The rational synthesis of chlorins via rearrangement of porphodimethenes: Influence of β-substituents on the regioselectivity and stereoselectivity of pyrroline ring formation

Article abstract of DOI:10.1021/jo020105f

The porphodimethene rearrangement methodology reported in this paper provides for a rational, step-by-step synthesis of chlorins from readily available pyrrole precursors. The intermediate porphodimethenes are furnished directly via the '2 + 2' MacDonald condensation, or by the less symmetry-constrained '3 + 1' condensation of a tripyrrane and bis-formyl pyrrole. The synthetic route is short and highly convergent, especially in the case of the '3 + 1' approach, and furnishes chlorins in good to moderate yields. The synthesis is highly regioselective and appears to be based on the ability of the β-substituent to stabilize excess electron density, with an electron-neutral hydrogen or an electron-withdrawing carbonyl β-substituent demonstrating the greatest influence on the formation of the pyrroline ring. The synthesis is highly stereoselective when epimerization of the pyrroline ring β-carbons is possible, furnishing only the trans-reduced sterioisomer. Finally, there is substantial evidence that a fifth, axial ligand is involved in the transposition of peripheral hydrogens during the rearrangement of the π-system from metalloporphodimethene to metallochlorin.

Full text of DOI:10.1021/jo020105f

4536
J . Org. Chem. 2002, 67, 4536-4546
Th e Ra tion a l Syn th esis of Ch lor in s via Rea r r a n gem en t of
P or p h od im eth en es: In flu en ce of â-Su bstitu en ts on th e
Regioselectivity a n d Ster eoselectivity of P yr r olin e Rin g
F or m a tion
Dennis H. Burns,* Yue H. Li,† Dong C. Shi,† and Timothy M. Caldwell
Department of Chemistry, Wichita State University, Wichita, Kansas 67260-0051
Dennis.Burns@wichita.edu
Received February 14, 2002
The porphodimethene rearrangement methodology reported in this paper provides for a rational,
step-by-step synthesis of chlorins from readily available pyrrole precursors. The intermediate
porphodimethenes are furnished directly via the ‘2 + 2’ MacDonald condensation, or by the less
symmetry-constrained ‘3 + 1’ condensation of a tripyrrane and bis-formyl pyrrole. The synthetic
route is short and highly convergent, especially in the case of the ‘3 + 1’ approach, and furnishes
chlorins in good to moderate yields. The synthesis is highly regioselective and appears to be based
on the ability of the â-substituent to stabilize excess electron density, with an electron-neutral
hydrogen or an electron-withdrawing carbonyl â-substituent demonstrating the greatest influence
on the formation of the pyrroline ring. The synthesis is highly stereoselective when epimerization
of the pyrroline ring â-carbons is possible, furnishing only the trans-reduced sterioisomer. Finally,
there is substantial evidence that a fifth, axial ligand is involved in the transposition of peripheral
hydrogens during the rearrangement of the π-system from metalloporphodimethene to metallochlo-
rin.
In tr od u ction
Like the porphyrin ring, the chlorin macrocycle con-
tains four pyrrole rings, but differs in that one pyrrole
(pyrroline) ring is saturated at the peripheral (â) mac-
rocyclic positions (Figure 1, chlorin shown with D-ring
reduced). The synthesis of an asymmetrically substituted
chlorin is no small task, for in the preparation of such a
macrocycle it is possible to produce eight isomers: four
pyrroline-ring regioisomers each of which could exhibit
cis or trans relative stereochemistry at their â-positions.
An efficient synthesis of the chlorin ring system requires
control over pyrroline ring formation (i.e., regioselective
control in the formation of the partially saturated pyrrole
ring), control over the stereochemistry of the pyrroline
ring, and the ability to create the desired substituent
pattern on the â-positions of the macrocyclic ring. Control
of the latter feature is imperative for the efficient
preparation of chlorins regioselectively functionalized for
supramolecular assembly, e.g., antenna arrays or molec-
ular wires, or to model the chlorophylls (indeed, the basic
functions of the chlorin protein cofactors are determined
not only by the type of metal inserted into the macrocycle,
but by the variation of the macrocyclic â-substituents).4,7
The development of methods to synthesize asymmetric
porphyrins from linear tetrapyrroles, and the flexibility
these methods have given for isotope labeling, has led to
advances in the understanding of structure and function
in heme proteins, as well as to new insights in the
coordination chemistry of the many metals that bind to
Chlorins (dihydroporphyrins) serve as prosthetic groups
for proteins that perform a diverse set of biological
functions. Iron chlorins are cofactors for a number of
redox proteins, such as the heme in sulfmyoglobin,1 in
the green catalases from Neurospora crassa and Escheri-
chia coli,2 as well as the heme (heme d) in cytochrome d
of E. coli.3 Several dihydroporphyrins have been isolated
from marine organisms, such as the sex-differentiating
pigment, bonellin, as well as (possible antioxidants)
tunichlorin, cyclopheophorbide, and chlorophyllone a.4
The most abundant chlorins are the magnesium chlorinss
chlorophylls a and b, found in the photosynthetic proteins
of green plants, and bacteriochlorophylls c, d, and e,
found in the green, red, and brown sulfur bacteria5s
where they are utilized in light-harvesting arrays and
electron-transfer reaction centers. Additionally, chlorins
have potential medical applications as photosensitizers
in photodynamic therapy6 and material science applica-
tions as superior chromophores for use in molecular wires
and antenna arrays.7
* To whom correspondence should be addressed. Phone: (316) 978-
7375. FAX: (316) 978-3431.
† Current address: GlaxoSmithKline.
(1) (a) Scharberg, M. A.; La Mar, G. N. J . Am. Chem. Soc. 1993,
115, 6513-6521. (b) Andersson, L. A.; Loehr, T. M.; Lim, A. R.; A. G.
Mauk, A. G. J . Biol. Chem. 1984, 259, 15340-15349.
(2) Ozawa, S.; Watanabe, Y.; Nakashima, S.; Kitagawa, T.; Mor-
ishima, I. J . Am. Chem. Soc. 1994, 116, 634-641.
(3) (a) Sotiriou, C.; Chang, C. K. J . Am. Chem. Soc. 1988, 110, 2264-
2270. (b) Barkigia, K. M.; Chang, C. K.; Fajer, J . J . Am. Chem. Soc.
1991, 113, 7445-7447.
(4) Montforts, F. P.; Gerlach, B.; Ho¨per, F. Chem. Rev. 1994, 94,
327-347.
(5) Scheer, H. In Chlorophylls; H. Scheer, Ed.; CRC Press: Boca
Raton, 1991; pp 3-30.
(6) Pandey, R.; Zheng, G. In The Porphyrin Handbook; Kadish, K.,
Smith, K., Guilard, R., Eds.; Academic Press: San Diego, CA, 2000;
Vol. 6, pp 157-230.
(7) (a) Strachan, J .-P.; O’Shea, D. F.; Balasubramanian, T.; Lindsey,
J . S. J . Org. Chem. 2000, 65, 3160-3172. (b) Balasubramanian, T.;
Strachan, J .-P.; Boyle, P. D.; Lindsey, J . S. J . Org. Chem. 2000, 65,
7919-7929.
10.1021/jo020105f CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/25/2002

Synthesis of Chlorins
J . Org. Chem., Vol. 67, No. 13, 2002 4537
F igu r e 2. A key feature in the lengthy synthesis of bonellin
by the Monfort’s group was their utilization of a nonoxidizable
gem-dialkyl pyrrolidinone ring to construct the chlorin pyrro-
line ring.
F igu r e 1. Ring structures of parent porphyrin and chlorin.
â- and meso-ring positions, as well as the pyrroline ring, are
labeled.
Lindsey7 and J acobi.12 However, this approach is not
amenable to the study of the most abundant naturally
occurring chlorins, the light-harvesting chlorophylls,
whose pyrroline rings are not fixed by gem-dialkyl groups.
the porphyrin core.8 Likewise, a more complete under-
standing of the chemistry of chlorins, as well as chlorin-
protein systems, will require methods of synthesizing
unsymmetrically substituted hydroporphyins in an ef-
ficient manner.
