Rational routes to formyl-substituted chlorins

Article abstract of DOI:10.1021/jo0707885

(Chemical Equation Presented) Two distinct approaches have been developed for the synthesis of chlorins bearing formyl groups: (1) reaction of an acetal-substituted 1-acyldipyrromethane with 2,3,5,6-tetrahydro-1,3,3- trimethyldipyrrin to give upon hydroly

Full text of DOI:10.1021/jo0707885

â-octaethylchlorin8,9 or meso-tetraarylchlorins10) so as to avoid
formation of regioisomers, although one notable exception is
the regioselective 20-formylation of selected naturally occurring
chlorins.8,11 A third approach entails the modification of
naturally occurring chlorins such as chlorophyll a. Examples
include (i) oxidation of a 3-vinyl group to give a 3-formyl
species,12 (ii) oxidation of an 8-vinyl group to give an 8-formyl
species,13 (iii) rupture of the isocyclic ring followed by
functional group transformations to give the 13-formylchlo-
rin12,14 or 15-formylchlorin,15 and (iv) derivatization of alkyl
groups at the 8- or 12-positions.5,16 The ability to place formyl
groups at designated sites in chlorins would benefit from more
versatile methods of synthesis, particularly methods that do not
rely on naturally occurring chlorins as starting materials.
We recently prepared a family of chlorins bearing auxo-
chromes at the 3- and 13-positions.17,18 The chlorins were
prepared by de novo synthesis and contained a geminal dimethyl
group in the reduced ring to ensure stability toward adventitious
oxidation. The substituents were introduced at the 3,13-positions
because the transition that gives rise to the long-wavelength
(Qy) band is polarized along this axis. The auxochromes included
phenyl, vinyl, TIPS-ethynyl, and acetyl, of which the acetyl
group gave the most pronounced changes in the absorption
spectra. The presence of a single acetyl group at the 13-position
caused a 26 nm red shift, whereas 3,13-diacetyl substitution
caused a 56 nm red shift. On the other hand, similar groups at
the 15-position caused much smaller effects.19 Extension of this
approach to synthetic chlorins bearing formyl groups at specific
positions is of great interest because the formyl group is
expected to be a more potent auxochrome than acetyl, ethynyl,
or vinyl. Toward this goal, we report herein two rational routes
to chlorins that enable placement of formyl groups at designated
sites, including the 5-, 13-, 15-, and 3,13-positions.
Rational Routes to Formyl-Substituted Chlorins
Chinnasamy Muthiah, Jayeeta Bhaumik, and
Jonathan S. Lindsey*
Department of Chemistry, North Carolina State UniVersity,
Raleigh, North Carolina 27695-8204
jlindsey@ncsu.edu
ReceiVed April 17, 2007
Two distinct approaches have been developed for the
synthesis of chlorins bearing formyl groups: (1) reaction of
an acetal-substituted 1-acyldipyrromethane with 2,3,5,6-
tetrahydro-1,3,3-trimethyldipyrrin to give upon hydrolysis a
5-formylchlorin and (2) Pd-mediated coupling of a bromo-
chlorin with a one-carbon synthon (hydroxymethyl tributyltin
or CO) to give a 13-, 15-, or 3,13-formylchlorin. The zinc
chlorins exhibit long-wavelength peak absorption maxima
ranging from 626 to 667 nm, indicating the wavelength
tunability afforded by formyl substitution.
Synthesis of a 5-Formylchlorin from an Acetal-Dipyr-
romethane. The synthesis of a 5-formylchlorin was approached
through use of a 1-acyldipyrromethane that contains a protected
formyl group (1).20 Other acetal-chlorins have been prepared
by reduction of the corresponding porphyrin21 or from the
Formyl-substituted porphyrins have proved valuable for
fundamental spectroscopic studies and as versatile synthetic
intermediates.1 Formyl-substituted chlorins have provoked inter-
est owing to the distinct spectra provided by chlorophyll b,
which contains a formyl group at the 7-position, versus
chlorophyll a, which contains a 7-methyl group. The formyl
group also provides a valuable site for synthetic elaboration of
chlorins,2-5 although the synthesis of formylchlorins has
presented a number of challenges.
