Enantioselective Total Synthesis of 3-epi-Ottelione A

Article abstract of DOI:10.1055/s-2003-42114

An enantioselective total synthesis of (+)-3-epi-ottelione A (2), the earlier proposed stereostructure of the antitumor natural product ottelione A (4), was achieved for the first time starting from the known tetracyclic compound 9. The synthesis involves the following three crucial steps: (i) a coupling reaction of aldehyde 8 and aryllithium 7 to introduce the aromatic portion, (ii) base-induced lactol-opening/epimerization at the C1 position of 6 to deliver the requisite hydrindane 15, and (iii) Corey-Winter's reductive olefination of the cyclic thiocarbonate 19 to install the C5-C6 double bond.

Full text of DOI:10.1055/s-2003-42114

LETTER
2401
Enantioselective Total Synthesis of 3-epi-Ottelione A
Enantioselective
T
i
otal Sy
r
nthesis
o
o
f
3-epi-Ottel
s
ione
A
hi Araki,a Munenori Inoue,b Tadashi Katoh*a,b
a
Department of Electronic Chemistry, Tokyo Institute of Technology, Nagatsuta, Yokohama 226-8502, Japan
Fax +81(467)774113; E-mail: katoh@sagami.or.jp
b
Sagami Chemical Research Center, 2743-1 Hayakawa, Ayase, Kanagawa 252-1193, Japan
Received 19 September 2003
OMe
OH
OMe
OH
Abstract: An enantioselective total synthesis of (+)-3-epi-ottelione
A (2), the earlier proposed stereostructure of the antitumor natural
product ottelione A (4), was achieved for the first time starting from
the known tetracyclic compound 9. The synthesis involves the fol-
lowing three crucial steps: (i) a coupling reaction of aldehyde 8 and
aryllithium 7 to introduce the aromatic portion, (ii) base-induced
lactol-opening/epimerization at the C1 position of 6 to deliver the
requisite hydrindane 15, and (iii) Corey-Winter’s reductive olefina-
tion of the cyclic thiocarbonate 19 to install the C5–C6 double bond.
O
O
10
H
H
H
4
7
3
1
5
6
3a
2
7a
9
H
8
11
3-epi-ottelione A (2)
ottelione B (1)
OMe
OH
OMe
OH
Key words: 3-epi-ottelione A, total synthesis, otteliones A and B,
natural products, antitumor agents
O
H
O
H
H
In 1998, Ayyad and Hoye et al. reported the isolation and
structure elucidation of two novel diastereomeric natural
products, otteliones A and B, from the fresh water plant
Ottelia alismoides.1 These substances were found to ex-
hibit remarkable cytotoxicity and tubulin polymerization
inhibitory activity.1,2 At the time that these natural prod-
ucts were isolated, the relative configuration of ottelione
B was elucidated as shown in the formulation 1
(Figure 1);1 however, ottelione A could not be assigned
unambiguously and both the formulations 2 and 3 were
proposed as possible stereostructures with more prefer-
ence for 2.1 In 2000, scientists at Rhône–Poulenc Rorer
(now Aventis) proposed an alternative stereostructure 4
for ottelione A which was assigned based on exhaustive
2D NMR spectral analyses,2 while its absolute configura-
tion was not elucidated at that time. A number of synthetic
approaches toward otteliones A and B have been reported
to date.3 The first total synthesis of racemic ( )-otteliones
A (4) and B (1) was achieved by Mehta and Islam in 2002,
which verified their relative stereostructure.4 More recent-
ly, Mehta’s5 and our6 groups independently accomplished
the first enantioselective total syntheses of (+)-ottelione A
(4) and (–)-ottelione B (1), leading to establishment of
their absolute configurations. However, at the beginning
of April in 2000 when we started this project, the formu-
lation 2 was considered as a most likely stereostructure for
ottelione A; therefore, our initial synthetic efforts were
targeted toward the structure 2.7 Herein, we wish to report
our preliminary results concerning an enantioselective
total synthesis of (+)-3-epi-ottelione A (2),8 which is the
earlier proposed formulation of ottelione A (4).
H
3
ottelione A (4)
Figure 1 Structures of ottelione B (1), ottelione A (4), and their
related compounds.
