Mirror image synthesis left ends of ciguatoxin and gambiertoxin 4b

Article abstract of DOI:10.1021/jo980088n

Three compounds related to the AB fragments of ciguatoxin and gambiertoxin 4b and two diastereomers (at the C-2 position) of the ABC fragment of ciguatoxin have been synthesized in enantiomeric form. The stereochemistry of the C-2 position was introduced selectively from the corresponding pentose derivative. Construction of the A ring with its side chain was completed by Nicholas type cyclization of an acetylene bis(cobalthexacarbonyl) complex followed by reductive decomplexation.

Full text of DOI:10.1021/jo980088n

J . Org. Chem. 1999, 64, 37-48
37
Mir r or Im a ge Syn th esis of Left En d s of Cigu a toxin a n d
Ga m bier toxin 4b
Seijiro Hosokawa and Minoru Isobe*
Laboratory of Organic Chemistry, School of Bioagricultural Sciences, Nagoya University Chikusa,
Nagoya 464-8601, J apan
Received J anuary 20, 1998
Three compounds related to the AB fragments of ciguatoxin and gambiertoxin 4b and two
diastereomers (at the C-2 position) of the ABC fragment of ciguatoxin have been synthesized in
enantiomeric form. The stereochemistry of the C-2 position was introduced selectively from the
corresponding pentose derivative. Construction of the A ring with its side chain was completed by
Nicholas type cyclization of an acetylene bis(cobalthexacarbonyl) complex followed by reductive
decomplexation.
Ciguatoxin 1, a polyether compound obtained from
moray eel Gymmothorax javanicus as a principal toxin
causing ciguatera poisoning,1,2 originally produced by
Gambierdiscus toxicus, is one of the most challenging
targets for chemical synthesis.3 During the earlier course
of our synthetic studies directed toward ciguatoxin, we
have established a series of methodologies: (i) to intro-
duce a carbon chain as an alkynyl group onto the di- or
tetrahydropyranyl ring of sugars at the C-1 position in
R orientation,4 (ii) to epimerize the alkynyl group into
the â orientation via a bis(cobalthexacarbonyl) complex,5
(iii) to open the dihydropyranyl ring to acyclic compounds,
and (iv) to recyclize the oxepene ring with high stereo-
F igu r e 1.
selectivity.6 All of these reactions include cationic inter-
mediates that are stabilized either by σ-π conjugation
with a silicon atom or by the Nicholas effect with the
acetylene bis(cobalthexacarbonyl) complex.7 Recently, we
have developed an effective synthesis giving unsaturated
medium-size (7, 8, 9, and 10 membered) ether rings based
on the cyclization reaction with acetylene bis(cobalthexa-
carbonyl) complex followed by reductive decomplexation.8
Here we report the application of such methodology to
F igu r e 2.
the synthesis of left end fragments of 1 and 2 (Figure
1).3
Our retrosynthetic analysis of the target molecules 3 and
4 is shown in Scheme 1. The oxepene ring A in 6 would
be derived through reductive decomplexation8 from the
corresponding cyclic acetylene-cobalt complex, which
may be derived from trans-allylic cation 7. This can be
equilibrated from the cis-allylic cation 8 as an open chain
intermediate from 9. This disaccharide could be synthe-
sized by combination of the oxocarbenium intermediate
10 and the silylacetylene 11. Coupling between the
silylacetylene 11 and either of the epimeric oxocarbenium
ions 10 should give the 2R isomer; thus, the precursor is
L-arabinal (12), since stereochemistry of the C-2 position
corresponds to the C-4 position of pentoses. Similarly,
D-xylal 13 should provide the 2S isomer by the coupling9
with 11 in the presence of a Lewis acid.4 Finally,
acetylene 11 would be obtained from tri-O-acetyl-D-glucal
14.
Our first synthetic plan includes construction of both
diastereomers of A ring with its side chain (Figure 2).
* Corresponding author. Tel.: (52) 789-4109. Fax: (52) 789-4111.
E-mail: isobem@agr.nagoya-u.ac.jp.
(1) (a) Yasumoto, T.; Murata, M. Chem. Rev. 1993, 93, 1897. (b)
Scheuer, P. J . Tetrahedron 1994, 50, 3.
(2) (a) Murata, M.; Lebrand, A. M.; Ishibashi, Y.; Yasumoto, T. J .
Am. Chem. Soc. 1989, 111, 8929. (b) Idem. Ibid. 1990, 112, 4380. (c)
Recently, absolute configuration of ciguatoxin was determined to be
the enantiomer of 1 as described in Satake, M.; Morohashi, A.; Oguri,
H.; Oishi, T.; Hirama, M.; Harada, N.; Yasumoto, T. J . Am. Chem.
Soc. 1997, 119, 11325.
(3) Related synthetic studies on the AB fragment of ciguatoxin: (a)
Suzuki, T.; Sato, O.; Hirama, M.; Yamamoto, Y.; Murata, M.; Yasu-
moto, T. Tetrahedron Lett. 1991, 32, 4505. (b) Oguri, H.; Hishiyama,
S.; Oishi, T.; Hirama, M. Synlett 1995, 1252. (c) Oka, T.; Fujiwara, K.;
Murai, A. Tetrahedron 1998, 54, 21.
(4) (a) Ichikawa, Y.; Isobe, M.; Konobe, M.; Goto, T. Carbohydr. Res.
1987, 171, 193. (b) Tsukiyama, T.; Isobe, M. Tetrahedron Lett. 1992,
33, 7911.
(5) (a) Tanaka, S.; Tsukiyama, T.; Isobe, M. Tetrahedron Lett. 1993,
34, 5757. (b) Tanaka, S.; Isobe, M. Tetrahedron 1994, 50, 5633.
(6) (a) Tanaka, S.; Isobe, M. Tetrahedron Lett. 1994, 35, 7801. (b)
Tanaka, S., Tatsuta, T., Yamashita, O.; Isobe, M. Tetrahedron 1994,
50, 12883.
Synthesis of the (trimethylsilyl)acetylene 11 is shown
in Scheme 2. The starting material, tri-O-acetyl-D-glucal,
14 was converted into the known diol 15.10 Selective
(7) Nicholas, K. M. Acc. Chem. Res. 1987, 20, 207.
(8) (a) Isobe, M.; Yenjai, C.; Tanaka, S. Synlett 1994, 916. (b) Yenjai,
C.; Isobe, M. Tetrahedron 1998, 54, 2509.
(9) (a) Whistler, R. L. et al. Methods in Carbohydrate Chemistry I;
Academic Press: New York, 1962; pp 84, 184. (b) Bredenkamp, M. W.;
Holzapfel, C. W.; Toerien, F. Synth. Commun. 1992, 22, 2459.
10.1021/jo980088n CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/10/1998

38 J . Org. Chem., Vol. 64, No. 1, 1999
Hosokawa and Isobe
Sch em e 1
Sch em e 3
Sch em e 2
The synthesis of (2R,5S)-AB fragment 25 is shown in
Scheme 3. Coupling of the silylacetylene 11 with arabinal
dipivalate 12 afforded the disaccharide 20 with exclusive
regio- and stereoselectivity. The disaccharide 20 was
converted into the acetylene bis(cobalthexacarbonyl)
complex 21 which was treated with pivalic anhydride and
TfOH, followed by addition of MeOH to give the open
chain product 22.6 Selective deacetylation gave 23, which
was then subjected to cationic cyclization to provide the
endo-acetylene cobalt complex 24 as a single isomer.
Decomplexation8 of 24 by hydrogenation at 100 kg/cm2
in the presence of Wilkinson catalyst afforded the AB-
fragment 25. The stereochemistry of 25 was confirmed
by NMR studies; thus, 2 protons at δ 3.96 (H-10) and δ
4.75 (H-5) showed a cross-peak in its NOESY spectrum
and J 9,10 ) 8.4 Hz indicating 2R, 5S-stereochemistry.13,14
The synthesis of (2S,5S)-AB fragment 27 was also
achieved by employing the same strategy as above
(Scheme 4). Coupling between silylacetylene 11 and
D-xylal 13 led to the formation of the disaccharide 26 as
a single isomer in this transformation.
(12) Lewis, M. D.; Cha, J . K.; Kishi, Y. J . Am. Chem. Soc. 1982,
104, 4976.
(13) Hosokawa, S.; Isobe, M. Synlett 1995, 1179.
(14) Related to this route, we examined direct formation of A ring
from disaccharide as shown below. Unfortunately, however, this
transformation was unsuccessful and only exo-cobalt complex was
afforded.
protections of the primary and secondary hydroxy groups
of 15 as pivalate and ethoxy ethyl ether, respectively,
were followed by LAH reduction to afford alcohol 16.
Iodination of the primary hydroxy group11 and subse-
quent treatment with lithium acetylide followed by
deprotection of ethoxy ethyl group gave the silylacetylene
18. Reprotection of the C-4 hydroxyl group and reduction
of the C-1 acetal with triethylsilane12 afforded the (tri-
methylsilyl)acetylene 11.
(10) (a) Isobe, M.; Ichikawa, Y.; Bai, D.-L.; Goto, T. Tetrahedron Lett.
1985, 26, 5203. (b) Isobe, M.; Ichikawa, Y.; Funabashi, Y.; Mio, S.; Goto,
T. Tetrahedron 1986, 42, 2863.
(11) Classon, B.; Liu, Z.; Samuelsson, B. J . Org. Chem. 1988, 53,
6128.

Synthesis of Left Ends of Ciguatoxin and Gambiertoxin 4b
J . Org. Chem., Vol. 64, No. 1, 1999 39
Sch em e 4
The stereochemistry of 20 and 26 was determined from
the coupling constant and NOE studies of their acetylene
bis(cobalthexacarbonyl) complex 21 and 28, respectively
(Figure 3).15
F igu r e 3.
Stereochemical course of the C-glycosylation is ratio-
nalized to give the syn products as shown in Figure 4;
thus, three conformations (30, 31, and 33) of the cation
intermediate 29 were considered to be destined to either
syn or anti stereochemistry. On the basis of the cation
intermediate 29, the conformers 30 and 31, which would
afford the anti-isomer 32, have steric repulsion between
the ligands of cobalt complex and olefinic group. On the
other hand, in the conformer 33 the bulky cobalt com-
plex is outside of the side chain and has less steric
repulsion; thus, 33 is ready to cyclize to obtain the syn-
isomer 34.16
F igu r e 4.
(H-10) and δ 4.63 (H-5) showing a cross-peak in its
NOESY spectrum as well as H-10 coupling with H-9 (8.0
Hz) indicating 5S-stereochemistry.
Sch em e 5
We have also applied above methodology for the
synthesis of (5S)-AB fragment of gambiertoxin 4b 5. The
difference between 5 and 25 locates on the side chain, so
that it could be synthesized through endo-cobalt complex
methodology. The synthetic route to 5 is shown in Scheme
5. Coupling between the lithium acetylide of 35 and the
aldehyde 3617 under Yamaguchi’s procedure18 using BF3‚
Et2O and deprotection of the ethoxy ethyl group afforded
the diol 37. This acetylene 37 was converted into the
cobalt complex 38 which cyclized rapidly (0 °C, 20 min,
90%) to give endo-cobalt complex 39. Finally, decomplex-
ation accompanying dehalogenation with tri-n-butyltin
hydride19 yielded 5, (5S)-AB fragment of gambiertoxin
4b, as a single stereoisomer. The stereochemistry of 5 was
proved from NMR analysis of the two protons at δ 4.00
(15) On this 1,4-anti stereoinduction: Hosokawa, S.; Isobe, M.
