A practical total synthesis of (+)-isogalbulin and (+)-galbulin

Article abstract of DOI:10.1016/j.tetlet.2014.09.090

A practical total synthesis of the natural products (+)-isogalbulin and (+)-galbulin has been achieved in 10 steps from readily available 3-(3,4-dimethoxyphenyl)propanoic acid. The total yields were 12.3% and 12.9%, respectively. The key steps involved Ev

Full text of DOI:10.1016/j.tetlet.2014.09.090

Accepted Manuscript
A practical total synthesis of (+)-isogalbulin and (+)-galbulin
Xiaoyu Li, Xiaozhen Jiao, Xiaoyu Liu, Chengsen Tian, Liang Dong, Yangyang
Yao, Ping Xie
PII:
S0040-4039(14)01605-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.09.090
TETL 45184
Reference:
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19 July 2014
15 September 2014
19 September 2014
Please cite this article as: Li, X., Jiao, X., Liu, X., Tian, C., Dong, L., Yao, Y., Xie, P., A practical total synthesis
of (+)-isogalbulin and (+)-galbulin, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.09.090
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Graphical Abstract
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A practical total synthesis of (+)-isogalbulin
and (+)-galbulin
Leave this area blank for abstract info.
Xiaoyu Li, Xiaozhen Jiao, Xiaoyu Liu, Chengsen Tian,
Liang Dong, Yangyang Yao, Ping Xie*

1
Tetrahedron Letters
j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m
A practical total synthesis of (+)-isogalbulin and (+)-galbulin
Xiaoyu Li, Xiaozhen Jiao, Xiaoyu Liu, Chengsen Tian, Liang Dong, Yangyang Yao, Ping Xie*
State key laboratory of Bioactive Substance and Function of Natural Medicine, Beijing Key Laboratory of Active Substance Discovery and Drugability
Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, No1, xiannongtan st., Beijing 100050, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A practical total synthesis of the natural products (+)-isogalbulin and (+)-galbulin has been
achieved in ten steps from readily available 3-(3,4-dimethoxyphenyl)propanoic acid. The total
yields were 12.3% and 12.9% respectively. The key steps involved Evans asymmetric
alkylation, Sharpless asymmetric epoxidation, and a highly regioselective opening of 1-
benzyloxy-2,3-epoxides with an organoaluminum ate-complex formed by Me3Al and n-BuLi.
Available online
Keywords:
(+)-isogalbulin
(+)-galbulin
Evans asymmetric alkylation
Sharpless asymmetric epoxidation
bimolecular nucleophilic substitution
2014 Elsevier Ltd. All rights reserved.
(+)-Isogalbulin (1) and (+)-galbulin (2) (Figure 1), which were
isolated from Himantandra baccata and Himantandra
belgraveana[1] belong to the category of tetrahydronaphthalene
lignans. Lignans, especially those with 1-arylnaphthalen
skeleton, possess a series of biological activities such as anti-
HIV, anti-tumor[2], anti-Parkinson’s disease and anti-Alzheimer’s
disease[3]. In addition, a recent study revealed that isogalbulin
could significantly increase osteoblast differentiation, and might
possess therapeutic potentials for osteoporosis[4]. In spite of the
particularly important pharmacological properties, efforts for
their synthetic study are scarce. Only a few synthesis of the
Figure 1. (+)-isogalbulin (1) and (+)-galbulin (2)
6
racemic isogalbulin and galbulin were reported[5-9]. Perry[
]
According to the retrosynthetic analysis (Figure 2), (+)-
isogalbulin (1) could be prepared by the intramolecular Friedel–
Crafts cyclization of diarylbutane alcohol 12[6]. In turn, the
compound 12 could be accessed from the nucleophilic addition
reaction of (3,4-dimethoxyphenyl)lithium and aldehyde 11. The
key intermediate 11 might be formed via attack of epoxide 7 with
Me3Al and subsequently treatment with NaIO4, while the
intermediate 7 could be obtained via the Sharpless asymmetric
epoxidation. Obviously, we could obtain the compound 6 by the
Wittig reaction of compound 4 and reduction. The aldehyde 4
could be prepared from compound 3, which should be available
through Evans asymmetric alkylation reaction from the
commercially available materials following a protocol previously
reported[10]. Likewise, the analysis of (+)-galbulin (2) can employ
a similar synthetic strategy.
