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Synlett 2003(14): 2193-2197  
DOI: 10.1055/s-2003-42093
LETTER
© Georg Thieme Verlag Stuttgart · New York

Microwave-Assisted Synthesis of α-Amino Phosphonates Derived from Formylporphyrins of Natural Origin

Vsevolod Yu. Pavlov*a, Maria M. Kabachnikb, Elena V. Zobninab, Vladimir P. Timofeevc, Igor O. Konstantinova, Boris G. Kimeld, Gelii V. Ponomareva, Irina P. Beletskayab
a V. N. Orekhovich Institute of Biomedical Chemistry, Russian Academy of Medical Sciences, 10, Pogodinskaya Str., Moscow, 119121, Russia
Fax: +7(095)9393618; e-Mail: vyupavlov@rambler.ru;
b Department of Chemistry, M. V. Lomonosov Moscow State University, Vorobyovy Gory, Moscow, 119899, Russia
c V. A. Engelghardt Institute of Molecular Biology, Russian Academy of Sciences, 32, Vavilov Str., Moscow, 119991, Russia
d N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47, Leninsky Prospect, Moscow, 119991, Russia
Further Information

Publication History

Received 26 July 2003
Publication Date:
15 October 2003 (online)

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Abstract

The first synthesis of α-amino phosphonates comprising porphyrin core was accomplished. Three methods of obtaining α-amino phosphonates 5-8 were compared. Conventional heating of formylporphyrins 1-4 with t-BuNH2 and (EtO)2P(O)H in various solvents was ultimately unsuccessful for preparing 5-8 whereas the use of microwave irradiation made it possible to obtain 5-8 in good yields. Regioselective preparation of 5-8 in excellent yields was achieved by combining microwave-assisting conditions and catalysis with CdI2. Efficient synthetic procedures of obtaining formylporphyrins 3,4 in large scale were also proposed.

Key words

α-amino phosphonates - photodynamic therapy - protoporphyrin IX - regioselectivity - Schiff bases

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Preparation of Photoprotoporphyrins 1,2:
Porphyrin 9 (7.083 g, 12.000 mmol) was dissolved in CH2Cl2 (2 l) and placed into a 2.5 L two-necked flask fitted with oxygen inlet and effective condenser. Stream of O2 was passed slowly through the mixture for 40 min. The solution was irradiated for 22 h by using two high-pressure mercury lamps with total capacity of 1.9 kW. Further repeated chromatography on alumina [16] with gradient elution [Et2O/CH2Cl2, 3-12% (v/v)] finally provided 1 (2.391 g, 32%) and 2 (2.244 g, 30%) with recovery of unreacted 9 (2.124 g, 30%).
Photoprotoporphyrin IX Dimethyl Ester 1: 1H NMR (400 MHz, CDCl3): δ = 10.13-10.12 (d, 1 H, CHO, J = 6.2 Hz), 9.63, 9.62, 8.29, 7.64 (all s, 4 H, meso-H), 7.98-7.90 (dd, J trans = 17.7 Hz, J cis = 11.3 Hz, 1 H, 8-CH=CH2), 6.25-6.21 (dd, J gem = 0.3 Hz, 1H, trans-8-CH=CH 2), 6.15-6.12 (dd, 1 H, cis-8-CH=CH 2), 6.07-6.05 (d, 1 H, 3-CHCHO), 4.37-4.12 (m, 4 H, 2 × CH 2CH2CO2CH3), 3.71 and 3.70 (2 s, 6 H, 2 × CH2CH2CO2CH 3), 3.38, 3.28 and 2.78 (all s, 9 H, 3 × CH3-ring), 3.27-3.18 (m, 4 H, 2 × CH2CH 2CO2CH3), 1.47 (s, 3 H, 2-CH3), -3.64 and -3.99 (2 br s, 2 H, 2 × NH).
MS (ESI+): 623.4 [C36H38N4O6 + H]. UV-VIS (CHCl3): λmax/nm (ε) = 395 (88700), 422 (81800), 570 (13100), 610 (10200), 669 (37100). Anal. Calcd for C36H38N4O6: C, 69.43; H, 6.15; N, 8.99. Found: C, 69.28; H, 6.21; N, 8.90.

