Efficient syntheses of the polyene fragments present in amphidinols

Article abstract of DOI:10.1055/s-2007-984910

The C53-C67 and C53-C65 polyene fragments of amphidinols have been synthesized in an efficient and convergent fashion from sorbic acid in good overall yields (30-31%) by employing a chemoselective cross-metathesis of a Weinreb amide and a Julia-Kocienski

Full text of DOI:10.1055/s-2007-984910

2286
LETTER
Efficient Syntheses of the Polyene Fragments Present in Amphidinols
S
ynthese
s
a
of the Poly
n
ene Fragme
n
i
ts
P
res
n
e
nt inAmph
e
idinols Cossy,*a Tomoki Tsuchiya,a Laurent Ferrié,a Sébastien Reymond,a Thomas Kreuzer,b Françoise Colobert,b
Pierre Jourdain,c István E. Markóc
a
Laboratoire de Chimie Organique, ESPCI, CNRS, 10 Rue Vauquelin, 75231, Paris Cedex 05, France
Fax +33(1)40794660; E-mail: janine.cossy@espci.fr
b
Laboratoire de Stéréochimie, Université Louis Pasteur, ECPM, CNRS, 25 Rue Becquerel, 67087 Strasbourg Cedex 2, France
c
Université Catholique de Louvain, Unité de Chimie Organique et Médicinale, Bâtiment Lavoisier, Place Louis Pasteur 1,
1348 Louvain-la Neuve, Belgium
Received 6 May 2007
Amphidinol 3 has shown a particularly potent biological
activity among the other amphidinols,2e and Paquette,3
Roush,4 and Rychnovsky5 have already been engaged in
the polyene-fragment synthesis. As we recently devel-
oped a chemoselective cross-metathesis with sorbam-
ides,6 and as Weinreb amides are versatile compounds, we
envisaged that we could use this type of reaction for the
synthesis of the polyene unit present in amphidinols.
Abstract: The C53–C67 and C53–C65 polyene fragments of
amphidinols have been synthesized in an efficient and convergent
fashion from sorbic acid in good overall yields (30–31%) by
employing a chemoselective cross-metathesis of a Weinreb amide
and a Julia–Kocienski olefination as the key steps.
Key words: cross-metathesis, Julia–Kocienski olefination, amphi-
dinols, polyenes
A convergent approach to synthesize the C53–C65 and
C53–C67 fragments (compounds 8 and 10) of AMs was
considered. A Julia–Kocienski olefination between sul-
fones 7a or 7b and aldehyde 5 would provide the polyenes
in an efficient and stereoselective manner. The aldehyde,
in turn, would be derived from sorbic acid 1 via sorbamide
2 by using the cross-metathesis reaction we reported
previously (Scheme 1).6
Unique structures and powerful bioactivities of
polyketide metabolites have often attracted attention of
synthetic chemists. Amphidinols (AMs) are a small class
of such polyketides isolated from the genus Amphidinium.
Amphidinol 1 was first reported by Satake et al. in 1991,1
and fourteen more congeners have been reported since.2
The amphidinols, all of which display varying degrees of
antifungal and hemolytic activities, have common struc-
tural features including two highly substituted tetrahydro-
pyran rings and a long carbon chain encompassing
multiple hydroxyl groups. They are also characterized by
their skipped polyene chain starting at C52 and ending
either at C65 as a terminal olefin (AMs 2, 4, 6, 8, 9 and 10)
or at C67 as a terminal E-diene (AMs 1, 3, 5, 7 and 11),
exemplified here as AM4 and AM3 (Figure 1).
