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Cite this: Org. Biomol. Chem., 2015, 13, 1992 Received 27th November 2014, Accepted 23rd December 2014 DOI: 10.1039/c4ob02491e
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Highly efficient synthesis of novel methyl 132methylene mesopyropheophorbide a and its stereoselective Michael addition reaction† Jiazhu Li,a Yang Liu,a Xi-Sen Xu,a Yan-Long Li,a Shan-Guo Zhang,a Il Yoon,b Young Key Shim,b Jin-Jun Wang*a and Jun-Gang Yin*c
www.rsc.org/obc
Treatment of methyl mesopyropheophorbide a with formaldehyde 2
under basic conditions gave a novel 13 -methylene derivative in 85% yield; under acidic conditions, the corresponding 20-hydroxymethyl derivative was obtained in 65% yield. The high reactivity of the enone structural motif existed in the former product provides a unique way to construct some novel chlorophyll a derivatives for various applications. Stereoselective Michael reaction of this compound is studied and discussed.
Naturally occurring chlorophylls are green photosynthetic pigments, many of their synthetic derivatives have also been applied as photosensitizers in the area of photodynamic therapy (PDT), dye-sensitized solar cells (DSSCs) and artificial photosynthetic reaction centers.1–4 Typical (bacterio)chlorophylls and their derivatives, for example, methyl pheophorbide a (Fig. 1, compound 1) possess a fused five-membered isocyclic ring E on which a highly reactive β-ketoester moiety exists.5 Various reactions at the ring E have been reported including ring cleavage to give chlorin e6 derivatives:6,7 air oxidation in alkaline solution to give purpurin 18 derivatives8–10 and pyrolyzation to give methyl pyropheophorbide a (Fig. 1, compound 2),11–13 which can be further reduced to give methyl 131-deoxypyropheophorbide a (Fig. 1, compound 3),14 or air oxidized via LiOH-promoted enolization to give methyl 132-oxopyropheophorbide a (Fig. 1, compound 4).15–17 Among them, methyl 132-oxopyropheophorbide a containing a bifunctional cyclopentanedione ring system is particularly important because it is the unique precursor till now to prepare verdinochlorins18,19 and construct polyaromatic ring systems such as quinoxaline, benzimidazole and perimidine
a College of Chemistry and Chemical Engineering, Yantai University, Yantai, 264005, China. E-mail: [email protected] b PDT Research Institute, School of Nano System Engineering, Inje University, Gimhae, 621-749, Korea c College of Life Sciences, Yantai University, Yantai, 264005, China. E-mail: [email protected] † Electronic supplementary information (ESI) available: Supporting tables and figures, general methods, synthetic procedures, details of spectroscopic data (UV-vis, 1D and 2D-1H NMR, 13C NMR and MS). See DOI: 10.1039/c4ob02491e
1992 | Org. Biomol. Chem., 2015, 13, 1992–1995
fused with the chromophore of (bacterio)chlorophylls.15,20–22 Such strategies have resulted in the production of a series of stable π-extended (bacterio)chlorophyll derivatives with nearinfrared (NIR) absorption and fluorescence, which is especially desirable in photodynamic therapy, bioimaging, photovoltaics and nonlinear optical materials.23–25 Unfortunately further studies of aromatic ring fused chlorophylls have been limited due to the lack of suitable reactive positions. It is vital to construct chlorophyll derivatives that are suitably functionalized at the ring E to allow access to novel ring fused structures. Since methyl (meso)pyropheophorbide a has a fused cyclopentanone moiety, the 132-carbon is directly connected with a ketone group and a chlorin π-system, so the 132-position has high chemical reactivity. It is thus assumed that the aldol condensation of the exocyclic ketone with other aldehydes or ketones might be possible. Aldol condensation provides a good way to form β-hydroxyaldehyde or β-hydroxyketone, followed by dehydration to give a conjugated enone,26,27 while it has not been well investigated to our knowledge in porphyrin chemistry. Considering the significance of enones, the known precursors or intermediates for ring system construction in various synthetic processes,28–31 here we report a simple and highly efficient method for the preparation of methyl 132methylene mesopyropheophorbide a (Scheme 1, compound 6) via an aldol condensation. This involved the pH-dependent
Fig. 1 Typical structures of chlorophyll derivatives possessing a fused five-membered isocyclic ring E.
