A convergent synthesis of the C1-C16 segment of goniodomin A via palladium-catalyzed organostannane-thioester coupling

Article abstract of DOI:10.1021/ol1031409

A convergent synthesis of the C1-C16 segment of goniodomin A, an actin-targeting marine polyether macrolide natural product, has been achieved via a 2-fold application of palladium-catalyzed organostannane-thioester coupling.(Figure Presented)

Full text of DOI:10.1021/ol1031409

ORGANIC
LETTERS
2011
Vol. 13, No. 5
1106–1109
A Convergent Synthesis of the C1-C16
Segment of Goniodomin A via Palladium-
Catalyzed Organostannane-Thioester
Coupling
Haruhiko Fuwa,* Motohiro Nakajima, Jinglu Shi, Yoshiyuki Takeda, Tomoyuki Saito,
and Makoto Sasaki*
Laboratory of Biostructural Chemistry, Graduate School of Life Sciences,
Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai 980-8577, Japan
hfuwa@bios.tohoku.ac.jp, masasaki@bios.tohoku.ac.jp
Received December 26, 2010
ABSTRACT
A convergent synthesis of the C1-C16 segment of goniodomin A, an actin-targeting marine polyether macrolide natural product, has been
achieved via a 2-fold application of palladium-catalyzed organostannane-thioester coupling.
Goniodomin A (1, Figure 1) was isolated by Murakami
and his colleagues from the dinoflagellate Alexandrium
hiranoi (formerly known as Goniodoma pseudogoniaulax)
collected in a rock pool at Jogashima, Japan.1 Later, this
natural product was also identified from the cultured cells
of the dinoflagellate Alexandrium monilatum.2 Extensive
NMR studies on 1 culminated in the determination of its
gross structure, which is characterized by the 32-mem-
bered macrocyclic architecture embedded with a 6/6-
spiroacetal (BC-ring), three cyclic ethers (A-, D-, and
E-rings), and a six-membered cyclic hemiacetal (F-ring).
Our group has recently reported the establishment of the
complete stereostructure of 1 on the basis of 2D NMR
analysis, degradation experiments of the authentic sam-
ple, and synthesis and spectroscopic analysis of designed
model compounds.3
Goniodomin A, originally isolated as an antifungal agent,
exhibits intriguing biological activities by targeting actin, such
Figure 1. Structures of goniodomin A (1) and the C1-C16
segment 2.
(1) Murakami, M.; Makabe, K.; Yamaguchi, K.; Konosu, S.;
Walchli, M. R. Tetrahedron Lett. 1988, 29, 1149.
(2) Hsia, M. H.; Morton, S. L.; Smith, L. L.; Beauchesne, K. R.;
Huncik, K. M.; Moeller, P. D. R. Harmful Algae 2006, 5, 290.
(3) Takeda, Y.; Shi, J.; Oikawa, M.; Sasaki, M. Org. Lett. 2008, 10,
1013.
as modulation of the activity of actomyosin ATPase,4-6 in-
duction of morphological changes in human astrocytoma
r
10.1021/ol1031409
Published on Web 02/10/2011
2011 American Chemical Society