We have recently communicated the synthesis of
chlorins 1 and 2 from the rearrangement of metalated
5,15-porphodimethenes 3 (Scheme 1) in 35-61% yield;13
the intermediate porphodimethene is the same oxidation
state as the chlorin product. Advantages to this method
are (1) the reaction conditions are relatively mild, (2) the
synthesis is highly regioselective, with only one out of
four possible pyrroline ring isomers formed as shown, and
(3) the synthesis is short, as the porphodimethene 3 is
furnished directly from the ‘2 + 2’ MacDonald condensa-
tion14 of 1,9-diformyldipyrromethane 4 and dipyrro-
methane 5, or the ‘3 + 1’ condensation13a of tripyrrane 7
and bis-formyl pyrrole 8.15 The method, utilizing readily
prepared precursor pyrroles, allows for a variable chlorin
peripheral substituent pattern and does not require the
pyrroline ring to be fixed by a gem-alkyl group or be
prepared prior to macrocyclic ring formation. Thus, we
thought that our approach might be a potential route for
a rational synthesis of the chlorophylls if we could
discover the factors responsible for the selectivity of
pyrroline ring formation observed in our initial studies.
The existing methods for the syntheses of hydropor-
phyrins are almost all variations on the same theme, i.e.,
the transformation of a parent porphyrin into the corre-
sponding dihydroporphyrin.4,6,9 The reactions proceed
with modest yields, generally involve conditions and
reagents that tolerate few functional groups, and are
limited to symmetrically substituted porphyrins to avoid
structural isomer formation. Besides Woodward’s artful
synthesis of chlorophyll a,10 access to the structurally
challenging chlorophylls (chlorins with isocyclic rings) is
obtained by extraction, an approach limited to those
macrocyclic structures that are stable to the extraction
conditions and that are found in nature in large quanti-
ties. To date, few general methods have been devised in
which a chlorin is built in the rational, step-by-step
fashion from linear tetrapyrroles as now commonly
employed in porphyrin synthesis. The groups of Bat-
tersby11 and Monforts4,9c have devised total syntheses of
the less common geminally disubstituted chlorins, such
as bonellin, Heme d, and Factor I, by utilizing a nonoxi-
dizable gem-dialkyl â-substituted reduced ring as one of
the four precursor pyrrole rings (Figure 2). Extensions
of this elegant, albeit lengthy and not highly convergent,
approach have been reported recently by the groups of
The regioselectivity of pyrroline ring formation in
chlorins 1 and 2 is truly remarkable. HPLC analysis
shows 1 to be 98% of the chlorin mixture, with 1-2% of
other unidentified chlorin isomers. Semiempirical calcu-
lations (PM316) show this regioisomer is not the most
thermodynamically stable reduced ring, yet in each case,
the only pyrroline ring formed in chlorins 1 and 2 was
the one that contained â-hydrogen substituents. These
results formed the basis of our hypothesis that the
formation of chlorin regioisomers was very sensitive to
the type of peripheral substituent on the porphodimethene,
and we undertook a project to examine the scope of the
rearrangement with regards to different peripheral groups.
We now report in full our findings on the influence that
â-substituents have on the regioselectivity and stereo-
selectivity of pyrroline ring formation in the rearrange-
ment of porphodimethene to chlorin.
(8) (a) Clezy, P. S. Aust. J . Chem. 1991, 44, 1163-1193. (b) Smith,
K. M.; Fujinari, E. M.; Langry, K. C.; Parish, D. W.; Tabba, H. D. J .
Am. Chem. Soc. 1983, 105, 6638-6646.
(9) (a) Vincente, M G. In The Porphyrin Handbook; Kadish, K.,
Smith, K., Guilard, R., Eds.; Academic Press: San Diego, CA, 2000;
Vol. 1, pp 149-199. (b) J aquinod, L. In The Porphyrin Handbook,
Kadish, K., Smith, K., Guilard, R., Eds.; Academic Press: San Diego,
CA, 2000; Vol. 1, pp 201-237. (c) Monforts, F.-P.; Glasenapp-Breiling,
M. Prog. Heterocycl. Chem. 1998, 10, 1-24. (d) Smith, K. In Chloro-
phylls; H. Scheer, Ed.; CRC Press: Boca Raton, 1991; pp 115-143. (e)
Flitsch, W. Adv. Heterocycl. Chem. 1988, 43, 73-126.
(10) Woodward, R.; Ayer, W.; Beaton, J .; Bickelhaupt, F.; Buch-
schacher, P.; Closs, G.; Dutler, H.; Hannah, J .; Hauck, F.; Ito, S.;
Langermann, A.; Le Goff, E.; Leimgruber, W.; Lwowski, W.; Sauer,
J .; Valenta, Z.; Volz, H. Tetrahedron 1990, 113, 7599-7659.
(11) (a) Snow, R. J .; Fookes, C. J .; Battersby, A. R. J . Chem. Soc.,
Chem. Commun. 1981, 524-526. (b) Battersby, A. R.; Dutton, C. J .;
Fookes, C. J .; Turner, S. P. J . Chem. Soc., Chem. Commun. 1983,
1235-1237. (c) Dutton, C. J .; Fookes, C. J .; Battersby, A. R. J . Chem.
Soc., Chem. Commun. 1983, 1237-1238. (d) Battersby, A. R.; Fookes,
C. J .; Snow, R. J . J . Chem. Soc., Perkin Trans. 1 1984, 2725-2732. (e)
Battersby, A. R.; Fookes, C. J .; Snow, R. J . J . Chem. Soc., Perkin Trans.
1 1984, 2733-2741. (f) Battersby, A. R.; Westwood, S. W. J . Chem.
Soc., Perkin Trans. 1 1987, 1679-1687. (g) Battersby, A. R.; Dutton,
C. J .; Fookes, C. J .; Turner, S. P. J . Chem. Soc., Perkin Trans. 1 1988,
1557-1567. (h) Battersby, A. R.; Dutton, C. J .; Fookes, C. J . J . Chem.
Soc., Perkin Trans. 1 1988, 1569-1576. (i) Battersby, a. R.; Turner,
S. P.; Block, M. H.; Sheng, Z.-C.; Zimmerman, S. C. J . Chem. Soc.,
Perkin Trans. 1 1988, 1577-1586.
(12) J acobi, P. A.; Lanz, S.; Ghosh. I.; Leung, S. H.; Lo¨wer, F.; Pippin,
D. Org. Lett. 2001, 3, 831-834.
(13) (a) Burns, D. H.; Shi, D. C.; Lash, T. D. Chem. Commun. 2000,
299-300. (b) Burns, D. H.; Li, Y. H.; Shi, D. C.; Delaney, M. O. Chem.
Commun. 1998, 1677-1678. (c) Burns, D. H.; Caldwell, T. L.; Burden,
M. W. Tetrahedron Lett. 1993, 34, 2883-2886.
(14) Arsenault, G.; Bullock, E.; MacDonald, S. F. J . Am. Chem. Soc.
1960, 82, 4384-4389.
(15) Lash, T. D. J . Porphyrins Phthalocyanines 1997, 1, 29-44.
(16) CAChe 3.9 MOPAC/PM3 (J ames Stewart), CAChe Scientific
(Oxford Molecular), Beaverton, OR 97076.

4538 J . Org. Chem., Vol. 67, No. 13, 2002
Burns et al.
Sch em e 1. Exa m p les of th e ‘2 + 2’ a n d ‘3 + 1’ Syn th esis of Ch lor in s via th e Rea r r a n gem en t of Meta lla ted
5,15-p or p h od im eth en es.
Resu lts a n d Discu ssion
would contain a substituent pattern of all alkyl (electron
donating) groups, with alkyl groups and one â-hydrogen
(electron neutral) substituent, and a porphodimethene
with a partial peripheral substitution pattern of â-hy-
drogen-meso-alkyl-â-alkyl. The latter pattern of â-sub-
stituents provides a steric effect responsible for the
(>95%) formation of one chlorin regioisomer upon dis-
solving metal reduction of the parent porphyrin (vide
infra). Dipyrromethanes 15-17 were prepared in typical
fashion,18a and dipyrromethane 18 was prepared by our
reported method,18e from pyrroles 9-14.18
In general, the ‘2 + 2” preparation of chlorins was as
follows. The bis-formyldipyrromethane 15 was condensed
with dipyrromethanes 16-18 under anaerobic (glovebox)
conditions, furnishing the respective porphodimethenes
19-21 (Scheme 3). We modified the MacDonald conden-
sation reaction conditions by utilizing the dilution prin-
ciple,19 adding a CHCl3 solution of dipyrromethanes
dropwise to a CHCl3/TsOH solution over a 3.5-4 h time
period. This modification usually resulted in a 2-fold
increase in macrocyclic yield, without apparent scram-
bling of intermediate porphodimethenes. After being
stirred for several more hours, the reaction mixture was
neutralized with carbonate and eluted through an alu-
mina gel plug. Subsequent metalation of the por-
phodimethene with excess Zn(OAc)2 and stirring at 55
°C over a 2 h time period resulted in rearrangement.
