Total synthesis of 8-methoxygoniodiol via chiron approach

Article abstract of DOI:10.1055/s-2008-1072511

A stereoselective synthesis of 8-methoxygoniodiol is accomplished using readily available δ-gluconolactone as a chiral source. The stereoselective addition of aryl Grignard reagent on aldehyde and regioselective opening of chiral epoxide by ethyl propiola

Full text of DOI:10.1055/s-2008-1072511

LETTER
1039
Total Synthesis of 8-Methoxygoniodiol via Chiron Approach
Total
S
ynt
.
hesis of 8-
M
S
ethoxygoniod
.iol Yadav,* B. Madhava Rao, K. Sanjeevarao, B. V. Subba Reddy
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Fax +91(40)27160512; E-mail: yadav@iict.res.in
Received 6 August 2007
al together with the novel structure prompted us to attempt
the total synthesis of (+)-8-methoxygoniodiol. In this ar-
ticle, we describe a concise synthesis of (+)-8-methoxy-
goniodiol in a stereoselective manner. This approach is
also useful for the synthesis of other stereoisomers and the
design of analogues. Retrosynthetic analysis of (+)-8-
methoxygoniodiol (1) is depicted in Scheme 1.
Abstract: A stereoselective synthesis of 8-methoxygoniodiol is ac-
complished using readily available d-gluconolactone as a chiral
source. The stereoselective addition of aryl Grignard reagent on al-
dehyde and regioselective opening of chiral epoxide by ethyl propi-
olate are the key steps involved in this synthesis.
Keywords: goniodiol, d-gluconolactone, chiron approach, chiral
epoxide
OH
O
OH
Ph
Ph
OMe
The genus Goniothalamus (Annonaceae) consists of 115
species, spread over entire the tropics and subtropics,1
some of them used extensively as traditional medicines.2
Several bioactive styryllactones have been isolated from
Goniothalamus species.3,4 The seeds of G. amuyon are re-
ported to be useful for the treatment of edema and rheu-
matism.5 In particular, 8-methoxygoniodiol was isolated
from the stems and leaves of Goniothalamus amuyon
along with seven styrylpyrones.6 These styryllactones are
found to possess significant cyctotoxicity against several
human tumors.7 The structures of some styryllactones are
depicted in Figure 1.
Ph
HO
O
O
OMe
O
OMe
O
1
12
10
O
O
O
O
HO
HO
O
OH
OH
O
OH
OH
4
δ-gluconolactone (2)
Scheme 1 Retrosynthetic analysis of (+)-8-methoxygoniodiol
Owing to its potent biological activity, and fascinating
structural architecture, several methods have been report-
ed for the synthesis of (+)-goniodiol and related mole-
cules.8 However, the reports on the synthesis of 8-
methoxygoniodiol are scarce.9
Retrosynthetic analysis of (+)-8-methoxygoniodiol illus-
trates that optically active epoxide 12 could be prepared
from d-gluconolactone (2) by a sequence of reactions.
Subsequently, epoxide 12 could be easily converted into
target molecule 1 by means of ring opening by ethyl pro-
In continuation of our interest on the total synthesis of nat-
ural products10 and extreme scarcity of the natural materi-
O
O
O
OAc
O
OH
O
OMe
O
OH
OH
OH
OH
OH
8-methoxygoniodiol
(+)-goniotriol
7-acetylgoniotriol
H
H
H
O
O
O
HO
O
O
O
O
O
O
H
HO
HO
H
HO
H
(+)-goniopypyrone
(+)-altholactone
9-deoxygoniopypyrone
Figure 1
SYNLETT 2008, No. 7, pp 1039–1041
x
x.
x
x.
2
0
0
8
Advanced online publication: 17.03.2008
DOI: 10.1055/s-2008-1072511; Art ID: D24207ST
© Georg Thieme Verlag Stuttgart · New York

1040
J. S. Yadav et al.
LETTER
piolate followed by partial hydrogenation using Lindlar’s room temperature resulted in aldehyde 9 in 95% yield.13
catalyst.
Reduction of 9 with NaBH4 in methanol gave the alcohol
10 in 90% yield which was then converted into the corre-
sponding iodide 11 by using I2, TPP, and imidazole. Upon
treatment of 11 with 1 N HCl in ethanol for 3 days fol-
lowed by addition of excess K2CO3 gave the hydroxy ep-
oxide 12 in 70% yield.14 The hydroxyl group was then
protected as its TBS ether 13 using TBSCl and imidazole.
