Synthesis of Derivatives of chlorin P6 trimethyl ester

Article abstract of DOI:10.1080/00397910902985440

The Vilsmeier reaction of nickel(II) chlorin P₆ trimethyl ester with 3-dimethyl-aminoacrolein yielded nickel(II) chlorin P₆ 20-(2-formylvinyl) trimethyl ester and nickel(II) chlorin P₆ 3-(1-hydroxyethyl)-3-devinyl-20-(2-fo

Full text of DOI:10.1080/00397910902985440

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Synthetic Communications1, 40: 400–406, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902985440
SYNTHESIS OF DERIVATIVES OF CHLORIN P6
TRIMETHYL ESTER
Guang-Fan Han, Wei Dai, Wen-Tao Zhang, Zheng Xing, and
Yu-Yuan Zhao
School of Material Science and Engineering, Jiangsu University of Science and
Technology, Zhenjiang, Jiangsu, China
The Vilsmeier reaction of nickel(II) chlorin P6 trimethyl ester with 3-dimethyl-amino-
acrolein yielded nickel(II) chlorin P6 20-(2-formylvinyl) trimethyl ester and nickel(II)
chlorin P6 3-(1-hydroxyethyl)-3-devinyl-20-(2-formylvinyl) trimethyl ester. Also, the
outgrowths of nickel(II) chlorin P6 20-(2-formyl) trimethyl ester and nickel(II) chlorin
P6 3-(2-formylvinyl)-3-devinyl-20-(2-formyl) trimethyl ester were obtained by Vilsmeier
reaction with dimethylformamide. By treating the derivatives of nickel(II) 20-(2-formyl)-
chlorin and nickel(II) 3-(2-formylvinyl)-20-(2-formyl)-chlorin with trifluoracetic acid, the
removal of the central nickel(II) ion was accomplished. The derivatives of 20-(2-formyl)-
chlorin and 3-(2-formylvinyl)-20-(2-formyl)-chlorin demonstrated considerable bathochro-
mic shift of the major absorption band in the red region of the optical spectrum.
Keywords: Chlorin P6 trimethyl ester; formyl-; formylvinyl-; photodynamic therapy; Vilsmeier reaction
Photodynamic therapy (PDT) is a very active field treatment the modality for
cure of tumors, based on the formation of reactive species by illuminating a photo-
sensitizer in the presence of oxygen.[1] PDT utilizes the ability of a selectively retained
photosensitizer to elicit an efficient photodynamic reaction upon activation with
tissue-penetrating light. An ideal photosensitizer should have definite structure in
chemistry, good amphiphilicity, reasonable stability, and lack of toxic compounds
with longer wavelength absorption near or beyond 700 nm.[2,3] As the degradation
products of a natural product, chlorophyl, chlorins derivatives have a good tumor
photodynamic curative effect.[4]
From early research in relative compound of chlorins, the presence and
position of the substitutes in the parent chlorins made a remarkable difference in bio-
logical activities.[5] It has great influence in bioactivity by the substituent at the
20-meso-position hydrogen of chlorines.[7–10] Substituents at the 3-position and
20-meso-position can extend absorption wavelength of visible spectra, which is an
important parameter to measure anticancer efficacy in PDT.[4,6] In our experiment,
Received February 1, 2009.
Address correspondence to Guang-Fan Han, School of Material Science and Engineering, Jiangsu
University of Science and Technology, Zhenjiang, Jiangsu, China. E-mail: gf552002@yahoo.com.cn
400

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CHLORIN P6 TRIMETHYL ESTER DERIVATIVES
401
formyl and formylvinyl structures were selected as substituted function groups
introduced to the 20-meso-position and the 3-position in the conjugated region
and electron-withdrawing formyl group to extend absorption wavelength. In this
work, several novel derivatives (5–10) of chlorin P6 trimethyl ester were obtained
by the Vilsmeier reaction (Scheme 1).
=
Scheme 1. R1 ¼ CH CHCHO; R2 ¼ CHO (a) air, Et2O, propanol, KOH, rt; (b) NaOH=CH3OH, rt;
(c) Ni(AcO)2, 65ꢀC; (d) DMF=POCl3, 0ꢀC; (e) 3-DMA=POCl3, 0ꢀC; (f) TFA, rt; and (g) TFA, rt.

