Porphyrins in 1,3-Dipolar Cycloadditions with Sugar Azomethine Ylides. Synthesis of Pyrrolidinoporphyrin Glycoconjugates

Abstract

Pyrrolidine-fused chlorins carrying an N- or C-linked ­galactose residue were prepared by 1,3-dipolar cycloadditions of meso-tetrakis(pentafluorophenyl)porphyrin to galactose-substi­tuted azomethine ylides.

Key words

porphyrins - chlorines - cycloadditions - ylides - glycosides

References

• 1 The Porphyrin Handbook - Applications: Past, Present and Future   Vol. 6:  Kadish KM. Smith KM. Guilard R. Academic Press; San Diego: 2000. 
• 2 Ackroyd R. Kelty C. Brown N. Reed M. Photochem. Photobiol.  2001,  74:  656 
• 3 Bonnett R. Chemical Aspects of Photodynamic Therapy   Gordon and Breach Science Publishers; Australia: 2000.  p.177-197  
• 4a Tomé AC. Lacerda PSS. Neves MGPMS. Cavaleiro JAS. Chem. Commun.  1997,  1199 
• 4b Silva AMG. Tomé AC. Neves MGPMS. Cavaleiro JAS. Tetrahedron Lett.  2000,  41:  3065 
• 5a Silva AMG. Tomé AC. Neves MGPMS. Silva AMS. Cavaleiro JAS. Chem. Commun.  1999,  1767 
• 5b Silva AMG. Tomé AC. Neves MGPMS. Cavaleiro JAS. Synlett  2002,  1155 
• 5c Silva AMG. Tomé AC. Neves MGPMS. Silva AMS. Cavaleiro JAS. J. Org. Chem.  2002,  67:  726 
• 5d Silva AMG. Tomé AC. Neves MGPMS. Silva AMS. Cavaleiro JAS. J. Org. Chem.  2005, in press
• 6 Cavaleiro JAS. Neves MGPMS. Tomé AC. Arkivoc  2003,  xiv:  107 
• 7 Silva AMG. Tomé AC. Neves MGPMS. Silva AMS. Cavaleiro JAS. Perrone D. Dondoni A. Tetrahedron Lett.  2002,  43:  603 
• 8 Dondoni A. Marra A. Tetrahedron Lett.  2002,  43:  1649 
• 10 Kolb HC. Finn MG. Sharpless KB. Angew. Chem. Int. Ed.  2001,  40:  2004 
• The preferred conformation for 1,2:3,4-di-O-isopropyl-idene-d-galactopyranose derivatives seems to be the ⁰ S ₂ skew, as proved by the coupling constant values in their ¹H NMR spectra. See:
• 11a Dondoni A. Catozzi N. Marra A. J. Org. Chem.  2004,  69:  5023 
• 11b Roslund MU. Klika KD. Lehtilä RL. Tähtinen P. Sillanpää R. Leino R. J. Org. Chem.  2004,  69:  18 
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9

Functionalized fullerenes have been reported to behave as HIV protease inhibitors, antioxidants, cytotoxics, and photodynamic agents for DNA cleavage. See ref.⁸ and references cited therein.

12

Procedure for the Synthesis of Chlorins 6a and 6b. To a refluxing solution of 5 (30.0 mg, 0.03 mmol) and N-methylglycine (11.0 mg, 0.12 mmol) in toluene (4 mL), in the presence of molecular sieves (2 g) and under nitrogen, was added dropwise during 4 h a solution of the aldehyde 3 (80.0 mg, 0.31 mmol) in toluene (1 mL). After the addition was complete, the reaction mixture was refluxed for an additional period of 15 min. The mixture was cooled and filtered. The filtrate was evaporated to dryness and purified by flash chromatography in CH₂Cl₂-EtOAc (9:1). The first fraction was the unchanged starting porphyrin 5 (11.6 mg, 39%). The second one was the minor chlorin (7.4 mg, 19% yield) and the third one was the major chlorin (12.6 mg, 32% yield). The last fraction was the chlorin 8 (2.6 mg, 8% yield).

13

Successful 1,3-dipolar cycloaddition of porphyrins to the azomethine ylide 4 is greatly dependent on the dipolaro-philic character of the former, which in turn is enhanced by the presence of electron-withdrawing groups. We observed that only the sugar-free cycloadduct was formed by the use of meso-tetraphenylporphyrin while the reaction of 2-nitro-5,10,15,20-tetrakis(pentafluoro-phenyl)porphyrin lead to a complex mixture of pyrrolidino-porphyrin glycoconjugates and no formation of the side-product of type 8.