The syntheses of polyenes 8 and 10 started from sorbic
acid 1 which was converted into the Weinreb amide 2
[1,1¢-carbonyldiimidazole (CDI), N,O-dimethyl-hydrox-
ylamine hydrochloride, CH2Cl2].7 A cross-metathesis be-
tween amide 2 and the TBS-protected pent-1-en-5-ol 3 in
the presence of Hoveyda–Grubbs catalyst [Ru-I (5
mol%), CH2Cl2, r.t., 2 h] yielded diene 4 in 57%. An E/Z
ratio of 20:1 was established by examining the 1H NMR
1
HO
OH
OH
OH
OH
OH
OH
OH
OH OH
OH
OH
OH
OH
O
OH
O
HO
OH
OH
OH
53
65
R
HO
OH
67
amphidinol 4, R = H
amphidinol 3, R =
Figure 1 Structure of amphidinols 3 and 4
SYNLETT 2007, No. 14, pp 2286–2288
0
3
.0
9
.2
0
0
7
Advanced online publication: 20.07.2007
DOI: 10.1055/s-2007-984910; Art ID: G10507ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Syntheses of the Polyene Fragments Present in Amphidinols
2287
R
OTBS
OH
8 R =
MeC(OMe)3
10 R = H
propionic acid (cat.)
92%
∆
N
N
O
O
O
N
OTBS
+
N
R
S
O2
H
Ph
6
5
7a R =
1) LiAlH4, THF
2) PTSH, DIAD, PPh3
DMF
3) Mo7O24(NH4)6·4H2O,
H2O2, EtOH, r.t.
Ph
7b R = H
N
N
76% over
3 steps
PTSH =
HS
N
O
O
N
N
HO
OMe
2
1
Ph
Scheme 1 Retrosynthesis of polyenes 8 and 10
N
N
O
N
N
S
spectrum. After reduction of 4 by DIBAL-H (–78 °C,
hexanes–CH2Cl2), the unstable aldehyde 5 was immedi-
ately used without purification in the subsequent Julia–
Kocienski olefination with sulfones 7a and 7b
(Scheme 2).
O
7a
5, KHMDS
THF
–78 °C
65%
Sulfone 7a was prepared from penta-1,4-dien-3-ol in 5
steps (Scheme 3). The starting alcohol was subjected to
the Johnson–Claisen rearrangement [MeC(OMe)3, propi-
onic acid, reflux]8 to produce dienic ester 6 in 92% yield.
OTBS
8
E/Z = 9:1
Scheme 3 Synthesis of polyene 8
This ester was reduced (LiAlH4, THF) to the correspond-
ing alcohol,9 which was then transformed to a thioether by
using a Mitsunobu reaction (PTSH, DIAD, PPh3, DMF).10
Without purification, the thioether was subjected to a mild
oxidation [Mo7O24(NH4)6·4H2O (13 mol%), H2O2, EtOH,
r.t.]10 and converted into the desired sulfone 7a in 76%
yield over the 3 steps.
Compound 7a and aldehyde 5 were coupled under the
Barbier-type conditions with KHMDS (1.3 equiv, THF,
–78 °C)11 to generate the desired polyene 8 in a 65% yield.
The E/Z ratio for the newly created double bond was eval-
O
O
MeNH(OMe)·HCl
N
HO
CDI
CH2Cl2, r.t.
85%
OMe
1
2
uated to be 9:1 by both GC-MS and H NMR analyses
1
(Scheme 3).12
By using the same methodology as described above, but
by condensing aldehyde 5 with sulfone 7b, the synthesis
of the skipped polyene fragment C53–C65 of AM4 (com-
pound 10) was also accomplished (Scheme 4). Sulfone 7b
was obtained in two steps and in 75% yield from pent-4-
en-1-ol (9) by using a Mitsunobu reaction (PTSH, DIAD,
PPh3, THF, r.t.), followed by an oxidation step
[Mo7O24(NH4)6·4H2O (13 mol%), H2O2, EtOH, r.t.]. The
obtained sulfone 7b was immediately condensed with the
freshly prepared aldehyde 5 (KHMDS, THF, –78 °C) to
afford the desired polyene 10 in 62% yield. An E/Z ratio
Ru-I (5 mol%)
CH2Cl2, r.t., 2 h
57%
OTBS
3
Mes
Cl
Cl
N
N
Mes
O
Ru
OTBS
N
O
OMe
4
Ru-I
DIBAL-H
hexanes–CH2Cl2
–78 °C
1
of 9:1 was determined by GC-MS and H NMR analy-
ses.13
O
H
To conclude, by using a cross-metathesis of a sorbamide
derivative and a Julia–Kocienski olefination as the key
steps, the polyene fragments (C53–C65 and C53–C67) of
the AMs were assembled. Starting from sorbic acid,
polyenes 8 and 10 were synthesized efficiently in 31%
and 30% yield, respectively, over 4 steps.