Treatment of 13 with ethyl propiolate in the presence of n-
BuLi and BF3·OEt2 afforded ring-opened product 14 in
80% yield. Partial hydrogenation of 14 under Lindlar’s
conditions followed by treatment with 1 N HCl gave the
target molecule 1 in 60% yield (Scheme 2).15
The synthesis of 8-methoxygoniodiol (1) began with d-
gluconolactone (2) which could be easily obtained from
commercial source. Accordingly, d-gluconolactone (2)
was treated with methanol in the presence of PTSA fol-
lowed by 2,2-dimethoxypropane to give compound 3 in
86% yield.11 Reduction of ester 3 with LAH gave the diol
4 in 96% yield, which upon treatment with NaIO4 fur-
nished the aldehyde 5 in 90% yield. Addition of phenyl-
magnesium bromide to an aldehyde 5 gave predominantly
compound 6 along with a minor amount of compound 7.
The diastereomeric ratio of 6 to 7 was 95:5, which could
be easily separated by column chromatography. The con- The structure of the (+)-8-methoxygoniodiol was con-
figuration of a newly formed hydroxyl group was as- firmed by comparing its spectral and physical data with
signed by converting the compound 6 into a known the natural product isolated by Wu et al,6 and also with
product.12 The hydroxyl group of major isomer 6 was pro- previous synthetic report.9 The spectroscopic analysis and
tected as its methyl ether 8 using methyl iodide and NaH optical rotation value, [a]D25 +24.9 (c 0.35, CHCl3) were
25
in THF. Hydrolysis of primary acetonide and the cleavage in agreement with the data reported in literature [a]D
of resulting diol occurred simultaneously with H5IO6 at +24.2 (c 0.68, CDCl3).6,9
O
O
a
O
O
O
HO
HO
O
O
O
O
a
c
b
OMe
OH
OH
O
OH
O
O
OH
OH
4
3
2
O
O
O
O
O
O
O
O
d
Ph
H
Ph
+
OH
O
O
O
O
OH
5
7 (minor)
6 (major)
O
O
O
O
O
O
O
O
Ph
Ph
g
e
Ph
OMe
f
H
O
OMe
O
OH
O
8
9
6 (major)
OH
O
O
Ph
j
Ph
OMe
Ph
OMe
h
i
I
HO
O
OMe
O
O
12
10
11
OH
OTBS
OTBS
Ph
Ph
k
l
Ph
EtO
O
OMe
OH OMe
O
OMe
O
O
1
14
13
Scheme 2 Reagents and conditions: (a) 2,2-DMP, PTSA, acetone, MeOH, 12 h, r.t., 86%; (b) LiAlH4, THF, 0 °C to r.t., 4 h, 96%; (c) NaIO4,
CH2Cl2, aq sat. NaHCO3, 5 h, 90%; (d) PhMgBr, THF, –5 °C to 0 °C to r.t. (6/7 = 95:5), 30 min, 95%; (e) NaH, MeI, THF, 0 °C to r.t., 2 h,
96%; (f) H5IO6, EtOAc, 0 °C to r.t., 1 h, 95%; (g) NaBH4, MeOH, 0 °C to r.t., 2 h, 90%; (h) TPP, I2, imidazole, MeCN–Et2O (1:3) 0 °C to r.t.,
2 h, 90%; (i) 1 N HCl, EtOH, 0 °C to r.t., 3 d then K2CO3, 70%; (j) imidazole, TBSCl, CH2Cl2, 0 °C to r.t., 2 h, 90%; (k) ethyl propiolate, n-
BuLi, BF3·OEt2, THF, –78 °C, 2 h, 80%; (l) (i) Lindlar, EtOAc; (ii) 1 N HCl, 60%.
Synlett 2008, No. 7, 1039–1041 © Thieme Stuttgart · New York

LETTER
Total Synthesis of 8-Methoxygoniodiol
1041
NMR (75 MHz, CDCl3): d = 25.1, 26.3, 26.6, 27.1, 72.6,
75.4, 76.7, 82.6, 83.6, 109.0, 110.0, 126.8, 127.74, 128.5,
140.0. IR (KBr): nmax = 3438, 2990, 2874, 1376, 1153, 1070,
843, 702 cm–1. HRMS: m/z calcd for C17H24O5 [M + Na]+:
331.1521; found: 331.1512.
