Synthetic study of strongylophorines: stereoselective construction of the characteristic lactone bridge

Article abstract of DOI:10.1016/j.tetlet.2016.07.067

Herein, we report an efficient construction of the lactone bridge of strongylophorine-2, which is a meroditerpenoid isolated from Strongylophora durissima and an inhibitor for HIF-1 transcriptional pathway. Starting from dehydroepiandrosterone acetate, the characteristic lactone has been constructed in 5.4% over 18 steps by employing, (1) modified oxy radical-mediated C–H functionalization at the C24 methyl group, and (2) four-step manipulation of C4 quaternary carbon stereogenic center. The lactone synthesized here is expected as a precursor for (8-desmethyl)strongylophorine-2 which is of particular interest in terms of structure–activity relationships in the inhibition of HIF-1 transcriptional pathway.

Full text of DOI:10.1016/j.tetlet.2016.07.067

Accepted Manuscript
Synthetic study of strongylophorines: Stereoselective construction of the char-
acteristic lactone bridge
Yuya Oikawa, Daiki Uchiyama, Takuya Shirasawa, Masato Oikawa, Yuichi
Ishikawa
PII:
S0040-4039(16)30913-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.07.067
TETL 47929
Reference:
Tetrahedron Letters
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16 July 2016
20 July 2016
Please cite this article as: Oikawa, Y., Uchiyama, D., Shirasawa, T., Oikawa, M., Ishikawa, Y., Synthetic study of
strongylophorines: Stereoselective construction of the characteristic lactone bridge, Tetrahedron Letters (2016),
doi: http://dx.doi.org/10.1016/j.tetlet.2016.07.067
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Yuya Oikawa, Daiki Uchiyama, Takuya Shirasawa, Masato Oikawa, Yuichi Ishikawa*

1
Tetrahedron Letters
Synthetic study of strongylophorines: stereoselective construction of the characteristic
lactone bridge
Yuya Oikawa¶, Daiki Uchiyama¶, Takuya Shirasawa, Masato Oikawa, Yuichi Ishikawa
Yokohama City University, Seto 22-2, Kanazawa-ku, Yokohama 236-0027, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Herein, we report an efficient construction of the lactone bridge of strongylophorine–2, which is
a meroditerpenoid isolated from Strongylophora durissima and an inhibitor for HIF–1
transcriptional pathway. Starting from dehydroepiandrosterone acetate, the characteristic lactone
has been constructed in 5.4% over 18 steps by employing, (1) modified oxy radical-mediated C–
H functionalization at the C24 methyl group, and (2) four-step manipulation of C4 quaternary
carbon stereogenic center. The lactone synthesized here is expected as a precursor for (8–
desmethyl)strongylophorine–2 which is of particular interest in terms of structure–activity
relationships in the inhibition of HIF–1 transcriptional pathway.
Available online
Keywords:
Strongylophorines
Meroditerpenoid
Hypoxia inducible factor–1
C–H functionalization
δ–lactone bridge
2009 Elsevier Ltd. All rights reserved.
Introduction
desmethyl)strongylophorine–2
(2).
Starting
from
dehydroepiandrosterone acetate, we have successfully established
a route for formation of the unique and characteristic δ–lactone
(A’–ring) which has been suggested to be important for the
biological activity.6 This is the first chemical synthesis of the δ–
lactone bridge fused to perhydrophenanthrene in the
strongylophorine synthesis.7
Hypoxia inducible factor–1 (HIF–1) upregulates expression of
genes and protein such as vascular endothelial growth factor
(VEGF) associated with tumor growth and progression.1 Inhibitor
for hypoxia-activated HIF–1 transcriptional pathway often acts as
an anticancer agent,2 and in 2008, strongylophorines–2 (1, Fig.
1)3,4 and –8 (structure not shown)4 were reported to belong to the
class of these inhibitors.5 Strongylophorine–2 (1), first isolated in
1978 from marine sponge,3,4 Strongylophora durissima, is a
meroditerpenoid composed of δ–lactone (A’–ring) and
hydroxychromane (DE–ring) fused to perhydrophenanthrene core
skeleton (ABC–ring). Because of the limited availability from
natural resources, the mode of action as the inhibitor for HIF–1
transcription pathway has not been unfortunately clarified. We,
therefore, started a program on synthesis of 1 and the analogs.
Here, we report our progress toward a synthesis of (8–
Results and discussion
As a model study, we first explored oxidation of methyl group
at C24 by oxy radical-mediated iodination followed by
Figure 1. Our design and synthetic strategy for analog of
strongylophorine–2. Numbering refers to that for
strongylophorine–8.5
Scheme 1. Model study for C–H oxidation of C24 methyl group using
cholesterol acetate (4).
———
 Corresponding author. Tel.: +81 45 787 2183; e-mail address: yu_iskw@yokohama-cu.ac.jp (Y. Ishikawa).
¶ These authors contributed equally to this work.

