Convergent synthesis of the FGHI ring system of yessotoxin: Stereoselective construction of the G ring

Article abstract of DOI:10.1016/j.tetlet.2005.04.040

A convergent synthetic route to the FGHI ring system of yessotoxin, a marine ladder polyether, has been developed. The synthesis features convergent coupling of the diol and the aldehyde to form α-cyano ethers via acetal formation followed by ring closing

Full text of DOI:10.1016/j.tetlet.2005.04.040

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3991–3995
Convergent synthesis of the FGHI ring system of yessotoxin:
stereoselective construction of the G ring
Koji Watanabe, Miho Suzuki, Michio Murata and Tohru Oishi*
Department of Chemistry, Graduate School of Science, Osaka University, Toyonaka, Osaka 560-0043, Japan
Received 9 March 2005; revised 8April 2005; accepted 11 April 2005
Abstract—A convergent synthetic route to the FGHI ring system of yessotoxin, a marine ladder polyether, has been developed. The
synthesis features convergent coupling of the diol and the aldehyde to form a-cyano ethers via acetal formation followed by ring
closing metathesis and reductive etherification to construct the oxocane ring G and tetrahydropyran ring H, respectively. The
b-methyl group on the G ring was stereoselectively introduced by alkylation of the corresponding ketone.
Ó 2005 Elsevier Ltd. All rights reserved.
Yessotoxin (1)1 is a marine polyether toxin produced by
the dinoflagellate Protoceratium reticulatum.2 Bivalve
mollusks, such as scallops and mussels, accumulate 1
and its analogs3 by filter feeding in waters containing
blooms of the algae. Besides the potent acute toxicity
against mice (LD50 = 28 6lg/kg, ip),4a yessotoxins have
recently been shown to exhibit intriguing biological
activities in humans, that is, (i) modulation of cytosolic
calcium levels of human lymphocytes,4b (ii) activation of
caspases,4c and (iii) cytotoxicity against human tumor
cell lines.4d The broad spectrum of biological activities
of 1, coupled with the unique arched molecular struc-
ture, prompted us to target its synthesis, although signifi-
cant advancements5 in the synthesis of 1 have already
been reported by Nakata,6 Mori,7 and Kadota.8 We
have recently developed a novel convergent strategy
via two-ring construction9 for synthesis of trans-fused
6/n/6/6 (n = 7,8) tetracyclic ether systems.10 Herein, we
describe a convergent synthesis of the FGHI ring
system (2) of 1 via a-cyano ethers based on our
methodology.
Scheme 1 outlines the synthesis plan of 2. In the final
stage, the tetrahydropyran ring H would be constructed
oxocane ring G, two synthetic routes (routes A and B)
by reductive etherification.11 For the construction of the
were envisaged by means of ring closing metathesis
(RCM)12 reaction of the diene 3 (or 4), which could be
derived from the a-cyano ether 5 (or 6).
Keywords: Yessotoxin; Convergent synthesis; Polyether; a-Cyano
ether; Acetal cleavage; Ring closing metathesis; Alkylation; Reductive
Synthesis of 5 and 6 commenced with the diol 8 pre-
pared from 7,13 and aldehyde 910 as shown in Scheme
2. Condensation of 9 using 1.4 equiv of 8 proceeded
etherification.
*
Corresponding author. Tel.: +81 6 6850 5775; fax: +81 6 6850
5785; e-mail: oishi@ch.wani.osaka-u.ac.jp
14
readily by treatment with Sc(OTf)3 in benzene to give
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.04.040

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K. Watanabe et al. / Tetrahedron Letters 46 (2005) 3991–3995
Scheme 3. Reagents and conditions: (a) 1-bromo-2-butene, CrCl2,
THF, 9 h, 92%; (b) CH2@CHCH2MgBr, THF, À40 °C, 1 h, 73%;
(c) 15, ClCH2CH2Cl, 60 °C.
Scheme 1. Synthesis plan of the FGHI ring system 2.
seven-membered ring acetal 10 in 92% yield as a mixture
of diastereomers (3:1) with respect to the stereogenic
center on the acetal carbon.
nitriles 5 and 6 were reduced with DIBAL-H at
À78 °C to afford the aldehydes 13 and 14, respectively.
Construction of the oxocane ring G via route A was
examined as shown in Scheme 3. Treatment of the alde-
hyde 13 with 1-bromo-2-butene in the presence of
CrCl2 provided diene 3 in 92% yield as a mixture of
two major diastereomers (the stereochemistry was not
After converting the MPM group of 10 to the NAP (2-
naphthylmethyl) group,15 regioselective opening of ace-
tal 11 was successfully achieved by a modified method of
the previous report10 using TMSCN in the presence of
Sc(OTf)3 to afford a-cyano ether 12 in 89% yield as a
mixture of diastereomers (5:1). Primary alcohol 12 was
converted to terminal olefins 5 and 6 through elimina-
tion of the corresponding selenoxide16 or by an oxida-
tion/Wittig olefination sequence, and the resulting
17
determined). Although diene
3 was subjected to
RCM12 using the second-generation Grubbs catalyst
15,18 cyclization did not occur and the starting material
was recovered. Presumably, formation of the ruthe-
nium–carbene intermediate was retarded due to the ste-
Scheme 2. Reagents and conditions: (a) t-Bu2Si(OTf)2, 2,6-lutidine, DMF, THF, 85%; (b) Pd/C, H2, EtOAc, MeOH, 81%; (c) Sc(OTf)3, benzene,
1.5 h, 92%; (d) DDQ, H2O, CH2Cl2; (e) 2-naphthylmethyl bromide, NHMDS, TBAI, THF, DMF, 76% (two steps); (f) TMSCN, Sc(OTf)3, CH2Cl2,
rt, 58h, then, K 2CO3, MeOH, 89%; (g) 2-NO2C6H4SeCN; Bu3P, THF; (h) 30% H2O2, NaHCO3 (aq), THF, 45 °C, 57% (two steps); (i) Dess–Martin
periodinane, CH2Cl2, 2 h; (j) Ph3P+CH3BrÀ, NHMDS, THF, 0 °C, 40 min, 87% (two steps); (k) DIBAL-H, CH2Cl2, À78 °C, 13: 90%, 14: 88%.

