Synthesis of Chlorins by Diels–Alder Cycloadditions of Pheophorbide a and Its Derivatives

Dedicated to Professor Ron Warrener on the occasion of his 80th birthday

Abstract

The Diels–Alder reaction was exploited for the preparation of novel long-wavelength chlorin photodynamic therapy photosensitizers. The styryl group and furan carboxamide substituents were used as diene components in [4+2] cycloaddition functionalizations.

Key words

cycloaddition - Diels–Alder reaction - photodynamic therapy - porphyrins

• References and Notes

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• 8 All novel compounds gave satisfactory ¹H, ¹³C NMR, and high-resolution mass spectra. Representative ¹H NMR spectroscopic data: Compound 3: Obtained as a 1:1 mixture of 2-epimers. ¹H NMR (300 MHz, CDCl₃): δ = –1.81, –1.76 (s, 1 H, NH), –0.98, –0.92 (s, 1 H, NH), 1.78 (t, J = 7.5 Hz, 3 H, 8²-CH₃), 2.36, 2.39 (s, 3 H, 18¹-CH₃), 2.93–3.01 (m, 1 H, 17-CH₂), 3.04–3.11 (m, 1 H, 17²-CH₂), 3.41 (s, 3 H, 7-CH₃), 3.46, 3.47 (s, 3 H, 2-CH₃), 3.70. 3.71 (s, 3 H, 12-CH₃), 3.74, 3.75 (s, 3 H, OCH₃), 3.79 (s, 3 H, OCH₃), 3.86 (s, 3 H, OCH₃), 3.91 (q, J = 7.5 Hz, 2 H, 8¹-CH₂), 3.96 (dd, J = 13.9, 5.1 Hz, 1 H, 17¹-CH₂), 4.05 (dd, J = 9.5, 3.1 Hz, 1 H, 17¹-CH₂), 4.09 (t, J = 4.1 Hz, 2 H, 3²- =CCH₂), 4.11–4.15 (m, 1 H, 17¹-CH₂), 6.77, 6.79 (s, 1 H, 15¹-CH), 7.01 (t, J = 4.1 Hz, 1 H, 3¹- =CH), 7.09 (t, J = 4.1 Hz, 1 H, 3¹- =CH), 9.12, 9.14 (s, 1 H, 20-CH), 9.21, 9.24 (s, 1 H, 5-CH), 9.78 (s, 1 H, 10-CH). Compound 5: ¹H NMR (300 MHz, CDCl₃): δ = –1.79 (s, 1 H, NH), –1.59 (br. s, 1 H, NH), 1.69 (t, J = 6.6 Hz, 3 H, 8²-CH₃), 1.71 (d, J = 7.3 Hz, 3 H, 18¹-CH₃), 1.76–1.84 (m, 1 H, 17-CH₂), 2.11–2.17 (m, 1 H, 17-CH₂), 2.18–2.25 (m, 1 H, 17-CH₂), 2.46–2.55 (m, 1 H, 17-CH₂), 3.31 (s, 3 H, 7-CH₃), 3.48 (s, 3 H, 12-CH₃), 3.53 (s, 3 H, 2-CH₃), 3.59 (s, 3 H, 15-OCH₃), 3.73 (s, 3 H, 17-OCH₃), 3.78 (q, J = 6.6 Hz, 2 H, 8¹-CH₂), 4.37 (dd, J = 10.4, 2.3 Hz, 1 H, 17-CH), 4.45 (q, J = 7.3 Hz, 1 H, 18-CH), 4.85 (dd, J = 15.3, 4.9 Hz, 1 H, 13²-CH₂), 5.04 (dd, J = 15.3, 4.9 Hz, 1 H, 13²-CH₂), 5.26 (d, J = 18.8 Hz, 1 H, 15¹-CH₂), 5.52 (d, J = 18.8 Hz, 1 H, 15¹-CH₂), 6.14 (dd, J = 11.6, 1.1 Hz, 1 H, 3²-C=CH₂), 6.35 (dd, J = 11.6, 1.1 Hz, 1 H, 3²-C=CH₂), 6.42 (dd, J = 3.3, 1.8 Hz, 1 H, 13²-ArH), 6.49 (d, J = 2.9 Hz, 1 H, 13⁷-ArH), 6.75 (t, J = 5.3 Hz, 1 H, 13²-NH), 7.49 (dd, J = 1.8, 0.8 Hz, 1 H, 13⁸-ArH), 8.08 (dd, J = 18.1, 11.5 Hz, 1 H, 3¹-CH=), 8.79 (s, 1 H, 20-H), 9.62 (s, 1 H, 5-H), 9.68 (s, 1 H, 10-H).
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