Studies toward the total synthesis of gymnocin A, a cytotoxic polyether: A highly convergent entry to the F-N ring fragment

Article abstract of DOI:10.1021/ol025814u

Matrix presented An efficient and highly convergent synthesis of the FGHIJKLMN ring fragment of gymnocin A, a cyctotoxic polycyclic ether isolated from the notorious red-tide forming dinoflagellate Gymnodinium mikimotoi, has been achieved. The present syn

Full text of DOI:10.1021/ol025814u

ORGANIC
LETTERS
2002
Vol. 4, No. 10
1747-1750
Studies toward the Total Synthesis of
Gymnocin A, a Cytotoxic Polyether: A
Highly Convergent Entry to the F−N
Ring Fragment
Makoto Sasaki,*,†,‡ Chihiro Tsukano,† and Kazuo Tachibana†
Department of Chemistry, Graduate School of Science, The UniVersity of Tokyo,
and CREST, Japan Science and Technology Corporation (JST), Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan, and Laboratory of Biostructural Chemistry,
Graduate School of Life Science, Tohoku UniVersity, Tsutsumidori-Amamiya, Aoba-ku,
Sendai 981-8555, Japan
msasaki@bios.tohoku.ac.j
Received March 4, 2002
ABSTRACT
An efficient and highly convergent synthesis of the FGHIJKLMN ring fragment of gymnocin A, a cyctotoxic polycyclic ether isolated from the
notorious red-tide forming dinoflagellate Gymnodinium mikimotoi, has been achieved. The present synthesis relied on extensive use of the
B-alkyl Suzuki−Miyaura coupling reaction.
Gymnocin A (1) was recently isolated from the notorious
red-tide forming dinoflagellate Gymnodinium mikimotoi by
Satake et al.1 The toxin displays in vitro cytotoxicity against
a murine P388 lymphocytic leukemia cell line (EC50 ) 1.3
µg/mL).2 The structure of gimnocin A, including the relative
and absolute stereochemistry, has been determined by a
combination of NMR analyses, FAB collision induced
dissociation (CID) MS/MS experiments, and a modified
Mosher method (Figure 1).1 Structurally, gymnocin A
consists of 14 contiguous and saturated ether rings, including
two repeating 6/6/7/6/6 ring systems, and a 2-methyl-2-
butenal side chain. The number of the contiguous ether rings
is the largest among the polycyclic ethers known to date.3
Given the structural complexity, intriguing biological activity,
and our continuing interest in the synthesis of polycyclic
ether marine toxins based on B-alkyl Suzuki-Miyaura
coupling,4-6 we have been engaged in the synthesis of
gymnocin A. Herein we describe a highly convergent
synthesis of the FGHIJKLMN ring fragment 3 that relies
on extensive use of the B-alkyl Suzuki-Miyaura coupling-
based methodology.
† The University of Tokyo and CREST, JST.
‡ Tohoku University.
(1) (a) Satake, M.; Ofuji, K.; Shoji, M.; Oshima, Y.; Yasumoto, T. Paper
Abstracts; 2000 International Chemical Congress of Pacific Basin Societies
(Pacifichem 2000), Honolulu, HI, 2000; ORGN-1780. (b) Satake, M.; Shoji,
M.; Oshima, Y.; Naoki, H.; Fujita, T.; Yasumoto, T. Submitted.
(2) Analogues of 1 of yet unknown structures showed far stronger
cyctotoxicity than 1; a private communication from Prof. M. Satake of
Tohoku University.
Figure 1. Structure of Gymnocin A (1).
10.1021/ol025814u CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/18/2002

