Synthesis of a novel sphingosine kinase inhibitor (-)-F-12509A and determination of its absolute configuration

Article abstract of DOI:10.1016/j.tetlet.2007.05.043

The synthesis of a novel sphingosine kinase inhibitor, (-)-F-12509A ((-)-1), was achieved in a highly efficient manner that included nine longest linear steps and 45% overall yield from (-)-bicyclic β-ketoester (-)-2, and its absolute configuration was de

Full text of DOI:10.1016/j.tetlet.2007.05.043

Tetrahedron Letters 48 (2007) 4865–4867
Synthesis of a novel sphingosine kinase inhibitor (ꢀ)-F-12509A
and determination of its absolute configuration
Nobuhiro Maezawa, Noriyuki Furuichi, Hiroshi Tsuchikawa and Shigeo Katsumura*
Department of Chemistry and Open Research Center on Organic Tool Molecules, School of Science and Technology,
Kwansei Gakuin University, Sanda, Hyogo 669-1337, Japan
Received 9 April 2007; revised 8 May 2007; accepted 10 May 2007
Available online 16 May 2007
Abstract—The synthesis of a novel sphingosine kinase inhibitor, (ꢀ)-F-12509A ((ꢀ)-1), was achieved in a highly efficient manner
that included nine longest linear steps and 45% overall yield from (ꢀ)-bicyclic b-ketoester (ꢀ)-2, and its absolute configuration
was determined to be (5S,9S,10S).
Ó 2007 Elsevier Ltd. All rights reserved.
As a novel sphingosine kinase (SphK) inhibitor, (ꢀ)-F-
12509A ((ꢀ)-1), was isolated from a culture broth of a
discomycete, Trichopezizella barbata SANK 25395, by
Kohama and co-workers in 2000.1,2 F-12509A is the first
SphK inhibitor isolated from natural sources, and inhib-
its rat liver SphK in a dose-dependent manner with an
IC50 value of 18 lM and in a competitive manner with
respect to sphingosine (SPH).1 This molecule showed
no inhibitory activity toward other enzymes such as
mammalian neutral sphingomyelinase, PI3-kinase, and
protein kinase C (PKC) at 100 lM. These results indi-
cated that F-12509A is a specific inhibitor of SphK,
which catalyzes the phosphorylation of SPH at its pri-
mary hydroxy group to biosynthesize sphingosine1-
phosphate (S1-P), and is known as a key enzyme that
regulates the cellular S1-P level. S1-P has been paid
much attention as a remarkable phospholipids based
on the discovery of its biological receptor3 in addition
to its quite attractive biological activities such as cell
division, cell growth, and platelet activation.4 (ꢀ)-F-
12509A ((ꢀ)-1) possesses a dihydroxybenzoquinone
moiety attached to a drimane sesquiterpene skeleton.
The unique dihydroxybenzoquinone moiety was found
in some biologically interesting natural products such
as maesaquinone.5 However, only a few methods for
preparation of this moiety have been reported in the lit-
erature.5,6 Our interest in the sphingolipid chemistry,
involving the design and synthesis of substrate analogs7
and the synthesis of tool molecules useful for following
sphingolipid metabolism,8 prompted us to synthesize
this novel and specific SphK inhibitor, (ꢀ)-F-12509A
((ꢀ)-1). We disclose herein the efficient synthesis of F-
12509A and its dihydroderivative, along with determi-
nation of the absolute configuration of naturally occur-
ring (ꢀ)-F-12509A ((ꢀ)-1) (see Fig. 1).
By searching the literature, we learned that hyatellaqui-
none is a mono-methyl ether of F-12509A and was syn-
thesized from (ꢀ)- and (+)-arbicanal (3).9 We then
planned to follow the reported synthesis in order to con-
struct the basic skeleton of F-12509A. According to our
established procedure,10 we easily synthesized (ꢀ)- and
(+)-b-ketoester 2 by the resolution of enantiomers using
an acetal formation with a chiral auxiliary, 1,4-O-dibenz-
yl-L-threitol (Scheme 1).
The Wittig olefination of (ꢀ)-2 with triphenylphos-
phonium methylide followed by reduction and then
Keywords: Sphingosine kinase inhibitor; Dihydroxyquinone; Synthesis;
Absolute configuration.
