Synthesis of hedychenone, yunnancoronarins and aframodial derivatives

Article abstract of DOI:10.1016/j.tetlet.2005.01.053

Starting with larixol, syntheses of furan and 1,4-enedial labdane-type diterpenes are presented, which has enabled a preparation of hedychenone (20% yield).

Full text of DOI:10.1016/j.tetlet.2005.01.053

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1713–1716
Synthesis of hedychenone, yunnancoronarins and
aframodial derivatives
Jamila Aslaoui, Haibing Li and Christophe Morin*
´
LEDSS-UMR 5616 (ICMG-IFR 2607), Universite Joseph Fourier BP 53, F-38041 Grenoble Cedex 9, France
Received 8 December 2004; revised 5 January 2005; accepted 11 January 2005
Available online 28 January 2005
This paper is dedicated to the memory of F. Aslaoui
Abstract—Starting with larixol, syntheses of furan and 1,4-enedial labdane-type diterpenes are presented, which has enabled a
preparation of hedychenone (20% yield).
Ó 2005 Elsevier Ltd. All rights reserved.
Extracts of Zingiberacaea, one of the major tropical plant
families, have long been used in traditional medicine1 and
their examination has resulted in the isolation of labdanes
such as the biogenetically-related coronarin E (1) and
aframodial (2).2,3 In particular, the rhyzomes4 of Hedych-
ium spicatum, H. yunnanense, H. coronarium and H. for-
restii were found to contain bioactive hedychenone (3)
yunnancoronarins A (4) and D (5);5–7 the structures of
these labdanes have been established by spectroscopic
methods8 and that of hedychenone confirmed by radio-
crystallographic analysis;9 in this work we disclose the
synthesis of 3–5 as well as a compound related to 2.
At first larixol (6), a labdane which is readily available
from larch oleoresin,10 was converted into the aldehyde
7
11 by a three-steps transformation based on an osmium
tetroxide/sodium periodate oxidation sequence;12 pro-
tection of the hydroxyl group as a silyl ether was
O
CHO
CHO
O
aframodial (2)
coronarin E (1)
O
O
O
OH
O
OH
yunnancoronarin A (4)
O
hedychenone (3)
yunnacoronarin D (5)
Keywords: Terpenes; Labdanes; Natural products; Hedychenone.
*
Corresponding author. Tel.: +33 0 476 514250; +33 0 476 514956; e-mail: Christophe.Morin@ujf-grenoble.fr
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.01.053

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J. Aslaoui et al. / Tetrahedron Letters 46 (2005) 1713–1716
followed by elimination of the tertiary acetate by use of
2,4,6-collidine;13 that the double bond was exo was
revealed by the presence of two vinylic protons (singlets
at 4.8 and 4.55 ppm). Then, addition of 3-furyl lithium14
to the aldehydic group of 8 afforded a ca. 1:1 mixture of
epimeric alcohols, which without separation, were mesyl-
ated in the presence of 2,6-lutidine; this gave the elimina-
tion product 9 with the desired trans-configuration
(J = 16 Hz). Cleavage of the silyl ether followed by oxi-
dation then afforded 10. This intermediate gives access
to both hedychenone (3), after isomerization, and yun-
nancoronarin A (4) after reduction with diisobutylalu-
minum hydride which, for steric reasons, occurs from
the alpha side (Scheme 1).
With a preparation of hedychenone in hand, a shorter
route based on the preferential reaction of an aldehyde
group (over a ketone) was explored (Scheme 2); after
CHO
CHO
OH
i
ii
OAc
OH
OH
OSi
6
7
8
iii
O
O
3
4
v
iv
OSi
O
vi
9
10
Scheme 1. Reagents and conditions: (i) Ref. 11 (50%); (ii) (1) Et3SiCl, DMAP cat, py, 8 h (94%), (2) 2,4,6-collidine as solvent, 170 °C, 12 h (79%); (iii)
(1) 3-furyllithium, À78 °C, 2 h (68%), (2) 2,6-lutidine (7 equiv), CH2Cl2, add MsCl (3 equiv), rt, 18 h (68%); (iv) (1) AcOH, THF–H2O (5:1:3), rt,
overnight (95%), (2) IBX (3 equiv) AcOEt, 60 °C, 3 h (85%); (v) MeONa (0.2 M in MeOH), 2 h (quant); (vi) THF, À78 °C, Dibal-H (6 equiv), 2 h
(95%).
O
CHO
i
ii
iii
7
5
O
O
11
hedychenone (3)
iv
COOCH3
COOCH3
COOCH3
CHO
CHO
(C6H5)3P=
COOCH3
v
OAc
OH
12
OH
OH
13
14
Scheme 2. Reagents and conditions: (i) (1) IBX (3 equiv), AcOEt, 70 °C, 3 h (84%); (2) 2,4,6-collidine, 160 °C, 2 h (90%); (ii) (1) 3-furyllithium,
À78 °C, (2) 2,6-lutidine, MsCl (59%, two steps); (iii) (1) SeO2 (1.5 equiv), dioxane, 80 °C—8 h; (2) NaBH4, EtOH, À78 °C (60% two steps); (iv) 12
(65%); (v) LAH, then IBX (56% overall), see Ref. 21.

