(-)-Astrogorgiadiol: A shorter route to A-ring synthon

Article abstract of DOI:10.1016/j.tet.2012.12.087

A new route to the key A-ring/C-ring precursor synthon of (-)-astrogorgiadiol is described, for the strategy based on Robinson annulation. This synthon is also key for the synthesis of other related calicoferols and astrogorgols. The route takes full adva

Full text of DOI:10.1016/j.tet.2012.12.087

Tetrahedron 69 (2013) 2348e2351
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(ꢀ)-Astrogorgiadiol: a shorter route to A-ring synthon
*
ꢀ
Guillaume Medard
The Christopher Ingold Laboratories, University College London, 20 Gordon Street, London WC1H 0AJ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A new route to the key A-ring/C-ring precursor synthon of (ꢀ)-astrogorgiadiol is described, for the
strategy based on Robinson annulation. This synthon is also key for the synthesis of other related cal-
icoferols and astrogorgols. The route takes full advantage of the opening of 6-methoxy-1-tetralol with
bis(sym-collidine) bromine(I) triflate. It involves a new protectionedeprotection sequence of an enone. It
is the shortest synthesis to date, consisting of seven steps.
Received 18 November 2012
Received in revised form 16 December 2012
Accepted 21 December 2012
Available online 11 January 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Tetralol opening
9,10-Secosteroid
Astrogorgiadiol
Calicoferol
Astrogorgol
Osteopontin
1. Introduction
(ꢀ)-Astrogorgiadiol 1, a 9,10-secosteroid of marine origin1 dis-
covered by Fusetani’s team in 19892 has since been the object of
great interest due to its unique property of osteopontin down-
regulation.3 Osteopontin seems indeed a privileged target as this
protein plays a key-role in metastatic diseases, such as cancers,4 in
demyelinating diseases, such as multiple sclerosis,5 in the de-
velopment of virulent asthma,6 and in osteoporosis.7 Moreover,
recently reported in vitro bioassays towards 16 human tumour
related protein kinases comparing (ꢀ)-astrogorgiadiol, calicoferols
and astrogorgols showed inhibitions in the micromolar range
against important kinases involved in cancer development.8
Two strategies have been developed by organic chemists for the
synthesis of this molecule. De Riccardis’ team chose a C-6eC-7
disconnection and implemented a semisynthetic route using
Grundmann’s ketone, obtained from (þ)-vitamin D3.9 Taber’s team
designed a total synthesis featuring as the key step a Robinson
annulation between the A-ring/C-ring precursor synthon 2 and the
D-ring synthon 3 (Scheme 1).10
Scheme 1. Taber’s retrosynthetic analysis.
the successful shorter synthesis of an equivalent of this key in-
termediate, using the opening of alcohol 5.
This synthon is of key importance not only for the synthesis of
(ꢀ)-astrogorgiadiol, but also for the growing family of 9,10-
secosteroids1,8dcalicoferols, astrogorgolsdwhich exhibit promis-
ing inhibitory activities and will therefore attract more and more
attention.
The recent publication in this journal by Taber et al.11 of a second
generation synthesis of this A-ring synthon prompts us to report
2. Results and discussion
2.1. A new reagent to open tetralols
* Current address: Department of Proteomics and Bioanalytics, Center of Life and
€
€
Food Sciences Weihenstephan, Technische Universitat Munchen, Emil-Erlenmeyer-
Forum 5, 85354 Freising, Germany. Tel.: þ49 (0)8161 712059; fax: þ49 (0)8161
715931; e-mail address: g.medard@tum.de.
Rousseau et al. demonstrated that Brþ(symcoll)2PF6 (BBH)
ꢀ
opens 6-methoxy-1-tetralol.12 The product of this reaction
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.12.087

ꢀ
G. Medard / Tetrahedron 69 (2013) 2348e2351
2349
constitutes a fairly advanced intermediate en route to the A-ring
synthon, which we decided to exploit. Commercially available
Iþ(symcoll)2PF6 failed to provide the iodo compound, but we
ꢀ
discovered that Brþ(symcoll)2TfOꢀ 6 is as efficient as BBH and 7 was
obtained efficiently in two steps starting from the commercially
available 6-methoxy-1-tetralone 4 (Scheme 2).