As shown in Scheme 1, our strategy for the synthesis of
optically active 3-epi-ottelione A (2) focused on the use of
the highly and properly functionalized intermediate 9,
which has previously been prepared in our laboratory
from tetracyclic compound 10 formed by Diels–Alder re-
action of cyclohexenone 11 and cyclopentadiene (12).6,9
We envisaged that intermediate 6 would be produced
through the coupling reaction of 8, accessible from 9 by
epimerization at the C3 position, with aryllithium 7. Inter-
mediate 6 would be converted into the target molecule 2
through the advanced key intermediate 5 by sequential
functional group manipulation and deprotection, or vice
versa; the sequence involves base-induced epimerization
of the masked C1 formyl group and subsequent construc-
tion of the 4-methylene-2-cyclhexenone substructure as
the pivotal steps.
At first, as shown in Scheme 2, we pursued the synthesis
of the key intermediate 5 starting from the known com-
pound 9.6 Epimerization at the C3 position of 9 occurred
smoothly by treatment with 1,8-diazabicyclo[5.4.0]un-
dec-7-ene (DBU) at ambient temperature, and the desired
b-formyl compound 8, the key substrate for the following
coupling reaction with the aromatic portion, was obtained
in quantitative yield. The crucial coupling reaction of 8
with aryllithium 7 was achieved by reaction of 4-bromo-
1-methoxy-2-(methoxymethoxy)benzene10 with n-butyl-
lithium in THF at –78 °C followed by addition of 8 at the
same temperature, which provided a quantitative yield of
the requisite coupling product 13 as a mixture of epimeric
SYNLETT 2003, No. 15, pp 2401–2403
0
1
.1
2
.2
0
0
3
Advanced online publication: 23.10.2003
DOI: 10.1055/s-2003-42114; Art ID: U19403ST
© Georg Thieme Verlag Stuttgart · New York

2402
H. Araki et al.
LETTER
OMe
OH
OMe
the two steps. The critical base-induced lactol-opening/
epimerization at the C1 position in 6 was effected by treat-
ment with DBU in refluxing toluene for 1.5 hours, which
afforded the desired product 15 in 52% yield along with
the starting material 6 (40% recovery). Compound 15 was
further converted to the key intermediate 512 in 79% over-
all yield via a two-step sequence involving Dess–Martin
oxidation followed by twofold Wittig methylenation of
the resulting keto-aldehyde 16.
O
TBSO
OMOM
H
H
H
H
O
O
5
3-epi-ottelione A (2)
OMe
OMOM
OMe
TBSO
CHO
H
TBSO
Having obtained the advanced key intermediate 5 in an ef-
ficient way, we next focused our attention on the synthesis
of 3-epi-ottelione A (2) as shown in Scheme 3, which in-
volves the critical elaboration of the sensitive 4-methyl-
ene-2-cyclohexenone substructure. Removal of both the
acetonide and MOM protecting groups from 5 and subse-
quent selective acetylation of the phenolic hydroxy group
in the resulting triol 17 furnished the acetate 18 in 68%
overall yield. Installation of the C5–C6 double bond was
conducted according to the Corey–Winter procedure13
with some modifications in the reaction conditions. Thus,
treatment of 18 with thiophosgene in the presence of 4-
(dimethylamino)pyridine (DMAP) followed by exposure
of the resulting thiocarbonate 19 to triethyl phosphite, led
to the formation of the expected olefinic product 20 in
73% yield for the two steps. Subsequent selective depro-
tection of the TBS group in 20 was carried out via a one-
pot two-step operation involving treatment with tetrabuty-
lammonium fluoride (TBAF) followed by addition of ace-
tic anhydride, giving rise to the desired 21 in 92% yield.
Finally, Dess–Martin oxidation of 21 and subsequent
deacetylation of the resulting dienone 22 provided the tar-
get 3-epi-ottelione A (2)14 in 95% yield for the two steps.
7
OMOM
H
H
3
Li
O
O
O
O
1
H
O
O
OH
OH
8 : β-CHO
9 : α-CHO
6
ref. 6
TBSO
TBSO
H
ref. 9
O
O
O
O
+
H
O
10
O
12
11
Scheme 1 Synthetic plan for 3-epi-ottelione A (2).