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Scheme 1 pH-dependent regioselective reaction of compound 5 with formaldehyde and the stereoselective Michael reaction of compound 6. Reagents and conditions: (a) HCHO, NaOMe, N2, 6 h; (b) HCHO, HCl/ H3PO4/AcOH, 3 days; (c) reactive methylene compounds, NaOMe, N2, 3 h; (d) TPAP/NMO, 1 h.
regioselective reaction of methyl mesopyropheophorbide a 5 with formaldehyde. Stereoselective Michael reactions with enone 6 are also reported. In our approach, methyl mesopyropheophorbide a (Scheme 1, compound 5)11 was used as the substrate for the synthesis of enone possessing chlorin 6 by aldol condensation with formaldehyde under base or acid catalyzed conditions (Scheme 1). Formalin (40%) or paraformaldehyde was used as the formaldehyde source, and several attempts were made to prepare the desired product 6 by varying the reaction conditions (Table S1, ESI†). It was found that regioselective products were obtained under different pH conditions. The desired 132-methylene chlorin 6 can only be obtained under basic conditions, while 20-hydromethyl chlorin 7 was formed as the unique product under acidic conditions. The best results for 132-methylene chlorin 6 were obtained by stirring the compound 5 and excess paraformaldehyde with sodium methoxide (10 eq.) in THF at room temperature under a N2 atmosphere for 6 h. The crude reaction product was readily purified by silica gel chromatography. Besides the expected compound 6 (m/z 563), observed as a dark green band (85% yield), a minor product 132-dihydromethyl chlorin 6a (m/z 611) was also isolated in 6% yield, which seems to be produced from the starting material 5 by reacting with 2 eq. formaldehyde. The structures of chlorins 6 and 6a were further confirmed by the 1H NMR spectrum. On comparing the resonances observed for 6 and 6a, the 132-methylene (vCH2) protons of chlorin 6 appeared at δ 5.24 (1H) and 5.09 (1H) as two singlets, while the 132-methylene protons of chlorin 6a appeared at δ 5.06 (1H), 4.84 (1H), 4.73 (1H) and 4.55 (1H) as four doublets.
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The yield of 20-hydromethyl chlorin 7 was optimized by using a combined acid (HCl/H3PO4/AcOH) as the catalyst and stirring the reaction mixture at room temperature for 3 days. After standard treatment with 5% sulphuric acid in methanol overnight, 20-hydroxymethyl chlorin 7 (m/z 581) was obtained in 65% yield. In the 1H NMR spectrum of 7, the proton resonances of the newly formed 20-hydroxymethyl (O–CH2) were observed at δ 6.36 (1H) and 6.01 (1H) as two doublets ( J = 12.8 Hz). The production of chlorin 7 seems to be derived from the Blanc reaction32,33 of methyl mesopyropheophorbide a 5. It is worth noting that this might be the first example of the Blanc reaction in porphyrin chemistry. Even though several strategies had been developed,34,35 the method reported here provides a simple and effective way to prepare hydroxymethyl-substituted porphyrin derivatives. To establish the reactivity of enone possessing compound 6, its Michael reaction was performed using acetylacetone, dimethyl malonate and ethyl acetoacetate as the reactive methylene compounds. As expected, these reactions in THF at room temperature under a N2 atmosphere for 3 h in the presence of sodium methoxide (10 eq.) produced the corresponding Michael reaction adducts 8a–8c (m/z 663, 695 and 693, respectively) in 90–94% yields. The products were analyzed by 1D- and 2D-1H NMR including 1H–1H COSY and NOESY in deuterated chloroform (CDCl3) at room temperature. The structural changes between the enone possessing chlorin 6 and the Michael reaction adducts 8a–8c are indicated clearly by the resonance changes in the 1H NMR spectra (Fig. S1, ESI†). The disappearance of 132a-methylene proton resonances (δ 5.24, 5.09, each singlet, each 1H) in 6 and the appearance of a set of proton resonances concerning the substituted groups linked with the 132-position confirmed the structures of the Michael reaction adducts 8a–8c. As an example, in the 1H NMR spectra of compound 8a, the 132-CH, 132a-CH2 and 132bCH proton signals were observed as a doublet of doublets at δ 5.24, multiplets at δ 3.37–3.31 and 3.04–2.96, and a triplet at δ 4.45, respectively, while the proton resonances of two methyl (–COCH3) at the 132c-position appeared as singlets at δ 2.37 and δ 1.68, respectively. It was interesting to