Scheme 4. Securing the allylic ketone 10.
oxidation proved very convenient and could be performed under an
atmosphere of air to secure 10.
2.3. Installing the methyl group Me-19
The second part of the construction was the installation of the
Me-19. This methylation could be envisioned at different stages, on
the aryl bromides 7, 9 or 10. Different conditions and types of re-
actions were attempted but none gave the expected methylated
product (Table 1).
Table 1
Scheme 2. Tetralol opening with Brþ(symcoll)2TfOꢀ 6.
Failed attempts of methylation at C-10
Substrate Coupling
type
Conditions
Reagent 6, already described by Brown’s team,13 was synthe-
sized according to Rousseau’s procedure, starting from silver tri-
flate, allowing atom economy14 compared to BBH (Scheme 3). It
acts as a bromonium donor, which is attacked by the aryl electrons
thanks to the donating effect of the methoxy group para. The col-
lidine then abstracts the hydrogen of the alcohol in an acid/base
reaction; the opening of the tetralol follows as the density of
electrons is displaced to produce the ketone and the aromaticity is
restored (Scheme 2).
7
9
9
9
10
10
10
10
Stille
Kumada
Substitution MeLi, Et2O
Suzuki
Stille
Suzuki
Suzuki
Stannation
Me4Sn, PdCl2(CH3CN)2, Ph3As, CuI, Et3N, DMF
MeMgBr, NiCl2(PPh3)2, THF
Trimethylboroxine, PdCl2(dppf), K2CO3, H2O, dioxane
Me4Sn, PdCl2(CH3CN)2, Ph3As, CuI, Et3N, DMF
Trimethylboroxine, PdCl2(dppf), K2CO3, H2O, DMF
Trimethylboroxine, Pd(PPh3)4, Et3N, DMF
(Bu3Sn)2, Pd(PPh3)4, toluene
It was therefore necessary to use a protectionedeprotection
sequence. We chose to protect the ketone using trimethyl ortho-
formate. What we obtained using a common procedure was the
protection of both the alkene and ketone of 10 (Scheme 5).
Scheme 3. Preparation of Brþ(symcoll)2TfOꢀ 6.
With the intermediate 7 in hand, the building of A-ring synthon
had to include the installation of Me-19 on the aromatic ring and
the construction of the conjugated ketone.
2.2. Construction of the conjugated ketone: the C-ring
precursor
The aldehyde 7 was reacted with vinylmagnesium bromide to
obtain the allylic alcohol 9 quickly and in quantitative yield
(Scheme 4). Oxidation of the latter with manganese dioxide or PDC
or PCC gave poor yields. Hence, a procedure with TEMPO/iodo-
benzene diacetate in dichloromethane15 was preferred. This
Scheme 5. Installation of the methyl in ortho via Suzuki-type reaction (with new
protectionedeprotection sequence).

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G. Medard / Tetrahedron 69 (2013) 2348e2351
2350
The reaction is not unprecedented: it was performed on ethyl
over the two steps as a white solid. The spectroscopic data matched
vinyl ketone to obtain 1,3,3-trimethoxypentane by Ansell et al.,16
but, to the best of our knowledge, it was never used as a pro-
tection previously. The trimethoxy compound 11 could then be
reacted with trimethylboroxine in a Suzuki-type reaction to get the
methylated aryl product 12 (Scheme 5). The use of methanol/water
1:1 as solvent proved to minimize the reduction of aryl bromide 11
during Suzuki coupling with trimethylboroxine.17 Trimethylbor-
oxine is not so commonly used for methylation, but its advantages
are wide. It is rather stable and cheaper than methylboronic acid.
