First synthesis of (+)-8-methoxygoniodiol and its analogue, 8-deoxygoniodiol, using a three component strategy

Article abstract of DOI:10.1016/j.tetlet.2006.05.005

We have described the first total synthesis of the natural product, (+)-8-methoxygoniodiol, and its analogue, 8-deoxygoniodiol using a catalytic asymmetric hetero-Diels-Alder/allylboration sequence involving three partners. The cytotoxic activity of these

Full text of DOI:10.1016/j.tetlet.2006.05.005

Tetrahedron Letters 47 (2006) 4545–4548
First synthesis of (+)-8-methoxygoniodiol and its analogue,
8-deoxygoniodiol, using a three component strategy
Franc¸ois Carreaux,a,* Annaick Favre,a Bertrand Carboni,a
Isabelle Rouaudb and Joel Boustieb
aInge´nie´rie chimique et mole´cules pour le vivant, UMR 6226 CNRS-Universite´ de Rennes 1, 35042 Rennes cedex, France
bEA Subtances liche´niques et Photoprotection, Universite´ de Rennes 1, 2 avenue du professeur Le´on Bernard,
35043 Rennes cedex, France
Received 4 April 2006; revised 26 April 2006; accepted 2 May 2006
Abstract—We have described the first total synthesis of the natural product, (+)-8-methoxygoniodiol, and its analogue, 8-deoxygo-
niodiol using a catalytic asymmetric hetero-Diels–Alder/allylboration sequence involving three partners. The cytotoxic activity of
these final compounds and of two synthetic intermediates has been evaluated against human cancer cell lines (A375P and
A375M), showing the importance of the lactone moiety.
Ó 2006 Elsevier Ltd. All rights reserved.
Asian trees of the genus Goniothalamus have been a
source of numerous families of compounds possessing
interesting biological properties including alkaloids,1
styryllactones2 and acetogenins.3 For example, some
styryllactones isolated from an ethanolic extract of stem
bark of Goniothalamus giganteus such as (+)-Goniodiol
1, show potent and cytotoxic activities against several
human tumors.4 Consequently, there have been impor-
tant synthetic efforts toward 1 resulting in the number
of total syntheses.5 However, there have been few re-
ports concerning the synthesis and biological evaluation
of structural analogues due to the lack of flexible and
versatile access to this class of compounds.5g
3
R1
Ph
H
R = OH, (+)-goniodiol, 1
1
R = OMe, (+)-8-methoxygoniodiol, 1a
1
8
O
OH
O
1
R = H, (+)-8-deoxygoniodiol, 1b
1
H
Figure 1.
(+)-goniodiol, depending on the type of human cancer
cell lines.6 We thus thought that it would be important
to be able to lay out some quantity of (+)-8-methoxygo-
niodiol to supplement its biological evaluation.8 How-
ever, to the best of our knowledge, no synthesis of this
natural product has been described to date. Herein, we
report the first synthesis of this natural product using
a three component strategy which is also useful for the
design of analogues such as 8-deoxygoniodiol 1b,
including cytotoxicity against two A375 melanoma cell
lines.
Recently, new members of the natural styryllactones
have been reported from Goniothalamus amuyon.6 The
structure and absolute stereochemistry of one of these
compounds, 1a, have been established as being similar
with those of (+)-goniodiol, except for the presence of
a methoxy group at C-8 as shown in Figure 1. There-
fore, the trivial name of 8-methoxygoniodiol was as-
signed to this compound.7 In spite of this structural
similarity, 1a exhibited a very different cytotoxicity from
In the course of our program directed toward the dis-
covery of new multicomponent reactions, we and others
have simultaneously developed a general method for the
asymmetric synthesis of a-hydroxyalkyl dihydropyrans
using a catalytic inverse electron demand hetero-Diels–
Alder (IEDHDA)/allylboration sequence.9 We have re-
cently employed this strategy with success in the synthe-
sis of (+)-Goniodiol proving that it is possible to create
three contiguous asymmetric centers in a high stereo-
selective manner using a chiral aldehyde in the allylbora-
tion step.5i In a similar way, we envisioned that this
Keywords: Natural product; Hetero-Diels–Alder; Allylboration reac-
tion; Asymmetric catalysis; (+)-8-Methoxygoniodiol; 8-Deoxygonio-
diol; Cytotoxicity.
