Synthesis of JKLM ring fragment of ciguatoxin via acetylene-cobalt strategy

Article abstract of DOI:10.1055/s-2003-37533

A stereoselective synthesis of the JKLM ring fragment has been achieved through a coupling between two segments via heteroconjugate addition, seven-membered ether ring formation mediated by an acetylene cobalt complex and spiroketalization reaction.

Full text of DOI:10.1055/s-2003-37533

LETTER
547
Synthesis of JKLM Ring Fragment of Ciguatoxin via Acetylene-Cobalt
Strategy
S
ynthesis of JK
a
LM
R
ing
F
k
ragment of
C
a
iguatoxin yuki Baba, Minoru Isobe*
Laboratory of Organic Chemistry, School of Bioagricultural Sciences, Nagoya University Chikusa, Nagoya 464-8601, Japan
Fax +81(52)7894111; E-mail: isobem@agr.nagoya-u.ac.jp
Received 25 December 2003
pound A provides B as a synthetic equivalent. The seven-
membered ring in B would be prepared via acetylene co-
balt complex C. Opening of the seven-membered ring K
in C gives compound D, which further leads us to the 2
segments E and F to be coupled between the C46 and C47
bond on the basis of a heteroconjugate addition.7
Abstract: A stereoselective synthesis of the JKLM ring fragment
has been achieved through a coupling between two segments via
heteroconjugate addition, seven-membered ether ring formation
mediated by an acetylene cobalt complex and spiroketalization re-
action.
Key words: acetylene cobalt complex, reductive decomplexation,
heteroconjugate addition, medium sized ring, ciguatoxin
Synthesis of the vinylsulfone E began with methyl-α-D-
glucopyranoside derivative (Scheme 2). Thus, hydroxyl
group at the C2 position in the acetonide 1 was selectively
protected by pivaloyl group.8 Remaining free hydroxyl
group was removed under modified Barton conditions9 to
afford compound 2. The protective groups in 2 were ma-
nipulated to provide 3, which was transformed to lacton 4
via acetolysis, hydrolysis and oxidation of the anomeric
position. Addition of allylmagnesium bromide to lactone
4, followed by Kishi’s silane reduction,10 provided hydro-
pyran system 5 as an exclusive diastereomer. Removal of
the pivaloyl group from 5 led to a diol which was convert-
ed to 6 through disilylation and selective removal of the
silyl group attached to the primary hydroxyl group.11 Ox-
idation of the primary alcohol followed by dibromo-olefi-
nation of the resulting aldehyde gave the vinyl
dibromide12 which was converted to the thiophenylacety-
lene 7 by further treatment with n-BuLi and PhSSO2Ph.
Hydrosilylation of thiophenylacetylene of 7 in the pres-
ence of catalytic amount of cobalt complex13 afforded
corresponding vinylsilane with extremely high regiose-
lectivity. Finally, removal of the acetyl group, followed
Ciguatoxin (CTX) is known as a principal toxin of
ciguatera food poisoning caused by carnivorous fishes in
the tropical and subtropical sea areas.1 Several synthetic
groups have been studying the total synthesis of CTX
(Figure 1).2,3 We also have endeavored to develop effec-
tive methodologies toward the synthesis of ciguatoxin.
We have already achieved the syntheses of ABC rings
with the side chain,4 BCDE rings5 and E′FGH′ rings6 us-
ing acetylene cobalt complex strategy. With regard to
right part of ciguatoxin, previously we reported a model
study of stereoselective synthesis of the H′IJK ring frag-
ment.7 In this communication, we report the synthesis of
the JKLM ring fragment as the right end of ciguatoxin.
The JKLM-ring fragment A, representing C39–C55 por-
tion of ciguatoxin, consists of trans-fused tricyclic 6/7/6-
membered ether ring and 6/5 spiroketal system. The ret-
rosynthetic analysis for compound A is illustrated in
Scheme 1. Opening of the terminal spiroketal in com-
OR
39
H
H
H
H
H
O
39
H
55
OH
H
O
O
K
O
J
O
H
M
H
L
I
RO
O
J
O
HO
K
O
OR
O
55
H
O
H
H
L
O
M
H
H
A
H
G
H
OH
H
H
H
O
H
O
H
H
H
H
H
H
O
F
O
E
D
C
B
O
A
ciguatoxin (CTX)
H
O
O
HO
H
H
OH
OH
Figure 1
Synlett 2003, No. 4, Print: 12 03 2003.