cells by increasing the filamentous actin content,7 and anti-
angiogenic activity via inhibition of actin reorganization in
endothelial cells.8
The latter would be derived from vinylstannane 6 and
thioester 7 by forming the C7-C8 bond.
These structural and biological aspects of 1 make it an
attractive synthetic target.9,10 As a part of our efforts toward
the total synthesis of 1, we report herein a convergent
synthesis of the A/BC-ring segment 2 (Figure 1) encompass-
ing the C1-C1611 carbon chain by means of palladium-
catalyzed organostannane-thioester coupling.12,13
Scheme 2. Synthesis of the A-Ring Thioester 7
Scheme 1. Synthesis Plan
Our synthesis plan toward the C1-C16 segment 2 is
illustrated in Scheme 1 (Tol = p-tolyl). We considered
that 2 could be constructed from its linear precursor,
enone 3, via spiroacetalization. The enone 3, in turn,
would be synthesized in a convergent manner by a 2-fold
use of palladium-catalyzed organostannane-thioester
coupling.12,13 Thus, the C11-C12 bond of 3 could be
formed via coupling of vinylstannane 4 and thioester 5.
(4) Furukawa, K.-I.; Sakai, K.;Watanabe, S.;Maruyama, K.; Murakami,
M.; Yamaguchi, K.; Ohizumi, Y. J. Biol. Chem. 1993, 268, 26026.
(5) Matsunaga, K.; Nakatani, K.; Murakami, M.; Yamaguchi, K.;
Ohizumi, Y. J. Pharmacol. Exp. Ther. 1999, 291, 1121.
(6) Yasuda, M.; Nakatani, K.; Matsunaga, K.; Murakami, M.;
Momose, K.; Ohizumi, Y. Eur. J. Pharmacol. 1998, 346, 119.
(7) Mizuno, K.; Nakataha, N.; Ito, E.; Murakami, M.; Yamaguchi,
K.; Ohizumi, Y. J. Pharm. Pharmacol. 1998, 50, 645.
(8) Abe, M.; Inoue, D.; Matsunaga, K.; Ohizumi, Y.; Ueda, H.;
Asano, T.; Murakami, M.; Sato, Y. J. Cell. Physiol. 2002, 190, 109.
(9) (a) Fujiwara, K.; Naka, J.; Katagiri, T.; Sato, D.; Kawai, H.;
Suzuki, T. Bull. Chem. Soc. Jpn. 2007, 80, 1173. (b) Katagiri, T.;
Fujiwara, K.; Kawai, H.; Suzuki, T. Tetrahedron Lett. 2008, 49, 233.
(c) Katagiri, T.; Fujiwara, K.; Kawai, H.; Suzuki, T. Tetrahedron Lett.
2008, 49, 3242.
(10) (a) Saito, T.; Fuwa, H.; Sasaki, M. Org. Lett. 2009, 11, 5274.
(b) Saito, T.; Fuwa, H.; Sasaki, M. Tetrahedron 2011, 67, 429.
(11) The carbon numbering corresponds to that of the natural
product.
The synthesis of the A-ring thioester 7 commenced with
ozonolysis of the known tetrahydropyran 814 followed by
reductive workup with NaBH4 to give diol 9 in 93% yield
(Scheme 2). Selective silylation of the primary alcohol
within 9 (TIPSCl, imidazole) delivered alcohol 10 in 98%
yield, which was oxidized with TPAP/NMO15 to afford
ketone 11 in 96% yield. Wittig methylenation of 11 yielded
olefin 12 in 91% yield, from which the silyl group was removed
with TBAF to give alcohol 13 in 99% yield. Benzylation of the
liberated hydroxy group gave benzyl ether 14 quantitatively.
(12) (a) Wittenberg, R.; Srogl, J.; Liebeskind, L. S. Org. Lett. 2003, 5,
3033. (b) Li, H.; Yang, H.; Liebeskind, L. S. Org. Lett. 2008, 10, 4375.
ꢀ
(13) For a review, see: Prokopcova, H.; Kappe, C. O. Angew. Chem.,
(14) Fuwa, H.; Sasaki, M.; Tachibana, K. Tetrahedron 2001, 57,
3019.
(15) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639.
Int. Ed. 2009, 48, 2276.
Org. Lett., Vol. 13, No. 5, 2011
1107

Methanolysis of the benzylidene acetal under acidic conditions
provided diol 15 in 90% yield. Bis-silylation of 15 and
subsequent acid treatment gave alcohol 16 in 84% yield for
the two steps. Oxidation of 16 to carboxylic acid 17 and
condensation with p-toluenethiol (DCC, DMAP) furnished
thioester 7 in 85% yield (three steps).
23 with MeMgBr20 provided methyl ketone 24 in 96% yield,
which was converted to vinylstannane 6 via Stille coupling
of the corresponding enol triflate with hexamethylditin
under the standard conditions (71%, two steps).21
Scheme 4. Synthesis of Vinylstannane 4
Scheme 3. Synthesis of Vinylstannane 6
The synthesis of vinylstannane 4 started with copper(I)-
catalyzed regioselective allylation of benzyl (S)-glycidyl
ether (25) (Scheme 4). Subsequent silylation and ozonolysis
provided aldehyde 26 in 69% overall yield. Aldehyde 26 was
transformed to alkyne 27 via a dibromoolefin according to
the Corey;Fuchs protocol (95%, two steps).22 Regioselec-
tive hydrostannylation of 27 was performed with (n-Bu3Sn)2-
Cu(CN)Li223 to afford vinylstannane 4 in 84% yield.
Having synthesized the requisite fragments 4, 6, and 7,
we proceeded to assemble these fragments toward com-
pletion of the synthesis (Scheme 5). Coupling of thioester
7 with vinylstannane 6 was best accomplished under the
influence of a Pd2(dba)3/Ph3As catalyst system and
copper(I) diphenylphosphinate (CuDPP) in THF at room
temperature. Under these conditions, enone 28 was isolated
in 96% yield. Chelate-controlled reduction24 of 28 with
Zn(BH4)2 (Et2O, -40 °C) gave a chromatographically
separable 5:1 mixture of allylic alcohol 29 and its C7 epimer
in 63% combined yield. Silylation of 29 and deprotection of
the MPM group led to alcohol 30 almost quantitatively.
Oxidation of 30 to carboxylic acid 31 followed by coupling
with p-toluenethiol delivered thioester 5 in 82% yield for
the three steps. This was coupled with vinylstannane 4
[Pd2(dba)3/Ph3As, CuDPP, THF, room temperature] to
afford enone 3 in 86% yield. Removal of the silyl groups
with tris(dimethylamino)sulfonium difluorotrimethylsilicate
(TASF)25 gave cyclization precursor 32 in 87% yield.
The vinylstannane 6 was prepared as summarized in
Scheme 3. Coupling of the known carboxylic acid 1816
with (R)-4-benzyloxazolidin-2-one (19) (PivCl, Et3N, THF,
-20 °C; then LiCl, 19, rt)17 delivered imide 20 in 89% yield.
Asymmetric methylation of 20 according to the Evans
protocol (NaHMDS, THF, -78 °C; then MeI, -78 to
-40 °C)18 afforded methylated product 21 in 95% yield
1
as a single stereoisomer, as judged by 500 MHz H
NMR. Removal of the chiral auxiliary by exposure to
alkaline peroxide19 yielded carboxylic acid 22 in 98%
yield, which was coupled with N,O-dimethylhydroxya-
mine to give Weinreb amide 23 in 73% yield. Treatment of
(21) Wulff, W. D.; Peterson, G. A.; Bauta, W. E.; Chan, K.-S.;
Faron, K. L.; Gilbertson, S. R.; Kaesler, R. W.; Yang, D. C.; Murray,
C. K. J. Org. Chem. 1986, 51, 277.
(16) Hirai, K.; Ooi, H.; Esumi, T.; Iwabuchi, Y.; Hatakeyama, S.
Org. Lett. 2003, 5, 857.
(17) Chakraborty, T. K.; Suresh, V. R. Tetrahedron Lett. 1998, 39,
7775.
(18) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc.
1982, 104, 1737.
(19) Evans, D. A.; Britton, T. C.; Ellman, J. A. Tetrahedron Lett.
(22) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769.
(23) Sharma, S.; Oehlschlager, A. C. J. Org. Chem. 1989, 54, 5064.
(24) Oishi, T.; Nakata, T. Acc. Chem. Res. 1984, 17, 338.
(25) (a) Noyori, R.; Nishida, I.; Sataka, J.; Nishizawa, M. J. Am.
Chem. Soc. 1980, 102, 1223. (b) Scheidt, K. A.; Chen, H.; Follows, B. C.;
Chemler, S. R.; Coffey, D. S.; Roush, W. R. J. Org. Chem. 1998, 63,
6436.
1987, 28, 6141.
(20) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
1108
Org. Lett., Vol. 13, No. 5, 2011

