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14
9
1
2
8
7
12
CO2H
10
a
5
11
3
4
6
OH
OH
13
15
O
O
3
2
4
Δ
3a
4(15)
b
3b
3c
Δ
Δ4(5)
OH
OH
6
Scheme 2. Reagents and conditions: (a) (i) ClCO2Et (1.5 equiv), Et3N (1.3 equiv), THF, 0 °C, 1.5 h; (ii) NaN3 (1.7 equiv), in H2O, 0 °C, 1.5 h, and aqueous treatment then toluene,
reflux, 1.5 h; (iii) HCl/H2O; (b) (i) CH3Li; (ii) HCl/H2O.
A. F.; Duarte, C. T. M.; Delarmelina, C.; Pinheiro, B. M. L.; Trigo, R. J.; Maia, L. N.
B. H. S. Phytochemistry 2008, 69, 1895.
6. Locksley, H. D.; Fayez, M. B. E.; Radwan, A. S.; Chari, V. M.; Cordell, G. A.;
Wagner, H. Planta Med. 1982, 45, 20.
7. Nanayakkara, N. P. D.; Fang, X. D.; Phoebe, C. H. Jr.; Pezzoto, J. M.; Kinghorn, A.
D.; Farnsworth, N. R. Annual Meeting, American Society of Pharmacognosy,
Austin, Texas, August, 1984, 19.
8. Mash, E. A.; Fryling, J. A. J. Org. Chem. 1987, 52, 3000.
9. Houghton, R. P.; Humber, D. C.; Pinder, A. H. Tetrahedron Lett. 1966, 7, 353.
10. Booker-Milburn, K. I.; Cox, B.; Grady, M.; Halley, F.; Marrison, S. Tetrahedron
Lett. 2000, 41, 4651.
11. Barrero, A. F.; Herrador, M. M.; Arteaga, P.; Catalán, J. V. Eur. J. Org. Chem. 2009,
3589.
12. Máñez, S.; Recio, M. C.; Gil, I.; Gómez, C.; Giner, R. M.; Waterman, P. G.; Ríos, J.
L. J. Nat. Prod. 1999, 62, 601.
13. Al-Dissi, N. M.; Salhab, A. S.; Al-Hajj, H. A. J. Ethnopharmacol. 2001, 77, 117.
14. (a) Sanz, J. F.; Ferrando, C.; Marco, J. A. Phytochemistry 1991, 30, 3653; (b)
Figure 1. X-ray crystal structure of ketone (4) (CCDC 815548).
Grande, M.; Bellido, I. S.; Torres, P.; Piera, F. J. Nat. Prod. 1992, 55, 1074; (c)
Barbetti, P.; Chiappini, I.; Fardella, G.; Menghini, A. Planta Med. 1985, 51, 471;
(d) Ceccherelli, P.; Curini, M.; Marcotullio, M. C.; Menghini, A. Phytochemistry
1985, 24, 2987; (e) Ulubelen, A.; Oksuz, S.; Goren, N. Phytochemistry 1987, 26,
1223; (f) Rustaiyan, A.; Jakupovic, J.; Chau-Thi, T. V.; Bohlmann, F.; Sadjadi, A.
Phytochemistry 1987, 26, 260; (g) Zarga, M. H. A.; Hamed, E. M.; Sabri, S. S.;
Voelter, W.; Zeller, K. J. Nat. Prod. 1998, 61, 798; (h) Zarga, M. H. A.; Sabri, S. S.;
Hamed, E. M.; Khanfar, M. A.; Zeller, K.; Atta-ur-Rahman Nat. Prod. Res. 2003,
17, 99; (i) Fontana, G.; La Rocca, S.; Passannanti, S.; Paternostro, M. P. Nat. Prod.
Res. 2007, 21, 824.
quent treatment of ketone 3a with ethereal CH3Li yielded
smol (5), quantitatively.18
a-eude-
The synthesis of cryptomeridiol (6) was conducted following a
similar sequence from ilicic acid (2) (Scheme 2). In this case, ketone
4 was obtained in a 52% yield. A large amount of the reaction prod-
uct was lost in the form of ketones 3a–c (45% yield).19 Ketone 4
was purified by column chromatography over silica gel and its
structure was confirmed by X-ray diffraction analysis20 (Fig. 1).
Treatment of compound 4 with an excess of ethereal methyl-
lithium followed by acid hydrolysis gave cryptomeridiol (6) in
quantitative yield.