*
Corresponding author. Tel.: +33 2 23 23 57 34; e-mail: francois.
carreaux@univ-rennes1.fr
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.005

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F. Carreaux et al. / Tetrahedron Letters 47 (2006) 4545–4548
methodology could be employed for the synthesis of 8-
methoxygoniodiol, via the key intermediate 6a, using
in the reactional sequence the following three partners:
ethyl vinyl ether, (2E)-3-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)prop-2-enal 310 and (2R)-meth-
oxy(phenyl)acetaldehyde 2a. Oxidation of protected lac-
tol 6a followed by migration of the double bond would
lead to the a,b-unsaturated d-lactone skeleton of 1a as
depicted in Scheme 1. This strategy should also allow
us to synthesize 8-deoxygoniodiol 1b, using phenylacet-
aldehyde in the IEDHDA/allylboration process. The
preparation of this analogue was envisaged in order to
determine the importance of the substituent at C-8 on
biological activity.
tion. The asymmetric synthesis of cyclic allylboronate
5 was achieved from ethyl vinyl ether and 3, following
an hetero-Diels–Alder reaction catalyzed with Jacob-
sen’s chiral Cr(III) complex 4.12 After completion of
the cycloaddition step, aldehyde 2a is added and the
mixture is warmed at 40 °C for 48 h to furnish interme-
diate 6a in 60% yield. It should be noted that the pres-
ence of the chiral catalyst does not seem to have
influence on the stereoselectivity of the allylboration
reaction, since dihydropyran 6a is obtained with the
same diastereoselectivity (>95%) as without a catalyst.
In order to reduce the number of steps of our synthesis,
we first oxidized ethyl lactol 6a into lactone without pro-
tecting the hydroxyl group, using a one pot procedure
described by Grieco.13 Unfortunately, under these
conditions, we mainly obtained the bicyclic acetal prod-
uct.14 Treatment of 6a with t-BuPh2SiCl in the presence
of imidazole and DMAP gave the protected alcohol in
73% yield. The one pot conversion of 7a into the corre-
sponding lactone using m-CPBA (1.3 equiv) with boron
trifluoride etherate was effected, in this case, cleanly in
90% yield. Isomerization of the double bond was real-
ized with a catalytic amount of DBU in CH2Cl2 at room
temperature to give the a,b-unsaturated d-lactone 8a in
80% yield. The natural product was obtained after desil-
ylation with TBAF in 28.9% overall yield from the ad-
vanced intermediate 6a. The spectroscopic data of
synthetic (+)-8-methoxygoniodiol are in full agreement
Although the O-methylation of mandelic acid can be
carried out without epimerization under certain condi-
tions,11 we chose to use the commercial (R)-O-methyl-
mandelic acid as starting material for the synthesis of
aldehyde 2a. After esterification with methanol in the
presence of p-TsOH, the reduction of the ester function
with i-Bu2AlH at ꢀ78 °C led to the expected O-methyl
mandelic aldehyde with some impurities (Scheme 2).
To preserve the enantiomeric purity, 2a was directly
used without further purification in the allylation reac-
R
R
with previously published data.6a The specific rotation,
Ph
O
O
OEt
Ph
O
23
½aꢁD +26.4 (c 0.32, CHCl3), was also in good agreement
OH
OH
O
25
R=OCH3, (+)-8-methoxygoniodiol, 1a
R=H, (+)-8-deoxygoniodiol, 1b
R=OCH3, 6a
R=H, 6b
with that reported for the natural product, ½aꢁD +24.2 (c
0.68, CHCl3) (Scheme 3).
O
The synthesis of 8-deoxygoniodiol began with the asym-
metric catalyzed hetero-Diels–Alder/allylboration se-
quence using phenylacetaldehyde in place of O-methyl
mandelic aldehyde. The tandem process was performed
in ‘one pot’ and provided the desired pyran 6b in 82% as
single diastereoisomer in 96% enantiomeric excess.9b
Silylation of the hydroxyl function using tert-butyl-
diphenylsilyl chloride, imidazole and DMAP provided
7b in 93% yield. Surprisingly, conversion of 7b into the
corresponding lactone using the one pot procedure cited
previously was achieved in a poor yield (32%). There-
fore, lactone 7b was obtained in two steps (76.5%), after
hydrolysis of the ethyl lactol followed by oxidation. The
final steps, isomerization of the double bond and of the
silyl protective group, produced the desired product 1b.