One popular synthetic approach has been to use chlorophyll
b directly in derivatization processes, including formation of
the imine,6 olefin,7 or the meso-carbon of an attached porphyrin.2
A second approach has been to formylate an intact chlorin. This
approach is largely restricted to simple substituted chlorins (e.g.,
(8) Smith, K. M.; Bisset, G. M. F.; Bushell, M. J. Bioorg. Chem. 1980,
9, 1-26.
(9) Kalisch, W. W.; Senge, M. O.; Ruhlandt-Senge, K. Photochem.
Photobiol. 1998, 67, 312-323.
(10) Mironov, A. F.; Moskalchuk, T. V.; Shashkov, A. S. Russ. J. Bioorg.
Chem. 2004, 30, 261-267.
(11) Ando, T.; Irie, K.; Koshimizu, K.; Takemura, T.; Nishino, H.;
Iwashima, A.; Nakajima, S.; Sakata, I. Tetrahedron 1990, 46, 5921-5930.
(12) Kunieda, M.; Tamiaki, H. J. Org. Chem. 2007, 72, 2443-2451.
(13) Sasaki, S.-I.; Tamiaki, H. Bull. Chem. Soc. Jpn. 2004, 77, 797-
800.
(14) Ma, L.; Dolphin, D. Tetrahedron Lett. 1995, 36, 7791-7794.
(15) Wray, V.; Ju¨rgens, U.; Brockmann, H., Jr. Tetrahedron 1979, 35,
2275-2283.
(16) Zheng, G.; Potter, W. R.; Camacho, S. H.; Missert, J. R.; Wang,
G.; Bellnier, D. A.; Henderson, B. W.; Rodgers, M. A. J.; Dougherty, T.
J.; Pandey, R. K. J. Med. Chem. 2001, 44, 1540-1559.
(17) Laha, J. K.; Muthiah, C.; Taniguchi, M.; McDowell, B. E.; Ptaszek,
M.; Lindsey, J. S. J. Org. Chem. 2006, 71, 4092-4102.
(18) Kee, H. L.; Kirmaier, C.; Tang, Q.; Diers, J. R.; Muthiah, C.;
Taniguchi, M.; Laha, J. K.; Ptaszek, M.; Lindsey, J. S.; Bocian, D. F.;
Holten, D. Photochem. Photobiol. 2007, 83, in press.
(19) Kee, H. L.; Kirmaier, C.; Tang, Q.; Diers, J. R.; Muthiah, C.;
Taniguchi, M.; Laha, J. K.; Ptaszek, M.; Lindsey, J. S.; Bocian, D. F.;
Holten, D. Photochem. Photobiol. 2007, 83, in press.
(20) Balakumar, A.; Muthukumaran, K.; Lindsey, J. S. J. Org. Chem.
2004, 69, 5112-5115.
(1) Ponomarev, G. V. Chem. Heterocycl. Compd. 1994, 30, 1444-1465.
(2) Wasielewski, M. R. Chem. ReV. 1992, 92, 435-461.
(3) Jaquinod, L.; Nurco, D. J.; Medforth, C. J.; Pandey, R. K.; Forsyth,
T. P.; Olmstead, M. M.; Smith, K. M. Angew. Chem., Int. Ed. Engl. 1996,
35, 1013-1016.
(4) Wang, J.-J.; Shim, Y. K.; Jiang, G.-J.; Imafuku, K. J. Heterocycl.
Chem. 2003, 40, 1075-1079.
(5) Li, G.; Dobhal, M. P.; Shibata, M.; Pandey, R. K. Org. Lett. 2004,
6, 2393-2396.
(6) Losev, A.; Mauzerall, D. Photochem. Photobiol. 1983, 38, 355-
361.