Tetrahedron Lett. 1998, 39, 1917.
(16) On the cyclization to afford bicyclic ether with endo-acetylene
bis(cobalthexacarbonyl) complex; Isobe, M.; Hosokawa, S.; Kira, K.
Chem. Lett. 1996, 473.
(17) Soullez, D.; Ple, G.; Duhamel, L.; Duhamel, P. J . Chem. Soc.,
Chem. Commun. 1995, 563.
(18) Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391.
(19) Hosokawa, S.; Isobe, M. Tetrahedron Lett. 1998, 39, 2609.

40 J . Org. Chem., Vol. 64, No. 1, 1999
Hosokawa and Isobe
in the form of 48 by an additional two-carbon extension
at the C-9 to construct the C ring (illustrated as a
silylacetylenic compound of the pseudo-enantiomer of 56
or 57). Hydroxylation of the terminal olefin was achieved
by hydroboration to give the primary alcohol 49, which
was tosylated to provide 50. The benzyl protecting groups
of 50 were removed23 into the 2,3,4-triol 51 in high yield.
Cyclization of the C-ring was facilitated with t-BuOK to
afford the bicyclic compound 52. Transformation of 52
to (trimethylsilyl)acetylene 57 is shown in Scheme 7. The
F igu r e 5.
On the basis of these results, we began to synthesize
the ABC fragments of ciguatoxin to prove the absolute
stereochemistry of ciguatoxin by comparing NMR and
CD spectra of their p-bromobenzoate derivatives (Figure
5).3
Sch em e 7
We started the synthesis from methyl 2, 3, 4-tri-O-
benzyl-R-D-glucopyranoside 4420 as shown in Scheme 6.
Sch em e 6
two hydroxy groups were protected as TMS ethers using
TMSOTf, which gave the best result since these survived
even under the workup of DIBAL with 10% acetic acid
at 0 °C. The direct substitution of this iodide 53 into
(trimethylsilyl)acetylene 56 was unsuccessful; thus, we
took alternative route to synthesize 56. The iodine of 53
was replaced with cyanide to provide nitrile 54, which
was reduced with DIBAL to afford the aldehyde 55.
Aldehyde 55 was converted to (trimethylsilyl)acetylene
56 by Corey’s protocol,24 which was transformed into
diacetate 57. In this scheme, all steps were higher than
95% yield, and (trimethylsilyl)acetylene 57 was afforded
in high yield.
The completion of (2S,5S)-ABC fragment is shown in
Scheme 8. The (trimethylsilyl)acetylene 57 was coupled
with D-xylal 13 to afford 58 stereoselectively (20:1) at the
C-5 position. This acetylene 58 was converted into
acetylene bis(cobalthexacarbonyl) complex 62, and its
stereochemistry of the C-5 position was determined
(Figure 6). The left six-membered ring of 62 was opened
via oxonium cation intermediate to obtain dipivalate 59.
Acetyl groups were removed, and the resulting diol was
cyclized to give 60 as a single stereoisomer at the C-5
position. The cobalt complex 60 received the reductive
decomplexation under high-pressure hydrogen atmo-
sphere to afford tricyclic ether 61, which was solvolyzed
to give (2S,5S)-ABC fragment 40.25 (2R,5S)-ABC frag-
ment 41 was prepared from L-arabinal using the same
sequence as that shown for 40 (Schemes 8 and 9). The
This primary alcohol 44 was converted to the correspond-
ing iodide 45. Its methyl acetal moiety was transformed
to the lactone 46 by three-step sequence including
acetolysis,21 hydrolysis, and oxidation. Treatment of 46
with allylmagnesium bromide and then silyl hydride in
the presence of Lewis acid produced the â-allyl-glycoside
47.22 At this point, 47 is pseudo-symmetrical product,
thus the enantiomer of the BC ring could be synthesized
(20) (a) Liptak, A.; J odal, I.; Nanasi, P. Carbohydr. Res. 1975, 44,
1. (b) Hashimoto, H.; Asano, K.; Fujii, F.; Yoshimura, J . Carbohydr.
Res. 1982, 104, 87.
(21) (a) Isobe. M.; Nishikawa, T.; Pikul, S.; Goto, T. Tetrahedron
Lett. 1987, 28, 6485. (b) Angibeoud, P.; Utille, J .-P. J . Chem. Soc.
Parkin Trans. 1 1990, 5, 1490. (c) Zottola, M.; Rao, B. V.; Fraser-Reid,
B. J . Chem. Soc., Chem. Commun. 1991, 969.
(22) Lewis, M. D.; Cha, J . K.; Kishi, Y. J . Am. Chem. Soc. 1982,
104, 4976.
(23) (a) Fuji, K.; Ichikawa, K.; Node, M.; Fujita, E. J . Org. Chem.
1979, 44, 1661. (b) Daly, S. M.; Armstrong, R. W. Tetrahedron Lett.
1989, 30, 5713.
(24) (a) Corey, E. J .; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769.
(b) J iang, B.; Ma, P. Synth. Comm. 1995, 25, 3641.
(25) Hosokawa, S.; Isobe, M. Synlett 1996, 351.

Synthesis of Left Ends of Ciguatoxin and Gambiertoxin 4b
J . Org. Chem., Vol. 64, No. 1, 1999 41
Sch em e 8
configuration of the C-2 substituent. CD spectra of these
isomers showed an opposite Cotton effect to the result of
Hirama and Yasumoto3 whose compounds are enantio-
meric analogues of our compounds.
We have synthesized (2R,5S)- and (2S,5S)-AB frag-
ments of ciguatoxin and (5S)-gambiertoxin 4b and two
isomers of the ciguatoxin ABC fragment and compared
NMR spectra and CD spectra of these tris(p-bromoben-
zoate) derivatives. In these syntheses, we have estab-
lished an effective methodology for construction of the
oxepene A ring with its side chains. The key steps were
C-glycosidation of (trimethylsilyl)acetylene, ring opening
of pyranoside with acetylene bis(cobalthexacarbonyl)
complex, cationic cyclization (Nicholas reaction), and
reductive decomplexation under a high-pressure hydro-
gen atmosphere. With this methodology, synthetic study
toward ciguatoxin is in progress.
Exp er im en ta l Section
Gen er a l. All proton NMR spectra were measured in CDCl3
solvent, and chemical shifts are reported as δ values in parts
per million relative to tetramethylsilane (δ 0.00) or CDCl3 (δ
7.26) as internal standard. Data are reported as follows:
chemical shift (integrated intensity or assignment, multiplicity,
coupling constants in hertz, assignment). All carbon NMR
spectra were measured in CDCl3 solvent, and chemical shifts
are reported as δ values in parts per million relative to CDCl3
(δ 77.0) as internal standard. The symbols (*) represent
interchangeable assignments. Infrared spectra are reported
in wavenumber (cm-1). Analytical thin-layer chromatography
(TLC) was conducted on precoated TLC plates (layer thickness
0.25 mm); preparative layer chromatography (PLC) (layer
thickness 0.5 mm or 2.0 mm). Tetrahydrofuran (THF) was
distilled from potassium metal in the presence of potassium
benzophenone ketyl as an inductor. Dichloromethane was
dried over molecular sieves 4A (nacalai tesque) and used
without distillation. Pyridine and triethylamine were dried
over KOH pellets and used without distillation.
stereochemistry of 40 and 41 were proved by NMR
analysis of two protons at δ 3.30 (H-10) and δ 4.58 (H-5)
Di-O-p iva loyl-L-a r a bin a l (12). To a solution of di-O-
triacetyl-L-arabinal (1.03 g, 5.15 mmol) in 20 mL of MeOH was
added 20 µL of NaOMe (28% in MeOH). After stirring for 3 h
at room temperature, the reaction mixture was concentrated
in vacuo, and the resulting residue was dissolved into CH2Cl2
(20 mL). To this solution were added triethylamine (10 mL,
72.1 mmol), pivaloyl chloride (3.2 mL, 25.8 mmol), and DMAP
(20 mg). After stirring overnight at room temperature, the
reaction mixture was concentrated in vacuo. The resulting
residue was purified by silica gel column chromatography
(ether/hexane ) 1:2) gave dipivalate 12 as colorless oil (1.26
F igu r e 6.
showing cross-peak in its NOESY spectrum as well as
H-10 coupling with H-9 (9.0 Hz) indicating 5S-stereo-
chemistry.
g, 4.44 mmol, 86%). [R]26 -208.1 (c 0.81, CHCl3); 1H NMR
D
(270 MHz, CDCl3) δ 1.19 (9H, s, OPiv), 1.21 (9H, s, OPiv), 3.96
(1H, dd, J ) 10.5, 9.5 Hz, H-5a), 4.02 (1H, ddd, J ) 10.5, 4.5,
1.5 Hz, H-5b), 4.87 (1H, dd, J ) 6, 5 Hz, H-2), 5.15 (1H, dt, J
) 9.5, 4 Hz, H-4), 5.37 (1H, brt, J ) 5 Hz, H-3), 6.48 (1H, d, J
) 6 Hz, H-1); 13C NMR (67.8 MHz, CDCl3) δ 26.98, 27.04, 38.6,
38.7, 62.6, 62.7, 66.1, 97.6, 147.4, 177.1, 177.3; IR (KBr) 2977,
1733, 1644, 1481, 1281, 1264, 1158, 1086 cm-1. Anal. Calcd
for C15H24O5: C, 63.36; H, 8.51. Found: C, 63.37; H, 8.38.
Di-O-p iva loyl-D-xyla l (13). Di-O-pivaloyl-D-xylal 13 was
Sch em e 9
prepared as 12 in 86%. Mp 35-35.5 °C; [R]27 -250.1 (c 0.82,
D
CHCl3); 1H NMR (270 MHz, CDCl3) δ 1.19 (18H, s × 2, OPiv),
3.95 (1H, dd, J ) 12, 2 Hz, H-5a), 4.17 (1H, ddd, J ) 12, 3.5,
1.5 Hz, H-5b), 4.88-4.98 (3H, m, H-2, H-3 and H-4), 6.57 (1H,
d, J ) 5.5 Hz, H-1); 13C NMR (67.8 MHz, CDCl3) δ 26.8, 26.9,
38.4, 63.4, 63.5, 66.8, 97.4, 147.7, 177.1, 177.2; IR (KBr) 2974,
1734, 1645, 1481, 1275, 1251, 1148, 1095 cm-1; EI-MS m/z 284
(M+), 183 (M - OPiv+). Anal. Calcd for C15H24O5: C, 63.36; H,
8.51. Found: C, 63.30; H, 8.68.
(2S*,5S*,6R*)-5-(1′-Eth oxyeth oxy)-6-(h yd r oxym eth yl)-
2-(isop r op yloxy)-5,6-d ih yd r o-2H-p yr a n (16). To a solution
of the diol 15 (23.4 g, 124 mmol) in CH2Cl2 (400 mL) were
successively added pyridine (34 mL, 420 mmol) and PivCl (16
Next, we converted 40 and 41 into tris(p-bromobenzoyl)
ester 42 and 43 (Figure 5), respectively, and took the
NMR spectra and CD spectra of 42 and 43. These isomers
can be distinguished by 1H NMR spectra with the
difference in chemical shifts of p-bromobenzoyl groups
and C-2 protons, although triols 40 and 41 and their 1,2-
dipivalates did not show difference clearly. It means that
a bulky group attached to the C-11 oxygen affects the

42 J . Org. Chem., Vol. 64, No. 1, 1999
Hosokawa and Isobe
mL, 130 mmol) at 0 °C. After stirring at 0 °C for 30 min, the
reaction mixture was quenched with H2O and extracted with
ether (×3). The extracts were washed with aq 1.0 N HCl, H2O,
and brine, dried over Na2SO4, and concentrated under reduced
pressure. The crude oil was dissolved in 500 mL of CH2Cl2.