8-Deoxygoniodiol was thus synthesized in 29.4% yield
from 3-boroacrolein pinacolate 3 (Scheme 4).15
B
R
+
+
asymmetric IEDHDA/
allylboration sequence
Ph
CHO
OEt
H
O
R=OCH3, 2a
3
R=H
Scheme 1. Retrosynthetic analysis.
N
O
Cr
Cl
O
OCH3
OCH3
a, b
(1S,2R)4
Ph
CHO
CO2H
Ph
2a
BPin
BPin
CH3O
CH3O
b,c
OEt
a
d
6a
1a
c
CH3O
Ph
O
Ph
O
Ph
O
+
TBDPSO
TBDPSO
O
OEt
OEt
O
5
OEt
H
O
7a
8a
OH
6a
3
Scheme 3. Reagents and conditions: (a) TBDPSCl (1.3 equiv), imid-
azole (2.4 equiv), DMAP (cat.), CH2Cl2, rt, 12 h, 73%; (b) m-CPBA
(1.3 equiv), BF3ÆOEt2 (1.3 equiv), CH2Cl2, 0 °C to rt, 15 h, 90%; (c)
DBU (0.01 equiv), THF, 0 °C to rt, 20 h, 80%; (d) TBAF (1.1 equiv),
THF, 0 °C, 2 h, 55%.
Pin = pinacolate
Scheme 2. Reagents and conditions: (a) MeOH, p-TsOH (0.01 equiv),
reflux, 3 h, 84%; (b) i-Bu2AlH (1.1 equiv), Et2O, ꢀ78 °C, 0.5 h; (c) (i) 4
˚
(0.01 equiv), 4 A MS, rt, 2 h; (ii) 2a (1.5 equiv), 40 °C, 48 h, 60%.

F. Carreaux et al. / Tetrahedron Letters 47 (2006) 4545–4548
4547
1 are gratefully acknowledged for financial support of
this research. We are grateful to Drs Marie-Do Galibert
and Aline Primot, UMR 6061, for their advice and sup-
plies in A375 cells cultivation.
BPin
b, c
a
+
OEt
O
Ph
Ph
O
OEt
H
O
HO
3
6b
d
e
References and notes
1b
Ph
O
O
O
TBDPSO
TBDPSO
1. Lu, S.-T.; Wu, Y.-C.; Leou, S.-P. Phytochemistry 1985, 24,
1829.
2. Blasquez, M. A.; Bermejo, A.; Zafra-Polo, M. C.; Cortes,
D. Phytochem. Anal. 1999, 10, 161.
3. Fang, X.-P.; Anderson, J. E.; Smith, D. L.; McLaughlin,
J. L.; Wood, K. V. J. Nat. Prod. 1992, 55, 1655, and
references cited therein.
7b
8b
˚
Scheme 4. Reagents and conditions: (a) (i) 4 (0.01 equiv), 4 A MS, rt,
2 h; (ii) PhCH2CHO (2 equiv), 45 °C, 24 h, 82%; (b) TBDPSCl
(1.3 equiv), imidazole (2.4 equiv), DMAP (cat.), CH2Cl2, rt, 18 h,
93%; (c) (i) 6 N HCl, THF, rt, 20 h, 85%; (ii) PDC (1.1 equiv), AcONa
˚
(1.1 equiv), 4 A MS, rt, 24 h, 90%; (d) DBU (0.01 equiv), THF, 0 °C to
rt, 20 h, 95%; (e) TBAF (1.1 equiv), THF, 0 °C to rt, 3 h, 53%.
4. (a) Talapatra, S. K.; Basu, D.; Deb, T.; Goswami, S.;
Talapatra, B. J. Ind. Chem. Soc. 1985, 24B, 29; (b) Fang,
X.-P.; Anderson, J. E.; Chang, C. J.; McLaughlin, J. L.