Regioselectivity of P yr r olin e Rin g F or m a tion :
Electr on ic ver su s Ster ic Effects of P er ip h er a l Su b-
stitu en ts. The synthesis of chlorins 1 and 2 demon-
strated that pure chlorin isomers could be prepared in
good to moderate yield without the need for a porphyrin
intermediate, long synthetic schemes, or extensive pu-
rification procedures to separate chlorin regioisomers.
However, it was not known if the high regioselectivity
observed in the rearrangement was limited to only
porphodimethenes containing a pyrrole ring with two
â-hydrogen substituents. It has been demonstrated that
the dissolving metal reduction of iron porphyrins to
furnish chlorins does exhibit partial regioselectivtiy in
pyrroline ring formation, and the regioselectivity is due
to peripheral substituent groups best able to stabilize
excess electron density.17 With this in mind, we initiated
an investigation to determine the substituent influence
over pyrroline ring formation with the synthesis of
porphodimethenes containing â-substituents of different
electronic character (i.e., electron withdrawing or electron
donating) or a set of substituents with defined steric
demands. Results from rearrangements of these types of
variously substituted porphodimethenes would outline
what kind of substituent is essential for the formation
of only one ring-reduced isomer. The purification of
chlorin isomers is tedious at best, so to be synthetically
useful, the rearrangement must produce (predominantly)
one regioisomer. The above studies would thus detail the
limitations to chlorin structure efficiently furnished from
our rearrangement methodology.
(17) Burns, D. H.; Lai, J .-J .; Smith, K. M. J . Chem. Soc., Perkin
Trans. 1 1988, 3119-3131.
(18) (a) Paine III, J . B. In The Porphyrins; Dolphin, D., Ed.;
Academic Press: New York, 1978; Vol 1, Part A, pp 163-198. (b) For
pyrroles 9 and 10, see J ohnson, A. W.; Markham, E.; Price, R.; Shaw,
K. B. J . Chem. Soc. 1958, 4254-4257. (c) For pyrrole 12, see Lash, T.
D.; Hoehner, M. C. J . Heterocycl. Chem. 1991, 28, 1671-1676. (d) For
pyrroles 11 and 13, see Burns, D. H.; J abara, C. S.; Burden, M. W.
Synth. Commun. 1995, 25, 379-387. (e) For pyrrole 14, see Burns, D.
H.; Smith, K. M. J . Chem. Res. (S) 1990, 178-179, and ibid., J . Chem.
Res. (M) 1990, 1349-1373.
Initially, the variously substituted porphodimethenes
were prepared by a ‘2 + 2’ MacDonald approach (a
condensation method normally used in the synthesis of
porphyrin rings), which required the synthesis of the
dipyrromethanes shown in Scheme 2. These dipyrro-
methanes were precursors to porphodimethenes which
(19) Cort, A.; Mandolini, L.; Roelens, S. J . Org. Chem. 1992, 57,
766-768.

Synthesis of Chlorins
J . Org. Chem., Vol. 67, No. 13, 2002 4539
Sch em e 2. Syn th esis of Dip yr r om eth a n es Utilized in th e ‘2 + 2’ Ap p r oa ch to th e P r ep a r a tion of Ch lor in s.
Sch em e 3. Th e Regioselective F or m a tion of Ch lor in s 22 - 24A via th e Rea r r a n gem en t of Meta lla ted
P or p h od im eth en es 19 - 21.
Demetalation with TFA and purification by alumina gel
chromatography furnished pure chlorins 22, 23, and 24a
in yields between 15 and 49%, with porphyrin byproduct
formed in 5-15% yield.
special pyrroline ring directing ability upon rearrange-
ment of the porphodimethene into chlorin. This is in stark
contrast to results obtained upon rearrangement of the
porphodimethenes which contain a pyrrole ring with two
â-hydrogen substituents (vide supra). These two opposite
results suggest that formation of the chlorin pyrroline
The unsymmetrically substituted chlorin 22 was fur-
nished in 15% yield from the condensation of 15 and 16
followed by rearrangement of porphodimethene 19. The
partial 1H NMR spectrum20 of chlorin 22 shown in Figure
3 illustrates formation of what appears to be all possible
chlorin regioisomers, as well as possible stereoisomers
(i.e., cis and trans reduced ring). In the meso proton
region alone, the spectrum exhibits at least 20 distinct
proton resonances between 9.5 and 9.8 ppm and between
8.6 and 9.0 ppm. For each regioisomer of chlorin 22 one
would expect a maximum of four meso proton resonances
(or a maximum of eight for its cis and trans stereoiso-
mers). Clearly, â-alkyl substituents demonstrate no
(20) The 1H NMR spectra of chlorins are quite distinctive, and are
quite indicative of their structure. The meso protons of chlorins
resonate in two separate downfield regions: between 8.5 and 9 ppm
for the two meso protons adjacent to the pyrroline ring, and between
9.5 and 10 ppm for the other two meso protons adjacent to only pyrrole
rings. Unsymmetrical chlorins will exhibit four resonances correspond-
ing to each meso proton. Protons attached as â-substituents on the
chlorin pyrrole rings resonate generally between 8 and 8.5 ppm, while
protons attached as â-substituents on the pyrroline ring resonate
between 4.3 and 5.0 ppm. Additionally, while protons on carbons
attached to the â-position of the chlorin pyrrole rings resonate between
3.4 and 4.2 ppm, the protons on carbons attached to the â-position of
the pyrroline ring resonate between 1.8 and 2.5 ppm.

4540 J . Org. Chem., Vol. 67, No. 13, 2002
Burns et al.
F igu r e 4. The dissolving metal reduction of metalated
phylloporphyrin to furnish metalated phyllochlorin is highly
regioselective.
F igu r e 3. Example of a partial 1H NMR spectrum of chlorins
22 (top) and 23 (bottom), illustrating the difference in the
meso-proton region of the two spectra due to the difference
in the regioselectivity of the porphodimethene rearrange-
ment.
Chlorin 23 was furnished in 49% yield from the
condensation of dipyrromethanes 15 and 17 followed by
the rearrangement of porphodimethene 20. Its H NMR
1
spectrum clearly shows formation of only the one ring-
reduced isomer (Figure 3). Only four meso proton reso-
nances are present (9.65, 9.63, 8.81, 8.78 ppm), no pyrrole
â-hydrogen resonance is observed, and a doublet at 1.97
ppm is due to the â-methyl group attached to the
pyrroline ring. The proton resonances of the methyl
propanoate and ethyl groups are observed only on the
fully aromatic pyrrole rings of the chlorin. The multiplets
at 4.89-4.93 and 4.38-4.28 ppm, corresponding to pyr-
roline ring â-hydrogens, integrate to three protons.
ring during the rearrangement is extremely sensitive to
electronic effects of the â-substituents, since such mark-
edly different results are observed with electron donating
as opposed to electron neutral substituents.