described the synthesis of isogalbulin using an acid-catalyzed
cyclization of 1,4-bis(3,4-dimethoxyphenyl)-2,3-dimethylbutan-
1-ol. Most recently, Whitby[7] and co-workers had completed the
total synthesis of ( )-isogalbulin and ( )-galbulin via zirconium-
promoted cyclization of 1,7-dienes[7]. Charlton[8] and co-workers
detailed another synthetic route of ( )-galbulin in 2001[8]. The
key step in their total synthesis is acid-catalyzed cyclization of
2,3-dibenzylidenesuccinates. The only asymmetric total synthesis
of (+)-galbulin (2) was presented by Bor-Cherng Hong[9]. Their
synthetic work utilized organocatalytic domino Michael–
Michael–aldol condensation and organocatalytic kinetic
resolution as the key steps[9]. Herein, we would like to report a
practical total synthesis of (+)-isogalbulin (1) and (+)-galbulin
(2).

2
Tetrahedron Letters
Figure 2, Retrosynthetic analysis of (+)-isogalbulin (1) and (+)-galbulin (2)
Scheme 1. Preparation of 10 and 16. Reagents and conditions: (a) DIBAL-H, CH2Cl2, −78°C, 80%; (b) Ph3P=CHCO2Me, toluene,
CH2Cl2, 50 °C , 89%; (c) DIBAL-H, CH2Cl2, 0°C, 87%; (d) Ti(O-iPr)4, D-(-)-DIPT, TBHP, 4Å MS, CH2Cl2, −78°C to -23°C, 81%; (e)
Ti(O-iPr)4, L-(+)-DIPT, TBHP, 4Å MS, CH2Cl2, −78°C to -23°C, 85%; (f) Me3Al, CH2Cl2, 0°C.
The synthesis of (+)-isogalbulin (1) began with compound 3
(Scheme 1) which was readily prepared from commercially
available 3-(3,4-dimethoxyphenyl)propanoic acid via Evans
epoxide 7 in good yield and diastereoselectivity (80%, de 92/8)
as shown in Scheme 1. The de% could be further improved to
99.7% by converting to their corresponding 3,5-
dinitrobenzoate[17] ester after epoxidation, followed by
chromatography purification (for 7) or recrystallization (for 13)
and subsequent hydrolysis. With the intermediate 7 in hand, we
initially planned to prepare 10 (Scheme 1) by attacking the
epoxide 7 with Me3Al directly[18]. Unfortunately, complex
mixtures were generated under the conditions.
asymmetric alkylation reaction according to
a
literature
procedure[10,11]. Direct reduction of compound 3 with DIBAL-H
provided the corresponding aldehyde 4[12]. The Wittig reaction
was employed to convert aldehyde 4 into α,β-unsaturated ester
5[13] followed by reduction with DIBAL-H to afford alcohol 6[14]
.
The Sharpless asymmetric epoxidation[15,16] of allylic alcohol 6
using D-(-)-DIPT, Ti(O-iPr)4 and TBHP in CH2Cl2 furnished the
Scheme 2. The synthesis of (+)-isogalbulin (1). Reagents and conditions: (a) NaH, Bu4NI, THF, BnBr, 90%; (b) Me3Al-n-BuLi(2:1),
toluene, −78°C to rt, 77%; (c) H2, Pd(OH)2, MeOH/CH3COOH(2:1), rt, 2 h, 90%; (d) NaIO4, THF/H2O(2:1), rt, 71%; (e) n-BuLi, THF,
−78°C, 75%; (f) HF-pyridine, CH3CN, rt, 75%.