J. Aslaoui et al. / Tetrahedron Letters 46 (2005) 1713–1716
1715
16, 64–68; Zhao, Q.; Hao, X.-J.; Chen, Y.-Z.; Zou,
C.; Hong, X. Acta Bot. Sinica 1999, 41, 528–530;
Yunnancorronarin D: Zou, C.; Zhao, Q.; Hao, X.;
Chen, Y.; Hong, X. Acta Bot. Yunnanica 1999, 21, 253–
255.
oxidation of 7 followed by conjugation of the exo dou-
ble bond, enone 11 was obtained.15 Pleasingly, the addi-
tion of 3-furyl lithium occurred preferentially on its
aldehyde group to afford 3 after mesylation/elimina-
tion.16 Hedychenone (3), identical to that prepared
according to Scheme 1, is now obtained in four steps
from 7 (22% overall yield from larixol).
9. Liu, X.-H.; Wang, W.; He, Z.-D.; Wang, H.-Q.; Yang,
C.-R.; Chen, B. Acta Crystallogr. Sect. C, Cryst. Struct.
Commun. 1999, C55.
10. Mills, J. S. Phytochemistry 1973, 12, 2407–2412.
11. Lagnel, B. M. F.; Morin, C.; de Groot, A. Synthesis 2000,
1907–1916; Bolster, M. G.; Jansen, B. J. M.; de Groot, A.
Tetrahedron 2001, 57, 5663–5679.
12. The work of S. Proskow on the oxidative degradation of
sclareol has remained unpublished but is quoted in: Corey,
E. J.; Sauers, R. R. J. Am. Chem. Soc. 1959, 81, 1739–
1743; for a mechanism see: Barrero, A. F.; Alvarez-
Manzaneda, E. J.; Altarejos, J.; Salido, S.; Ramos, J. M.
Tetrahedron 1993, 49, 10405–10412.
13. Barrero, A. F.; Manzaneda, E. A.; Altarejos, J.; Salido, S.;
Ramos, J. M.; Simmonds, M. S. J.; Blaney, W. M.
Tetrahedron 1995, 51, 7435–7450.
14. Prepared by lithiation (n-BuLi, THF, À78 °C, 15 min) of
3-bromofuran, which is expensive but can be prepared;
see: Kraus, G. A.; Wang, X. Synth. Commun. 1998, 28,
1093–1096.
Yunnancoronarin D (5) could be synthesized from
hedychenone in only two steps: oxidation of the allylic
methyl group, followed by reduction of the aldehyde
group thus formed (Scheme 2); as other yunnancorona-
rins have been obtained by photooxydation17 of hedy-
chenone, this work also constitutes their formal
preparation. Finally, the availability of 7 led us to con-
sider introduction of the 1,4-enedial (3-formyl-3-bute-
nal) structural unit as this pharmacophore is found in
a number of bioactive terpenoids.18 Reaction of ylide
1219 with 7 afforded 13 (only the E isomer was ob-
tained);20 reduction of 13, followed by selective oxida-
tion21 then afforded the desired 1,4-enedial 1422
(Scheme 2).
15. This material should be prepared freshly before use;
