Selective 3- and 6-OH modification of (-)-clausenamide

Article abstract of DOI:10.1016/j.cclet.2011.01.026

(-)-Clausenamide is a drug candidate under Phase I clinical trial for treatment of Alzheimer's disease (AD). In order to elucidate the substituent related structure-activity relationship, six one-substituent modified (-)-clausenamide analogues were designed, and four of them, namely 3-O-methyl, 6-O-methyl, 3-des-hydroxyl and 6-des-hydroxyl analogues were prepared by selective 3- and 6-OH modification of (-)-clausenamide.

Full text of DOI:10.1016/j.cclet.2011.01.026

Available online at www.sciencedirect.com
Chinese Chemical Letters 22 (2011) 761–764
www.elsevier.com/locate/cclet
Selective 3- and 6-OH modification of (ꢀ)-clausenamide
*
Jian Jun Xue, Xiao Ming Yu
Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
Received 29 November 2010
Available online 17 April 2011
Abstract
(ꢀ)-Clausenamide is a drug candidate under Phase I clinical trial for treatment of Alzheimer’s disease (AD). In order to elucidate
the substituent related structure–activity relationship, six one-substituent modified (ꢀ)-clausenamide analogues were designed, and
four of them, namely 3-O-methyl, 6-O-methyl, 3-des-hydroxyl and 6-des-hydroxyl analogues were prepared by selective 3- and 6-
OH modification of (ꢀ)-clausenamide.
# 2011 Xiao Ming Yu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: (ꢀ)-Clausenamide; Derivatives; Synthesis; Alzheimer’s disease
Racemic clausenamide ((ꢁ)-1, Fig. 1) is a natural product isolated from aqueous extract of the leaves of Clausena
lansium (Lour) skeels [1]. The racemate showed remarkable nootropic activity in a number of in vivo biological tests,
but the levo rotatory enantiomer, ((ꢀ)-clausenamide 1, Fig. 1), was eventually found to be the active isomer [2,3].
Presently, this chiral compound is under clinical trial for treatment of Alzheimer’s disease. In order to get the insight
view of stereochemistry related structure–activity relationship (SAR), all 16 stereoisomers of (ꢀ)-1 were prepared and
their biological activities evaluated in an earlier study [4].
As the molecule of (ꢀ)-clausenamide is featured not only with the four chiral centers but also with the four
substituents: 3-OH, 6-OH, 4-Ph and 6-Ph, it is interesting to find how the presence of these substituents is related to its
biologicalactivity. Inordertogetthisquestionanswered, sixone-substituentmodified(ꢀ)-clasuenamideanalogues(2–5,
6 and 7, Fig. 1) were designed. In this letter, we describe the preparation of compound 2–5, using (ꢀ)-clausenamide as
starting material since it provides the fastest access to the target molecules in the forms of pure enantiomers.
Compound 2 and 3 are simple mono-O-methylated derivatives of (ꢀ)-1. Because the 3-OH of (ꢀ)-1 is trans to both
C4 and C5 substituents and less hindered, compound 2 was expected to be prepared by selective 3-O-methylation of
the starting material. After screening of several commonly used O-methylation conditions including MeI/NaH in
DMF, MeI/K2CO3 in acetone and Me2SO4/KOH in toluene/H2O, reaction under the last biphasic condition was found
to give the best result, and (ꢀ)-1 was converted into compound 2 as single product in excellent yield (90%)
(Scheme 1). This encouraged us to go one step further to carry out the 3-OH selective protection of (ꢀ)-1 with TBS
under classic silylation condition [5], and compound 8 was isolated in 81% yield. Subsequent 6-OH methylation of 8
followed by release of the 3-OH with TBAF afforded compound 3 in 65% yield over two steps (Scheme 1).
* Corresponding author.
E-mail address: mingxyu@imm.ac.cn (X.M. Yu).
1001-8417/$ – see front matter # 2011 Xiao Ming Yu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2011.01.026