Retrosynthetically, gymnocin A (1) can be disconnected
at the E ring into the ABCD and FGHIJKLMN fragments
(2 and 3, respectively) that could be joined via B-alkyl
Suzuki-Miyaura coupling (Scheme 1). We envisioned that
Scheme 2a
Scheme 1. Retrosynthetic Analysis of Gymnocin A (1)
a Reagents and conditions: (a) 10, n-BuLi, THF/HMPA, -78
°C; then 9, 96%; (b) Na(Hg), NaH2PO4, MeOH, rt, 75%; (c)
KOt-Bu, BnBr, THF, rt; (d) OsO4, NMO, acetone/H2O, rt; (e)
NaIO4, THF/H2O, rt; (f) NaBH4, MeOH, 0 °C, 81% (four steps);
(g) KOt-Bu, BnBr, THF, rt; (h) TBAF, THF, rt, 97% (two steps);
(i) SO3‚pyr, Et3N, DMSO, CH2Cl2, rt; (j) NaClO2, NaH2PO4,
2-methyl-2-butene, t-BuOH/H2O, 0 °C; (k) TFA, CH2Cl2, 0 °C,
62% (two steps); (l) 2,4,6-Cl3C6H2COCl, Et3N, THF, rt; then
DMAP, toluene, 110 °C, 62%; (m) KHMDS, (PhO)2P(O)Cl, THF/
HMPA, -78 °C.
10,8 gave â-hydroxy sulfone 11, which upon treatment with
sodium amalgam provided alcohol 12 in 72% overall yield
from 9. After protection of the alcohol as its benzyl ether,
the double bond was oxidatively cleaved and the resultant
aldehyde was reduced to give 13 in 81% overall yield.
Alcohol 13 was then converted to 14 in two steps. Oxidation
of the primary alcohol 14 to carboxylic acid by a two-step
procedure followed by removal of the methoxymethyl
(MOM) group with TFA afforded hydroxy acid 15 in 62%
yield (three steps). Lactonization under Yamaguchi condi-
tions provided lactone 16, which was readily converted to
the enol phosphate 7.
the latter compound could be further divided into two
fragments, the GHI (4) and KLMN (5) rings, both of which
would be derived from a common precursor, 6. The key
intermediate 6, in turn, could be prepared by convergent
union of monocyclic units 7 and 8.
The synthesis of enol phosphate 7 commenced with the
known epoxide 9,7 derived from geraniol (Scheme 2).
Reaction of 9 with a lithium anion, generated from sulfone
(3) For reviews on marine polycyclic ethers, see: (a) Yasumoto, T.;
Murata, M. Chem. ReV. 1993, 93, 1897-1909. (b) Murata, M.; Yasumoto,
T. Nat. Prod. Rep. 2000, 293-314. (c) Yasumoto, T. Chem. Rec. 2001, 3,
228-242.
Construction of exocyclic enol ether 8 began with the
known alcohol 17,9 which was protected as the TBS ether
18 (Scheme 3). Routine protective and functional group
manipulations allowed the conversion to primary alcohol 19,
(4) (a) Sasaki, M.; Fuwa, H.; Inoue, M.; Tachibana, K. Tetrahedron Lett.
1998, 39, 9027-9030. (b) Sasaki, M.; Fuwa, H.; Ishikawa, M.; Tachibana,
K. Org. Lett. 1999, 1, 1075-1077. (c) Sasaki, M.; Noguchi, K.; Fuwa, H.;
Tachibana, K. Tetrahedron Lett. 2000, 41, 1425-1428. (d) Fuwa, H.; Sasaki,
M.; Tachibana, K. Tetrahedron Lett. 2000, 41, 8371-8375. (e) Fuwa, H.;
Sasaki, M.; Tachibana, K. Tetrahedron 2001, 57, 3019-3033. (f) Takakura,
H.; Noguchi, K.; Sasaki, M.; Tachibana, K. Angew. Chem., Int. Ed. 2001,
40, 1090-1093. (g) Fuwa, H.; Sasaki, M.; Tachibana, K. Org. Lett. 2001,
3, 3549-3552.
Scheme 3a
(5) For reviews on Suzuki cross-coupling reaction, see: (a) Miyaura,
N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483. (b) Suzuki, A. J.
Organomet. Chem. 1999, 576, 147-168.
(6) For a recent comprehensive review on application of the B-alkyl
Suzuki-Miyaura reaction in natural product synthesis, see: Chemler, S.
R.; Trauner, D.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2001, 40, 4544-
4568.
(7) Epoxide 9 is available in five steps from geraniol via Sharpless
asymmetric epoxidation, see: (a) Hashimoto, M.; Kan, T.; Nozaki, K.;
Yanagiya, M.; Shirahama, H.; Matsumoto, T. J. Org. Chem. 1990, 55,
5088-5107. (b) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.;
Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765-
5780.
a Reagents and conditions: (a) TBSCl, imidazole, DMF, rt, 81%;
(b) EtSH, Zn(OTf)2, NaHCO3, CH2Cl2, rt, 99%; (c) KOt-Bu, BnBr,
THF, rt; (d) OsO4, NMO, acetone/H2O, rt; (e) NaIO4, THF/H2O,
rt; (f) NaBH4, MeOH, 0 °C, 83% (four steps); g) I2, PPh3, imidazole,
CH2Cl2, rt; (h) KOt-Bu, THF, 0 °C, quant.
1748
Org. Lett., Vol. 4, No. 10, 2002