To this solution were added EVE (26 mL, 272 mmol) and PPTS
(500 mg, 1.99 mmol). After stirring at room temperature
overnight, the reaction was quenched with sat. NaHCO3 and
extracted with CH2Cl2 (×2). The extracts were dried over Na2-
SO4 and concentrated under reduced pressure. The resulting
crude oil was dissolved in 500 mL of Et2O. To this solution
was added LAH (5.05 g, 133 mmol) in small portions at 0 °C.
After stirring at 0 °C for 5 min, to the reaction mixture were
successively added AcOEt, sat. NH4Cl, and aq 3 N HCl and
then extracted with ether (×3). The extracts were washed with
brine, dried over Na2SO4, and concentrated under reduced
pressure. Purification of the residue with silica gel column
chromatography (ether/hexane ) 50:50) gave the colorless oil
5.06 (1H, m, H-1), 5.74 (1H, ddd, J ) 10, 3, 2 Hz, H-3*), 5.90
(1H, m, H-2*); IR (KBr) 3433 (br), 2967, 2901, 2180, 1383,
1314, 1250, 1031, 839 cm-1; MS(EI) m/z ) 268 (M+). Anal.
Calcd for C14H24O3Si: C, 61.90; H, 8.44. Found: C, 61.77; H,
8.61.
(2S*,5S*,6R*)-5-Acetoxy-6-(3-(tr im eth ylsilyl)-2-p r op y-
n yl)-2-(isop r op yloxy)-5,6-d ih yd r o-2H-p yr a n (19). To the
solution of allyl alcohol 18 (201 mg, 750 µmol) in 6.0 mL of
CH2Cl2 were successively added pyridine (600 µL, 7.42 mmol),
Ac2O (200 µL, 1.99 mmol), and DMAP (50 mg, 0.41 mmol).
After stirring for 3 h, to the reaction mixture was added H2O.
The resulting mixture was extracted with CH2Cl2 (×2). The
extracts were dried over Na2SO4 and concentrated under
reduced pressure. The crude residue was purified by silica gel
column chromatography (ether/hexane ) 30:70) to give 19 (228
mg, 94%). [R]25 +88.1 (c 0.99, CHCl3); 1H NMR (270 MHz,
D
CDCl3) δ 0.15 (9H, s, TMS), 1.18, 1.28 (each 3H, each d, J )
6.3 Hz, OCH(CH3)2), 2.08 (3H, s, OAc), 2.44 (1H, dd, J ) 17.6,
8.6 Hz, H-6a), 2.58 (1H, dd, J ) 17.6, 3.4 Hz, H-6b), 4.08 (1H,
dt, J ) 8.6, 3.4 Hz, H-5), 4.11 (1H, m, OCH(CH3)2), 5.14 (2H,
m, H-1, H-4), 5.82 (2H, m, H-2, H-3); IR (KBr) 2971, 2181,
1744, 1373, 1236, 1034, 844 cm-1. Anal. Calcd for C16H26O4Si:
C, 61.90; H, 8.44. Found: C, 61.74; H, 8.45.
1
16 (24.6 g, 76%, in three steps). H NMR (270 MHz, CDCl3) δ
1.14-1.25 (9H, m, OCH(CH3)2, OCH(CH3)OCH2CH3), 1.32 (3H,
d, J ) 5.2 Hz, OCH(CH3)OCH2CH3), 1.94, 2.33 (total 1H, each
m, OH), 3.45-3.71 (2H, m, H-6), 3.71-3.87 (3H, m, H-5, OCH-
(CH3)OCH2CH3), 3.90-4.01 (1H, m, OCH(CH3)2), 4.18,4.28
(total 1H, each m, H-4), 4.78,4.81 (total 1H, each q, J ) 5.2
Hz, OCH(CH3)OCH2CH3), 5.08 (1H, m, H-1), 5.66-5.73 (1H,
m, H-3), 5.97 (d, J ) 10.2 Hz, H-2), [6.04 (d, J ) 10.3 Hz, H-2)];
IR (KBr) 3464(br), 2976, 2920, 1465, 1453, 1379, 1309, 1131,
1031, 934 cm-1. Anal. Calcd for C13H24O5: C, 59.98; H, 9.29.
Found: C, 59.90; H, 9.07.
(2R*,3S*)-3-Acetoxy-2-(3-(tr im eth ylsilyl)-2-p r op yn yl)-
5,6-d ih yd r o-2H-p yr a n (11). To the solution of allyl acetate
19 (228 mg, 735 µmol) in 2.5 mL of CH2Cl2 and 2.5 mL of CH3-
CN were successively added triethylsilane (590 µL, 3.69 mmol)
and BF3‚OEt2 (135 µL, 1.47 mmol). After stirring for 2 h, the
reaction mixture was poured into a cooled sat. NaHCO3. The
resulting mixture was extracted with CH2Cl2 (×2). The
extracts were dried over Na2SO4 and concentrated under
reduced pressure. The crude residue was purified by silica gel
column chromatography (ether/hexane ) 30:70) to give 11 (142
(2S*,5S*,6R*)-5-(1′-Eth oxyeth oxy)-6-(iodom eth yl)-2-(iso-
p r op yloxy)-5,6-d ih yd r o-2H-p yr a n (17). To a solution of the
alcohol 16 (215 mg, 826 µmol) in PhH (5 mL) were successively
added imidazole (140 mg, 2.06 mmol), PPh3 (540 mg, 2.06
mmol), and iodine (251 mg, 1.98 mmol). After stirring at room
temperature for 30 min, the reaction mixture was quenched
with sat. Na2SO3 and extracted with ether (×3). The extracts
were washed with brine, dried over Na2SO4, and concentrated
under reduced pressure. Purification of the residue with silica
gel column chromatography (ether/hexane ) 10:90) gave
mg, 77%). [R]25 +0.8 (c 0.77, CHCl3); 1H NMR (270 MHz,
D
CDCl3) δ 0.13 (9H, s, TMS), 2.06 (3H, s, Ac), 2.48 (1H, dd, J )
17, 6.5 Hz, H-6a), 2.56 (1H, dd, J ) 17, 5 Hz, H-6b), 3.66 (1H,
td, J ) 7, 5 Hz, H-5), 4.19 (2H, m, H-1), 5.18 (1H, dddd, J )
7, 4, 2.5, 2 Hz, H-4), 5.73 (1H, dq, J ) 10.5, 2.5 Hz, H-3), 5.91
(1H, dq, J ) 10.5, 2 Hz, H-2); 13C NMR (67.8 MHz, CDCl3) δ
0.00, 21.43, 23.45, 64.58, 68.11, 74.00, 85.48, 102.21, 123.88,
129.61, 170.28; IR (KBr) 3048, 2962, 2830, 1741, 1417, 1374,
1236, 1043 cm-1. Anal. Calcd for C13H20O3Si: C, 61.87; H, 7.99.
Found: C, 61.67; H, 8.04.
1
colorless oil 17 (298 mg, 98%). H NMR (270 MHz, CDCl3) δ
1.15-1.62 (12H, m, OCH(CH3)2, OCH(CH3)OCH2CH3), 3.31-
3.38 (1H, m, H-6), 3.44-3.72 (4H, m, H-5, H-6, OCH(CH3)OCH2-
CH3), 3.96, 4.06 (total 1H, each m, H-4), 4.11 (1H, m,
OCH(CH3)2), 4.80, 4.85, (total 1H, each q, J ) 5.3 Hz,
OCH(CH3)OCH2CH3), 5.10 (1H, brs, H-1), 5.65-5.75 (1H, m,
H-3), 5.94 (d, J ) 12.0 Hz, H-2), [5.99 (d, J ) 10.5 Hz, H-2)];
IR (KBr) 2973, 2900, 1735, 1653, 1446, 1382, 1301, 1124, 1025,
943 cm-1. Anal. Calcd for C13H23O4I: C, 42.18; H, 6.26.
Found: C, 42.11; H, 6.21.
Disa cch a r id e 20. To a mixture of silylacetylene 11 (47.7
mg, 189 µmol) and arabinal 12 (68.4 mg, 241 µmol) in 1.5 mL
of CH2Cl2 was added TiCl4 (25 µL, 228 µmol) at -20 °C. After
stirring for 30 min at -20 °C, the reaction mixture was poured
into a cold mixture of sat. NaHCO3 aq. and sat. aq NaK(CH-
(OH)COO)2. The resulting mixture was extracted with Et2O
(×2). The extracts were washed with brine, dried over Na2-
SO4, and concentrated. The crude mixture was purified by
silica gel column chromatography (ether/hexane ) 50:50) to
(2S*,5S*,6R*)-5-Hyd r oxy-6-(3-(tr im eth ylsilyl)-2-p r op y-
n yl)-2-(isop r op yloxy)-5,6-d ih yd r o-2H-p yr a n (18). To a
solution of 220 µL of (trimethylsilyl)acetylene (1.56 mmol) in
4.0 mL of THF was added 770 µL (1.23 mmol) of n-BuLi (1.6
M in hexane) at -78 °C. The resulting colorless solution was
warmed to 0 °C and stirred for 30 min. To this solution were
successively added a solution of iodide 17 (397 mg, 1.02 mmol)
in 4.0 mL of THF via cannula and 2.0 mL of HMPA at 0 °C.
After stirring for 30 min at 0 °C, the reaction mixture was
poured into a cold sat. NH4Cl and extracted with ether (×3).
The extracts were washed with brine, dried over Na2SO4, and
concentrated under reduced pressure. Purification of the
residue with silica gel column chromatography (ether/hexane
) 10:90) gave colorless oil, ethoxyethyl ether of 17′ (267 mg,
740 mmol, 73%). Because of its instability, this compound was
subjected to the next reaction right away. To a solution of the
ethoxy ether (267 mg, 740 mmol) in 6.0 mL of i-PrOH was
added PPTS (23.0 mg, 0.09 mmol). The resulted solution was
stirred for 1 h at room temperature and concentrated. The
crude oil was purified by silica gel column chromatography
(ether/hexane ) 40:60) to give allyl alcohol 18 (201 mg, 100%).