To examine the sensitivity of the rearrangement to
â-substituent steric effects, porphodimethenes 20 and 21
were prepared from dipyrromethanes 15, 17, and 18 via
MacDonald condensation reactions. The rearrangement
of porphodimethene 20 into chlorin 23 demonstrates the
electronic effect of only one hydrogen â-substituent on
pyrroline ring formation, with no obvious steric factors
influencing the outcome. On the other hand, the partial
peripheral substitution pattern of â-hydrogen-meso-
ethanoate-â-propanoate of porphodimethene 21 is simi-
lar to, if not more sterically congested than, the pattern
of â-substituents found on phylloporphyrin: â-hydrogen-
meso-methyl-â-propanoate. Dissolving metal reduction
of phylloporphyrin results in 95% formation of the
thermodynamically favored D-ring chlorin regioisomer
(Figure 4).17 Reduction of the phylloporphyrin’s D-ring
places its â-substituents out of the plane of the macro-
cyclic ring and eliminates steric compression between the
meso-methyl substituent and the D-ring â-propanoate
group. Indeed, this is the only example of a highly
regioselective synthesis of a chlorin by dissolving metal
reduction of a porphyrin. In the same manner, if pyrroline
ring formation was predominantly influenced by steric
effects, one would expect the rearrangement of por-
phodimethene 21 to largely furnish chlorin isomer 24b,
shown in Figure 4. It was felt that structure of 24b would
lend itself to further elaboration that could furnish a
C-ring isocyclic ring, providing for a model synthesis of
the chlorophyll macrocycle using our rearrangement
methodology. If electronic effects were most important,
however, then one would expect the results of the
rearrangement to be similar to those observed in the
rearrangement of 20, since both porphodimethenes have
one â-hydrogen substituent.
1
Overwhelmingly, the H NMR data shows the pyrroline
ring is formed only from the precursor pyrrole with
attached â-hydrogen and â-methyl groups. Consequently,
only one â-hydrogen is required to selectively direct
pyrrole ring-reduction via the rearrangement of the
porphodimethene. Porphodimethene 21 rearranged to
furnish only one chlorin regioisomer 24a , but in low
yields (4-8%) unless high temperature was employed
(refluxing diglyme: 15% yield; sealed tube + chloroform,
90 °C: 24%). The chlorin 1H NMR exhibited only one
meso-hydrogen resonance (8.69 ppm) adjacent to the
reduced ring, no aromatic â-hydrogen resonance, three
pyrroline ring hydrogens (multiplet at 4.73-4.82, dd at
4.59, dd at 4.03 ppm), and a methyl doublet at 1.95 ppm,
all indicating the chlorin isomer is the one shown in
Scheme 3. Once again, the only pyrroline ring formed is
from a precursor pyrrole that contains an attached
â-hydrogen substituent, regardless of the opposing steric
effect.21 This result strongly suggests that the chlorin
product is a kinetic product of the rearrangement, and
that the highly regioselective porphodimethene rear-
rangement is extremely sensitive to the nature of the
electronic effects of its â-substituents.
Whether the sensitivity of the rearrangement to â-hy-
drogens was due to their greater ability to stabilize (or
at least not destabilize) excess electron density placed
in the ring during the transformation of the macrocycle’s
π-system, or to some unknown factors particular to the
mechanism of the rearrangement, was not clear at this
point in our study. To illuminate this point in question,

Synthesis of Chlorins
J . Org. Chem., Vol. 67, No. 13, 2002 4541
Sch em e 4. ‘3 + 1’ Syn th esis of Acetylch lor in 32.
porphodimethene 31 (Scheme 4), with an electron-
withdrawing â-carbonyl in resonance with the ring’s
π-system, was targeted for synthesis. The preparation of
this porphodimethene proved much more difficult than
anticipated via a 2 + 2 condensation approach. While we
were able to construct the 1-formyl-3-acetyldipyrromethane
2622 (Scheme 4), the preparation of an acetylpor-
phodimethene using this dipyrromethane proved prob-
lematic.23
the construction of the porphyrin macrocycle could also
be used for the synthesis of chlorins via the por-
phodimethene rearrangement.13a The advantage of this
approach to the construction of an acetyl porphodi-
methene is that the carbonyl group, attached to the
middle pyrrole of the tripyrrane, would not retard the
end pyrroles ability to undergo aromatic electrophilic
addition with the bisformyl pyrrole 8. Tripyrranes 29 and
30 (Scheme 4) were therefore targeted for synthesis,
and the challenge to their preparation was several-
fold. Tripyrrane 29 is not symmetric and required more
that the usual one-pot reaction to prepare it. Tripyrranes
are extremely sensitive to even slightly acidic conditions,
and their reported syntheses commonly use acetic acid
as the proton source, and ethanol as the solvent.24 In
ethanol, the tripyrrane usually precipitates out of solu-
tion when it is formed, removing it from the mild acid
conditions and obviating the need for further deleterious
purification procedures. The filtered tripyrranes are then
used without further elaboration to condense with a
bisformyl pyrrole. Our strategy dictated the delicate
tripyrrane be modified with an acetyl group, and there-
We have communicated a model study which demon-
strated that the recently developed ‘3 + 1’ approach for
(21) The only time a steric effect promoting regioselectivity was
observed occurred in the rearrangement of porphodimethene i where
no â-hydrogen substituents were present. In this case, the all alkyl-
substituted i rearranged to > 70% chlorin regioisomer ii (determined
by 1H NMR) presumably due to the relief of steric compression between
the isocyclic hexyl ring and the now out-of-the-plane reduced-ring ethyl
group. This results suggest that with an appropriate isocyclic ring
placed in a precursor porphodimethene, our rearrangement method
could furnish a chlorophyll macrocycle in an efficient manner. Ad-
ditionally, this result begs the question, does the isocyclic ring in
protochlorophyllide play
a part in the regioselectivity of D-ring
reduction in the biosynthesis of the chlorophyll precursor chlorophyllide
by protochlorophyllide reductase, or is the regioselectivity of D-ring
reduction solely a result of protein regiochemical control?
(22) Burns, D. H.; Burden, M. W.; Li, Y. H. J . Porphyrins Phtha-
locyanines 1998, 2, 295-304.
(23) Porphyrin macrocycles that contain electron-withdrawing â-sub-
stituents are typically synthesized from the ring closure of â-bilenes
and not from MacDonald condensations. See Clezy, P. S. Aust. J . Chem.
1991, 44, 1163-1193.
(24) For an overview, see ref 15, and (a) Lash, T. D. Chem. Eur. J .
1996, 2, 1197-1200. (b) Boudif, A.; Momenteau, M. J . Chem. Soc.,
Perkin Trans. 1 1996, 1235-1242.

4542 J . Org. Chem., Vol. 67, No. 13, 2002
Burns et al.
fore both tripyrranes 29 and 30 would require purifica-
tion routines.
The synthetic route for 30 and chlorin 32 is detailed
in Scheme 4. Dipyrromethane 28 was made from pyrroles
9 and 2725 in 85% yield. Selective removal of the tert-
butyl ester, decarboxylation, and reaction with pyrrole
9 furnished tripyrrane 29 in 30% overall yield. Best yields
of tripyrrane 29 were afforded with the use of 1,2-
dichloroethane as solvent rather than ethanol or 2-pro-
panol. It was necessary to purify the crude reaction
material by chromatography, and the best resolution with
the least amount of carnage was attained with Florisil.
Acetylation of tripyrrane 29 in the usual manner (acetyl
chloride or acetic anhydride and SnCl4, BF3-etherate,
AlCl3, in various solvents) furnished only decomposition
products. Addition of various bases to the reaction
mixture to neutralize the acid byproduct proved fruitless.
Acetylation succeeded only with the use of the reactive
electrophile CCl3COCl and 3 equiv of DMAP, as an
activator and strong base. Purification of the crude
reaction material by Florisil furnished the tripyrrane 30a
in 87% yield. Hydrogenation removed the benzyl groups
and also resulted in complete dehalohydrogenolysis to
produce tripyrrane 30b in 79% yield. Decarboxylation of
30b and condensation with bisformyl 8, followed by our
rearrangement protocol, furnished chlorin 32 in 46%
F igu r e 5. A schematic drawing of the hypothetical mecha-
nism for the rearrangement of metalated 5,15-porphodimethene
into metalated chlorin.
â-proton resonances, and only one pyrroline â-methyl
resonance (vide supra). NOE experiments carried out on
the two pyrroline â-hydrogens and â-methyl group show
that the diastereoisomer is in the trans configuration.
