A new shortcut synthesis route for (±)raphidecursinol

Article abstract of DOI:10.1016/j.cclet.2009.10.027

The new shortcut synthesis route of (±)raphidecursinol 1, a racemic 8,4′-oxyneolignan compound, can be more easily achieved by the synthesis route, starting from readily available inexpensive 3,4,5-trimethoxy-benzaldehyde and 1,2,3-trihydroxybenzene. All structures were confirmed by ¹H NMR, IR and MS.

Full text of DOI:10.1016/j.cclet.2009.10.027

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Chinese Chemical Letters 21 (2010) 127–130
www.elsevier.com/locate/cclet
A new shortcut synthesis route for (ꢀ)raphidecursinol
*
Hua Jie Yuan, Yao Yao Cheng, Shan Qian, Xiang Xiao, Yong Wu
Key Laboratory of Drug Targeting of Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
Received 2 July 2009
Abstract
The new shortcut synthesis route of (ꢀ)raphidecursinol 1, a racemic 8,40-oxyneolignan compound, can be more easily achieved
by the synthesis route, starting from readily available inexpensive 3,4,5-trimethoxy-benzaldehyde and 1,2,3-trihydroxybenzene. All
1
structures were confirmed by H NMR, IR and MS.
# 2009 Yong Wu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: 8,40-Oxyneolignan; Raphidecursinol; Racemic compound
Raphidecursinol, isolated from myristicaceae and other primitive plant families in neotropical regions, is a natural
8,40-oxyneolignan compound, which displays interesting and varied biological properties spanning from anti-malarial
[1–3] to anti-fungal [4], anti-leishmanial [5], anti-oxidant [6], and anti-schistosomial [7] activities. However,
obtaining supplies from nature is an arduous task due to the scarce quantity of isolable compounds and the fact that
most of the isolated neolignans reported present themselves as racemic mixtures [8,9]. Therefore, it has attracted
continued interest to develop a convenient total synthesis route to obtain the natural 8,40-oxyneolignan compound and
more optical derivates.
Lee and Ley [10] reported the preparation of the target compound 1. However, this approach was not economical
because it included the application of costly enzyme and polymer catalyst. Recently, Claudio et al. [11] have used (S)-
methyl lactate as start material to synthesize 1. But this route was also too complicated and the ee% was poor. Because
of favorable biological activity of 1, we want to search for a potential total synthesis route and modify its structure to
discover more potential derivatives. Herein, we have reported a new efficient shortcut synthesis route for 1.
As shown in Scheme 1, we believed that the target compound 1 could be derived from the activated
methanesulfonate 2 or 3 and phenol 4. If successful, this approach would enable us to introduce different substituents
as hydroxyl derivatives at a late stage of the synthesis and thereby facilitate the preparation of this series of analogues.
The synthesis of the two parts has been shown respectively in Schemes 2 and 3.
The synthesis method of new compound 2 has been shown in Scheme 2. Knoevenagel reaction of 3,4,5-
trimethoxybenzaldehyde 5 with malonic acid led to acid 6. In the reduction from 6 to 7, we first tried to get 7 by
esterifying 6 followed by reduction with LiAlH4 [12]. However, it failed to get the target compound. Instead of 7,
unsatisfied saturated compound 3-(3,4,5-trimethoxyphenyl)-propan-1-ol was unexpectedly generated. Then acid 6
* Corresponding author.
E-mail address: tgxx903@163.com (Y. Wu).
1001-8417/$ – see front matter # 2009 Yong Wu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2009.10.027

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H.J. Yuan et al. / Chinese Chemical Letters 21 (2010) 127–130
Scheme 1. The retrosynthesis route of the compound 1.
Scheme 2. The synthetic route of key compound 2. Condition and regent: (a) pyridine, piperidine, malonic acid, 120 8C, 6 h, 80%; (b) i: SOCl2,
CH2Cl2, r.t., 12 h; ii: NaBH4, THF, CH3OH, 4 h, 86% in two steps; (c) VO(acac)2, TBHP, CH2Cl2, r.t., 2 h, 75%; (d) benzoic acid, titanium
tetraisopropoxide, CH2Cl2, 0 8C, 3 h, 85%; (e) 2,2-dimethoxypropane, pyridine, TsOH, CH3CN, 40 8C, 3 h, 90%; (f) K2CO3, MeOH, H2O, r.t., 4 h,
95%; (g) i: 4-methoxybenzylchloride, NaH, DMF, r.t., 2 h; ii: THF, 2 mol/L HCl, r.t., 3 h, 70% in two steps; (h) TsCl, pyridine, 0 8C, 18 h, 71%; (i)
LiAlH4, THF, 4 h, r.t., 81%; (j) Et3N, CH2Cl2, MsCl, 1 h, r.t., 80%.
Scheme 3. The synthetic route of key compound 4. Condition and regent: (a) CH3I, 6 h, 80%; (b) AlCl3, CH2Cl2, r.t., 12 h, 82%; (c) 3-bromopropene
K2CO3, CH2Cl2, r.t., 2 h, 75%; (d) 170 8C, 20 h, 85%.