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Preparation of 3-Formyl-8-vinyldeuteroporphyrin IX Dimethyl Ester 3 and 8-Formyl-3-vinyldeutero-porphyrin IX Dimethyl Ester 4:
Photoprotoporphyrin IX dimethyl ester 1 (1.555 g, 2.500 mmol) was dissolved in CHCl3-MeOH [300 mL, 1:1 (v/v)] and NaBH4 (1.555 g, 41.104 mmol) was added to the solution with stirring. After 10 min reaction mixture was carefully diluted with 10% aq AcOH (400 mL) to decompose the excess of NaBH4. Stirring was continued for 15 min. The reaction mixture was diluted with CHCl3 (250 mL). The organic phase was washed with sat. aq solution of NaHCO3 (500 mL) and then with water until pH of the water phase become neutral. Organic layer was separated and evaporated to dryness. The residue was dissolved in freshly distilled 1,4-dioxane (200 mL) and poured into 200 mL of dioxane containing H5IO6 (2.945 g, 12.920 mmol). Reaction mixture was protected from light and stirred vigorously for 45 min at ambient temperature. Wet NaHCO3, prepared by mixing 6 g of NaHCO3 with 2 mL of water, was added and stirring was continued for 5 min. Then inorganic salts were removed on a glass filter under reduced pressure and 1,4-dioxane was evaporated. The remaining solid was dissolved in CHCl3 and flashed on a short column equipped with 150 g of alumina (Merck, 230-400 mesh, Brockmann Grade IV, elution with 2% Et2O in CHCl3) to yield 962 mg (65%) of porphyrin 3. Following the above method, iso-photoproto-porphyrin IX dimethyl ester 2 was converted into porphyrin 4 in 66% yield.
3-Formyl-8-vinyldeuteroporphyrin IX dimethyl ester 3: 1H NMR (400 MHz, CDCl3): δ = 11.30 (s, 1 H, CHO), 10.67, 9.92, 9.85, 9.79 (all s, 4 H, meso-H), 8.23-8.16 (dd, J trans = 17.7 Hz, J cis = 11.5 Hz, 1 H, 8-CH=CH2), 6.42-6.38 (d, 1 H, trans-8-CH=CH 2), 6.24-6.21 (d, 1 H, cis-8-CH=CH 2), 4.41-4.37 and 4.29-4.25 (2 t, 4 H, 2 × CH 2CH2CO2CH3), 3.76, 3.67, 3.65, 3.63, 3.57, 3.50 (all s, 18 H, 2 × CH2CH2CO2CH 3 and 4 × CH3-ring), 3.26-3.21 (2 overlapping t, 4 H, 2 × CH2CH 2CO2CH3), -4.01 (br s, 2 H, 2 × NH). MS (ESI+): 593.4 [C35H36N4O5 + H]. UV-VIS (CHCl3): λmax/nm (ε) = 419 (155200), 517 (11400), 557 (15100), 583 (9900), 641 (2300). Anal. Calcd for C35H36N4O5: C, 70.92; H, 6.12; N, 9.45. Found: C, 70.84; H, 6.20; N, 9.48.