However, when crude material from the rearrangement
is not subject to demetalation or alumina gel chroma-
1
tography, the H NMR spectrum of the chlorin indicates
both trans and cis stereoisomers are present in ap-
proximately a 4:1 ratio, respectively (a second doublet
at 5.80 ppm corresponds to the pyrroline â-proton on the
same carbon as the â-acetyl group in the cis-reduced
ring). The conditions of the reaction, demetalation, and
purification allow for the epimerization of the pyrroline
ring to selectively form the most thermodynamically
stable stereoisomer, presumably due to the reactive
â-carbonyl group. Consequently, while the rearrange-
ment is not intrinsically stereoselective, a chlorin stereo-
isomer can be selectively produced if epimerization of the
pyrroline â-carbons is possible.
1
yield. The H NMR spectrum of the acetyl chlorin shows
only four meso proton resonances (9.76, 9.74, 8.89, and
8.85 ppm), and that the pyrroline ring contains two
hydrogens with a splitting pattern of a doublet and a
doublet of quartets, along with a â-methyl doublet at 2.02
ppm. All the NMR data is consistent with the production
of the one chlorin regioisomer wherein the pyrroline ring
contains the acetyl group. This result, coupled with our
previous ones, further corroborates our hypothesis that
the high regioselectivity observed in the rearrangement
of porphodimethene to chlorin is due to the ability of
â-substituents to accommodate excess electron density
that builds up in the macrocyclic ring during the trans-
formation of its π-system.
Mech an ism of P or ph odim eth en e Rear r an gem en t.
We have shown with UV/Visible spectrophotometry that
both the ‘2 + 2’ and ‘3 + 1’ condensation reactions lead
to an equilibrium mixture of phlorin and 5,15-por-
phodimethene, and that metalation shifts the equilibrium
to the metalated 5,15-porphodimethene.13 The por-
phodimethene does not undergo rearrangement without
metalation, and only a small amount of chlorin is
produced if the reaction is not heated after metalation
27
of the porphodimethene. When excess Zn(acac)2 (with
a more basic ligand than acetate) was added to the
neutralized reaction mixture, metalation was immediate
but no rearrangement took place upon heating. Further
experiments demonstrated that the formation of chlorin
was slow to nonexistent when 1-1.5 equiv of Zn(OAc)2
were used, but rearrangement was essentially complete
within a 1 h time frame when more than 2 equiv were
used. Additionally, when the saturated Zn(OAc)2/metha-
nol solution was removed (water wash) and the metalated
porphodimethene in chloroform was heated to 55 °C,
rearrangement occurred in a normal manner. In a heated
anaerobic cuvette, no chlorin was produced from meta-
lated porphodimethene when the cuvette solution was
made slightly basic with triethylamine, nor was rear-
rangement observed when the cuvette solution was made
slightly acidic with acetic acid.
Ster eoselectivity of P yr r olin e Rin g F or m a tion . To
examine the stereoselectivity of the rearrangement,
octaethylchlorin was prepared in 19% yield utilizing our
rearrangement protocol. Only one chlorin regioisomer can
be furnished because of the symmetrical structure of the
ring, making it easy to distinguish the formation of both
1
cis and trans stereoisomers by H NMR. The octaethyl-
chlorin furnished from our rearrangement protocol ex-
hibits a 60-40 cis-trans stereoisomer ratio as deter-
mined from integration of meso proton resonances in its
1H NMR spectrum. Metalation of an authentic sample
of cis-octaethylchlorin (p-toluenesulfonhdrazide reduction
of octaethylporphyrin26) with excess Zn(OAc)2 and heat-
ing the reaction mixture at 55 °C for 2 h results in no
epimerization of the chlorin. Both stereoisomers are
therefore formed during the rearrangement.
The above data is consistent with the possibility that
a second equivalent of Zn(OAc)2, bound as a fifth, axial
ligand to the metalloporphodimethene via an acetate,
uses its other acetate to shuttle protons about the
periphery of the ring while the whole group rotates about
the metal, as depicted in Figure 5.28 Triethylamine is a
On the other hand, acetyl chlorin 32 is produced with
high diastereoselectivity upon rearrangement of the
precursor porphodimethene 31. Only one diastereoisomer
is observed in its H NMR spectrum, as indicated by only
four meso proton resonances, only one set of pyrroline
1
(25) (a) Donohoe, T. J .; Guyo, P. M. J . Org. Chem. 1996, 61, 7664-
7665. (b) J ackson, A. H.; Kenner, G. W.; Smith, K. M. J . Chem. Soc.
(C) 1971, 502 -509.
(26) Whitlock, H. W.; Hanauer, R.; Oester, M. Y.; Bower, B. K. J .
Am. Chem. Soc. 1969, 91, 7485-7489.
(27) Lahiri, G.; Summers, J . Inorg. Chem. 1991, 30, 5049-5052.
(28) For a similar rearrangement in the synthesis of porphyrinogen
to corphin, see Eschenmoser, A. Angew. Chem., Int. Ed. Engl. 1988,
27, 5-39.

Synthesis of Chlorins
J . Org. Chem., Vol. 67, No. 13, 2002 4543
1
F igu r e 6. Synthesis of deuterated chlorin 34, and partial H NMR spectra of chlorins 1 (top) and 34 (bottom).
better ligand for Zn(II) than acetate, and acetic acid could
hydrogen bond to the acetate ligands. In either case, the
added reagent would act to displace the acetate from the
metalloporphodimethene, not allowing it to participate
in any shifting of ring peripheral protons. Metalation of
the porphodimethene with Zn(acac)2 and heating did not
furnish chlorin, corroborating the need for more than
simple metalation for the rearrangement to proceed. The
need for a minimum of 2 equiv of Zn(OAc)2 for a facile
preparation of chlorin suggests that a second Zn(OAc)2
is involved in the rearrangement. Additionally, removal
of excess Zn(OAc)2 with concomitant rearrangement
suggests the shifting of hydrogens is intramolecular in
origin.
A deuteration study was undertaken to shed more light
on the mechanism of the rearrangement and to provide
direct evidence for the intramolecular shifting of protons
about the ring. MacDonald condensation of 4 and 5 with
p-toluenesulfonic acid-d‚xD2O in CDCl3, followed by a
D2O/bicarbonate wash, produced 5,15-tetradeuteriopor-
phodimethene 33 (Figure 6).29 Metalation of 33 with a
saturated solution of Zn(OAc)2‚xD2O in CH3OD, followed
by a second D2O wash, removal of all solvent, reintroduc-
tion of chloroform and use of typical rearrangement and
purification protocols, furnished chlorin 34. The rear-
rangement of 33 resulted in the deuteration of 50% of
the â-carbons in the reduced ring and 50% of all meso-
carbons, as determined from its 1H NMR spectrum
(Figure 6). The experiment firmly establishes that during
the rearrangement of the π-system, protons are shifted
about the periphery of the macrocyclic ring. This result
is certainly consistent with the view that a fifth ligand
is involved in aiding the movement of protons about the
ring.
The high regioselectivity of the rearrangement is
consistent with a fifth, axial ligand shuttling protons
about the ring. As protons are removed from the ring,
excess electron density will build up in the π-system. The
shifted protons find final placement on the carbons where
the excess electron densitiy is stabilized the most, i.e.,
those carbons with attached electron stabilizing or neu-
tral â-substituents. That the rearrangement to chlorin
24a works best with high temperatures may be ascribed
to differing conformational stability of the intermediates,
and its affect on the axial fifth ligand’s ability to shift
protons about the ring. Porphodimethenes are relatively
flexible, and take on angled rooflike conformations, where
the meso-methylene carbons have substituents in axial-
and equatorial-like conformations. CPK models of 21
show the methine hydrogen to be buried between the
(29) Our procedure for the tetradeuteration of both methylene
positions of a porphodimethene was a modification of a reported
method. Cavalairo, J .; Gonsalves, A.; Kenner, G.; Smith, K. J . Chem.
Soc., Perkin Trans. 1 1974, 1771-1781.

4544 J . Org. Chem., Vol. 67, No. 13, 2002
Burns et al.
was used for column chromatography, and analytical thin-
layer chromatography was performed using precoated silica
gel GF plates. Alumina (60-325 mesh) and Florosil (100-200
mesh) were also used for column chromatography. Some
samples that underwent spectral and analytical analysis were
purified by radial chromatography using a Chromatotron.
Analytical samples were dried under vacuum in a drying pistol
at 112 °C for a minimum of 2 days. All oxygen-sensitive
reactions (i.e., the ‘2 + 2’ or ‘3 + 1’ synthesis of chlorins) were
preformed in a glovebox.