[R]25D +66.7 (c 0.39, CHCl3); 1H NMR (270 MHz, CDCl3) δ 0.16
(9H, s, TMS), 1.18, 1.26 (each 3H, each d, J ) 6.2 Hz, -CH-
(CH3)2), 1.95 (1H, brd, J ) 7.0 Hz, OH), 2.54 (1H, ddd, J ) 17,
3, 2 Hz, H-6a), 2.70 (1H, dd, J ) 17, 5 Hz, H-6b), 3.80 (1H,
ddd, J ) 9, 7.3, 5 Hz, H-5), 3.98-4.12 (2H, m, H-4, OCH(CH3)2),
give 20 (37.0 mg, 54%). [R]28 +10.3 (c 0.70, CHCl3); 1H NMR
D
(270 MHz, CDCl3) δ 1.19 (9H, s, Piv), 2.07 (3H, s, Ac), 2.50
(1H, ddd, J ) 17, 7, 2 Hz, H-8a), 2.59 (1H, ddd, J ) 17, 5, 2
Hz, H-8b), 3.67 (1H, td, J ) 7, 5 Hz, H-9), 3.76 (1H, ddd, J )
13, 2, 1 Hz, H-1a), 4.18 (1H, dd, J ) 13, 3.5 Hz, H-1b), 4.21
(2H, m, H-13), 4.92 (1H, m, H-5), 5.01 (1H, m, H-2), 5.19 (1H,
m, H-10), 5.74 (1H, dq, J ) 10.5, 2.5 Hz, H-3*), 5.87(1H, dddd,
J ) 10, 4.5, 2.5, 1 Hz, H-11*), 5.93 (1H, dq, J ) 10.5, 2.0 Hz,
H-4*), 6.02 (1H, ddd, J ) 10, 4.5, 1 Hz, H-12*); IR (KBr) 2972,
2871, 2222, 1732, 1719, 1482, 1370, 1278, 1236, 1156 cm-1
;
MS(EI) m/z 362 (M+). Anal. Calcd for C20H26O6: C, 66.28; H,
7.23. Found: C, 66.22; H, 7.37.
Acetylen ecoba lth exa ca r bon yl Com p lex 21. To a solu-
tion of acetylene 20 (44.5 mg, 141 µmol) in 2.0 mL of CH2Cl2
was added a solution of Co2(CO)8 (61.4 mg, 174 µmol) in 0.75
mL of CH2Cl2 at room temperature. After stirring for 2 h, the
solvent was removed in vacuo. The residue was purified by
silica gel column chromatography (ether/hexane ) 40:60) to
give a dark red oil 21 (71.5 mg, 84%). [R]28 +168.5 (c 0.10,
D
1
CHCl3); H NMR (270 MHz, CDCl3) δ 1.21 (9H, s, Piv), 2.11
(3H, s, Ac), 2.98 (1H, dd, J ) 16.5, 10 Hz, H-8a), 3.11 (1H, dd,
J ) 16.5, 2.5 Hz, H-8b), 3.58-3.66 (1H, m, H-9), 3.67 (1H, dd,
J ) 11.5, 7 Hz, H-1a), 4.16 (2H, m, H-13), 4.28(1H, dd, J )

Synthesis of Left Ends of Ciguatoxin and Gambiertoxin 4b
J . Org. Chem., Vol. 64, No. 1, 1999 43
11.5, 5 Hz, H-1b), 5.23, 5.25, 5.33 (each 1H, each m, H-2*, H-5*,
H-10*), 5.75 (1H, m, H-3*), 5.89 (1H, dt, J ) 10.5, 2.0 Hz,
H-11*), 5.96 (1H, dq, J ) 10.5, 2.0 Hz, H-12*), 6.04 (1H, m,
H-4*); 13C NMR (67.8 MHz, CDCl3) δ 20.90, 27.00, 36.62, 38.66,
64.13, 65.27, 68.95, 73.99, 76.63, 92.69, 96.91, 124.45, 125.37,
129.52, 132.09, 170.60, 178.06, 199.77 (br); IR (KBr) 2975,
2934, 2874, 2092, 2053, 2013, 1734, 1481, 1372, 1278, 1234,
1153, 1091, 1032 cm-1; MS(FAB) m/z 649 (M + H+), 592 (M -
2×CO), 564 (M - 3xCO), 536 (M - 4×CO), 508 (M - 5×CO),
480 (M - 6×CO); HRMS(FAB) calcd for C22H26O8Co2, 536.0291,
found 536.0278.
H-11*), 5.87 (1H, dd, J ) 16, 5 Hz, H-3), 5.89-5.96 (1H, m,
H-12*), 5.94 (1H, dd, J ) 16, 4 Hz, H-4); 13C NMR (67.8 MHz,
CDCl3) δ 27.00, 27.03, 31.49, 38.72, 38.75, 64.97, 64.99, 70.82,
75.38, 78.88, 80.97, 91.95, 100.22, 124.97, 127.05, 128.31,
132.15, 177.25, 178.09, 199.04 (br); IR (KBr) 2975, 2935, 2972,
2841, 2094, 2051, 2026, 1735, 1577, 1481, 1280, 1146 cm-1
;
MS(FAB) m/z 691.2 (M + H), 606.2 (M - 3×CO), 578 (M -
4×CO); HRMS(FAB) calcd for C29H33O12Co2 691.0635, found
691.0621.
(2R,5S)-AB Segm en t 25. To a solution of endo-acetylene-
cobalt complex 24 (5.3 mg, 7.36 µmol) in 1.0 mL of PhH was
added Wilkinson catalyst (0.7 mg, 0.76 µmol). After stirring
for 5 h at 60 °C under 100 kg/cm2, the reaction mixture was
filtered, concentrated in vacuo, and purified by silica gel
column chromatography (ether/hexane ) 30:70) to give 25 (2.5
Acetylen ecoba lth exa ca r bon yl Com p lex 22. To a solu-
tion of Piv2O (100 µL, 493 µmol) in 0.75 mL of CH2Cl2 was
added TfOH (25 µL, 283 µmol) at -20 °C under N2. After
stirring for 20 min at -20 °C, to this mixture was added a
solution of cobalt complex 21 (33.0 mg, 51.1 µmol) in 1.5 mL
of CH2Cl2 via cannula. After stirring for 1 h at -20 °C, to the
resulting dark red solution was added 300 µL of MeOH. The
reaction mixture was poured into a cooled sat. NaHCO3 aq.
and extracted with CH2Cl2 (×2). The extracts were dried over
Na2SO4, concentrated in vacuo, and purified by silica gel
column chromatography (ether/hexane ) 40:60) to give dark
mg, 84%). Mp 96-96.5 °C; [R]26 -54.6 (c 0.75, CHCl3); 1H
D
NMR (270 MHz, CDCl3) δ 1.18, 1.21 (each 9H, each s, Piv),
2.38 (1H, ddq, J ) 15.9, 10.6, 3 Hz, H-8a), 2.59 (1H, ddd, J )
15.9, 8, 3.9 Hz, H-8b), 3.24 (1H, ddd, J ) 10.6, 8.9, 3.9 Hz,
H-9), 3.98 (1H, m, H-10), 4.08 (1H, dd, J ) 11.8, 7.2 Hz, H-1a),
4.15 (2H, m, H-13), 4.25 (1H, dd, J ) 11.8, 3.5 Hz, H-1b), 4.58
(1H, m, H-4), 5.54 (1H, m, H-2), 5.66-5.91 (5H, m, H-3, H-6,
H-7, H-11, H-12), 5.86 (1H, dd, J ) 15.5, 4.8 Hz, H-4); 13C NMR
(67.8 MHz, CDCl3) δ 27.08, 34.63, 38.77, 64.86, 65.52, 70.93,
74.65, 79.39, 124.98, 127.76, 134.29, 177.44, 178.14; IR (KBr)
2975, 1735, 1482, 1280, 1142, 1106 cm-1; MS(EI) m/z 406 (M+),
304 (M+ - PivOH). Anal. Calcd for C23H34O6: C, 67.98; H,8.37.
Found: C, 67.99; H, 8.60.
1
red oil 22 (38.0 mg, 98%). H NMR (270 MHz, CDCl3) δ 1.19,
1.20 (total 18H, each s, Piv), 2.09 (3H, s, Ac), 2.84-3.07 (2H,
m, H-8), 3.57-3.69 (1H, m, H-9), 4.04 (dd, J ) 11.5, 7.5 H-1a),
4.17 (2H, m, H-13), 4.27 (dd, J ) 11.5, 3.5 Hz, H-1b), [4.31
(dd, J ) 11.5, 3.5 Hz, H-1b)], 4.75 (1H, m, H-5), 5.20 (1H, m,
H-10), 5.57 (1H, m, H-2), 5.73-6.00 (4H, m, H-3, H-4, H-11,
H-12); 13C NMR (67.8 MHz, CDCl3) δ 20.90, 26.92, 27.01, 27.04,
36.23, 36.34, 38.65, 38.71, 56.76, 56.99, 62.48, 62.71, 64.41,
68.86, 70.47, 71.91, 71.99, 76.63, 80.25, 80.50, 89.58, 89.79,
95.65, 95.88, 124.31, 129.46, 129.68, 131.25, 131.68, 131.89,
132.29, 170.61, 177.20, 177.53, 177.99, 199.51 (br); IR (KBr)
2973, 2940, 2881, 2090, 2053, 2024, 1733, 1482, 1372, 1282,
1233, 1140 cm-1; MS(FAB) m/z 732.8 (M + H - MeOH), 679.8
(M - 3×CO); HRMS(FAB) calcd for C31H25O13Co2 733.0741,
found 733.0704.
(2S,5S)-AB Segm en t 27. (2S,5S)-AB Fragment 27 was
derived from 11 and D-xylal 13 as 25. [R]26 -17.2 (c 0.47,
D
CHCl3); 1H NMR (270 MHz, CDCl3) δ 1.18, 1.21 (each 9H, each
s, Piv), 2.38 (1H, ddq, J ) 16, 10.5, 3 Hz, H-8a), 2.59 (1H, ddd,
J ) 16, 8, 3.6 Hz, H-8b), 3.24 (1H, ddd, J ) 10.5, 8.4, 3.6 Hz,
H-9), 3.98 (1H, m, H-10), 4.08 (1H, dd, J ) 11.8, 7 Hz, H-1a),
4.15 (2H, m, H-13), 4.24 (1H, dd, J ) 11.8, 3.5 Hz, H-1b), 4.59
(1H, m, H-5), 5.54 (1H, ddd, J ) 7, 6.5, 3.5 Hz, H-2), 5.65-
5.88 (5H, m, H-3, H-6, H-7, H-11, H-12), 5.88 (1H, dd, J )
15.5, 4.8 Hz, H-4); 13C NMR (67.8 MHz, CDCl3) δ 27.06, 34.63,
38.71, 38.77, 64.79, 65.49, 71.03, 74.65, 77.54, 79.29, 125.03,
127.71, 127.82, 134.24, 134.78, 177.44, 178.12; IR (KBr) 2967,
1729, 1482, 1286, 1146, 1020 cm-1; MS(EI) m/z 406 (M+), 304
(M+ - PivOH); EI HRMS calcd for C23H34O6 406.2355, found
406.2340.
Acetylen ecoba lth exa ca r bon yl Com p lex 23. To a solu-
tion of cobalt complex 22 (152 mg, 199 µmol) in 1.5 mL of
MeOH was added K2CO3 (21.0 mg, 152 µmol) at 0 °C. After
warming up to room temperature, the reaction mixture was
stirred for 30 min. The resulting mixture was quenched with
sat. NH4Cl aq. and extracted with Et2O (×2). The extracts were
washed with brine, dried over Na2SO4, concentrated in vacuo,
and purified by silica gel column chromatography (ether/
(2R*,3S*)-3-(1′-Eth oxyeth oxy)-2-(2-p r op yn yl)-2, 3-d ih y-
d r o-6H-p yr a n (35). To a solution of allyl acetate 11 (142 mg,
563 µmol) in 4.0 mL of MeOH was added K2CO3 (190 mg, 1.37
mmol). After stirring for 2 h, to the reaction mixture was added
sat. NH4Cl at 0 °C. The resulting mixture was extracted with
Et2O (×2). The extracts was washed with brine, dried over
Na2SO4, and concentrated under reduced pressure. The crude
residue was purified by silica gel column chromatography
(ether/hexane ) 65:35) to give allyl alcohol (78 mg, 100%).
