Toward the total synthesis of goniodomin A, an actin-targeting marine polyether macrolide: Convergent synthesis of the C15-C36 Segment

Article abstract of DOI:10.1021/ol902217q

Stereoselective convergent synthesis of the C15-C36 segment of goniodomin A, an actin-targeting marine polyether macrolide natural product, has been achieved. The present synthesis features palladium(0)-catalyzed, copper(I)-mediated Liebeskind-Srogl cross

Full text of DOI:10.1021/ol902217q

ORGANIC
LETTERS
2009
Vol. 11, No. 22
5274-5277
Toward the Total Synthesis of
Goniodomin A, An Actin-Targeting
Marine Polyether Macrolide: Convergent
Synthesis of the C15-C36 Segment
Tomoyuki Saito, Haruhiko Fuwa, and Makoto Sasaki*
Graduate School of Life Sciences, Tohoku UniVersity, 1-1 Tsutsumidori-amamiya,
Aoba-ku, Sendai 981-8555, Japan
masasaki@bios.tohoku.ac.jp
Received September 25, 2009
ABSTRACT
Stereoselective convergent synthesis of the C15-C36 segment of goniodomin A, an actin-targeting marine polyether macrolide natural product,
has been achieved. The present synthesis features palladium(0)-catalyzed, copper(I)-mediated Liebeskind-Srogl cross-coupling as the fragment
assembly process.
Goniodomin A (1, Figure 1) was isolated as a potent
antifungal agent by Murakami and co-workers from the
dinoflagellate Alexandrium hiranoi (formerly Goniodoma
pseudogoniaulax) collected in a rock pool at Jogashima in
Japan in 1988.1 More recently, it was reported that the
dinoflagellate Alexandrium monilatum produced goniodomin
A.2 The gross structure of goniodomin A was determined
by Murakami and co-workers on the basis of the NMR
studies to be a novel polyether macrolide, which is character-
ized by a spiroacetal ring (B/C-ring), an additional four
oxacycles (A-, D-, E-, and F-rings), and 17 stereogenic
centers embedded within a 36-carbon chain.1 We have
recently defined the absolute configuration of goniodomin
A on the basis of detailed 2D NMR studies and degradation
experiments of the natural product, the synthesis of suitable
model compounds for NMR spectroscopic comparisons, and
by correlation with synthetic reference compounds.3
Figure 1. Structure of goniodomin A (1).
From a biological perspective, goniodomin A has profound
effects on reorganization of the actin cytoskeleton. Go-
niodomin A has been found to stimulate actomyosin ATPase
activity by binding to and altering the conformation of
actin.4,5 It also modulates actomyosin ATPase activity
between ventricular and atrial muscles.6 It has been reported
(1) Murakami, M.; Makabe, K.; Yamaguchi, K.; Konosu, S.; Walchli,
M. R. Tetrahedron Lett. 1988, 29, 1149–1152.
(2) Hsia, M. H.; Morton, S. L.; Smith, L. L.; Beauchesne, K. R.; Huncik,
K. M.; Moeller, P. D. R. Harmful Algae 2006, 5, 290–299.
(3) Takeda, Y.; Shi, J.; Oikawa, M.; Sasaki, M. Org. Lett. 2008, 10,
1013–1016.
10.1021/ol902217q CCC: $40.75
Published on Web 10/26/2009
 2009 American Chemical Society

