Synthesis of the common left-half part of pectenotoxins

Article abstract of DOI:10.1016/j.tetlet.2005.05.062

The common left-half [C31-C33(OC1-C7)-C40] part of pectenotoxins has been synthesized convergently from the C31-C35, C36-C40, and C1-C7 parts. The C31-C35 part, prepared via a new route shorter than our previous route, was coupled with the C36-C40 part through reductive lithiation and addition reactions to give an adduct stereoselectively, which was converted to a cyclic acetal corresponding to the C31-C40 part. The left-half was synthesized by a three-step process including esterification of the C31-C40 part with the C1-C7 part.

Full text of DOI:10.1016/j.tetlet.2005.05.062

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5067–5069
Synthesis of the common left-half part of pectenotoxins
Kenshu Fujiwara,* Masanori Kobayashi, Fuyuki Yamamoto, Yu-ichi Aki,
Mariko Kawamura, Daisuke Awakura, Seiji Amano, Azusa Okano, Akio Murai,
Hidetoshi Kawai and Takanori Suzuki
Division of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan
Received 19 April 2005; revised 2 May 2005; accepted 16 May 2005
Available online 9 June 2005
Abstract—The common left-half [C31–C33(OC1–C7)–C40] part of pectenotoxins has been synthesized convergently from the C31–
C35, C36–C40, and C1–C7 parts. The C31–C35 part, prepared via a new route shorter than our previous route, was coupled with
the C36–C40 part through reductive lithiation and addition reactions to give an adduct stereoselectively, which was converted to a
cyclic acetal corresponding to the C31–C40 part. The left-half was synthesized by a three-step process including esterification of the
C31–C40 part with the C1–C7 part.
Ó 2005 Elsevier Ltd. All rights reserved.
The pectenotoxin (PTX) family of diarrhetic shellfish
toxins, represented by pectenotoxin 2 (1), was isolated
from toxicated scallop Patinopecten yessoensis and dino-
flagellate Dinophysis fortii by the Yasumoto group.1 All
PTXs have a polyether macrolide structure including a
spirocyclic acetal, a six-membered cyclic hemiacetal, a
bicyclic acetal, and three oxolanes. The unusual and
complex structural features of PTXs as well as their
interesting bioactivity,1a,2 such as potent cytotoxicity
against cancer cells3 and actin-depolymerizing activity,4
have attracted the attention of synthetic chemists.5 As
part of our program aiming at total synthesis of PTXs,6
we describe here the synthesis of the common left-half
[C31–C33(OC1–C7)–C40] part (2) of PT Xs (Scheme 1).
The synthesis of 3 is illustrated in Scheme 2. First, the
aldehyde 5 was prepared from the known epoxide 77
(P95%ee). Regioselective cleavage of 7 with AlMe3 gave
diol 8,8 which was selectively converted to the aldehyde
5 through a three-step process [(i) benzylidene acetal for-
mation, (ii) reductive acetal cleavage, and (iii) Dess–
Martin oxidation9]. Next, an alternative short synthesis
of the known 66b was examined. Homoallyl alcohol 11,10
readily obtainable from D-glyceraldehyde acetonide
10,11 was converted to 12 through protection with p-
methoxybenzyl (PMB) chloride (99%), hydrolysis of
the acetonide part, and selective protection with
TBDPSCl (68% for two steps). Oxidative cleavage
of the olefin part in 12 afforded cyclic hemiacetal
13 (94%), which was transformed into a-phenyl-
thiotetrahydrofuran 6 (85%, a mixture of anomeric
isomers) by acetylation and the subsequent treatment
with thiophenol in the presence of Et2OÆBF3. Thus, this
route could provide 6 more facilely than the previous
route.6b The assembly of 5 and 6 was undertaken
according to our procedure.6b,12 Treatment of 6 with
2 equiv of lithium 4,40-di-tert-butylbiphenylide (LDBB)
at À95 °C followed by the reaction with 5 (1.8 equiv)
produced alcohol 14 as a mixture of diastereomers in
71% yield. Swern oxidation13 of 14 gave 15 (98%) as
a 4.2:1 mixture of diastereomers at C35. The major dia-
stereomer of 15 was proved to have the desired stereo-
chemistry by detailed NMR analysis. After detach-
ment of two PMB groups of 15 with DDQ, the desired
diastereomer was isolated as a cyclic hemiacetal (70%),
The left-half 2 was planned to be synthesized from C1-
C7 part 4 and C31–C40 part 3 (Scheme 1). Although
we have previously synthesized a similar C31–C40 part
to 3 using a coupling reaction of a chiral a-lithio-
tetrahydrofuran,6b it appeared later that the chirality
of the synthetic C31–C40 part was opposite to that of
natural PTXs.1c Therefore, we intended to construct 3
from C36–C40 part 5 and C31–C35 part 66b by our
established method with proper chirality.6b
Keywords: Pectenotoxin 2; Reductive coupling reaction; Natural pro-
duct synthesis; Polyether macrolide.