7[()TD$FIG] 62
J.J. Xue, X.M. Yu / Chinese Chemical Letters 22 (2011) 761–764
Fig. 1. (ꢀ)-Clausenamide and designed derivatives.
[()TD$FIG]
Scheme 1. Synthesis of 2 and 3. Reagents and conditions: (a) Me2SO4/KOH in toluene/H2O; (b) TBSCl/imidazole; (c) MeI/NaH; (d) TBAF.
In our initial plan (Scheme 2), an S-methyl xanthate mediate dehydroxylation was designed as the first step to
realize the transformation of 8 into compound 4. Unfortunately, treatment of 8 with CS2/NaH and MeI failed to give 9.
Therefore, an alternative plan en route intermediate 10 was proposed. Compound 8 was thus treated with POCl3/Py, a
commonly used dehydration reagent [6], but afforded an unexpected product 11, which was believed to form from
double bond migration of the original elimination product 10 in 87% yield. To our delight, when the TBS group was
removed by treatment of 11 with TBAF, the location of C C double bond switched back to C5–C6 with the restoration
of R configuration at C4 [7], and 12 was isolated in 77% yield. With intermediate 12 in hand, a variety of
hydrogenation conditions were tested, and the reaction in anhydrous THF with Raney Ni as catalyst was found to give
the optimal yield of 4 (74% after crystallization of the crude product from ethyl acetate).
Similar to that of 4, synthesis of 5 was also started with intermediate 8, which was first treated with benzyl bromide/
NaH to have the 6-OH protected, and then with TBAF to remove the 3-O-TBS group to give key intermediate 13 in
[()TD$FIG]
OTBS
O
OTBS
O
OH
a
H
H
O
N
N
N
S
O
HO
Me
Me
Me
SMe
8
9
4
b
d
OH
OTBS
OTBS
4
4
4
c
5
5
5
O
O
N
N
O
6
6
N
6
Me
Me
Me
11
12
10
Scheme 2. Synthesis of 4. Reagents and conditions: (a) 1—NaH, imidazole; 2—CS2; 3—MeI; (b) POCl3/Py; (c) TBAF; (d) 10% Pd/C, H2.

[()TD$FIG]
J.J. Xue, X.M. Yu / Chinese Chemical Letters 22 (2011) 761–764
763
S
O
OH
O
OTBS
O
H
a, b
S
Me
c
H
H
O
N
N
N
BnO
Me
BnO
HO
Me
Me
14
8
13
d
f
H
H
H
+
e
O
O
O
N
N
Me
N
BnO
BnO
HO
Me
Me
5
15
16
Scheme 3. Synthesis of 5. Reagents and conditions: (a) NaH, BnBr; (b) TBAF; (c) 1—NaH, imidazole; 2—CS2; 3—MeI; (d) ((n-Bu)4N)2S2O8,
HCOONa; (e) T-1 Raney Ni, H2; (f) 10% Pd/C, H2.
63% yield over two steps (Scheme 2). Unlike compound 8, conversion of 13 into the corresponding S-methyl xanthate
proved to be easy and 14 was isolated in 78% yield. Treatment of S-methyl xanthate 14 with sodium formate in the
presence of ((n-Bu)4N)2S2O8 as radical initiator [8] afforded an inseparable 1:1 [9] mixture of dehydroxylation
product 16 and elimination product 15 in a total yield of 66%. Raney Ni catalyzed hydrogenation of this mixture,
during which compound 15 was saturated with the incoming hydrogen atoms attacking the less hindered a face, gave
16 in pure form in 91% yield. Deprotection of 6-OH was then furnished by palladium catalyzed hydrogenolysis of 16
to afford target molecule 5 in 96% yield (Scheme 3).
In conclusion, a small library consists of six one-substituent modified (ꢀ)-clausenamide analogues was designed as
probe for structure–activity relationship elucidation, and four members possessing retained carbon skeletons were
synthesized in optical active form by selective OH modifications using readily available (ꢀ)-clausenamide as starting
material [10]. It was demonstrated for the first time that the steric hindrance margin between the 3- and 6-OH in the
molecule of (ꢀ)-clausenamide provided a sufficiently wide open window for manipulation of OH protective groups.
Des-hydroxyl modifications to the 6- or 3-OH could then be carried out by adoption of an elimination–hydrogenation
sequence or an S-methyl xanthate mediated dehydroxylation procedure, respectively. Synthesis of the other two
library members, 6 and 7, as well as the results from biological studies on the nootropic effect of compound 2–7 will be
published separately.
Acknowledgment
This project was financially supported by Natural Science Foundation of China (No. 30672530).
References
[1] M.H. Yang, Y.H. Cao, W.X. Li, et al. Acta Pharmacol. Sin. 22 (1) (1987) 33.
[2] W. Hartwig, L. Born, J. Org. Chem. 52 (1987) 4352.
[3] J.T. Zhang, X.Y. Jiang, Collection of the Academic Papers of Scientific Annual Meeting of Peking Union Medical College, Beijing Medical
University & Peking Union Medical College Publishing House, Beijing, 1994, 356.
[4] Z. Feng, X. Li, G. Zheng, et al. Bioorg. Med. Chem. Lett. 19 (8) (2009) 2112.
[5] E.J. Corey, A. Venkateswarlu, J. Am. Chem. Soc. 94 (17) (1972) 6190.
[6] W.G. Dauben, G.A. Boswell, J. Am. Chem. Soc. 83 (24) (1961) 5003.
[7] The trans geometry between 3-OH and 4-Ph was validated by 1H NMR of 12; (S)-(ꢀ)-O-actylmandelation of compound 4 was carried out later
and only one product was detected by 1H NMR of the reaction mixture, therefore the possible C-3 epimerization could be precluded.

