Synthesis of (-)-Hyatellaquinone and Revision of Absolute Configuration of Naturally Occurring (+)-Hyatellaquinone

Full text of DOI:10.1021/jo9910886

9318
J . Org. Chem. 1999, 64, 9318-9320
Syn th esis of (-)-Hya tella qu in on e a n d
Revision of Absolu te Con figu r a tion of
Na tu r a lly Occu r r in g (+)-Hya tella qu in on e
Ste´phane Poigny, Thomas Huor, Miche`le Guyot, and
Mohammad Samadi*
Laboratoire de Chimie, ESA 8041 CNRS, Muse´um National
d'Histoire Naturelle, 63 rue Buffon, F-75005 Paris, France
Received J uly 7, 1999
More than a hundred sesquiterpene quinones or quinols
from marine sources have been reported, the majority of
which have been isolated from sponges. Many of them
exhibit a variety of promising biological activities such
as antimicrobial, antiviral, cytotoxic, and immunomodu-
latory effects.1 However, their absolute configuration has
been difficult to establish and still remains the subject
of controversy. Among them is the marine natural
product (+)-hyatellaquinone 1, which was isolated from
the active anti-HIV RTs extracts of the sponge Hyatella
intestinalis (Spongidae) by Kashman et a1.2 Although the
authors correctly assigned the relative configuration of
(+)-hyatellaquinone as 1a on the basis of comparison of
spectral data with that of naturally occurring (+)-zonarol
2a ,3 the absolute configuration of zonarol, a seaweed
metabolite, was later revised after chemical degradation4
and two enantiomerically controlled syntheses5,6 and
assigned as 2b with (1R,4aR,8aR) stereochemistry at the
chiral centers of the drimane skeleton. The same ses-
quiterpene quinone 1a was reported by Capon et al7 from
Spongia sp. as an isomer of spongiaquinone, but the
absolute configuration was not firmly established because
of the paucity of available material (Figure 1).
F igu r e 1.
Sch em e 1
As a part of our program directed toward the synthesis
of bioactive marine natural products, we undertook the
synthesis of 1a , starting from the optically active (+)-
sclareolide (3) bearing the right stereochemistry of the
chiral centers at C-1, C-4a, and C-8a required for the
drimane skeleton. The strategy that we adopted for the
synthesis of 1a (vide infra) is based on coupling the
aldehyde 10 derived from sclareolide with the lithium
anion of 1,2,4,5-tetramethoxybenzene as precursor of the
8
quinone moiety. Previously, we have reported that a
quinone system such as 1 could be prepared by oxidation
of substituted 1,2,4,5-tetramethoxybenzene with ceric
ammonium nitrate (CAN), which provokes formation of
* Corresponding author. Phone: 33-1-40-79-31-44. Fax: 33-1-40-
79-31-45. E-mail: Samadi@mnhn.fr.
(1) Capon, R. J . Marine Sesquiterpene/Quinones. In Studies in
Natural Products Chemistry; Atta-ur-Rahman, Ed.; Elsevier Science:
New York, 1995; Vol. 15, pp 289-326.
(2) Talpir, R.; Rudi, A.; Kashman, Y.; Loya, Y.; Hizi, A. Tetrahedron
1994, 50, 4179.
(3) Fenical, W.; Sims, J . J .; Squatrito, D.; Wing, R. M.; Radlick, P.
J . Org. Chem. 1973, 38, 2383.
(4) Cimino, G.; de Stephano, S.; Fenical, W.; Minale, L.; Sims, J . J .
Experientia 1975, 31, 1250.
(5) Mori, K.; Komatsu, M. Bull. Soc. Chim. Belg. 1986, 95, 771.
(6) Akita, H.; Nozawa, M.; Shimizu, H. Tetrahedron: Asymmetry
1998, 9, 1789.
(7) Capon, R. J .; Groves, D. R.; Urban, S.; Watson, R. Aust. J . Chem.
