Total Synthesis of Gymnocin-A

Article abstract of DOI:10.1021/ja038547b

A highly convergent total synthesis of gymnocin-A, a cyctotoxic polyether marine natural product, has been achieved. The synthesis features Suzuki?Miyaura coupling of the ABCD and FGHIJKLMN rings, stereoselective introduction of the C17 hydroxyl group, ring-closure of the F ring, and a late-stage incorporation of a 2-methyl-2-butenal side chain. Copyright

Full text of DOI:10.1021/ja038547b

Published on Web 11/04/2003
Total Synthesis of Gymnocin-A
Chihiro Tsukano and Makoto Sasaki*
Laboratory of Biostructural Chemistry, Graduate School of Life Sciences, Tohoku UniVersity,
Tsutsumidori-Amamiya, Aoba-ku, Sendai 981-8555, Japan
Received September 16, 2003; E-mail: masasaki@bios.tohoku.ac.jp
Gymnocin-A (1) is a polyether toxin isolated by Satake and co-
workers in 2001 from the notorious red tide dinoflagellate, Karenia
mikimotoi, which is a representative species that causes devastating
damage worldwide.1 The toxin is a rare polyether natural product
that displays in vitro cytotoxicity against P388 leukemia cells (EC50
) 1.3 µg mL-1).2 The structure of gymnocin-A, including the rel-
ative and absolute stereochemistry, has been established by a com-
bination of extensive 2D-NMR analyses, FAB collision-induced
dissociation MS/MS experiments, and modified Mosher’s method
(Figure 1).1 Structurally, gymnocin-A is characterized by 14 con-
tiguous 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 contiguous ether rings exceeds those of other polyethers hitherto
synthesized.3,4 The structural complexity as well as intriguing bio-
logical activity compelled us to embark on a program aimed at its
total synthesis. Herein, we describe a convergent and efficient total
synthesis of gymnocin-A, which is realized by extensive use of
our developed B-alkyl Suzuki-Miyaura coupling-based method-
ology.5-7
Figure 1. Structure of gymnocin-A.
Scheme 1. Retrosynthetic Plan for Gymnocin-A
The retrosynthetic plan is outlined in Scheme 1. Clearly,
construction of the large polyether skeleton constituted the major
challenge in the synthesis of 1. Simplification of the 2-methyl-2-
butenal side chain in 1 would lead to tetradecacyclic polyether core
2, which was envisioned to arise from convergent coupling of the
ABCD and FGHIJKLMN ring fragments (38b and 4,8a respectively)
through the B-alkyl Suzuki-Miyaura coupling-based strategy.4
Following their convergent union, stereoselective introduction of
the C17 hydroxyl group and reductive ring closure of the E ring
would complete the assembly of the polyether skeleton.
Enol triflate 4 required for cross-coupling with 3 was obtained
from lactone 5 through kinetic deprotonation (KHMDS, THF/
HMPA, -78 °C) and triflate formation by use of Comins’ reagent9
(Scheme 2). Suzuki-Miyaura coupling of the alkylborane derived
from exocyclic enol ether 3 (9-BBN, THF, room temperature) with
4 proceeded smoothly in the presence of aqueous Cs2CO3 and Pd-
(PPh3)4 in DMF at room temperature to produce the desired cross-
coupled product 6 in excellent yield (81%). Subsequent hydrobor-
ation of endocyclic enol ether 6 with a borane-dimethyl sulfide
complex in THF proceeded stereoselectively (75%).10 The resulting
secondary alcohol 711 was protected as the TES ether, and the PMB
group was oxidatively removed to afford alcohol 8 in 79% yield
for the two steps. For the introduction of the C17 hydroxyl group,
alcohol 8 was oxidized with TPAP/NMO12 to give ketone 9 in 95%
yield. Conversion to the corresponding silyl enol ether followed
by oxidation with OsO4/NMO installed the C17 hydroxyl group,
and subsequent protection of the resultant alcohol delivered the
desired R-siloxy ketone 1011 as a single stereoisomer in high overall
yield.
yield of 12. After some experiments, it was found that the choice
of solvent was critical for this cyclization. Use of nitromethane as
a solvent produced the desired mixed thioketal 12 and its desilylated
product 11 in 38 and 40% yield, respectively. The latter compound
was resilylated to 12 in 71% yield. Finally, reductive desulfurization
of 12 was achieved under radical conditions (Ph3SnH, AIBN,
toluene, 110 °C)13 to furnish the target polyether core 2 in excellent
yield.
