First asymmetric total synthesis of novel and cytotoxic 2′-R-hydroxylanneaquinol

Article abstract of DOI:10.1016/j.tetlet.2008.09.076

A novel cytotoxic alkylated hydroquinone 2′-R-hydroxylanneaquinol (1), isolated from the organic extract of the plant Lannea welwitschii, has been synthesized for the first time using commercially available 4-methoxyphenol. The key step of this process involves the kinetic resolution of epoxide 6 using Jacobsen's reaction conditions.

Full text of DOI:10.1016/j.tetlet.2008.09.076

Tetrahedron Letters 49 (2008) 7358–7360
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Tetrahedron Letters
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First asymmetric total synthesis of novel and cytotoxic
20-R-hydroxylanneaquinol
*
V. Suresh, K. Rajesh, J. Jon Paul Selvam, Y. Venkateswarlu
Organic Chemistry Division-I, Natural Products Laboratory, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
A novel cytotoxic alkylated hydroquinone 20-R-hydroxylanneaquinol (1), isolated from the organic
extract of the plant Lannea welwitschii, has been synthesized for the first time using commercially avail-
able 4-methoxyphenol. The key step of this process involves the kinetic resolution of epoxide 6 using
Jacobsen’s reaction conditions.
Article history:
Received 12 July 2008
Revised 10 September 2008
Accepted 14 September 2008
Available online 18 September 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Dedicated to Professor A. S. R. Anjaneyulu
and Professor Goverdhan Mehta for their
encouragements and for nurturing many
students in the field of chemistry on the
occasion of Teachers’ day
Keywords:
20-R-Hydroxylanneaquinol
Jacobsen’s resolution
Asymmetric synthesis
Hydroquinone and quinone subunits feature in a variety of nat-
ural products.1 Alkylated hydroquinones exhibit many interesting
biological properties such as cytotoxic,2 antioxidant,3 antitumor,4
inhibition of HIV 1 reverse transcriptase,5 antifungal,6 and antimi-
crobial7 activities. Two novel, cytotoxic alkylated hydroquinones,
20-R-hydroxylanneaquinol 1 and lanneaquinol 2, were isolated by
Boyd and co-workers8 from the organic extract of Lannea welwit-
schii (Hiern) Engl. (family Anacardiaceae). Interestingly, both com-
pounds exhibited modest cytotoxicity against the NCI panel of 60
human tumor cells.9,10 The bark of the medicinal plant L. welwit-
schii is used to treat abdominal pain and skin ulcers and is used
to prepare ADD-199, herbal preparation11 used by some Ghanaian
patients to manage diabetes.
(1). To the best of our knowledge, there is no report on the total
synthesis of 20-R-hydroxylanneaquinol. Herein, we report the first
asymmetric total synthesis of 20-R-hydroxylanneaquinol (1) by
kinetic resolution of racemic epoxide 5 under Jacobsen’s resolution
conditions.
Our synthesis (Scheme 1) started from 2,5-dimethoxyallyl
benzene 4, which was prepared from commercially available
4-methoxyphenol 3 according to the reported procedure.12 Epoxi-
dation of the olefin moiety of 4 with m-CPBA (70%) in CH2Cl2 at
room temperature afforded the racemic epoxide 5 in 90% yield.
Compound 5 was subjected to Jacobsen’s hydrolytic kinetic resolu-
tion13 with 0.55 equiv of water using (S,S)-(salen)Co(III)(OAc) as
the catalyst to give enantiomerically pure 6 (87% ee) and diol 7
each in 47% yield. Ring opening of enantiomerically pure epoxide
6 with Grignard reagent 8 using CuI in dry THF at ꢀ78 °C afforded
The biological potential of these compounds has stimulated
significant interest in the synthesis of 20-R-hydroxylanneaquinol
OH
OH
OH
2
OH
1
OH
* Corresponding author. Tel.: +91 40 27193167; fax: +91 40 27160512.
E-mail address: luchem@iict.res.in (Y. Venkateswarlu).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.076