The wide-ranging biological properties of goniodomin A,
in conjunction with the architecturally complex structure,
prompted us to initiate studies on the total synthesis of this
natural product.9 We describe herein a stereoselective
construction of the C15-C36 segment 2 of goniodomin A.
Scheme 1. Retrosynthetic Analysis
Our synthetic strategy toward goniodomin A (1) by way
of the C15-C36 segment 2 is outlined in Scheme 1. We
planned to construct the segment 2 by Liebeskind-Srogl
cross-coupling10-12 between the C15-C25 vinyl stannane
4 and the C26-C36 thiol ester 5 of comparable complexity,
followed by stereoselective reduction of the C26 ketone
within 3. We envisioned that two ether rings (D- and E-rings)
of 4 would be constructed via 5-exo and 6-exo cyclizations
of the respective hydroxy epoxide precursors. Thiol ester 5
could, in turn, arise from the coupling of alkyne 6 and
aldehyde 73 by means of a Carreira asymmetric alkynylation
protocol.13
The synthesis of vinyl stannane 4 started with the known
compound 8,14 which is available in two steps from (S)-
benzyl glycidyl ether (Scheme 2). Ozonolysis of the double
bond, followed by the Horner-Wadsworth-Emmons (HWE)
reaction of the resultant aldehyde under Ando conditions,15
provided (Z)-enoate 9 in 79% yield, along with an 8:1
mixture of the corresponding (E)- and (Z)-isomers (19%).
DIBALH reduction, oxidation with MnO2, and the HWE
reaction gave dienoate 10 in high overall yield. DIBALH
reduction was followed by desilylation to afford diol 11
(97%, two steps), which upon Sharpless asymmetric epoxi-
dation using cumyl hydroperoxide (CHP)16 underwent
concomitant 6-exo cyclization of the derived epoxy alcohol
that goniodomin A causes morphological changes in human
astrocytoma cells by increasing the filamentous actin con-
tent.7 It also exhibits antiangiogenetic activity via inhibition
of actin reorganization in endothelial cells.8
Scheme 2. Synthesis of Vinyl Stannane 4
Org. Lett., Vol. 11, No. 22, 2009
5275

