials
science and medicine. For example, the tolylporphin class
of bacteriochlorins has been found to reverse tumor multidrug
resistance (MDR).2 Agents of this type might provide new
tools for cancer chemotherapy. Also, semisynthetic chlorins
are being evaluated in tumor photodynamic therapy (PDT).3
This technique uses an absorbed pigment to eradicate
malignant tissue by photostimulated production of singlet
oxygen.
Figure 1. Aromatic macrocyclic tetrapyrroles.
exceptional stability. Compounds of this class are found in
geological shale (geoporphyrins) and have even been detected
spectroscopically in interstellar space.1e Representative hy-
(1) (a) Flitsch, W. In AdVances in Heterocyclic Chemistry; Katritzky,
A. R., Ed.; Academic Press: San Diego, 1988; Vol. 43. (b) Montforts, F.-
P.; Gerlach, B.; Ho¨per, F. Chem. ReV. 1994, 94, 327. (c) Montforts, F.-P.;
Glasenapp-Breiling, M. Prog. Heterocycl. Chem. 1998, 10, 1. (d) 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. (e)
Montforts, F.-P.; Glasenapp-Breiling, M.; Kusch, D. Houben-Weyl 2000,
577.
(2) (a) Prinsep, M. R.; Caplan, F. R., Moore, R. E.; Patterson, G. M. L.;
Smith, C. D. J. Am. Chem. Soc. 1992, 114, 385. (b) Minchan, T. G.; Cook-
Blumerg, L.; Kishi, Y.; Prinsep, M. R.; Moore, R. E. Angew. Chem. 1999,
111, 975, and references therein.
(3) (a) Kozyrev, A. N.; Suresh, V.; Das, S.; Senge, M. O.; Shibata, M.;
Dougherty, T. J.; Pandey, R. K. Tetrahedron 2000, 56, 3353, and references
therein. (b) Montforts, F.-P.; Meier, A.; Haake, G.; Ho¨oper, F. Tetrahedron
Lett. 1991, 32, 3481.
10.1021/ol006983m CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/21/2001

Not surprisingly, porphyrins are the easiest of the mac-
rocyclic tetrapyrroles to prepare, since the ring itself is very
stable and has no stereogenic centers. Successful synthetic
efforts in this area date back over 65 years.4a In contrast,
few general methods are available for synthesizing members
of the hydroporphyrin class of tetrapyrroles. Most efforts in
this area have focused on “semisynthesis”, involving trans-
formations of more readily accessible precursors. These
include reactions occurring at the periphery of porphyrins,4
such as oxidation,4b reduction,4c and various cycloadditions;4d
tautomerization of porphyrinogens and related materials;4e
and modifications of naturally occurring chlorins and
bacteriochlorins.1e,3
and sulfolane as solvent (110 °C), these authors obtained
yields of bonellin derivatives in the range 55-75%, on scales
of 10-20 mg. Finally, Lindsey et al. have recently extended
this methodology to include the synthesis of meso-substituted
chlorins. Zn(II)-complexed chlorins were obtained in up to
a 10% yield, on an ∼20 mg scale.9
A number of challenges remain in chlorin synthesis. For
example, the preparation of monocyclic precursors of type
1-4 is not trivial and often requires separation of mixtures
after lengthy reaction sequences. Second, it would be useful
to have more flexibility in the introduction of meso-
substituents, of potential importance in the design of PDT
agents (vide supra). Third, new methodology should be
adaptable to the synthesis of enantiomerically pure chlorins.
And finally, experimental procedures should be simplified
and be capable of implementation on larger scales.9b
One means of addressing these issues would employ a
variant of the MacDonald porphyrin synthesis (Figure 3).
The vast majority of de novo chlorin syntheses are
modeled after the Battersby methodology (Figure 2), which
Figure 2. Battersby-Montforts synthesis of chlorins.
was elegantly employed in the first rational synthesis of
bonellin.5 In its most general form, this strategy is based
upon either a photochemical or thermally induced ring
closure of a properly substituted bilatriene 5 (X ) OMe,
Br). Bilatrienes 5, in turn, are constructed from monocyclic
building blocks of type 1-4, which are typically joined by
means of either a sulfide contraction6 or a thio-Wittig
reaction7 or a related technique. The thermal cyclization
conditions require copper chelation for activation (X ) Br)
and afford chlorins 6 in 5-10% yield after decomplexation.
The photochemical ring closure is higher yielding (∼20%;
X ) OMe) but requires up to 1 week of irradiation of very
dilute solutions. Both procedures are carried out on milligram
quantities.
Figure 3. “MacDonald-Like” Approach to Chlorins.
The precursors 7 and 8 are in the proper oxidation state for
direct condensation to afford chlorins 9 (-2 H2O), and
macrocycle formation should be facile.10 Surprisingly, how-
ever, this approach to chlorins has not been described, most
likely due to difficulties in preparing A,B-ring dialdehydes
of type 7. In this paper we describe a general synthesis of 7
and the successful incorporation into chlorins of type 9.