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Microwave irradiation:
Appropriate aldehyde (1/2, 20.5 mg, 0.033 mmol; 3/4, 19.5 mg, 0.033 mmol), absolute ClCH2CH2Cl (4.0 mL), anhyd t-BuNH2 (0.9 mL), CdI2 (5.1 mg, 0.014 mmol) and freshly distilled (EtO)2P(O)H (0.9 mL) were placed into 25 mL flask and exposed to microwave irradiation at 102 W using domestic oven (Daewoo KOR-4125G) for 9-10 min. Solvents were completely removed at 0.1 mmHg; the residue was dissolved in CH2Cl2 and flashed on a small alumina column (Merck, 230-400 mesh, Brockmann Grade IV) eluting with CH2Cl2/Et2O/pyridine (100:5:0.5). Solvents were evaporated under reduced pressure and the respective α-amino phosphonate 5-8 was precipitated from CH2Cl2/hexane. 1H NMR, 31P NMR and microanalytical data for some newly obtained α-amino phosphonates 5-8 are as follows:
α-Amino Phosphonate Derived from Photoprotopor-phyrin IX Dimethyl Ester 5: 1H NMR (400 MHz, CDCl3): δ = 9.86, 9.67, 9.29, 9.22 (all s, 4 H, meso-H), 8.23-8.15 (dd, J trans = 17.7 Hz, J cis = 11.5 Hz, 1 H, 8-CH=CH2), 7.08-7.04 (dd, 1 H, 31-CH), 6.38-6.33 (dd, J gem = 1.4 Hz, 1 H, trans-8-CH=CH 2), 6.17-6.14 (dd, 1 H, cis-8-CH=CH 2), 5.36-5.27 (dd, 1 H, 32-CH), 4.33-4.27 [q, 4 H, 32-P(O)(OCH 2CH3)2], 4.19-4.08 (2 t, 4 H, 2 × CH 2CH2CO2CH3), 3.66 and 3.64
(2 s, 6 H, 2 × CH2CH2CO2CH 3), 3.59, 3.48, 3.40 (all s, 9 H, 3 × CH3-ring), 3.21-3.14 (2 overlapping t, 4 H, 2 × CH2CH 2CO2CH3), 2.14 (s, 3 H, 2-CH3), 1.46 [s, 9 H, 32-NHC(CH 3)3], 1.35-1.31 [t, 6 H, 32-P(O)(OCH 2CH 3)2], -2.41 -2.54 (2 br s, 2 H, 2 × NH-ring). 31P NMR (32 MHz, CDCl3): δ = 24.00 [s, 32-P(O)(OCH2CH3)2]. MS (ESI+): 816.1 [C44H58N5O8P + H]. UV-VIS (CHCl3): λmax/nm (ε) = 407 (168400), 502 (13400), 538 (11100), 604 (4300), 664 (32900). Anal. Calcd for C44H58N5O8P: C, 64.76; H, 7.16; N, 8.58. Found: C, 64.51; H, 7.09; N, 8.54.
α-Amino Phosphonate Derived from 3-Formyl-8-vinyldeuteroporphyrin IX Dimethyl Ester 7: 1H NMR (400 MHz, CDCl3): δ = 10.24, 9.99, 9.85, 9.84 (all s, 4 H, meso-H), 8.25-8.17 (dd, J trans = 17.7 Hz, J cis = 11.8 Hz, 1 H, 8-CH=CH2), 6.37-6.33 (dd, J gem = 0.5 Hz, 1 H, trans-8-CH=CH 2), 6.20-6.16 (m, 2 H, cis-8-CH=CH 2 and 31-CH), 4.34-4.28 (2 overlapping t, 4 H, 2 × CH 2CH2CO2CH3), 4.22-4.12 [2 overlapping q, 4 H, 31-P(O)(OCH 2CH3)2], 3.65, 3.65, 3.64, 3.57, 3.55, 3.52 (all s, 18 H, 2 × CH2CH2CO2CH 3 and 4 × CH3-ring), 3.23-3.19 (2 over-lapping t, 4 H, 2 × CH2CH 2CO2CH3), 1.30-1.26 [t, 6 H, 31-P(O)(OCH2CH 3)2], 1.24 and 1.23 [2 s, 9 H, 31-NHC(CH 3)3], -4.21 (br s, 2 H, 2 × NH-ring). 31P NMR (32 MHz, CDCl3): δ = 19.49 [s, 32-P(O)(OCH2CH3)2]. MS (ESI+): 729.2 [C43H56N5O7P - t-Bu + H]. UV-VIS (CHCl3): λmax/nm (ε) = 407 (164100), 503 (11500), 539 (10300), 575 (8900), 628 (3300). Anal. Calcd for C43H56N5O7P: C, 65.71; H, 7.18; N, 8.91. Found: C, 65.64; H, 7.11; N, 8.89.