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402
G.-F. HAN ET AL.
RESULTS AND DISCUSSION
In our approach, methyl pheophorbide-a (MP-a, 1) was used as a starting
material and converted into purpurin-18-methyl ester (2) by atmospheric oxidization.
Chlorin P6 trimethyl ester (3) was obtained by reaction with NaOH from 2 in meth-
anol solution in good yield. Then, the reaction of 3 with excess nickel acetate in
methanol was employed after reflux for 12 h, 3 was converted into its nickel complex
(4) (Scheme 1). The maximum absorption of compound 4 was observed at 666 nm.
Nickel(II) chlorin P6 20-(2-formylvinyl) trimethyl ester (5) and nickel(II)
chlorin P6 3-(1-hydroxyethyl)-3-devinyl-20-(2-formylvinyl) trimethyl ester (7) were
prepared by the treatment of 4 with dimethylformamide (DMF) in POCl3 at 0ꢀC
(Scheme 1). In the correlation (COSY) spectrum of 5, one hydrogen at d 7.42 (dd,
J ¼ 11.4 Hz, 17.75 Hz) is coupled to one hydrogen at d 5.93 (d, J ¼ 11.35 Hz) and
the other hydrogen at d 5.8 (d, J ¼ 17.8 Hz). It is clear that the peaks at d 7.42, d
5.93, and d 5.8 are due to the hydrogen atoms of the vinyl group in position 3 of
compound 5. Two hydrogen atoms at d 3.3 are coupled to the three hydrogen atoms
at d 1.4. It is quite obviously the ethyl group in position 8. One hydrogen atom at d
4.3 is coupled to the three hydrogen atoms at d 1.3, which showed the H18 and the
methyl group at C18. Two hydrogen atoms at d 1.7 are coupled to the two hydrogen
atoms at d 2.3 and one hydrogen atom at d 5.0, which allowed us to assign the H17
and the ethyl group at C17. The 2-formylvinyl group in position 20 was confirmed by
the coupling relationship between the hydrogen at d 5.7 (dd, J ¼ 7.8 Hz, 15.35 Hz)
and d 9.6 (d, 7.79 Hz), d 8.2 (J ¼ 15.31 Hz). In the 1H NMR spectra of 5, two singlet
peaks at d 8.7 and d 8.6 with one-proton intensity were assigned to H5 and H10
respectively, and the six singlet peaks to the methyl groups at C2, C7, and C12
and three ester groups. Mass spectra of compound 5 exhibited an intensive peak
of molecular ions, m=z 735.4 [Mþ]. As the COSY spectrum of 7 shows, one hydrogen
atom at d 5.8 is coupled to the three hydrogen atoms at d 2.0. In the meantime, the
mass spectra of compound 7 exhibited an intensive peak of molecular ions, m=z
753.5 [Mþ], which is just larger than the molecular weight of compound 5 with 18.
It is clear that the vinyl group in position 3 was converted to the hydroxyethyl group
by deoxidization. The absorptions maxima of these compounds were observed at 692
and 698 nm, respectively.
A significant shift (by 26 nm) of the absorption maximum to long wavelengths
was observed when a hydrogen atom in position 20 was replaced by a formylvinyl
group for 5. There is also a significant shift (by 32 nm) of the absorption maximum
to long wavelengths observed when the both structures of positions 3 and 20 were
changed for 7. Constructing conjugated group at 20-meso and deoxidizing in pos-
ition 3 greatly increased wavelength absorption. Nickel(II) chlorin P6 20-(2-formyl)
trimethyl ester (6) and nickel(II) chlorin P6 3-(2-formylvinyl)-20-(2-formyl) trimethyl
ester (8) were obtained from 4 by the Vilsmeier reaction with 3-dimethyl-
1
aminoacrolein (3-DMA). In the H NMR spectra of 6, the single at d 10.82 with
one-proton intensity was assigned to the hydrogen of 20-CHO-group. The analysis
1
of the other groups of compound 6 according to the H NMR and COSY spectra
was similar to the explanation of the compound 5. Compound 8 is the same as 6
but one hydrogen atom of the vinyl group in the 3-position was replaced by a formyl
group. In the COSY spectra of compound 8, the coupling relationship of the

