Convergent synthesis of trans-fused 6/n/6/6 (n=7, 8) tetracyclic ether system via α-cyano ethers

Article abstract of DOI:10.1016/S0040-4039(03)01862-8

A convergent method for synthesizing 6/n/6/6 (n=7, 8) tetracyclic ether system via two-rings construction of the central n/6 ring system was developed. The key steps of the present synthesis involve a ring-closing metathesis reaction for the construction of the seven- and eight-membered rings, and reductive etherification for the tetrahydropyrans. Unification of the two fragments through acetal formation, followed by regioselective cleavage of the acetal using TMSCN/TMSOTf in the presence of 2,6-di-tert-butyl-4-methylpyridine, afforded the α-cyano ether, of which the nitrile group was manipulated to give the precursors of the ring-closing reactions.

Full text of DOI:10.1016/S0040-4039(03)01862-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7315–7319
Convergent synthesis of trans-fused 6/n/6/6 (n=7, 8) tetracyclic
ether system via a-cyano ethers
Tohru Oishi,* Koji Watanabe and Michio Murata
Department of Chemistry, Graduate School of Science, Osaka University, Toyonaka, Osaka 560-0043, Japan
Received 15 July 2003; revised 29 July 2003; accepted 31 July 2003
Abstract—A convergent method for synthesizing 6/n/6/6 (n=7, 8) tetracyclic ether system via two-rings construction of the central
n/6 ring system was developed. The key steps of the present synthesis involve a ring-closing metathesis reaction for the
construction of the seven- and eight-membered rings, and reductive etherification for the tetrahydropyrans. Unification of the two
fragments through acetal formation, followed by regioselective cleavage of the acetal using TMSCN/TMSOTf in the presence of
2,6-di-tert-butyl-4-methylpyridine, afforded the a-cyano ether, of which the nitrile group was manipulated to give the precursors
of the ring-closing reactions.
© 2003 Elsevier Ltd. All rights reserved.
Because of their unique structures and potent biological
activities,1 ladder polyether toxins of marine origin
have attracted much attention among synthetic
chemists. In 1987, yessotoxin (1) was isolated from the
digestive glands of the scallop Patinopecten yessoensis
in association with diarrhatic shellfish poisoning
(DSP).2 Recent reports on its apoptosis-inducing
activities3 and unique arched molecular structure have
prompted us to synthesize 1 and its analogs.4 Although
significant advancements in the total syntheses of
polyether natural products have been made in the last
decade,5 practical and reliable methods based on the
convergent strategy via two-rings construction6 are still
required for the efficient synthesis of 1, because the
yields and stereoselectivities of the precedent coupling
reactions (e.g. alkylative-coupling6a–d) or subsequent
ring-forming reactions (e.g. radical cyclization6h–k and
intramolecular allylation6l) are highly depending on the
substrates. It is worth noting that Nakata7a,b and
Mori7c,d have reported on alternative approaches that
involve the convergent and iterative strategies. Herein,
we describe a convergent method for synthesizing the
6/7/6/6 and 6/8/6/6 tetracyclic ether systems (2a and
2b), as a model case for the construction of the CDEF-
and FGHI-ring frameworks of 1 via a-cyano ether 3
through the convergent assemblage of diol 4 and alde-
hyde 5 (Scheme 1).
As shown in Scheme 2, the synthesis of the diol 4 and
the aldehyde 5 commenced with a common intermedi-
ate 6,8 which was prepared from 2-deoxy-
D-ribose. For
the diol 4, p-methoxybenzylidene acetal 6 was con-
verted to the corresponding di-tert-butylsilylene 7, then
subjected to rhodium catalyzed hydroboration9 using
catecholborane to give the diol. Alternatively, for the
aldehyde 5, ozonolysis of 6 followed by benzylation of
the resulting diol gave 8. Regioselective opening of the
p-methoxybenzylidene acetal of 8 with DIBAL-H gave
the primary alcohol, which was converted to nitrile 9
through mesylation followed by treatment with NaCN.
Reduction of the nitrile 9 with DIBAL-H afforded the
aldehyde 5 in 83% yield.
Keywords: convergent synthesis; polyether; a-cyano ether; acetal
cleavage; ring-closing metathesis; reductive etherification; yessotoxin.
* Corresponding author. Tel.: +81-6-6850-5775; fax: +81-6-6850-5785;
e-mail: oishi@ch.wani.osaka-u.ac.jp
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01862-8