*
Corresponding author. Tel.: +81 79 565 8314; fax: +81 79 565
9077; e-mail: katsumura@ksc.kwansei.ac.jp
Figure 1. Sphingosine kinase inhibitor (ꢀ)-F-12509A.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.05.043

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N. Maezawa et al. / Tetrahedron Letters 48 (2007) 4865–4867
23
the optical rotation, ½aꢁD ꢀ95.2 (c 0.20, MeOH), (lit.1
25
½aꢁD ꢀ96 (c 0.25, MeOH)). Thus, the absolute configura-
tion of the natural (ꢀ)-F-12509A ((ꢀ)-1) was confirmed
as (5S,9S,10S) by the present synthesis. Using the same
23
procedure, unnatural enantiomer (+)-1 (½aꢁD +92.8
(c 0.28, MeOH)) was also synthesized from bicyclic b-
ketoester (+)-2. In addition, the dihydro analog ( )-9
of F-12509A was synthesized from ( )-8 by a sequence
of hydrogenation of its exo-olefin, oxidation to the qui-
none, and replacement to the hydroxyl groups.15
Synthesized natural (ꢀ)-1 and unnatural congener (+)-1
showed almost the same inhibitory activity toward
SphK, and moreover, both ( )-1 and its dihydro analog
( )-9 also showed inhibitory effects equal to natural (ꢀ)-
1 (IC50 values of four compounds were 17–19 lM). The
detailed results of these biological activities will be
reported elsewhere.
In summary, we achieved the total synthesis of the novel
sphingosine kinase inhibitor, (ꢀ)-F-12509A ((ꢀ)-1), in
an efficient manner (nine steps and 45% overall yield
from bicyclic b-ketoester (ꢀ)-2), and determination of
its absolute configuration as (5S,9S,10S). All the synthe-
sized compounds such as ( )- and each enantiomer of
F-12509A, and its dihydro analog ( )-9, showed an
effective biological activity toward SphK.
Acknowledgments
Scheme 1. Reagents and conditions: (a) Ph3P+CH3Brꢀ, NaNH2, THF,
rt, 1 h; (b) LiAlH4, THF, rt, 20 h (99%, two steps); (c) TPAP, NMO,
CH2Cl2, rt, 30 min (100%); (d) n-BuLi, TMEDA, THF, rt, 1 h then
(ꢀ)-3, rt, 5 min (94%); (e) (i) NaHMDS, THF, ꢀ78 °C, 30 min; (ii)
CS2, ꢀ60 °C, 1 h; (iii) MeI, 0 °C, 2 h; (f) n-Bu3SnH, AIBN, C6H6,
80 °C, 2 h (92%, two steps); (g) 2 N HCl aq, AcOH, MeOH, rt, 24 h
(100%); (h) salcomine (7), O2, DMF, rt, 20 h (89%); (i) 4 N KOH aq,
MeCN, reflux, 3 h (93%); (j) PtO2, H2, MeOH, rt, 8 h; (k) CAN, H2O,
MeCN, 0 °C, 20 min (100%, two steps); (l) 4 N KOH aq, MeCN,
reflux, 15 h (89%).
We are grateful to Dr. Kohama (Sankyo Co. Ltd.) for
his kind gift of natural (ꢀ)-F12509A. We also thank
Professor Y. Igarashi and his co-workers (Graduate
School of Pharmaceutical Sciences, Hokkaido Univer-
sity) for conducting the SphK assay. This work was par-
tially supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture,
Sports, Science, and Technology, Japan, and JSPS
(Research Fellowship for N.F.). This study was also
supported by a Matching Fund Subsidy for a Private
University.
oxidation, quantitatively produced (ꢀ)-arbicanal (3).
Then, the aryllithium generated in situ by treatment of
the benzenetriol derivative 4, which was prepared from
commercially available 2,5-dimethoxybenzaldehyde
according to the reported procedure,11 with n-BuLi in
the presence of TMEDA was allowed to react with
(ꢀ)-3 to produce the corresponding alcohol (ꢀ)-5 in
good yield. The resulting hydroxyl group was removed
using the Barton method via the xanthate ester12 to pro-
vide (ꢀ)-6 in 92% yield over two steps. The MOM group
was removed by treatment with acid and the subsequent
oxidation of the obtained phenol was achieved using sal-
comine (N,N-bis(salicylidene)ethylenediimino cobalt(II)
(7) under an oxygen atmosphere11 to successfully obtain
para-quinone (ꢀ)-813 in 89% yield without the formation
of its ortho-isomer. Finally, the two methoxy groups of 8
were replaced by 1,4-addition of a hydroxyl anion to
dimethoxyquinone6a in acetonitrile to achieve the syn-
thesis of (ꢀ)-F-12509A ((ꢀ)-1). The spectral and physi-
cal data of the synthesized compound14 were in good
agreement with those of the natural product including
References and notes
1. Kono, K.; Tanaka, M.; Ogita, T.; Hosoya, T.; Kohama,
T. J. Antibiot. 2000, 53, 459.
2. Kono, K.; Sugiura, M.; Kohama, T. J. Antibiot. 2002, 55,
99.