Such a reagent, used in Suzuki couplings, makes it possible to avoid
using less convenient methyl Grignard reagents. Deprotection with
aqueous HCl yielded the A-ring synthon 13, analogous to 2, ready
for Robinson annulation.
that reported.13
4.3. 6-Methoxy-1-tetralol (5)
Sodium borohydride (4.54 g, 120 mmol) was added portionwise
to a solution of 6-methoxy-1-tetralone (7.05 g, 40 mmol) in
methanol (130 mL) at 0 ꢂC over 90 min. The mixture was concen-
trated under vacuum and water (50 mL) was added to the residue.
The aqueous phase was extracted with ether (3ꢁ50 mL), the
combined organic phase was dried on MgSO4, filtered and con-
centrated under vacuum, yielding 96% 5 (6.85 g, 38.4 mmol) as
a clear oil. The spectroscopic data matched that reported.12
4.4. 4-(2-Bromo-5-methoxyphenyl)butyraldehyde (7)
3. Conclusion
Compound 6 (2.83 g, 6 mmol) was added to a solution of 5
(891 mg, 5 mmol) in DCM (50 mL). After 15 min, the mixture was
poured in water (50 mL). The two phases were separated and the
aqueous phase further extracted with DCM (50 mL). The combined
organic phase was dried on MgSO4, filtered, concentrated under
vacuum and purified by column chromatography (silica, petroleum
ether/ethyl acetate 5:1) yielding 84% 7 (1.08 g, 4.2 mmol) as a clear
oil. The spectroscopic data matched that reported.12
We have discovered a concise route (seven linear steps, 17.4%
yield) to the A-ring/C-ring precursor synthon of (ꢀ)-astrogorgia-
diol, taking advantage of the opening of 6-methoxy-1-tetralol with
bis(sym-collidine) bromine(I) triflate. The challenging methylation
at C-10 (Me-19) fostered the development of
a new pro-
tectionedeprotection sequence of the enone (converted in 9,9,12-
trimethoxy). This synthesis constitutes a valuable tool for the ex-
ploration of calicoferols, astrogorgols and analogues.
4.5. 6-(2-Bromo-5-methoxyphenyl)hex-1-en-3-ol (9)
4. Experimental section
4.1. General
A solution of vinylmagnesium bromide in THF (1 M, 8.6 mL) was
added to a solution of 7 (2.0 g, 7.78 mmol) in THF (78 mL) under
nitrogen at rt (water bath). After 30 min, a saturated solution of
NH4Cl in water (80 mL) and ether (80 mL) were added. The two
phases were separated and the aqueous phase was further
extracted with ether (40 mL). The combined organic phase was
dried on MgSO4 and concentrated under vacuum yielding pure 9
quantitatively (2.23 g, 7.78 mmol) as a clear oil. Rf 0.30 (petroleum
All starting materials were obtained commercially from Aldrich,
Avocado, Acros, Lancaster, BDH or Strem and used without further
purification. All solvents were dried prior to use except when in-
dicated otherwise. Flash chromatography was conducted using
Merck silica gel 60 (40e60
mm). TLC was carried out on pre-coated
glass-backed plates (Merck Kiesel-gel 60 F254), visualized at
254 nm and stained with anisaldehyde or phosphomolybdic acid.
Infra-red (IR) spectra were recorded on a Perkin Elmer Spectrum
100 FT-IR spectrometer. The wave number is given in cmꢀ1 with
peak intensity signified as s, m and w for strong, medium and
weak, respectively. Mass spectra (FAB, CI or EI) were recorded at
the Departmental Mass Spectrometry Service of the University
College London on a VG Analytical 70S instrument by Dr. Lisa
Harris and John Hill. Proton Nuclear Magnetic Resonance spectra
were recorded on Bruker AMX-500, 400 or 300 NMR Spectrome-
ters. The NMR spectra were recorded with reference to the residual
solvent peak (CHCl3 in CDCl3 at 7.24 ppm for 1H NMR and 77.0 ppm
for 13C NMR). 13C DEPT, HMQC, HMBC and COSY were used to
determine structures. In the description of the spectra, the num-
bering of the carbon atoms refers to the numbering that the carbon
atoms would have in (ꢀ)-astrogorgiadiol (steroids numbering) as
seen in Scheme 1.