Solvents were dried and purified according to literature
methods.32 Tetrahydrofuran (THF) and diethyl ether were
distilled from sodium and benzophenone; dichloromethane was
distilled first from phosphorus pentoxide and then from
calcium hydride; dimethylformamide (DMF) and acetonitrile
were distilled from calcium hydride; 1,2-dichloroethane was
distilled from phosphorus pentoxide, (dimethylamino)pyridine
(DMAP) was sublimed at 80-85 °C under vacuum before use.
Solvents were degassed either by bubbling argon through the
solvent overnight (methanol, chloroform, water, hexane, and
ethyl acetate) or bubbling argon using Teflon tubing for 6 h
(TFA). All solvents used in the glovebox were first degassed
by the methods mentioned above followed by sonication for
30 min in the glovebox before use.
meso-acetic and â-propanoic substituents when it is in
the “equatorial” position, which force field calculations30
show to be the most stable conformation. This conforma-
tion is similar to the bis-methylated porphodimethenes
of Buchler, whose meso-methyl groups are both in the
“axial” position.31 In porphodimethene 21, the “equa-
torial” hydrogen cannot be readily reached by the acetate
ligand. Rearrangement is slowed, and high temperatures
are needed to place the porphodimethene in its higher
energy conformation with an “axial” methine hydrogen,
which is then accessible to removal via the acetate ligand.
The stereochemical outcome of the rearrangement is
not as easily rationalized using the fifth, axial ligand
model. Both cis and trans stereoisomers are formed
during the rearrangement. While production of the cis
isomer is consistent with the model (proton shifts all
on one side of the ring), production of the trans isomer
needs additional explanation. One possibility is that the
Zn(II)porphodimethene is six-coordinate, allowing the
shifting of protons on either side of the ring (resulting in
the trans-reduced pyrroline ring). This scenario seems
unlikely since the metal prefers to be five-coordinate over
six-coordinate, and the porphodimethene conformation
is angled, not flat, such that a sixth ligand would face
steric repulsion from the angled ring. As peripheral
protons are shifted about the ring, and the π-system is
being transformed, it is likely that the ring becomes less
angular and more flat. Since the acetate ligand is
kinetically labile, ligand exchange could occur on opposite
sides of the incipient chlorin ring, and in that way, a
trans chlorin could be produced.
All melting points are uncorrected. 1H and 13C NMR spectra
were recorded at either 400 MHz or 300 MHz in CDCl3 or
DMSO-d6 as solvent and Me4Si as an internal standard (0
ppm) unless otherwise specified. Elemental analyses were done
by MHW Laboratories, Phoenix, AZ.
‘2 + 2’ Ap p r oa ch to th e Ch lor in Ma cr ocycle. 3,7-
Diet h yl-2,8,12,18-t et r a m et h yl-13-(2-m et h oxyca r b on yl-
eth yl)-17,18-d ih yd r op or p h yr in (23). All reactants and re-
agents were exposed to the atmosphere of the glovebox for 24
h before the experiment was started. A solution of dipyr-
romethane 17 (0.23 g, 0.65 mmol) and dipyrromethane 15 (0.20
g, 0.71 mmol) in CH3Cl (27 mL) and CH3OH (14 mL) was
added dropwise over the course of 3.5 h to para-toluenesulfonic
acid monohydrate (0.54 g, 2.8 mmol) dissolved in CHCl3 (90
mL) and CH3OH (20 mL). The reaction mixture was stirred
an additional 4 h, and then quenched with aqueous Na2CO3
(1.3 g in 50 mL water). The organic layer was separated and
the aqueous phase was extracted by chloroform. The combined
organic phases were run through a alumina plug (10 cm) and
the column was washed with CH3Cl until the eluent was clear.
A saturated solution of zinc acetate in CH3OH (10 mL) was
added to the CH3Cl solution, and the mixture was stirred at
65 °C for 2 h, and then allowed to stir at ambient temperature
overnight. The solvent was removed under vacuum, and
degassed TFA (10 mL) was added and the solution stirred for
10 min under nitrogen at 0 °C. The demetalation reaction was
quenched with 5% ammonium hydroxide, and the mixture was
extracted with CH2Cl2. The combined organic layers were dried
over sodium sulfate, and the solvent was removed under
vacuum. The crude dark solid was chromatographed on
alumina gel (grade III) eluting with benzene/CH2Cl2 (99/1) to
yield the title chorin (0.1632 g, 0.32 mmol, 49.3%). mp: 183-
185 °C; UV/Visible: CH2Cl2 λmax nm (ꢀ): 390 nm (7.44 × 104),
488 nm (1.02 × 104), 496 nm (9.83 × 103), 646 nm (1.55 ×
Con clu sion
The porphodimethene rearrangement methodology
provides for a rational, step-by-step synthesis of chlorins
from readily available pyrrole precursors. The intermedi-
ate porphodimethenes are furnished directly via the ‘2
+ 2’ MacDonald condensation, or by the ‘3 + 1’ condensa-
tion of a tripyrrane and bis-formyl pyrrole. The synthetic
route is short and highly convergent, and furnishes
chlorins in good to moderate yields. The reaction condi-
tions are relatively mild, so many types of substituent
functional groups are expected to be tolerated. The
synthesis is highly regioselective, and appears to be based
on the ability of the â-substituent to stabilize excess
electron density, with an electron-neutral hydrogen or
an electron-withdrawing carbonyl â-substituent demon-
strating the greatest influence on the formation of the
chlorin’s pyrroline ring. The synthesis is highly stereo-
selective when epimerization of the pyrroline ring â-car-
bons is possible, furnishing only the trans-reduced ste-
rioisomer. Finally, there is substantial evidence that a
fifth, axial ligand is involved in the intramolecular
transposition of peripheral hydrogens during the rear-
rangement of the π-system from metalloporphodimethene
to metallochlorin.
1
104); H NMR (CDCl3, 400M Hz): δ 9.66, 9.65 (s, 2H), 8.83,
8.80 (s, 2H), 4.96-4.86 (m, 2H), 4.37-4.24 (m, 1H), 4.18 (t,
2H, J ) 8.01 Hz), 3.97 (q, 2H, J ) 7.64 Hz), 3.84 (q, 2H, J )
7.64 Hz), 3.69, 3.50, 3.39, 3.37 (s, 12H), 3.13 (t, 2H, J ) 8.01
Hz), 1.97 (d, 3H, J ) 6.62 Hz), 1.77 (t, 3H, J ) 7.64 Hz), 1.75
(t, 3H, J ) 7.64 Hz), -2.38 (br s, 2H); 13C NMR (CDCl3, 75
MHz): δ 173.53, 170.70, 163.58, 150.36, 149.78, 143.00, 139.94,
138.60, 136.76, 135.82, 133.44, 132.74, 132.48, 130.40, 127.86,
99.14, 98.69, 92.45, 92.10, 51.69, 44.39, 41.70, 36.66, 23.64,
21.47, 19.79, 19.54, 17.77, 17.34, 11.43, 11.23, 10.94; LRMS
m/z (relative intensity) 510 (M+, 30), 495 (3), 437 (2). Anal.
Calcd for C32H38N4O2: C, 75.26; H, 7.50; N, 10.96. Found: C,
75.19; H, 7.53; N, 10.55.
Exp er im en ta l Section
Ma ter ia ls a n d P r oced u r es. The following chemicals were
used as indicated: benzoyl chloride and oxalyl chloride were
distilled just before use; silica gel (Davisil 633) (Silica Gel 60)
(30) CAChe 3.9 MM2, CAChe Scientific (Oxford Molecular), Bea-
verton, OR 97076.
(31) (a) Buchler, J . W.; Puppe, L.; Rohbock, K.; Schneehage, H. H.
Ann. N. Y. Acad. Sci. 1973, 206, 116-137. (b) Dwyer, P. N.; Buchler,
J . W.; Scheidt, W. R. J . Am. Chem. Soc. 1974, 96, 2789-2795.
(32) Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory
Chemicals; Pergamon: New York, 1988.