In summary, we have described a concise and highly ste-
reoselective synthetic route for the synthesis of (+)-8-
methoxygoniodiol using a readily available d-gluconolac-
tone as a chiral precursor. The synthesis involves direct
and straightforward reactions such as the aryl Grignard
addition, epoxide formation from iodohydrin, and stereo-
selective ring opening of epoxide by an alkyne, which
makes it quite simple and more convenient for up-scaling
the products.
Compound 8: [a]D25 +67.6 (c 0.5, CHCl3). 1H NMR (300
MHz, CDCl3): d = 1.41, 1.37, 1.34, 1.32 (4 s, 12 H), 3.23 (s,
3 H), 3.94–4.15 (m, 5 H), 4.25 (d, J = 4.5 Hz, 1 H), 7.13 (m,
5 H). 13C NMR (75 MHz, CDCl3): d = 25.1, 26.3, 26.5, 27.2,
56.4, 72.3, 75.4, 76.6, 82.5, 83.4, 109.0, 110.0, 126.0, 127.7,
128.5, 138.5. IR (KBr): nmax = 2987, 1456, 1372, 1214, 1076,
848, 706 cm–1. HRMS: m/z calcd for C18H26O5 [M + Na]+:
345.1676; found: 345.1669.
Acknowledgment
Compound 10: [a]D25 +37.2 (c 1.7, CHCl3). 1H NMR (300
MHz, CDCl3): d = 1.26 (s, 3 H), 1.39 (s, 3 H), 2.85 (m, 1 H),
3.12 (dd, J = 3.0, 3.7 Hz, 1 H), 3.30 (s, 3 H), 3.70 (m, 1 H),
4.05 (dd, J = 6.7, 8.3 Hz, 1 H), 4.25 (d, J = 6.7 Hz, 1 H),
7.25–7.36 (m, 5 H). 13C NMR (75 MHz, CDCl3): d = 26.0,
29.0, 56.0, 62.0, 78.0, 79.0, 85.0, 109.0, 127.0, 128.0, 136.0.
IR (KBr): nmax = 3462, 2987, 1455, 1375, 1097, 860, 705
cm–1. HRMS: m/z calcd for C14H20O4 [M + Na]+: 275.1259;
found: 175.1250.
BMR thanks UGC, New Delhi for financial assistance.
References and Notes
(1) Bermejo, A.; Lora, M. J.; Blázquez, M. A.; Rao, K. S.;
Cortes, D.; ZafraPolo, M. C. Nat. Prod. Lett. 1995, 7, 117.
(2) Surivet, J.-P.; Vatèle, J.-M. Tetrahedron 1999, 55, 13011.
(3) Fang, X.-p.; Anderson, J. E.; Qiu, X.-x.; Kozlowski, J. F.;
Chang, C.-j.; McLaughlin, J. L. Tetrahedron 1993, 49, 1563.
(4) Wang, S.; Zhang, Y.-J.; Chen, R.-Y.; Yu, D.-Q. J. Nat. Prod.
2002, 65, 835.
(5) Kan, W. S. Pharmaceutical Botany; National Research
Institute of Chinese Medicine: Taipei, 1979, 247.
(6) Lan, Y.-H.; Chang, F.-R.; Yu, J.-H.; Yang, Y.-L.; Chang, Y.-
L.; Lee, S.-J.; Wu, Y.-C. J. Nat. Prod. 2003, 66, 487.
(7) Fang, X. P.; Anderson, J. E.; Chang, C. J.; Fanwick, P. E.;
McLaughlin, J. L. J. Chem. Soc., Perkin Trans. 1 1990,
1655.
(8) (a) Deligny, M.; Carreaux, F.; Carboni, B. Synlett 2005,
1462. (b) Shing, T. K. M.; Tsui, H.-C.; Zhou, Z.-H. J. Org.
Chem. 1995, 60, 3121. (c) Prasad, K. R.; Gholap, S. L.
Tetrahedron Lett. 2007, 48, 4679.
(9) Carreaux, F.; Favre, A.; Carboni, B.; Rouaud, I.; Boustie, J.
Tetrahedron Lett. 2006, 47, 4545.