J. Nat. Prod. 1991, 54, 1034.
Table 1. Cytotoxic Activity of 8-methoxygoniodiol 1a and its ana-
logues against cancer cell lines
´
`
5. (a) Survivet, J.-P.; Gore, J.; Vatele, J.-M. Tetrahedron
1996, 52, 14877; (b) Mukai, C.; Hirai, S.; Hanaoka, M. J.
Org. Chem. 1997, 62, 6619; (c) Dixon, D. J.; Ley, S. V.;
Tate, E. W. J. Chem. Soc., Perkin Trans. 1 1998, 3125; (d)
a
a
Compound
A375P IC50 (lM)
A375M IC50 (lM)
1a
1b
35.1 ( 4.5)
36.9 ( 3.9)
>100
75.7 ( 11.8)
82.6 ( 8.8)
>150
`
Survivet, J.-P.; Vatele, J.-M. Tetrahedron 1999, 55, 13011;
(e) Tsubuki, M.; Kanai, K.; Nagase, H.; Honda, T.
Tetrahedron 1999, 55, 2493; (f) Banwell, M. G.; Coster, M.
J.; Karunaratne, O. P.; Smith, J. A. J. Chem. Soc., Perkin
Trans. 1 2002, 1622; (g) Chen, J.; Lin, G.-Q.; Wang, Z.-
M.; Liu, H.-Q. Synlett 2002, 1265; (h) Ramachandran, P.
V.; Chandra, J. S.; Reddy, M. V. R. J. Org. Chem. 2002,
67, 7547; (i) Deligny, M.; Carreaux, F.; Carboni, B.
Synlett 2005, 1462.
6a
6b
>100
>200
5FU
20.6 ( 5.9)
22.6 ( 4.2)
a Values are means of three experiments, standard deviation is given in
parentheses. 5FU = 5-Fluorouracile (standard).
6. (a) 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; (b) Lan, Y.-H.; Chang, F.-R.; Liaw, C.-C.; Wu,
C.-C.; Chiang, M.-Y.; Wu, Y.-C. Planta Med. 2005, 71,
153.
7. The IUPAC name of 8-deoxygoniodiol is (6R)-6-[(1R)-1-
hydroxy-2-phenylethyl]-5,6-dihydro-2H-pyran-2-one.
8. 3.4 kg of fresh leaves of G. amuyon is necessary to extract
only 3 mg of 1a.
9. (a) Deligny, M.; Carreaux, F.; Carboni, B.; Toupet, L.;
Dujardin, G. Chem. Commun. 2003, 276; (b) Deligny, M.;
Carreaux, F.; Toupet, L.; Carboni, B. Adv. Synth. Catal.
2003, 345, 1215; (c) Gao, X.; Hall, D. G. J. Am. Chem.
Soc. 2003, 125, 9308; (d) Gao, X.; Hall, D. G.; Deligny,
M.; Favre, A.; Carreaux, F.; Carboni, B. Chem. Eur. J.
2006, 12, 3132.
The cytotoxicity of compounds 1a, 1b, 6a and 6b against
low (A375P) and medium (A375M) metastatic human
melanoma cell lines using the MTT assay16 is reported
in Table 1. These melanoma cell lines appear to be
slightly less sensitive to 8-methoxygoniodiol 1a than
the Hep G2 and Hep 3B hepatic cell lines previously tes-
ted.6b However, 1a is at least eightfold more active with
respect to A375 cells compared to the NUGC (human
gastric cancer) and HONE-1 (human nasopharyngeal
carcinoma) cancer cell lines.6a Although cytotoxicity
values are moderate, the 8-methoxy substituent does
not appear to have any incidence on activity. On the
contrary, the presence of the lactone ring is found to
be necessary for the activity, since the corresponding
2-O-ethyl derivatives were shown to be dramatically less
active.
´
10. Gravel, M.; Toure, B. B.; Hall, D. G. Org. Prep. Proced.
Int. 2004, 36, 573.