find that the Michael reaction, occurred at the enone structure in the exocyclic ring of compound 6, was almost entirely stereoselective, especially for the reactions with relatively bulky reactive methylene compounds. The stereoselective products 8b and 8c were formed as the only Michael reaction adducts when compound 6 reacted with dimethyl malonate and ethyl acetoacetate, respectively, while the same reaction with acetylacetone produced an epimerically non-separated (80 : 20) mixture of 132R- and 132S-isomer 8a, which also showed relatively higher stereoselectivity. Since the stereochemistry at the 17-stereogenic position of methyl mesopyropheophorbide a and its derivatives was fixed in the S-configuration,36,37 and the 17-H was located near the 132-H or 132a-CH2, it is therefore possible to confirm the stereochemistry of the Michael reaction adducts 8a–8c by their NOESY spectra (Fig. S2, ESI†). The NOESY spectrum of 8b or 8c showed that their 17-H was correlated with the 132a-CH2 but
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not with 132-H, suggesting that the 132a-CH2 was located in the same direction as the 17-H based on the chlorin π-plane, and in the reverse of the propionate residue at the 17-position. The stereochemistry at the 132-position of 8b or 8c was therefore confirmed to have an R-configuration. The major isomer of 8a showed a similar NOESY spectrum to that of 8b and 8c. The stereoselectivity might have been derived from the existence of the bulky 17-propionate residue, which pushed the substituted groups at the 132-position away from the same direction as itself based on the chlorin π-plane. Actually the steric influence of the 17-propionate residue on the stereoselective reactions at the ring E has only been reported recently.36,37 In order to obtain 20-formyl mesopyropheophorbide a 9, 20-hydroxymethyl chlorin 7 was oxidized by tetrapropylammonium perruthenate (TPAP) in the presence of 4-methylmorpholine N-oxide (NMO) to give the desired product 9 (m/z 579) in 68% yield. The progress of the transformation was clearly shown by the disappearance of the 20-CH2OH proton resonance (δ 6.36 and 6.01) and the appearance of the 20-CHO proton resonance at δ 11.80 as a singlet in their 1H NMR spectra. It should be noted that several attempts had been made previously to introduce a formyl group at the 20-position of methyl mesopyropheophorbide a by Vilsmeier formylation but all failed.11,38,39 To the best of our knowledge, this is the first report so far about the 20-formyl methyl mesopyropheophorbide a 9. The absorption and fluorescence characteristics of chlorins 6, 7, 8a (as an epimeric mixture) and 9 were measured in dichloromethane (Fig. 2) and are summarized in Table 1. These chlorins exhibited the long-wavelength absorptions (Qy maxima) at 664, 666, 656 and 689 nm and fluorescence at 667, 669, 661 and 670 nm, respectively, with distinct intensities. It was found that all the tested compounds except 8a demonstrated bathochromic shifts, more or less, of their Qy maxima as compared to the starting material 5. Among them, 20-formyl mesopyropheophorbide a 9 showed the Qy maxima at 689 nm with the largest red shift (33 nm). It should be noted that the 132-methylene group in 6 causes not only the bathochromic shift of the Qy maxima but also a characteristic peak broadening of the Soret band, especially compared to the other tested chlorins.
Table 1
Fig. 2 Electronic absorption spectra (3.3 μM in CH2Cl2) of compounds 5, 6, 7, 8a and 9 (A); and fluorescence spectra (1 μM in CH2Cl2) of compounds 6 (λex = 427 nm), 7 (λex = 412 nm), 8a (λex = 410 nm) and 9 (λex = 413 nm) (B).
In summary, the pH-dependent regioselective reaction of methyl mesopyropheophorbide a 5 with formaldehyde has been accomplished. This methodology opens a simple and efficient way for the preparation of the novel methyl 132methylene mesopyropheophorbide a 6, and provides an effective way to prepare the 20-hydroxymethyl and formyl chlorins especially, as these cannot be prepared by a Vilsmeier formylation. This synthetic approach developed here as well as the stereoselective Michael reaction of compound 6 also provides great potential for designing novel aromatic ring fused chlorin systems. Further studies are underway to explore the reactivity of enone possessing chlorin 6 for the preparation of novel chromophores with extended π-conjugation, e.g.
