Synthesis and structure revision of the C43-C67 part of amphidinol 3

Article abstract of DOI:10.1021/ol401176a

Stereoselective synthesis of the C43-C67 part of amphidinol 3 (AM3) and its C51-epimer was achieved starting from a common intermediate corresponding to the tetrahydropyran moiety of AM3, via asymmetric oxidations and Julia-Kocienski olefination. By comparing NMR data of the synthetic specimens with those of AM3, the absolute configuration at C51 of AM3 was revised from R to S.

Full text of DOI:10.1021/ol401176a

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Synthesis and Structure Revision
of the C43ÀC67 Part of Amphidinol 3
Makoto Ebine,† Mitsunori Kanemoto,‡ Yoshiyuki Manabe,†,§ Yosuke Konno,†
Ken Sakai,† Nobuaki Matsumori,‡,§ Michio Murata,‡,§ and Tohru Oishi*,†
Department of Chemistry, Faculty and Graduate School of Sciences, Kyushu University,
6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan, Department of Chemistry,
Graduate School of Science, Osaka University, 1-1 Machikaneyama, Toyonaka,
Osaka 560-0043, Japan, and JST ERATO Lipid Active Structure, 1-1 Machikaneyama,
Toyonaka, Osaka 560-0043, Japan
oishi@chem.kyushu-univ.jp
Received April 26, 2013
ABSTRACT
Stereoselective synthesis of the C43ÀC67 part of amphidinol 3 (AM3) and its C51-epimer was achieved starting from a common intermediate
corresponding to the tetrahydropyran moiety of AM3, via asymmetric oxidations and JuliaÀKocienski olefination. By comparing NMR data of the
synthetic specimens with those of AM3, the absolute configuration at C51 of AM3 was revised from R to S.
Amphidinol 3 (AM3, 1, Figure 1), produced by the
dinoflagellate Amphidinium klebsii, elicits high antifungal
efficacy with submicromolar IC50 values despite its rela-
tively potent hemolytic activity (EC50 = 0.25 μM).1,2
These biological activities can be accounted for by forma-
tion of ion-permeable pores in a sterol dependent manner.3
The striking structural features of AM3 have attracted
considerable attention from the synthetic community.4À9
Because of the limited availability of the natural product, and
the presence of a number of stereogenic centers on the long
acyclic carbon chain, it has been difficult to determine the
molecular structure of AM3. Although the stereochemistry
of AM3 was determined in 1999 based on the J-based
(3) (a) Echigoya, R.; Rhodes, L.; Oshima, Y.; Satake, M. Harmful
Argae 2005, 4, 383–389. (b) Meng, Y.; Van Wagoner, R. M.; Misner, I.;
Tomas, C.; Wright, J. L. C. J. Nat. Prod. 2009, 73, 409–415. (c) Doi, Y.;
Ishibashi, M.; Nakamichi, H.; Kosaka, T.; Ishikawa, T.; Kobayashi, J.
J. Org. Chem. 1997, 62, 3820–3823. (d) Kubota, T.; Tsuda, M.; Doi, Y.;
Takahashi, A.; Nakamichi, H.; Ishibashi, M.; Fukushi, E.; Kawabata,
J.; Kobayashi, J. Tetrahedron 1998, 54, 14455–14464. (e) Huang, X.-C.;
Zhao, D.; Guo, Y.-W.; Wu, H.-M.; Lin, L.-P.; Wang, Z.-H.; Ding, J.;
Lin, Y.-S. Bioorg. Med. Chem. Lett. 2004, 14, 3117–3120. (f) Huang,
X.-C.; Zhao, D.; Guo, Y.-W.; Wu, H.-M.; Trivellone, E.; Cimino, G.
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Tsuda, M.; Kobayashi, J. Marine Drugs 2005, 3, 113–118. (h) Washida,
K.; Koyama, T.; Yamada, K.; Kita, M.; Uemura, D. Tetrahedron Lett.
2006, 47, 2521–2525. (i) Van Wagoner, R. M.; Deeds, J. R.; Satake, M.;
Ribeiro, A. A.; Place, A. R.; Wright, J. L. C. Tetrahedron Lett. 2008, 49,
6457–6461. (j) Huang, S.-J.; Kuo, C.-M.; Lin, Y.-C.; Chen, Y.-M.; Lu,
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† Kyushu University.
‡ Osaka University.
§ ERATO.
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J. Am. Chem. Soc. 1991, 113, 9859–9861. (b) Murata, M.; Matsuoka, S.;
Matsumori, N.; Paul, G. K.; Tachibana, K. J. Am. Chem. Soc. 1999, 121,
870–871. (c) Swasono, R. T.; Kanemoto, M.; Matsumori, N.; Oishi, T.;
Murata, M. Heterocycles 2011, 82, 1359–1369. (d) Manabe, Y.; Ebine, M.;
Matsumori, N.; Murata, M.; Oishi, T. J. Nat. Prod. 2012, 75, 2003–2006.
(2) Amphidinol congeners: (a) Paul, G. K.; Matsumori, N.; Konoki,
K.; Murata, M.; Tachibana, K. J. Mar. Biotechnol. 1997, 5, 124–128. (b)
Houdai, T.; Matsuoka, S.; Matsumori, N.; Murata, M. Biochim.
Biophys. Acta 2004, 1667, 91–100. (c) Houdai, T.; Matsuoka, S.; Morsy,
N.; Matsumori, N.; Satake, M.; Murata, M. Tetrahedron 2005, 61, 2795–
2802. (d) Morsy, N.; Houdai, T.; Konoki, K.; Matsumori, N.; Oishi, T.;
Murata, M. Bioorg. Med. Chem. 2008, 16, 3084–3090. (e) Swasono, R.;
Mouri, R.; Morsy, N.; Matsumori, N.; Oishi, T.; Murata, M. Bioorg.
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r
10.1021/ol401176a
XXXX American Chemical Society