1993, 46, 1245.
the quinone and deprotection of the more hindered
methyl ether in one step to provide the desired 2-hydroxy-
5-methoxy-1,4-benzoquinone. As outlined below, herein
we report the total synthesis of (1S,4aS,8aS)-hyatel-
laquinone 1a , which enabled us to assign the (1R,4aR,-
8aR) stereochemistry to the naturally occurring (+)-
hyatellaquinone 1b by comparison of optical rotations.
The commercially available sclareolide 3 was trans-
formed to the known acetate 4 over two steps according
(8) (a) Poigny, S.; Guyot, M.; Samadi, M. J . Org. Chem. 1998, 63,
5890. (b) Poigny, S.; Guyot, M.; Samadi, M. Tetrahedron 1998, 54,
14791.
10.1021/jo9910886 CCC: $18.00 © 1999 American Chemical Society
Published on Web 11/19/1999

Notes
J . Org. Chem., Vol. 64, No. 25, 1999 9319
Sch em e 2
to the procedure described in the literature.9 Dehydration
of tertiary alcohol 4 (2.5 equiv of SOCl2, 1 equiv of
4-DMAP, pyridine) afforded, in quantitative yield, an
slow addition of a solution of ceric ammonium nitrate (2.5
equiv, CH3CN-H2O) to compound 14 at 0 °C and stirring
for 4 h at room temperature afforded the desired hya-
tellaquinone 1a (58%) along with compound 15 (26%)
(Scheme 2).
inseparable mixture of exo and endo olefins 5 (∆2,9:∆2,3
:
1,2
∆
in a ratio of 6.25:2.5:1.25). To circumvent this
difficulty, partial epoxidation of the crude mixture of
olefins 5 by careful treatment with 0.375 equiv of
m-CPBA at 0 °C for 1 h gave the more polar epoxides 6
and 7 and left the unreacted pure ∆2,9-exo-olefin 8 in 60%
yield over two steps. Deprotection of acetate 8 (3 equiv
of KOH, MeOH) provided alcohol 9, which was identical
in all respects (IR, NMR, MS, [R]D) with the known
naturally occurring (+)-albicanol, a potent fish antifeed-
ant, isolated both from the liverwort Diplophyllum albi-
cans10 and the marine dorid nudibranch Cadlina luteo-
marginata.11 Oxidation of alcohol 9 with PDC in CH2Cl2
furnished the desired aldehyde 1012 in 84% yield (Scheme
1).
Coupling the above aldehyde 10 with the lithium anion
of 1,2,4,5-tetramethoxybenzene 118b,13 (3 equiv of 11, 2.5
equiv of BuLi, THF, 0 °C) afforded the addition compound
12 as a mixture of diastereomers in 74% yield. Benzylic
deoxygenation was accomplished by first acetylating 12
(Ac2O, catalytic 4-DMAP, pyridine, room temperature)
to give 13 and then deacetoxylating this (10 equiv of Li,
liquid NH3, THF, -78 °C) to provide 14 in 93% yield over
two steps. Finally, compound 14 was treated with ceric
ammonium nitrate to accomplish deprotection of the
methyl ether and formation of the quinone system. Thus,
The synthetic hyatellaquinone 1a obtained here was
identical by IR, NMR, and MS with natural hyatel-
laquinone. However, the optical rotation for the synthetic
product 1a ([R]D -16.1) was of opposite sign to that of
the natural product ([R]D +15.6).1 Moreover, the optical
rotation of the synthetic dimethoxy p-quinone 15 ([R]D
-37) has the opposite sign to the methylated natural
hyatellaquinone7 ([R]D +37) prepared by Capon et al.
These results confirm that the absolute configuration at
the stereogenic centers of the natural (+)-hyatellaquinone
1b is (1R,4aR,8aR), as depicted in Figure 1.
