Construction of the diene moiety (C9-C18) of amphidinolide B, a 26- membered macrolide

Article abstract of DOI:10.1055/s-1999-2690

The diene moiety (C₉-C₁₈) of amphidinolide B, a potent cytotoxic macrolide isolated from the marine dinoflagellate Amphidinium sp., has been synthesized by a coupling reaction of an alkynyl anion of 5 and the aldehyde 7, followed by Michael addition and methylenation.

Full text of DOI:10.1055/s-1999-2690

LETTER
571
Construction of the Diene Moiety (C9-C18) of Amphidinolide B, a 26-
Membered Macrolide
Katsuhide Ohi, Shigeru Nishiyama*
Department of Chemistry, Faculty of Science and Technology, Keio University, Hiyoshi, Yokohama 223-8522, Japan
Fax:+81-45-563-5967; E-mail: nisiyama@chem.keio.ac.jp
Received 1 February 1999
At the outset, we intended to synthesize this moiety by
coupling of allyl anion 2a with methyl ketone 3a, fol-
lowed by dehydration (Scheme 1). Unfortunately, all at-
tempts using the allyl anion equivalents (2b–d) and
methyl ketone 3a were unsuccessful, although the anion-
generation from 2 under BuLi conditions was confirmed
by D2O-exchange experiments. It was noticed that
D2O-interruption of this reaction provided 3a carrying a
partially deuterated methyl ketone. Since even the
Horner-Wadsworth-Emmons reaction of 3a with
(MeO)2POCH2CO2Me (NaH) did not proceed, facile eno-
lization of 3a under the reaction conditions may interfere
with the desired nucleophilic reaction. Upon employing
3b possessing no active hydrogen (Scheme 2), coupling
reactions of 2b or 2c produced diene 4 in low yields,6
probably owing to steric hindrance of a BOM protective
group.7
Abstract: The diene moiety (C9-C18) of amphidinolide B, a potent
cytotoxic macrolide isolated from the marine dinoflagellate Amphi-
dinium sp., has been synthesized by a coupling reaction of an alky-
nyl anion of 5 and the aldehyde 7, followed by Michael addition and
methylenation.
Key words: marine natural products, Amphidinolide B, cytotoxic
activity
In connection with the synthesis of amphidinolide B (1), a
cytotoxic 26-membered macrolide isolated from cultured
marine dinoflagellates of the genus Amphidinium.,1 we
have reported syntheses of two synthetic intermediates
(C1-C132 and C14-C253). Coupling of these fragments at the
diene and lactone moieties will accomplish construction
of the macrolide framework. Although several synthetic
studies on the amphidinolide family have been reported,4
the diene moiety has not been produced with the excep-
tion of a synthetic approach to amphidinolide G, H and L,5
regarded as C16-deoxy derivatives of 1. To complete the
total synthesis of 1, we required a practical method to syn-
thesize the diene system. We disclose herein the process
of our investigation.
BOMO
OTBS
BOMO
X
H
OTBS
+
O
OTBS
OTBS
2
3b
4
OH
18
O
HO
RO
18
OR
OH
Scheme 2
Reagents and Conditions:
2b: X=S(O)Ph i) tBuLi, THF, –40 °C; ii) Na-Hg, Na2HPO4, MeOH,
23% in 2 steps.
14
14
HO
2c: X=P(O)Ph2, NaHMDS, THF, –40 °C, 25%.
O
OR
9
O
9
O
diene model
In the next stage, we turned our strategy to an alkynone
approach. As can be seen in Scheme 3, propargyl ether 5
prepared from 6 was coupled with aldehyde 7, followed
by MnO2 oxidation to give 8 in good overall yield. The
Michael addition reaction effected introduction of a meth-
yl group to 8 to give a,b-unsaturated ketone 9,8 which on
treatment with Tebbe reagent9 afforded the desired diene
carrying the C16 substituent 10.10
Amphidinolide B (1)
R1
BOMO
R2
13
18
+
OTBS
9
OTBS
2a R1=CH2
3a R2=COCH3
3b R2=CHO
To the best of our knowledge, this is the first example of
the construction of the characteristic diene moiety of 1.
Further investigation toward the total synthesis is in
progress.
2b R1=CH2S(O)Ph
2c R1=CH2P(O)Ph2
2d R1=CH2P(O)(OMe)2
Scheme 1
Synlett 1999, No. 5, 571–572 ISSN 0936-5214 © Thieme Stuttgart · New York