(7) Tamiaki, H.; Kouraba, M. Tetrahedron 1997, 53, 10677-10688.
10.1021/jo0707885 CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/22/2007
J. Org. Chem. 2007, 72, 5839-5842
5839

SCHEME 1
SCHEME 2
Zn(OAc)2‚2H2O afforded the zinc chelate ZnC-F5P10 in quan-
titative yield.
Synthesis of Formylchlorins from Bromochlorins. For the
more general introduction of formyl groups at various â-posi-
tions, we first investigated Stille coupling of a bromochlorin
and hydroxymethyltributyltin25,26 to give the corresponding
hydroxymethylchlorin (Scheme 2). The zinc chelate of the 13-
bromochlorin (ZnC-M10Br13)17 gave limited conversion upon
refluxing with THF. Demetalation of ZnC-M10Br13 with TFA
afforded the crude free base chlorin. Coupling of the latter and
Bu3SnCH2OH in the presence of Pd(PPh3)4 in THF for 30 h
gave the 13-hydroxymethylchlorin 5 in 51% yield. The oxidation
of 5 with MnO2 in toluene at room temperature afforded the
13-formylchlorin FbC-M10F13 in 91% yield. The free base
formylchlorin FbC-T5M10F13 was obtained similarly (Scheme
2). A streamlined procedure including demetalation, Pd-
coupling, and oxidation gave FbC-T5M10F13 in 47% yield
starting from ZnC-T5M10Br13.
formylchlorin.22 1-Acyldipyrromethane 1 was treated with
NBS23 at -78 °C for 1 h to afford the corresponding 1-bromo-
9-acyldipyrromethane (2) in 79% yield (Scheme 1). Reduction
of 2 with NaBH4 afforded the 1-bromodipyrromethane-9-
carbinol (Eastern half). The latter was immediately subjected
to condensation23 with tetrahydrodipyrrin 324 (Western half) in
the presence of TFA to obtain the tetrahydrobilene a derivative,
which upon oxidative cyclization gave the 5-acetal-substituted
zinc chlorin 4 in 16% yield. The acetal group was hydrolyzed
(and the zinc chlorin was demetalated) by treatment with TFA/
H2O in CH2Cl2, thereby affording the free base formylchlorin
FbC-F5P10 in 84% yield. Treatment of FbC-F5P10 with
(21) Balaban, T. S.; Linke-Schaetzel, M.; Bhise, A. D.; Vanthuyne, N.;
Roussel, C. Eur. J. Org. Chem. 2004, 3919-3930.
(25) (a) Kosugi, M.; Sumiya, T.; Ogata, T.; Sano, H.; Migita, T. Chem.
Lett. 1984, 1225-1226. (b) Kosugi, M.; Sumiya, T.; Ohhashi, K.; Sano,
H.; Migita, T. Chem. Lett. 1985, 997-998.
(26) (a) Åhman, J.; Somfai, P. Synth. Commun. 1994, 24, 1117-1120.
(b) Danheiser, R. L.; Romines, K. R.; Koyama, H.; Gee, S. K.; Johnson, C.
R.; Medich, J. R. Org. Synth. 1993, 71, 133-139.
(22) Tamiaki, H.; Kubo, M.; Oba, T. Tetrahedron 2000, 56, 6245-6257.
(23) Taniguchi, M.; Ra, D.; Mo, G.; Balasubramanian, T.; Lindsey, J.
S. J. Org. Chem. 2001, 66, 7342-7354.
(24) Ptaszek, M.; Bhaumik, J.; Kim, H.-J.; Taniguchi, M.; Lindsey, J.