The absorption and emission properties of the novel chlorins in dichloromethane
Absorption λmax (nm) (ε × 105 M−1 cm−1)
Emission λmax (nm)
Compound
Soret
ΔSoret (Δε)
Qy
ΔQy (Δε)
Excitation
Emission
Stokes shift (nm)
5b 6 7 8a 9
409 (1.36) 427 (1.52) 412 (1.53) 410 (1.72) 412 (1.55)
0 19 (0.16) 3 (0.17) 1 (0.36) 3 (0.19)
656 (0.55) 664 (0.75) 666 (0.56) 656 (0.69) 689 (0.44)
0 8 (0.20) 10 (0.01) 0 (0.14) 33 (−0.11)
— 427 412 410 412
— 667 669 661 670
—
a
a
3 3 4 −19
ΔSoret, ΔQy and Δε represent the change of the Soret band, Qy band and absorbance intensity, respectively, between the novel chlorin and the starting material 5. b Reference data.11
a
1994 | Org. Biomol. Chem., 2015, 13, 1992–1995
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benzene, pyridine and quinolone fused chlorins as photosensitizers for photodynamic therapy and models for photosynthetic reaction centers.
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Acknowledgements This work was supported by the National Natural Science Foundation of China (no. 21272048 to J.J.W.) and the Doctoral Science Foundation of Yantai University (HY13B11 to J.L.).
Notes and references 1 H. Ali and J. E. van Lier, in Handbook of Porphyrin Science, ed. K. M. Kadish, K. M. Smith and R. Guilard, World Scientific Publishing Co. Pte. Ltd., Singapore, 2010, vol. 4, pp. 1–119. 2 M. Ethirajan, N. J. Patel and R. K. Pandey, in Handbook of Porphyrin Science, ed. K. M. Kadish, K. M. Smith and R. Guilard, World Scientific Publishing Co. Pte. Ltd., Singapore, 2010, vol. 4, pp. 249–323. 3 X. F. Wang and H. Tamiaki, Energy Environ. Sci., 2010, 3, 94–106. 4 V. L. Gunderson and M. R. Wasielewski, in Handbook of Porphyrin Science, ed. K. M. Kadish, K. M. Smith and R. Guilard, World Scientific Publishing Co. Pte. Ltd., Singapore, 2012, vol. 20, pp. 45–105. 5 H. Tamiaki and M. Kunieda, in Handbook of Porphyrin Science, ed. K. M. Kadish, K. M. Smith and R. Guilard, World Scientific Publishing Co. Pte. Ltd., Singapore, 2011, vol. 11, pp. 223–290. 6 R. G. W. Jinadasa, X. K. Hu, M. G. H. Vicente and K. M. Smith, J. Med. Chem., 2011, 54, 7464–7476. 7 J.-Z. Li, B.-C. Cui, J.-J. Wang and Y.-K. Shim, Bull. Korean Chem. Soc., 2011, 32, 2465–2468. 8 G. Zheng, W. R. Potter, S. H. Camacho, J. R. Missert, G. S. Wang, D. A. Bellnier, B. W. Henderson, M. A. J. Rodgers, T. J. Dougherty and R. K. Pandey, J. Med. Chem., 2001, 44, 1540–1559. 9 J. Z. Li, L. Li, J. H. Kim, B. C. Cui, J. J. Wang and Y. K. Shim, J. Porphyrins Phthalocyanines, 2011, 15, 264– 270. 10 J. Li, P. Zhang, N.-N. Yao, L.-L. Zhao, J.-J. Wang and Y. K. Shim, Tetrahedron Lett., 2014, 55, 1086–1089. 11 K. M. Smith, D. A. Goff and D. J. Simpson, J. Am. Chem. Soc., 1985, 107, 4946–4954. 12 A. J. Pallenberg, M. P. Dobhal and R. K. Pandey, Org. Process Res. Dev., 2004, 8, 287–290. 13 J. Z. Li, J. J. Wang, I. Yoon, B. C. Cui and Y. K. Shim, Bioorg. Med. Chem. Lett., 2012, 22, 1846–1849. 14 R. K. Pandey, A. B. Sumlin, S. Constantine, M. Aoudia, W. R. Potter, D. A. Bellnier, B. W. Henderson, M. A. Rodgers, K. M. Smith and T. J. Dougherty, Photochem. Photobiol., 1996, 64, 194–204.