11. Page, P. C. B.; Chan, Y.; Heaney, H.; McGrath, M. J.;
In summary, the first total synthesis of (+)-8-meth-
oxygoniodiol and its analogue, 8-deoxygoniodiol, was
accomplished using a three component hetero-Diels–Al-
der/allylboration process. The route outlined above con-
tains sufficient flexibility to provide additional analogues
at C-8, and also at C-3 using substituted enol ether,17
opening interesting perspectives for structure-activity
relationship studies. Efforts in this area will be reported
in due course.
Moreno, E. Synlett 2004, 2606, and references cited
therein.
12. Gademann, K.; Chavez, D. E.; Jacobsen, E. N. Angew.
Chem., Int. Ed. 2002, 41, 3059.
13. Grieco, P. A.; Oguri, T.; Yokoyama, Y. Tetrahedron Lett.
1978, 419.
14.
m-CPBA (1.3 equiv),
Ph
BF .OEt (1.3 equiv)
O
3
2
CH3O
6a
CH Cl , r.t., 1h
2
2
O
50%
Acknowledgements
15. Yields refer to isolated and chromatographically pure
compounds. All the compounds exhibited spectral data
(1H, 13C NMR, elemental analysis or HRMS) consistent
`
A. Favre thanks the Ministere de l’Education nationale,
23
de la Recherche et de la Technologie (MENRT) for a
PhD Grant. The CNRS and the University of Rennes
with their structures. For example, compound 6a: ½aꢁD
+67.8 (c 0.3, CH2Cl2). 1H NMR (300 MHz, CDCl3):

4548
F. Carreaux et al. / Tetrahedron Letters 47 (2006) 4545–4548
7.35–7.30 (m, 5H), 5.86 (m, 1H), 5.68 (dd, 1H, J = 1.8 and
6H), 7.22–7.11 (m, 3H), 6.85 (dd, 2H, J = 2.6 and 7.6 Hz),
5.93 (m, 1H), 5.72 (m, 1H), 4.69 (m, 1H), 3.97 (m, 1H),
3.19–3.02 (m, 3H), 2.63 (dd, 1H, J = 5.2 and 14.1 Hz),
1.04 (s, 9H). 13C NMR (75 MHz, CDCl3): 168.9, 137.4,
136.1, 136.0, 135.9, 135.8, 133.4, 133.1, 130.1, 129.8, 129.6,
128.4, 127.9, 127.7, 126.4, 124.0, 123.0, 79.1, 76.2, 38.9,
30.3, 26.9, 19.4. HRMS (EI): m/z Calcd for C29H32O3Si
10.1 Hz), 4.85 (dd, 1H, J = 5.0 and 5.6 Hz), 4.74 (d, 1H,
J = 1.8 Hz), 4.28 (d, 1H, J = 8.5 Hz), 4.03 (dq, 1H, J = 7.1
and 9.5 Hz), 3.67 (m, 2H), 3.26 (s, 3H), 2.46 (d, 1H,
J = 8.1 Hz), 2.30 (m, 2H), 1.31 (t, 3H, J = 7.1 Hz). 13C
NMR (75 MHz, CDCl3): 139.5, 128.3, 128.0, 127.9, 127.4,
124.8, 98.3, 83.2, 75.6, 73.5, 64.5, 56.8, 30.9, 15.2. Anal.