S. Org. Process Res. DeV. 2005, 9, 651-659.
5840 J. Org. Chem., Vol. 72, No. 15, 2007

TABLE 1. Scope of Pd-Mediated Carbonylation of Chlorins
bromochlorin
R5
R15
R3
R13
formylchlorin
R15
R3
R13
yield, %
aZnC-M10Br13
H
p-tolyl
H
H
H
H
Br
H
H
Br
H
Br
Br
Br
H
ZnC-M10F13
H
H
H
CHO
H
H
CHO
H
CHO
CHO
CHO
H
68
72
52
35
bZnC-T5M10Br13
aZnC-Br3M10Br13
cZnC-T5M10Br15
ZnC-T5M10F13
ZnC-F3M10F13
ZnC-T5M10F15
p-tolyl
a Reference 17. b Reference 29. c Reference 30.
TABLE 2. Spectral Properties of Chlorinsa
Selected absorption spectra of the ZnC-M10 series are shown
in Figure 1 (see the Supporting Information for additional
spectra).
λ
B (fwhm)
in nm
λQ (fwhm)
∆υ
d
y
c
compdb
in nm
IB/IQ
(cm-1
)
ZnC-M10
405 (13)
405 (13)
418 (18)
418 (20)
425 (29)
439 (20)
436 (21)
606 (12)
605 (11)
632 (14)
634 (12)
650 (36)
667 (17)
662 (18)
4.3
4.1
2.1
2.2
6.2
1.4
1.5
The presence of a formyl group at the 3-, 5-, 13-, or 15-
positions causes a red shift of the long-wavelength absorption
(Qy) band. However, the magnitude of the red shift, the
sharpness of the Qy band, and the intensity of the Qy band
relative to the band in the blue region (B band) depend on the
position of substitution. The major observations are as follows:
(1) A 13-formyl group causes a red shift of 730 cm-1 (28
nm; ZnC-M10F13 versus ZnC-M10), to be compared with only
680 cm-1 (26 nm) for the corresponding 13-acetylchlorin17
(ZnC-M10A13). The relative intensity of the Qy band increases
by approximately 2-fold for ZnC-M10F13 versus ZnC-M10 while
the sharpness (fwhm) remains relatively constant (12 nm). Note
that the 10-mesityl and 10-phenyl groups give essentially
identical spectra.19
ZnC-P10
ZnC-M10A13
ZnC-M10F13
ZnC-F5P10
680
730
1100
1500
1400
ZnC-F3M10F13
ZnC-A3M10A13
ZnC-T5M10
412 (13)
417 (16)
424 (15)
608 (11)
626 (20)
637 (13)
5.0
5.6
2.6
ZnC-T5M10F15
ZnC-T5M10F13
470
750
FbC-M10
400 (34)
403 (34)
414 (35)
422 (36)
416 (41)
637 (9)
637 (9)
659 (11)
663 (11)
672 (27)
2.7
2.8
1.9
2.2
5.0
FbC-P10
FbC-M10F13
FbC-T5M10F13
FbC-F5P10
520
620
820
a In toluene at room temperature. b All compounds that are not synthe-
sized herein are described in ref 19. c Ratio of the intensities of the B and
Qy bands. d The red shift of the Qy band relative to that of the parent chlorin
(ZnC-M10, ZnC-T5M10, or FbC-M10).
(2) 3,13-Diformyl groups cause a red shift of 1500 cm-1 (61
nm; ZnC-F3M10F13 versus ZnC-M10), to be compared with
1400 cm-1 (56 nm) for the corresponding 3,13-diacetylchlorin17
(ZnC-A3M10A13). A further increase in relative intensity of the
We next investigated the more direct method of Pd-mediated
reductive carbonylation.27,28 A short survey of conditions
(solvent, palladium source, and amount of sodium formate)
identified effective conditions. Thus, treatment of ZnC-M10Br13
(10 mM) with sodium formate (20 mM) in the presence of
(PPh3)2PdCl2 (20 mol %) and PPh3 (20 mol %) in DMF at 108
°C under an atmosphere of CO afforded the 13-formylchlorin
ZnC-M10F13 in 68% yield. This Pd-mediated carbonylation
method was successfully applied to introduce the formyl group
into the chlorin macrocycle at the 13-, 3,13-, and 15-positions
(Table 1).