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15 A. Kozyrev, M. Ethirajan, P. Chen, K. Ohkubo, B. C. Robinson, K. M. Barkigia, S. Fukuzumi, K. M. Kadish and R. K. Pandey, J. Org. Chem., 2012, 77, 10260–10271. 16 A. N. Kozyrev, T. J. Dougherty and R. K. Pandey, Chem. Commun., 1998, 481–482. 17 A. Rosenfeld, J. Morgan, L. N. Goswami, T. Hulchanskyy, X. Zheng, P. N. Prasad, A. Seroff and R. K. Pandey, Photochem. Photobiol., 2006, 82, 626–634. 18 A. N. Kozyrev, J. L. Alderfer, T. J. Dougherty and R. K. Pandey, Chem. Commun., 1998, 1083–1084. 19 A. N. Kozyrev, J. L. Alderfer, T. J. Dougherty and R. K. Pandey, Angew. Chem., Int. Ed., 1999, 38, 126–128. 20 A. N. Kozyrev, J. L. Alderfer, T. Srikrishnan and R. K. Pandey, J. Chem. Soc., Perkin Trans. 1, 1998, 837–838. 21 A. N. Kozyrev, V. Suresh, S. Das, M. O. Senge, M. Shibata, T. J. Dougherty and R. K. Pandey, Tetrahedron, 2000, 56, 3353–3364. 22 X. Xu, N. Yao, Y. Liu, J. Yin, C. Qi and J. Wang, Chin. J. Org. Chem., 2014, 34, 938–947. 23 M. Ethirajan, Y. Chen, P. Joshi and R. K. Pandey, Chem. Soc. Rev., 2011, 40, 340–362. 24 H. Mori, T. Tanaka and A. Osuka, J. Mater. Chem. C, 2013, 1, 2500. 25 Z. Guo, S. Park, J. Yoon and I. Shin, Chem. Soc. Rev., 2014, 43, 16–29. 26 Z. Wang, G. Yin, J. Qin, M. Gao, L. Cao and A. Wu, Synthesis, 2008, 3675–3681. 27 J. Zhou and B. List, J. Am. Chem. Soc., 2007, 129, 7498– 7499. 28 M. C. Bagley, C. Glover and E. A. Merritt, Synlett, 2007, 2007, 2459–2482. 29 Y. Wei and N. Yoshikai, J. Am. Chem. Soc., 2013, 135, 3756– 3759. 30 J. Horn, S. P. Marsden, A. Nelson, D. House and G. G. Weingarten, Org. Lett., 2008, 10, 4117–4120. 31 P. Zhou, L. Zhang, S. Luo and J.-P. Cheng, J. Org. Chem., 2012, 77, 2526–2530. 32 Y. T. Pratt, J. Am. Chem. Soc., 1951, 73, 3803–3807. 33 R. E. Sammelson and M. J. Kurth, Chem. Rev., 2000, 101, 137–202. 34 T. Takanami, J. Matsumoto, Y. Kumagai, A. Sawaizumi and K. Suda, Tetrahedron Lett., 2009, 50, 68–70. 35 Z. Yao, J. Bhaumik, S. Dhanalekshmi, M. Ptaszek, P. A. Rodriguez and J. S. Lindsey, Tetrahedron, 2007, 63, 10657–10670. 36 H. Tamiaki, R. Monobe, S. Koizumi, T. Miyatake and Y. Kinoshita, Tetrahedron: Asymmetry, 2013, 24, 677–682. 37 S. Ogasawara and H. Tamiaki, Tetrahedron Lett., 2014, 55, 3618–3621. 38 K. M. Smith, G. M. F. Bisset and M. J. Bushell, J. Org. Chem., 1980, 45, 2218–2224. 39 R. K. Pandey, S. Constantine, D. A. Goff, A. N. Kozyrev, T. J. Dougherty and K. M. Smith, Bioorg. Med. Chem. Lett., 1996, 6, 105–110.
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Cite this: Org. Biomol. Chem., 2015, 13, 1992 Received 27th November 2014, Accepted 23rd December 2014 DOI: 10.1039/c4ob02491e
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Highly efficient synthesis of novel methyl 132methylene mesopyropheophorbide a and its stereoselective Michael addition reaction† Jiazhu Li,a Yang Liu,a Xi-Sen Xu,a Yan-Long Li,a Shan-Guo Zhang,a Il Yoon,b Young Key Shim,b Jin-Jun Wang*a and Jun-Gang Yin*c
www.rsc.org/obc
Treatment of methyl mesopyropheophorbide a with formaldehyde 2
under basic conditions gave a novel 13 -methylene derivative in 85% yield; under acidic conditions, the corresponding 20-hydroxymethyl derivative was obtained in 65% yield. The high reactivity of the enone structural motif existed in the former product provides a unique way to construct some novel chlorophyll a derivatives for various applications. Stereoselective Michael reaction of this compound is studied and discussed.
