Synthesis of (+)-zerumin B using a regioselective singlet oxygen furan oxidation

Article abstract of DOI:10.1021/jo7025405

(Chemical Equation Presented) A short and efficient synthesis of the antitumor diterpenoid (+)-zerumin B has been accomplished starting from (+)-sclareolide. At the heart of the synthetic strategy lies the regioselective formation of the α-substituted γ-hydroxybutenolide moiety of zerumin B. This was achieved by means of a [1,4] O→C triisopropylsilyl migration followed by singlet oxygen (¹O₂) oxidation of the resulting 2-triisopropylsilyl-3-(α-hydroxy)alkylfuran.

Full text of DOI:10.1021/jo7025405

SCHEME 1. The Concept
Synthesis of (+)-Zerumin B Using a
Regioselective Singlet Oxygen Furan Oxidation
Ioannis Margaros and Georgios Vassilikogiannakis*
Department of Chemistry, UniVersity of Crete, Vasilika Vouton,
71003 Iraklion, Crete, Greece
Vasil@chemistry.uoc.gr
ReceiVed NoVember 27, 2007
A short and efficient synthesis of the antitumor diterpenoid
(+)-zerumin B has been accomplished starting from (+)-
sclareolide. At the heart of the synthetic strategy lies the
regioselective formation of the R-substituted γ-hydroxy-
butenolide moiety of zerumin B. This was achieved by means
of a [1,4] OfC triisopropylsilyl migration followed by
singlet oxygen (1O2) oxidation of the resulting 2-triisopro-
pylsilyl-3-(R-hydroxy)alkylfuran.
been prepared by photooxygenation of 3-substituted furans;5
however, Boukouvalas avoided employing this strategy because
it was deemed unsuitable, since it provides either mixtures of
R- and â-substituted γ-hydroxybutenolides5a-c (C and B,
Scheme 1) or solely the â-regiomers when Ηunig’ s base is
included.5c-j Very recently, a regioselective photooxygenation
of 3-bromofuran to 2-bromo-4-hydroxybutenolide (using DBU
as base) was published, thus providing the first specific example
of a way to counter this general lack of selectivity.6 In the
zerumin B system (Scheme 1), we predicted that regioselective
formation of R-substituted γ-hydroxybutenolides might also be
possible by utilization of the secondary hydroxyl group.
Specifically, 3-(R-trialkylsilyloxy)alkylfurans of type D are
known to undergo a [1,4] OfC silyl migration7 to furnish
2-trialkylsilyl-3-(R-hydroxy)alkylfurans of type E (Scheme 1).
The latter may then undergo a regioselective singlet oxygen
(1O2) oxidation8 yielding an R-substituted γ-hydroxybutenolide
moiety (C, Scheme 1) such as is present in (+)-zerumin B.
Based on this analysis, we hoped to employ just such a strategy
to synthesize (+)-zerumin B.
(+)-Zerumin B was first isolated in 1996 from the Chinese
medicinal plant Alpinia zerumbet.1 In 2005, the same molecule
was isolated, together with a number of other labdane diterpenes,
from the popular vegetable Curcuma mangga.2 This vegetable
is a member of the Zingiberaceae family and is commonly
grown in Thailand, Peninsular Malaysia, and Java.3 The tips of
young rhizomes and the shoots of C. mangga are consumed
raw with rice and have a smell reminiscent of mango fruit. The
rhizomes are used in Asian folk medicine to treat chest pains,
fever, and general debility. It is also used in postpartum care,
specifically to aid womb healing. Recently, however, perhaps
a more important medicinal characteristic was discovered when
(+)-zerumin B was also found to possess potent cytotoxicity
(IC50 value of 0.59 µM) against the MCF-7 (breast cancer) cell
line.
(5) For recent examples, see: (a) Held, C.; Fro¨hlich, R.; Metz, P. Angew.
