Rapid construction of the tricyclic cores of the abietane- and icetexane-type diterpenoids

Article abstract of DOI:10.1016/j.cclet.2011.01.009

A short synthesis of the tricyclic 6-6-6 and 6-7-6 ring systems of the abietane- and icetexane-type diterpenoids from a common intermediate is presented, using alkylation and acid-catalyzed cyclization as key steps.

Full text of DOI:10.1016/j.cclet.2011.01.009

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Chinese Chemical Letters 22 (2011) 774–776
www.elsevier.com/locate/cclet
Rapid construction of the tricyclic cores of the
abietane- and icetexane-type diterpenoids
*
De Lin Chen, Xiao Yu Liu, Hang Cheng, Feng Peng Wang
Department of Chemistry of Medicinal Natural Products, West China College of Pharmacy,
Sichuan University, Chengdu 610041, China
Received 3 November 2010
Available online 17 April 2011
Abstract
A short synthesis of the tricyclic 6–6–6 and 6–7–6 ring systems of the abietane- and icetexane-type diterpenoids from a common
intermediate is presented, using alkylation and acid-catalyzed cyclization as key steps.
# 2011 Feng Peng Wang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Abietanes; Icetexanes; Alkylation; Cyclization
The diterpenoids are a big family of natural products, which exhibited a variety of structural types and biological
activities. Among them, the abietanes are a group of diterpenoids bearing a tricyclic 6–6–6 framework, while the 6–7–
6 rings of icetexanes are believed to arise from the abietanes through an oxidative-induced rearrangement in Nature
[1]. Most of the compounds in the two types have an aromatic C ring (or the quinone form) in common. Some selected
abietane- and icetexane-type diterpenoids are listed in Fig. 1.
The compounds of the two classes isolated to date have showed diverse array of structures and intriguing biological
activities, which in turn have generated significant interests from the synthetic community [1–6]. In this letter, we
report an efficient approach of constructing the tricyclic 6–6–6 and 6–7–6 cores of abietane- and icetexane-type
diterpenoids from a common intermediate, using alkylation and acid-catalyzed cyclization as the key steps.
First of all, our synthetic efforts focused on the preparation of the key intermediate 8, as shown in Scheme 1. The
sequence started with aromatic alkene 5, which was conveniently prepared in large scale by known procedures [7].
After cleavage of the terminal alkene in 5, the aldehyde was subsequent reduced to alcohol, which was then converted
to iodide 6 using Ph3P/I2. The anion of N-cyclohexylidenecyclohexylamine (7) was prepared with lithium
diisopropylamide (LDA), and alkylated with iodide 6 to furnish the key intermediate 8 in 93% yield, after hydrolysis of
the resulting imine with oxalic acid.
With the intermediate 8 in hand, we first investigated its cyclization under acidic conditions. Gratifying, treatment
of 8 with 1 mol/L HCl in THF under reflux (Scheme 2), a new product with strong fluorescence was obtained (88%),
whose structure was finally established as the tricyclic 9 [8].
* Corresponding author.
E-mail address: wfp@scu.edu.cn (F.P. Wang).
1001-8417/$ – see front matter # 2011 Feng Peng Wang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2011.01.009

D.L. Chen et al. / Chinese Chemical Letters 22 (2011) 774–776
775
In order to synthesize the tricyclic 6–7–6 ring system of icetexane-type diterpenoids, one more carbon must be
incorporated into the ring B. As described in Scheme 3, the carbonyl group was first homologated utilizing the Wittig
[()TD$FIG]
O
OH
O
O
O
OH
H
H
OH
abietane skeleton
salviphlomone (1)
royleanone (2)
O
OMe
OH
O
O
H
H
OH
komaroviquinone (4)
icetexane skeleton
isopisiferin (3)
[()TD$FIG]
Fig. 1. Selected abietane- and icetexane-type diterpenoids.
OMe
OMe
a, b, c
MeO
I
OMe
OMe
OMe
OMe
O
OMe
OMe
d
5
6
N
8
7
Scheme 1. Preparation of the key intermediate 8. Conditions and reagents: (a) O3, CH2Cl2, À78 8C; then PPh3, 0 8C, 58%; (b) NaBH4, MeOH, rt,
75%; (c) I2, PPh3, imidazole, CH2Cl2, rt, 92%; (d) LDA, 7, 0 8C, then 6, À20 8C; oxalic acid, THF, rt, 93%.
protocol. Methyl enol ether was generated from 8 with the in situ formed Wittig reagent Ph3P CHOCH3, which could
be transformed to the aldehyde as a pair of inseparable isomers, after the treatment of 1 mol/L HCl. Epimerization was
then tested under acidic and basic conditions. Exposure of 10 with mild acids generally resulted in a new product,
which was confirmed to be the cyclized isomers. On the other hand, base treatment can give the thermodynamic stable
trans isomer. After careful optimization, the trans/cis ratio can reach 7:1 using 4 equivalents of NaOMe in MeOH–
THF (2:1) at 40 8C for 24 h. Finally, the tricyclic 12 [9] with 6–7–6 framework of icetexanes was yielded smoothly
[()TD$FIG]
from the intermediate 11, treating with 1 mol/L HCl in THF.
MeO
MeO
OMe
OMe
O
OMe
OMe
a
9
8
Scheme 2. Construction of the 6–6–6 core of the abietanes. Conditions and reagents: (a) 1 mol/L HCl, THF, reflux, 88%.