OTBS
5
Scheme 2 Synthesis of aldehyde 5
Synlett 2007, No. 14, 2286–2288 © Thieme Stuttgart · New York

2288
T. Tsuchiya et al.
LETTER
Conference on Toxic Phytoplankton; Yasumoto, T.; Oshima,
Y.; Fukuyo, Y., Eds.; UNESCO: Sendai / Japan, 1996, 503–
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Harmful Algae 2005, 4, 383. (g) Morsy, N.; Houdai, T.;
Matsuoka, S.; Matsumori, N.; Adachi, S.; Oishi, T.; Murata,
M.; Iwashita, T.; Fujita, T. Bioorg. Med. Chem. 2006, 14,
6548.
OH
9
Ph
1) PTSH, DIAD,
PPh3, THF, r.t.
N
N
75% over
2 steps
PTSH =
N
2) Mo7O24(NH4)6
H2O2, EtOH, r.t.
N
HS
(3) Chang, S.-K.; Paquette, L. A. Synlett 2005, 2915.
(4) Hicks, J. D.; Flamme, E. M.; Roush, W. R. Org. Lett. 2005,
7, 5509.
(5) de Vicente, J.; Huckins, J. R.; Rychnovsky, S. D. Angew.
Chem. Int. Ed. 2006, 45, 7258.
Ph
N
N
N
N
S
O2
(6) Ferrié, L.; Amans, D.; Reymond, S.; Bellosta, V.;
Capdevielle, P.; Cossy, J. J. Organomet. Chem. 2006, 691,
5456.
(7) Ley, S. V.; Cox, L. R.; Meek, G.; Metten, K.-H.; Piqué, C.;
Worrall, J. M. J. Chem. Soc., Perkin Trans. 1 1997, 3299.
(8) Spino, C.; Crawford, J. Tetrahedron Lett. 1994, 35, 5559.
(9) Ware, R. W.; Day, C. S.; King, S. B. J. Org. Chem. 2002, 67,
6174.
(10) Trost, B. M.; Crawley, M. L. Chem. Eur. J. 2004, 10, 2237.
(11) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A.
Synlett 1998, 26.
(12) tert-Butyl-dimethyl-{[(4E,6E,8E,12E)-pentadeca-
4,6,8,12,14-pentaenyl]oxy}-silane (8)
7b
5, KHMDS
THF
–78 °C
62%
OTBS
10
E/Z = 9:1
Scheme 4 Synthesis of polyene 10
A 9:1 mixture of inseparable E- and Z-isomers; Rf = 0.63
(PE–Et2O, 9:1). IR (neat): 3012, 2927, 2855, 1651, 1603,
1253, 1100 cm–1. 1H NMR (400 MHz, C6D6): d = 6.29 (dtd,
J = 17.0, 10.2, 0.7 Hz, 1 H), 6.18–5.97 (m, 5 H), 5.62 (m, 1
H), 5.54 (dt, J = 14.5, 6.7 Hz, 2 H), 5.06 (d, J = 17.0 Hz, 1
H), 4.93 (d, J = 10.1 Hz, 1 H), 3.51 (t, J = 6.2 Hz, 2 H), 2.14
(td, J = 7.4, 7.1 Hz, 2 H), 2.05–1.99 (m, 4 H), 1.56 (tt,
J = 7.6, 6.3 Hz, 2 H), 1.00–0.96 (m, 9 H), 0.06–0.03 (m, 6
H). 13C NMR (100 MHz, C6D6): d = 137.6 (d), 134.4 (d),
134.0 (d), 133.2 (d), 132.0 (d), 131.7 (d), 131.6 (d), 131.5
(d), 131.4 (d), 115.2 (t), 62.5 (t), 32.5 (t), 32.8 (t), 32.7 (t),
29.5 (t), 26.1 (q), 18.5 (s), -5.2 (q). MS (EI): m/z = 322 (7)
[M+], 275 (20), 265 (20), 133 (100), 67 (37). ESI-HRMS:
m/z calcd for C21H36OSi + Na+: 355.2428; found: 355.2429.