Absorption Spectra of Formylchlorins. The absorption
spectra of the formylchlorins (in toluene at room temperature)
are summarized in Table 2. Three classes are noted: zinc
chlorins bearing a 10-mesityl group (ZnC-M10 series); zinc
chlorins bearing a 5-p-tolyl group and a 10-mesityl group (ZnC-
T5M10 series); and various free base chlorins (FbC series).
(27) Pri-Bar, I.; Buchman, O. J. Org. Chem. 1984, 49, 4009-4011.
(28) Okano, T.; Harada, N.; Kiji, J. Bull. Chem. Soc. Jpn. 1994, 67,
2329-2332.
FIGURE 1. Absorption spectra (normalized) in toluene at room
(29) Laha, J. K.; Muthiah, C.; Taniguchi, M.; Lindsey, J. S. J. Org. Chem.
2006, 71, 7049-7052.
temperature of ZnC-M10 (trace a, λQ 606 nm),17 ZnC-M10F13 (trace
y
b, λQ 634 nm), ZnC-F5P10 (trace c, λQ 650 nm), and ZnC-F3M10F13
(30) Taniguchi, M.; Kim, M. N.; Ra, D.; Lindsey, J. S. J. Org. Chem.
2005, 70, 275-285.
y
y
(trace d, λQ 667 nm).
y
J. Org. Chem, Vol. 72, No. 15, 2007 5841

Qy band occurs (IB/IQ ) 1.4 for ZnC-F3M10F13 versus 4.3 for
ZnC-M10) while the sharpness (fwhm) decreases only modestly
(17 nm).
Schlenk flask for 1 h. DMF (1.2 mL) was added, and CO gas was
bubbled through the reaction mixture for 2 h at 108 °C. Then the
reaction mixture was heated at 108 °C under a balloon containing
CO for 24 h. After cooling to room temperature, the reaction
mixture was treated with CH2Cl2 and water. The organic layer was
separated, washed (water, brine), dried (Na2SO4), and concentrated.
The resulting residue was chromatographed [silica, hexanes/CH2-
Cl2 (1:2) f CH2Cl2 f CH2Cl2/ethyl acetate (7:1)] to afford a trace
amount (∼5% of the total) of a mono-formylated chlorin followed
by the title compound as a green solid (6.1 mg, 52%): 1H NMR
(300 MHz) δ 1.82 (s, 6H), 2.03 (s, 6H), 2.60 (s, 3H) 4.53 (s, 2H),
7.23 (s, 2H), 8.38 (d, J ) 4.5 Hz, 1H), 8.62 (s, 1H), 8.87 (d, J )
4.5 Hz, 1H), 9.00 (s, 1H), 9.26 (s, 1H), 9.61 (s, 1H), 10.3 (s, 1H),
10.88 (s, 1H), 11.15 (s, 1H); 13C NMR δ 188.8, 188.7, 172.8, 167.4,
162.1, 161.5, 160.8, 144.0, 141.9, 140.2, 138.9, 137.9, 137.5, 135.8,
135.7, 131.9, 130.6, 128.2, 128.1, 110.3, 107.7, 98.3, 96.6, 94.5,
50.5, 44.3, 31.0, 21.4, 21.2; LDMS obsd 576.8; FAB-MS obsd
576.1499, calcd 576.1504 (C33H28N4O2Zn); λabs (toluene) 439, 667
nm.