K. Watanabe et al. / Tetrahedron Letters 46 (2005) 3991–3995
3993
ric hindrance arising from both the allylic methyl groups
of 3. Therefore, the less hindered diene 16, derived from
13 in an analogous sequence using allylmagnesium bro-
mide, was subjected to RCM. However, the reaction was
still sluggish and the product, obtained in low yield,
turned out to be not the desired 18 but the seven-mem-
bered ring ether 19. The eight-membered ring formation
might be retarded because of the proximity of the angu-
lar methyl group on the F ring to the terminal olefin,
and isomerization19 of the other terminal olefin occurred
prior to the ring closure.
with PtO2, was subjected to base-induced epimerization.
However, the reaction was too sluggish and did not con-
verge on a desirable diastereomer (a-H:b-H = ꢀ5:1 at
C28, a-Me:b-Me = ꢀ3:1 at C26). Based on these results,
we next tried to introduce the methyl group under
kinetic conditions.
In an analogous sequence, a,b-unsaturated ketone 22
was prepared by the addition of vinyl lithium to alde-
hyde 14, followed by RCM of the diene and oxidation
of the resulting alcohol. In contrast to the ketone 21,
epimerization of 22 proceeded completely, and concom-
itant isomerization of the C@C double bond occurred to
afford b,c-unsaturated ketone 24 as a single isomer in
54% yield. The structure of 24 was unambiguously
determined by NOE experiments. The results of isomer-
ization under thermodynamic controlled conditions
were supported by an MM3* calculation on Macro-
ModelÒ software as shown in Figure 1,21 which shows
In the next stage, construction of the oxocane ring G via
route B was examined starting with 14, in which the ter-
minal olefin was linked with one more carbon (n = 1)
than 13 (Scheme 4). Addition of 2-propenyl lithium to
aldehyde 14 gave diene 4, which was subjected to
RCM using Grubbs catalyst 15. As expected, RCM
reaction successfully proceeded to afford an eight-mem-
bered ring ether in 58% yield, which was further oxidized
to give a,b-unsaturated ketone 21 as an inseparable mix-
ture of epimers at the C2820 position. Unfortunately, the
major product turned out to possess undesirable stereo-
chemistry (a-H:b-H = 1:8), as confirmed by subsequent
transformations.
Attempts of isomerization to obtain the desirable epimer
by heating with DBU were not successful to give an
equilibrated mixture (a-H:b-H = 2:1). Alternatively, sat-
urated ketone 23, derived from 21 by hydrogenation
Figure 1. Differences of the steric energies (kJ/mol) between 24 and its
isomers by MM3* calculation.
Scheme 4. Reagents and conditions: (a) 2-bromopropene, t-BuLi, THF, À78 °C, 89%; (b) (CH2@CH)4Sn, MeLi, THF, À78 °C, 80%; (c) 15,
(CH2Cl)2, 60 °C, 2 h, 58%; (d) Dess–Martin periodinane, CH2Cl2, 90%; (e) Dess–Martin periodinane, CH2Cl2; (f) 15, toluene, 100 °C, 3 h, 66% (two
steps); (g) PtO2, H2, EtOAc, 2 h; (h) DBU, toluene, 80 °C, 60 h, 60% (two steps); (i) DBU, toluene, reflux, 18h, 54%; (j) PtO 2, H2, EtOAc, 4 h, 85%;
(k) MeI, LHMDS, THF, À78to À20 °C, 5 h, 61% (recovery of 26, 8%); (l) DDQ, CH2Cl2, H2O; (m) Et3SiH, TMSOTf, CH2Cl2, À60 to À30 °C, 1 h,
74% (two steps).