(13) tert-Butyl-dimethyl-{[(4E,6E,8E)-tetradeca-4,6,8,12-
tetraenyl]oxy}-silane (10)
In addition, the general synthetic route presented here
could provide a rapid access to a wide range of skipped
polyenes with a conjugated triene moiety. Efforts towards
the total synthesis of amphidinol 3 are ongoing, and
further results will be reported in due course.
Acknowledgment
We are grateful to Prof. J. Y. Lallemand (ICSN/CNRS) for financial
support.
References and Notes
(1) Satake, M.; Murata, M.; Yasumoto, M.; Fujita, T.; Naoki, H.
J. Am. Chem. Soc. 1991, 113, 9859.
(2) (a) Paul, G. K.; Matsumori, N.; Murata, M.; Tachibana, K.
Tetrahedron Lett. 1995, 36, 6279. (b) Houdai, T.;
Rf = 0.53 (PE–Et2O, 98:2). IR (neat): 3013, 2928, 2856,
1641, 1101, 993 cm–1. 1H NMR (400 MHz, CDCl3): d =
6.12–6.01 (m, 4 H), 5.81 (ddt, J = 17.1, 10.3, 6.4 Hz, 1 H),
5.72–5.61 (m, 2 H), 5.02 (ddd, J = 17.1, 3.4, 1.5 Hz, 1 H),
4.97 (m, 1 H), 3.61 (t, J = 6.4 Hz, 2 H), 2.21–2.11 (m, 6 H),
1.64–1.54 (m, 2 H), 0.91–0.87 (m, 9 H), 0.06–0.02 (m, 6 H).
13C NMR (100 MHz, CDCl3): d = 138.2 (d), 134.0(d), 133.4
(d), 131.4 (d), 131.1 (d), 130.9 (d), 130.8 (d), 114.8 (t), 62.5
(t), 33.5 (t), 32.4 (t), 32.2 (t), 29.1 (t), 26.0 (q), 18.4 (s), –5.3
(q). MS (EI): m/z = 306 (6) [M+], 249 (74), 175 (10), 133
(87), 131 (46), 91 (100), 81 (11), 75 (96), 55 (14). ESI-
HRMS: m/z calcd for C19H34OSi + Na+: 329.2271; found:
329.2271.
Matsuoka, S.; Murata, M.; Satake, M.; Ota, S.; Oshima, Y.;
Rhodes, L. L. Tetrahedron 2001, 57, 5551. (c) Murata, M.;
Matsuoka, S.; Matsumori, N.; Paul, G. K.; Tachibana, K. J.
Am. Chem. Soc. 1999, 121, 870. (d) Paul, G. K.; Matsumori,
N.; Konoki, K.; Murata, M.; Tachibana, K. J. Mar. Biotech.
1997, 5, 124. (e) Paul, G. K.; Matsumori, N.; Konoki, K.;
Sasaki, M.; Murata, M.; Tachibana, K. In Harmful and
Toxic Algal Blooms. Proceedings of Seventh International
Synlett 2007, No. 14, 2286–2288 © Thieme Stuttgart · New York

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