7[()TD$FIG] 76
D.L. Chen et al. / Chinese Chemical Letters 22 (2011) 774–776
MeO
CHO
MeO
O
OMe
OMe
OMe
a, b
c
OMe
10
8
MeO
MeO
CHO
OMe
OMe
OMe
OMe
d
H
12
11
Scheme 3. Synthesis of the 6–7–6 system of the icetexanes. Conditions and reagents: (a) Ph3PCH2OCH3Cl, t-BuOK, rt; (b) 1 mol/L HCl, THF–H2O
(3:1), 55 8C, 3 h, two steps 87%; (c) NaOMe, MeOH–THF (2:1), 40 8C; (d) 1 mol/L HCl, THF, reflux, 85%.
In summary, we have described an efficient and rapid approach of constructing the tricyclic 6–6–6 and 6–7–6 cores
of abietane- and icetexane-type diterpenoids from a common intermediate 8, using alkylation and acid-catalyzed
cyclization as key steps. This short synthesis may produce a feasible way to design analogues for a structure–activity
relationship study; further work will focus on this aspect and on the synthesis of a fully functionalized icetexane
diterpenoid through the strategy shown in this letter.
Acknowledgments
We are grateful for the financial support provided by the National Science Foundation of China (No. 30873147).
References
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[8] Compound 9: colorless needle crystals, mp 99–100 8C, IR (KBr): 2929, 1595, 1488, 1463, 1319, 1080 cmÀ1; 1H NMR (400 MHz, CDCl3): d
1.62–1.68 (m, 4H), 1.96 (t, 2H, J = 8.0 Hz), 2.19 (s, 2H), 2.53 (s, 2H), 2.66 (t, 2H, J = 7.6 Hz), 3.72 (s, 3H), 3.78 (s, 3H), 3.86 (s, 3H), 6.38 (s,
3H); 13C NMR (100 MHz, CDCl3): d 22.01 (CH2), 22.95 (CH2), 23.97 (CH2), 28.40 (CH2), 31.26 (CH2), 55.79 (CH3), 56.23 (CH3), 60.58 (CH3),
119.73 (CH), 127.28 (C), 132.23 (C), 133.07 (C), 139.50 (C), 150.93 (C), 152.72 (C). HR-ESIMS: m/z: C17H23O3 [M+H]+ 275.1637 (calcd.
275.1647).
[9] Compound 12: colorless needle crystals, mp 93–95 8C, IR (KBr): 2927, 1592, 1481, 1465, 1340, 1092 cmÀ1; 1H NMR (400 MHz, CDCl3): d
3.09 (dd, 1H, J = 14.4, 9.8 Hz), 3.68 (s, 3H), 3.82(s, 3H), 3.86 (s, 3H), 6.34 (s, 1H), 6.53 (s, 1H); 13C NMR (100 MHz, CDCl3): d 24.0 (CH2), 26.3
(CH2), 28.5 (CH2), 35.2 (CH2), 35.4 (CH2), 40.3 (CH2), 45.6 (CH), 55.8 (CH3), 56.1 (CH3), 61.1 (CH3), 94.5 (CH), 115.4 (CH), 118.1 (C), 137.7
(C), 139.2 (C), 144.8 (C), 151.2 (C), 153.4 (C). HR-ESIMS: m/z: C18H25O3 [M+H]+ 289.1799 (calcd. 289.1804).