3
Scheme 3. The synthesis of (+)-galbulin (2). Reagents and conditions: (a) NaH, Bu4NI, THF, BnBr, 92%; (b) Me3Al-n-BuLi(2:1),
toluene, −78°C to rt, 76%; (c) H2, Pd(OH)2, MeOH/CH3COOH(2:1), rt, 2 h, 93%; (d) NaIO4, THF/H2O(2:1), rt, 72%; (e) n-BuLi, THF,
−78°C, 73%; (f) HF-pyridine, CH3CN, rt, 72%.
2.
3.
4.
5.
Ayres D. C.; Loike J. D. Lignans: chemical, biological andclinical
properties, Cambridge University Press, 1990.
Ma, C. J.; Kim, S. R.; Kim, J.; Kim, Y. C. Brit. J. Pharmacol. 2005,
146(5), 752.
Lee, M. K.; Yang, H.; Ma, C.J.; Kim, Y. C. Biol. Pharm. Bull. 2007,
30(4), 814.
(a) Muller, A.; Vajda, M. J. Org. Chem. 1952, 17, 800; (b) Carnmalm,
B. Acta Chem. Scand. 1954, 8, 1827; (c) Schrecker, A. W.; Hartwell, J.
L. J. Am. Chem. Soc. 1955, 77, 432; (d) Birch, A. J.; Milligan, B.;
Smith, E.; Speake, R. N. J. Chem. Soc. 1958, 4471; (e) Crossley, N. S.;
Djerassi, C. J. Chem. Soc. 1962, 1459; (f) Biftu, T.; Hazra, B. G.;
Stevenson, R.; Williams, J. R. J. Chem. Soc., Perkin Trans. 1 1978,
1147; (g) Liu, J. S.; Huang, M. F.; Gao, Y. L.; Findlay, J. A. Can. J.
Chem. 1981, 59, 1680; (h) Landais, Y.; Lebrun, A.; Lenain, V.; Robin,
J. P. Tetrahedron Lett. 1987, 28, 5161; (i) Buckleton, J. S.; Cambie, R.
C.; Clark, G. R.; Craw, P. A.; Rickard, C. E. F.; Rutledge, P. S.;
Woodgate, P. D. Aust. J. Chem. 1988, 41, 305.
After many failed attempts, we decided to use Pfalts’s method,
thus the hydroxyl group of epoxy alcohol 7 was protected as
benzyl ether 8 (Scheme 2). But, under Pfalts’s condition[19a]
,
using Me3Al in the presence of catalytic amounts of butyllithium
proved to be unsatisfactory with our substrate as the substrate
was not completely consumed. It was then observed that the ratio
of Me3Al and n-BuLi is critical, and a condition (Me3Al/n-
BuLi=2:1) which Flippin used in related study on the 1-
(benzyloxy)-3,4-epoxyhexane[19b]
system
could
highly
regioselectively open the epoxide core of intermediate 8[20] to
provide alcohol 9 as a single epimer in 5 hours. The latter was
deprotected over Pd(OH)2 to afford the diol 10[21], which was
followed by oxidative cleavage with NaIO4 to give aldehyde
11[18,22]. Then, treatment of compound 11 with aryllithium,
formed in situ from 4-Bromoveratrole and n-BuLi, gave the
diarylbutane alcohol 12. Finally, we smoothly obtained (+)-
isogalbulin (1)[23] exclusively by stirring alcohol 12 at room
temperature with HF-pyridine, through the cyclisation of
6.
7.
8.
9.
Perry, C. W.; Kalnins, M. V.; Deitcher, K. H. J. Org. Chem. 1972, 37,
4371.
Kasatkin, A. N.; Checksfield, G.; Whitby, R. J. J. Org. Chem. 2000,
65, 3236.