Synthesis of Chlorins
J . Org. Chem., Vol. 67, No. 13, 2002 4545
3,7-Dieth yl-2,8,12,18-tetr a m eth yl-13-(2-m eth oxyca r bo-
n yleth yl)-15-(2-m eth oxyca r bon ylm eth yl)-17,18-d ih yd r o-
p or p h yr in (24a ). All reactants and reagents were exposed
to the atmosphere of the glovebox for 24 h before the experi-
ment was started. A solution of dipyrromethane 18 (0.198 g,
0.47 mmol) and dipyrromethane 15 (0.123 g, 0.43 mmol) in
CH3Cl (16.4 mL) and CH3OH (8.5 mL) was added dropwise
over the course of 2 h to p-toluenesulfonic acid monohydrate
(0.82 g, 4.3 mmol) dissolved in CHCl3 (7.2 mL) and CH3OH
(12 mL). The reaction mixture was stirred an additional 20 h,
and then quenched with aqueous Na2CO3 (1.0 g in 30 mL
water). The organic layer was separated, and the aqueous
phase was extracted with chloroform. The organic phases were
combined and run through a alumina column (3 cm), and the
column was washed with CHCl3 until the eluent was clear (2
mL of CH3OH was used at the end of elution). The eluent was
collected in a 500 mL pressure bottle with stir bar, and a
saturated solution of zinc acetate in CH3OH (5 mL) was added
into the pressure bottle. The pressure bottle was sealed inside
the glovebox and then taken out of the box and stirred at 98
°C for 2.5 h. The reaction mixture was allowed to cool to room
temperature and stir for an additional 24 h, at which time
the solvent was removed under vacuum. Degassed TFA (7 mL)
was added to the crude mixture and the solution stirred for
10 min under nitrogen at 0 °C. The demetalation reaction was
quenched with 5% NH4OH, and the mixture was extracted
with CH2Cl2. The combined organic layers were washed with
brine and water and dried with sodium sulfate, and the solvent
was removed under vacuum. The crude dark solid was chro-
matographed on alumina gel (grade III) eluting with cyclo-
hexane/ethyl acetate (80/20) to yield the title chorin (0.061 g,
0.11 mmol, 24.3%). mp:172-174 °C; UV/Visible: CH2Cl2 λmax
nm (ꢀ): 394 (7.82 × 104), 498 (1.17 × 104), 656 (2.65 × 104);
1H NMR (CDCl3, 300 MHz): δ 9.73, 9.48 (s, 2H), 8.76 (s, H),
5.19-5.07 (m, 2H), 4.82-4.73 (m, 1H, 8-H), 4.56 (dd, 1H, J )
16.04 Hz and J ) 9.3 Hz), 4.11 (t, 2H, J ) 6.71 Hz), 4.03 (dd,
1H, J ) 16.04 Hz and J ) 3.96 Hz), 3.86 (q, 2H, J ) 7.52 Hz),
3.79 (q, 2H, J ) 7.52 Hz), 3.79 (s, 6H), 3.53, 3.39, 3.38 (s, 9H),
3.01-2.97 (m, 2H), 1.97 (d, 3H, J ) 3.9 Hz), 1.79-1.71 (m,
6H), -1.69 (br s, 1H). -2.05 (br s, 1H); 13C NMR: 173.19,
173.11, 170.26, 164.52, 151.73, 149.17, 142.55, 139.97, 138.57,
136.83, 136.63, 135.90, 134.43, 130.17, 128.92, 100.80, 100.31,
97.80, 92.29, 92.21, 52.33, 52.19, 51.90, 51.76, 43.46, 41.88,
41.77, 38.83, 36.32, 23.89, 19.70, 19.46, 17.66, 17.25, 11.64,
11.54, 11.48, 11.41, 10.99; HRMS (FAB) Calcd for C35H42N4O4
583.3284, found 583.3275. Anal. Calcd for C35H42N4O4: C,
72.14, H, 7.26, N, 9.61. Found: C, 71.81, H, 6.98, N, 9.37.
‘3 + 1’ Ap p r oa ch to th e Ch lor in Ma cr ocycle. Ben zyl
9-(t er t -B u t o x y c a r b o n y l)-3-e t h y l-2,8-d im e t h y ld ip y r -
r om eth a n e-1-ca r boxyla te (28). tert-Butyl 3-methylpyrrole-
2-carboxylate (27) (0.1156 g, 0.638 mmol) and Benzyl 5-ace-
toxymethyl-4-ethyl-3-methylpyrrole-2-carboxylate (9) (0.100 g,
0.319 mmol) were dissolved in 1,2-dichloroethane (1.19 mL),
and glacial acetic acid (0.1 mL) was added to the reaction
mixture. After being refluxed under a N2 atmosphere for 36
h, the reaction mixture was cooled to room temperature and
diluted with CHCl3, and the organic phase was washed
sequentially with water, 5% aqueous NaHCO3 solution, and
water and then dried over anhydrous Na2SO4. The solvent was
removed under vacuum, and the crude material was purified
by column chromatography (silica gel, hexane/ethyl acetate,
85/15) and recrystallized using hexane/ethyl acetate (85/15)
to yield orange crystals (0.117 g, 0.270 mmol, 85%), mp: 189-
190 °C; 1H NMR (CDCl3, 300 MHz): δ 9.18 (br s, 1H), 8.96 (br
s, 1H), 7.25-7.37 (m, 5H), 5.80 (s, 1H), 5.26 (s, 2H), 3.83 (s,
2H), 2.4 (q, 2H, J ) 7.32 Hz), 2.28 (s, 3H), 2.25 (s, 3H), 1.51
(s, 9H), 1.03 (t, 3H, J ) 7.32 Hz); 13C NMR (CDCl3, 100.5
MHz): δ 161.62, 161.29, 136.51, 131.69, 129.32, 128.59, 128.48,
127.98, 124.48, 120.03, 117.58, 111.25, 80.48, 65.62, 28.47,
24.67, 17.17, 15.47, 12.89, 10.58; LRMS (electrospray): m/z
(relative intensity) 435 (M - 1, 100), 367(20), 319 (18). Anal.
Calcd for C26H32O4N2: C, 71.53; H, 7.39; N, 6.42. Found: C,
71.18; H, 7.27; N, 6.41.
butoxycarbony)-3-ethyl-2,8-dimethyldipyrromethane-1-carbox-
ylate 28 (0.500 g, 1.15 mmol) and the solution stirred for 20
min at the ambient temperature under N2. The reaction
mixture was diluted with CH2Cl2, and neutralized by a
saturated solution of NaHCO3 and washed with water. The
organic phase was dried over anhydrous Na2SO4, and the
solvent was removed under vacuum. The crude product
mixture, pyrrole 9 (1.08 g, 3.45 mmol), and glacial acetic acid
(0.27 mL) were dissolved in 1,2-dichloromethane (5.3 mL), and
the reaction mixture was allowed to reflux for 2 h under N2.
The reaction mixture was cooled to room temperature, washed
with water, 5% aqueous NaHCO3 solution, and water, and then
dried over anhydrous Na2SO4. The solvent was removed under
vacuum, and the crude product material was purified by
column chromatography (Florisil, hexane/ethyl acetate, 85/15)
and recrystallized using hexane/ethyl acetate to yield a yellow
powder (0.2089 g, 0.352 mmol, 30%). mp: 209 °C (decomposed);
1H NMR (CDCl3, 400 MHz): δ 11.00 (br s, 2H), 8.88 (br s, 1H),
7.29-7.02 (m, 10H), 5.73 (d, 1H, J ) 2.4 Hz), 4.39 (s, 4H),
3.57 (s, 2H), 3.49 (s, 2H), 2.38-2.28 (m, 4H), 2.23, 2.06 (s, 9H),
0.95 (t, 6H, J ) 7.81 Hz); 13C NMR (CDCl3, 100.5 MHz): δ
162.69, 136.99, 132.86, 132.76, 128.14, 127.24, 126.82, 126.63,
123.89, 123.24, 117.30, 117.15, 112.86, 106.77, 65.30, 24.27,
22.04, 17.17, 17.09, 15.69, 15.65, 10.98; LRMS (electrospray):
m/z (relative intensity) 590 (M-1, 85), 335 (20). Anal. Calcd
for C37H41N3O4: C, 75.10; H, 6.98; N, 7.10. Found: C, 75.36;
H, 6.68; N, 7.28.