572
K. Ohi, S. Nishiyama
LETTER
BOMO
OTBS
O
H
OTBS
BOMO
O
O
i
ii
OTBS
OH
OTBS
5
6
7
8
BOMO
BOMO
OTBS
OTBS
iii
iv
O
OTBS
OTBS
9
10
Scheme 3
Reagents and Conditions: i a) TBSCl, Imid., DMF; b) TMS-CCH, nBuLi, THF, -78 °C, 96% in 2 steps;
c) BOMCl, iPr2NEt, NaI,CH2Cl2, 85%; d) K2CO3, MeOH, 94%. ii, a) 5, nBuLi, THF, -78 °C, then 7, 96%;
b) MnO2, CH2Cl2, 85%. iii Me2CuLi, Et2O, -23 °C, 55%. iv Tebbe reagent, THF, -40 °C, then 0 °C, 81%
(7) This protective group was employed for compatibility with
other functional groups in our synthetic process.
(8) Upon using excess amounts of Me2CuLi, b,b-dimethyl
ketones were obtained as by-products. Other reagents
examined also provided 9 [MeMgBr-CuI (42%),
Me2Cu(CN)Li (36%), Me2CuLi-BF3·OEt2 (28%)].
(9) Wittig reaction (Ph3PCH3I, nBuLi) of 9 afforded the olefinic
isomer 10’ (20%), along with 10 (15%).
References and Notes
(1) a) planar structure: Ishibashi, M.; Ohizumi, Y.; Hamashima,
M.; Nakamura, H.; Hirata, Y.; Sasaki, T.; Kobayashi, J. Chem.
Commun. 1987, 1127. b) revised planar structure: Kobayashi,
J.; Ishibashi, M.; Nakamura, H.; Ohizumi, Y.; Yamasu, T.;
Hirata, Y.; Sasaki, T.; Ohta, T.; Nozoe, S. J. Nat. Prod. 1989,
52, 1036. c) relative stereochemistry: Bauer, I.; Maranda, L.;
Shimizu, Y.; Peterson, R. W.; Cornell, L.; Steiner, J. R.;
Clardy, J. J. Am. Chem. Soc. 1994, 116, 2657. d) absolute
stereochemistry: Ishibashi, M; Ishiyama, H.; Kobayashi, J.
Tetrahedron Lett. 1994, 35, 8241.
(10) The geometry of the diene was confirmed by the NOE
experiments.
BOMO
7%
(2) Ohi, K.; Shima, K.; Hamada, K.; Saito, Y.; Yamada, N.; Ohba,
S.; Nishiyama, S. Bull. Chem. Soc. Jpn. 1998, 71, 2433.
(3) Ohi, K.; Nishiyama, S. Synlett 1999, 573.
OTBS
15%
(4) a) Chakraborty, T. K.; Suresh, V. R. Chem. Lett. 1997, 565.
b) Lee, D.-H.; Lee, S.-W. Tetrahedron Lett. 1997, 38, 7909.
c) Kobayashi, J.; Hatakeyama, A.; Tsuda, M. Tetrahedron
1998, 54, 697. d) Cid, M. B.; Pattenden, G. Synlett 1998, 540.
(5) a) Chakraborty, T. K.; Suresh, V. R. Tetrahedron Lett., 39
1998, 7775. B) Chakraborty, T. K.; Suresh, V. R. Tetrahedron
Lett. 1998, 39, 9109.
OTBS
9
Figure 2
(6) In the case of 2b, elevated reaction temperature (-40 ∞C Æ
Selected data for 10:1H NMR (CDCl3) d 0.04 (12H, s), 0.89 (18H,
s), 1.20-1.60 (4H, complex), 1.45 (3H, s), 1.72 (3H, s), 1.94
(2H, t, J = 7.5 Hz), 2.08 (2H, d, J = 7.6 Hz), 3.55-3.70 (4H,
complex), 4.54 (1H, d, J = 11.5 Hz), 4.70-4.75 (3H, complex),
4.78 (1H, s), 5.02 (1H, s), 5.84 (1H, s), and 7.27-7.35 (5H,
complex); 13C NMR (CDCl3) d 145.8, 139.3, 138.0, 128.2,
127.9, 127.7, 127.4, 113.4, 89.6, 80.7, 69.6, 63.1, 59.6, 42.3,
37.5, 32.5, 26.1, 24.5, 23.8, 18.5, 18.4, 14.2, and -5.1.
0 ∞C) caused isomerization of the olefinic bond to give 4’.
OMOB
R
OTBS
OTBS
Article Identifier:
1437-2096,E;1999,0,05,0571,0572,ftx,en;Y02799ST.pdf
4' R=H
10' R=Me
Figure 1
Synlett 1999, No. 5, 571–572 ISSN 0936-5214 © Thieme Stuttgart · New York