Streamlined Procedure via Hydroxymethylation: 13-Formyl-
17,18-dihydro-18,18-dimethyl-10-mesityl-5-p-tolylporphyrin (FbC-
T5M10F13). A sample of chlorin ZnC-T5M10Br13 (7.50 mg, 0.0108
mmol) was treated with TFA (25.0 µL, 0.324 mmol) in CH2Cl2
(1.0 mL). The reaction mixture was stirred at room temperature
for 3 h. The reaction mixture was quenched by the addition of a
mixture of saturated aqueous NaHCO3 and CH2Cl2. The organic
layer was separated, washed (water, brine), dried (Na2SO4), and
concentrated to afford the free base chlorin. Following a procedure
for Stille coupling with chlorins,17 a mixture of free base chlorin
(∼0.0108 mmol) and Pd(PPh3)4 (2.50 mg, 0.00216 mmol) was dried
in a Schlenk flask for 30 min. Hydroxymethyltributyltin (13.8 mg,
0.0432 mmol) in THF (1.0 mL) was added, and the reaction mixture
was refluxed for 30 h. The reaction mixture was concentrated. The
resulting residue was dissolved in toluene (0.20 mL), and MnO2
(47.0 mg, 0.540 mmol) was added. The reaction mixture was stirred
at room temperature for 1 h. The reaction mixture was concentrated
and chromatographed [silica, hexanes f hexanes/CH2Cl2 (1:1) f
(2:8)] to afford a purple solid (3.0 mg, 47%) with characterization
data (1H NMR, 13C NMR, LD-MS, FAB-MS, UV-vis) consistent
with those for the product obtained via individual stepwise
procedures (see the Supporting Information).
(3) A 5-formyl group causes a strong red shift of 1100 cm-1
(44 nm; ZnC-F5P10 versus ZnC-P10), which is more pronounced
than at any other single site examined herein. However, the Qy
band is relatively broad (fwhm ) 36 nm).
(4) A 15-formyl group causes a modest red shift of 470 cm-1
(18 nm; ZnC-T5M10F15 versus ZnC-T5M10), band broadening
(fwhm ) 20 nm), and no increase in the relative intensity of
the Qy band (IB/IQ ) 5.6 for ZnC-T5M10F15 versus 5.0 for ZnC-
T5M10).
Thus, the formyl group is a slightly more potent auxochrome
than the acetyl group at those positions where comparisons can
be made (13- or 3,13-positions), causing bathochromic and
hyperchromic effects without substantial band broadening. The
bathochromic shift increases in order of positions 5 < 13 <
15, whereas the band-broadening effect increases in order of
positions 13 < 15 < 5. Similar trends were noted in the free
base chlorins where comparisons can be made.
In summary, we have developed rational approaches for the
synthesis of formylchlorins. Pd-mediated formylation is attrac-
tive where suitable bromochlorins are available (positions 3,
13, 15, etc.), otherwise a complementary route entails construc-
tion of a chlorin with use of an acetal-substituted precursor (e,g.,
5-position). Both approaches were successfully implemented to
give milligram quantities of formylchlorins. The absorption
spectra of zinc chelates of 5-, 13-, 3,13-, and 15-formylchlorins
revealed a significant effect of the formyl group depending on
the position of substitution. The long-wavelength absorption
band can now be tuned over the range of 606-667 nm. For
applications in flow cytometry, the chlorins with distinct and
sharp bands could provide a panel of fluorophores. For
applications in solar energy conversion, the collection of
wavelength-tunable chlorins, including the chlorins with broad
bands, could provide enhanced solar coverage. Taken together,
the routes described herein afford versatile access to formyl-
chlorins for use in fundamental spectroscopic studies and further
synthetic elaboration.
Acknowledgment. This work was supported by the NIH
(GM36238).
Experimental Section
Carbonylation Procedure: Zn(II)-3,13-Diformyl-17,18-dihy-
dro-18,18-dimethyl-10-mesitylporphyrin (ZnC-F3M10F13). Fol-
lowing a procedure for CO-mediated formylation,28 a mixture of
ZnC-Br3M10Br13 (13.8 mg, 0.0203 mmol), (PPh3)2PdCl2 (2.85 mg,
0.00406 mmol, 20 mol %), PPh3 (1.06 mg, 0.00406 mmol, 20 mol
%), and sodium formate (3.50 mg, 0.0507 mmol) was dried in a
Supporting Information Available: Spectral data (absorption,
1H NMR, LD-MS) for all new chlorins, and additional experimental
procedures. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO0707885
5842 J. Org. Chem., Vol. 72, No. 15, 2007