2
Tetrahedron
etherification using cholesterol as a model compound (Scheme
planned to be constructed in a stepwise manner, and Scheme 2
shows the synthesis of hydroxymethylated intermediate 17. First,
homoallylic alcohol 9 was synthesized over 3 steps from 8
according to the procedure shown in Scheme 1. The yield (57%
for 3 steps) was higher than that reported previously (36%).11
Protecting group manipulation of 9 gave secondary alcohol 10 in
95% yield for 2 steps. Oppenauer oxidation12 provided enone 11
with concomitant migration of the olefin in good yield (95%).
The C3 carbonyl group was then selectively removed to give rise
to 12 via dithiane (structure not shown),13 which was subjected to
stereoselective reduction14 followed by protection (MOMCl,
iPr2NEt). Hydroboration of trisubstituted olefin 13 furnished
alcohol 14 after work-up with NaOH and H2O2. Although alcohol
14 was an inseparable diastereomeric mixture (1:1), the desired
(5R)–isomer was isolated after oxidation in 53% yield. The
1). In 1985, Sucrow et al have reported the 3-step synthesis of
alcohol 7 from cholesterol acetate (4) (50% total yield),8 and we
decided to improve the reactions in the present study. Thus,
hypobromous acid (BrOH)-mediated bromination of cholesterol
acetate (4) readily provided bromohydrin 5 in 58% with the
diastereomer (17%, structure not shown).9 We next attempted to
improve the procedure for construction of tetrahydrofuran 6 by
Pb(OAc)4-mediated unfunctionalized C–H iodination and
spontaneous ether formation. As mentioned above, the same
reaction had been reported by Sucrow et al in 1985 under
irradiation conditions with 500 W lamp.8 Here we found the
reaction proceeded without irradiation to give rise to 6
quantitatively, when the reagents were added to a solution of the
substrate 5 in refluxing benzene to drive the reaction smoothly. It
should be noted that other reaction conditions employing
PhI(OAc)2 and I2 under ultrasonication10 gave 5,6–β–epoxide in
42% yield (structure not shown), and the yield for desired 6 was
quite low (18%). Reductive opening of bromo ether 6 readily
provided homoallylic alcohol 7 in 89% yield. While our total
yield (51% for 3 steps) for alcohol 7 from cholesterol acetate (4)
is only comparable to that in Sucrow’s procedure (50% for 3
steps),8 our irradiation-free procedure significantly simplified the
oxy radical-mediated remote functionalization of methyl group.
structure was determined on the basis of NMR analysis (3JH5,H6
=
12.0, 4.0 Hz). It should be also noted here that the conversion
yield for the desired (5R)–isomer 15 from olefin 13 is actually
much higher, since the undesired epimer, (5S)–15, can be
thermodynamically epimerized under alkaline conditions (K2CO3,
MeOH) to give desired (5R)–15 in 57% yield. Toward
elaboration of C4 quaternary carbon center, Wittig reaction
(Ph3PMeBr, KOtBu) and hydroboration (BH3 ・ THF; NaOH,
H2O2) were successively carried out here to furnish alcohol 17 in
94% yield for 2 steps.15,16
With the improved procedure shown in Scheme 1 in hand, we
started our synthetic study of 2 from dehydroepiandrosterone
acetate (8). The quaternary carbon stereogenic center at C4 was
Scheme 3. Elaboration of the C4 stereogenic center and the lactone bridge
toward 3.
Introduction of methyl group at C4 was next investigated
(Scheme 3). We expected that electrophilic substitution would
deliver quaternary carbon stereogenic center at C4
stereoselectively under kinetic conditions.16,17 Indeed, we were
gratified to find that aldehyde 18, prepared by IBX oxidation18 of
17 in 96% yield, underwent deprotonation followed by
stereoselective methylation to give rise to carboxylic acid 20 in
42% yield as a sole product after Pinnick oxidation.19 The 4S–
stereochemistry was determined after formation of the lactone
bridge (see below). The low yield was due to the inherent
instability of the substrate 18 and the product 19, which suffer
decomposition in one day even at 0 °C. Finally, acidic hydrolysis
(6 M HCl, THF) induced concomitant deprotection of MOM
groups of 20 and lactonization to furnish desired lactone 3 in
81% yield.
The structure of lactone 3 was unequivocally determined by
de novo NMR spectroscopic analysis, which also supported 4S–
stereoselectivity in the methylation (1819). In addition, we
were gratified to find that the 13C NMR chemical shift values of
synthetic 3 around A– and A’–rings are nearly identical to those
of natural 13,4 (Table 1), to indicate their identical configuration
and conformation.
Scheme 2. Functionalization at C4 and C24 positions starting from
dehydroepiandrosterone acetate (8).