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CHLORIN P6 TRIMETHYL ESTER DERIVATIVES
403
hydrogen at d 9.9 (d, J ¼ 7.6 Hz), d 8.2 (d, J ¼ 16.15 Hz), and d 6.8 (dd, J ¼ 7.6 Hz,
16.15 Hz) allowed us to assigned the structure of the 2-formylvinyl group. Mass spec-
tra of these compounds exhibited intensive peaks of molecular ions at m=z 709.22 (6)
and 737.32 (8). The absorptions maxima of these compounds are observed at 685
and 715 nm, respectively, which are significant changes compared with the absorp-
tion maximum of 4. The treatment of 6 and 8 with dichloromethane and then
trifluoroacetic acid resulted in two compounds, 9 and 10, without the central
nickel(II) ion. The Qy absorptions, as the longest absorption band in chlorin, in
products 9 and 10 displayed a red shift compared with corresponding absorption
band in nickel chlorin, 6 and 8. This change was attributed to the extension of the
conjugated system by removing nickel, which shortened the conjugated carbonyl
group by withdrawing electron outside the macrocycle.
CONCLUSIONS
Introduction of hydroxy groups in chlorins is known to significantly change the
hydrophilicity of such compounds. The hydroxyl group attached to 3-position of
compound 7 was obtained by the reaction with HCl hydrolyzed by phosphoryl
chloride. The Vilsmeier reaction is used in various industrial processes to attach
an aldehyde group to an aromatic compound. The major product, the aldehyde
group, attached to 20-meso aromatic compound nickel(II) chlorin P6 20-(2-formyl)
trimethyl ester obtained by the Vilsmeier reaction. In this reaction with dimethyl-
formamide, the aldehyde group attached to the 3-positon, and compound 8 was
unexpectedly obtained in a novel synthetic method. All the compounds (5–10)
showed significant changes, which met the requirements of an improved photo-
dynamic therapeutic agent.
EXPERIMENTAL
Methyl pheophorbide-a was obtained according to the Smith method, whereas
purpurin-18-methyl ester and chlorin P6 trimethyl ester followed Refs. 9 and 10,
respectively.
Nickel(II) Chlorin P6 Trimethyl Ester (4)
Ni(AcO)2 in methanol (30 mL) was added to compound 3 (300 mg, 0.48 mmol)
in dichloromethane (50 mL) and was then stirred at 65ꢀC for 12 h. After it cooled,
water (400 ml) was added to the mixture and then extracted with dichloromethane
(20 ml). The combined organic layers were washed with water (2 ꢁ 50 mL) and dried
over Na2SO4, and the solvent was removed under vacuum. After esterification by dia-
zomethane, the residue was purified with a silica-gel column with hexane–ethyl acet-
ate (2:1, v=v) to give 4 (60%). Mp 162–163ꢀC. UV-vis (CHCl3) k max: 413 (1.288), 504
1
(0.097), 547 (0.131), 666 (0.536); H NMR (CDCl3) d: 1.49 (d, J ¼ 6.8 Hz, 3H, 181-
Me), 1.55 (t, J ¼ 7.2 Hz, 3H, 82-Me), 1.62–1.69 (m, 2H, 171ꢂCH2), 2.30–2.37 (m,
2H, 172ꢂCH2), 3.02, 3.02, 3.31, 3.59, 3.83, 4.13 (each s, each 3H, 18H, MeþOMe),
3.50 (q, J ¼ 7.2 Hz, 2H, 81ꢂCH2), 4.01 (m, 1H, H17), 5.23 (m, 1H, H18), 5.94 (d,
J ¼ 11.5 Hz, 1H, 32ꢂCH2), 6.01 (d, J ¼ 17.7 Hz, 1H, 32ꢂCH2), 7.70 (dd, J ¼ 17.8 Hz,