Art Id.1437-2096,E;2003,0,04,0547,0551,ftx,en;U14802ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

548
T. Baba, M. Isobe
LETTER
SO2Ph
OH
Me
OR
39
H
H
H
O
H
OH
55
O
O
O
J
O
K
OR
H
O
M
L
RO
O
H
OR
O
H
H
O
H
Me
Me
Me
Me
OR
RO
A
H
B
SO2Ph
SO2Ph
Co2(CO)6
O
Co2(CO)6
Me
H
H
H
H
46
O
X
OR
OR
H
O
K
OR
47
OH
O
H
Me
RO
H
H
OMe Me
Me
OR
RO
H
C
D
SiEt3
SO2Ph
46
H
H
H
Me
X
OR
47
O
OR
39
RO
+
55
OH
OMe Me
H
F
E
Scheme 1 Retrosynthetic Analysis of JKLM Segment of CTX
by treatment with m-CPBA in the presence of sodium hy- after the removal of TBS group of 10 to afford the diol 11.
drogen phosphate provided the vinyl sulfone 8.14
Opening of the pyranose ring of 11 with 1,3-propanedithi-
ol under strongly acidic condition provided open-chain
triol compound, which was subsequently protected with
TBS and isopropylidene group to give 12. Coupling reac-
tion of the lithio derivative of dithiane 12 with glycidyl-
methoxybenzyl ether uneventfully proceeded under mild
condition15 and afforded an alcohol that was protected
with benzyl group together with the primary alcohol after
desilylation. Subsequent acidic hydrolysis of the ace-
tonide group afforded 13. Oxidative cleavage of the 1,2-
diol of 13 by Pb(OAc)4 provided corresponding aldehyde.
The aldehyde was treated with lithium TMS acetylide and
The construction of the other requisite subsegment F (in
Scheme 1) is shown in Scheme 3. Thus, tri-O-acetyl-D-
gulcal was converted to the enone 9 by 4-step sequence
(O-glycosidation, deacetylation, silylation and oxidation),
which could be used in a large scale operation. 1,4-Addi-
tion of lithiumdimethyl cuprate to α,β-unsaturated carbo-
nyl of 9, followed by treatment with MeI in the presence
of N,N-dimethylacetamide as a co-solvent provided 10 as
an exclusive diastereomer. The carbonyl group was
stereoselectively reduced to the alcohol by NaBH(OAc)3
H
H
H
H
H
H
H
H
H
H
MeO
HO
O
MeO
PivO
O
MeO
BnO
O
O
O
O
a
c
O
OPiv
OPiv
b
OPiv
OPiv
d
O
O
BnO
H
OH
H
H
H
H
H
1
2
3
4
SiEi3
SPh
H
H
H
H
H
H
H
H
H
O
O
O
O
SO2Ph
OPiv
OH
e
g
f
BnO
OH
BnO
OPiv
Co2(CO)6
BnO
OAc
BnO
OTBS
H
H
H
H
H
H
5
6
7
8 ( = E )
OH
Scheme 2 Reagents and conditions: a) i) Piv-Cl, Py, CH2Cl2, 68%; ii) thiophosgene, imidazole, CHCl3, toluene, 90 °C; iii) AIBN, NaH2PO2,
2-methoxy-ethanol, reflux, 87% in 2 steps. b) i) NaOMe, MeOH, 80%; ii) KOH, BnCl; iii) Amberlyst 15E®, MeOH, 86% in 2 steps; iv) Piv-Cl,
Py, CH2Cl2. c) i) H2SO4, Ac2O, 96% in 2 steps; ii) HCl, DME, H2O, 63%; iii) Ac2O, DMSO, 98%. d) i) CH2=CHCH2MgBr, THF, –78 °C; ii)
Et3SiH, BF3·OEt2, CH3CN, –10 °C, 66% in 2 steps. e) i) NaOMe, MeOH, 93%; ii) TBS-Cl, imidazole, DMF; iii) CSA, MeOH, 88% in 2 steps.
f) i) (ClCO)2, DMSO, CH2Cl2; ii) CBr4, PPh3, CH2Cl2, 91% in 2 steps; iii) n-BuLi, THF, –78 °C to 0 °C, then PhSSO2Ph; iv) TBAF, THF; v)
Ac2O, Py, 77% in 3 steps. g) i) Et3SiH, biscobalthexacarbonyl-2-methyl-but-3-yn-2-ol (cat.), ClCH2CH2Cl; ii) K2CO3, MeOH; iii) m-CPBA,
Na2HPO4, CH2Cl2, 85% in 3 steps.