Chem., Int. Ed. 2001, 40, 1058-1060. (b) de la Torre, M. C.; Garc´ıa, I.;
Sierra, M. A. J. Nat. Prod. 2002, 65, 661-668. (c) Held, C.; Fro¨hlich, R.;
Metz, P. AdV. Synth. Catal. 2002, 344, 720-727. (d) Demeke, D. Forsyth,
C. J. Tetrahedron 2002, 58, 6531-6544. (e) Brohm, D.; Philippe, N.;
Metzger, S.; Bhargava, A; Mu¨ller, O.; Lieb, F.; Waldmann, H. J. Am. Chem.
Soc. 2002, 124, 13171-13178. (f) Demeke, D.; Forsyth, C. J. Org. Lett.
2003, 5, 991-994. (g) Miyaoka, H.; Yamanishi, M.; Kajiwara, Y.; Yamada,
Y. J. Org. Chem. 2003, 68, 3476-3479. (h) Cheung, A. K.; Murelli, R.;
Snapper, M. L. J. Org. Chem. 2004, 69, 5712-5719. (i) Izzo, I.; Avallone,
E.; Della Monica, C.; Casapullo, A.; Amigo, M.; De Riccardis, F.
Tetrahedron 2004, 60, 5587-5593. (j) Basabe, P.; Delgado, S.; Marcos, I.
S.; Diez, D.; Diego, A.; De Roma´n, M.; Urones, J. G. J. Org. Chem. 2005,
70, 9480-9485.
The first total synthesis of this interesting bioactive diterpe-
noid was recently reported by Boukouvalas and co-workers.4
Addition of a silyloxyfuryltitanium reagent to an aldehyde and
a silyloxyfuran oxyfunctionalization lie at the heart of their rapid
synthesis. It is well-known that γ-hydroxybutenolides have often
(1) Xu, H.-X.; Dong, H.; Sim, K.-Y. Phytochemistry 1996, 42, 149-
151.
(2) Abas, F.; Lajis, N. H.; Shaari, K.; Israf, D. A.; Stanslas, J.; Yusuf,
U. K.; Raof, S. M. J. Nat. Prod. 2005, 68, 1090-1093.
(3) Larsen, K.; Ibrahim, H.; Khaw, S. H.; Saw, L. G. Gingers of
Peninsular Malaysia; Natural History Publication (Borneo): Kota Kinabalu,
1999.
(6) Aquino, M.; Bruno, I.; Riccio, R.; Gomez-Paloma, L. Org. Lett. 2006,
8, 4831-4834.
(7) Bures, E. J.; Keay, B. A. Tetrahedron Lett. 1987, 28, 5965-
5968.
(4) Boukouvalas, J.; Wang, J.-X.; Marion, O.; Ndzi, B. J. Org. Chem.
2006, 71, 6670-6673.
10.1021/jo7025405 CCC: $40.75 © 2008 American Chemical Society
Published on Web 02/02/2008
J. Org. Chem. 2008, 73, 2021-2023
2021

SCHEME 2. Synthesis of Furanols 5
SCHEME 3. Regioselective Preparation of 7a and 7b Using
[1,4] OfC Silyl Migration and Subsequent
Photooxygenation to (+)-epi-Zerumin B and (+)-Zerumin B
In order to validate the proposal, deconvoluting a rapid
synthesis of the requisite 3-substituted furan 59 (Scheme 2) was
essential. A good source of the intact labdane skeleton is the
commercially available lactone 2, known as (+)-sclareolide, so
we chose to start our investigation from this compound. A
protocol was developed that converted (+)-sclareolide (2) into
furan 5 in just three high-yielding steps (Scheme 2). The lactone
moiety of (+)-sclareolide was used to quench the 3-lithiofuran
anion, obtained from 3-bromofuran, on treatment with n-BuLi,
to afford hydroxy ketone 3 in 85% yield. Effective conditions
by which to affect the dehydration of 3, while maximizing the
exo-/endocyclic double bond ratio, took some experimentation
to find. It was discovered, finally, that a combination of SOCl2
and pyridine4,9,10 (yield 95%) gave excellent results. This
combination of reagents gave an exo-/endocyclic ratio of 14:1
(∆8,17/∆7,8 Scheme 2). This ratio is in stark contrast to those
obtained earlier when using other common dehydration methods
where unacceptably poor ratios had been obtained. The furylic
ketone 4 was then reduced to the corresponding diastereomeric
mixture (equimolar and separable using column chromatogra-
phy) of natural alcohols 511 using LiAlH4 in 97% yield. The
very fact that the alcohols 5a or 5b (Scheme 2) are naturally
occurring compounds suggests that our strategy of direct
photooxygenation (1O2) might represent a biomimetic proposal
for the synthesis of (+)-zerumin B.