14

Spectroscopic data for the major chlorin: ¹H NMR (400 MHz, CDCl₃): δ = -1.78 and 1.71 (2 s, 2 H, NH), 1.40, 1.42, 1.53, 1.55 and 1.98 (5 s, 15 H, 5 × CH₃), 2.79 (dd, 1 H, J = 9.8 and 3.9 Hz, H-2³ _trans ), 3.46 (dd, 1 H, J = 9.8 and 9.1 Hz, H-2³ _cis ), 3.90 (d, 1 H, J = 6.2 Hz, H-2¹), 3.95 (d, 1 H, J = 6.2 Hz, H-5-sugar), 4.32 (dd, 1 H, J = 4.8 and 2.0 Hz, H-2-sugar), 4.39 (d, 1 H, J = 7.7 Hz, H-4-sugar), 4.64 (dd, 1 H, J = 7.7 and 2.0 Hz, H-3-sugar), 5.28 (ddd, 1 H, J = 9.1, 8.2 and 3.9 Hz, H-3), 5.33 (d, 1 H, J = 4.8 Hz, H-1-sugar), 5.62 (d, 1 H, J = 8.2 Hz, H-2), 8.36 and 8.42 (2 d, 2 H, J = 4.8 Hz, H-β), 8.46 (AB, 2 H, H-β), 8.67 and 8.70 (2 d, 2 H, J = 4.8 Hz, H-β). MS (LSIMS): 1260 [M + H]⁺, 1259 [M⁺], 1031 [M - C₁₁H₁₇O₅ + H]⁺, 975 [porphyrin 5 + H]⁺. UV/Vis (CH₂Cl₂): λ_max (log ε) = 653 (4.66), 599 (3.69), 505 (5.19), 408 (5.24) nm. Anal. Calcd for C₅₈H₃₃F₂₀N₅O₅: C, 55.29; H, 2.64; N, 5.56. Found: C, 55.32; H, 2.70; N, 5.42.

15

Spectroscopic data for the minor chlorin: ¹H NMR (400 MHz, CDCl₃): δ = -1.87 and 1.82 (2 s, 2 H, NH), 1.31, 1.40, 1.50, 1.55 and 1.57 (5 s, 15 H, 5 × CH₃), 3.06 (dd, 1 H, J = 12.1 and 3.5 Hz, H-2³ _trans ), 3.50-3.54 (m, 1 H, H-2³ _cis ), 3.57 (d, 1 H, J = 10.2 Hz, H-5-sugar), 3.67 (d, 1 H, J = 10.2 Hz, H-2¹), 4.32 (dd, 1 H, J = 4.8 and 2.1 Hz, H-2-sugar), 4.43 (dd, 1 H, J = 8.2 and 1.5 Hz, H-4-sugar), 4.54 (dd, 1 H, J = 8.2 and 2.0 Hz, H-3-sugar), 5.04 (dt, 1 H, J = 8.4 and 3.5 Hz, H-3), 5.43 (d, 1 H, J = 4.8 Hz, H-1-sugar), 5.50 (d, 1 H, J = 8.4 Hz, H-2), 8.40 and 8.44 (2 d, 2 H, J = 4.8 Hz, H-β), 8.48 and 8.50 (2 d, 2 H, J = 4.8 Hz, H-β), 8.71 (AB, 2 H, H-β). MS (LSIMS): 1260 [M + H]⁺, 1259 [M⁺], 1031 [M - C₁₁H₁₇O₅ + H]⁺, 975 [porphyrin 5 + H]⁺. UV/Vis (CH₂Cl₂): λ_max (log ε) = 652 (4.60), 598 (3.65), 505 (4.13), 406 (5.18) nm. HRMS-FAB (exact mass): m/z calcd for C₅₈H₃₄N₅O₅F₂₀ [M + H]⁺: 1260.2235; found: 1260.2202.

18

Procedure for the Synthesis of Chlorin 11.
A solution of N-galactosyl glycine 9 (23.2 mg, 0.06 mmol) and K₂CO₃ (17.0 mg, 0.12 mmol) in toluene (2.5 mL) was stirred at r.t. during 5 min. Paraformaldehyde (5.0 mg, 0.15 mmol) and porphyrin 5 (15.0 mg, 0.015 mmol) were then added and the reaction mixture was heated at reflux, under nitrogen, during 2 h. The mixture was cooled, filtered and washed with CH₂Cl₂ (10 mL). The solvents were evaporated to dryness and the residue was purified by flash chromatography using CH₂Cl₂-EtOAc (30:1) as eluent. The unchanged starting porphyrin 5 (11.9 mg, 79%) was the first fraction, followed by chlorin 11 (3.7 mg, 19% yield).

19

Spectroscopic data for chlorin 11: ¹H NMR (300 MHz, CDCl₃): δ = -1.82 (s, 2 H, NH), 1.30, 1.39, 1.46, 1.55 (4 s, 12 H, 4 × CH₃), 2.41-2.50 (m, 2 H, H-2¹ or H-2³), 2.52 and 2.70 (2 d, 2 H, J = 12.8 Hz, CH₂-Gal), 3.34-3.39 and 3.45-3.51 (2 m, 2 H, H-2¹ or H-2³), 3.85 (d, 1 H, J = 7.6 Hz, H-5-Gal), 4.15 (d, 1 H, J = 7.6 Hz, H-4-Gal), 4.34 (dd, 1 H, J = 5.4 and 2.2 Hz, H-2-Gal), 4.59 (dd, 1 H, J = 7.6 and 2.2 Hz, H-3-Gal), 5.25-5.34 (m, 2 H, H-2, H-3), 5.57 (d, 1 H, J = 5.2 Hz, H-1-Gal), 8.41 and 8.48 (2 d, 2 H, J = 4.3 Hz, H-β), 8.52 (s, 2 H, H-12, H-13), 8.74 (AB, 2 H, H-β). MS (LSIMS): 1260 [M + H]⁺, 1259 [M⁺], 1031 [M - C₁₁H₁₇O₅ + H]⁺, 975 [porphyrin 5 + H]⁺. UV/Vis (CH₂Cl₂): λ_max
(log ε) = 651 (4.59), 597 (3.61), 504 (4.12), 406 (5.16) nm. Anal. Calcd for C₅₈H₃₃F₂₀N₅O₅: C, 55.29; H, 2.64; N, 5.56. Found: C, 55.38; H, 2.64; N, 5.77.