which upon iodination followed by base treatment provided
the desired 8.
poor stereoselectivity in this reaction is presumably due to
the steric hindrance of the pseudoaxial methyl group on the
seven-membered ring. Oxidation of 21a with TPAP/NMO10
provided ketone 22a in excellent yield. On the other hand,
the undesired isomer 21b can be converted to 22a. Thus,
21b was oxidized with TPAP/NMO to ketone 22b, which
upon treatment with DBU in benzene provided 22a in
48% yield (two steps) along with the recovered 22b (48%
yield). Acidic treatment of 22a in methanol resulted in
removal of the silyl group with concomitant formation of a
mixed methyl ketal in 84% yield. Exposure of the resultant
Hydroboration of 8 with 9-BBN-H, followed by cross-
coupling with 7 under the conditions previously optimized
(aqueous NaHCO3, PdCl2(dppf), DMF, 50 °C)4e afforded the
desired endocyclic enol ether 20, but the yield was low (ca.
30%). The use of Cs2CO3 instead of NaHCO3 gave a better
result, and an 86% yield of 20 was obtained (Scheme 4).
Scheme 4a
11
methyl ketal to Et3SiH and BF3‚OEt2 furnished tricyclic
ether 23 as the sole product in quantitative yield. The
stereostructure of 23 was established by NOE experiments
as shown in Figure 2. Conversion of 23 into the key
Figure 2. NOE experiments on compound 23 (C6D6, 500 MHz).
Benzyl groups were replaced with methyl groups for clarity.
intermediate 6 was accomplished without incident in a five-
step procedure as shown. Treatment of 6 with potassium tert-
butoxide provided the GHI ring exocyclic enol ether 4 in
91% yield. On the other hand, radical reduction of 6 followed
by oxidative removal of the p-methoxybenzyl (PMB) group
and protection as its silyl ether provided 24 in 59% overall
yield. The benzyl groups were removed by hydrogenolysis,
and the derived diol was oxidized with TPAP/NMO to
furnish lactone 25 (61% for two steps), which was then
converted to enol phosphate 5. Due to its instability, 5 was
used immediately in the next coupling reaction without
purification.
a Reagents and conditions: (a) 8, 9-BBN-H, THF, rt;, then
aqueous Cs2CO3, 7, PdCl2(dppf), DMF, 50 °C, 86%; (b) BH3‚THF,
THF, rt; then aqueous NaOH, H2O2, rt, 21a: 55%, 21b: 37%; (c)
TPAP, NMO, MS4 Å, CH2Cl2, rt, 98%; (d) TPAP, NMO, MS 4
Å, CH2Cl2, rt, 84%; (e) DBU, benzene, rt, 48% (+ recovered
ketone, 48%); (f) p-TsOH, MeOH, rt, 84%; (g) Et3SiH, BF3‚OEt2,
CH2Cl2, rt, quant; (h) H2, Pd(OH)2/C, MeOH, rt; (i) p-MeOC6H4CH
(OMe)2,PPTS, CH2Cl2, rt, 84% (two steps); (j) KOt-Bu, BnBr, THF,
rt; (k) DIBALH, CH2Cl2, rt, 67% (two steps); (l) I2, PPh3, imidazole,
benzene, rt, 92%; (m) KOt-Bu, THF, 0 °C, 91%; (n) n-Bu3SnH,
AIBN, toluene, 100 °C; (o) DDQ, CH2Cl2/phosphate buffer (pH
7), rt, 63% (two steps); (p) TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C,
94%; (q) H2, Pd(OH)2/C, MeOH, rt; (r) TPAP, NMO, MS 4 Å,
CH2Cl2, rt, 61% (two steps); (s) KHMDS, (PhO)2P(O)Cl, THF/
HMPA, -78 °C.
With the requisite coupling partners in hand, we next
investigated their B-alkyl Suzuki-Miyaura coupling reaction
(Scheme 5). Coupling of enol phosphate 5 with an alkylbo-
rane generated from 4 proceeded smoothly (aqueous Cs2-
CO3, Pd(PPh3)4, DMF, 50 °C), leading to the desired cross-
(8) Sulfone 10 was prepared from 1,3-propanediol in three steps: (i)
TBSCl, Et3N, CH2Cl2, rt; (ii) PhSSPh, n-Bu3P, DMF, rt; (iii) mCPBA,
NaHCO3, CH2Cl2, 0 °C, 77% yield for three steps.
(9) Compound 17 is available in nine steps from 2-deoxy-D-ribose, see:
(a) Nicolaou, K. C.; Nugiel, D. A.; Couladouros, E.; Hwang, C.-K.
Tetrahedron 1990, 46, 4517-4552. (b) Reference 4e.
(10) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639-666.
(11) Lewis, M. D.; Cha, J. K.; Kishi, Y. J. Am. Chem. Soc. 1982, 104,
4976-4978.
Subsequent hydroboration of the enol ether moiety produced
a separable mixture of the desired alcohol 21a (55%) and
the corresponding diastereomer 21b (37%). The observed
Org. Lett., Vol. 4, No. 10, 2002
1749