Naturally occurring chlorophylls are green photosynthetic pigments, many of their synthetic derivatives have also been applied as photosensitizers in the area of photodynamic therapy (PDT), dye-sensitized solar cells (DSSCs) and artificial photosynthetic reaction centers.1–4 Typical (bacterio)chlorophylls and their derivatives, for example, methyl pheophorbide a (Fig. 1, compound 1) possess a fused five-membered isocyclic ring E on which a highly reactive β-ketoester moiety exists.5 Various reactions at the ring E have been reported including ring cleavage to give chlorin e6 derivatives:6,7 air oxidation in alkaline solution to give purpurin 18 derivatives8–10 and pyrolyzation to give methyl pyropheophorbide a (Fig. 1, compound 2),11–13 which can be further reduced to give methyl 131-deoxypyropheophorbide a (Fig. 1, compound 3),14 or air oxidized via LiOH-promoted enolization to give methyl 132-oxopyropheophorbide a (Fig. 1, compound 4).15–17 Among them, methyl 132-oxopyropheophorbide a containing a bifunctional cyclopentanedione ring system is particularly important because it is the unique precursor till now to prepare verdinochlorins18,19 and construct polyaromatic ring systems such as quinoxaline, benzimidazole and perimidine
a College of Chemistry and Chemical Engineering, Yantai University, Yantai, 264005, China. E-mail: [email protected] b PDT Research Institute, School of Nano System Engineering, Inje University, Gimhae, 621-749, Korea c College of Life Sciences, Yantai University, Yantai, 264005, China. E-mail: [email protected] † Electronic supplementary information (ESI) available: Supporting tables and figures, general methods, synthetic procedures, details of spectroscopic data (UV-vis, 1D and 2D-1H NMR, 13C NMR and MS). See DOI: 10.1039/c4ob02491e
1992 | Org. Biomol. Chem., 2015, 13, 1992–1995
fused with the chromophore of (bacterio)chlorophylls.15,20–22 Such strategies have resulted in the production of a series of stable π-extended (bacterio)chlorophyll derivatives with nearinfrared (NIR) absorption and fluorescence, which is especially desirable in photodynamic therapy, bioimaging, photovoltaics and nonlinear optical materials.23–25 Unfortunately further studies of aromatic ring fused chlorophylls have been limited due to the lack of suitable reactive positions. It is vital to construct chlorophyll derivatives that are suitably functionalized at the ring E to allow access to novel ring fused structures. Since methyl (meso)pyropheophorbide a has a fused cyclopentanone moiety, the 132-carbon is directly connected with a ketone group and a chlorin π-system, so the 132-position has high chemical reactivity. It is thus assumed that the aldol condensation of the exocyclic ketone with other aldehydes or ketones might be possible. Aldol condensation provides a good way to form β-hydroxyaldehyde or β-hydroxyketone, followed by dehydration to give a conjugated enone,26,27 while it has not been well investigated to our knowledge in porphyrin chemistry. Considering the significance of enones, the known precursors or intermediates for ring system construction in various synthetic processes,28–31 here we report a simple and highly efficient method for the preparation of methyl 132methylene mesopyropheophorbide a (Scheme 1, compound 6) via an aldol condensation. This involved the pH-dependent
Fig. 1 Typical structures of chlorophyll derivatives possessing a fused five-membered isocyclic ring E.
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Scheme 1 pH-dependent regioselective reaction of compound 5 with formaldehyde and the stereoselective Michael reaction of compound 6. Reagents and conditions: (a) HCHO, NaOMe, N2, 6 h; (b) HCHO, HCl/ H3PO4/AcOH, 3 days; (c) reactive methylene compounds, NaOMe, N2, 3 h; (d) TPAP/NMO, 1 h.
