Synthetic study on top-half (C14-C25) fragment of amphidinolide B, a 26-membered macrolide

Article abstract of DOI:10.1055/s-1999-2697

The top-half fragment (C₁₄-C₂₅) of amphidinolide B, a potent cytotoxic macrolide isolated from the marine dinoflagellate Amphidinium sp., has been synthesized using a coupling reaction of iodide 16 corresponding to the C₁₄

Full text of DOI:10.1055/s-1999-2697

LETTER
573
Synthetic Study on Top-Half (C14-C25) Fragment 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 15 February 1999
Our retrosynthetic analysis indicated that the top-half
fragment 2 would be constructed by a coupling reaction of
3 with 4.6 According to this synthetic plan, the synthesis
was initiated by the Wittig reaction of the aldehyde 5, pre-
Abstract: The top-half fragment (C14-C25) of amphidinolide B, a
potent cytotoxic macrolide isolated from the marine dinoflagellate
Amphidinium sp., has been synthesized using a coupling reaction of
iodide 16 corresponding to the C14-C19 part and a,b-unsaturated
dithioacetal 9 possessing the remaining carbon framework (C20-C25) pared by the Shier protocol,7 leading to a,b-unsaturated
as the key step.
ester 6 in 84% yield. Compound 6 was submitted to a
three-step procedure via aldehyde 7 to give the corre-
sponding dithioacetal 8, which on protection as a TBDPS
ether afforded 9 carrying the C20-C25 sequence.
Key words: marine natural products, Amphidinolide B, cytotoxic
activity, umpolung, asymmetric dihydroxylation
Previously, we reported the construction of the C1-C13
segment of amphidinolide B,1 isolated from cultured ma-
rine dinoflagellates of the genus Amphidinium, which was
originally found living inside Okinawan marine flat-
worms of the genus Amphiscolps.2 This marine natural
product has attracted wide attention among synthetic
chemists for its 26-membered macrolactone structure in-
cluding the characteristic exomethylene and allylic ep-
oxide, as well as for its powerful antitumor activities [IC50
values against L1210 (0.00014 mg/ml) and KB cell
(0.0042 mg/ml)]. Since determination of its absolute con-
figuration by Kobayashi et al.,3 at least five synthetic
groups including us, have competed for the total synthesis
of 1.4 Such a situation prompted us to report our own syn-
thetic approach to the top-half fragment 2 consisting of
the C14-C25 positions. We described herein the synthetic
process.5
O
OHC
i
ii
MeO
OTBS
OTBS
6
5
O
H
S
iii
S
OTBS
OR
8
9
R= H
R= TBDPS
7
Scheme 2
Reagents and Conditions: i) Ph3P=CHCOOMe, CH2Cl2, 84%. ii) a)
DIBAL-H, PhMe, -78 °C, 88%; b) MnO2, CH2Cl2, 99%. iii) a)
HS(CH2)3SH, HCl aq., THF, 0 °C, 93%; b) TBDPSCl, Imid., DMF,
98%.
OH
O
HO
OH
O
20
OR
O
20
RO
14
OR
HO
20
OR
OR
18
RO
25
+
RO
14
RO
O
25
OR
25
3
4
O
2 (19: R=H)
O
OR
Amphidinolide B (1)
O
H
+
OR
OR
OR
O
Bottom-half fragment
Scheme 1
Synlett 1999, No. 5, 573–575 ISSN 0936-5214 © Thieme Stuttgart · New York