characteristic spectroscopic data: 1H NMR (300 MHz,
CDCl3) d: 9.89 (s, 1H, CHO), 5.78 (large s, 1H, H-7); 13C
NMR (75 MHz, CDCl3) d: 200.8 (C@O); 199.4(CHO);
155.9 (C-8); 128.9 (C-7).
Acknowledgements
MNRT (to J.A.) and EGIDE (to H.L.) fellowships are
gratefully acknowledged.
16. This step was carried out as in Scheme 1 (e.g., 8 to 9) but
without purification of the intermediates.
17. Zhao, Q.; Hao, X. J.; Chen, Y. Z.; Zou, C. Chin. Chem.
Lett. 1996, 7, 25–28.
References and notes
18. For a review on biologically active unsaturated 1,4-
dialdehydic terpenoids, see: Jonassohn, M.; Sterner, O.
Trends Org. Chem. 1997, 6, 23–43.
1. Pancharoen, O.; Prawat, U.; Tuntiwachwuttikul, P. Stud.
Nat. Prod. Chem. 2000, 23(Part D), 797–865.
2. Jung, M.; Ko, I.; Lee, S. J. Nat. Prod. 1998, 61, 1394–
1396; Jung, M.; Ko, I.; Lee, S.; Choi, S. J.; Youn, B. H.;
Kim, S. K. Bioorg. Med. Chem. Lett. 1998, 8, 3295–3298;
19. Compernolle, F.; Joly, G.; Peeters, K.; Toppet, S.;
Hoornaert, G.; Kilonda, A.; Babady-Bila Tetrahedron
1997, 53, 12739–12754; For use of this ylide with a
drimane keto aldehyde, see: Kim, T. H.; Isoe, S. J. Chem.
Soc., Chem. Commun. 1983, 730–731.
Muller, M.; Schro¨der, J.; Magg, C.; Seiffert, K. Tetrahe-
¨
dron Lett. 1998, 39, 4655–4656; Nozawa, M.; Ono, E.;
Akita, H. Heterocycles 2000, 53, 1811–1819; Villamizar, J.;
Fuentes, J.; Salazar, F.; Tropper, E.; Alonso, R. J. Nat.
Prod. 2003, 66, 1623–1627; Villamizar, J.; Salazar, F.;
Fuentes, J.; Tropper, E.; Alonso, R. J. Chem. Res. (S).
2003, 504–506; Oh, S.; Jeong, I. H.; Shin, W.-S.; Lee, S.
Bioorg. Med. Chem. Lett. 2003, 13, 2009–2012.
20. This configuration was assigned after observation of a
NOE effect between H-11 and H-14.
21. IBX/AcOEt was used under the conditions described by:
More, J. D.; Finney, N. S. Org. Lett. 2002, 4, 3001–3003,
6-keto by-products are obtained but the overall yield of
the reaction scheme is fair enough to avoid a protection/
deprotection sequence of the secondary hydroxyl group
(OH-6).
3. Itokawa, H.; Morita, H.; Katou, I.; Takeya, K.; Caval-
heiro, A. J.; De Oliveira, R. C. B.; Ishige, M.; Motimode,
M. Planta Med. 1988, 54, 311–315; Nyasse, B.; Lenta-
Ndjakou, B. Pharmazie 2000, 55, 703–704.
4. Srimal, R. C.; Sharma, S. C.; Tandon, J. S. Ind. J.
Pharmacol. 1984, 16, 143–147; For a review about
chemical and pharmacological studies on diterpenoids