*
Corresponding author. Tel.: +81 11 706 2701; fax: +81 11 706
4924; e-mail: fjwkn@sci.hokudai.ac.jp
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.05.062

5068
K. Fujiwara et al. / Tetrahedron Letters 46 (2005) 5067–5069
OPMB
Me
O 1
HO
OTBS
O
8
Left-half Part
Me
Me
35
31
1
OTBS
7
O
O
O
Me
O 1
PhS
O
OPMB
7
CHO
7
O
O
4
+
6
TBDPSO
O
33
O
33
OH
Me
O
OH
+
BnO
HO
Me
30
O
TBSO
Me
21
TBSO
Me
O
31
36
Me
31
Me
O
31
CHO
40 OPMB
O
20
OH
40 O
Me Me
OMe
40
O
OMe
40 O
3
5
Pectenotoxin 2 (PTX2: 1)
2
Scheme 1.
RO
reaction to afford 18 (overall 63%), which was treated
with K2CO3 in MeOH to produce 3 (86%). Since 3
was obtained as crystals (colorless needles from hex-
ane–Et2O, mp 131–133 °C), the stereochemistry of 3
was confirmed by X-ray crystallographic analysis (Fig.
1).16 Thus, the C31–C40 part 3 having the proper abso-
lute stereochemistry was concisely synthesized from 7
and 11.
O
a
d
OH
OH
5
OPMB
PMBO
b, c
Me
8
7
: R = H
9: R = Bn
PMBO
OTBDPS
HO
OHC
ref. 10
e, f, g
Me
O
O
O
OH
12
O
Me
Me
Me
10
11
The synthesis of the C1–C7 part 4 and the left-half part
2 is shown in Scheme 3. Evansꢀ aldol reaction17 of 19
with 2018 exclusively produced aldol 21, which was con-
verted to 4 through protection with TBSOTf and hydro-
lysis of the ester part. Thus, the C1–C7 part 4 was
simply prepared in only three steps in 92% overall yield
from 20. Finally, the condensation reaction of 4 with 3
using DCC and DMAP (82%) followed by detachment
of PMB and Swern oxidation (overall 52%) successfully
produced the left-half part 2.19
OPMB
H
OPMB
BnO
H
H
h
k
m, n
Me
R
O
O
5
TBDPSO
X
TBDPSO
13: R = OH
6: R = SPh
14: X = H, OH
15: X = O
PMBO
i, j
l
OR1
OBz
R2O
TBSO
H
H
H
H
r, s, t
Me
Me
u
3
O
O
OMe
OMe
O
O
TBDPSO
16: R1 = H, R2 = Bn
18
o, p, q
17: R1 = Bz, R2 = TBS
Scheme 2. Reagents and conditions: (a) Me3Al, CH2Cl2, 0 °C, 2 h,
94%; (b) CSA, PhCHO, PhH, reflux, 1 h, 94%; (c) DIBALH, PhH,
0 °C, 1.5 h, 74%; (d) DMPI, NaHCO3, CH2Cl2, 0 °C, 30 min, 97%; (e)
PMBCl, NaH, Bu4NI, DMF, 23 °C, 2 h, 99%; (f) 2 M HCl aq–THF
(1:2), 23 °C, 1.5 h, 90%; (g) TBDPSCl, Et3N, DMAP, CH2Cl2, 23 °C,
19 h, then separation, 76%; (h) OsO4, NMO 1,4-dioxane–H2O (3:1),