3
Conclusion
In conclusion, we have successfully established construction
of the characteristic lactone bridge of strongylophorine–2 for the
first time,7 which is suggested to be important for the inhibitory
activity for HIF–1 transcriptional pathway.6 The synthesis of the
key segment 3 was achieved in 5.4% yield over 18 steps starting
from dehydroepiandrosterone acetate (8) by developing improved
References and notes
1.
2.
3.
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Mol. Cancer Ther. 2004, 3, 647-654.
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During preparation of this manuscript, a synthesis of 1 has been
reported by Yu et al, see; Yu, W.; Hjerrild, P.; Overgaard, J.;
Poulsen, T. B. Angew. Chem. Int. Ed. 2016, published online.
Sucrow, W.; Howard, S. Chem. Ber. 1985, 118, 4341-4346.
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1536.
Table 1. Comparison of the 13C NMR spectroscopic data for natural 13,4
and synthetic 3.
4.
5.
position
1
2
3
4
5
δc (natural, ppm)a
38
22.6
40.3
43.2
50
δc (3, ppm)b
38.4
23.5
40.1
43.5
Δδ (ppm)
-0.4
-0.9
0.2
-0.3
0.7
6.
7.
49.3
8.
9.
10
24
25
26
36.5
73.4
23.5
176
35.9
74.3
23.6
176.1
0.6
-0.9
-0.1
-0.1
10. Costa, S. C. P.; Moreno, M. J. S. M.; Sáe Melo, M. L.; Campos
Neves, A. Tetrahedron Lett. 1999, 40, 8711-8714.
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A. Helv. Chim. Acta 1963, 46, 1361-1369; Terasawa, T.; Okada,
T. Tetrahedron 1986, 42, 537-45.
a) Extracted from Faulkner paper (pyridine–d5).4
b) Collected in pyridine–d5 at 100 MHz.
12. Coustal, S.; Fagart, J.; Davioud, E.; Marquet, A. Tetrahedron
1995, 51, 3559-3570.
13. Numazawa, M.; Kamiyama, T.; Tachibana, M.; Oshibe, M. J.
Med. Chem. 1996, 39, 2245-2252.
oxidative C–H functionalization at the C24 methyl group,
followed by stereoselective construction of the C4 quaternary
carbon stereogenic center in a stepwise manner. Current efforts
14. Stastna, E.; Rath, N. P.; Covey, D. F. Org. Biomol. Chem. 2011, 9,
4685-4694.
15. The hydroboration is highly α–selective. In a related example,16
the hydroboration of exo-methylene at C4 has been reported to
selectively take place from the α–side. Our observation is
consistent with the report and the selectivity can be attributed to
the presence of the sterically demanding axial MOMOCH2– group
at C10. See reference 16.
are
now
focused
on
the
synthesis
of
(8–
desmethyl)strongylophorine–2 (2), which would be achieved in