A convenient method for the extraction and isolation of isoco-
stic acid (1) and ilicic acid (2) on multigram scale from the aerial
parts of D. viscosa has been developed. Compound 1 was used for
the first time as a starting material for the three-step synthesis
15. (a) Herz, W.; Chikamatsu, H.; Tether, L. R. J. Org. Chem. 1966, 31, 1632; (b)
Geissman, T. A.; Toribio, F. P. Phytochemistry 1967, 6, 1563; (c) Toribio, F. P.;
Geissman, T. A. Phytochemistry 1969, 8, 313.
16. Typical procedure for the preparation of ketones 3a and 4:
A solution
containing 1 g of acid 1 or 2 and 1.7 equiv of Et3N in 100 mL of THF was
cooled to À10 °C. Then, 1.8 equiv of ethyl chloroformate were added and the
reaction mixture was stirred at this temperature for 1.5 h. A solution of NaN3
(1.5 equiv) in 35 mL of H2O was then added and the mixture was stirred for
1.5 h at 0 °C. The crude acyl azide product was dissolved in 50 mL of toluene
and the solution refluxed for 2 h. Acidified H2O (10% HClaq) was added and the
resulting mixture was refluxed for 2 h. The mixture was allowed to cool and
the organic layer decanted and washed with H2O (30 mL) and brine (30 mL),
dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the
corresponding ketone, which was purified by column chromatography on silica
gel.
of a-eudesmol (5) with an overall 70% yield. The same synthetic se-
quence transformed ilicic acid (2) into cryptomeridiol (6) with an
overall 52% yield.
Ketone 3a: (600 mg, 70%); MS, m/z: 206 (M+); 1H NMR (300 MHz, CDCl3, 25 °C):
d = 0.8 (3H, s, H-13), 1.17–1.38 (4H, m, H-1, H-9), 1.52 (1H, dt, J1 = 12.4Hz;
J2 = 1.2Hz, H-2), 1.63 (3H, s, H-14), 1.64–1.78 (2H, m, H-6), 1.88–1.96 (2H, m,
H-8), 2.00 (1H, m, H-5), 2.09 (1H, m, H-7), 2.17 (3H, s, H-12), 5.35 (1H, br s, H-
3); 13C NMR (75 MHz, CDCl3, 25 °C): d = 16.00 (CH3, C-13), 21.50 (CH3, C-14),
24.50 (CH2, C-8), 25.60 (CH2, C-6), 27.08 (CH2, C-2), 28.11 (CH3, C-12), 33.88 (C,
C-10), 37.26 (CH2, C-9), 39.13 (CH2, C-1), 47.12 (CH, C-5), 52.57 (CH, C-7),
121.40 (CH, C-3), 134.22 (C, C-4), 211.85 (C, C-11).
Acknowledgments
This work was supported by the Moroccan Scientific and Tech-
nical Research Center (CNRST) and RéPAM.
Ketone 4: (443 mg, 52%); MS m/z: 224 (M+); 1H NMR (300 MHz, CDCl3, 25 °C):
d = 0.90 (3H, s, H-13), 1.10 (3H, s, H-14), 1.10–1.70 (11 H, m, 2H-1, 2H-2, H-3a,
H-5
H-6
a
a
, H-6b, 2H-8, 2H-9), 1.80 (1H, d, J = 12.3 Hz, H-3
a), 1.91 (1H, d, J = 12.5 Hz,
); 13C NMR (75 MHz, CDCl3),
References and notes
), 2.10 (3H, s, H-12), 2.3 (1H, m, H-7
a
d = 18.44 (CH3, C-12), 19.96 (CH2, C-2), 22.55 (CH3, C-13), 22.85 (CH2,C-6),
23.51 (CH2, C-8), 28.15 (CH3,C-14), 34.37 (C,C-10), 40.85 (CH2, C-9), 43.23 (CH2,
C-1), 43.74 (CH2, C-3), 55.22 (CH, C-7), 53.89 (CH, C-5), 71.78 (C, C-4), 212.21
(C, C-11).
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17. Kutney, P. J.; Ashokk, K. S. Can. J. Chem. 1984, 62, 1407.
18. General method for alkylation of the ketones: 500 mg of the ketones in Et2O
(30 mL) was cooled to À10 °C and then 1.5 equiv of methyllithium (ether
5. (a) Díaz, T.; Mora, F. D.; Velasco, J.; Díaz, T.; Rojas, L. B.; Usubillaga, A.; Juan, C. A.
Nat. Prod. Commun. 2008, 3, 937–940; (b) Costa, V. E.; Teixeira, D. S.; Marques,