Synlett 2003, No. 4, 547–551 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of JKLM Ring Fragment of Ciguatoxin
549
H
H
H
H
H
H
H
OPri
Me
H
O
OPri
Me
O
O
O
OPri
AcO
AcO
a
b
c
HO
TBSO
TBSO
HO
O
O
OAc
Me
10 Me
9
11
TBSO
S
OH
OBn
d
e
f
S
S
BnO
OPMB
S
O
O
O
OPMB
OH
12
13
OTBS
OBn
OBn
S
S
g
OPMB
OPMB
OMe
OMe
14
15 ( = F )
Scheme 3 Reagents and conditions: a) i) i-PrOH, BF3⋅OEt2, CH2Cl2; ii) Et3N, MeOH, H2O, 84% in 2 steps; iii) TBS-Cl, imidazole, DMF; iv)
Ac2O, DMSO, 97% in 2 steps. b) CuI, MeLi, Et2O, 0 °C, then MeI, DMA, 92%. c) i) TBAF, THF, 82%; ii) NaBH(OAc)3, CH3CN, AcOH, 93%.
d) i) 1,3-propanedithiol, HCl, CHCl3; ii) TBS-Cl, Et3N, DMAP, CH2Cl2, 89% in 2 steps; iii) 2,2-dimethoxypropane, PPTS, CH2Cl2, quant. e)
i) (2S)-glycidylmethoxybenzyl ether, THF, HMPA, 96%; ii) TBAF, THF; iii) NaH, BnBr, DMF; iv) 80% AcOH, 70% in 3 steps. f) i) Pb(OAc)4,
CH2Cl2, 99%; ii) n-BuLi, TMS-acetylene, THF, then MeI; iii) TBAF, THF, 86% in 2 steps. g) i) NCS, AgNO3, 2,4,6-collidine, CH3CN, H2O;
ii) NaBH4, MeOH; iii) TBSOTf, Py, CH3CN, 54% in 3 steps.
SO2Ph
OTBS
H
H
H
H
a
b
O
OBn
46
8
OPMB
BnO
OH
OMe
16
SO2Ph
SO2Ph
Co2(CO)6
H
H
H
H
H
OAc
Co2(CO)6
H
O
OBn
O
K
OPMB
O
c
BnO
OH
H
OH
H
BnO
OMe
H
OBn
OAc
17
18
syn
SO2Ph
SO2Ph
H
H
H
H
d
46
46
O
H
O
H
+
O
O
H
OH
H
OH
H
H
BnO
BnO
OBn
OBn
OAc
OAc
19
20
Scheme 4 Reagents and conditions: a) i) 15, n-BuLi, THF; ii) TBAF, THF, 87% in 2 steps. b) i) ethylvinylether, PPTS, CH2Cl2, quant.; ii)
TBAF, THF, 88%; iii) Ac2O, DMAP, Py; iv) CSA, MeOH, quant. in 2 steps; v) Co2(CO)8, CH2Cl2. c) BF3·OEt2, CH2Cl2, 93% in 2 steps. d)
bis-trimethylsilylacetylene, Bu3SnH, toluene, 87% (19: 68%, 20: 19%).
Synlett 2003, No. 4, 547–551 ISSN 0936-5214 © Thieme Stuttgart · New York

550
T. Baba, M. Isobe
LETTER
MeI, and then desilylated with TBAF to give the acetylene Bu3SnH under heating for 1 hour at 60 °C in toluene17 in
14. Finally, removal of the dithiane group was performed the presence of bis-trimethylsilylacetylene18 to afford the
by brief treatment of 14 with N-chlorosuccinimide and desired endocyclic olefin 19 and C46-epimer 20 as chro-
AgNO3 in wet acetonitrile containing 2,4,6-trimethylpyri- matographically separable products.
dine. The unmasked ketone was reduced to an alcohol,
which was protected by TBS group to afford the targeted
compound 15.16
NOESY
The coupling between 8 and 15 and subsequent K ring cy-
clization are depicted in Scheme 4. Thus, generation of
the lithium acetylide of 15 with n-BuLi, followed by addi-
tion of 8, gave a mixture of diastereomeric isomers of 16
(3.6:1 ratio with regard to newly formed C46 asymmetric
center). Our previous report of the studies on controlling
the stereochemistry of the methyl group in ring K7a has
shown that the heteroconjugate addition reaction of lithi-
um acetylides and vinyl sulfone with non-protected β-hy-
droxyl group proceed with extremely high
stereoselectivity. The heteroconjugate addition in the
present study, however, keeps agreeable stereoselectivity
(3.6:1), so we decided to push forward the work of synthe-
sis. TBS group of 16 was exchanged to acetyl group under
usual conditions, and then treatment with Co2(CO)8 in
dichloromethane provided the acetylene cobalt complex
17. Upon treatment of 17 with boron trifluoride etherate,
the K ring cyclization took place to afford the bicyclic
compound 18 having syn stereochemistry. Reductive de-
complexation of 18 was conducted with 10 equivalents of
H
45
O
Me
OH
H
41
H
48
O
O
BnO
H
O
OBn
42
44
O
51
53
49
H
H
H
50
Me
Me
H
H
H
26
Figure 2
The final stage of the synthesis of the JKLM ring fragment
is illustrated in Scheme 5. Removal of the acetyl group in
19, followed by selective protection of the primary alco-
hol by TBS group and oxidation with IBX,19 furnished ke-
tone 21. The terminal olefin in 21 was oxidized to give the
methyl ketone 22. The stereoselective dihydroxylation of
the endocyclic olefin in 22 was achieved by Sharpless
reagent20 to afford 23 and 24 as an equilibrium mixture.
Desilylation and spiroketalization were conducted with
Scheme 5 Reagents and conditions: a) i) NaOMe, MeOH; ii) TBSCl, Et3N, DMAP, CH2CH2, 95% in 2 steps; iii) IBX, DMSO, 97%. b) PdCl2,
CuCl, DMF, H2O, O2, 85%. c) AD-mix-β, CH3SO2NH2, t-BuOH, H2O. d) HF⋅Py, CH3CN, 72% in 2 steps. e) Na·Hg, Na2HPO4, MeOH, 82%.
Synlett 2003, No. 4, 547–551 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of JKLM Ring Fragment of Ciguatoxin
551
(13) (a) Isobe, M.; Nishizawa, R.; Nishikawa, T.; Yoza, K.
HF⋅pyridine in acetonitrile to afford the tetracyclic com-
pound 25 as a major product. Finally, reduction with sodi-
um-amalgam in methanol gave desulfonylation product
26.21 The stereochemistry of 26 was confirmed from the
Tetrahedron Lett. 1999, 40, 6927. (b) Jiang, Y.; Isobe, M.
Tetrahedron 1996, 52, 2877.
(14) Physical data for 8. 1H NMR (CDCl3, 300 MHz) d 0.58–0.88
[15 H, m, -Si(CH2CH3)3], 1.47 (1 H, q, J = 11.5 Hz, H-43a),
2.16 (1 H, m, allylic), 2.55 (1 H, m, allylic), 2.73 (1 H, dt,
J = 12.0 Hz, 4.5 Hz, H-43b), 3.01 (1 H, d, J = 9.0 Hz, -OH),
3.11–3.27 (2 H, m, H-41, 42), 3.34 (1 H, m, H-44), 4.45 (1
H, d, J = 11.5 Hz, -OCH2Ph), 4.63 (1 H, d, J = 11.5 Hz,
-OCH2Ph), 4.68 (1 H, ddd, J = 11.5 Hz, 9.5 Hz, 4.5 Hz, H-
44), 4.76 (1 H, t, J = 9.0 Hz, H-45), 4.97–5.05 (2 H, m,
olefinic), 5.68–5.83 (1 H, m, olefinic), 6.40 (1 H, d, J = 9.0
Hz, H-46), 7.26–7.40 (5 H, m, aromatic), 7.48–7.63 (3 H, m,
aromatic), 7.83–7.90 (2 H, m, aromatic).
NOESY experiments and the couplong constants (J44,45
9.0Hz, J48,49 = 9.5Hz) as shown in Figure 2.
=
We have achieved an efficient synthesis of the JKLM ring
fragment based on the convergent strategy. Further stud-
ies toward the synthesis of the right part of CTX along this
line are now in progress.
Acknowledgment
(15) Smith, A. B.; Condon, S. M.; McCauley, J. A.; Leazer, J. L.
Jr.; Leahy, J. W.; Maleczka, R. E. Jr. J. Am. Chem. Soc.
1997, 119, 947.
This work was supported by a grant-in-aid from the Ministry of
Education, Science and Technology. Dr. B. Kirshbaum and Dr.
G.-B. Huang contributed to this study in earlier stages.
(16) Physical data for 15. 1H NMR (CDCl3, 300M Hz) d 0.00–
0.08 [6 H, m, -Si(CH3)2t-Bu], 0.86–1.03 [15 H, m, -
Si(CH3)2t-Bu, CH3-59, CH3-60], 1.62–1.99 (4 H, m, H-50,
51, 53a, 53b), 2.36–2.45 (1 H, m, H-47), 3.32–3.40 (3 H, m,
-OCH3), 3.48–4.06 (5 H, m, H-49, 52, 54, 55a, 55b), 3.83 (3
H, s, -OC6H4OCH3), 4.49–4.76 (4 H, m, -OCH2Ar), 6.90 (2
H, br d, J = 8.0 Hz, aromatic), 7.27–7.39 (7 H, m, aromatic).
(17) Hosokawa, S.; Isobe, M. Tetrahedron Lett. 1998, 39, 2609.
(18) Bis(trimethylsilyl)acetylene was added to prevent
isomerization of the terminal olefin to the inner olefin. For
the detail of bis(trimethylsilyl)-acetylene effect in the
reductive decomplexation, see: Kira, K.; Tanda, H.;
Hamajima, A.; Baba, T.; Takai, S.; Isobe, M. Tetrahedron
2002, 58, 6485.
References
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(21) Physical data for 26. IR (KBr) 3447, 2926, 1717, 1636,
1456, 1355, 1077, 1025, 938, 739, 698, 419 cm–1. 1H NMR
(CDCl3, 400 MHz) d 1.01 (3 H, d, J = 6.5 Hz, CH3-60), 1.06
(3 H, d, J = 6.5 Hz, CH3-59), 1.12 (3 H, d, J = 7.5 Hz, CH3-
58), 1.40 (1 H, q, J = 11.5 Hz, H-43a), 1.48 (1 H, dq, J = 11.0
Hz, 6.5 Hz, H-51), 1.61 (1 H, ddq, J = 11.0 Hz, 10.0 Hz, 6.5
Hz, H-50), 2.00 (1 H, qdd, J = 7.5 Hz, 5.0 Hz, 3.5 Hz, H-46),
2.08 (1 H, dd, J = 14.0 Hz, 4.0 Hz, H-53a), 2.13 (1 H, dd,
J = 14.0 Hz, 6.5 Hz, H-53b), 2.45 (1 H, dd, J = 15.5 Hz, 9.0
Hz, H-40a), 2.54 (1 H, dt, J = 12.0 Hz, 4.5 Hz, H-43), 2.79
(1 H, dd, J = 15.5 Hz, 3.5 Hz, H-40b), 1.61 (1 H, ddq, J =
11.0 Hz, 10.0 Hz, 6.5 Hz, H-50), 2.95 (1 H, dd, J = 9.5 Hz,
5.0 Hz, H-45), 3.15 (1 H, ddd, J = 11.5 Hz, 9.0 Hz, 4.5 Hz,
H-42), 3.26 (1 H, t, J = 9.5 Hz, H-49), 3.59 (1 H, td, J = 9.0
Hz, 3.5 Hz, H-41), 3.62 (1 H, dd, J = 9.5 Hz, 2.0 Hz, H-48),
3.65 (1 H, dd, J = 3.5 Hz, 2.0 Hz, H-47), 3.69 (1 H, ddd, J =
11.5 Hz, 9.5 Hz, 4.5 Hz, H-44), 3.85 (1 H, dd, J = 9.5 Hz, 5.0
Hz, H-55a), 3.96 (1 H, dd, J = 9.5 Hz, 2.0 Hz, H-55b), 4.26
(1 H, dddd, J = 6.5 Hz, 5.0 Hz, 4.0 Hz, 2.0 Hz, H-54), 4.39
(2 H, d, J = 11.5 Hz, -OCH2Ph), 4.45 (2 H, d, J = 12.0 Hz,
-OCH2Ph), 4.47 (2 H, d, J = 12.0 Hz, -OCH2Ph), 4.63 (2 H,
d, J = 11.5 Hz, -OCH2Ph), 7.20–7,37 (10 H, m, aromatic).
ESI Q-TOF MS calcd for C35H47O8 595.327 [M + H]+, found
595.336.
(11) Nicolaou, K. C.; Nugiel, D. A.; Couladouros, E.; Hwang,
C.-K. Tetrahedron 1990, 46, 4517.
(12) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769.
Synlett 2003, No. 4, 547–551 ISSN 0936-5214 © Thieme Stuttgart · New York