The last stage of the synthesis involved the incorporation of a
2-methyl-2-butenal side chain. Since attempts to cleave the TBS
and TIPS groups at the ultimate step of our initial total synthesis
effort were fruitless, the TBS and TIPS groups were exchanged
for TES at the stage of 2. Subsequent reductive removal of the
benzyl ether with LiDBB14 afforded primary alcohol 13 in 73%
overall yield from 2. Oxidation with TPAP/NMO followed by
Wittig reaction of the derived aldehyde with methyl 2-(triph-
enylphosphoranilidene)propionate and subsequent reduction with
DIBAL-H generated allylic alcohol 14 in 66% overall yield. Finally,
removal of the TES groups with tris(dimethylamino)sulfonium
difluorotrimethylsilicate (TASF)15 in THF/DMF was followed by
chemoselective oxidation of the allylic alcohol moiety with MnO2
to furnish gymnocin-A (1) in 91% yield for the two steps. The
With ketone 10 in hand, ring-closure to mixed thioketal 12 was
next investigated. In contrast to precedent methodology,8a treatment
of 10 with EtSH and Zn(OTf)2 in CH2Cl2 resulted in only a low
9
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10.1021/ja038547b CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2 a
a Reagents and conditions: (a) KHMDS, THF/HMPA, -78 °C, Comins’ reagent, -78 f 0 °C, 80%; (b) 3, 9-BBN, THF, rt, then 4, 3M Cs2CO3,
Pd(PPh3)4, DMF, rt, 81%; (c) BH3‚SMe2, THF, 0 °C f rt, then NaOH, H2O2, rt, 75%; (d) TESOTf, 2,6-lutidine, CH2Cl2, rt; (e) DDQ, CH2Cl2/pH 7
phosphate buffer, 0 °C, 79% (two steps); (f) TPAP, NMO, 4Å MS, CH2Cl2, rt, 95%; (g) LiHMDS, TMSCl, Et3N, THF, -78 °C; (h) OsO4, NMO, THF/H2O,
rt; (i) TIPSOTf, 2,6-lutidine, CH2Cl2, rt, 85% (three steps); (j) EtSH, Zn(OTf)2, MeNO2, 0 °C f rt, 11: 40%; 12: 38%; (k) TBSOTf, 2,6-lutidine, CH2Cl2,
rt, 71%; (l) Ph3SnH, AIBN, toluene, 110 °C, 98%; (m) TBAF, 4Å MS, MeCN, 70 °C; (n) TESOTf, 2,6-lutidine, CH2Cl2, rt; (o) LiDBB, THF, -78 °C, 73%
(three steps); (p) TPAP, NMO, 4 Å MS, CH2Cl2, rt; (q) Ph3PdC(Me)CO2Me, CH2Cl2, rt; (r) DIBAL-H, CH2Cl2, -78 °C, 66% (three steps); (s) TASF,
THF/DMF, 0 °C f rt; (t) MnO2, CHCl3, rt, 91% (two steps).
1
(3) For reviews on marine polyethers, see: (a) Yasumoto, T.; Murata, M.
synthetic gymnocin-A was identical to the natural sample by H
Chem. ReV. 1993, 93, 1897. (b) Murata, M.; Yasumoto, T. Nat. Prod.
Rep. 2000, 17, 293. (c) Yasumoto, T. Chem. Rec. 2001, 3, 228.
and 13C NMR and MS spectra, thus confirming the structure of
gymnocin-A.
(4) For total synthesis of large polyether natural products, see: (a) Brevetoxin
B: Nicolaou, K. C.; Rutjes, F. P. J. T.; Theodorakis, E.; Tiebes, J.; Sato,
M.; Untersteller, E. J. Am. Chem. Soc. 1995, 117, 1173. (b) Brevetoxin
A: Nicolaou, K. C.; Yang, Z.; Shi, G.-Q.; Gunzner, J. L.; Agrios, K. A.;
Gatner, P. Nature 1998, 392, 264. (c) Ciguatoxin CTX3C: Hirama, M.;
Oishi, T.; Uehara, H.; Inoue, M.; Maruyama, M.; Oguri, H.; Satake, M.