Compound 12: [a]D25 +37.9 (c 2.9, CHCl3) 1H NMR (300
MHz, CDCl3): d = 2.48–2.54 (m, 2 H), 2.70 (dd, J = 3.0, 3.7
Hz 1 H), 3.27 (s, 3 H), 3.65 (dd, J = 2.2, 7.5 Hz, 1 H), 4.17
(d, J = 7.5 Hz, 1 H), 7.30 (m, 5 H). 13C NMR (75 MHz,
CDCl3): d = 45.0, 52.0, 57.0, 75.0, 86.0, 127.0, 128.0, 129.0,
138.0. IR (KBr): nmax = 3424, 2927, 1724, 1453, 1102, 760,
701 cm–1. HRMS: m/z calcd for C11H14O3 [M + Na]+:
217.0840; found: m/z 217.0843.
Compound 14: [a]D25 +61.0 (c 1.4, CHCl3). 1H NMR (300
MHz, CDCl3): d = 0.16 (s, 3 H), 0.18 (s, 3 H), 0.93 (s, 9 H),
1.29 (t, J = 7.0 Hz, 3 H), 2.40 (dd, J = 3.1, 6.2 Hz, 2 H), 3.12
(s, 3 H), 3.25 (m, 1 H), 3.89 (d, J = 7.8 Hz, 1 H), 4.11 (d,
J = 7.8 Hz, 1 H), 4.18 (q, J = 7.0 Hz, 2 H), 7.30 (m, 5 H). 13
NMR (75 MHz, CDCl3): d = –4.9, –3.7, 14.0, 25.1, 26.2,
C
29.7, 56.3, 61.8, 68.7, 76.6, 85.3, 85.8, 127.8, 128.3, 128.6,
138.1, 150.4. IR (KBr): nmax = 3423, 3300, 2927, 1742, 1458,
1105, 760 cm–1. LC-MS: m/z = 429 [M + Na]+.
(10) Yadav, J. S.; Raju, A. K.; Rao, P. P.; Rajaiah, G.
Tetrahedron: Asymmetry 2005, 16, 3283.
(11) Long, D. D.; Smith, M. D.; Martín, A.; Wheatley, J. R.;
Watkin, D. G.; Müller, M.; Fleet, G. W. J. J. Chem. Soc.,
Perkin Trans. 1 2002, 1982.
Compound 1: [a]D25 +24.9 (c 0.35, CHCl3); lit.: +24.2 (c
0.68, CDCl3. 1H NMR (300 MHz, CDCl3): d = 2.04 (ddd,
J = 4.0, 6.2, 18.5 Hz, 1 H), 2.94 (ddd, J = 2.4, 13.0, 18.5 Hz,
1 H), 3.27 (s, 3 H), 3.56 (d, J = 8.5 Hz, 1 H), 3.92 (ddd,
J = 3.9, 12.5, 17.9 Hz, 1 H), 4.55 (d, J = 8.5 Hz, 1 H), 5.93
(dd, J = 3.1, 10.2 Hz, 1 H), 6.82 (ddd, J = 2.3, 6.2, 9.4 Hz, 1
H), 7.30–7.39 (m, 5 H). 13C NMR (75 MHz, CDCl3): d =
25.8, 56.8, 61.8, 75.7, 75.8, 83.4, 120.7, 127.7, 128.6, 128.7,
137.3, 145.7, 163.8. IR (KBr): nmax = 3445, 2909, 1719,
1380, 1109, 1057, 757 cm–1. HRMS: m/z calcd for C14H16O4
[M + Na]+: 271.0946; found: 271.0945.
(12) Babjak, M.; Kapitán, P.; Gracza, T. Tetrahedron 2005, 61,
2471.
(13) Wu, W.; Wu, Y. J. Org. Chem. 1993, 58, 3586.
(14) Yun, H.; Chou, T.-C.; Dong, H.; Li, Y.-m.; Tian, Y.;
Danishefsky, S. J. J. Org. Chem. 2005, 70, 10375.
(15) Compound 6: [a]D25 +15.8 (c 1.0, CHCl3). 1H NMR (300
MHz, CDCl3): d = 1.41, 1.37, 1.34, 1.32 (4 s, 12 H), 3.90–
4.20 (m, 5 H), 4.25 (d, J = 4.6 Hz, 1 H), 7.3 (m, 5 H). 13
C
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