1
hexane ) 50:50) to give a dark red oil 23 (125 mg, 87%). H
NMR (270 MHz, CDCl3) δ 1.19, 1.20, 1.21 (total 18H, each s,
Piv), 2.15-2.30 (1H, m, -OH), 2.81 (dd, J ) 15, 10 Hz, H-8a),
2.94 [(dd, J ) 15, 10 Hz, H-8a)], 3.30-3.40 (2H, m, H-8b, H-9),
3.41, 3.42 (total 3H, each s, OMe), 4.00-4.15 (4H, m, H-1a,
H-10, H-13), 4.26 (dd, J ) 11.5, 3.5 Hz, H-1b), [4.29(dd, J )
11.5, 3.0 Hz, H-1b)], 4.75 (1H, m, H-5), 5.51 (1H, m, H-2), 5.71-
5.92 (4H, m, H-3, H-4, H-11, H-12); 13C NMR (67.8 MHz,
CDCl3) δ 26.96, 27.01, 27.04, 36.76, 38.72, 56.83, 56.94, 62.56,
62.82, 64.51, 65.78, 67.41, 71.94, 72.07, 79.92, 79.98, 80.33,
80.51, 89.39, 96.43, 128.23, 130.84, 131.77, 132.08, 132.14,
177.41, 177.63, 178.22, 199.62 (br); IR (KBr) 3482 (br), 2974,
2939, 2873, 2090, 2051, 2022, 1734, 1482, 1287, 1165, 1146,
1029 cm-1; MS(FAB) m/z 691.1 (M + H - MeOH), 638.1 (M -
3×CO); HRMS(FAB) calcd for C29H33O12Co2 691.0635, found
691.0618.
[R]25 +0.3 (c 1.94, CHCl3); 1H NMR (270 MHz, CDCl3) δ 1.90
D
(1H, d, J ) 6.6 Hz, -OH), 2.08 (1H, t, J ) 2.7 Hz, H-8), 2.60
(1H, ddd, J ) 16.9, 6.1, 2.7 Hz, H-6a), 2.67 (1H, ddd, J ) 2.7,
5.2, 16.9 Hz, H-6b), 3.45 (1H, ddd, J ) 7.6, 6.1, 5.2 Hz, H-5),
4.19 (3H, m, H-1, H-4), 5.84 (2H, m, H-2, H-3); IR (KBr) 3407
(br), 3041, 2889, 1653, 1636, 1541, 1419, 1375, 1127, 1084,
1032 cm-1. Anal. Calcd for C8H10O2: C, 69.53; H, 7.30.
Found: C, 69.52; H, 7.50.
To the solution of this allyl alcohol (236 mg, 1.71 mmol) in
5.0 mL of CH2Cl2 was successively added EVE (350 µL, 3.66
mmol) and PPTS (31 mg, 0.12 mmol). After stirring for 6 h, to
the reaction mixture was added sat. NaHCO3. The resulting
mixture was extracted with CH2Cl2 (×2). The extracts were
dried over Na2SO4 and concentrated under reduced pressure.
The crude residue was purified by silica gel column chroma-
tography (ether/hexane ) 17:83) to give 35 (364 mg, 100%).
1H NMR (270 MHz, CDCl3) δ 1.22 (3H, t, J ) 6.9 Hz, OCH-
(CH3)OCH2CH3), 1.34, 1.35 (total 3H, each d, J ) 5.2 Hz, OCH-
(CH3)OCH2CH3), 2.04, 2.06 (total 1H, each t, J ) 2.5H, H-8),
2.52-2.76 (2H, m, H-6), 3.53 (2H, m, OCH(CH3)OCH2CH3),
3.67 (1H, m, H-5), 4.14 (1H, m, H-4), 4.21 (2H, m, H-1), 4.81,
4.87 (total 1H, each q, J ) 5.2 Hz, OCH(CH3)OCH2CH3), 5.86
(2H, m, H-2, H-3); 13C NMR (67.8 MHz, CDCl3) δ 15.1, 20.3,
en d o-Acet ylen ecob a lt h exa ca r b on yl Cyclic E t h er 24.
To a solution of cobalt complex 23 (6.5 mg, 9.02 µmol) in 1.3
mL of CH2Cl2 was added BF3‚OEt2 (0.1 M in 1,2-dichlo-
romethane, 70 µL, 7.58 µmol) at 0 °C. After stirring for 40 min
at 0 °C, the reaction mixture was quenched by sat. aq NH4Cl
and extracted with Et2O (×1). The extracts were washed with
brine, dried over Na2SO4, concentrated in vacuo, and purified
by silica gel column chromatography (ether/hexane ) 25:75)
to give a dark red oil 24 (4.9 mg, 79%). [R]29 -309.0 (c 0.11,
D
CHCl3); 1H NMR (270 MHz, CDCl3) δ 1.18, 1.21 (each, 9H,
each s, Piv), 2.86-2.99 (1H, m, H-8a), 3.45-3.58 (2H, m, H-8b,
H-9), 3.99-4.08 (1H, m, H-10), 4.04 (1H, dd, J ) 11.5, 7.5 Hz,
H-1a), 4.14 (2H, m, H-13), 4.29 (1H, dd, J ) 11.5, 3 Hz, H-1b),
5.13 (1H, d, J ) 4 Hz, H-5), 5.61 (1H, m, H-2), 5.76 (1H, m,

44 J . Org. Chem., Vol. 64, No. 1, 1999
Hosokawa and Isobe
20.5, 21.7, 60.6, 60.9, 65.28, 65.31, 68.4, 69.7, 70.1, 71.1, 74.8,
74.9, 80.4, 80.7, 98.3, 100.8, 125.8, 127.1, 127.6, 128.0; IR (KBr)
2980, 2931, 2913, 2887, 1717, 1653, 1541, 1508, 1457, 1390,
1128, 1083, 1053, 1034 cm-1. Anal. Calcd for C12H18O2: C,
68.54; H, 8.63. Found: C, 68.42; H, 8.83.
µL, 1.51 mmol) in benzene (3.5 mL) was degassed (×3) and
stirred at 65 °C. After 1 h, the reaction mixture was cooled
and concentrated in vacuo. The residue was purified by silica
gel column chromatography to afford colorless oil 5 (20.5 mg,
10.0 µmol, 81%). [R]29 -9.2 (c 0.45, CHCl3); 1H NMR (400
D
(2R*,3S*)-3-(1′-Eth oxyeth oxy)-2-(5-h yd r oxy-1-iod oocta -
1,3-d ien -6-yn yl)-2,3-d ih yd r o-6H-p yr a n (37). To the solution
of acetylene 35 (72.1 mg, 343 µmol) in THF (2.0 mL) was added
n-BuLi (1.6 M in hexane, 260 µL, 412 µmol) at -78 °C under
N2. After stirring at 0 °C for 30 min, this reaction mixture
was recooled to -78 °C. At this temperature, to this solution
was added BF3‚OEt2 (0.54 M in THF, 630 µL, 378 µmol). After
stirring for 10 min, aldehyde 36 (107 mg, 515 µmol) in THF
(2.0 mL) was added. After additional stirring for 20 min, the
reaction mixture was poured into a cooled sat. NaHCO3 and
extracted by ether (×3). The extracts were washed with brine
and dried over Na2SO4. Evaporation, concentration, and puri-
fication by silica gel column chromatography gave colorless
adduct (92.0 mg, 220 µmol, 63%) which received next reaction
immediately because of instability. The adduct was dissolved
in MeOH (5.0 mL), and to the resulting solution was added
PPTS (3.0 mg). After stirring for 1 h, to this reaction mixture
was added sat. NaHCO3 at 0 °C. Extraction with ether (×3)
and evaporation gave crude residue which was purified by
silica gel column chromatography (ethyl acetate/hexane ) 1:1)
to afford colorless oil 37 (65.6 mg, 190 µmol, 88%). 1H NMR
(300 MHz, CDCl3) δ 2.65-2.74 (2H, m, H-8), 3.40-3.50 (1H,
m, H-9), 4.11-4.20 (3H, m, H-10, H-13), 4.90, 4.98 (total 1H,
each m, H-5), 5.76-5.91 (2H, m, H-11, H-12), 6.02-6.10, 6.29-
6.47, 6.55-6.65 (total 3H, each m, H-2, H-3, H-4), 6.76, 6.78,
7.04, 7.07 (total 1H, each d, J ) 11 Hz, 10 Hz, 14 Hz, 14.5 Hz,
respectively, H-1); IR (KBr) 3375 (br), 2882, 2843, 2219, 1669,
1613, 1417, 1259, 1120, 1079, 1029, 977, 810, 696 cm-1. Anal.
Calcd for C13H15O3I: C, 45.11; H, 4.37. Found: C, 45.11; H, 4.47.
Acetylen e Biscoba lth exa ca r bon yl Com p lex 38. To the
solution of acetylene 37 (26.6 mg, 76.8 µmol) in CH2Cl2 (1.0
mL) was added a solution of Co2(CO)8 (50 mg, 146 µmol) in
CH2Cl2 (1.0 mL) at 0 °C. After stirring for 1 h at room
temperature, the reaction mixture was concentrated in vacuo.
Purification by silica gel column chromatography (ethyl acetate/
hexane ) 1:2) gave a dark red oil 38 (48.5 mg, 76.7 µmol,
MHz, CDCl3) δ 2.38 (1H, ddq, J ) 16, 10.5, 3 Hz, H-8a), 2.61
(1H, ddd, J ) 16, 8, 3.5 Hz, H-8b), 3.27 (1H, ddd, J ) 10.5, 8,
3.5 Hz, H-9), 4.00 (1H, dt, J ) 8, 3 Hz, H-10), 4.08-4.25 (2H,
m, H-13), 4,63 (1H, m, H-5), 5.10-5.15 (1H, m, H-1a), 5.19-
5.26 (1H, m, H-1b), 5.65-5.90 (5H, m, H-4*, H-6, H-7, H-11,
H-12), 6.28-6.40 (2H, m, H-2, H-3*); 13C NMR (75.4 MHz,
CDCl3) δ 34.5, 65.5, 74.8, 78.2, 79.1, 117.8, 127.3, 127.7, 127.9,
131.5, 133.9, 134.5, 136.5; IR (KBr) 2931, 2858, 1733, 1288,
1139, 1108, 1072, 1020, 902, 676 cm-1. Anal. Calcd for
C13H16O2: C,76.44; H, 7.89. Found: C, 76.56; H, 7.62.