23 °C, 19 h, then NaIO4, pH 7 buffer, 24 °C, 12 h, 94%; (i) Ac2O, Et3N,
DMAP, CH2Cl2, 24 °C, 1.5 h, 98%; (j) PhSH, Et2OÆBF3, CH2Cl2,
À40 °C, 15 min, 87%; (k) LDBB (2 equiv), THF, À95 °C, 1 min, then 5
(1.8 equiv), À78 °C, 40 min, 71%; (l) (COCl)2, DMSO, CH2Cl2,
À78 °C, 10 min, then Et3N, À78 ! 0 °C, 20 min, 98%; (m) DDQ,
CH2Cl2–H2O (10:1), 0 °C, 1 h, then separation, 70%; (n) CSA, MeOH–
(MeO)3CH (1:1), 21 °C, 2 h, 83%; (o) BzCl, DMAP, pyridine, CH2Cl2,
0 ! 24 °C, 21 h, 100%; (p) DDQ, CH2Cl2-pH 7 buffer (1:1), 25 °C,
3.5 h, 86%; (q) TBSOTf, 2,6-lutidine, DMAP, CH2Cl2, 24 °C, 2 h,
90%; (r) TBAF, AcOH, DMF, 23 °C, 3.3 h, 88%; (s) (COCl)2, DMSO,
CH2Cl2, À78 °C, 10 min, then Et3N, À78 ! 0 °C, 20 min; (t)
Ph3PCH3Br, NHMDS, THF, 23 °C, 1 h, then aldehyde, À78 ! 0 °C,
1 h, 63% for two steps; (u) K2CO3, MeOH, 23 °C, 3.5 h, 86%.
Figure 1. ORTEP diagram of 3: one of the two crystallographically
independent molecules is shown.
O
O
O
O
OR
a
c
4
2
O
N
O
N
OHC
Me
Me
PMBO
d, e, f
3
Bn
19
Bn
PMBO
21: R = H
22: R = TBS
b
20
which was stereoselectively converted to cyclic methyl
acetal 16 (83%). Protection of the secondary hydroxy
group of 16 as a benzoate ester followed by removal
of the benzyl group with DDQ14 and protection of the
resulting alcohol with TBSOTf produced 17 (overall
77%). After the TBDPS group of 17 was selectively re-
moved by Hashimotoꢀs conditions15 (88%), the resulting
alcohol was subjected to oxidation followed by Wittig
Scheme 3. Reagents and conditions: (a) Bu2BOTf, Et3N, CH2Cl2,
0 °C, 1 h, then 19 (0.5 equiv), À78 ! 0 °C, 4 h, ꢀ100% from 19; (b)
TBSOTf, 2,6-lutidine, 0 °C, 1 h, 98%; (c) LiOH, 30% H2O2 aq, THF–
H2O, 24 °C, 4 h, 94%; (d) 3 (0.25 equiv), DCC, DMAP, CH2Cl2, 23 °C,
2 h, 82% from 3; (e) DDQ, CH2Cl2–H2O (10:1), 0 °C, 50 min, 82%; (f)
(COCl)2, DMSO, CH2Cl2, À78 °C, 10 min, then Et3N, À78 ! 0 °C,
20 min, 52%.

K. Fujiwara et al. / Tetrahedron Letters 46 (2005) 5067–5069
5069
(d) Paquette, L. A.; Peng, X.; Bonder, D. Org. Lett. 2002,
4, 937; (e) Pihko, P. M.; Aho, J. E. Org. Lett. 2004, 6,
3849; (f) Peng, X.; Bonder, D.; Paquette, L. A. Tetrahe-
dron 2004, 60, 9589; (g) Bonder, D.; Liu, J.; Muller, T.;
Paquette, L. A. Org. Lett. 2005, 7, 1813.