3. Lee, M.-J.; Van Brocklyn, J. R.; Thangada, S.; Liu, C. H.;
Hand, A. R.; Menzeleev, R.; Spiegel, S.; Hla, T. Science
1998, 279, 1552.
4. Yatomi, Y.; Ruan, F.; Hakomori, S.; Igarashi, Y. Blood
1995, 86, 193.
5. Fukuyama, Y.; Yaso, H.; Kiriyama, H.; Takahashi, H.;
Minami, H.; Kamikawa, T. Tetrahedron 1997, 53, 16969.
6. For example, (a) Pirrung, M. C.; Deng, L.; Li, Z.; Park, K.
J. Org. Chem. 2002, 67, 8374; (b) Weider, P. R.; Hegedus,
L. S.; Asada, H.; D’Andreq, S. V. J. Org. Chem. 1985, 50,
4276.
7. (a) Hakogi, T.; Fujii, S.; Morita, M.; Ikeda, K.; Katsu-
mura, S. Bioorg. Med. Chem. Lett. 2005, 15, 2141; (b)
Hakogi, T.; Taichi, M.; Katsumura, S. Org. Lett. 2003, 5,

N. Maezawa et al. / Tetrahedron Letters 48 (2007) 4865–4867
4867
2801; (c) Hakogi, T.; Monden, Y.; Taichi, M.; Iwama, S.;
Fujii, S.; Ikeda, K.; Katsumura, S. J. Org. Chem. 2002, 67,
4839; (d) Hakogi, T.; Monden, Y.; Iwama, S.; Katsumura,
S. Org. Lett. 2000, 2, 2627.
1.46–1.63 (m, 2H), 1.39 (m, 1H), 1.36 (m, 1H), 1.29 (m,
1H), 1.21 (m, 1H), 1.14 (dd, J = 12.7, 2.4 Hz, 2H), 0.86 (s,
3H), 0.81 (s, 3H), 0.76 (s, 3H); 13C NMR (CDCl3,
100 MHz) d 183.3, 182.8, 158.9, 156.0, 148.8, 130.9, 106.7,
105.3, 61.2, 56.3, 55.6, 55.0, 42.1, 40.2, 38.7, 38.4, 33.6,
33.6, 24.5, 21.7, 19.5, 19.2, 14.1; ESI HRMS m/z calcd for
C23H32O4 [M+Na]+ 395.2198, found 395.2188.
8. (a) Hasegawa, H.; Yamamoto, T.; Hatano, S.; Hakogi, T.;
Katsumura, S. Chem. Lett. 2004, 33, 1592; (b) Shigenari,
T.; Hakogi, T.; Katsumura, S. Chem. Lett. 2004, 33,
594; (c) Hakogi, T.; Shigenari, T.; Katsumura, S.; Sano,
T.; Kohno, T.; Igarashi, Y. Bioorg. Med. Chem. Lett.
2003, 13, 661; (d) Murakami, M.; Iwama, S.; Fujii, S.;
Ikeda, K.; Katsumura, S. Bioorg. Med. Chem. Lett. 1997,
7, 1725.