Meth yl 6-Deoxyiod o-tr i-O-ben zyl-D-glu cop yr a n osid e
(45). To a solution of the alcohol 44 (770 mg, 1.66 mmol) in
PhH (18 mL) were successively added imidazole (282 mg, 415
mmol), PPh3 (1,08 g, 415 mmol), and iodine (841 mg, 3.32
mmol). After stirring at room temperature for 3 h, the reaction
mixture was quenched with sat. Na2SO3 and extracted with
ether (×3). The extracts were washed with brine, dried over
Na2SO4, and concentrated under reduced pressure. Purification
of the residue by silica gel column chromatography (ether/
hexane ) 30: 70) gave colorless oil 45 (910 mg, 96%). [R]28
D
+34.1 (c 2.33, CHCl3); 1H NMR (300 MHz, CDCl3) δ 3.29 (1H,
dd, J ) 11, 6.5 Hz, H-6a), 3.34 (1H, t, J ) 9.0 Hz, H-4), 3.42
(3H, s, OMe), 3.41-3.48 (1H, m, H-5), 3.45 (1H, t, J ) 9.5 Hz,
H-3), 3.47 (1H, dd, J ) 11, 2.5 Hz, H-6b), 3.54 (1H, dd, J )
9.5, 3.4 Hz, H-2), 4.02 (1H, dd, J ) 9.5, 9 Hz, H-3), 4.61 (1H,
d, J ) 3.4 Hz, H-1), 4.66 (1H, d, J ) 11.8 Hz, CH2Ph), 4.68
(1H, d, J ) 10.6 Hz, CH2Ph), 4.81 (1H, d, J ) 11.8 Hz, CH2-
Ph), 4.81 (1H, d, J ) 10.8 Hz, CH2Ph), 4.94 (1H, d, J ) 10.8
Hz, CH2Ph), 4.99 (1H, d, J ) 10.6 Hz, CH2Ph), 7.30-7.39 (15H,
m, Ph); IR (KBr) 3063, 3030, 2906, 1952, 1497, 1455, 1360,
1198, 1089(br), 738, 696. Anal. Calcd for C28H31O5I: C, 58.52;
H, 5.44. Found: C, 58.51; H, 5.46.
6-Deoxyiod o-tr i-O-ben zyl-1,5-D-glu con ola cton e (46). To
a solution of 45 (75.8 g, 146 mmol) in 1.00 L of acetic anhydride
was added 100 mL of TFA at 0 °C. After removal of the ice-
water bath, the reaction mixture was stirred for 1 day at room
temperature. The resulting mixture was poured into cooled
aq NaHCO3 and extracted with Et2O (×3). The extracts were
washed with H2O (×2), aq NaHCO3 (×1), and brine, dried over
Na2SO4, and concentrated under reduced pressure. The crude
oil was suspended in 1.20 L of AcOH and 0.50 L of H2O. The
suspension was turned to clear solution at 100 °C. After
stirring for 1 day at 100 °C, the reaction mixture was extracted
with ether-hexane (1:1) (×3). The extracts were washed with
H2O (×2), NaHCO3 aq. (×1), brine, dried over Na2SO4, and
concentrated under reduced pressure. The crude oil was
dissolved in 300 mL of CH2Cl2. In another three-necked flask,
to a solution of (COCl)2 (16.0 mL, 222 mmol) in 300 mL of CH2-
Cl2 was dropwise added a solution of DMSO (26 mL, 444 mmol)
in 400 mL of CH2Cl2 at -78 °C. After stirring for 20 min, to
this mixture was dropwise added a solution of crude substrate
at -78 °C. After stirring for 30 min, triethylamine (67 mL,
555 mmol) was dropwise added to this mixture at -78 °C. After
raising the temperature to 0 °C, the resulting mixture was
poured into H2O and extracted with CH2Cl2 (×3). The extracts
were dried over Na2SO4 and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (ether/hexane ) 25:75) to give colorless oil
1
100%). H NMR (300 MHz, CDCl3) δ 2.95-3.17 (1H, m, H-9),
3.22-3.45, 3.45-3.66 (each 1H, each m, H-8), 3.95-4.30 (3H,
m, H-10, H-13), 5.26-5.36 (1H, m, H-5), 5.76-5.94 (2H, m,
H-11, H-12), 5.36-5.48, 6.03-6.17, 6.27-6.47, 6.48-6.65,
6.69-6.82, 6.93-7.14 (total 4H, each m, H-1, H-2, H-3, H-4).
All peaks are broadened, due to the paramagnetic susceptibil-
ity of cobalt; IR (KBr) 3402 (br), 2930, 2889, 2854, 2091, 2049,
2017, 1602, 1117, 1078, 1027, 979, 701, 518 cm-1; MS(FAB)
m/z 631 (M - H), 615 (M + H - H2O), 604 (M - CO), 576 (M
- 2×CO), 548 (M - 3×CO), 492 (M - 5×CO), 464 (M -
6×CO); HRMS(FAB) calcd for C19H14O9Co2 630.8479, found
630.8330.
Cyclic Acetylen ecoba lth exa ca r bon yl Com p lex 39. To
the solution of cobalt complex 38 (29.2 mg, 46.2 µmol) in 30
mL of CH2Cl2 (degassed ×3) was added CSA (21.4 mg, 92.4
µmol) at 0 °C. After stirring for 40 min at 0 °C, the reaction
mixture was poured on silica gel column. Purification by
column chromatography (ether/hexane ) 1:4) gave a dark red
1
oil 39 (25.5 mg, 41.5 µmol, 90%). H NMR (300 MHz, CDCl3)
δ 2.86-3.00 (1H, m, H-9), 3.44-3.62 (2H, m, H-8), 3.98-4.20
(3H, m, H-10, H-13), 5.05-5.23 (1H, m, H-5), 5.70-5.98 (3H,
m, H-4*, H-11, H-12), 6.27-6.48, 6.49-6.65, 6.72-6.86, 6.96-
7.13 (total 3H, each m, H-1*, H-2*, H-3*). All peaks are
broadened, due to the paramagnetic susceptibility of cobalt.
13C NMR (75.4 MHz, CDCl3) δ 38.8, 65.0, 75.5, 75.7, 79.0, 80.3,
81.2, 127.0, 128.5, 130.4, 130.9, 132.5, 136.5, 144.3196.8-199.8
(br); IR (KBr) 2934, 2858, 2093, 2051, 2034, 1732, 1579, 1264,
1120, 1089, 1053, 1012, 982, 646, 515 cm-1; MS(FAB) m/z 615
(M + H), 586 (M - CO), 576 (M - 2×CO), 558 (M - 2×CO),
530 (M - 3×CO), 502 (M - 4×CO), 474 (M - 5×CO), 446 (M
- 6×CO); HRMS(FAB) calcd for C18H13O7Co2 585.8371, found
585.8355.
46 (46.0 g, 62% in three steps). [R]28 +73.6 (c 0.73, CHCl3);
D
1H NMR (300 MHz, CDCl3) δ 3.44 (1H, dd, J ) 11, 4 Hz, H-6a),
3.53 (1H, dd, J ) 11, 3.6 Hz, H-6b), 3.76 (1H, dd, J ) 9, 6.2
Hz, H-4), 3.97 (1H, dd, J ) 6.2, 5.5 Hz, H-3), 4.13 (1H, d, J )
5.5 Hz, H-2), 4.18 (1H, td, J ) 9, 4 Hz, H-5), 4.53 (1H, d, J )
11.5 Hz, CH2Ph), 4.62 (1H, d, J ) 11.0 Hz, CH2Ph), 4.64 (1H,
d, J ) 11.5 Hz, CH2Ph), 4.68 (1H, d, J ) 11.0 Hz, CH2Ph),
4.74 (1H, d, J ) 11.5 Hz, CH2Ph), 4.96 (1H, d, J ) 11.5 Hz,
CH2Ph), 7.24-7.41 (15H, m, Ph); IR (KBr) 3064, 3032, 2933,
2879, 1760, 1498, 1456, 1365, 1214, 1117, 1090, 1070, 738, 698
cm-1. Anal. Calcd for C27H27O5I: C, 58.08; H, 4.87. Found: C,
58.20; H, 4.74.
(5S)-Ga m bier toxin AB Segm en t 5. The mixture of cobalt
complex 39 (76.5 mg, 126 µmol) and tributyltin hydride (400

Synthesis of Left Ends of Ciguatoxin and Gambiertoxin 4b
J . Org. Chem., Vol. 64, No. 1, 1999 45
(2S*,3S*,4R*,5S*,6S*)-6-(Iod om et h yl)-2-(2-p r op en yl)-
3,4,5-tr is(ben zyloxy)tetr a h yd r op yr a n (47). To a solution
of 46 (37.0 g, 66.3 mmol) in 1.00 L of Et2O was added a solution
of allylmagnesium bromide (1.0 M in ether, 80 mL, 80 mmol)
at -78 °C. After stirring for 30 min, the reaction mixture was
poured into a solution of cold sat. aq NH4Cl and extracted with
Et2O (×3). The extracts were washed with brine, dried over
Na2SO4, and concentrated in vacuo. The residue was dissolved
in 800 mL of CH3CN. To this solution were added triethylsi-
lane (21 mL, 131 mmol) and BF3‚OEt2 (7.1 mL, 77.2 mmol) at
0 °C. After stirring for 30 min, the reaction mixture was poured
into cooled sat. aq NaHCO3 and extracted with Et2O (×3). The
extracts were washed with brine, dried over Na2SO4, and
concentrated in vacuo. The residue was purified by silica gel
column chromatography (ether/hexane ) 25:75) to give 47
(28.0 g, 72% in two steps). Mp 79.5-80 °C; [R]30D +23.3 (c 2.04,
(×3). The extracts were washed with brine, dried over Na2-
SO4, and concentrated in vacuo. The residue was purified by
silica gel column chromatography (ethyl acetate/hexane ) 75:
1
25) to give 51 (78.4 mg, 90%). [R]28 +6.1 (c 0.77, CHCl3); H
D
NMR (300 MHz, CDCl3) δ 1.45-1.57 (1H, m, H-3a), 1.72-1.89
(1H, m, H-3b), 1.89-2.03 (2H, m, H-2), 2.45 (3H, s, ArCH3),
3.06 (1H, m, H-4), 3,18-3.27 (2H, m, H-5, H-9a), 3.29 (1H, t,
J ) 9.0 Hz, H-7), 3.47-3.55 (2H, m, H-6, H-9b), 4.03-4.17
(2H, m, H-1), 7.36 (2H, d, J ) 8.4 Hz, C6H4CH3), 7.79 (2H, d,
J ) 8.4 Hz, C6H4CH3); IR (KBr) 3341 (br), 2964, 2923, 2904,
2854, 1597, 1351, 1174, 1093, 946 cm-1. Anal. Calcd for
C16H23O7IS: C, 39.52; H, 4.77. Found: C, 39.39; H, 4.83.
(2S*,3S*,4R*,4a S*,8a S*)-3,4-Dih yd r oxy-2-(iod om eth yl)-
1,4-d ioxa bicyclo[4.0.4]octa n e (52). To a solution of 51 (217
mg, 446 µmol) in 16.0 mL of THF was added t-BuOK (55.3
mg, 491 µmol) at 0 °C. After raising the temperature to room
temperature, the reaction mixture was stirred for 30 min at
room temperature. The resulting pale green suspension was
quenched with sat. aq NH4Cl and extracted by AcOEt (×3).
The extracts were washed with brine, dried over Na2SO4,
concentrated in vacuo, and purified by silica gel column
chromatography (methanol/dichloromethane ) 1:6) to give 52
(111 mg, 79%). Mp 165-165.5 °C; [R]27D +36.4 (c 0.17, CHCl3);
1H NMR (300 MHz, CDCl3)δ 1.43-1.58 (1H, m, H-3a), 1.60-
1.70 (2H, m, H-2), 2.13 (1H, m, H-3b), 2.94 (1H, t, J ) 9 Hz,
H-5), 3.08 (1H, ddd, J ) 9, 5.6, 2.5 Hz, H-8), 3.20 (1H, ddd, J
) 10.5, 9, 4.4 Hz, H-4), 3.37 (1H, m, H-1a), 3.38 (1H, dd, J )
10.5, 5.6 Hz, H-9a), 3.44 (1H, t, J ) 9 Hz, H-7), 3.56 (1H, dd,
J ) 10.5, 2.5 Hz, H-9b), 3.62 (1H, t, J ) 9 Hz, H-6), 3.97 (1H,
m, H-1b); IR (KBr) 3415 (br), 2948, 2867, 1435, 1360, 1319,
1128, 1091, 1064 cm-1; EI-MS m/z 314 (M+), 187 (M+ - I).