Diben zyl 8-Tr ich lor oacetyl-3,12-dieth yl-2,7,13-tr im eth -
yltr ipyr r an e-1,14-dicar boxylate (30a). Tripyrrane 29 (0.102
g, 0.172 mmol) and DMAP (0.101 g, 0.827 mmol) were
dissolved in 1,2-dichloromethane (10 mL) at ambient temper-
ature under N2. Three portions of trichloroacetyl chloride (3
× 31.27 mg, 3 × 0.172 mmol) were added dropwise into the
reaction mixture every 10 min. After 30 min, the reaction was
quenched with ice-water, and the solution was washed with
10% HCl, a saturated solution of Na2CO3, and water. The
reaction mixture was dried over anhydrous Na2SO4, and the
solvent was removed under vacuum. The crude material was
purified by column chromatography (Florisil, hexane/ethyl
acetate, 85/15) to yield a brown solid (0.1098 g, 0.149 mmol,
87%). mp; 103-104.5 °C; IR (CH2Cl2, cm-1) 3289, 2960, 2927,
1
2868, 1653, 1497, 1450, 1278, 1148, 1084, 751, 693; H NMR
(DMSO, 400 MHz): δ 11.07 (s, 1H), 11.03 (s, 1H), 10.69 (s,
1H), 7.31-7.43 (m, 10H), 5.24, 5.23 (s, 4H), 4.04, 3.75, (s, 4H),
2.19 (q, 2H, J ) 7.33 Hz), 2.10 (q, 2H, J ) 7.33 Hz), 2.15, 2.13
(s, 9H), 0.73 (t, 3H, J ) 7.33 Hz), 0.72 (t, 3H, J ) 7.33 Hz);
13C NMR (DMSO, 100.5 MHz): δ 181.30, 160.56, 160.50,
137.83, 136.87, 136.84, 131.00, 129.75, 128.36, 127.77, 127.71,
127.66, 126.55, 126.19, 126.11, 123.49, 122.88, 116.33, 115.92,
113.24, 113.09, 64.37, 24.40, 21.58, 16.51, 16.39, 14.96, 12.29,
10.26, 10.22; LRMS: m/z (relative intensity) 736 (M+1, 30),
700 (86), 665 (30); HRMS (FAB): Calcd for C39H39Cl3N3O5:
734.1955 (M-H). Found: 734.1925.
8-Acetyl-3,12-d ieth yl-2,7,13-tr im eth yltr ip yr r a n e-1,14-
d ica r boxylic Acid (30b). Tripyrrane 30a (0.187 g, 0.254
mmol), palladium (10% on carbon, 0.0255 g), and triethylamine
(0.09 mL) were suspended in THF (19.6 mL), placed under a
hydrogen atmosphere, and stirred for 1 h and 40 min at
ambient pressure and room temperature. The reaction mixture
was filtered through Celite, and the solvent was removed
under vacuum. The residue was cooled to 0 °C using an ice
bath and dissolved using a 5% NH4OH solution. The solution
was washed with CH2Cl2 and then acidified by adding glacial
acetic acid dropwise until precipitation was complete. The
precipitate was filtered, washed with water, and dried over
P2O5 in a vacuum oven to yield acetyl-tripyrrane diacid (0.0913
g, 0.020 mmol, 79.3%) as a brown powder, mp: 125.5-126.5
°C; 1H NMR (DMSO, 400 MHz): δ 11.83 (s, br, 2H, -COOH),
10.81 (s, 1H), 10.68 (s, 1H), 10.52 (s, 1H), 4.04 (s, 2H), 3.70 (s,
2H), 2.31 (s, 3H), 2.22 (q, 4H, J ) 7.81 Hz), 2.14, 2.13, 2.11 (s,
9H), 0.81-0.76 (m, 6H);13C NMR (DMSO, 100.5 MHz):
δ
195.12, 162.41, 162.35, 134.20, 130.36, 129.94, 125.03, 124.93,
122.85, 122.23, 120.24, 117.08, 116.89, 113.78, 30.85, 23.90,
21.38, 16.62, 16.44, 15.28, 15.16, 11.78, 10.12, 10.08; LRMS
(electrospray): m/z (relative intensity) 452 (M-1, 30), 436 (50),
Diben zyl 3,12-Dieth yl-2,7,13-tr im eth yltr ip yr r a n e-1,14-
d ica r boxyla te (29). TFA (3.0 mL) was added to benzyl 9-(tert-

4546 J . Org. Chem., Vol. 67, No. 13, 2002
Burns et al.
1
408 (48); HRMS (FAB): Calcd for C25H31N3O5, 453.2264 (M+).
Found: 453.2253.
642 (0.354); H NMR (CDCl3, 400 MHz): δ 9.76, 9.74 (s, 2H),
8.89, 8.84 (s, 2H), 5.44 (d, 1H, J ) 3.42 Hz), 5.12 (qd, 1H, J )
7.32 and 3.42 Hz), 3.96-3.83 (m, 8H), 3.54, 3.53 (s, 6H), 2.02
(d, 3H, J ) 7.32 Hz), 1.94 (s, 3H), 1.82-1.69 (m, 12H), -2.56
(br s, 2H,); 13C NMR (CDCl3, 100.5 MHz): δ 206.78, 167.50,
157.94, 150.29, 149.90, 143.04, 142.81, 137.95, 137.00, 135.54,
135.34, 133.67, 133.23, 132.96, 99.75, 99.23, 92.92, 91.79,
71.60, 46.65, 29.70, 25.90, 23.60, 19.69, 19.39, 19.29, 18.63,
18.60, 17.23, 17.09, 11.21, 11.18; LRMS (electrospray): m/z
(relative intensity) 508 (M - 1, 100), 465 (50), 154 (32); HRMS
(FAB): Calcd for C33H41N4O, 509.3280 (M + H). Found:
509.3279.
18-Acetyl-2,7,8,13-tetr a eth yl-3,12,17-tr im eth yl-17,18-d i-
h yd r op or p h yr in (32). Tripyrrane 30b (0.029 g, 0.052 mmol)
was stirred with TFA (1.0 mL) under a nitrogen atmosphere
in a glovebox for 25 min. The mixture was diluted with CHCl3
(8 mL) followed immediately by the addition of 2,5-diformylpyr-
role 8 (0.0085 g, 0.047 mmol), and the resulting mixture was
stirred for an additional 2 h. The reaction mixture was placed
into a separatory funnel and washed with an aqueous solution
of Na2CO3 (2.73 g in 100 mL of water), and the separated
organic layer was run through an alumina plug. The eluted
solution was added to a methanolic saturated solution of zinc
acetate (2 mL), and the mixture was stirred at room temper-
ature for 10 min and then heated to 55 °C and stirred for 2 h.
The reaction mixture was allowed to cool to ambient temper-
ature and stirred overnight. The crude reaction mixture was
then removed from the glovebox, and the solvent was removed
under vacuum. The product was cooled on an ice bath and TFA
(4 mL) was added and the solution stirred for 10 min under
N2. A 5% aqueous NaHCO3 solution was added to quench the
demetalation reaction, and it was then extracted with CH2-
Cl2. The combined organic layers were dried over Na2SO4, and
the solvent was removed under vacuum. The crude chlorin
product was purified using column chromatography (alumina,
grade III, 60/40, CH2Cl2/benzene in glovebox) which furnished
a green powder (0.011 g, 0.022 mmol, 46.0%); mp: 165 °C
(decomposed); IR 3438, 3343, 2961, 2926, 2866, 1700, 1613;
UV/Visible (CH2Cl2) λmax nm (ꢀ × 105) 388 (1.34), 492 (0.113),
Ack n ow led gm en t. D.H.B. wishes to gratefully ac-
knowledge the support of this work by the National
Science Foundation (CHE - 9508653) and for the
support of NSF in the purchase of a departmental 400
MHz NMR (CHE - 9700421).
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
spectra of chlorins 1, 2, 22, 23, 24a , 32, ii, the partial 1H NMR
spectrum of octaethylchlorin showing cis and trans isomers,
the NOE spectrum of chlorin 32 illustrating trans configura-
tion, and experimental details and characterization data of
dipyrromethanes 5a , 16, 17, tripyrranes 6 and 7, chlorins 1,
2, and deuterated chlorin 34. This material is available free
of charge via the Internet at http://pubs.acs.org.
J O020105F