In summary, we have described the first total synthesis
of the enantiomer 1a of the naturally occurring (+)-
hyatellaquinone 1b, which allowed us to establish its
absolute stereochemistry and a short synthesis of (+)-
albicanol14 from the readily available sclareolide. Pre-
liminary biological study showed that the synthetic (-)-
hyatellaquinone 1a is cytotoxic, with an IC50 of 14 µM
against KB cells. Further biological evaluation of 1a is
currently underway.
Exp er im en ta l Section
All of the reactions were carried out under an argon atmo-
sphere. All reagents were obtained from commercial suppliers
and used without further purification. THF was freshly distilled
from sodium/benzophenone. Methylene chloride was distilled
from CaH2. Flash chromatography was carried out using silica
(9) Kuchkova, K. I.; Chumakov, Y. M.; Simonov, Y. A.; Bocelli, G.;
Panasenko, A. A.; Vlad, P. F. Synthesis 1997, 1045.
(10) Ohta, Y.; Andersen, N. H.; Liu, C. B. Tetrahedron 1977, 33,
617.
(11) Hellou, J .; Andersen, R. J .; Thompson, J . E. Tetrahedron 1982,
38, 1875.
(12) Toyota, H.; Ooisa, Y.; Kusuyama, T.; Asakawa, Y. Phytochem-
istry 1994, 35, 1263. Weyerstahl, P.; Schwieger, R.; Schwope, I.;
Hashem, M. A. Liebigs Ann. 1995, 1389.
(13) Benington, F.; Morin, R. D. J . Org. Chem. 1955, 20, 102.
Keegstra, E. M. D.; Huisman, B.-H.; Paardekooper, E. M.; Hoogesteger,
F. J .; Zwikker, J . W.; J enneskens, L. W.; Kooijman, H.; Schouten, A.;
Veldman, N.; Spek, A. L. J . Chem. Soc., Perkin Trans. 2 1995, 229.
(14) For previous synthesis of racemic and (+)-albicanol, see:
Armstrong, R. J .; Harris, F. L.; Weiler, L. Can. J . Chem. 1986, 64,
10002. Ragoussis, V.; Liapis, M.; Ragoussis, N. J . Chem. Soc., Perkin
Trans. 1 1987, 987. Shishido, K.; Tokunaga, Y.; Omachi, N.; Hiroya,
K.; Fukumoto, K.; Kamentani, T. J . Chem. Soc., Perkin Trans. 1 1990,
2481. Nakano, T.; Villamizar, J .; Maillo, M. A. J . Chem. Res., Synop.
1995, 330. Banerjee, A. K.; Correa, J . A.; Laya-Mimmo, M. J . Chem.
Res., Synop. 1998, 710.

9320 J . Org. Chem., Vol. 64, No. 25, 1999
Notes
gel 60 F254 (Merck) with mixtures of ethyl acetate and hexane
as eluent unless specified otherwise. TLC analyses were per-
formed on thin-layer analytical plates 60 F254 (Merck).
additional 30 min at 25 °C, quenched with saturated NH4Cl,
and extracted with ether. The organic layer was washed with
water and brine, dried over MgSO4, and concentrated. The
residue was purified over silica gel (hexanes-EtOAc, 7:3) to give
compound 12 (106 mg, 74%), which was dissolved in pyridine (2
mL), followed by addition of 4-DMAP (0.05 mmol, 6 mg) and
acetic anhydride (2.5 mmol, 0.24 mL). The mixture was stirred
overnight at 25 °C and concentrated in vacuo. The residue was
dissolved in ether, washed successively with water, saturated
