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,
1940. (b) Mehta, G.; Islam, K. Org. Lett. 2002, 4, 2881.
(c) Mehta, G.; Islam, K. Synlett 2000, 1473. (d) Trembleau,
L.; Patiny, L.; Ghosez, L. Tetrahedron Lett. 2000, 41, 6377.
(e) Mehta, G.; Reddy, D. S. Chem. Commun. 1999, 2193.
(4) Mehta, G.; Islam, K. Angew. Chem. Int. Ed. 2002, 41, 2396.
(5) Mehta, G.; Islam, K. Tetrahedron Lett. 2003, 44, 6733.
(6) Araki, H.; Inoue, M.; Katoh, T. Org. Lett. 2003, 5, 3903.
(7) In 2002 Mehta and Islam reported the total synthesis of
racemic ( )-3-epi-ottelione A derivative (3-epi-O-
Synlett 2003, No. 15, 2401–2403 © Thieme Stuttgart · New York