(see the table in Scheme 5). Treatment of 32 with CSA in
CH2Cl2 at 0 °C for 3 h gave fused acetal 33 (21%),
unnatural (11R)-spiroacetal 34 (48%), and natural
(11S)-spiroacetal 2 (21%) (entry 1). These products
were separated by reverse-phase HPLC and structu-
rally characterized by extensive NMR analysis (see the
Supporting Information for details). We could improve
the yield of the desired 2 by running the cyclization of
32 using PPTS in CH2Cl2 at 0 °C for 30.5 h, which
afforded 33 (15%), 34 (46%), and 2 (36%) (entry 2).
However, spiroacetalization of 32 under low tempera-
ture conditions (-20 to -10 °C) was not effective for
improving the yield of 2 (entry 3). Careful monitoring
of the acetalization indicated that a mixture of 34 and 2
was initially generated but fused acetal 33 increased as
the reaction progressed. This observation suggested
that 33 might be formed from 34 and/or 2 as a result
of thermodynamic equilibration.26 The predominant
formation of unnatural 34 over natural 2 could be
reasoned by the double anomeric stabilization effect,
whereas the S configuration of the C11 stereogenic
center of the natural product would be ascribed to the
macrocyclic contraint.3,9c,27 Our result is in sharp con-
trast to the observation made by Fujiwara and co-
workers, who reported that acid-catalyzed cyclization
of a closely related ketotriol derived from tris-silyl ether
35 afforded unnatural (11R)-spiroacetal 36 as the sole
product.9c
Scheme 5. Synthesis of the C1-C16 Segment 2 via Acid-Cata-
lyzed Acetalization of Ketotriol 32
In conclusion, we have developed a convergent syn-
thetic entry to the C1-C16 segment 2 of goniodomin A
via a 2-fold use of palladium-catalyzed organostannane-
thioester coupling. Further efforts toward the total synth-
esis of goniodomin A are currently underway and will be
reported in due course.
Acknowledgment. This work was supported in part by a
Grant-in-Aid for Scientific Research (A) (No. 21241050)
from the Japan Society for the Promotion of Science
(JSPS) and the Tohoku University Global COE program
“International Center of Research & Education for Mo-
lecular Complex Chemistry”. T.S. is grateful for a SUN-
BOR Scholarship.
Supporting Information Available. Detailed experimen-
tal procedures, spectroscopic data, stereochemical assign-
1
ments of selected compounds, and copies of H and 13C
NMR spectra for all new compounds. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(26) Since individual treatment of 2, 33, and 34 with CSA (CH2Cl2,
0 °C, 3 h) uniformly gave an approximately 1:2:1mixture of 2, 33, and 34,
formation of these isomers during acid treatment of 32 could be ascribed
to thermodynamic equilibration.
(27) In the present study, we could only isolate natural (11S)-
spiroacetal 2 as a minor product. However, we expect that we would
be able to control the C11 stereochemistry in a real system by construct-
ing the macrocyclic framework of 1 prior to spiroacetalization.
Finally, we investigated acid-catalyzed cyclization of
ketotriol 32 to construct the spiroacetal BC-ring system
Org. Lett., Vol. 13, No. 5, 2011
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