NaHCO3, 0.5 N HCl, and brine, dried over MgSO4, and concen-
trated. Flash chromatography gave acetylated compound 13 (116
mg, 100%), which was dissolved in dry THF and added dropwise
to a stirred solution of Li (2.54 mmol, 18 mg, 10 equiv) in liquid
ammonia at -78 °C. The reaction was stirred for an additional
15 min at -78 °C. Solid ammonium chloride was added, and
NH3 was allowed to evaporate. Water was added, and the
mixture was extracted with ether. The combined organic layers
were dried over MgSO4 and concentrated under reduced pres-
sure. The residue was purified over silica gel using hexanes-
EtOAc (9:1) as eluent to give 14 (94 mg, 93%) as a white solid:
mp 181 °C; Rf 0.29 (hexanes-EtOAc, 9:1); [R]D -34.2 (c 1.03,
CHCl3); MS m/z (EI) 402 (M+); IR (KBr) 2926, 1629, 1596, 1490,
1-Na p h th a len em eth a n ol, Deca h yd r o-5,5,8a -tr im eth yl-2-
m eth ylen e Aceta te (1S,4a S,8a S)- [(+)-Albica n yl a ceta te
(8)]. To a solution of acetate 4 (1 mmol, 294 mg) and 4-DMAP
(1 mmol, 122 mg) in dry pyridine (5 mL) at -30 °C was added
SOCl2 (2.5 mmol, 0.182 mL) dropwise. The mixture was stirred
for 1 h at this temperature and then warmed to 0 °C. The
reaction was quenched with ice, and the pyridine was removed
in vacuo. The residue was dissolved in ether, washed succes-
sively with water, saturated NaHCO3, and brine, and dried over
MgSO4. The solvent was evaporated under reduced pressure to
give compound 5, which was dissolved in a 1:1 mixture of CH2-
Cl2 and 5% aqueous NaHCO3 (10 mL) followed by addition of
m-CPBA (0.375 mmol, 65 mg) at 0 °C. The mixture was stirred
at this temperature for 1 h, extracted with CH2Cl2, and washed
with water and brine. The organic layer was dried over MgSO4
and concentrated. The residue was purified over silica gel using
hexanes-EtOAc (98:2) as eluent to afford the exo-olefin 8 (161
mg, 61%) as a colorless oil: Rf 0.48 (hexanes-EtOAc, 95:5); [R]D
+23.1 (c 1.1, CHCl3); lit. [R]D +22 (c 0.37, CHCl3); MS m/z (CI)
1
265 (MH+); IR (neat) 1735, 1640, 895 cm-1; H NMR (CDCl3) δ
1089, 895 cm-1 1H NMR (CDCl3) δ 6.39 (s, 1H), 5.01 (s, 1H),
;
4.85 (d, J ) 1.2 Hz, 1H), 4.51 (d, J ) 1.2 Hz, 1H), 4.33 (dd, J )
11.4 Hz, 3.9 Hz, 1H), 4.18 (dd, J ) 11.2 Hz, 9.0 Hz, 1H), 2.40
4.67 (d, J ) 0.9 Hz; 1H), 3.82 (s, 6H), 3.75 (s, 6H), 2.76 (m, 2H),
2.58 (m, 1H), 2.24 (m, 1H), 1.90 (m, 2H), 0.86 (s, 3H), 0.82 (s,
3H), 0.81 (s, 3H); 13C NMR (CDCl3) δ 148.8, 148.7, 141.2, 130.6,
106.9, 96.3, 60.7, 56.0, 55.7, 55.5, 42.2, 40.1, 38.6, 38.5, 33.7,
33.6, 24.5, 21.8; 20.1, 19.6, 14.1; HRMS (EI) calcd for C25H38O4
(M+) 402.2770, found 402.2758.
(m, 1H), 2.02 (s, 3H), 0.88 (s, 3H), 0.86 (s, 3H), 0.78 (s, 3H); 13
C
NMR (CDCl3) δ 171.4, 146.8, 107.1, 61.5, 60.5, 55.0, 54.7, 41.9,
39.0, 37.6, 33.6, 33.4, 23.9, 21.7, 21.1, 19.1, 15.1; HRMS (CI)
calcd for C17H29O2 (MH+) 265.2168, found 265.2163.