Anal. Calcd for C9H15O4I: C, 34.41; H, 4.81. Found: C, 34.50;
H, 4.79.
1
CHCl3); H NMR (300 MHz, CDCl3) δ 2.31 (1H, td, J ) 15, 7
Hz, H-3a), 2.58 (1H, dddt, J ) 15, 6.5, 3, 1.5 Hz, H-3b), 3.03
(1H, ddd, J ) 9.5, 6, 3 Hz, H-4), 3.29-3.45 (3H, m, H-5, H-8,
H-9a), 3.41 (1H, t, J ) 9.5 Hz, H-7), 3.49 (1H, dd, J ) 11, 3
Hz, H-9b), 3.73 (1H, t, J ) 9.5 Hz, H-6), 4.66 (1H, d, J ) 10.7
Hz, CH2Ph), 4.74 (1H, d, J ) 10.6 Hz, CH2Ph), 4.88 (1H, d, J
) 10.7 Hz, CH2Ph), 4.90 (1H, m, CH2Ph), 4.93 (1H, d, J ) 10.6
Hz, CH2Ph), 5.07-5.15 (2H, m, H-1), 7.26-7.37 (15H, m, Ph);
IR (KBr) 3031, 2904, 2864, 1497, 1455, 1361, 1210, 1065(br),
915, 735, 697. Anal. Calcd for C30H33O4I: C, 61.63; H, 5.69.
Found: C, 61.62; H, 5.48.
(2S*,3S*,4R*,5S*,6S*)-2-(3-Hydr oxypr opyl)-5-(iodom eth -
yl)-3,4,5-tr is(ben zyloxy)tetr a h yd r op yr a n (49). To a solu-
tion of 47 (337 mg, 577 µmol) in 7.0 mL of THF was added a
solution of diborane (1.0 M in THF, 1.0 mL, 1.00 mmol) at 0
°C. After stirring for 1 h, to the reaction mixture was
successively added 1.0 mL of EtOH, 2.0 mL of 2.5 N aq NaOH,
and 2.0 mL of 30% aq H2O2. After stirring for 30 min, the
reaction mixture was poured into cooled sat. aq Na2SO3 and
extracted with Et2O (×3). The extracts was washed with brine,
dried over Na2SO4, and concentrated in vacuo. The residue was
purified by silica gel column chromatography (ether/hexane
(2R*,3S*,4R*,4a S*,8a S*)-3,4-Bis(t r im et h ylsilyloxy)-2-
(cya n om eth yl)-1,4-d ioxa bicyclo[4.0.4]octa n e (54). To a
solution of 52 (100 mg, 318 µmol) in 3.0 mL of CH2Cl2 were
added Et3N (270 µL, 955 µmol) and TMSOTf (185 µL, 955
µmol) at 0 °C. After stirring for 1 h, the reaction mixture was
poured into cooled sat. aq NaHCO3 and extracted with Et2O
(×3). The extracts were washed with brine, dried over Na2-
SO4, and concentrated in vacuo. The residue was dissolved in
4.5 mL of DMSO, and NaCN (20.3 mg, 417 µmol) was added.
After the temperature was raised to 75 °C, the reaction
mixture was stirred for 30 min. After being cooled to room
temperature, the reaction mixture was diluted with H2O and
extracted with Et2O (×2). The extracts were washed with H2O
(×2) and brine, dried over Na2SO4, concentrated in vacuo, and
purified by silica gel column chromatography (ether/hexane
) 70:30) to give 49 (298 mg, 86%). Mp 118-118.5 °C; [R]27
D
+11.6 (c 0.48, CHCl3); 1H NMR (300 MHz, CDCl3) δ 1.48 (1H,
m, H-3a), 1.67-1.79 (2H, m, H-2), 1.90-2.01 (1H, m, H-3b),
3.08 (1H, ddd, J ) 9, 6, 2.5 Hz, H-4), 3.28 (1H, dd, J ) 10.6,
6 Hz, H-9a), 3.26-3.36 (1H, m, H-7), 3.39 (1H, t, J ) 9 Hz,
H-5), 3.48 (1H, dd, J ) 10.6, 2.5 Hz, H-9b), 3.67 (2H, q, J ) 6
Hz, H-1), 3.73 (1H, t, J ) 9 Hz, H-6), 4.66, 4.73, 4.90, 4.91
(each 1H, each d, J ) 10.6 Hz, CH2Ph), 4.88, 4.92 (each 1H,
each d, J ) 10.8 Hz, CH2Ph), 7.26-7.38 (15H, m, Ph); IR (KBr)
3389 (br), 3033, 3013, 2859, 1454, 1356, 1130, 1059 cm-1. Anal.
Calcd for C30H35O5I: C, 59.79; H, 5.86. Found: C, 59,76; H,
5.91.
) 25:75) to give 54 (96% in two steps). Mp 94-94.5 °C; [R]28
D
+29.4 (c 0.22, CHCl3); 1H NMR (300 MHz, CDCl3) δ 0.04 (9H,
s, TMS), 0.09 (9H, s, TMS), 1.40-1.54 (1H, m, H-3a), 1.65-
1.75 (2H, m, H-2), 2.05-2.15 (1H, m, H-3b), 2.57 (1H, dd, J )
17, 5.5 Hz, H-9a), 2.74 (1H, dd, J ) 17, 3 Hz, H-9b), 2.82 (1H,
t, J ) 9.0 Hz, H-5), 3.10 (1H, ddd, J ) 11, 9.5, 4.5 Hz, H-4),
3.28 (1H, ddd, J ) 11.5, 9, 6.3 Hz, H-1a), 3.37-3.52 (3H, m,
H-7, H-8, H-6), 3.90 (1H, m, H-1b); IR (KBr) 2957, 2896, 1415,
1381, 1251, 1152, 1098, 1078, 884, 842, 759 cm-1. Anal. Calcd
for C16H31O4NSi2: N, 3.92; C, 53.75; H, 8.75. Found: N, 3.70;
C, 53.75; H, 9.04.
(2S*,3S*,4R*,5S*,6S*)-2-(3-p-Tolu en esu lfon yl)-5-(iod o-
m eth yl)-3,4,5-tr ih yd r oxytetr a h yd r op yr a n (51). To a solu-
tion of 49 (116 mg, 193 µmol) in 4.0 mL of CH2Cl2 were added
pyridine (200 µL, 2.48 mmol) and TsCl (108 mg, 568 µmol) at
0 °C. After stirring for 1 day at room temperature, the reaction
mixture was poured into cooled sat. aq NaHCO3 and extracted
with Et2O (×3). The extracts was washed with brine, dried
over Na2SO4, and concentrated in vacuo. The residue was
purified by silica gel column chromatography (ether/hexane
) 25:75) to give tosylate 50 (98.0 mg, 67%). Mp 105-105.5
(2S*,3S*,4R*,4a S*,8a S*)-3,4-Bis(t r im et h ylsilyloxy)-2-
(for m ylm eth yl)-1,4-d ioxa bicyclo[4.0.4]octa n e (55). To a
solution of 54 (100 mg, 280 µmol) in 3.0 mL of CH2Cl2 was
added a solution of DIBAL (1.0 M in hexane, 310 µL, 310 µmol)
at -78 °C. After stirring for 1.5 h at -78∼-20 °C, to the
reaction mixture was added 10% aq AcOH, and it was
extracted with ether:hexane (1:1) (×2). The extracts were
washed with H2O, sat. aq NaHCO3, and brine, dried over Na2-
SO4, concentrated in vacuo, and purified by silica gel column
chromatography (ether/hexane ) 33:67) to give aldehyde 55
1
°C; [R]27 +9.5 (c 0.27, CHCl3); H NMR (300 MHz, CDCl3), δ
D
1.40-1.47 (1H, m, H-3a), 1.68-1.78 (1H, m, H-3b), 1.82-1.91
(2H, m, H-2), 2.42 (3H, s, ArCH3), 2.99 (1H, m, H-4), 3.15-
3.22 (3H, m, H-5, H-8, H-9a), 3.32 (1H, t, J ) 9.0 Hz, H-7),
3.42 (1H, dd, J ) 10.3, 2.5 Hz, H-9b), 3.66 (1H, m, H-6), 4.06
(2H, m, H-1), 4.59, 4.70, 4.85, 4.91 (each 1H, each d, J ) 10.5
Hz, CH2Ph), 4.87, 4.90 (each 1H, each d, J ) 11.0 Hz, CH2-
Ph), 7.26-7.36 (17H, m, CH2Ph, C6H4CH3), 7.78 (2H, d, J )
8.0 Hz, C6H4CH3). Anal. Calcd for C37H41O7IS: C, 58.73; H,
5.46. Found: C, 58.56; H, 5.50.
(97.3 mg, 96%). [R]28 +14.2 (c 0.31, CHCl3); 1H NMR (300
D
To a solution of the tosylate 50 (135 mg, 174 µmol) in 4.0
mL of CH2Cl2 were added EtSH (250 µL, 3.31 mmol) and BF3‚
OEt2 (250 µL, 2.61 mmol) at -78 °C. After being stirred
overnight at room temperature, the reaction mixture was
poured into cooled sat. aq NaHCO3 and extracted with Et2O
MHz, CDCl3) δ 0.14, 0.15 (each 9H, each s, TMS), 1.32-1.46
(1H, m, H-3), 1.64-1.74 (2H, m, H-2), 2.00-2.09 (1H, m, H-3),
2.46 (1H, ddd, J ) 16.5, 9, 3.5 Hz, H-9a), 2.73 (1H, ddd, J )
16.5, 3.5, 1.5 Hz, H-9b), 2.78 (1H, ddd, J ) 11, 9, 4.5 Hz, H-4),
3.21-3,30 (1H, m, H-1a), 3.33 (1H, dd, J ) 9, 8 Hz, H-6), 3.50

46 J . Org. Chem., Vol. 64, No. 1, 1999
Hosokawa and Isobe
(1H, t, J ) 9 Hz, H-7), 3.75 (1H, td, J ) 9, 3.5 Hz, H-8), 3.89
(1H, m, H-1b), 9.76 (1H, dd, J ) 3.5, 1.5 Hz, CHO); IR (KBr)
2954, 2944, 2893, 2852, 2734, 1731, 1250, 1153, 1101, 1093,
851, 842 cm-1. Anal. Calcd for C16H32O5Si2: C, 53.29; H, 8.94.
Found: C, 53.28; H, 9.10.
(ether/hexane ) 60:40) to give a colorless oil 58 (723 mg, 96%).