an additional 7–9 steps from 3 and the inhibitory activity is of
particular interest in terms of the structure–activity relationships
to develop more efficient inhibitor, and the results will be
reported in due course.20
16. Alvarez-Manzaneda, E.; Chahboun, R.; Alvarez, E.; Ramos, J. M.;
Guardia, J. J.; Messouri, I.; Chayboun, I.; Mansour, A. I.;
Dahdouh, A. Synthesis 2010, 2010, 3493-3503.
17. Thompson, T. N.; Sierra, M. G.; McChesney, J. D. J. Org. Chem.
1985, 50, 4447-4450; Ling, T.; Chowdhury, C.; Kramer, B. A.;
Vong, B. G.; Palladino, M. A.; Theodorakis, E. A. J. Org. Chem.
2001, 66, 8843-8853; Toyota, M.; Asano, T.; Ihara, M. Org. Lett.
2005, 7, 3929-3932.
18. Frigerio, M.; Santagostino, M.; Sputore, S.; Palmisano, G. J. Org.
Chem. 1995, 60, 7272-7276; Gobbini, M.; Armaroli, S.; Banfi, L.;
Benicchio, A.; Carzana, G.; Ferrari, P.; Giacalone, G.; Marazzi,
G.; Moro, B.; Micheletti, R.; Sputore, S.; Torri, M.; Zappavigna,
M. P.; Cerri, A. Bioorg. Med. Chem. 2010, 18, 4275-4299.
19. Kraus, G. A.; Taschner, M. J. J. Org. Chem. 1980, 45, 1175-1176;
Bal, B. S.; Childers Jr, W. E.; Pinnick, H. W. Tetrahedron 1981,
37, 2091-2096; Ziegler, F. E.; Wallace, O. B. J. Org. Chem. 1995,
60, 3626-3636.
Acknowledgments
Financial support (a Grant-in-Aid for Scientific Research
(25350967)) from the Ministry of Education, Science, Sports,
Culture and Technology, Japan, is gratefully acknowledged. We
also thank Ms. Mikiko Kiuchi (Thermo Fisher Scientific K.K.)
for collecting HRMS data of all new compounds. Thanks are also
due to one of the reviewers for suggestion of stereochemical
control in the reactions at C4.
Supplementary data
Supplementary data (experimental procedures, 1H and 13C
NMR spectra, and NOESY analysis of 17) associated with this
article can be found, in the online version, at
http://dx.doi.org/10.1016/.
20. Our future work will also focus on methylation of 3 at C8 position
by C–H functionalization technology toward synthesis of 1.

4
Tetrahedron
Highlights
Strongylophorine-2 is a meroditerpenoid isolated
from marine sponge, Strongylophora durissima.
This compound is an inhibitor for HIF–1
transcriptional pathway.
Oxidative C–H functionalization at the C24 methyl
group proceeded smoothly.
Construction of the C4 quaternary carbon
stereogenic center was accomplished.
The characteristic lactone bridge was constructed
in a stepwise manner.