ether/ethyl acetate 3:1). 1H NMR (400 MHz, CDCl3,
d): 7.37 (d,
J¼8.7 Hz, 1H, H-1), 6.74 (d, J¼3.0 Hz, 1H, H-4), 6.60 (dd, J¼8.7,
3.0 Hz, 1H, H-2), 5.85 (m, 1H, H-11), 5.20 (d, J¼17.2 Hz, 1H, H-12
trans to H-11), 5.09 (d, J¼10.4 Hz, 1H, H-12 cis to H-11), 4.11 (m, 1H,
H-9), 3.75 (s, 3H, OMe), 2.69 (m, 2H, H-6), 1.71e1.57 (m, 5H, H-7 &
H-8 & OH). 13C NMR (125 MHz, CDCl3,
d): 158.9 (C-3), 142.5 (C-5),
141.0 (C-11), 133.2 (C-1), 116.0 (C-4), 114.8 (C-10), 114.9 (C-12), 113.0
(C-2), 73.0 (C-9), 55.4 (OMe), 36.5 (C-8), 36.1 (C-6), 25.7 (C-7). IR
(neat, cmꢀ1): 3369 (s br), 2936 (m), 2963 (w), 1716 (w), 1594 (m),
1571 (m), 1471 (s), 1415 (m), 1277 (m), 1239 (s), 1191 (w), 1161 (m),
1136 (w), 1051 (m), 1013 (m), 990 (m), 922 (m), 868 (w), 852 (w),
799 (m), 688 (w).
4.6. 6-(2-Bromo-5-methoxyphenyl)-hex-1-en-3-one (10)
A turbid mixture of allylic alcohol 9 (860 mg, 3 mmol), iodo-
benzene diacetate (1.45 g, 4.5 mmol) and TEMPO (70 mg,
0.45 mmol) in DCM (3 mL) was stirred at rt under an atmosphere of
air for 3 h. The mixture was diluted with DCM (15 mL), and a sat-
urated solution of Na2S2O3 in water (15 mL) and water (15 mL) were
added. The two phases were separated and the aqueous phase was
further extracted with DCM (2ꢁ15 mL). The combined organic
phase was dried on MgSO4, concentrated under vacuum and pu-
rified by column chromatography (silica, petroleum ether/ethyl
acetate 9:1) yielding 82% 10 (693 mg, 2.45 mmol) as a clear oil. Rf
0.50 (petroleum ether/ethyl acetate 3:1). 1H NMR (500 MHz, CDCl3,
4.2. Bromonium bis(sym-collidine)triflate (6)
2,4,6-Collidine (25 mL, 189 mmol) was added dropwise over
30 min to a solution of silver triflate (19.4 g, 75.5 mmol) in water
(125 mL) maintained at rt by a water bath. The mixture was then
filtered and the white solid (Agþ(sym-collidine)2TfOꢀ) was washed
with water (2ꢁ50 mL) and dried in a desiccator with P2O5 under
vacuum over the weekend. The complex was then dissolved in DCM
(250 mL). Bromine (3.9 mL, 75.5 mmol) was then added dropwise
to the solution under nitrogen, maintained at rt by a water bath.