Science 2001, 294, 1904.
(5) (a) Sasaki, M.; Fuwa, H.; Inoue, M.; Tachibana, K. Tetrahedron Lett.
1998, 39, 9027. (b) Sasaki, M.; Fuwa, H.; Ishikawa, M.; Tachibana, K.
Org. Lett. 1999, 1, 1075. (c) Fuwa, H.; Sasaki, M.; Tachibana, K.
Tetrahedron 2001, 57, 3019. (d) Fuwa, H.; Sasaki, M.; Tachibana, K.
Org. Lett. 2001, 3, 3549. (e) Sasaki, M.; Ishikawa, M.; Fuwa, H.;
Tachibana, K. Tetrahedron 2002, 58, 1889. (f) Takakura, H.; Sasaki, M.;
Honda, S.; Tachibana, K. Org. Lett. 2002, 4, 2771. (g) Fuwa, H.; Kainuma,
N.; Tachibana, K.; Sasaki, M. J. Am. Chem. Soc. 2002, 124, 14983 and
references therein.
(6) For reviews on SuzukisMiyaura coupling reaction, see: (a) Miyaura, N.;
Suzuki, A. Chem. ReV. 1995, 95, 2457. (b) Suzuki, A. J. Organomet.
Chem. 1999, 576, 147. (c) Suzuki, A.; Brown, H. C. Organic Syntheses
Via Boranes; Aldrich Chem. Co. Inc.: Wisconsin, 2003; Vol. 3.
(7) 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.
(8) (a) Sasaki, M.; Tsukano, C.; Tachibana, K. Org. Lett. 2002, 4, 1747. (b)
Sasaki, M.; Tsukano, C.; Tachibana, K. Tetrahedron Lett. 2003, 44, 4351.
(9) Comins, D.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299.
(10) For similar stereoselective hydroboration, see ref 8a.
In conclusion, we have accomplished the first total synthesis of
gymnocin-A, a marine polyether with the largest number of
contiguous ether rings. The synthesis heavily relied on the B-alkyl
Suzuki-Miyaura coupling-based strategy, which undoubtedly is an
important and general fragment-coupling process in polyether
synthesis. Extension of this chemistry to the synthesis of structural
analogues of gymnocin-A to explore the structure-activity relation-
ship is currently under way and will be reported in due course.
Acknowledgment. We are most grateful to Professor K.
Tachibana (University of Tokyo) for helpful discussions. We also
thank Professor M. Satake (Tohoku University) for measurement
of NMR spectra and valuable information. This work was finan-
cially supported in part by CREST, Japan Science and Technology
Corporation (JST), and Suntory Institute for Bioorganic Research
(SUNBOR).
Supporting Information Available: Experimental procedures and
spectral data for all new compounds, stereochemical determination for
compounds 7 and 10, and comparison data for natural and synthetic
gymnocin-A (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
(11) For stereochemical determination for compounds 7 and 10, see Supporting
Information.
(12) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994,
639.
(13) Nicolaou, K. C.; Prasad, C. V. C.; Hwang, C.-K.; Duggan, M. E.; Veale,
C. A. J. Am. Chem. Soc. 1989, 111, 5321. See also refs 4d, f, g, and 7.
(14) (a) Freeman, P. K.; Hutchinson, L. L. J. Org. Chem. 1980, 45, 1924. (b)
Ireland, R. E.; Smith, M. G. J. Am. Chem. Soc. 1988, 110, 854.
(15) (a) Noyori, R.; Nishida, I.; Sakata, J.; Nishizawa, M. J. Am. Chem. Soc.
1980, 102, 1223. (b) Sheidt, K. A.; Chen, H.; Follows, B. C.; Chemler,
S. R.; Coffey, D. S.; Roush, W. R. J. Org. Chem. 1998, 63, 6436.
References
(1) Satake, M.; Shoji, M.; Oshima, Y.; Naoki, H.; Fujita, T.; Yasumoto, T.
Tetrahedron Lett. 2002, 43, 5829.
(2) While the structures were not disclosed, congeners of 1 displayed far
stronger cytotoxicity than 1; a private communication from Prof. M. Satake
of Tohoku University.
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