1-Na p h th a len em eth a n ol, Deca h yd r o-5,5,8a -tr im eth yl-2-
m eth ylen e-(1S,4a S,8a S)- [(+)-Albica n ol (9)]. To a solution
of olefin 8 (0.6 mmol, 160 mg) in MeOH (4 mL) was added KOH
(3 mmol, 168 mg), and the mixture was stirred at room
temperature for 1 h. The solvent was removed in vacuo, and
the residue was dissolved with ether. The organic layer was
washed with water and brine, dried over MgSO4, and concen-
trated. Purification over silica gel using hexanes-EtOAc (8:2)
gave compound 9 (134 mg, 100%) as a white solid: mp 67-68
°C; lit.11 mp 68-69 °C; Rf: 0.42 (hexanes-EtOAc, 8:2); [R]D +13.4
(c 0.84, CHCl3); lit. [R]D +13.0 (c 0.6, CHCl3); MS m/z (CI) 223
2,5-Cycloh exadien e-1,4-dion e, 3-[[(1S,4aS,8aS)-Decahydr o-
5,5,8a -t r im e t h yl-2-m e t h yle n e -1-n a p h t h a le n yl]m e t h yl]-
2-h yd r oxy-5-m eth oxy- [(-)-Hya tella qu in on e (1a )] a n d
2,5-Dim eth oxy-2,5-cycloh exa d ien e-1,4-d ion e, 3-[[(1S,4a S,-
8a S)-Deca h yd r o-5,5,8a -tr im eth yl-2-m eth ylen e-1-n a p h th a -
len yl]m eth yl]- (15). To a solution of olefin 13 (40.2 mg, 0.1
mmol) in CH3CN (5 mL) was added a solution of ammonium
cerium(IV) nitrate (137 mg, 0.25 mmol) in CH3CN-H2O (2 mL,
1:1) dropwise at 0 °C over 1 h. The reaction was allowed to stir
at room temperature for 4 h, and the mixture diluted with ether.
The organic layer was washed with water and brine, dried over
Na2SO4, and concentrated in vacuo. The residue was purified
over silica gel using hexanes-EtOAc (7:3) as eluent to give
compounds 15 (9.6 mg, 26%), and hyatellaquinone 1a (20.7 mg,
58%).
1
(MH+); IR (KBr) 3350, 2920, 1635, 900 cm-1; H NMR (CDCl3)
δ 4.95 (s, 1H), 4.64 (d, J ) 1.1 Hz, 1H), 3.84 (dd, J ) 10.9 Hz,
1H), 3.75 (t, J ) 10.9 Hz, 1H), 2.42 (m, 1H), 2.05 (m, 1H), 0.86
(s, 3H), 0.82 (s, 3H), 0.76 (s, 3H); 13C NMR (CDCl3) δ 147.7, 106.3,
59.0, 58.6, 55.1, 41.9, 38.9 (2C), 37.8, 33.6, 33.4, 24.1, 21.7; 19.1,
15.2; HRMS (CI) calcd for C15H27O (MH+) 223.2062, found
223.2059.
(-)-Hya tella qu in on e 1a : yellow oil; Rf 0.28 (hexanes-
EtOAc, 7:3); [R]D -16.1 (c 0.4, CHCl3); lit.2 [R]D +15.6 (c 0.5,
CHCl3); MS m/z (CI) 359 (MH+); IR: 3400, 2930, 1640 cm-1; 1H
NMR (CDCl3) δ 7.30 (s, 1H), 5.80 (s, 1H), 4.70 (s, 1H), 4.67 (s,
1H), 3.84 (s, 3H), 2.58 (dd, J ) 13.6 Hz, 10.6 Hz, 2H), 2.47 (dd,
J ) 14.0 Hz, 3.0 Hz, 1H), 2.37 (d, J ) 10.0 Hz, 1H), 2.30 (ddd,
J ) 12.5 Hz, 3.8 Hz, 2.3 Hz, 1H), 1.92 (td, J ) 12.6 Hz, 4.8 Hz,
1H), 1.72 (d, J ) 12.3 Hz, 1H), 1.09 (dd, J ) 12.5 Hz, 2.2 Hz,
1H), 0.87 (s, 3H), 0.81 (s, 3H), 0.77 (s, 3H); 13C NMR (CDCl3) δ
182,5, 182.0, 161.2, 151.5, 148.8, 119.3, 106.6, 102.0, 56.7, 55.4,
54.2, 42.1, 40.1, 38.7, 38.3, 33.6, 29.7, 24.4, 21.7, 19.5, 18.8, 14.1;
HRMS (CI) calcd for C22H31O4 (MH+) 359.2222, found 359.2228.