After 1 h, the mixture was filtered to remove the precipitate of AgBr,
which was washed with ether (3ꢁ100 mL). The combined filtrate
was concentrated under vacuum to yield 96% 6 (34.0 g, 72.1 mmol)
d
): 7.38 (d, J¼8.7 Hz, 1H, H-1), 6.75 (d, J¼3.1 Hz, 1H, H-4), 6.61 (dd,
J¼8.7, 3.1 Hz, 1H, H-2), 6.34 (dd, J¼17.7, 10.5 Hz, 1H, H-11), 6.19 (dd,
J¼17.7,1.2 Hz,1H, H-12 trans to H-11), 5.80 (dd, J¼10.5,1.2 Hz,1H, H-
12 cis to H-11), 3.76 (s, 3H, OMe), 2.72 (m, 2H, H-8), 2.63 (t, J¼7.3 Hz,
2H, H-6), 1.95 (m, 2H, H-7). 13C NMR (100 MHz, CDCl3,
d): 200.4 (C-

ꢀ
G. Medard / Tetrahedron 69 (2013) 2348e2351
2351
9), 158.9 (C-3), 141.9 (C-5), 136.5 (C-11), 133.3 (C-1), 128.1 (C-12),
116.0 (C-4), 114.9 (C-10), 113.4 (C-2), 55.4 (OMe), 38.7 (C-8), 35.4
(C-6), 23.9 (C-7).
mixture was then extracted with water (10 mL) and ether
(2ꢁ10 mL). The combined organic phase was dried on MgSO4,
concentrated under vacuum and purified by column chromatog-
raphy (silica, petroleum ether/diethyl ether 3:1) yielding 60% 13
(34 mg, 0.13 mmol) as a clear oil. Rf 0.32 (petroleum ether/diethyl
4.7. 1-Bromo-4-methoxy-2-(4,4,6-trimethoxyhexyl)benzene
(11)
ether 3:1) two elutions. 1H NMR (500 MHz, CDCl3,
d): 7.03 (d,
J¼7.8 Hz, 1H, H-1), 6.66 (d, J¼2.7 Hz, 1H, H-4), 6.65 (dd, J¼7.8,
2.7 Hz, 1H, H-2), 3.80 (s, 3H, OMe), 3.72 (t, J¼6.6 Hz, 2H, H-12), 2.85
(t, J¼6.6 Hz, 2H, H-11), 2.56 (t, J¼7.7 Hz, 2H, H-6), 2.48 (t, J¼7.3 Hz,
2H, H-8), 2.21 (s, 3H, Me-19), 1.87 (m, 2H, H-7). 13C NMR (125 MHz,
CDCl3, d): 207.1 (C-9), 157.8 (C-3), 140.8 (C-5), 131.0 (C-1), 128.0
(C-10), 114.8 (C-4), 111.0 (C-2), 55.2 (OMe), 45.0 (C-11), 42.6 (C-8),
38.3 (C-12), 32.6 (C-6), 23.6 (C-7), 18.3 (C-19).
A solution of 10 (493 mg, 1.74 mmol), trimethyl orthoformate
(380
mL, 3.48 mmol) and pyridinium p-toluenesulfonate (PPTS)
(44 mg, 0.174 mmol) in methanol (8.7 mL) was heated to 70 ꢂC
under a nitrogen atmosphere. After 24 h, the mixture was extracted
with ether (30 mL) and brine (30 mL). The organic phase was dried
on MgSO4, concentrated under vacuum and purified by column
chromatography (silica, petroleum ether/diethyl ether 3:1) yielding
61% 11 (383 mg, 1.06 mmol) as a clear oil. Rf 0.25 (petroleum ether/
Acknowledgements
diethyl ether 3:1) two elutions. 1H NMR (500 MHz, CDCl3,
d): 7.38
(d, J¼8.7 Hz, 1H, H-1), 6.75 (d, J¼3.1 Hz, 1H, H-4), 6.60 (dd, J¼8.7,
3.1 Hz, 1H, H-2), 3.76 (s, 3H, OMe on C-3), 3.32 (t, J¼7.3 Hz, 2H, H-
12), 3.28 (s, 3H, OMe on C-12), 3.12 (s, 6H, 2ꢁ OMe on C-9), 2.67 (m,
2H, H-6), 1.89 (t, J¼7.3 Hz, 2H, H-11), 1.61 (m, 4H, H-7 & H-8). 13C
Novartis Pharma AG and University College London are thanked
for financial support.
