Synthesis of 7,8-Dihydroxy-5-hydroxymethyl-2-phenyl-chroman-4-one; the Aglycon of Actinoflavoside

Abstract

The first synthesis of 7,8-dihydroxy-5-hydroxymethyl-2-phenyl-chroman-4-one, the aglycon part of a new-type glucoside, actinoflavoside, was accomplished. The regioselective oxidation of the methyl group at the 5-position in 7,8-dihydroxy-5-methyl-2-phenyl-chroman-4-one derived from 3,4,5-trimethoxytoluene was performed by use of ammonium cerium(VI) nitrate (CAN).

flavanon - natural product - oxidation - CAN - DDQ

References

1 Pigman W. Horton D. The Carbohydrate   Vol. IIA:  Academic Press; New York: 1970. 

2 Jiang ZD. Jensen PR. Fenical W. Tetrahedron Lett.  1997,  38:  5065 

3

Compound 2 was reported as a recemic form. [2] Actinoflavoside 1 was also isolated as a 1:1 diastereomeric mixture. It is not to be denied completely that isomerization of 1 occurred in the process of isolation.

4 Reichel L. Proksch G. Liebigs Ann. Chem.  1971,  745:  59 

5 McOmie JFW. West DE. Org. Synth., Coll. Vol. V   Wiley and Sons; New York: 1973.  p.412 

6 Jackman LM. Advances in Organic Chemistry, Methods and Results   Vol. II:  Raphael RA. Taylor EC. Wynberg H. Interscience; New York: 1960.  p.329 

7 Walker D. Hiebert JD. Chem. Rev.  1967,  67:  153 

8 Becker H.-D. Chemistry of the Quinonoid Compounds   Patai S. Wiley; New York: 1974.  p.335 

9 Turner AB. Synthetic Reagents   Pizey JS. Wiley; New York: 1977.  p.193 

10 Ho TL. Synthesis  1973,  347 

11 Matsuura S. Iinuma M. Ishikawa K. Kagei K. Chem. Pharm. Bull.  1978,  26:  305 

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To an HOAc solution (100 mL) of 7,8-di-benzyloxy-5-methyl-2-phenyl-chloman-4-one (11) (500 mg, 1.11 mmol) was added CAN (2.4 g, 4.44 mmol). The mixture was stirred for 12 h at r.t., then neutralized with 1 M NaOH. A solution was diluted with CH₂Cl₂ and washed with H₂O. The organic layer was dried over MgSO₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography (benzene:acetone = 99:1) to afford 7,8-di-benzyloxy-5-acetoxymethyl-2-phenyl-chloman-4-one (18) (303 mg, 54%) and 7,8-di-benzyloxy-5-nitroxymethyl-2-phenyl-chloman-4-one (19) (79 mg, 14%), respectively. Compound 18. ¹H NMR (400 MHz, CDCl₃, 25 °C): δ = 7.20-7.48 (m, 15 H, Ph), 6.74 (s, 1 H, H-6), 5.52 (q, 2 H, J = 15.4 Hz, H-11), 5.39 (dd, 1 H, J = 2.9, 12.8 Hz, H-2), 5.22, 5.05 (each s, 4 H, benzyl), 3.01 (dd, 1 H, J = 16.7, 12.8 Hz, H-3a), 2.86 (dd, 1 H, J = 16.7, 2.9 Hz, H-3b), 2.11 (s, 3 H, Ac). ¹³C NMR (100 MHz, CDCl₃, 25 °C): δ = 191.8, 170.4, 157.1 (C-9), 156.9 (C-8), 138.7, 137.2, 136.2, 135.6 (C-7), 135.4 (C-10), 128.7, 128.5, 128.2, 128.1, 128.0, 127.2, 125.9, 113.3 (C-5), 106.1 (C-6), 79.2 (C-2), 75.3, 70.9, 64.8 (C-11), 45.5 (C-3), 21.0. Compound 19. ¹H NMR (400 MHz, CDCl₃, 25 °C):
δ = 7.20-7.44 (m, 15 H, Ph), 6.72 (s, 1 H, H-6), 5.88 (q, 2 H, J = 15.0 Hz, H-11), 5.39 (dd, 1 H, J = 3.2, 13.2 Hz, H-2), 5.20, 5.05 (each s, 4 H, benzyl), 3.03 (dd, 1 H, J = 16.9, 13.2 Hz, H-3a), 2.88 (dd, 1 H, J = 16.9, 3.2 Hz, H-3b). ¹³C NMR (100 MHz, CDCl₃, 25 °C): δ = 192.0, 157.2 (C-9), 157.1 (C-8), 138.4, 137.0, 136.5 (C-7), 135.7, 131.5 (C-10), 128.8, 128.7, 128.6, 128.5, 128.3, 128.2, 128.1, 127.4, 126.0, 113.4 (C-5), 106.7 (C-6), 79.3 (C-2), 75.3, 72.7 (C-11), 71.0, 45.3 (C-3).

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Selected spectral data for synthetic aglycon 2: ¹H NMR (400 MHz, CD₃OD, 25 °C): δ = 7.23-7.45 (m, 5 H, Ph), 6.67 (s, 1 H, H-6), 5.50 (dd, 1 H, J = 3.1, 12.1 Hz, H-2), 4.69 (q, 2 H, J = 15.2 Hz, H-11), 3.08 (dd, 1 H, J = 16.7, 12.1 Hz, H-3a), 2.82 (dd, 1 H, J = 16.7, 3.1 Hz, H-3b). ¹³C NMR (100 MHz, CD₃OD, 25 °C): δ = 194.8 (C-4), 153.5 (C-9), 153.2 (C-8), 140.4, 137.8 (C-10), 133.1 (C-7), 129.7, 129.7, 127.5, 112.9 (C-5), 110.0 (C-6), 80.8 (C-2), 64.4 (C-11), 46.1 (C-3).