OMe
OMOM
X
H
TBSO
CHO
TBSO
H
H
3
O
O
b
O
O
e
1
H
O
O
OH
OR
9 : α-CHO
8 : β-CHO
13 : X = OH, R = H
14 : X = OAc, R = Ac
6 : X = H, R = H
a
c
OMe
OMe
d
TBSO
OR2
RO
OAc
H
H
H
OMe
a
d
R1O
R1O
OMe
5
6
5
6
5
TBSO
TBSO
H
OMOM
g
OMOM
H
H
H
O
O
17 : R1 = R2 = H
20 : R = TBS
21 : R = H
b
c
O
O
18 : R1 = H, R2 = Ac
19 : R1 = -C(S)-, R2 = Ac
e
H
CHO
X
5
15 : X = α-OH, β-H
16 : X = O
f
OMe
OR
O
H
Scheme 2 Synthesis of the key intermediate 5. Reagents and condi-
tions: (a) DBU, THF, r.t., 100%; (b) 4-bromo-1-methoxy-2-(me-
thoxymethoxy)benzene, n-BuLi, THF, –78 °C; at –78 °C, add 8,
100%; (c) Ac2O, DMAP, pyridine, r.t., 100%; (d) Li, liq. NH3,
THF, –78 °C, 87%; (e) DBU, toluene, reflux, 52%; (f) Dess–Martin
periodinane, CH2Cl2, r.t., 90%; (g) Ph3P+CH3Br–, t-BuOK, benzene,
r.t.→reflux, 88%.
f
H
22 : R = Ac
g
2 : R = H ( 3-epi-ottelione A )
Scheme 3 Synthesis of 3-epi-ottelione A (2). Reagents and conditi-
ons: (a) TFA, THF–H2O, 0 °C, 76%; (b) Ac2O, 2 M NaOH, i-PrOH,
r.t., 90%; (c) CSCl2, DMAP, CH2Cl2, r.t., 96%; (d) (EtO)3P, reflux,
76%; (e) TBAF, THF, r.t.; Ac2O, 92%; (f) Dess–Martin periodinane,
CH2Cl2, r.t., 97%; (g) K2CO3, MeOH, 0 °C, 98%.
alcohols (9:1 by 500 MHz 1H NMR) that were very diffi-
cult to separate. Removal of the sterically hindered hy-
droxy group in 13 was attained by simultaneous
acetylation of the two hydroxy groups in 13 followed by
treatment of the resulting diacetate 14 with a large excess
of lithium (50 equiv) in liquid ammonia/THF at –78 °C,
resulting in the formation of the lactol 611 in 87% yield for
The structure and stereochemistry of 2 was unambiguous-
ly confirmed by extensive spectroscopic analysis includ-
Synlett 2003, No. 15, 2401–2403 © Thieme Stuttgart · New York

LETTER
Enantioselective Total Synthesis of 3-epi-Ottelione A
2403
isopropylottelione A) (see, ref.3b), while, to the best of our
knowledge, 3-epi-ottelione A (2) itself has not yet been
synthesized.
ing NOESY experiment in the 500 MHz 1H NMR spectra.
The selected NOESY correlation of 2 is depicted in
Figure 2, wherein clear NOE interactions between H3a and
H2b, H7a, H10a, H10b, between H7a and H2b, H8, and finally
between H2a and H3, H1 are respectively observed, reveal-
ing that both the C1 and C3 substituents are syn to the
bridgehead protons H3a and H7a in the cis-fused hydrin-
dane skeleton.
(8) In May 2002, we achieved the total synthesis of 2 in an
enantiomerically pure form; however, to our
disappointment, spectral data of the synthetic 2 did not
match those of the natural product ottelione A.
(9) (a) Izuhara, T.; Katoh, T. Tetrahedron Lett. 2000, 41, 7651.
(b) Izuhara, T.; Katoh, T. Org. Lett. 2001, 3, 1653.