of the hydroxyl group of 5a and 5b under standard conditions
(2,6-lutidine, TIPSOTf, Scheme 3) gave triisopropylsilyl ethers
6a or 6b in 91% and 90% yield, respectively. Treatment of 6a
or 6b with 1.2 equiv of n-BuLi in the presence of 1.2 equiv of
HMPA7 cleanly transformed them to the corresponding 2-tri-
isopropylsilyl-3-(R-hydroxy)alkylfurans 7a or 7b in 90% and
91% yield, respectively (Scheme 3).
The stage was now set for the singlet oxygen-mediated
oxidation of furans 7a and 7b. Visible light irradiation of a
solution of 7a or 7b (maximum amount used ) 150 mg) in
CH2Cl2, containing catalytic amounts of methylene blue (10-4
M), with O2 bubbling through it, for just 1 min, resulted in the
complete consumption of the starting materials accompanied
by the formation of the stable silyl esters8 8a or 8b (Scheme
3). In situ hydrolysis of silyl esters 8a or 8b yielded the
corresponding γ-hydroxybutenolides (+)-12-epi-zerumin B (9)
and (+)-zerumin B (1) and was easily achieved on addition of
a small amount of silica gel (SiO2) and a few drops of water.
1H and 13C NMR data for 9 and 1 matched exactly that reported
in the literature.4 As expected, both compounds are equimolar
mixtures of diasteromeric γ-hydroxybutenolides. It is worth
mentioning that only one of the two diastereomers of (+)-12-
epi-zerumin B was detected by 1H NMR right after the
hydrolysis of the intermediate silyl ester 8a. An equimolar
With diastereomeric alcohols 5a and 5b in hand, the hurdle
of regioselective silylation of the more sterically hindered
2-position of the furan ring now needed to be tackled. All
attempts at direct silylation (n-BuLi followed by a TMSCl
quench) of this position utilizing the directing effect of hydroxyl
at C-12 resulted in the formation of a mixture of different mono-
and bis-silylated products. In order to overcome this problem,
a two-step procedure was therefore adopted. Thus, silylation
(8) For the silyl stabilization concept, see: Adam, W.; Rodriguez, A.
Tetrahedron Lett. 1981, 22, 3505-3508. For direct comparisons between
the photoxygenations of silyl- and unsubstituted furans, see: (a) Bury, P.;
Hareau, G.; Kocien´ski, P.; Dhanak, D. Tetrahedron 1994, 50, 8793-8808.
(b) Shiraki, R.; Sumino, A.; Tadano, K.; Ogawa, S. J. Org. Chem. 1996,
61, 2845-2852.
(9) For a recent synthesis from us, see: Margaros, I. Vassilikogiannakis,
G. J. Org. Chem. 2007, 72, 4826-4831.
(10) Kolympadi, M.; Liapis, M.; Ragoussis, V. Tetrahedron 2005, 61,
2003-2010.
(11) (a) Jung, M.; Ko, I.; Lee, S. J. J. Nat. Prod. 1998, 61, 1394-1396.
(b) Villamizar, J.; Fuentes, J.; Salazar, F.; Tropper, E.; Alonso, R. J. Nat.
Prod. 2003, 66, 1623-1627.
1
mixture of diastereoisomers were observed in H NMR after
chromatographic purification using silica gel.12
2022 J. Org. Chem., Vol. 73, No. 5, 2008

4.47 (s, 1H), 2.41 (ddd, J1 ) 12.8 Hz, J2 ) 3.8 Hz, J3 ) 2.6 Hz,
1H), 2.16 (br d, J ) 11.3 Hz, 1H), 2.13-1.92 (m, 2H), 1.86-1.48
(m, 5H), 1.45-1.15 (m, 8H), 1.10 (d, J ) 7.4 Hz, 9H), 1.07 (d, J
) 7.4 Hz, 9H), 0.88 (s, 3H), 0.81 (s, 3H), 0.69 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ ) 152.8, 148.8, 146.8, 140.6, 107.9, 106.2,
64.2, 55.4, 52.2, 42.1, 39.4, 39.0, 38.3, 33.61, 33.58, 32.3, 24.5,
21.7, 19.4, 18.8 (3C), 18.7 (3C), 14.6, 11.7 (3C); HRMS (ESI+)
calcd for C29H50O2SiNa 481.3478 [M + Na+], found 481.3473.
In conclusion, a fast (six steps in total) and efficient (overall
yield 53%) synthesis of (+)-zerumin B and (+)-12-epi-zerumin
B has been accomplished. The key step of the synthesis involved
the regioselective transformation of a 3-substituted furan into
the R-substituted γ-hydroxybutenolide moiety13 of the natural
compound by the utilization of a [1,4] OfC silyl migration
1
followed by an oxidation with O2.
7a: 1H NMR (300 MHz, CDCl3) δ ) 7.63 (d, J ) 1.6 Hz, 1H),
6.49 (d, J ) 1.6 Hz, 1H), 4.88 (d, J ) 1.1 Hz, 1H), 4.79 (s, 1H),
4.74 (t, J ) 7.1 Hz, 1H), 2.34 (ddd, J1 ) 12.8 Hz, J2 ) 3.9 Hz, J3
) 2.4 Hz, 1H), 2.05-1.13 (m, 14H), 1.11 (d, J ) 7.4 Hz, 9H),
1.04 (d, J ) 7.4 Hz, 9H), 1.00-0.84 (m, 2H), 0.82 (s, 3H), 0.78
(s, 3H), 0.70 (s, 3H); 13C NMR (125 MHz, CDCl3) δ ) 154.5,
149.3, 147.0, 139.4, 107.6, 107.0, 65.7, 55.2, 52.6, 41.9, 39.6, 38.9,
38.0, 33.5(2C), 31.8, 24.2, 21.7, 19.3, 18.9 (3C), 18.7 (3C), 14.4,
11.8 (3C); HRMS (ESI+) calcd for C29H50O2SiNa 481.3478 [M
+ Na+], found 481.3473.
Experimental Section
Diastereomeric (1-(Furan-3-yl)-2-((1S,8aS)-5,5,8a-trimethyl-
2-methylenedecahydronaphthalen-1-yl)ethoxy)triisopropylsi-
lane (6a,b). To a solution of furanol 5b (66 mg, 0.22 mmol, 1.0
equiv, less polar diastereoisomer) in dry DCM (3 mL) was added
2,6-lutidine (53 µL, 0.46 mmol, 2.1 equiv). The reaction mixture
was cooled to -5 °C, and TIPSOTf (92 µL, 0.34 mmol, 1.56 equiv)
was added dropwise. Stirring was continued for 15 min before the
reaction was quenched with NaHCO3 (2 mL). The reaction mixture
was diluted with Et2O (10 mL) and washed with H2O (5 mL). The
organic layer was dried (MgSO4), filtered, and concentrated under
reduced pressure. Purification by flash column chromatography
(silica gel, hexanes/EtOAc ) 50:1 v/v) afforded TIPS-protected
alcohol 6b (90 mg, 90%). Exactly the same experimental procedure
was applied in the case of furanol 5a (60 mg, 0.20 mmol, of the
more polar diastereoisomer) to give the TIPS-protected alcohol 6a
(83 mg, 91%).
(+)-Zerumin B (1) and (+)-epi-Zerumin B (9). A solution of
the furan 7b (82 mg, 0.18 mmol, 1.0 equiv) in DCM (8 mL)
containing methylene blue (10-4 M) was placed in a test tube, and
oxygen was bubbled gently through it. The solution was cooled to
0 °C and irradiated with a xenon 300 W lamp for 1 min after which
complete consumption of the starting material was observed (based
on TLC). SiO2 and a few drops of H2O were added, and the mixture
was stirred vigorously for 1 h. The solvent was removed in vacuo,
and the residue was purified by flash column chromatography (silica
gel, hexanes/EtOAc ) 2:1 f 1:2 v/v) to afford (+)-zerumin B (1,
50 mg, 83%, 1/1 ratio of diastereoisomers). Exactly the same
experimental procedure was applied to the case of furan 7a (75
mg, 0.16 mmol) to afford (+)-epi-zerumin B (45 mg, 82%, 1/1
ratio of diastereoisomers).