Supplementary data
NMR (125 MHz, CDCl3, d): 158.9, 142.3, 133.2, 116.1, 114.9, 113.1,
102.1 (C-9), 68.4 (C-12), 58.7 (OMe on C-12), 55.4 (OMe on C-3), 47.7
(2ꢁ OMe on C-9), 36.3 (C-8), 32.8 (C-6), 32.4 (C-11), 24.1 (C-7). IR
(neat, cmꢀ1): 2952 (m), 2830 (w), 1595 (w), 1572 (m), 1471 (s), 1278
(m), 1239 (s), 1162 (m), 1107 (s), 1050 (s), 1013 (m), 961 (w), 903 (w),
870 (w), 851 (w), 800 (m). HRMS (positive FAB) calculated for
C16H25BrO4 (MþH): 361.10144, found 361.10194.
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2012.12.087.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
References and notes
4.8. 4-Methoxy-1-methyl-2-(4,4,6-trimethoxyhexyl)benzene
(12)
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mL, 4.24 mmol) followed by K3PO4
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(900 mg, 4.24 mmol) and Pd(PPh3)4 (122 mg, 0.106 mmol) were
added to an emulsion of 11 (383 mg, 1.06 mmol) in water (4.25 mL)
and methanol (4.25 mL) at rt. After 5 min, the mixture was heated
to 90 ꢂC for 24 h. The reaction was then quenched with brine
(20 mL) and extracted with ether (3ꢁ20 mL). The combined organic
phase was dried on MgSO4, concentrated under vacuum and pu-
rified by column chromatography (silica, petroleum ether/diethyl
ether 3:1) yielding 69% 12 (218 mg, 0.735 mmol) as a clear oil. Rf
0.38 (petroleum ether/diethyl ether 3:1) two elutions. 1H NMR
6. (a) Kurokawa, M.; Konno, S.; Takahashi, A.; Plunkett, B.; Rittling, S. R.; Matsui,
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Zervas, E.; Vittorakis, S.; Semitekolou, M.; Alissafi, T.; Bossios, A.; Gogos, H.;
(500 MHz, CDCl3,
d
): 7.01 (d, J¼8.2 Hz, 1H, H-1), 6.69 (d, J¼2.7 Hz,
1H, H-4), 6.63 (dd, J¼8.2, 2.7 Hz, 1H, H-2), 3.75 (s, 3H, OMe on C-3),
3.30 (t, J¼7.3 Hz, 2H, H-12), 3.27 (s, 3H, OMe on C-12), 3.11 (s, 6H, 2ꢁ
OMe on C-9), 2.55 (m, 2H, H-6), 2.22 (s, 3H, Me-19),1.89 (t, J¼7.3 Hz,
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2H, H-11), 1.58 (m, 4H, H-7 & H-8). 13C NMR (125 MHz, CDCl3,
d):
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157.8 (C-3), 141.5 (C-5), 130.8 (C-1), 127.8 (C-10), 114.7 (C-4), 110.8
(C-2), 102.1 (C-9), 68.4 (C-12), 58.6 (OMe on C-12), 55.1 (OMe on C-
3), 47.6 (2ꢁ OMe on C-9), 33.4 (C-8), 32.9 (C-6), 32.3 (C-11), 24.3
(C-7), 18.3 (C-19). IR (neat, cmꢀ1): 2949 (m), 2830 (w), 1609 (m),
1580 (w), 1500 (m), 1461 (m), 1251 (m), 1160 (m), 1108 (s), 1049 (s),
962 (w), 903 (m), 872 (w), 800 (m), 713 (w).
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(13)
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A solution of HCl in water (6 M, 2 mL) was added to 12 (66 mg,
0.22 mmol) and the emulsion was stirred at 50 ꢂC for 4 h. The