(10) 4-Bromo-1-methoxy-2-(methoxymethoxy)benzene has
previously been reported in our laboratory, see ref.6
(11) Data for 6: Colorless needles, mp 113–114 °C, [a]D20 –36.6
(c 0.77, CHCl3). 1H NMR (500 MHz, CDCl3): d = 0.10 (3 H,
s), 0.13 (3 H, s), 0.91 (9 H, s), 1.36 (3 H, s), 1.47 (3 H, s),
1.43–1.49 (1 H, m), 1.62 (1 H, ddd, J = 13.5, 6.3, 3.0 Hz),
1.90–1.95 (1 H, m), 1.96–2.03 (1 H, m), 2.07 (1 H, dd,
J = 13.1, 10.4 Hz), 2.15 (1 H, d, J = 2.1 Hz), 2.64–2.70 (1 H,
m), 2.93–2.99 (1 H, m), 3.34 (1 H, dd, J = 13.1, 3.7 Hz), 3.52
(3 H, s), 3.85 (3 H, s), 3.93 (1 H, dd, J = 7.7, 4.1 Hz), 4.23–
4.27 (1 H, m), 4.46–4.49 (2 H, m), 5.07 (1 H, d, J = 2.1 Hz),
5.20 (2 H, s), 6.97 (1 H, dd, J = 8.2, 1.9 Hz), 6.80 (1 H, d,
J = 8.2 Hz), 6.91 (1 H, d, J = 1.9 Hz). 13C NMR (125 MHz,
CDCl3): d = –4.50, –4.42, 18.22, 25.25, 25.96, 27.88, 36.87,
41.18, 42.46, 43.84, 49.05, 49.57, 55.97, 56.21, 72.85,
76.37, 76.91, 77.83, 95.71, 103.49, 107.32, 111.75, 117.43,
122.50, 134.69, 146.18, 148.01. IR (KBr): 3449, 2955, 1516,
1257, 1132, 1082, 1006, 837, 779 cm–1. MS (EI): m/z = 550
(M+). Anal. Calcd for C29H46O8Si: C, 63.24; H, 8.42. Found:
C, 63.3; H, 8.55.
OMe
H10α
H10β
O
OH
H3a
H3
H1
3
1
H2β
H2α
H7a
H8
3-epi-ottelione A (2)
Figure 2 Selected NOESY correlation of 3-epi-ottelione A (2).
In summary, we have succeeded in developing an effi-
cient synthetic pathway to (+)-3-epi-ottelione A (2), the
earlier proposed structure of ottelione A (4), starting from
the known tetracyclic compound 9 (16% overall yield in
14 steps). The explored method features a coupling reac-
tion of aldehyde 8 and aryllithium 7 to introduce the aro-
matic portion (8 + 7 → 13, Scheme 2), base-induced
lactol-opening/epimerization at the C1 position of 6 to de-
liver the requisite hydrindane 15 (6 → 15, Scheme 2), and
Corey–Winter’s reductive olefination of the cyclic thio-
carbonate 19 to install the C5–C6 double bond (19 → 20,
Scheme 3) as the crucial steps. Biological evaluations for
a novel unnatural (+)-3-epi-ottelione A (2) are currently
under investigation and will be reported in due course.
(12) Data for 5: Colorless viscous oil, [a]D20 +9.8 (c 0.77,
CHCl3). 1H NMR (500 MHz, CDCl3): d = 0.03 (1 H, s), 0.04
(3 H, s), 0.83 (9 H, s), 1.09–1.19 (1 H, m), 1.35 (3 H, s), 1.49
(3 H, s), 1.78–1.84 (1 H, m), 2.17–2.25 (1 H, m), 2.26–2.32
(1 H, m), 2.45 (1 H, dd, J = 13.4, 8.9 Hz), 2.46–2.54 (1 H,
m), 2.61–2.68 (1 H, m), 2.78 (1 H, dd, J = 13.4, 5.5 Hz), 3.50
(3 H, s), 3.63–3.67 (1 H, m), 3.85 (3 H, s), 4.18 (1 H, dd,
J = 7.4, 3.0 Hz), 4.61 (1 H, d, J = 7.4 Hz), 4.94 (1 H, dd,
J = 10.3, 1.0 Hz), 5.00–5.08 (3 H, m), 5.18–5.23 (2 H, m),
5.81 (1 H, ddd, J = 17.4, 10.3, 7.3 Hz), 6.77 (1 H, dd, J = 8.2,
1.9 Hz), 6.80 (1 H, d, J = 8.2 Hz), 6.97 (1 H, d, J = 1.9 Hz).
13C NMR (125 MHz, CDCl3): d = –4.73, –4.37, 17.92, 24.01,
25.68, 26.37, 40.52, 41.01, 41.08, 42.87, 45.07, 48.39,
55.95, 56.13, 70.20, 78.39, 79.17, 95.60, 108.73, 111.60,
112.25, 113.62, 117.23, 122.53, 134.19, 143.01, 145.61,
146.30, 147.86. IR (neat): 2928, 2856, 1512, 1462, 1379,
1261, 1209, 1155, 1080, 1030, 902, 837, 810, 775 cm–1.
HRMS (EI) m/z calcd for C31H48O6Si (M+): 544.3220.
Found: 544.3224.
Acknowledgment
We are grateful to Professor Thomas R. Hoye (Department of
Chemistry and Medicinal Chemistry, University of Minnesota) for
providing us with copies of the IR, 1H and 13C NMR, and MS spec-
tra of natural otteliones A (4) and B (1) and for useful discussions
and encouragement.
(13) (a) Corey, E. J.; Winter, R. A. E. J. Am. Chem. Soc. 1963, 85,
2677. (b) Corey, E. J.; Carey, F. A.; Winter, R. A. E. J. Am.
Chem. Soc. 1965, 87, 934.
(14) Data for 3-epi-ottelione A (2): White cloudy viscous oil,
[a]D20 +15.6 (c 0.32, CHCl3). 1H NMR (500 MHz, CDCl3):
d = 1.20 (1 H, ddd, J = 17.7, 10.3, 7.4 Hz), 1.98 (1 H, dt,
J = 13.1, 7.8 Hz), 2.19–2.28 (1 H, m), 2.54–2.60 (2 H, m),
2.73 (1 H, dd, J = 10.6, 8.4 Hz), 2.79 (1 H, dd, J = 13.7, 7.1
Hz), 2.90–2.98 (1 H, m), 3.85 (3 H, s), 4.84–4.89 (1 H, m),
4.97–5.02 (1 H, m), 5.36 (1 H, s), 5.53 (1 H, s), 5.64 (1 H,
ddd, J = 17.0, 10.2, 8.1 Hz), 5.88–5.92 (1 H, m), 6.73 (1 H,
dd, J = 8.1, 1.9 Hz), 6.77 (1 H, d, J = 8.1 Hz), 6.81 (1 H, d,
J = 1.9 Hz), 6.94 (1 H, d, J = 9.9 Hz). 13C NMR (125 MHz,
CDCl3): d = 37.52, 41.34, 41.91, 48.69, 50.16, 53.73, 55.97,
110.61, 115.35, 115.85, 120.34, 121.51, 126.51, 133.88,
140.49, 140.65, 144.89, 145.33, 145.58, 199.83. IR(neat):
3423, 2920, 1655, 1589, 1510, 1440, 1273, 1234, 1130,
1028, 912, 804, 760 cm–1. HRMS (EI) m/z calcd for
C20H22O3 (M+): 310.1569. Found: 310.1565.
References
(1) Ayyad, S.-E. N.; Judd, A. S.; Shier, W. T.; Hoye, T. R. J.
Org. Chem. 1998, 63, 8102.
(2) Combeau, C.; Provost, J.; Lancelin, F.; Tournoux, Y.;
Prod’homme, F.; Herman, F.; Lavelle, F.; Leboul, J.;
Vuilhorgne, M. Mol. Pharm. 2000, 57, 553.
(3) (a) Clive, D. L. J.; Fletcher, S. P. Chem. Commun. 2002,
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(c) Mehta, G.; Islam, K. Synlett 2000, 1473. (d) Trembleau,
L.; Patiny, L.; Ghosez, L. Tetrahedron Lett. 2000, 41, 6377.
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racemic ( )-3-epi-ottelione A derivative (3-epi-O-
Synlett 2003, No. 15, 2401–2403 © Thieme Stuttgart · New York