from Hedychium see: Zhao, Q.; Zou, C.; Hao, X.; Chen,
Y. Tianran Chanwu Yanjiu Yu Kaifa 1999, 11, 85–91.
5. Morikawa, T.; Matsuda, H.; Sakamoto, Y.; Ueda, K.;
Yoshikawa, M. Chem. Pharm. Bull. 2002, 50, 1045–1049;
Matsuda, H.; Morikawa, T.; Sakamoto, Y.; Toguchida, I.;
Yoshikawa, M. Heterocycles 2002, 56, 45–50.
22. Under Ar, to a solution of 7 (167 mg, 0.539 mmol) in dry
toluene (3 mL) was added ylide 1218 (875 mg, 2.16 mmol,
4equiv) and the mixture was heated at 115 °C for 72 h.
After cooling and evaporation of the volatiles the residue
was purified by column chromatography on silica gel
(cyclohexane/AcOEt 8:2) to afford 13 (oil, 158 mg,
0.361 mmol, 67%) which was then added as a THF
solution (2 mL) to a suspension of LiAlH4 (10 equiv) in
dry THF (4mL) at 4 °C. After 12 h stirring at rt the
solution was cooled to 4 °C and 1 M aqueous HCl was
added before extractive work-up with ethyl acetate. After
evaporation of the volatiles, the residue was taken-up in
ethyl acetate (4mL) and IBX (prepared according to
Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994, 35,
8019–8022) (4equiv) added before stirring 4h at 60 °C.
After cooling and evaporation of the volatiles, column
chromatography (cyclohexane/AcOEt 6:4) afforded 14 in
56% yield. 1H NMR (300 MHz, CDCl3) d: 9.69 (s, 1H,
H-16); 9.45 (large s, 1H, H-15); 7.01 (t, J14À15 = 7 Hz, 1H,
6. Zhao, Q.; Hao, X. J.; Chen, Y. Z.; Zou, C. Acta Pharm.
Sinica 1995, 30, 119–122.
7. Matsuda, H.; Morikawa, T.; Sakamoto, Y.; Toguchida, I.;
Yoshikawa, M. Bioorg. Med. Chem. 2002, 10, 2527–2534.
8. Hedychenone: Sharma, S. C.; Tandon, J. S.; Uprety,
H.; Shukla, Y. N.; Dhar, M. M. Phytochemistry 1975,
14, 1059–1061; Yunnancorronarin A: Zhao, Q.; Hao,
X.-J.; Chen, Y.-Z.; Zou, C. Chem. J. Chin. Univ. 1995,

1716
J. Aslaoui et al. / Tetrahedron Letters 46 (2005) 1713–1716
H-12); 4.10 (m, 1H, H-6); 3.45 and 3.55 (AB system,
39.4(C-1); 39.0 (C-10); 35.8 (C-1)4; 32.3 (C-18); 29.6
(C-4); 25.9 (C-11); 22.4, 21.9 (C-19, C-17); 18.0 (C-2); 16.3
(C-20). For data on aframodial: see: Kimbu, S. F.; Njimi,
T. K.; Sondengam, L.; Akinniyi, J. A.; Connoly, J. D.
J. Chem. Soc., Perkin Trans. 1 1979, 1303–1305.
JAB = 16 Hz, 2H, H-14); 1.53 (s, CH3-17); 1.21, 0.95, 0.84
(3 s, CH3-18, -19, -20). 13C NMR (75 MHz, CDCl3) d:
198.3 (C-16); 193.3 (C-15); 160.4(C-12); 133.8 (C-13); 76.0
(C-8); 66.4 (C-6); 62.2 (C-9, C-5); 42.5 (C-7); 40.8 (C-3);