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J.J. Xue, X.M. Yu / Chinese Chemical Letters 22 (2011) 761–764
[8] H.S. Park, H.Y. Lee, Y.H. Kim, Org. Lett. 7 (15) (2005) 3187.
[9] The proportions of the two compounds were determined by 1H NMR of the mixture.
20
[10] Analytical data for compounds 2–5. Compound 2: mp: 191.0–191.9 8C; ½aꢂD ꢀ184.3 (c 1.07, CHCl3); 1H NMR (300 MHz, CDCl3): d 2.84 (s,
3H), 3.55 (s, 3H), 3.83 (d, 1H, J = 9.0 Hz), 3.81 (dd, 1H, J = 9.0, 8.7 Hz), 4.15 (dd, 1H, J = 4.2, 8.7 Hz), 4.75 (d, 1H, J = 4.2 Hz), 6.85–7.37 (m,
10H); 13C NMR (100 MHz, DMSO-d6): d 172.7, 140.9, 135.7, 128.6, 127.6, 127.2, 126.4, 126.3, 77.4, 71.1, 65.2, 57.3, 47.3, 29.5; FT-IR
(cmꢀ1): 1681.1; EI-MS (m/z, %): 312 (M++1, 2), 204 (100), 176 (100); HRMS (M++H) calcd. for C19H21NO3 312.1600, found 312.1590;
20
Compound 3: mp: 157.5–58.4 8C; ½aꢂD ꢀ146.4 (c 1.11, CHCl3); 1H NMR (300 MHz, DMSO-d6): d 2.71 (s, 3H), 2.77 (s, 3H), 3.55 (dd, 1H,
J = 11.1, 8.1 Hz), 3.77 (dd, 1H, J = 6.3, 11.1 Hz), 4.12 (d, 1H, J = 4.2 Hz), 4.25 (dd, 1H, J = 4.2, 8.1 Hz), 5.44 (d, 1H, J = 6.3 Hz), 6.68–7.38
(m, 10H); 13C NMR (100 MHz, DMSO-d6): d 174.1, 137.1, 136.2, 128.6 ꢃ 2, 127.9, 126.6, 82.6, 68.3, 63.7, 55.9, 49.5, 30.6; FT-IR: 1672.6;
EI-MS (m/z, %): 312 (M+ + 1, 2), 191 (84), 162 (96), 134 (100); HRMS (M++H) calcd. for C19H21NO3 312.1600, found 312.1517; Compound
20
4: mp: 143.3–144.0 8C; ½aꢂD ꢀ267.4 (c 0.87, CHCl3); 1H NMR (300 MHz, CDCl3): d 2.44 (dd, 1H, J = 8.1, 14.1 Hz), 2.62 (s, 3H), 2.64 (dd,
1H, J = 4.2, 14.1 Hz), 3.73 (dd, 1H, J = 8.1, 10.8 Hz), 4.04 (ddd, 1H, J = 8.1, 8.1, 4.2 Hz), 4.59 (d, 1H, J = 10.8 Hz), 6.83–7.42 (m, 10H); 13C
NMR (100 MHz, CDCl3): d 174.3, 137.6, 135.9, 129.1, 128.8, 128.5, 128.1, 127.4, 126.7, 70.0, 63.0, 51.7, 37.0, 30.3; FT-IR (cmꢀ1): 1763.4,
1603.4; MS (m/z, %): 281 (M+, 1), 190 (100), 91 (85); HRMS (M++H) calcd. for C18H20NO2 282.1488, found 282.1489; Compound 5: mp:
20
104.5–105.8 8C; ½aꢂD ꢀ119.7 (c 0.8, CHCl3); 1H NMR (300 MHz, CDCl3): d 2.35 (d, 2H, J = 9.9), 2.75 (s, 3H), 3.92 (dd, 1H, J = 9.9, 7.8 Hz),
4.15 (dd, 1H, J = 5.1, 7.8, 3.9 Hz), 4.73 (d, 1H, J = 5.1 Hz), 6.91–7.40 (m, 10H); 13C NMR (100 MHz, CDCl3): d 174.7, 139.7, 137.0, 128.7,
128.3, 128.27, 127.5, 127.3, 73.7, 68.8, 41.9, 33.7, 30.9; FT-IR (cmꢀ1): 1671.5, 1602.6, 1484.9; FAB-MS (m/z, %): 282 (M++1, 100); HRMS
(M+ + 1): calcd. for C18H20NO2 282.1494, found 282.1501.