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K. Watanabe et al. / Tetrahedron Letters 46 (2005) 3991–3995
of yessotoxin (1) resemble closely those of the natural
product as shown in Table 1.1a
In conclusion, we have established a highly convergent
route to the FGHI ring system of yessotoxin via a-cyano
ethers. The present synthesis features construction of the
central GH ring system based on ring closing metathesis,
stereoselective alkylation, and reductive etherification.
Further studies directed towards the total synthesis of
yessotoxin are currently in progress in our laboratory.
Acknowledgments
This research was financially supported in part by a
Grant-in-Aid for Scientific Research (B), a Grant-in-
Aid for Scientific Research on Priority Areas ÔExploit-
ation of Multi-Element Cyclic MoleculesÕ and ÔCreation
of Biologically Functional MoleculesÕ from The Minis-
try of Education, Culture, Sports, Science and Technol-
ogy, Japan. K.W. is grateful to the 21st Century COE
Program for financial support.
Figure 2. Working model of the stereoselective alkylation.
that the desirable isomer 24 is most stable among the
regio- and stereoisomers.
The next task was the stereoselective introduction of the
methyl group to the G ring. The b,c-unsaturated ketone
24 was converted to the saturated ketone 25 by hydroge-
nation using PtO2. The lithium enolate, generated from
25 with LHMDS, was treated with methyl iodide. For-
tunately, the alkylation proceeded regio- and stereose-
lectively to afford the desired b-oriented diastereomer
26 (as determined by NOE) in 61% yield. The stereo-
chemical outcome can be rationalized as follows. Under
kinetically controlled conditions, deprotonation would
occur at the less hindered C26 position of the ketone
25 to form the (E)-enolate with the electrophile
approaching from the less hindered side of the enolate
in the boat-chair conformation of the G ring (Fig. 2). Fi-
nally, construction of the H ring was achieved through
oxidative removal of the NAP group with DDQ,
followed by reductive etherification11 with Et3SiH/
TMSOTf to afford the FGHI ring system 2 in 74%
yield for two steps. The stereochemistry of 2 was sup-
ported by NOE experiments and coupling constants
(JH27–H28 = 9.5 Hz, JH26–H27 = 9.5 Hz).22 1H and 13C
NMR signals of 2 corresponding to the C22–C28part
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and the FGHI ring system (2) in CD3OD
Position
1H (500 MHz)
13C (125 MHz)
1
2
1
2
22
23
3.53
—
3.52
—
87.3
77.0
20.7
87.3
78.3
21.0
23-Me
24
24
1.20
1.54
1.77
1.51
1.75
1.74
1.07
2.81
3.34
1.21
1.4847.0
1.73
46.6
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25
1.4832.832.9
1.70
1.65
26
40.840.8
22.4
89.4
26-Me
27
28
0.99
2.71
22.4
88.6
84.3
3.32
84.1

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1.20 (3H, s, Me), 1.39 (1H, ddd, J = 11.5, 11.5, 11.5 Hz,
H32ax), 1.42 (3H, s, Me), 1.44–1.52 (3H, m, H24, H25),
1.58(1H, ddd, J = 11.5, 11.5, 11.5 Hz, H29ax), 1.61–1.68
(1H, m, H26), 1.74 (1H, dd, J = 14.0, 9.0 Hz, H24), 1.79
(1H, ddd, J = 12.0, 12.0, 12.0 Hz, H21ax), 1.91 (1H, dt,
J = 12.0, 4.0 Hz, H21eq), 2.28(1H, dt, J = 11.5, 4.5 Hz,
H29eq), 2.52 (1H, dt, J = 11.5, 4.5 Hz, H32eq), 2.68(1H,
dd, J = 9.5, 9.5 Hz, H27), 2.87 (1H, ddd, J = 11.5, 9.0,
4.5 Hz, H31), 3.03 (1H, ddd, J = 11.5, 9.0, 4.5 Hz, H30),
3.22 (1H, ddd, J = 11.5, 9.5, 4.5 Hz, H28), 3.37 (1H, dd,
J = 12.0, 4.0 Hz, H22), 3.39 (1H, ddd, J = 9.5, 5.0, 2.0 Hz,
H34), 3.49 (1H, ddd, J = 11.5, 9.5, 4.5 Hz, H33), 3.64 (1H,
dd, J = 10.5, 5.0 Hz, H35), 3.66 (1H, d, J = 10.0 Hz, H18),
3.81 (1H, d, J = 10.0 Hz, H18), 3.74 (1H, dd, J = 10.5,
2.0 Hz, H35), 3.87 (1H, dd, J = 12.0, 4.0 Hz, H20), 4.36
(1H, d, J = 11.5 Hz, benzyl), 4.53 (1H, d, J = 12.0 Hz,
benzyl), 4.56 (1H, d, J = 11.5 Hz, benzyl), 4.60 (1H, d,
J = 12.0 Hz, benzyl), 7.18–7.33 (10H, m, Ph); ESI-MS 736
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