1-Na p h t h a len eca r b oxa ld eh yd e, Deca h yd r o-5,5,8a -t r i-
m eth yl-2-m eth ylen e-(1S,4a S,8a S)- [(-)-Albica n a l (10)]. To
a solution of alcohol 9 (0.92 mmol, 204 mg) in dry CH2Cl2 (5
mL) was added PDC (1.83 mmol, 690 mg) at 0 °C, and the
reaction was stirred for 4 h at room temperature. The CH2Cl2
was evaporated in vacuo, the residue was triturated with ether
and filtered, and the solvent was evaporated under reduced
pressure. The residue was subjected to flash chromatography
using hexanes-EtOAc (95:5) as eluent to give aldehyde 10 (170
mg, 84%) as a colorless oil; Rf: 0.72 (hexanes-EtOAc, 95:5); [R]D
-67.3 (c 1.83, CHCl3); lit.12 [R]D -69.8 (c 0.5, CHCl3); MS m/z
(CI) 237 (MH+ + CH4); IR (neat) 2929, 2726, 1720; 1643, 1472,
Com p ou n d 15: yellow oil; Rf 0.48 (hexanes-EtOAc, 7:3); [R]D
-37.1 (c 0.15, CHCl3); lit.7 [R]D +37 (c 0.4, CHCl3); MS m/z (CI)
373 (MH+); 1H NMR (CDCl3) δ 5.67 (s, 1H), 4.68 (s, 1H), 4.67 (s,
1H), 4.06 (s, 3H), 3.78 (s, 3H), 2.68 (dd, J ) 13.7 Hz, 10.8 Hz,
1H), 2.50 (dd, J ) 13.7 Hz, 3.1 Hz, 1H), 2.29 (m, 2H), 1.91 (td,
J ) 12.1 Hz, 4.5 Hz, 1H), 0.87 (s, 3H), 0.81 (s, 3H), 0.76 (s, 3H);
HRMS (CI) calcd for C23H33O4 (M + H+) 373.2379, found
373.2372.
1
892 cm-1; H NMR (CDCl3) δ 9.79 (d, J ) 4.5 Hz, 1H), 4.84 (s,
1H), 4.43 (s, 1H), 2.36 (m, 2H), 2.03 (m, 1H), 1.63 (m, 1H), 1.52
(m, 1H), 1.15 (m, 2H), 1.07 (s, 3H), 0.81 (s, 3H), 0.79 (s, 3H); 13
C
NMR (CDCl3) δ 205.0, 144.8, 109.0; 67.6, 53.7; 41.7, 39.6, 38.8,
36.5, 33.3, 33.2, 22.9, 21.7, 18.5, 15.8; HRMS (CI) calcd for
C
15H25O (MH+) 221.1905, found 221.1903.
3-[[(1S,4aS,8aS)-Decah ydr o-5,5,8a-tr im eth yl-2-m eth ylen e-
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C NMR of
(-)-hyatellaquinone 1a and compounds 8-10 and 12-15. This
material is available free of charge via the Internet at
http://pubs.acs.org.
1-n a p h th a len yl]m eth yl]-2,3,5,6-tetr a m eth oxyben zen e (14).
To a solution of 1,2,4,5-tetramethoxybenzene 11 (1.02 mmol, 202
mg) in dry THF (2 mL) was added dropwise n-BuLi (1.6 M in
hexane, 0.53 mL, 0.85 mmol) at 0 °C. After 30 min of stirring at
this temperature, a solution of aldehyde 10 (0.34 mmol, 75 mg)
in dry THF (2 mL) was added. The reaction was stirred for an
J O9910886