regioselective reaction of methyl mesopyropheophorbide a 5 with formaldehyde. Stereoselective Michael reactions with enone 6 are also reported. In our approach, methyl mesopyropheophorbide a (Scheme 1, compound 5)11 was used as the substrate for the synthesis of enone possessing chlorin 6 by aldol condensation with formaldehyde under base or acid catalyzed conditions (Scheme 1). Formalin (40%) or paraformaldehyde was used as the formaldehyde source, and several attempts were made to prepare the desired product 6 by varying the reaction conditions (Table S1, ESI†). It was found that regioselective products were obtained under different pH conditions. The desired 132-methylene chlorin 6 can only be obtained under basic conditions, while 20-hydromethyl chlorin 7 was formed as the unique product under acidic conditions. The best results for 132-methylene chlorin 6 were obtained by stirring the compound 5 and excess paraformaldehyde with sodium methoxide (10 eq.) in THF at room temperature under a N2 atmosphere for 6 h. The crude reaction product was readily purified by silica gel chromatography. Besides the expected compound 6 (m/z 563), observed as a dark green band (85% yield), a minor product 132-dihydromethyl chlorin 6a (m/z 611) was also isolated in 6% yield, which seems to be produced from the starting material 5 by reacting with 2 eq. formaldehyde. The structures of chlorins 6 and 6a were further confirmed by the 1H NMR spectrum. On comparing the resonances observed for 6 and 6a, the 132-methylene (vCH2) protons of chlorin 6 appeared at δ 5.24 (1H) and 5.09 (1H) as two singlets, while the 132-methylene protons of chlorin 6a appeared at δ 5.06 (1H), 4.84 (1H), 4.73 (1H) and 4.55 (1H) as four doublets.
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The yield of 20-hydromethyl chlorin 7 was optimized by using a combined acid (HCl/H3PO4/AcOH) as the catalyst and stirring the reaction mixture at room temperature for 3 days. After standard treatment with 5% sulphuric acid in methanol overnight, 20-hydroxymethyl chlorin 7 (m/z 581) was obtained in 65% yield. In the 1H NMR spectrum of 7, the proton resonances of the newly formed 20-hydroxymethyl (O–CH2) were observed at δ 6.36 (1H) and 6.01 (1H) as two doublets ( J = 12.8 Hz). The production of chlorin 7 seems to be derived from the Blanc reaction32,33 of methyl mesopyropheophorbide a 5. It is worth noting that this might be the first example of the Blanc reaction in porphyrin chemistry. Even though several strategies had been developed,34,35 the method reported here provides a simple and effective way to prepare hydroxymethyl-substituted porphyrin derivatives. To establish the reactivity of enone possessing compound 6, its Michael reaction was performed using acetylacetone, dimethyl malonate and ethyl acetoacetate as the reactive methylene compounds. As expected, these reactions in THF at room temperature under a N2 atmosphere for 3 h in the presence of sodium methoxide (10 eq.) produced the corresponding Michael reaction adducts 8a–8c (m/z 663, 695 and 693, respectively) in 90–94% yields. The products were analyzed by 1D- and 2D-1H NMR including 1H–1H COSY and NOESY in deuterated chloroform (CDCl3) at room temperature. The structural changes between the enone possessing chlorin 6 and the Michael reaction adducts 8a–8c are indicated clearly by the resonance changes in the 1H NMR spectra (Fig. S1, ESI†). The disappearance of 132a-methylene proton resonances (δ 5.24, 5.09, each singlet, each 1H) in 6 and the appearance of a set of proton resonances concerning the substituted groups linked with the 132-position confirmed the structures of the Michael reaction adducts 8a–8c. As an example, in the 1H NMR spectra of compound 8a, the 132-CH, 132a-CH2 and 132bCH proton signals were observed as a doublet of doublets at δ 5.24, multiplets at δ 3.37–3.31 and 3.04–2.96, and a triplet at δ 4.45, respectively, while the proton resonances of two methyl (–COCH3) at the 132c-position appeared as singlets at δ 2.37 and δ 1.68, respectively. It was interesting to find that the Michael reaction, occurred at the enone structure in the exocyclic ring of compound 6, was almost entirely stereoselective, especially for the reactions with relatively bulky reactive methylene compounds. The stereoselective products 8b and 8c were formed as the only Michael reaction adducts when compound 6 reacted with dimethyl malonate and ethyl acetoacetate, respectively, while the same reaction with acetylacetone produced an epimerically non-separated (80 : 20) mixture of 132R- and 132S-isomer 8a, which also showed relatively higher stereoselectivity. Since the stereochemistry at the 17-stereogenic position of methyl mesopyropheophorbide a and its derivatives was fixed in the S-configuration,36,37 and the 17-H was located near the 132-H or 132a-CH2, it is therefore possible to confirm the stereochemistry of the Michael reaction adducts 8a–8c by their NOESY spectra (Fig. S2, ESI†). The NOESY spectrum of 8b or 8c showed that their 17-H was correlated with the 132a-CH2 but