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T. Oishi et al. / Tetrahedron Letters 44 (2003) 7315–7319
11
TMSCN in the presence of TiCl4 was unsuccessful
due to the formation of a complex mixture with con-
comitant removal of the MPM group. Alternatively,
after converting the MPM to the NAP (2-naphthyl-
methyl) group,5b,12 regioselective cleavage6i–k of the
acetal 12 was successfully achieved using TMSCN
and TMSOTf in the presence of 2,6-di-tert-butyl-4-
,
methylpyridine and MS 4 A in CH2Cl2 to afford
nitrile 3b in 87% yield without the removal of the
NAP group. Subsequently, primary alcohol 3b was
converted to terminal olefin 13 via 2-nitrobenzense-
lenide through the elimination of the selenoxide.13
Attempts to obtain ketone 15 directly from 13 using
allylmagnesium bromide or allylzinc chloride14 were
unsuccessful due to the formation of diallylamine 14,
and, therefore, stepwise reaction was examined via
aldehyde 16 (Scheme 4). Nitrile 13 was reduced with
the careful gradual addition of DIBAL-H at −78°C
(carefully monitored by TLC) to afford 16 in 63%
yield, which was treated with allylmagnesium bromide
at −50°C to give alcohol 17 as an inseparable mixture
of four diastereomers in 81% yield. Ring-closing
metathesis reaction of diene 17 using Grubbs
catalyst15 proceeded smoothly to give eight-membered
ring alcohol 18, which was further oxidized to enones
19 and 20 as an inseparable mixture (19:20=1.3:1).
Undesirable epimer 20 was successfully isomerized to
19 by treating with DBU in toluene at 80°C for 15 h.
Finally, construction of the tetrahydropyran ring was
achieved through the removal of the NAP group in
72% yield, followed by the reductive etherification of
the resulting hemiacetal to give 6/8/6/6 tetracyclic
ether 2b as a single isomer in 68% yield.16
Scheme 1. Synthesis plan.
In an analogous sequence, 6/7/6/6 tetracyclic ether 2a
was synthesized as shown in Scheme 5. Treatment of
aldehyde 16 with vinyllithium, generated from tetra-
vinylstannane and methyllithium, followed by ring-
closing metathesis reaction of the resulting diene
using Grubbs catalyst15 gave 21 in 20% yield along
with 22 as an inseparable mixture of three
diastereomers in 44% yield. Dess–Martin oxidation of
21 gave enone 23, whose stereochemistry was unam-
biguously determined using NOE experiments.
Removal of the NAP group of 23 yielded an equi-
librium mixture of the corresponding hydroxy ketone
and hemiacetal in a 1.3:1 ratio, which were subjected
to reductive etherification using triethylsilane and
TMSOTf to give 2a as a single isomer.16 On the
other hand, oxidation of 22 gave an inseparable mix-
ture of enones 24 and 23 with a ratio of 4.4:1.
Although isomerization of 24 using DBU or imida-
zole afforded the b,g-unsaturated enone 25 in low
yield (ꢀ40%) as compared to the eight-membered
ring system, conversion to the desired isomer was
achieved through the 1,4-reduction of the enones
using NaBH4/CoCl2,17 followed by treatment with
DBU to yield the desired ketone 26 (7.7:1). Successive
removal of the NAP group and reductive etherifica-
tion gave saturated 6/7/6/6 tetracyclic system 27 in
70% yield.
Scheme 2. Reagents and conditions: (a) p-TsOH, H2O,
MeOH, rt, 30 min; (b) t-Bu2Si(OTf)2, 2,6-lutidine, DMF,
0°C, 30 min, 97% (two steps); (c) catecholborane,
Rh(PPh3)3Cl, THF, rt, 14 h, then 30% H2O2, NaHCO3
(aq.), 66%; (d) O3, CH2Cl2, MeOH, −78°C, then, NaBH4,
96%; (e) BnBr, NaH, THF, DMF, rt, 24 h, 96%; (f)
DIBAL-H, CH2Cl2, −78 to −20°C, 20 h, 90%; (g) MsCl,
Et3N, CH2Cl2, 0°C to rt; (h) NaCN, DMF, 50°C, 24 h,
84% (two steps); (i) DIBAL-H, CH2Cl2, −78°C, 83%.
The synthesis of 6/8/6/6 tetracyclic ether 2b is shown
in Schemes 3 and 4. Condensation of 5 using 2 equiv.
of
4 was successfully achieved by treating with
10
Sc(OTf)3 in benzene to give seven-membered ring
acetal 10 in 84% yield as a mixture of diastereomers
(1.3:1) with respect to the stereogenic center on the
acetal carbon.5a,b,6j Attempts to obtain nitrile 3a by
means of regioselective opening of acetal 10 using