574
K. Ohi, S. Nishiyama
LETTER
In the next stage, diol ester 108 was transformed via Wein-
reb amide 12 into ketone 13 in good overall yield.9 Treat-
ment of 13 with the alkynyl anion, generated by reaction
of trimethylsilylacetylene with nBuLi, effected the de-
sired coupling reaction to give 14 in 96% yield (syn-14:
anti-14 = 2:1).10 After chromatographic separation, the
cyclohexylidene group of syn-14 was removed, and the
resulting triol was selectively tosylated, followed by intro-
duction of an isopropylidene group, leading to 15, which
on treatment with NaI gave 16 in 66% yield from 14.
O
OH
O
O
i
ii
O
OH
MeO
R
10
11 R= OMe
12 R= N(OMe)Me
13 R= Me
O
O
O
OH
iii
O
X
The anion of 9 could successfully be generated under
nBuLi-HMPA conditions: D2O-exchange experiments in-
dicated the anion was localized at the C20-position. Ac-
cordingly, the anion was reacted with iodide 16 to produce
the expected coupling product 17, with abstraction of the
terminal TMS group. Dihydroxylation of this sulfur-con-
taining 17 with AD-mix-a11 was unsuccessful, probably
owing to steric hindrance. Among deprotective proce-
dures examined to remove the bulky dithioacetal of 17,
only the (CF3COO)2IPh conditions12 effected the desired
reaction pathway to the ketone 18. Oxidation of 18 em-
ploying AD-mix-a gave the target tetraol 19 in 54% yield,
along with a diastereoisomer (3% yield).13
TMS
TMS
14
15 X= OTs
16 X= I
Scheme 3
Reagents and Conditions: i, a) cyclohexanone dimethy lacetal, PPTS,
CH2Cl2, 86%; b) MeNH(OMe)-HCl, iPrMgCl, THF, -30 °C, 74%; c)
MeMgBr, THF, -30 °C, then HCl aq., 94%. ii) TMS-CCH, nBuLi,
HMPA, THF, -78 °C, 96% (syn : anti = 2 :1). iii, a) 80% AcOH aq.,
98%; b) TsCl, Pyr., 0 °C, 90%; c) acetone dimethyl acetal, PPTS,
CH2Cl2, 85%; d) NaI, acetone, reflux, 88%
In conclusion, we have synthesized the top-half fragment
of amphidinolide B. Further investigation toward the cou-
pling with the bottom-half fragment is in progress.
S
O
O
+
i
20
I
S
16
OTBDPS
TMS
9
References and Notes
(1) Ohi, K.; Shima, K.; Hamada, K.; Saito, Y.; Yamada, N.; Ohba,
S.; Nishiyama, S. Bull. Chem. Soc. Jpn. 1998, 71, 2433.
(2) a) Ishibashi, M.; Ohizumi, Y.; Hamashima, M.; Nakamura,
H.; Hirata, Y.; Sasaki, T.; Kobayashi, J. Chem. Commun.
1987, 1127. The initially proposed planer structure was
revised: Kobayashi, J.; Ishibashi, M.; Nakamura, H.;
Ohizumi, Y.; Yamasu, T.; Hirata, Y.; Sasaki, T.; Ohta, T.;
Nozoe, S. J. Nat. Prod. 1989, 52, 1036.
O
O
S
S
17
H
OTBDPS
ii
b) Bauer, I.; Maranda, L.; Shimizu, Y.; Peterson, R. W.;
Cornell, L.; Steiner, J. R.; Clardy, J. J. Am. Chem. Soc. 1994,
116, 2657.
OH OH
O
(3) Ishibashi, M; Ishiyama, H.; Kobayashi, J. Tetrahedron Lett.
1994, 35, 8241.
18
H
H
OTBDPS
OTBDPS
(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) Parts of this study have been presented at the Annual Meeting
of the Chemical Society Japan (1996, 4C7 09).
(6) Successful conversion of the resulting propargyl alcohol of 2
into the natural diene system will be reported in the following
paper.
iii
OH OH
O
OH
19
OH
Scheme 4
(7) Imaeda, T.; Hamada, Y.; Shioiri, T. Tetrahedron Lett. 1994,
35, 591.
Reagents and Conditions: i) nBuLi, HMPA, THF, -78 °C, 74%. ii, a)
80% AcOH aq., 71%; b) (CF3COO)2IPh, MeCN, H2O, 0 °C, 63%. iii)
AD-mix-a, MeSO2NH2, tBuOH, H2O, 0 °C, 54%.
(8) Saito, S.; Hasegawa, T.; Inaba, M.; Nishida, R.; Fujii, T.;
Nomizu, S.; Moriwake, T. Chem. Lett. 1984, 1389.
(9) Williams, J. M.; Jobson, R. B.; Yasuda, N.; Marchesini, G.;
Dolling, U.-H.; Grabowski, E. J. J. Tetrahedron Lett. 1995,
36, 5461.
(10) Although another synthetic strategy (Scheme 5) was
attempted, total yield of this process was lower than in the case
of direct addition (13 Æ 14). Further elaboration of the
strategy is under way to improve the selectivity of this step.
Synlett 1999, No. 5, 573–575 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthetic Study on Top-Half (C14-C25) Fragment of Amphidinolide B, a 26-Membered Macrolide
575
(11) Kolb, H. C.; VanNieuwenhze, M. S.; Shrapless, K. B. Chem.
Rev. 1994, 94, 2483
i
(12) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 287.
(13) Selected data for 19: [a]D23 -17.8∞ (c 1.22, CHCl3): IR
(film):3440, 3320, and 1715 cm-1; 1H NMR (CDCl3) d 0.86
(1H, m), 0.87 (3H, d, J = 6.8 Hz), 1.04 (9H, s), 1.10 (3H, d,
J = 6.4 Hz), 1.19 (1H, m), 1.60 (3H, s), 1.69 (1H, m), 1.80-
2.10 (2H, complex), 2.42-2.55 (3H, complex), 2.91 (1H, dd,
J = 8.2, 16.0 Hz), 3.63 (1H, d, J = 8.2 Hz), 3.92 (1H, m), 4.56
(1H, m), 7.43-7.44 (6H, complex), and 7.65-7.72 (4H,
complex); 13C NMR (CDCl3) d 211.4, 136.0, 129.6, 129.5,
127.6, 127.4, 87.6, 78.0, 75.4, 71.8, 67.7, 67.2, 66.2, 47.5,
45.1, 43.3, 33.0, 29.8, 27.0, 24.3, 19.3, and 16.1.
O
O
O
O
ii
O
O
MeO
O
13
O
O
O
OH
iii
O
O
Cl
O
O
TMS
14
Similar selectivities of related asymmetric dihydroxylation
were reported (references 4a, d).
Scheme 5
Reagents and Conditions: i, a) (MeO)2P(O)CH2COOMe, NaH, THF;
b) AD-mix b, MeSO2NH2, tBuOH/H2O=1/1, 0 °C;
c) acetone dimethyl acetal, PPTS, CH2Cl2, (55% in 3 steps).
ii, a) LiAlH4, THF, -78 °C; b) PPh3, CCl4, reflux (59% in 2 steps).
iii) nBuLi, THF, -78 °C, then TMSCl, 93%.
Article Identifier:
1437-2096,E;1999,0,05,0573,0575,ftx,en;Y18498ST.pdf
Synlett 1999, No. 5, 573–575 ISSN 0936-5214 © Thieme Stuttgart · New York