Datta, P. K.; Yau, C.; Hooper, T. S.; Yvon, B. L.; Charlton J. L. J. Org.
Chem. 2001, 66, 8606.
carbocation [5d, 5e, 6, 24]
.
Similarly, the total synthesis of (+)-galbulin (2)[25] could be
achieved via the Sharpless asymmetric epoxidation of compound
6 induced by L-(+)-DIPT and followed above synthetic strategy
(Scheme 3). The 1H-NMR, 13C-NMR, optical rotations, MS data
and physical properties of synthetic (+)-isogalbulin (1) and (+)-
Hong, B. C.; Hsu, C. S.; Lee, G. H. Chem. Commun. 2012, 48, 2385.
10. So, M.; Kotake, T.; Matsuura, K.; Inui, M.; Kamimura, A. J. Org.
Chem. 2012, 77, 4017.
11. Prashad, M.; Kim, H. Y.; Har, D.; Repic, O.; Blacklock, T. J.
Tetrahedron Lett. 1998, 39, 9369.
12. Compound 4: [α]2D0 -0.492° (C 0.54, CHCl3); 1H NMR (CDCl3, 400
MHz) δ 9.72 (s, 1H), 6.81-6.79 (d, J = 8.0 Hz, 1H), 6.72-6.70 (d, J =
8.0 Hz, 1H), 6.69 (s, 1H), 3.87 (s, 3H), 3.86 (s, 3H), 3.05-3.00 (dd, J =
13.5, 5.9 Hz, 1H), 2.68-2.63 (m, 1H), 2.60-2.54 (dd, J = 13.5, 8.2 Hz,
1H), 1.11-1.09 (d, J = 6.9 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ
204.5, 148.9, 147.6, 131.3, 121.0, 112.1, 111.2, 55.9, 55.8, 48.1, 36.3,
13.2; HR-MS (ESI) calcd for C12H16O3Na (M+Na)+: 231.09971, Found
231.09869.
galbulin (2) were consistent with reported data[5c, 5g, 9]
.
In summary, an efficient strategy for the synthesis of (+)-
isogalbulin (1) and (+)-galbulin (2) has been successfully
achieved in 10 steps from a common intermediate. The total
yields were 12.3% and 12.9% respectively. The principal features
of our synthetic strategy include using Evans asymmetric
alkylation, Sharpless asymmetric epoxidation reaction, and a
highly regioselective bimolecular nucleophilic substitution as the
key steps. This method might be of great value in terms of
simplicity and efficiency in elaboration of natural products which
possess 1-arylnaphthalen carbon skeleton.
13. Compound 5: [α]2D0 +54.0° (C 0.50,CHCl3); 1H NMR (CDCl3, 400
MHz) δ 6.98-6.93 (dd, J=15.6, 6.4 Hz, 1H), 6.79-6.77 (d, J = 8.0 Hz,
1H), 6.68-6.66 (d, J = 8.0 Hz, 1H), 6.64 (s, 1H), 5.76-5.72 (d, J = 15.6
Hz, 1H), 3.86 (s, 6H), 3.71 (s, 3H), 2.70-2.67 (m, 1H), 2.60-2.52 (m,
1H), 1.06-1.05 (d, J = 6.1 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ
167.1, 153.8, 148.6, 147.3, 132.0, 121.0, 119.5, 112.3, 111.0, 55.8,
55.7, 51.4, 42.0, 38.3, 18.7; HR-MS (ESI) calcd for C15H20O4Na
(M+Na)+: 287.12538, Found 287.12454.