(three steps from 25). The stereochemistry at C37 and C38
positions12 of 27 was confirmed by coupling constant analysis
of the corresponding acetate derivative (J37,38 ) 9 Hz).
Silylation followed by oxidative removal of the PMB group
afforded alcohol 28, which was oxidized with TPAP/NMO
to afford ketone 29. At this stage, the stereochemistry at C35
was unambiguously established by NOE between H31 and
H35. Treatment of ketone 29 with EtSH and Zn(OTf)2
afforded mixed thioketal 30 (87%), which was then reduced
under radical conditions to yield octacyclic ether 31 in 92%
yield. Finally, removal of the benzyl groups and oxidation
Scheme 5a
13
of the resultant diol with RuCl2(PPh3)3 completed the
synthesis of the target FGHIJKLMN ring fragment 3 (93%
yield for two steps).
In conclusion, a convergent synthesis of the FGHIJKLMN
ring fragment 3 of gymnocin A (1) has been achieved on
the basis of extensive use of the B-alkyl Suzuki-Miyaura
coupling-based methodology. The present synthesis demon-
strated the usefulness and generality of our approach to a
fused polycyclic ether class of marine natural products.
Synthesis of the ABCD ring fragment 2 and its coupling
with 3 leading to the total synthesis of 1 is currently
underway and will be reported in due course.
Acknowledgment. We thank Prof. M. Satake of Tohoku
University for valuable discussions. This work was finan-
cially supported in part by a grant from Suntory Institute
for Bioorganic Research (SUNBOR).
a Reagents and conditions: (a) 4, 9-BBN-H, THF, rt; then
aqueous Cs2CO3, 5, Pd(PPh3)4, DMF; (b) BH3‚THF, THF, -20 f
0 °C; then aqueous NaOH, H2O2, rt, 72% from 25; (c) TESOTf,
2,6-lutidine, CH2Cl2, 0 °C, 81%; (d) DDQ, CH2Cl2/phosphate buffer
(pH 7), rt, 90%; (e) TPAP, NMO, MS4 Å, CH2Cl2, 91%; (f) EtSH,
Zn(OTf)2, CH2Cl2, rt, 87%; (g) Ph3SnH, AIBN, toluene, 100 °C,
92%; (h) H2, Pd(OH)2/C, EtOAc/MeOH, rt; (i) RuCl2(PPh3)3,
toluene, 93% (two steps).
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds; H and
13C NMR spectra for compound 3. This material is available
1
free of charge via the Internet at http://pubs.acs.org.
OL025814U
(12) The numbering of carbon atoms of all compounds in this paper
corresponds to that of gymnocin A.
(13) Tomioka, H.; Takai, K.; Oshima, K.; Nozaki, H. Tetrahedron Lett.
1981, 22, 1605-1608.
coupled product 26 in good yield. Subsequent hydroboration
provided alcohol 27 as the sole product in 72% overall yield
1750
Org. Lett., Vol. 4, No. 10, 2002