Our synthetic plan for 7 took advantage of the ready
availability of alkyne acids 10 and iodopyrroles 11 (Scheme
1).11 Recently we employed these materials to prepare
enantiomerically pure dihydropyrromethenones 13, the first
step of which involved Pd0-initiated coupling-cyclization
to afford enelactones 12.11a Aminolysis of 12 at -33 °C,
followed by keto-amide cyclization, then gave 13 in excellent
overall yield. We hoped to extend this work to the synthesis
A significant improvement to this methodology was
developed by Montforts et al., who employed Zn(II) as a
template and carried out the cyclization of 5 by employing
base catalysis (Figure 2, X ) Br, I).8 With DBU as base,
(4) (a) Rothemund, P. J. Am. Chem. Soc. 1935, 57, 2010. (b) Inhoffen,
H. H.; Nolte, W. Liebigs Ann. Chem. 1969, 167. (c) Bonnett, R.; White, R.
D.; Winfield, U.-J.; Berenbaum, M. C. Biochem. J. 1989, 261, 277. (d)
Tome´, A. C.; Lacerda, P. S. S.; Neves, M. G. P. M. S.; Cavaleiro, J. A. S.
Chem. Commun. 1997, 1199. (e) Burns, D. H.; Shi, D. C.; Lash, T. D.
Chem. Commun. 2000, 299. See also refs 1 and 9a.
(5) (a) Battersby, A. R.; Dutton, C. J.; Fookes, C. J. R.; Turner, S. P.
D.; J. Chem. Soc., Chem. Commun. 1983, 1235. (b) Battersby, A. R.; Dutton,
C. J.; Fookes, C. J. R. J. Chem. Soc., Perkin Trans. 1 1988, 1569.
(6) Eschenmoser, A. Angew. Chem., Int. Ed. Engl. 1988, 27, 5, and
references therein.
(8) (a) Montforts, F.-P.; Schwartz, U. M.; Liebigs Ann. Chem. 1991, 709.
(b) Abels, Y.; Montforts, F.-P. Tetrahedron Lett. 1997, 38, 1745, and
references therein.
(9) (a) Strachan, J.-P.; O’Shea, D. F.; Balasubramanian, T.; Lindsey, J.
S. J. Org. Chem. 2000, 65, 3160. (b) According to one practitioner, “rational
routes to chlorins ... have typically required such synthetic mastery that
implementation has been confined to Elite specialists”.9a
(10) Arsenault, G. P.; Bullock, E.; MacDonald, S. F. J. Am. Chem. Soc.
1960, 82, 4384.
(11) (a) Jacobi, P. A.; Liu, H. J. Org. Chem. 1999, 64, 1778, and
references therein. See also: (b) Schreiber, S. L.; Klimas, M. T.; Sammakia,
T. J. Am. Chem. Soc. 1987, 109, 5749.
(7) Bishop, J. E.; O’Connell, J. F.; Rapoport, H. J. Org. Chem. 1991,
56, 5079.
832
Org. Lett., Vol. 3, No. 6, 2001

4-methylpyridine. Surprisingly, however, triflate 14a was
relatively unreactive toward nucleophilic displacement,
returning mainly starting material with various “formyl
anion” equivalents.13 We also investigated several Pd0-
catalyzed formylations, all without success.14 Ultimately, only
one organocopper species afforded even modest yields of
displacement products. This was the Bertz reagent,15 which
gave 36% of the methyl substitution product 16a. We were
hopeful that 16a might be converted to the desired 15a by
oxidation. However, we could not isolate sufficient quantities
of 16a by this route to test this idea.
Scheme 1
Much better results were obtained with the thioimidate
derivative 18a (Scheme 3), which was derived from lactam
Scheme 3
of 7 by adding CHO groups to C1 and C9. In principle, the
C9 formyl group could be introduced by initial conversion
to activated imidoyl derivatives of type 14 (X ) leaving
group), followed by displacement with a “formyl anion”
equivalent (14 f 15). Decarboxylative formylation at C1 in
15 was expected to be straightforward.12
Our initial studies were carried out with the alkyne acid
10a (Scheme 2), which gave a 96% yield of the enelactone
Scheme 2
13a by sulfonation with Lawesson’s reagent (99%), followed
by S-methylation (MeI, 72%) (Z,E-mixtures are indicated
by a wavy bond). This approach built upon the studies of
Fukuyama16a and Liebeskind,16b,c who have investigated the
(13) Gro¨bel, B.-T.; Seebach, D. Synthesis 1977, 357.
(14) See, for example: Bernabe´, P.; Rutjes, F. P. J. T.; Hiemstra, H.;
Speckamp, W. N. Tetrahedron Lett. 1996, 37, 3561.
(15) Bertz, S. H.; Eriksson, M.; Miao, G.; Snyder, J. J. Am. Chem. Soc.
1996, 118, 10906. The methyl transfer reagent was prepared by following
the procedure given for the corresponding n-butyl species.
(16) (a) Tokuyama, H.; Yokoshima, S.; Yamashita, T.; Fukuyama, T.