Scheme 2. Synthesis of the C43ÀC67 Part of AM3 (2a)
Figure 1. Proposed structure of amphidinol 3 (AM3, 1).
Scheme 1. Synthetic Plan of the Partial Structures Corresponding
to the C43ÀC67 Part of AM3 (2a) and Its C51-Epimer (2b)
of AM3 (2a) and its 51-epimer (2b), which was derived by
JuliaÀKocienski olefination using sulfone 3and aldehydes 4a
and 4b (Scheme 1). NMR spectra of 2a and 2b were then
compared with those of the natural product.
configuration analysis (JBCA) method,10 modified Mosher
method,11 and degradation of the natural product via oxida-
tive cleavage, the absolute configuration at C2 was later
revised to be R by comparing synthetic specimens with a
fragment of AM3 by GCÀMS.12 The stereochemistry at C51
also remained controversial because the observed J values
were in the intermediate range for anti and gauche con-
formations.1 Therefore, chemical synthesis of the partial
structure might provide clues that could confirm the stereo-
chemistry. Herein, we report a synthesis of the C43ÀC67 part
Our synthesis of the C43ÀC67 part of AM3 (2a) is
shown in Scheme 2. We previously reported a concise
synthesis of the tetrahydropyran ring system correspond-
ing to the C43ÀC52 part 5,13 a common intermediate of
both 2a and 2b. As reported, olefin 5 was converted to 6 via
Sharpless asymmetric dihydroxylation using AD-mix-R14
(97%), followed by protection of the resulting diol as TBS
ethers (96%). After protecting group manipulation, via (i)
hydrogenolysis of the benzyl ether with Raney Ni (quant),
(ii) protection of the resulting primary alcoholwithTBSCl/
imidazole (96%), and (iii) removal of the PMB group with
DDQ (89%), the resulting primary alcohol was oxidized
with DessÀMartin periodinane15 to give aldehyde 4a.
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Tachibana, K. J. Org. Chem. 1999, 64, 866–876.
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M. Org. Lett. 2008, 10, 5203–5206.
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B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 3. Synthesis of the C51-Epimer (2b)
Figure 2. Stereoview for the core structure of 11 in the crystalline
state, where all the tert-butyldimethysilyl groups, attached to
the six O atoms labeled in this figure, have been omitted for
clarity.
JuliaÀKocienski olefination16,17 of 4a with sulfone 3,6b
prepared from alcohol 7,4b,6b via Mitsunobu reaction with
1-phenyl-1H-tetrazole-5-thiol (8) and oxidation, afforded
an olefin (89%, two steps) as a single geometrical isomer.
Removal of all the TBS groups with HF Py in THF at
3
Figure 3. Differences in 13C NMR (150 MHz, 1:2 C5D5N/
CD3OD, 30 °C) chemical shifts between AM3 and the synthetic
fragments (a) 2a and (b) 2b. The x- and y-axes represent carbon
number and Δδ (Δδ = δAM3 À δsynthetic 2 in ppm), respectively.
3.1 mg of 2a and 4.6 mg of 2b in 200 μL of the solvents were used.
50 °C furnished the C43ÀC67 part of AM3 (2a).
The C51-epimer (2b) was synthesized from the common
intermediate 5 as shown in Scheme 3. Removal of the PMB
group with DDQ gave an allylic alcohol (94%), which was
subjectedto KatsukiÀSharpless asymmetric epoxidation18
with D-(À)-diethyl tartrate (DET) to yield epoxy alcohol 9
(89%). Ring-opening of the epoxide with thiophenol via
Payne rearrangement19,20 under basic conditions pro-
ceeded regioselectively to afford sulfide 10 with concomitant
(16) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A.
Synlett 1998, 26–28.
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1831–1844.
¨
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5976. (b) Gao, Y.; Klunder, J. M.; Hanson, R. M.; Masamune, H.; Ko,
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Org. Lett., Vol. XX, No. XX, XXXX
C

