Convergent synthesis of the trans-fused 6-n-6-6 (n = 7-10) tetracyclic ether system based on a ring-closing metathesis reaction

Article abstract of DOI:10.1039/a801678j

A convergent synthesis of the trans-fused 6-n-6-6 (n = 7-10) tetracyclic ether system was achieved via stereoselective alkylation and ring-closing metathesis reaction.

Full text of DOI:10.1039/a801678j

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Convergent synthesis of the trans-fused 6-n-6-6 (n = 7–10) tetracyclic ether
system based on a ring-closing metathesis reaction
Tohru Oishi,a,b Yoko Nagumoa and Masahiro Hirama*a,b
†
a Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
b CREST, Japan Science and Technology Corporation (JST), Japan
A convergent synthesis of the trans-fused 6-n-6-6 (n = 7–10)
tetracyclic ether system was achieved via stereoselective
alkylation and ring-closing metathesis reaction.
was converted to 2c in the same manner as 2a and 2b. Syntheses
of 2d and 2e were performed using triflate chemistry.10
Treatment of the triflate derived from alcohol 13 using lithium
acetylide in the presence of 1,3-dimethyl-3,4,5,6-tetrahydro-
2(1H)-pyrimidone (DMPU) followed by partial hydrogenation
gave 2d, whereas treatment of the same triflate using allylmag-
nesium bromide in the presence of CuBr gave 2e.
The synthesis of ciguatoxin1 has received considerable attention
because of its striking structure and biological activity.
Although numerous techniques have been developed for the
synthesis of medium ring ethers,2 efficient methods for
assembling fragments are still needed. In the course of our
synthetic study of ciguatoxin,3 we developed a convergent route
to the trans-fused 6-7-6 tricyclic ether system via formation of
the central oxepene ring by alkene metathesis.4–6 Here we
describe a new technique for synthesizing trans-fused 6-n-6-6
(n = 7–10) tetracyclic polyether systems (1a–e) from glycolate
3 (Scheme 1). The central n-6 bicyclic rings of these systems are
efficiently constructed by stereoselective alkylation and the
subsequent ring-closing metathesis reaction of dienes (2).
Syntheses of the dienes 2a and 2b, precursors for 6-7-6-6
systems (1a and 1b), are shown in Scheme 2. Coupling of tert-
butyl ester 3 with iodide 4‡ using LDA in the presence of
HMPA gave 5 and the diastereomer 6 in a 3:1 ratio. These
compounds were separated using silica gel column chromato-
graphy. Removal of the TIPS group of 5 using TBAF followed
by treatment with TsOH·H2O in toluene at 90 °C gave lactone
7. The addition of vinylmagnesium bromide to 7 gave
hemiacetal 8, and reduction of 8 with Et3SiH in the presence of
Ring-closing metathesis reactions of dienes 2a–e using
Grubbs’ catalyst (PCy3)2Cl2RuNCHPh (14) were examined
(Table 1). The reactions of 2a and 2b in benzene gave 6-7-6-6
tetracyclic ethers 1a, and 1b having an angular methyl group in
Table 1 Ring-closing metathesis reaction of 2a–ea
Diene
Product
J/Hzb
Yield (%)
H
O
H
H
O
7
81d
2a
12.9
O
H
H
O
H
1a
H
O
Me
O
H
94d
82e
7
2b
2c
12.8
11.0
O
7
BF3·OEt2 proceeded stereoselectively, giving 10 as a single
H
H
O
H
isomer. Methylation of the hemiacetal 8 using Me3Al and
1b
8
BF3·OEt2 gave 11 only in low yield ( ~ 4%); however, the
alkylation of the corresponding methyl acetal 9 under the same
reaction conditions gave 11 in good yield (72%) as a single
isomer. Reductive removal of the benzyl groups of 10 and 11
using lithium naphthalenide9 followed by Swern oxidation and
subsequent Wittig olefination gave dienes 2a and 2b, respec-
tively.
Syntheses of dienes 2c–e, precursors for 1c–e, respectively,
are also shown in Scheme 2. Treatment of 7 with allylmagne-
sium bromide followed by reduction of the resulting hemiacetal
(Et3SiH, BF3·OEt2) gave 12 as a single isomer. The olefin 12
H
O
H
H
O
8
94e
O
H
H
O
H
1c
H
O
H
O
9
H
10.5c
87e
2d
O
H
H
H
O
m
1d
m
l
l
H
O
R
O
H
R
O
H
O
H
O
O
H
H
H
H
H
O
H
10
O
H
O
H
O
2e
68e
O
2
H
10.9
1a R = H, I = m = 0
b R = Me, l = m = 0
c R = H, l = 0, m = 1
d R = H, l = m = 1
e R = H, l = 2, m = 1
H
H
O
H
O
OBn
1e
OBut
a Reactions were carried out in the presence of 12–21 mol% of catalyst 14.
O
b
c
Coupling constants between the olefin protons. The value at 240 °C.
O
3
d In benzene at 50–60 °C for 5–7 days (0.04 m). e In CH2Cl2 at 35 °C for 1–2
days (0.004–0.04 m).
Scheme 1
Chem. Commun., 1998
1041