V. Suresh et al. / Tetrahedron Letters 49 (2008) 7358–7360
7359
OH
OH
OH
OH
OH
OH
2
1
OMe
OMe
OMe
OMe
Ref-12
a
b
OH
O
O
+
OH
OMe
OMe
OMe
3
OMe
7
OMe
6
5
4
OMe
OMe
O
O
O
O
MgBr
c
O
+
OH
OMe
6
OMe
9
8
OMe
OMe
O
O
d
OH
e
O
O
O
O
O
10
OMe
OMe
O
OMe
11
O
O
g
f
6
6
O
O
OMe
13
12
OH
h
i
6
1
O
O
OH
14
Scheme 1. Reagents and conditions: (a) m-CPBA, CH2Cl2, rt, 90%; (b) (S,S)-(salen)Co(III)(OAc), 0.55 equiv H2O, 47%; (c) CuI, THF, ꢀ78 °C, 5 h, 70%; (d) Ac2O, pyridine, DMAP
(10 mol %), CH2Cl2, rt, 95%; (e) p-TSA (10 mol %), MeOH, rt, 2 h, 98%; (f) (i) IBX, DMSO, DCM, rt, 4 h, 95%; (ii) CH3ðCH2Þ7CH2PPh þBrꢀ, n-BuLi, THF–HMPA, ꢀ78 °C, 2 h, 75%; (g)
3
CAN, 1:1 CH3CN/H2O, rt, 15 min, 85%; (h) Na2S2O4, Et2O, H2O, rt, 5 min, (80%); (i) NaOCH3, MeOH, 0 °C, 2 h, (90%).
secondary alcohol 9 in 70% yield.14 Grignard reagent 8 was
prepared by reaction of the THP ether of 5-bromo-1-pentanol
and Mg in dry THF. The THP ether of 5-bromo-1-pentanol was itself
prepared from 1,5-pentanediol. The secondary hydroxyl group in
compound 9 was acetylated using Ac2O, pyridine, and DMAP in
CH2Cl2 to afford 10 in 95% yield. Deprotection of the THP ether
10 with p-TSA in methanol afforded primary alcohol 11 in 98%
yield. The alcohol 11 was oxidized using iodoxybenzoic acid
(IBX) in dry DMSO and dry CH2Cl2 to afford the corresponding alde-
hyde in 95% yield (not isolated), which was subjected to a Wittig
olefination15 with nonyl tri phenyl phosphonium bromide in tetra-
hydrofuran–hexamethyl phosphoric acid triamide (THF–HMPA)
and n-butyllithium at ꢀ78 °C to afford Z-olefin 12 in 75% yield.
Deprotection of the two aromatic methoxy groups in 12 was
attempted using MeMgI,16 TMSI,17 NaSEt,18 BBr3,19 and PhSH/
K2CO3,20 which all gave mixtures of products. However, the
demethoxylation was achieved using CAN in 1:1 CH3CN–H2O
medium to afford 1,4-quinone 13 in 85% yield.21 Reduction of the
quinone 13 with Na2S2O4 in Et2O–H2O afforded hydroquinone 14
in 80% yield. Finally, the acetate in 14 was cleaved with NaOMe
in methanol to give the desired 20-R-hydroxylanneaquinol (1) in
90% yield. The physical and spectroscopic data22 (MS, 1H and 13C
NMR, IR, and optical rotation) of 1 were found to be identical
with those reported in the literature.8
In conclusion, we have achieved the first asymmetric total syn-
thesis of 20-R-hydroxylanneaquinol (1) from the readily available
starting material 4-methoxyphenol (3) by 10 distinct steps with
an overall yield of 13%. The synthesis involves utilization of Jacob-
sen’s hydrolytic kinetic resolution and a Wittig reaction as key
steps.
Acknowledgments
The authors are thankful to UGC, CSIR, New Delhi, Ministry of
Earth Sciences (MoES), and Department of Biotechnology (DBT)
New Delhi, India, respectively, for the financial support, and Dr.
J. S. Yadav, Director, Indian Institute of Chemical Technology (IICT)
for his encouragement.