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not with 132-H, suggesting that the 132a-CH2 was located in the same direction as the 17-H based on the chlorin π-plane, and in the reverse of the propionate residue at the 17-position. The stereochemistry at the 132-position of 8b or 8c was therefore confirmed to have an R-configuration. The major isomer of 8a showed a similar NOESY spectrum to that of 8b and 8c. The stereoselectivity might have been derived from the existence of the bulky 17-propionate residue, which pushed the substituted groups at the 132-position away from the same direction as itself based on the chlorin π-plane. Actually the steric influence of the 17-propionate residue on the stereoselective reactions at the ring E has only been reported recently.36,37 In order to obtain 20-formyl mesopyropheophorbide a 9, 20-hydroxymethyl chlorin 7 was oxidized by tetrapropylammonium perruthenate (TPAP) in the presence of 4-methylmorpholine N-oxide (NMO) to give the desired product 9 (m/z 579) in 68% yield. The progress of the transformation was clearly shown by the disappearance of the 20-CH2OH proton resonance (δ 6.36 and 6.01) and the appearance of the 20-CHO proton resonance at δ 11.80 as a singlet in their 1H NMR spectra. It should be noted that several attempts had been made previously to introduce a formyl group at the 20-position of methyl mesopyropheophorbide a by Vilsmeier formylation but all failed.11,38,39 To the best of our knowledge, this is the first report so far about the 20-formyl methyl mesopyropheophorbide a 9. The absorption and fluorescence characteristics of chlorins 6, 7, 8a (as an epimeric mixture) and 9 were measured in dichloromethane (Fig. 2) and are summarized in Table 1. These chlorins exhibited the long-wavelength absorptions (Qy maxima) at 664, 666, 656 and 689 nm and fluorescence at 667, 669, 661 and 670 nm, respectively, with distinct intensities. It was found that all the tested compounds except 8a demonstrated bathochromic shifts, more or less, of their Qy maxima as compared to the starting material 5. Among them, 20-formyl mesopyropheophorbide a 9 showed the Qy maxima at 689 nm with the largest red shift (33 nm). It should be noted that the 132-methylene group in 6 causes not only the bathochromic shift of the Qy maxima but also a characteristic peak broadening of the Soret band, especially compared to the other tested chlorins.
Table 1
Fig. 2 Electronic absorption spectra (3.3 μM in CH2Cl2) of compounds 5, 6, 7, 8a and 9 (A); and fluorescence spectra (1 μM in CH2Cl2) of compounds 6 (λex = 427 nm), 7 (λex = 412 nm), 8a (λex = 410 nm) and 9 (λex = 413 nm) (B).
In summary, the pH-dependent regioselective reaction of methyl mesopyropheophorbide a 5 with formaldehyde has been accomplished. This methodology opens a simple and efficient way for the preparation of the novel methyl 132methylene mesopyropheophorbide a 6, and provides an effective way to prepare the 20-hydroxymethyl and formyl chlorins especially, as these cannot be prepared by a Vilsmeier formylation. This synthetic approach developed here as well as the stereoselective Michael reaction of compound 6 also provides great potential for designing novel aromatic ring fused chlorin systems. Further studies are underway to explore the reactivity of enone possessing chlorin 6 for the preparation of novel chromophores with extended π-conjugation, e.g.
The absorption and emission properties of the novel chlorins in dichloromethane
Absorption λmax (nm) (ε × 105 M−1 cm−1)
Emission λmax (nm)
Compound
Soret
ΔSoret (Δε)
Qy
ΔQy (Δε)
Excitation
Emission
Stokes shift (nm)
5b 6 7 8a 9
409 (1.36) 427 (1.52) 412 (1.53) 410 (1.72) 412 (1.55)
0 19 (0.16) 3 (0.17) 1 (0.36) 3 (0.19)
656 (0.55) 664 (0.75) 666 (0.56) 656 (0.69) 689 (0.44)
0 8 (0.20) 10 (0.01) 0 (0.14) 33 (−0.11)
— 427 412 410 412
— 667 669 661 670
—
a
a
3 3 4 −19
ΔSoret, ΔQy and Δε represent the change of the Soret band, Qy band and absorbance intensity, respectively, between the novel chlorin and the starting material 5. b Reference data.11
a
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benzene, pyridine and quinolone fused chlorins as photosensitizers for photodynamic therapy and models for photosynthetic reaction centers.
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Acknowledgements This work was supported by the National Natural Science Foundation of China (no. 21272048 to J.J.W.) and the Doctoral Science Foundation of Yantai University (HY13B11 to J.L.).
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