formation of an isomer in a 10:1 ratio as an inseparable
mixture (79%). Slow addition of thiophenol and aqueous
NaOH using a syringe pump was necessary to improve the
ratio of 10. Removal of the benzyl group with DDQ in
dichloroethane in the presence of pH 7 buffer at 50 °C
followed by treatment of the resulting alcohol with
TBSOTf/2,6-lutidine gave 11, which was separated from
its regioisomerbysilicagel columnchromatography(72%,
two steps). The structure of 11 was unambiguously deter-
mined by X-ray crystallography (Figure 2). Next, sulfide
11 was converted to aldehyde 4b via (i) oxidation with
m-CPBA giving a sulfoxide and (ii) Pummerer rearrange-
ment21,22 by treatment with Ac2O/AcONa (55%, two
steps),23 and (iii) reduction of the resulting mixed thioace-
tal 12 with DIBALH and oxidation of the resulting primary
alcohol. In contrast to the synthesis of 2a, JuliaÀKochienski
olefination of aldehyde 4b with sulfone 3 was sluggish to
furnish the corresponding olefin (65%). Removal of the
Figure 4. Revised structure of AM3.
Starting from the common intermediate 5, the vic-diol
moieties at C50ÀC51 of 2a and 2b were introduced by
Sharpless asymmetric dihydroxylation, and Katsuki-
Sharpless asymmetric epoxydation followed by epoxide
opening via Payne rearrangement, respectively. The poly-
ene part was introduced by JuliaÀKocienski olefination
via coupling of the aldehydes (4a and 4b) with the sulfone
(3). Judging from the comparison of 13C NMR data of the
synthetic specimens with those of AM3, the absolute
configuration at C51 should be revised to be S.
TBS groups with HF Py afforded the diastereomer at C51
of the C43ÀC67 part of AM3 (2b).
3
Having obtained the diastereomers corresponding to the
C43ÀC67 part, the 13C NMR spectra of 2a and 2b were
compared with those of AM3. The differences in the car-
bon chemical shifts of C43 to C55 between AM3, 2a and 2b
(150 MHz, 1:2 C5D5N/CD3OD) are shown in Figure 3.
The x- and y-axes represent carbon number and Δδ
(Δδ = δAM3 À δsynthetic 2 in ppm), respectively. For both
diastereomers, chemical shifts at C56ÀC67 corresponding
to the polyene moiety are identical to those of AM3, but
those at the C43 terminus deviate because the structures
are different from AM3. Although the deviations of 2a at
C49, C51, C52, and C53 are larger than 1 ppm, those of
51-epimer (2b) are almost null. These results indicate that
the absolute configuration at C51 of AM3 should be
revised from R to S (Figure 4).24
Acknowledgment. We are grateful to Prof. Tsutomu
Katsuki and Tatsuya Uchida, Kyushu University, for
measurement of mass spectra. We thank Dr. Kohei Torikai,
Kyushu University, for helpful discussions. This work
was supported in part by a fund from Kyushu University,
Funds for the Development of Human Resources in
Science and Technology originating from the Ministry of
Education, Culture, Sports, Science and Technology
(MEXT), and by a Grant-in-Aid for Young Scientists
(B) (No. 24750092) from the Japan Society for the Promo-
tion of Science (JSPS).
In conclusion, stereoselective syntheses of the C43ÀC67
part of AM3 (2a) and its C51-epimer (2b) were achieved.
(21) (a) Pummerer, R. Ber. Dtsch. Chem. Ges. 1909, 42, 2282–2291.
(b) Pummerer, R. Ber. Dtsch. Chem. Ges. 1910, 43, 1401–1412.
(22) For recent reviews, see: (a) Feldman, K. S. Tetrahedron 2006, 62,
5003–5034. (b) Smith, L. H. S.; Coote, S. C.; Sneddon, H. F.; Procter,
D. J. Angew. Chem., Int. Ed. 2010, 49, 5832–5844.
Supporting Information Available. Experimental de-
tails and spectroscopic data. This material is available
free of charge via the Internet at http://pubs.acs.org.
(23) Iriuchijima, S.; Maniwa, K.; Tsuchihashi, G. J. Am. Chem. Soc.
1974, 96, 4280–4283.
(24) In our previous study,1c C51 was again assigned to be R. This
erroneous configuration was caused by complication in 1H signal
assignment due to large chemical shift changes by peracetylation of
AM3. M.M. deeply apologizes for publishing the wrong conclusion.1c
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX