Convergent synthesis of the A-F ring segment of yessotoxin and adriatoxin

Article abstract of DOI:10.1016/j.tetlet.2003.10.010

A convergent synthesis of the A-F ring segment of yessotoxin and adriatoxin was achieved via the intramolecular allylation of an α-chloroacetoxy ether and subsequent ring-closing metathesis.

Full text of DOI:10.1016/j.tetlet.2003.10.010

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8935–8938
Convergent synthesis of the A–F ring segment of yessotoxin
and adriatoxin
Isao Kadota,a,* Hirokazu Uenob and Yoshinori Yamamotob,*
aResearch Center for Sustainable Materials Engineering, Institute of Multidisciplinary Research for Advanced Materials,
Tohoku University, Sendai 980-8578, Japan
bDepartment of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
Received 21 August 2003; revised 20 September 2003; accepted 3 October 2003
Abstract—A convergent synthesis of the A–F ring segment of yessotoxin and adriatoxin was achieved via the intramolecular
allylation of an a-chloroacetoxy ether and subsequent ring-closing metathesis.
© 2003 Elsevier Ltd. All rights reserved.
Yessotoxin (1), a disulfated polycyclic ether, was iso-
lated from the digestive glands of scallops, Patinopecten
yessoensis, as one of the causative toxins of DSP (Diar-
rethic Shellfish Poisoning).1 Recently, a trisulfated
derivative, adriatoxin (2) was found from the DSP-
infested mussels, Mytilus galloprovincialis.2 Due to their
novel structural futures and biological activities, both
compounds have attracted the attention of synthetic
chemists.3 Recently, we developed an efficient method
for the convergent synthesis of polycyclic ethers via the
intramolecular allylation of an a-acetoxy ether and
subsequent ring-closing metathesis.4 As part of our
total synthetic studies of 1 and 2, we wish to report the
convergent synthesis of the common A–F ring segment
based on our methodology.
Scheme 1 shows the synthesis of the ABC ring segment.
Reduction of the known ester 33b with LiAlH4 followed
by selective TBS protection of the resulting primary
alcohol gave 4 in 74% yield. Treatment of 4 with ethyl
propiolate and 4-methylmorpholine followed by desilyl-
ation with TBAF afforded the acrylate 5 in 88% yield.
Oxidation of the alcohol 5 with SO3·py/DMSO/Et3N
gave 6 in 88% yield. The aldehyde 6 was then subjected
to the Nakata cyclization. Thus, treatment of 6 with
SmI2 in the presence of MeOH afforded 7 as the sole
product in 92% yield.5 Reduction of the ester of 7 with
LiAlH4 followed by TIPS protection of the resulting
diol gave the bis-silyl ether 8, which was treated with
H2/Pd(OH)2-C to give the diol 9 in 79% yield. Selective
tosylation of the primary alcohol of 9 gave 10 in 86%
Keywords: yessotoxin; adriatoxin; polycyclic ethers; convergent synthesis.
* Corresponding
authors.
Tel.:
+81-22-217-6581;
fax:
+81-22-217-6784;
e-mail:
ikadota@mail.cc.tohoku.ac.jp;
yoshi@
yamamoto1.chem.tohoku.ac.jp
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.010

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I. Kadota et al. / Tetrahedron Letters 44 (2003) 8935–8938
Scheme 1. Reagents and conditions: (a) (i) LiAlH4, ether, 0°C; (ii) TBSCl, imidazole, DMF, 0°C, 74% (two steps); (b) (i) ethyl
propiolate, 4-methylmorpholine, CH2Cl2, rt; (ii) TBAF, THF, rt, 88% (two steps); (c) SO3·py, DMSO, Et3N, CH2Cl2, 0°C, 88%;
(d) SmI2, MeOH, THF, 0°C, 92%; (e) (i) LiAlH4, ether, 0°C; (ii) TIPSOTf, 2,6-lutidine, CH2Cl2, 0°C to rt; (f) H2, Pd(OH)2-C,
EtOAc, rt, 79% (three steps); (g) TsCl, pyridine, CH2Cl2, rt, 86%; (h) (i) NaCN, DMSO, 50°C; (ii) TMS-imidazole, CH2Cl2, reflux,
72% (two steps); (i) (i) DIBAL-H, CH2Cl2, −78°C; (ii) Ph3PꢀC(Me)CO2Et, CH2Cl2, reflux, 72% (two steps); (j) (i) DIBAL-H,
i
,
CH2Cl2, −78°C, 95%; (ii) t-BuOOH, Ti(O Pr)4, (+)-DET, 4 A MS, CH2Cl2, −20°C, 90%; (k) (i) SO3·py, DMSO, Et3N, CH2Cl2,
0°C; (ii) Ph3P+CH3Br−, NaHMDS, THF, 0°C, 93% (two steps); (iii) TBAF, THF, rt, 92%; (l) PPTS, CH2Cl2, rt, 90%; (m) (i)
BnBr, KH, THF, reflux; (ii) (c-Hex)2BH, THF, 0°C, then 30% H2O2, 3N NaOH, 0°C; (n) (i) BnBr, KH, THF, reflux; (ii) CSA,
CH2Cl2–MeOH, 0°C to rt, 77% (four steps).
yield. Treatment of the tosylate 10 with NaCN followed
by TMS protection of the remaining secondary alcohol
gave the nitrile 11 in 72% yield. DIBAL-H reduction of
11 and subsequent Wittig reaction of the resulting
aldehyde gave the a,b-unsaturated ester 12 in 72%
yield. DIBAL-H reduction of the ester 12 followed by
Sharpless oxidation of the resulting allylic alcohol gave
the epoxide 13 as a single stereoisomer in 86% yield
(two steps). Oxidation of the alcohol 13 with SO3·py/
DMSO/Et3N, Wittig reaction of the resulting aldehyde,
and selective removal of the TMS group with TBAF
afforded the epoxy alcohol 14 in 86% yield (three
steps). Acid catalyzed cyclization of 14 was performed
using PPTS according to the Nicolaou’s procedure to
furnish the tricyclic compound 15 as the sole product in
90% yield.6 Benzyl protection of the secondary alcohol
15 with BnBr/KH followed by hydroboration gave the
primary alcohol 16. Benzyl protection of 16 followed by
selective removal of the primary TIPS group with CSA
afforded the ABC segment 17 in 77% yield.
bis-silyl derivative, which was treated with CSA in
MeOH to give the primary alcohol 21 in 75% yield.
Swern oxidation of 21 followed by Wittig reaction of
the resulting aldehyde afforded the olefin 22. Desilyla-
Scheme 2. Reagents and conditions: (a) (i) MPMCl, KH,
THF, reflux; (ii) (c-Hex)2BH, THF, 0°C, then 30% H2O2, 3N
NaOH, 0°C, 92% (two steps); (b) (i) MPMCl, KH, THF,
reflux; (ii) CSA, MeOH, rt, 82% (two steps); (c) (i) TBSOTf,
2,6-lutidine, CH2Cl2, 0°C to rt; (ii) CSA, MeOH, 75% (two
steps); (d) (COCl)2, DMSO, CH2Cl2 −78°C, then Et3N, −78°C
to rt; (ii) Ph3P+CH3Br−, NaHMDS, THF, 0°C; (e) TBAF,
THF, rt, 76% (three steps).
Preparation of the F ring segment is described in
Scheme 2. Transformation of the known alcohol 187 to
the corresponding MPM ether followed by hydrobora-
tion gave the alcohol 19 in 92% yield. MPM protection
of 19 and subsequent removal of the benzylidene acetal
with CSA afforded the diol 20 in 82% yield. Protection
of 20 with TBSOTf/2,6-lutidine gave the corresponding

I. Kadota et al. / Tetrahedron Letters 44 (2003) 8935–8938
8937
Scheme 3. Reagents and conditions: (a) (i) TEMPO, NaClO, KBr, NaHCO3, CH2Cl2–H2O, 0°C; (ii) NaClO2, 2-methyl-2-butene,
NaH2PO4, t-BuOH/THF/H2O, rt; (iii) 2,4,6-trichlorobenzoyl chloride, Et3N, THF, rt, then 23, DMAP, toluene, rt, 97% (three
steps); (b) TBAF, THF, rt, 86%; (c) 26, CSA, CH2Cl2, 0°C, 90%; (d) TMSI, HMDS, CH2Cl2, −15°C, 55% for 28, 27% for 29;
(e) TBAF, THF, rt, 100%; (f) TBDPSCl, imidazole, DMF, rt, 87%; (g) DIBAL-H, CH2Cl2, −78°C, then (CH2ClCO)2O, pyridine,
DMAP, −78°C, 89%; (h) BF3·OEt2, CH3CN–CH2Cl2 (20:1), −45 to 0°C, 65%; (i) 33, benzene, 70°C, 78%.
C-16 positions were unambiguously determined by the
large coupling constant, J15,16=9.0 Hz, and the NOE
observed between 16-H and 19-Me.
tion of 22 with TBAF furnished the F ring segment 23
in 76% yield.
Scheme 3 illustrates the coupling of the ABC and F
ring segments. TEMPO oxidation of 17 followed by
further oxidation of the resulting aldehyde with
NaClO2 gave the carboxylic acid, which was subjected
to the Yamaguchi esterification8 with the alcohol 23 to
give the ester 24 in 97% yield. Removal of the TIPS
group of 24 with TBAF gave the alcohol 25 in 86%
yield. Reaction of 25 with the g-methoxyallylstannane
26 in the presence of catalytic CSA afforded the mixed
acetal 27 in 90% yield. Treatment of 27 with TMSI/
HMDS promoted the acetal cleavage efficiently, as
expected.9 However, selective cleavage of the primary
MPM ether was accomplished due to an excess amount
of TMSI/HMDS, to give a mixture of the deprotected
primary alcohol 28 and its TMS ether 29 in 55% and
27% yields, respectively.10 The selective removal of the
TMS group of 29 was carried out upon treatment with
TBAF, affording 28 in a quantitative yield. Protection
of the primary alcohol 28 with TBDPSCl/imidazole
gave 30 in 87% yield. Modified Rychnovsky acetylation
including the partial reduction of 30 with DIBAL-H
followed by trapping of the resulting aluminum hemiac-
etal with chloroacetic anhydride gave the cyclization
precursor 31 in 89% yield.11,12 Intramolecular allylation
of 31 was carried out using BF3·OEt2 to afford 32 as a
single stereoisomer in 65% yield. Finally, the diene 32
was subjected to the ring-closing metathesis using the
Grubbs catalyst 3313 to furnish the A–F ring segment
34 in 78% yield.14 The stereochemistries at the C-15 and
In conclusion, we have achieved the convergent and
stereoselective synthesis of the common A–F ring seg-
ment of yessotoxin (1) and adriatoxin (2) via the
intramolecular allylation of an a-chloroacetoxy ether
and subsequent ring-closing metathesis. Further studies
toward the total syntheses of 1 and 2 are now in
progress in our laboratories.
Acknowledgements
This work was financially supported by the Grant-in-
Aid for Scientific Research from the Ministry of Educa-
tion, Culture, Sports, Science and Technology, Japan.
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