6b: 1H NMR (300 MHz, CDCl3) δ ) 7.34 (t, J ) 1.5 Hz, 1H),
7.30 (s, 1H), 6.43 (d, J ) 1.0 Hz, 1H), 4.86 (d, J ) 1.4 Hz, 1H),
4.80 (dd, J1 ) 10.0 Hz, J2 ) 1.5 Hz, 1H), 4.47 (s, 1H), 2.41 (ddd,
J1 ) 12.7 Hz, J2 ) 4.0 Hz, J3 ) 2.3 Hz, 1H), 2.14 (br d, J ) 11.0
Hz, 1H), 2.07-1.05 (m, 12H), 1.05-0.93 (m, 21H), 0.90 (s, 3H),
0.81 (s, 3H), 0.65 (s, 3H); 13C NMR (125 MHz, CDCl3) δ ) 149.2,
142.7, 138.0, 131.1, 108.9, 106.6, 65.7, 55.8, 52.3, 42.3, 39.3, 38.9,
38.2, 35.2, 33.7, 33.6, 24.4, 21.7, 19.4, 18.2 (3C), 18.0 (3C), 14.7,
12.6 (3C) ppm; HRMS (ESI+) calcd for C29H50O2SiNa 481.3478
[M + Na+], found 481.3473.
24
(+)-Zerumin B (1): [R]D24 +41.7 (c ) 4.0, acetone) [lit.4 [R]D
+42.8 (c ) 0.25, acetone)]; 1H NMR (300 MHz, CDCl3) δ ) 7.04
(s, 1H + 1H), 6.11 (s, 1H + 1H), 4.91 (br s, 1-OH + 1-OH), 4.88
(s, 1H + 1H), 4.67 (s, 1H + 1H), 4.53 (br d, J ) 9.9 Hz, 1H +
1H), 2.76 (br s, 1-OH + 1-OH), 2.41 (md, J ) 12.9 Hz, 1H +
1H), 2.09-0.95 (m, 13H + 13H), 0.88 (s, 3H + 3H), 0.80 (s, 3H
+ 3H), 0.67 (s, 3H + 3H); 13C NMR (75 MHz, CDCl3) δ ) 170.4
(2C), 148.2 (2C), 143.1 (2C), 141.4 (2C), 107.2 (2C), 97.1, 96.9,
65.5 (2C), 55.5 (2C), 51.8 (2C), 42.0 (2C), 39.3 (2C), 39.0 (2C),
38.2 (2C), 33.6 (4C), 29.7 (2C), 24.3 (2C), 21.7 (2C), 19.3 (2C),
14.6 (2C); HRMS (ESI+) calcd for C20H30O4Na 357.2042 [M +
Na+], found 357.2036.
6a: 1H NMR (300 MHz, CDCl3) δ ) 7.36 (t, J ) 1.5 Hz, 1H),
7.22 (s, 1H), 6.40 (d, J ) 1.1 Hz, 1H), 4.87 (s, 1H), 4.82 (dd, J1
) 10.5 Hz, J2 ) 4.3 Hz, 1H), 4.69 (s, 1H), 2.36 (ddd, J1 ) 12.7
Hz, J2 ) 4.1 Hz, J3 ) 2.4 Hz, 1H), 1.99-1.05 (m, 12H), 1.05-
0.96 (m, 21H), 0.92 (m, 1H), 0.82 (s, 3H), 0.78 (s, 3H), 0.70 (s,
3H); 13C NMR (125 MHz, CDCl3) δ ) 149.0, 142.8, 139.1, 129.5,
108.8, 106.2, 66.2, 55.4, 52.6, 42.0, 39.3, 38.6, 38.3, 33.8, 33.5,
33.46, 24.4, 21.7, 19.3, 18.1 (3C), 18.0 (3C), 14.8, 12.3 (3C); HRMS
(ESI+) calcd for C29H50O2SiNa 481.3478 [M + Na+], found
481.3473.