23
14. Data for (ꢀ)-F-12509A ((ꢀ)-1): ½aꢁD ꢀ95.2 (c 0.20,
25
MeOH), (lit.1 ½aꢁD ꢀ96 (c 0.25, MeOH)); IR (KBr,
cmꢀ1) 3322, 2928, 1640, 1616, 1352, 1318, 1190; 1H
NMR (CDCl3, 400 MHz) d 7.76 (br s, 2H), 5.98 (s, 1H),
4.67 (d, J = 1.2 Hz, 1H), 4.66 (d, J = 1.2 Hz, 1H), 2.66
(dd, J = 14.2, 11.0 Hz, 1H), 2.54 (dd, J = 14.4, 3.2 Hz,
1H), 2.40 (br d, J = 11.5 Hz, 1H), 2.32 (ddd, J = 12.4, 3.9,
2.4 Hz, 1H), 1.94 (dt, J = 12.9, 4.8 Hz, 1H), 1.79 (br dt,
J = 12.4, 3.7 Hz, 1H), 1.72 (m, 1H), 1.50–1.68 (m, 2H),
1.41 (m, 1H), 1.35 (m, 1H), 1.32 (m, 1H), 1.25 (m, 1H),
1.17 (dd, J = 12.7, 2.7 Hz, 1H), 0.88 (s, 3H), 0.82 (s, 3H),
0.77 (s, 3H); 13C NMR (CDCl3, 100 MHz) d 148.6, 116.9,
106.6, 102.0, 55.6, 54.1, 42.1, 40.1, 38.9, 33.6, 24.5, 21.7,
19.5, 18.8, 14.0; ESI HRMS m/z calcd for C21H28O4
[MꢀH]ꢀ 343.1909, found 343.1901.
9. (a) Poigny, S.; Hour, T.; Guyot, M.; Samadi, M. J. Org.
Chem. 1999, 64, 9318; (b) Bernet, A.; Schroder, J.; Seifert,
K. Helv. Chem. Acta 2003, 86, 2009.
10. (a) Furuichi, N.; Hata, T.; Soetjipto, H.; Kato, M.;
Katsumura, S. Tetrahedron 2001, 57, 8425; (b) Soetjipto,
H.; Furuichi, N.; Hata, T.; Katsumura, S. Chem. Lett.
2000, 1302; (c) Furuichi, N.; Kato, M.; Katsumura, S.
Chem. Lett. 1999, 1247; (d) Hata, T.; Tanaka, K.;
Katsumura, S. Tetrahedron Lett. 1999, 40, 1731.
11. Kubo, I.; Kim, M.; Ganjian, I. Tetrahedron 1987, 43,
2653.
15. Data for ( )-9: IR (KBr, cmꢀ1) 3304, 2926, 2849, 1615,
1196, 829; 1H NMR (CDCl3, 400 MHz) d 5.99 (s, 1H),
2.53 (m, 2H), 1.88 (m, 1H), 1.81 (dt, J = 12.0, 3.2 Hz, 1H),
1.71 (m, 1H), 1.67 (m, 1H), 1.62 (ddt, J = 13.6, 13.6,
3.9 Hz, 1H), 1.61 (m, 1H), 1.53 (m, 1H), 1.42–1.52 (m,
2H), 1.38 (m, 1H), 1.30 (m, 1H), 1.20 (dd, J = 12.6,
4.1 Hz, 1H), 1.13 (m, 1H), 0.99 (d, J = 7.3 Hz, 3H), 0.93
(s, 3H), 0.85 (s, 3H), 0.82 (s, 3H); 13C NMR (CDCl3,
100 MHz) d 127.0, 102.1, 56.8, 52.7, 39.3, 34.8, 33.4, 31.0,
30.7, 29.7, 21.6, 20.2, 18.5, 16.2, 15.9, 15.2; ESI HRMS
m/z calcd for C23H34O4 [M+MeOHꢀH]ꢀ 377.2328, found
377.2334.
12. (a) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc.,
Perkin Trans. 1 1975, 1574; (b) Katoh, T.; Nakatani, M.;
Shikita, S.; Sampe, R.; Ishiwata, A.; Ohmori, O.; Naka-
mura, M.; Terashima, S. Org. Lett. 2001, 3, 2701.
23
13. Data for (ꢀ)-8: ½aꢁD ꢀ67.6 (c 0.56, CHCl3); IR (KBr,
1
cmꢀ1) 2938, 2866, 1728, 1659, 1601, 1215, 1047, 849; H
NMR (CDCl3, 400 MHz)
d 5.69 (s, 1H), 4.68 (d,
J = 1.5 Hz, 1H), 4.66 (d, J = 1.5 Hz, 1H), 4.06 (s, 3H),
3.78 (s, 3H), 2.69 (dd, J = 13.6, 10.7 Hz, 1H), 2.51 (dd,
J = 13.9, 2.9 Hz, 1H), 2.29 (m, 1H), 1.90 (dt, J = 13.4,
2.9 Hz, 1H), 1.78 (br d, J = 12.2 Hz, 1H), 1.71 (m, 1H),