14. Compound 6: [α]2D0 +34.71° (C 0.53, CHCl3); 1H NMR (CDCl3, 400
MHz) δ 6.79-6.77 (d, J = 8.1 Hz, 1H), 6.68-6.66 (m, 2H), 5.69-5.64
(dd, J = 15.5, 6.3 Hz, 1H), 5.60-5.54 (m, 1H), 4.08-4.06 (d, J = 5.5 Hz,
2H), 3.87 (s, 3H), 3.86 (s, 3H), 2.65-2.60 (m, 1H), 2.50-2.41 (m, 2H),
1.00-0.99 (d, J = 6.4 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 148.5,
147.1, 138.0, 133.1, 127.4, 121.0, 111.0, 63.6, 55.8, 55.7, 42.8, 38.0,
19.5; HR-MS (ESI) calcd for C28H41O6 (2M+H)+: 473.28977, Found
473.28979.
Acknowledgment
We are grateful to Professor Jiangong Shi and Ying Guo for
helpful discussions.
Supplementary data
Supplementary data (experimental procedures and analytical
data for all the new compounds) associated with this article can
be found, in the online version, at
15. Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, Y. S.; Masamune, H.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765.
16. Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 101, 5974.
17. Mori K.; Nakazono Y. Tetrahedron 1986, 42, 6459.
References and notes
18. (a) Suzuki, T.; Saimoto, H.; Tomioka, H.; Oshima, K.; Nozaki, H.
Tetrahedron Lett. 1982, 23, 3597; (b) Roush, W. R.; Adam, M. A.;
Peseckis, S. M. Tetrahedron Lett. 1983, 24, 1377.
1.
Hughes, G. K.; Ritchie, E. Aust. J. Chem. 1954, 7, 104.

4
Tetrahedron Letters
19. (a) Pfaltz, A.; Mattenberger, A. Angew. Chem. Int. Ed. Engl. 1982, 21,
71; (b) Flippin, L. A.; Brown, P. A.; Jalali-Araghi, K. J. Org. Chem.
1989, 54, 3588
10.1; HR-MS (ESI) calcd for C14H21O3 (M+H)+: 237.14852, Found
237.14812.
23. (+)-isogalbulin (1): [α]2D0 +44.25° (C 0.52, CHCl3) [lit.5c, 5g [α]D20 +46°(c
0.10, CHCl3)]; 1H NMR (CDCl3, 600 MHz) δ 6.75-6.74 (d, J = 8.2 Hz,
1H), 6.60 (s, 1H), 6.57 (d, J = 1.8 Hz, 1H), 6.52-6.50 (dd, J = 8.2, 1.8
Hz, 1H), 6.34 (s, 1H), 3.87 (s, 3H), 3.85 (s, 3H), 3.80 (s, 3H), 3.69-3.68
(d, J = 5.4 Hz, 1H), 3.67 (s, 3H), 2.88-2.84 (dd, J = 16.5, 5.4 Hz, 1H),
2.48-2.44 (dd, J = 16.5, 8.0 Hz, 1H), 2.04-2.02 (m, 1H), 1.95-1.93 (m,
1H), 0.92-0.91 (d, J = 2.8 Hz, 3H), 0.91-0.90 (d, J = 2.7 Hz, 3H); 13C
NMR (CDCl3, 100 MHz) δ 148.5, 147.2, 147.0, 139.8, 129.4, 128.4,
121.3, 113.2, 112.1, 111.1, 110.5, 55.81, 55.76, 55.72, 55.67, 50.8,
40.7, 34.7, 28.5, 16.5, 15.3; HR-MS (ESI) calcd for C22H28O4Na
(M+Na)+: 379.18798, Found 379.18784.
20. Compound 8: [α]2D0 +51.48° (C 0.81, CHCl3); 1H NMR (CDCl3, 400
MHz) δ 7.36-7.28 (m, 5H), 6.75-6.73 (d, J = 8.4 Hz, 1H), 6.67-6.65
(m, 2H), 4.55-4.48 (m, 2H), 3.84 (s, 6H), 3.60-3.57 (dd, J = 11.5, 2.6
Hz, 1H), 3.31-3.27 (dd, J = 11.5, 5.6 Hz, 1H), 2.74-2.73 (m, 1H), 2.68-
2.67 (m, 1H), 2.59-2.57 (m, 2H), 1.69-1.62 (m, 1H), 1.06-1.05 (d, J =
6.7 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 148.7, 147.3, 138.0, 132.5,
128.3, 127.7, 127.6, 120.9, 112.1, 111.0, 73.1, 70.0, 59.7, 57.0, 55.8,
55.7, 39.9, 38.0, 17.0; HR-MS (ESI) calcd for C21H26O4Na (M+Na)+:
365.17233, Found 365.17175.