In conclusion, the common left-half [C31–C33(OC1–
C7)–C40] part (2) of PTXs has been synthesized conver-
gently from the C31–C35, C36–C40, and C1–C7 parts
(6, 5, and 4, respectively). Connection of 6, prepared
via a new route shorter than our previous route, with
5 through reductive lithiation and addition reactions
gave adduct 14 stereoselectively, which was converted
to the C31–C40 part 3. The left-half was synthesized
by a three-step process including esterification of 3 with
4. Further studies toward the total synthesis of PTXs are
currently underway in this laboratory.
6. (a) Awakura, D.; Fujiwara, K.; Murai, A. Synlett 2000,
1733; (b) Amano, S.; Fujiwara, K.; Murai, A. Synlett
1997, 1300.
7. Oka, T.; Murai, A. Chem. Lett. 1994, 1611.
8. Roush, W. R.; Adam, M. A.; Peseckis, S. M. Tetrahedron
Lett. 1983, 24, 1377.
9. (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155;
(b) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113,
7277.
10. Hafner, A.; Duthaler, R. O.; Marti, R.; Rihs, G.; Rothe-
Streit, P.; Schwarzenbach, F. J. Am. Chem. Soc. 1992, 114,
2321, and references cited therein.
11. Schmid, C. R.; Bryant, J. D. Org. Synth. 1995, 72, 6.
12. Amano, S.; Fujiwara, K.; Murai, A. Chem. Lett. 1998,
409.
13. Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem.
1978, 43, 2048.
Crystallographic data (excluding structure factors) of 3
have been deposited with the Cambridge Crystallo-
graphic Data Center as supplementary publication num-
bers CCDC 269076. Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK [fax: +44 (0) 1223
336033 or e-mail: deposit@ccdc.cam.ac.uk].
14. Ikemoto, N.; Schreiber, S. L. J. Am. Chem. Soc. 1992, 114,
2524.
Acknowledgements
15. Higashibayashi, S.; Shinko, K.; Ishizu, T.; Hashimoto, K.;
Shirahama, H.; Nakata, M. Synlett 2000, 1306.
16. Crystal data of 3: C19H36O5Si, M 372.58, orthorhombic
We thank Mr. Kenji Watanabe and Dr. Eri Fukushi
(GC-MS & NMR Laboratory, Graduate School of
Agriculture, Hokkaido University) for the measure-
ments of mass spectra. This work was supported by a
Grant-in-Aid for Scientific Research from the Ministry
of Education, Culture, Sports, Science, and Technology
of Japanese Government.
˚
˚
P21212 (No. 18), a = 18.181(4) A, b = 22.563(5) A, c =
3
10.657(2) A, U = 4371(1) A Dc (Z = 8) = 1.132 g/cm3,
T = 153 K, l = 1.30 cmÀ1. The final R value is 0.030 for
4944 independent reflections with I > 3rI and 452
parameters.
˚
˚
17. Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc.
1981, 103, 2127.
References and notes
18. Morimoto, Y.; Iwahashi, M.; Kinoshita, T.; Nishida, K.
Chem. Eur. J. 2001, 7, 4107.
23
1. (a) Yasumoto, T.; Murata, M.; Oshima, Y.; Sano, M.;
Matsumoto, G. K.; Clardy, J. Tetrahedron 1985, 41, 1019;
(b) Sasaki, K.; Wright, J. L. C.; Yasumoto, T. J. Org.
Chem. 1998, 63, 2475; (c) Sasaki, K.; Satake, M.;
Yasumoto, T. Biosci. Biotech. Biochem. 1997, 61, 1783.
2. (a) Ishige, M.; Sato, N.; Yasumoto, T. Report Hokkaido
Inst. Public Health 1988, 38, 15; (b) Terao, K.; Ito, E.;
Yanagi, T.; Yasumoto, T. Toxicon 1986, 24, 1141.
3. Jung, J. H.; Sim, C. J.; Lee, C.-O. J. Natural Product 1995,
58, 1722.