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V. Suresh et al. / Tetrahedron Letters 49 (2008) 7358–7360
17. (a) Jung, M.-E.; Lyster, M.-A. J. Org. Chem. 1977, 42, 3761; (b) Jung, M.-E.; Lyster,
References and notes
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22. All new compounds were fully characterized on the basis of IR, 1H NMR, 13C
NMR and mass spectroscopic data. Spectral data of selected compounds:
Compound 6: pale yellow oil; ½a D25
ꢁ
+1.7 (c 2.6, CHCl3). IR (film): 2996, 2943,
;
2834, 1500, 1226, 1046, 806, 707 cmꢀ1
1H NMR (200 MHz, CDCl3): d 6.63–6.76
(m, 3H), 3.79 (s, 3H), 3.75 (s, 3H), 3.10 (m, 1H), 2.88 (dd, 1H, J = 14.0, 8.5), 2.76
(dd, 1H, J = 10.9, 5.4), 2.70 (dd, 1H, J = 5.4, 3.9), 2.49 (dd, 1H, J = 5.4, 2.3); 13C
NMR (75 MHz, CDCl3): d 153.4, 151.8, 126.8, 116.9, 111.9, 111.2, 55.9, 55.6,
51.6, 47.1, 33.4; ESIMS m/z (rel int.) 195 [M+1]. Compound 11: colour less
liquid, ½a 2D5
ꢁ
ꢀ5.71 (c 0.36, CHCl3). IR (film): 3442, 2930, 2857, 1733, 1500,
1226, 1048, 1024, 803, 709 cmꢀ1
;
1H NMR (200 MHz, CDCl3): d 6.56 (m, 3H),
5.08 (q, 1H, J = 6.6), 3.77 (s, 3H) 3.72 (s, 3H), 3.58 (t, 2H, J = 6.6), 2.86 (dd, 1H,
J = 13.9, 5.87), 2.67 (dd, 1H, J = 13.2, 7.3), 1.94 (s, 3H), 1.08–1.61 (br m, 10H);
13C NMR (75 MHz, CDCl3): d 170.6, 153.1, 152.0, 127.3, 117.4, 111.7, 111.1,
73.7, 62.8, 55.8, 55.6, 34.9, 33.7, 32.6, 29.1, 25.5, 25.2, 21.0; EIMS m/z (rel int.)
324 [M+], 264 (M–CH3COOH), 177, 151, 121. Compound 12: colour less liquid,
½
a 2D5
ꢁ
ꢀ6.2 (c 0.36, CHCl3). IR (film): 2927, 2858, 1736, 1502, 1458, 1234,
1043 cmꢀ1 1H NMR (300 MHz, CDCl3): d 6.66–6.75 (m, 3H), 5.27–5.37 (m, 2H),
;
5.11 (q, 1H, J = 6.0), 3.77(s, 3H), 3.74 (s, 3H), 2.90 (dd, 1H, J = 13.5, 5.2), 2.69 (dd,
1H, J = 13.5, 7.5), 1.96–2.04 (br m, 4H), 1.95 (s, 3H), 1.52 (2H), 1.27–1.40 (18H),
0.88 (t, 3H, J = 6.7); 13C NMR (75MHz, CDCl3): d 170.5, 153.1, 152.0, 130.0,
129.6, 127.3, 117.3, 111.7, 111.1, 73.8, 55.8, 55.6, 34.9, 33.8, 31.8, 29.7, 29.6,
29.5, 29.3, 29.2, 29.1, 27.2, 27.1, 25.2, 22.6, 21.1, 14.0; ESIMS m/z (rel int.) 455
[M+Na], 373, 268. Compound 1: white solid, ½a D25
ꢁ
+0.65 (c, 1.0, CHCl3). IR (film):
3346, 3164, 2921, 2851, 1462, 1204, 1021, 811, 722, 614 cmꢀ1
;
1H NMR
(300 MHz, CDCl3): d 7.71 (br–OH, 1H), 6.73 (d, 1H, J = 9.0), 6.57 (dd, 1H, J = 8.3,
3.0), 6.49 (d, 1H, J = 3.0), 5.33 (m, 2H), 4.96 (br–OH, 1H), 3.93 (dddd,1H, J = 12.0,
9.8, 5.2, 3.0), 2.75 (dd, 1H, J = 14.3, 3.0), 2.70 (dd, 1H, J = 14.3, 7.5), 1.92–2.04
(m, 4H), 1.70 (br s, 1H), 1.50 (m, 2H), 1.26 (br s, 17H), 0.88 (t, 3H, J = 6.7); 13C
NMR (75 MHz, CDCl3): d 149.2, 148.9, 130.2, 129.4, 126.5, 118.0, 117.8, 114.7,
74.4, 38.8, 36.9, 31.9, 29.7, 29.5, 29.4, 29.3, 29.1, 29.0, 27.2, 27.0, 25.5, 22.6,
14.0; HREIMS m/z: found 385.27 [M+Na] C23H38O3.
14. (a) Ramu, E.; Bhaskar, G.; Venkateswara Rao, B.; Ramanjaneyulu, G. S.
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