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K. Suzuki et al.
LETTER
(6) Jackman, L. M. Advances in Organic Chemistry, Methods
and Results, Vol. II; Raphael, R. A.; Taylor, E. C.; Wynberg,
H., Eds.; Interscience: New York, 1960, 329.
(7) Walker, D.; Hiebert, J. D. Chem. Rev. 1967, 67, 153.
(8) Becker, H.-D. Chemistry of the Quinonoid Compounds;
Patai, S., Ed.; Wiley: New York, 1974, 335.
(9) Turner, A. B. Synthetic Reagents; Pizey, J. S., Ed.; Wiley:
New York, 1977, 193.
(10) Ho, T. L. Synthesis 1973, 347.
To an acetic acid solution of O-benzylated substrate 11
was added CAN (4 equiv) and stirred at room tempera-
ture. The reaction proceeded smoothly to give a mixture
of acetoxy derivative 18 and nitrate derivative 19 which
was converted into hydroxymethyl derivative 20, respec-
tively (Scheme 2).12 The removal of the O-benzyl group
in compound 20 by hydrogenolysis under neutral condi-
tions was efficient to give 7,8-dihydroxy-5-hydroxymeth-
yl-2-phenyl-chroman-4-one (2), the aglycon of 1. The
NMR spectrum of 2 completely agreed with that of the
natural product described in a previous report.13
(11) Matsuura, S.; Iinuma, M.; Ishikawa, K.; Kagei, K. Chem.
Pharm. Bull. 1978, 26, 305.
(12) 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): d = 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): d = 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):
d = 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): d = 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).
OBn
a) 77%
b) 77%
18
19
O
O
BnO
Ph
c)
2
75%
HO
20
Scheme 2 Synthesis of 7,8-dihydroxy-5-hydroxymethyl-2-phenyl-
chroman-4-one. Reagents and conditions: a) Et3N, MeOH; b) NaNO2,
1,4-dioxane, H2O; c) H2, Pd-C, EtOH.
Thus, the first synthesis of 7,8-dihydroxy-5-hydroxy-
methyl-2-phenyl-chroman-4-one (2), the aglycon of acti-
noflavoside (1), was accomplished by the regioselective
oxidation of a methyl group at the position-5 of 7,8-diben-
zyloxy-5-methyl-2-phenyl-chroman-4-one. This route is
promising to supply 2 in short steps and to help toward the
total synthesis of 1.
References
(1) Pigman, W.; Horton, D. The Carbohydrate, Vol. IIA;
Academic Press: New York, 1970.
(2) Jiang, Z. D.; Jensen, P. R.; Fenical, W. Tetrahedron Lett.
1997, 38, 5065.
(13) Selected spectral data for synthetic aglycon 2: 1H NMR (400
MHz, CD3OD, 25 °C): d = 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): d = 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).
(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, J. F. W.; West, D. E. Org. Synth., Coll. Vol. V;
Wiley and Sons: New York, 1973, 412.
Synlett 2004, No. 1, 116–118 © Thieme Stuttgart · New York