21. Compound 10: [α]2D0 -13.26° (C 0.86, CHCl3); 1H NMR (CDCl3, 400
MHz) δ 6.80-6.77 (d, J = 8.0 Hz, 1H), 6.73-6.72 (m, 2H), 3.88 (s, 3H),
3.86 (s, 3H), 3.82-3.79 (m, 1H), 3.67-3.62 (m, 1H), 3.52-3.48 (m, 1H),
2.79-2.77 (d, J = 10.0 Hz, 1H), 2.21-2.11 (m, 4H), 0.87-0.85 (m, 6H);
13C NMR (CDCl3, 100 MHz) δ 148.6, 147.0, 134.4, 120.9, 112.4,
111.0, 73.7, 65.2, 55.8, 55.7, 40.8, 37.2, 35.2, 17.5, 10.9; HR-MS (ESI)
calcd for C30H49O8 (2M+H)+: 537.34219, Found 537.34235.
24. Jiao, X. Z.; Jiang, Y. J.; Feng, W. H.; Xie, P.; Liang, X. T. Chin. J.
Syn. Chem. 2007, 15(1), 34.
25.
(+)-galbulin (2): [α]D20 +7.95° (C 0.64,CHCl3) [lit.9 [α]2D0 +8.0°(c 0.3,
1
CHCl3)]; H NMR (CDCl3, 400 MHz) δ 6.81-6.79 (d, J = 8.1 Hz, 1H),
6.72-6.69 (dd, J = 8.1, 1.9 Hz, 1H), 6.58-6.57 (d, J = 1.9 Hz, 1H), 6.56
(s, 1H), 6.16 (s, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 3.81 (s, 3H), 3.56 (s,
3H), 3.44-3.42 (d, J = 10.3 Hz, 1H), 2.79-2.74 (dd, J = 16.2, 4.6 Hz
1H), 2.65-2.58 (dd, J = 16.2, 11.6 Hz, 1H), 1.67-1.63 (m, 1H), 1.55-
1.50 (m, 1H), 1.09-1.08 (d, J = 6.4 Hz, 3H), 0.88-0.86 (d, J = 6.4 Hz,
3H); 13C NMR (CDCl3, 125 MHz) δ 148.8, 147.3, 147.0, 146.9, 139.0,
132.5, 129.1, 121.9, 112.8, 112.1, 110.7, 110.6, 55.9, 55.82, 55.78,
54.3, 43.8, 39.0, 35.6, 20.0, 17.2; HR-MS (ESI) calcd for C22H29O4
(M+H)+: 357.20658, Found 357.20657.
22. Compound 11: [α]2D0 +39.16° (C 0.41, CHCl3); 1H NMR (CDCl3, 400
MHz) δ 9.70 (s, 1H), 6.80-6.78 (d, J = 7.9 Hz, 1H), 6.70-6.68 (m, 2H),
3.88 (s, 3H), 3.86 (s, 3H), 2.70-2.65 (dd, J = 13.5, 5.6 Hz, 1H), 2.38-
2.32 (m, 2H), 2.20-2.18 (m, 1H), 1.15-1.13 (d, J = 7.0 Hz, 3H), 0.97-
0.95 (d, J = 6.8 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 205.1, 148.7,
147.3, 132.8, 121.0, 112.2, 111.0, 55.8, 55.7, 50.5, 39.2, 36.5, 17.0,