4. (a) Zhou, Z.-H.; Komiyama, M.; Terao, K.; Shimada, Y.
Nat. Toxins 1994, 2, 132; (b) Hori, M.; Matsuura, Y.;
Yoshimoto, R.; Ozaki, H.; Yasumoto, T.; Karaki, H.
Folia Pharmacol. Jpn. 1999, 114(Suppl 1), 225; (c) Spector,
I.; Braet, F.; Chochet, N.; Bubb, M. R. Microsc. Res.
Technol. 1999, 47, 18; (d) Leira, F.; Cabado, A. G.;
Vieytes, M. R.; Roman, Y.; Alfonso, A.; Botana, L. M.;
Yasumoto, T.; Malaguti, C.; Rossini, G. P. Biochem.
Pharmacol. 2002, 63, 1979.
19. Selected spectral data of 2: ½aꢁD À31 (c 0.195, CHCl3); 1H
NMR (300 MHz, C6D6) d 0.02 (3H, s), 0.09 (3H, s), 0.11
(3H, s), 0.13 (3H, s), 0.82–0.92 (1H, m), 0.83 (3H, d,
J = 7.2 Hz), 0.99 (9H, s), 1.00 (9H, s), 1.27 (3H, d,
J = 7.2 Hz), 1.35–1.55 (6H, m), 1.73–1.91 (3H, m), 2.05–
2.25 (3H, m), 2.58 (1H, dq, J = 5.1, 7.2 Hz), 3.28 (1H, d,
J = 1.5 Hz), 3.45 (3H, s), 3.48 (1H, ddd, J = 2.9, 11.2,
13.0 Hz), 3.74 (1H, br dd, J = 4.4, 11.2 Hz), 4.10 (1H, br q,
J = 5.1 Hz), 4.41 (1H, tdd, J = 1.5, 4.2, 5.7 Hz), 4.87 (1H,
dd, J = 7.0, 9.5 Hz), 5.16 (1H, td, J = 1.5, 10.5 Hz) 5.41–
5.47 (1H, m), 5.46 (1H, td, J = 1.5, 17.3 Hz), 6.01 (1H,
ddd, J = 5.7, 10.5, 17.3 Hz), 9.29 (1H, t, J = 1.5 Hz); 13C
NMR (75 MHz, C6D6, 13C12C5D6 as 128.0 ppm) d À4.3
(CH3), À4.1 (CH3), À3.4 (CH3), À2.6 (CH3), 11.8 (CH3),
17.8 (C), 18.3 (CH2), 19.0 (C), 19.1 (CH3), 26.1 (CH3), 26.7
(CH3), 27.2 (CH2), 30.1 (CH), 33.7 (CH2), 35.1 (CH2),
43.6 (CH2), 45.0 (CH), 50.1 (CH3), 62.3 (CH2), 73.29
(CH), 73.34 (CH), 76.1 (CH), 81.1 (CH), 81.8 (CH), 99.2
(C), 117.2 (CH2), 134.5 (CH), 173.9 (C), 200.1 (CH); IR
(film) mmax 3082, 2952, 2929, 2884, 2857, 2712, 1729, 1658,
1473, 1463, 1389, 1361, 1253, 1220, 1172, 1127, 1099, 1054,
1006, 995, 931, 837, 809, 776, 666 cmÀ1; LR-FDMS, m/z
643 (7%, [M+H]+), 610 (19%, [MÀMeOH]+), 585 (bp,
5. For total synthesis of pectenotoxins-4 and -8, see: (a)
Evans, D. A.; Rajapakse, H. A.; Stenkamp, D. Angew.
Chem., Int. Ed. 2002, 41, 4569; (b) Evans, D. A.;
Rajapakse, H. A.; Chiu, A.; Stenkamp, D. Angew. Chem.,
Int. Ed. 2002, 41, 4573. Other synthetic studies, see: (c)
Micalizino, G. C.; Roush, W. R. Org. Lett. 2001, 3, 1949;
t
[MÀ Bu]+); HR-FDMS, calcd for C33H63O8Si2 [M+H]+:
643.4062, found: 643.4087.