Tetrahedron Lett. 1998, 39, 3189. (b) Srogl, J.; Liu, W.; Marshall, D.;
Liebeskind, L. S. J. Am. Chem. Soc. 1999, 121, 9949. (c) Savarin, C.; Srogl,
J.; Liebeskind, L. S. Org. Lett. 2000, 2, 3229. We gratefully acknowledge
stimulating discussions with Professor Liebeskind on this subject. (d) For
best results, the MeZnI reagent must be prepared by following the procedure
of Fukuyama et al. (ref 16a). The reagent derived by treatment of MeMgCl
with ZnI was considerably less reactive.
12a upon Pd0-initiated coupling-cyclization with the io-
dopyrrole 11a (>20 g scales). Aminolysis of 12a, followed
by cyclodehydration with Montmorillonite clay, then afforded
the desired enamide 13a (68%). At this point we explored a
number of methods for enamide activation.11a The most direct
of these involved imidoyl triflate formation, which was
accomplished in 92% yield using Tf2O and 2,6-di-tert-butyl-
(12) Gossauer, A.; Hinze, R.-P. J. Org. Chem. 1978, 43, 283.
Org. Lett., Vol. 3, No. 6, 2001
833

Table 1. Summary of Yieldsa
Scheme 4
compd
12
13
17
19
2019
7
a
b
c
d
96%
98%
85%
74%
68%
89%
75%
76%
99%
91%
86%
49%
68%
68%
71%
41%
62%
71%
73%
57%
99%
68%
62%
99%
a Compound numbers correspond to Schemes 1-3.
Pd0-catalyzed cross-coupling reaction of thioester derivatives
with various organometallic compounds. In particular, re-
agents RZnI cleanly afford the product of formal nucleophilic
displacement (no reaction is observed in the absence of Pd0).
These results were readily extended to the case of thioimidate
18a, which gave an 88% yield of methyl derivative 16a upon
reaction with MeZnI/Pd0.16d With ample quantities of 16a
in hand, we could obtain reasonable quantities of formyl
derivative 15a by oxidation with SeO2.17 Unexpectedly,
however, we were unable to accomplish the decarboxylative
formylation of 15a leading to 7a, presumably due to the
inductive influence of the C9-formyl group. This was
remedied by reversing the order of decarboxylation and
oxidation. Thus, methyl derivative 16a was cleanly converted
to the formyl compound 20a (TFA/TMOF), which gave an
essentially quantitative yield of the desired dialdehyde 7a
upon oxidation with SeO2.
Finally, we were able to streamline the synthesis of 7a by
effecting the methylation and decarboxylative formylation
of 17a concomitantly (TFA/TMOF). This transformation was
modeled after a similar reaction reported by Battersby et al.18
and gave a 68% yield of 19a directly. The structure of 19a
was confirmed by decarboxylative formylation of the S-
methyl derivative 18a, which gave identical material but in
a less efficient fashion. It remained now to carry out the
cross-coupling reaction of 19a with MeZnI, a potentially
complex step. However, this reaction proved to be remark-
ably selective and gave a 62% yield of 20a with no evidence
of nucleophilic attack at the aldehyde group.19 Previously
we had converted 20a to 7a in 99% yield using SeO2, thereby
completing the synthesis. This route to A,B-ring precursors
of type 7 appears to be quite general (Table 1) and is
compatible with a wide range of functionality.
representative examples to attempt the synthesis of chlorins
9 (Scheme 4). The condensation of 7 and 8 turned out to be
straightforward, requiring no particular precautions against
air or light and no metal complexation. For example, simple
dissolution of 7a and 8e in neat TFA afforded 44% of chlorin
9ae after 1.5 h at ambient temperature. In analogous fashion,
we prepared chlorins 9af-cf in the yields summarized in
Scheme 4. Thus far we have made no efforts to optimize
these conditions.
We believe this approach is useful because of its flexibility
and the simplicity of the experimental conditions. Currently
we are extending this work to the synthesis of unsymmetrical
C,D-ring chlorins, as well as to bacteriochlorins and other
biologically important hydroporphyrins.
Acknowledgment. Financial support of this work by the
National Institutes of Health, NIGMS Grant GM38913, is
gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds reported.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL006983M
Numerous C,D-ring precursors of general structure 8 are
readily available.9a,20 We chose dipyrromethanes 8e,f as
(19) Yields refer to those obtained with the major Z-isomers of 19. The
corresponding E-isomers underwent cross-coupling either very slowly or
not at all.
(17) Werner, A.; Sa´nchez-Migallo´n, A.; Fruchier, A.; Elguero, J.;
Ferna´ndez-Castano, C.; Foces-Foces, C.; Tetrahedron 1995, 51, 4779.
(18) 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.
(20) See, for example: (a) Okada, K.; Saburi, K.; Nomura, K.; Tanino,
H. Tetrahedron Lett. 1998, 39, 2365. (b) Littler, B. J.; Miller, M. A.; Hung,
C.-H.; Wagner, R. W.; O’Shea, D. F.; Boyle, P. D.; Lindsey, J. S. J. Org.
Chem. 1999, 64, 1391.
834
Org. Lett., Vol. 3, No. 6, 2001