Calcd for C16H22O4: C, 69.04; H, 7.97. Found: C, 69.11;
23
[M]+: 456.2121. Found 456.2132. Compound 8b: ½aꢁD
23
1
H, 8.02. Compound 7a: ½aꢁD +66.7 (c 0.25, CH2Cl2). H
NMR (300 MHz, CDCl3): 7.73 (m, 2H), 7.62 (m, 2H),
7.51–7.28 (m, 11H), 5.22 (m, 1H), 5.06 (ddd, 1H, J = 1.2,
1.3 and 10.1 Hz), 4.42 (m, 2H), 4.20 (m, 2H), 3.89 (dq, 1H,
J = 7.1 and 9.7 Hz), 3.43 (dq, 1H, J = 7.1 and 9.7 Hz),
3.17 (s, 3H), 2.09 (m, 1H), 1.96 (m, 1H), 1.25 (t, 3H,
J = 7.1 Hz), 0.78 (s, 9H). 13C NMR (75 MHz, CDCl3):
139.6, 136.3, 135.5, 134.5, 133.1, 129.5, 129.0, 127.9, 127.4,
127.0, 126.5, 124.0, 122.3, 99.5, 83.5, 77.0, 75.6, 62.3, 56.4,
31.4, 26.6, 19.5, 15.2. Anal. Calcd for C32H40O4Si: C,
74.38; H, 7.80. Found: C, 74.45; H, 7.86. Compound 8a:
ꢀ33.1 (c 0.50, CH2Cl2). 1H NMR (300 MHz, CDCl3): 7.75
(dd, 2H, J = 1.4 and 6.5 Hz), 7.64 (dd, 2H, J = 1.4 and
7.8 Hz), 7.57–7.38 (m, 6H), 7.22–7.11 (m, 3H), 6.91 (dd,
2H, J = 2.3 and 7.6 Hz), 6.85 (m, 1H), 5.97 (dd, 1H,
J = 2.4 and 9.7 Hz), 4.11 (m, 1H), 3.94 (m, 1H), 3.23 (dd,
1H, J = 8.7 and 13 Hz), 2.80–2.66 (m, 2H), 2.06 (m, 1H),
1.06 (s, 9H). 13C NMR (75 MHz, CDCl3): 164.3, 145.5,
137.5, 136.1, 136.0, 135.9, 133.3, 133.2, 130.1, 129.8, 129.6,
129.5, 128.5, 128.4, 127.9, 127.7, 126.4, 121.1, 76.9, 75.5,
38.8, 27.0, 25.6, 19.5. HRMS (EI): m/z Calcd
for C29H32O3Si [M]+: 456.2121. Found 456.2129. Com-
23
23
½aꢁD +111.5 (c 0.48, CH2Cl2). 1H NMR (300 MHz,
pound 1b: ½aꢁD +19.4 (c 0.28, CH2Cl2). 1H NMR
CDCl3): 7.69 (d, 2H, J = 7.3 Hz), 7.50 (d, 2H,
J = 7.6 Hz), 7.52–7.23 (m, 11H), 6.56 (m, 1H), 5.86 (dd,
1H, J = 2.1 and 9.5 Hz), 4.76 (m, 1H), 4.54 (d, 1H,
J = 7.9 Hz), 3.93 (d, 1H, J = 7.9 Hz), 3.16 (s, 3H), 2.29 (m,
1H), 1.56 (m, 1H), 0.63 (s, 9H). 13C NMR (75 MHz,
CDCl3): 164.1, 145.2, 139.2, 136.3, 133.8, 130.0, 129.5,
128.8, 128.5, 128.4, 127.7, 127.5, 120.9, 82.6, 76.8, 76.3,
56.5, 26.4, 26.2, 19.4. HRMS (EI): m/z Calcd for
C30H34O4Si [M]+: 486.2226. Found: 486.2229. Compound
(300 MHz, CDCl3): 7.44–7.18 (m, 5H), 6.95 (ddd, 1H,
J = 1.9, 6.3 and 9.7 Hz), 6.05 (dd, 1H, J = 2.7 and 9.7 Hz),
4.40 (dt, 1H, J = 3.4 and 12.7 Hz), 3.89 (m, 1H), 2.99 (m,
2H), 2.75 (m, 1H), 2.25 (ddd, 1H, J = 3.8, 6.2 and
18.4 Hz). 13C NMR (75 MHz, CDCl3): 164.4, 145.7, 137.2,
129.4, 128.7, 126.8, 120.9, 78.5, 73.4, 39.3, 25.9. HRMS
(EI): m/z Calcd for C13H14O3 [M]+: 218.0943. Found
218.0958.
´
´
´ ´
16. Bezivin, C.; Tomasi, C.; Lohezic-Le Devehat, F.; Boustie,
23
7b: Mp 114–116 °C. ½aꢁD ꢀ36.4 (c 0.34, CH2Cl2). 1H
J. Phytomedicine 2003, 10, 499.
17. Gao, X.; Hall, D. G. J. Am. Chem. Soc. 2005, 127,
1628.
NMR (300 MHz, CDCl3): 7.74 (dd, 2H,J = 1.6 and
7.9 Hz), 7.63 (dd, 2H, J = 1.5 and 8.5 Hz), 7.56–7.35 (m,