T. Oishi et al. / Tetrahedron Letters 44 (2003) 7315–7319
7317
Scheme 3. Reagents and conditions: (a) Sc(OTf)3, benzene, 1.5 h, 84% (11: 11%); (b) DDQ, NaHPO3 (aq.), CH2Cl2; (c)
2-naphthylmethyl bromide, NaH, TBAI, THF, DMF, 82% (two steps); (d) TMSCN, TMSOTf, 2,6-di-tert-butyl-4-methylpyridine,
,
MS 4 A, CH2Cl2, rt, 36 h, then, K2CO3, MeOH, 87%; (e) 2-NO2C6H4SeCN; Bu3P, THF; (f) 30%H2O2, NaHCO3 (aq.), THF,
40°C, 69% (two steps).
Scheme 4. Reagents and conditions: (a) DIBAL-H, −78°C, CH2Cl2, 63%; (b) CH2ꢀCHCH2MgBr, THF, −50°C, 35 min, 81%; (c)
(PCy3)2Cl2RuꢀCHPh, CH2Cl2, 40°C, 93%; (d) Dess–Martin periodinane, CH2Cl2, quant.; (e) DBU, toluene, 80°C, 15 h, 71%; (f)
DDQ, CH2Cl2, H2O, 72%; (g) Et3SiH, BF3·Et2O, CH2Cl2, −45°C, 68%.
In conclusion, convergent synthesis of the 6/n/6/6
(n=7, 8) ring system has been achieved via pivotal
a-cyano ethers through the construction of the central
n/6 ring system based on the ring-closing metathesis
and reductive etherification with control of the newly
formed stereogenic centers. The present method
would be useful for synthesizing ladder polyether nat-
ural products, and further studies directed towards
the total synthesis of yessotoxin will be reported in
due course.

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T. Oishi et al. / Tetrahedron Letters 44 (2003) 7315–7319
Scheme 5. Reagents and conditions: (a) (CH2ꢀCH)4Sn, MeLi, THF, −78°C, 81%; (b) (PCy3)2Cl2RuꢀCHPh, CH2Cl2, 40°C, 24 h,
20% (for 21), 44% (for 22); (c) Dess–Martin periodinane, CH2Cl2, quant.; (d) DDQ, CH2Cl2, H2O, 90%; (e) Et3SiH, TMSOTf,
CH2Cl2, −50°C, 30 min, 77%; (f) Dess–Martin periodinane, CH2Cl2, quant. (23:24=1:4.4); (g) DBU, toluene, 80°C, 15 h, ꢀ40%
(for 25); (h) NaBH4, CoCl2, MeOH, 0°C, 15 h (ketone 40%, alcohol 38%); (i) Dess–Martin periodinane, CH2Cl2, 85%; (j) DBU,
toluene, reflux, 12 h, 74%; (k) DDQ, CH2Cl2, H2O, 83%; (l) Et3SiH, TMSOTf, CH2Cl2, −50°C, 30 min, 70%.
Acknowledgements
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This research was supported by a Grant-in-Aid for
Scientific Research on Priority Areas (A) ‘Exploitation
of Multi-Element Cyclic Molecules’ from the Ministry
of Education, Culture, Sports, Science and Technology,
Japan.
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