12 to provide dihydropyran 13 in 88% yield. The use of tert-
butylhydroperoxide instead of CHP resulted in a low yield
of 13. Conversion to epoxide 14 was performed by selective
tosylation17 and base treatment (80% yield, two steps). The
stereochemistry of 14 was confirmed by an NOE as shown.
Subsequent reaction with allylmagnesium chloride and CuI
provided, after acylation, acetate 15 in 93% yield (two steps).
Chemoselective dihydroxylation of the terminal olefin was
best accomplished under the influence of AD-mix ꢀ, cat.
OsO4, and (DHQD)2PHAL (77% after one recycling).
Scheme 3. Synthesis of Thiol Ester 5
18
Oxidative cleavage of the resultant diol with NaIO4/SiO2
followed by the Wittig reaction produced an enoate (96%
for the two steps, >20:1 E/Z), which was then reduced with
DIBALH to afford allylic alcohol 16 (98%). The asymmetric
epoxidation/5-exo cyclization sequence proceeded efficiently
to give diol 17 in 88% yield (>10:1 dr). The vic-diol moiety
of 17 was converted into methyl ketone in a three-step
sequence, including NaIO4 oxidation, alkynylation with
Ohira-Bestmann reagent,19 and hydration of the terminal
alkyne.20 Ketone 18 thus obtained was transformed to the
corresponding enol triflate (KHMDS, PhNTf2, 79%), which
was treated with (Me3Sn)2, LiCl, and Pd(PPh3)4 (THF, 70
°C)21 to furnish the desired vinyl stannane 4 in 90% yield.22
The synthesis of thiol ester partner 5 commenced with a
(4) Furukawa, K.-I.; Sakai, K.; Watanabe, S.; Maruyama, K.; Murakami,
M.; Yamaguchi, K.; Ohizumi, Y. J. Biol. Chem. 1993, 268, 26026–26031.
(5) Matsunaga, K.; Nakatani, K.; Murakami, M.; Yamaguchi, K.;
Ohizumi, Y. J. Pharmacol. Exp. Ther. 1999, 291, 1121–1126.
(6) Yasuda, M.; Nakatani, K.; Matsunaga, K.; Murakami, M.; Momose,
K.; Ohizumi, Y. Eur. J. Pharmacol. 1998, 346, 119–123.
(7) Mizuno, K.; Nakahata, N.; Ito, E.; Murakami, M.; Yamaguchi, K.;
Ohizumi, Y. J. Pharm. Pharmacol. 1998, 50, 645–648.
fragment coupling of alkyne 6 (a 1.2:1 mixture of epimers)23
and the previously described aldehyde 7,3 which is available
in 14 steps from (-)-dimenthyl fumarate. Thus, the reaction
of 7 with 6 (2 equiv) under Carreira asymmetric alkynylation
conditions (Zn(OTf)2, (+)-N-methyl ephedrine, Et3N, toluene,
room temperature)13 gave the desired alcohol24 with an ap-
proximately 9:1 diastereoselectivity (Scheme 3). Subsequent
deprotection of the benzylidene acetal by treatment with PPTS
afforded triol 19 in 82% yield for the two steps. At this stage,
the undesired diastereomer at C31 could be removed by column
chromatography on silica gel. After Lindlar reduction of the
triple bond, a three-step sequence of protective group manipula-
tions led to primary alcohol 20 in 72% overall yield. Oxidation
of 20 to the corresponding carboxylic acid (IBX, DMSO; then
NaClO2) and esterification with p-tolylthiol (PyBOP, i-Pr2NEt2,
(8) Abe, M.; Inoue, D.; Matsunaga, K.; Ohizumi, Y.; Ueda, H.; Asano,
T.; Murakami, M.; Sato, Y. J. Cell. Physiol. 2002, 190, 109–116.
(9) Fujiwara and co-workers have reported their synthetic studies for
the stereochemical assignment of goniodomin A, see: (a) Fujiwara, K.; Naka,
J.; Katagiri, T.; Sato, D.; Kawai, H.; Suzuki, T. Bull. Chem. Soc. Jpn. 2007,
80, 1173–1186. (b) Katagiri, T.; Fujiwara, K.; Kawai, H.; Suzuki, T.
Tetrahedron Lett. 2008, 49, 233–237. (c) Katagiri, T.; Fujiwara, K.; Kawai,
H.; Suzuki, T. Tetrahedron Lett. 2008, 49, 3242–3247.
(10) Wittenberg, R.; Srogl, J.; Egi, M.; Liebeskind, L. S. Org. Lett. 2003,
5, 3033–3035. (b) Li, H.; Yang, H.; Liebeskind, L. S. Org. Lett. 2008, 10,
4375–4378.
(11) For a review, see: Prokopcova´, H.; Kappe, C. O. Angew. Chem.,
Int. Ed. 2009, 48, 2276–2286.
(12) For applications of Liebeskind-Srogl coupling to natural products
synthesis, see: (a) Morita, A.; Kuwahara, S. Org. Lett. 2006, 8, 1613–1616.
(b) Yang, H.; Liebeskind, L. S. Org. Lett. 2007, 9, 2993–2995.
(13) (a) Frantz, D. E.; Fa¨ssler, R.; Carreira, E. M. J. Am. Chem. Soc.
2000, 122, 1806–1807. (b) Frantz, D. E.; Fa¨ssler, R.; Tomooka, C. S.;
Carreira, E. M. Acc. Chem. Res. 2000, 33, 373–381. (c) Sasaki, H.; Boyall,
D.; Carreira, E. M. HelV. Chim. Acta 2001, 84, 964–971. (d) Boyall, D.;
Frantz, D. E.; Carreira, E. M. Org. Lett. 2002, 4, 2605–2606.
(14) (a) Ramachandran, P. V.; Prabhudas, B.; Chandra, J. S.; Reddy,
M. V. R. J. Org. Chem. 2004, 69, 6294–6304. (b) Huang, H.; Mao, C.;
Jan, S.-T.; Uckun, F. M. Tetrahedron Lett. 2000, 41, 1699–1702. (c) Bonini,
C.; Chiummiento, L.; Pullez, M.; Solladie, G.; Colobert, F. J. Org. Chem.
2004, 69, 5015–5022.
(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, 277–279.
(22) For stereochemical assignment of compound 4, see Supporting
Information.
(23) Alkyne 6 was readily available in three steps from (S)-glycidol:
(1) trimethylsilylacetylene, n-BuLi, BF3·OEt2, THF, -78 to 0 °C; (2)
PhCH(OMe)2, cat. CSA, CH2Cl2; (3) K2CO3, MeOH, 81% yield for the
three steps.
(24) The stereochemistry of the newly generated stereogenic center at
C31 was equivocally confirmed by conversion to the known compound A3
by a four-step sequence: (1) Ac2O, Et3N, DMAP, CH2Cl2; (2) PPTS, EtOH;
(3) TBSOTf, 2,6-lutidine, CH2Cl2; (4) DIBALH, CH2Cl2.
(15) (a) Ando, K. Tetrahedron Lett. 1995, 36, 4105–4108. (b) Ando,
K. J. Org. Chem. 1997, 62, 1934–1939.
(16) Gao, Y.; Klunder, J. M.; Hanson, R. M.; Masamune, H.; Ko, S. Y.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765–5780.
(17) Martinelli, M. J.; Nayyar, N. K.; Moher, E. D.; Dhokte, U. P.;
Pawlak, J. M.; Vaidyanathan, R. Org. Lett. 1999, 1, 447–450.
(18) Zhong, Y.-L.; Shing, T. K. M. J. Org. Chem. 1997, 62, 2622–
2624.
(19) (a) Ohira, S. Synth. Commun. 1989, 19, 561–564. (b) Muller, S.;
Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett 1996, 521–522.
(20) Larock, R. C.; Leong, W. W. In ComprehensiVe Organic Synthesis;
Trost, B. M., Flemming, I., Semmelhack, M. F., Eds.; Pergamon: Oxford,
UK, 1991; Vol. 4, pp 269-327.
5276
Org. Lett., Vol. 11, No. 22, 2009