24
(+)-epi-Zerumin B (9): [R]D +5.9 (c ) 0.84, acetone) [lit.4
24
1
[R]D +5.5 (c ) 0.85, acetone)]; H NMR (300 MHz, CDCl3) δ
) 7.04 (s, 1H), 6.99 (s, 1H), 6.11 (br s, 1H + 1H), 5.44 (br s,
1-OH + 1-OH), 4.88 (br s, 1H + 1H), 4.68 (br s, 1H + 1H), 4.51
(br t, J ) 6.5 Hz, 1H + 1H), 3.30 (br s, 1-OH + 1-OH), 2.39 (br
d, J ) 12.5 Hz, 1H + 1H), 2.10-0.88 (m, 13H + 13H), 0.86 (s,
3H + 3H), 0.78 (s, 3H + 3H), 0.67 (s, 3H + 3H) ppm; 13C NMR
(75 MHz, CDCl3) δ ) 171.1, 170.7, 149.3, 149.1, 145.4, 144.8,
139.6, 138.5, 107.1, 106.9, 97.52, 97.37, 67.2, 66.5, 55.44 55.40,
53.3, 53.0, 42.0 (2C), 39.9, 39.8, 38.93, 38.89, 38.18, 38.13, 33.54
(2C), 33.47 (2C), 29.8, 29.4, 24.3 (2C), 21.7 (2C), 19.24, 19.22,
14.44, 14.39; HRMS (ESI+) calcd for C20H30O4Na 357.2042 [M
+ Na+], found 357.2036.
Diastereomeric 1-(2-(Triisopropylsilyl)furan-3-yl)-2-((1S,8aS)-
5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)etha-
nol (7a,b). To a stirred solution of TIPS-protected furanol 6b (90
mg, 0.20 mmol, 1.0 equiv) in dry THF (3 mL) at ambient
temperature was added dry HMPA (41 µL, 0.24 mmol, 1.2 equiv)
followed by dropwise addition of n-BuLi (1.6 M in Hex, 147 µL,
0.24 mmol, 1.2 equiv). After 15 min of stirring, the reaction mixture
was quenched with satd NH4Cl (1 mL), diluted with Et2O (10 mL),
and washed with H2O (5 mL). The organic layer was dried
(MgSO4), filtered, and concentrated under reduced pressure.
Purification with flash column chromatography (silica gel, hexanes/
EtOAc ) 50:1 v/v) afforded TIPS furanol 7b (82 mg, 91%). Exactly
the same experimental procedure was applied in the case of 6a (83
mg, 0.18 mmol) to afford 75 mg of 7a (90%).
Acknowledgment. We thank Dr. Tamsyn Montagnon for
helpful discussions. The project was cofunded by the European
Social Fund and National Resources (B EPEAEK, Pythagoras
program) and with a National Fellowship Institute (IKY)
fellowship (I.M.).
7b: 1H NMR (300 MHz, CDCl3) δ ) 7.61 (d, J ) 1.6 Hz, 1H),
6.51 (d, J ) 1.6 Hz, 1H), 4.82 (s, 1H), 4.72 (d, J ) 10.4 Hz, 1H),
(12) For a very recent example of base-assisted regio- and diastereose-
lective conversion of 3-substituted furans to 3-substituted 4-hydroxybuteno-
lides, see: Patil, S. N.; Liu, F. Org. Lett. 2007, 9, 195-198.
(13) After completion of this work, a very interesting fluoride-assisted
regioselective conversion of 3-substituted furans to R-substituted γ-hy-
droxybutenolides using singlet oxygen was reported: Patil, S. N.; Liu, F.
J. Org. Chem. 2007, 72, 6305-6308.
1
Supporting Information Available: Copies of H NMR and
13C NMR spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO7025405
J. Org. Chem, Vol. 73, No. 5, 2008 2023