H.J. Yuan et al. / Chinese Chemical Letters 21 (2010) 127–130
129
Scheme 4. The synthesis strategy of the compound 19.
was chlorinated with SOCl2 to give the activated chloride derivative, which was easily reduced to give alcohol 7 by the
method reported by Kang and Lee [13]. Alcohol 7 was oxidized under the effectiveness of VO(acac)2 catalyst to give
the racemic epoxy derivative 8 [14]. Besides, the optical epoxide 8 could also be obtained under the standard sharpless
condition. On the whole, this method can efficiently get more analogues and optical derivatives. Compound 8 was
substituted regioselectivity by benzoic acid under the effectiveness of titanium tetraisopropoxide by ring cleavage to
obtain diol 9. Diol 9 was protected by 2,2-dimethoxypropane to get 10, followed by hydrolysis to get alcohol 11. 11
was substituted by 4-methoxybenzylchloride under the effectiveness of NaH, then deprotected isopropylidene group
to obtain diol 12. 12 was esterified regioselectivity with TsCl in pyridine to get alcohol 13, followed by reduction with
LiAlH4 to give alcohol 14. Secondary alcohol 14 can be converted with MsCl to obtain key intermediate 2 by
methylsulfonylation.
The synthetic route of compound 4 has been shown in Scheme 3. By modifying the method reported by Jing and
Wang [15], the treatment of 1,2,3-trihydroxybenzene 15 with CH3I afforded the corresponding trimethylated product
16, which was regioselectively demethylated by AlCl3 to get dimethylated product 17. 17 was first converted to give 18
by reaction with 3-bromopropene, then followed by rearrangement at 170 8C to get the key intermediate 4.
The etherification reaction between 2 and 4 has been investigated. We have probed different etherification methods
in the experiment. Cs2CO3, K2CO3, etc., have been employed to promote the etherification. Unfortunately, as shown in
Scheme 4, all tested conditions failed to give any desired product 19, owing to the stereospecific blockade of 1-
methoxy-4- benzyl of 2 when effected by attack of 4-allyl-2,6-dimethoxyphenol 4.
Therefore, the stepwise transformation of 1-methoxy-4-benzyl compound 2 into the known acetyl compound 3 [11]
was investigated alternatively by the deprotection under the effectiveness of DDQ, then esterification with AcCl,
which is outlined in Scheme 5.
With key intermediates 3 and 4 in hand [16], we can easily get the target compound 1 by the method reported by
Claudio et al. [11], which is outlined in Scheme 6.
In summary, we have provided a new shortcut synthesis route, starting from readily available and inexpensive 3,4,5-
trimethoxybenzaldehyde and 1,2,3-trihydroxybenzene, for the preparation of (ꢀ)raphidecursinol. The studies for
optical compounds and synthesis of derivatives are underway.
Scheme 5. The synthetic route of key point compound 3. Condition and regent: (a) DDQ, CH2Cl2, r.t., 18 h, 90%; (b) AcCl, CH2Cl2, Et3N, DMAP,
r.t., 6 h, 83%.

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H.J. Yuan et al. / Chinese Chemical Letters 21 (2010) 127–130
Scheme 6. The synthetic route of target compound 1. Condition and regent: (a) Cs2CO3, 18-crown-6, DMF, sonication, then MW (200 W, 2 bar,
120 8C, 10 min), 72%; (b) NaOMe, MeOH, 99%.
Acknowledgment
The financial support from the National Natural Science Foundation of China (No. 29972013) is gratefully
acknowledged.
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[16] All new compounds were characterized by elemental analysis, IR, MS and 1H NMR spectra data. Selected analytical data: 2: 1H NMR
(400 MHz, CDCl3): d 7.22 (dd, 2H, J = 6.4, 2.0 Hz), 6.88 (dd, 2H, J = 6.4, 2.0 Hz), 6.54 (s, 2H), 4.79 (m, 1H) 4.43 (d, 1H, J = 11.2 Hz), 4.21–
4.27 (m, 2H), 3.87 (s, 9H), 3.81 (s, 3H), 2.92 (s, 3H), 1.06 (dd, 2H, J = 6.4, 57.2 Hz); MS (EI): 441.15 (M+) IR (KBr/cmꢁ1): 3415, 2931, 2873,
1612, 1511, 1350, 1245, 1120, 1085, 987, 819, 782, 531, 507; (Found: C, 57.31; H, 6.38. Calcd. for C20H18O8 C, 57.26; H, 6.41%). 3: 1H NMR
(400 MHz, CDCl3): d 6.55(d, 2H, J = 2 Hz), 5.70 (d, 1H, J = 7.2 Hz), 4.99 (qd, 1H, J = 6.2, 4.8 Hz), 3.87 (s, 6H), 3.83 (s, 3H), 2.91 (s, 3H), 2.16
(s, 3H), 1.06 (dd, 3H, J = 6.4, 57.2 Hz); MS(EI): 363.10 (M+) IR (KBr/cmꢁ1): 2950, 2870, 1750, 1609, 1511, 1487, 1411, 1351, 1304, 1271,
1250, 1220, 1130, 1063, 987, 819, 803, 760, 713, 531, 507. (Found: C, 49.66; H, 6.25. Calcd. for C15H22O8S C, 49.71; H, 6.12%); 4: 1H NMR
(400 MHz, CDCl3): d 6.41 (s, 2H), 5.93 (m, 1H), 5.38 (s, 1H), 5.05–5.11 (m, 2H), 3.88 (s, 3H), 3.32 (d, 2H, J = 6.8 Hz), 2.16 (s, 3H), 1.06 (dd,
3H, J = 6.4, 57.2 Hz); MS (EI):195.07 (M+) IR (KBr/cmꢁ1): 3550, 2980, 2890, 1610, 1510, 1463, 1412, 1351, 1220, 1100, 921, 850, 855
(Found: C, 68.08; H, 7.23. Calcd. for C11H14O3 C, 68.02; H, 7.27%).