of several reaction conditions, it was found that a cross-
coupling reaction of 5 with 4 (1.1 equiv) could be achieved
by treatment with copper(I) diphenylphosphinate (CuDPP,
2.0 equiv), Pd2(dba)3 (0.1 equiv), and triethylphosphite (0.8
equiv) in THF/hexanes (1:2) at room temperature10b (Scheme
4). Thus, the desired cross-coupling product 3 was obtained
in 68% yield. In this coupling reaction, small amounts (ca.
10%) of homocoupling product of vinyl stannane 4 were
produced. Finally, stereoselective reduction of enone 3 was
performed under Luche conditions (NaBH4, CeCl3·7H2O,
EtOH, -40 °C)26 to furnish the desired alcohol 2 in 66%
yield as the only detectable diastereomer. The stereochem-
istry at C26 was unambiguously confirmed by conversion
to the acetonide 21 and NMR analysis as shown in Scheme
5. The stereochemical outcome of this reduction can be
rationalized by the Felkin-Ahn model.27
Scheme 4. Synthesis of C15-C36 Segment 2
In conclusion, we have developed a convergent synthetic
route to the C15-C36 segment 2 of goniodomin A.
Particularly noteworthy is a Pd(0)-catalyzed, Cu(I)-mediated
Liebeskind-Srogl cross-coupling of complex fragments for
the critical bond-forming step. Further studies toward the
total synthesis of goniodomin A are currently underway in
our laboratories and will be reported in due course.
Scheme 5
.
Synthesis of Acetonide Derivative 21 for
Stereochemical Confirmation
Acknowledgment. This work was supported 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 Molecular Complex
Chemistry”. T.S. is grateful for a SUNBOR Scholarship.
Supporting Information Available: Experimental pro-
cedures, spectroscopic data for new compounds, stereochem-
1
ical assignment of compound 4, and copies of H and 13C
NMR spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL902217Q
(25) (a) Coste, J.; Le-Nguyen, D.; Castro, B. Tetrahedron Lett. 1990,
31, 205–208. (b) Kajihara, Y.; Yoshihara, A.; Hirano, K.; Yamamoto, N.
Carbohydr. Res. 2006, 341, 1333–1340.
CH2Cl2)25 completed the synthesis of thiol ester 5 in 70% yield
for the three steps.
With the requisite fragments in hand, we then turned our
attention to the pivotal fragment union. After investigation
(26) (a) Luche, J.-L.; Gemal, A. L. J. Am. Chem. Soc. 1979, 101, 5848–
5849. (b) Gemal, A. L.; Luche, J.-L. J. Am. Chem. Soc. 1981, 103, 5454–
5459.
(27) For a review, see: Mengel, A.; Reiser, O. Chem. ReV. 1999, 99,
1191–1124.
Org. Lett., Vol. 11, No. 22, 2009
5277