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O
because the reaction of 2b in CH2Cl2 proceeded smoothly and
was completed within two days. This method was also quite
effective in the construction of the larger rings. Cyclic
polyethers 1c (6-8-6-6), 1d (6-9-6-6) and 1e (6-10-6-6 system)
were synthesized from 2c–e, respectively, in good yields. The
structures of these products were unambiguously determined by
NMR and mass spectroscopy.
The present technique will serve as a versatile synthetic tool
for the synthesis of polyether marine toxins. Further synthetic
studies of ciguatoxin are presently being conducted in our
laboratory.
This work was supported in part by a Grant-in-aid for
Scientific Research from the Ministry of Education, Science,
Sports, and Culture of Japan, the Naito Foundation and the
Uehara Memorial Foundation. We also wish to thank Dr M.
Ueno and Mr T. Sato, Instrumental Analysis Center for
Chemistry, Faculty of Science, Tohoku University for the
measurement of NMR and mass spectra.
TIPSO
I
OBn
OBut
+
O
O
O
3
4
i
BnO
H
BnO
H
H
O
H
TIPSO
TIPSO
ButO2C
O
O
ButO2C
+
O
O
H
H
H
H
O
H
H
3 : 1
6
5
ii
NOE
H
BnO
H
RO
H
O
H
O
O
O
H
O
viii
O
O
Notes and References
O
H
H
H
H
H
† E-mail: hirama@ykbsc.chem.tohoku.ac.jp
H
O
‡ Compounds 3 and 4 were prepared from (2R,3S)- and (2S,3R)-
2-(benzyloxymethyl)tetrahydropyran-3-ol, respectively, by standard proce-
dures.4
NOE
12 R = Bn
13 R = H
7
ix
iii
x or xi or xii
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BnO
H
OR
O
H
O
O
l
H
O
H
O
H
O
H
H
H
O
H
H
8 R = H
9 R = Me
iv
H
O
O
H
2c l = 0
2d l = 1
2e l = 2
v or vi
NOE
BnO
H
H
R
R
O
H
O
O
vii
O
O
O
4 T. Oishi, Y. Nagumo and M. Hirama, Synlett, 1997, 980.
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1996, 118, 6634 and references cited therein.
H
H
O
H
H
H
H
10 R = H
11 R = Me
2a R = H
2b R = Me
6 For recent applications of the metathesis reactions to the synthesis of
monocyclic and terminal cyclic ether systems, see: K. C. Nicolaou,
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Scheme 2 Reagents and conditions: i, LDA, HMPA, THF, 278 to 0 °C,
61%; ii, Bu4NF, THF, TsOH·H2O (cat.), toluene, 90 °C, 84%; iii,
H2CNCHMgBr, THF, 278 °C, 80%; iv, CH(OMe)3, CSA, CH2Cl2, 80; v,
Et3SiH, BF3·OEt2, MeCN, 220 °C, 71%; vi, Me3Al, BF3·OEt2, CH2Cl2,
0 °C to room temp., 72%; vii, Li, C10H8, THF; (COCl)2, Et3N, DMSO,
CH2Cl2, 278 to 240 °C; Ph3P+MeBr2 NaN(SiMe3)2, THF, 0 °C to room
temp., 72% (for 2a), 64% (for 2b); viii, H2CNCHCH2MgBr, THF, Et2O,
278 °C; Et3SiH, BF3·OEt2, MeCN, 220 °C to room temp., 90%; ix, Li,
C10H8, THF, 91%; x, (COCl)2, Et3N, DMSO, CH2Cl2, 278 to 0 °C;
Ph3P+MeBr2, NaN(SiMe3)2, THF, 0 °C to room temp., 83%; xi, Tf2O, Py,
CH2Cl2, 215 °C; LiC·CH, DMPU, THF, 278 to 0 °C; H2, Lindlar cat.
AcOEt, 47%; xii, Tf2O, Py, CH2Cl2, 215 °C; H2CNCHCH2MgBr, CuBr,
Et2O, 0 to 10 °C, 84%
9 H.-J. Liu, J. Yip and K.-S. Shia, Tetrahedron Lett., 1997, 38, 2253.
10 H. Kotsuki, I. Kadota and M. Ochi, Tetrahedron Lett., 1989, 30, 1281;
H. Kotsuki, I. Kadota and M. Ochi, Tetrahedron Lett., 1990, 31, 4609.
81 and 94% yield, respectively. These reactions required five to
seven days. However, we found a remarkable solvent effect
Received in Cambridge, UK, 2nd March 1998; 8/01678J
1042
Chem. Commun., 1998