[R]28 +158.1 (c 0.69, CHCl3); 1H NMR (300 MHz, CDCl3) δ
D
1.21 (9H, s, Piv), 1.46-1.56 (1H, m, H-14a), 1.68-1.76 (2H,
m, H-15), 2.04, 2.06 (each 3H, each s, Ac), 2.01-2.17 (1H, m,
H-14b), 2.45 (1H, ddd, J ) 12.5, 6.4, 2.4 Hz, H-8a), 2.53 (1H,
ddd, J ) 12.5, 5, 2.5 Hz, H-8b), 3.08 (1H, t, J ) 9.5 Hz, H-12),
3.22 (1H, ddd, J ) 11, 9.5, 4.5 Hz, H-13), 3.28-3.37 (1H, m,
H-16a), 3.58 (1H, ddd, J ) 10, 6, 4.5 Hz, H-9), 3.79 (1H, m,
H-1a), 3.94 (1H, m, H-16b), 4.19 (1H, dd, J ) 13.5, 3.5 Hz,
H-1b), 4.90 (1H, m, H-5), 4.93 (1H, t, J ) 9.5 Hz, H-10), 5.02
(1H, m, H-2), 5.12 (1H, t, J ) 9.5 Hz, H-11), 5.89 (1H, m, H-4*),
6.01 (1H, dd, J ) 10.5, 3.6 Hz, H-3*); 13C NMR (75.4 MHz,
CDCl3) δ 20.75, 20.92, 22.64, 24.87, 27.10, 28.97, 38.74, 63.13,
63.68, 64.28, 67.80, 72.20, 73.87, 75.38, 75.87, 77.91, 79.26,
82.14, 122.55, 132.09, 169.79, 170.62, 178.24; IR (KBr) 2968,
2946, 2864, 1751, 1725, 1368, 1243, 1159, 1098, 1051, 945, 736
cm-1. Anal. Calcd for C25H34O9: C, 62.75; H, 7.16. Found: C,
62.76; H, 7.31.
(2S*,3S*,4R*,4a S*,8a S*)-3,4-bis(tr im eth ylsilyloxy)-2-(3-
(t r im et h ylsilyl)-2-p r op yn yl)-1,4-d ioxa b icyclo[4.0.4]oc-
ta n e (56). To a solution of CBr4 (2.23 g, 6.72 mmol) in 10 mL
of CH2Cl2 was added a solution of PPh3 (3.53 g, 13.5 mmol) in
10 mL of CH2Cl2 at 0 °C via cannula. After stirring for 5 min,
a solution of aldehyde 55 (605 mg, 1.68 mmol) in 10 mL of
CH2Cl2 was added to this reaction mixture at 0 °C via cannula.
After stirring for 30 min, to the reaction mixture was added
Et3N (2.4 mL, 16.8 mmol), and the resulting orange mixture
was poured into cooled sat. aq NaHCO3 and extracted with
CH2Cl2 (×2). The extracts were dried over Na2SO4, concen-
trated in vacuo, and purified by short silica gel column
chromatography (ether/hexane ) 33:67) to give a colorless oil,
which was used to next reaction right away. To a solution of
colorless dibromide in 24 mL of THF was added a solution of
n-BuLi (1.6M in hexane, 2.3 mL, 1.44 mmol) at -78 °C. After
stirring for 30 min at -78 °C, to the resulting dark green
solution was added TMSCl (640 µL, 5.04 mmol). After stirring
for 20 min at -78 °C, into this solution was poured a cooled
aq NaHCO3, and it was extracted with Et2O:hexane ) 1:1 (×2).
The extracts were washed with brine, dried over Na2SO4,
concentrated in vacuo, and purified by silica gel column
chromatography (ether/hexane ) 15:85) to give 56 (589 mg,
95% in two steps). Mp 63-63.5 °C; [R]28D +26.3 (c 0.48, CHCl3);
1H NMR (300 MHz, CDCl3) δ 0.14, 0.15, 0.19 (each 9H, each
s, TMS), 1.41-1.53 (1H, m, H-3), 1.64-1.74 (2H, m, H-2),
2.05-2.13 (1H, m, H-3), 2.53 (1H, dd, J ) 17.5, 5 Hz, H-9a),
2.63 (1H, dd, J ) 17.5, 3.5 Hz, H-9b), 2.79 (1H, t, J ) 9.5 Hz,
H-5), 3.07 (1H, ddd, J ) 11, 9.5, 4.5 Hz, H-4), 3.32-3.23 (2H,
m, H-1a, H-8), 3.46 (1H, t, J ) 8.5 Hz, H-7), 3.57 (1H, dd,
J ) 9.5, 8.5 Hz, H-6), 3.88 (1H, m, H-1b); IR (KBr) 2950,
2900, 2859, 2176, 1249, 1151, 1079, 850, 838 cm-1. Anal.
Calcd for C20H40O4Si3: C, 56.02; H, 9.40. Found: C, 56.09; H,
9.66.
(2S*,3S*,4R*,4a S*,8a S*)-3,4-Dia cetoxy-2-(3-(tr im eth yl-
silyl)-2-p r op yn yl)-1,4-d ioxa bicyclo[4.0.4]octa n e (57). To
a solution of 56 (693 mg, 1.62 mmol) in 25 mL of MeOH was
added PPTS (6.0 mg, 23.9 µmol). After stirring for 1 h at room
temperature, the reaction mixture was concentrated in vacuo,
and the residue was dissolved in 25 mL of CH2Cl2. To this
solution were added Ac2O (3.0 mL, 29.9 mmol), pyridine (6.0
mL, 74.2 mmol), and DMAP (10 mg, 81.9 µmol). After stirring
for 1.5 h at room temperature, to this reaction mixture was
added H2O, and it was extracted with Et2O. The extracts were
washed with sat. aq CuSO4, H2O, and brine and dried over
Na2SO4. Evaporation and concentration gave crude oil which
was purified by silica gel column chromatography (ether/
hexane ) 40:60) to give 57 (577 mg, 97%). Mp 79.5-80 °C;
[R]26D +32.9 (c 4.68, CHCl3); 1H NMR (300 MHz, CDCl3) δ 0.15
(9H, s, TMS), 1.44-1.57 (1H, m, H-3a), 1.68-1.77 (2H, m, H-2),
2.03 (3H, s, Ac), 2.06 (3H, s, Ac), 2.11-2.19 (1H, m, H-3b), 2.48
(1H, dd, J ) 17, 6 Hz, H-9a), 2.50 (1H, dd, J ) 17, 5 Hz, H-9b),
3.08 (1H, t, J ) 9.5 Hz, H-5), 3.23 (1H, ddd, J ) 11, 9.5, 4.5
Hz, H-4), 3.28-3.37 (1H, m, H-1a), 3.58 (1H, ddd, J ) 9.5, 6,
5 Hz, H-8), 3.94 (1H, m, H-1b), 4.92 (1H, t, J ) 9.5 Hz, H-7),
5.12 (1H, t, J ) 9.5 Hz, H-6); 13C NMR (67.9 MHz, CDCl3) δ
20.83, 20.92, 23.81, 24.87, 27.08, 28.91, 67.78, 72.43, 73.89,
75.38, 76.14, 79.32, 86.74, 101.71, 169.77, 179,64; IR (KBr)
2957, 2868, 2180, 1749 (br), 1363, 1242 (br), 1104, 1040, 840,
762 cm-1. Anal. Calcd for C18H28O6Si: C, 58.67; H, 7.66.
Found: C, 58.53; H, 7.72.
Acetylen ecoba lth exa ca r bon yl Com p lex 62. To a solu-
tion of 58 (42.7 mg, 89.2 µmol) in 2.0 mL of CH2Cl2 was added
a solution of Co2(CO)8 (136 mg, 398 µmol) in 1.5 mL of CH2Cl2
via cannula. After being stirred for 30 min at room tempera-
ture, the reaction mixture was concentrated in vacuo and
purified by silica gel column chromatography (ether/hexane
) 40:60) to give dark red oil 62 (52.0 mg, 76%). This compound
was labile and was used to next reaction right away. [R]30
D
+85.9 (c 0.10, CHCl3); 1H NMR (300 MHz, CDCl3) δ 1.21 (9H,
s, Piv), 1.44-1.52 (1H, m, H-14a), 1.66-1.75 (2H, m, H-15),
2.06, 2.08 (each 3H, each s, Ac), 2.09-2.16 (1H, m, H-14b),
2.89 (1H, J ) 16.5, 3.5 Hz, H-8a), 2.95 (1H, dd, J ) 16.5, 8
Hz, H-8b), 3.12 (1H, t, J ) 9.5 Hz, H-12), 3.19 (1H, dt, J )
9.5, 4.5 Hz, H-13), 3.28-3.37 (1H, m, H-16a), 3.58 (1H, ddd, J
) 9.5, 8, 3.5 Hz, H-9), 3.64 (1H, dd, J ) 11.5, 7 Hz, H-1a),
3.94 (1H, m, H-16b), 4.24 (1H, dd, J ) 11.5, 5 Hz, H-1b), 4.94
(1H, t, J ) 9.5 Hz, H-10), 5.16 (1H, t, J ) 9.5 Hz, H-11), 5.25
(1H, m, H-2), 5.29 (1H, dd, J ) 4, 2 Hz, H-5), 5.90 (1H, dt, J
) 10.5, 2 Hz, H-4), 6.02 (1H, ddd, J ) 10.5, 2, 1.5 Hz, H-3);
13C NMR (67.9 MHz, CDCl3) δ 20.70, 20.93, 24.87, 27.13, 28.77,
35.33, 38.78, 64.11, 65.41, 67.83, 72.47, 73.62, 73.87, 75.13,
78.81, 79.15, 92.72, 96.17, 125.48, 132.16, 170.20, 178.06,
199.42 (br); IR (KBr) 2959, 2947, 2862, 2092, 2052, 2018, 1754,
1732, 1365, 1239, 1155, 1093, 522 cm-1; FAB-MS m/z 765 (M
+ H), 708 (M - 2×CO), 680 (M - 3×CO), 652 (M - 4×CO),
596 (M - 6×CO); HR-FAB-MS calcd for C29H34O13Co2 708.0663,
found 708.0641.
5-Meth yl Eth er 59. To a solution of pivalic anhydride (105
µL, 523 µmol) in 3.0 mL of CH2Cl2 was added TfOH (25 µL,
262 µmol) at -20 °C. After stirring for 30 min at -20 °C, to
the mixture was added a solution of cobalt complex 62 (39.9
mg, 52.3 µmol) in 2.0 mL of CH2Cl2 via cannula. After stirring
for 30 min at -20 °C, to the reaction mixture was added MeOH
(200 µL), and the resulting dark red solution was poured into
cooled sat. aq NaHCO3 and extracted with Et2O (×2). The
extracts were washed with brine, dried over Na2SO4, concen-
tration in vacuo, and purified by silica gel column chromatog-
raphy (ether/hexane ) 40:60) to give a dark red oil 59 (44.8
1
mg, 97%). H NMR (300 MHz, CDCl3) δ 1.19, 1.20, 1.21, 1.22
(total 18H, each s, Piv), 1.44-1.56 (1H, m, H-14a), 1.70 (2H,
m, H-15), 2.05, 2.06 (each 3H, each s, Ac), 2.07 (6H, s, Acx2),
2.09-2.16 (1H, m, H-14b), 3.11 (1H, t, J ) 9 Hz, H-12), 3.20
(1H, m, H-13), 3.27-3.36 (1H, m, H-16a), 3.38, 3.42 (total 3H,
each s, OMe), 3.57 (1H, m, H-9), 3.95 (1H, m, H-16b), 4.04 (1H,
ddd, J ) 12, 7.5, 5 Hz, H-1a), 4.29 (1H, ddd, J ) 12, 6, 3.5 Hz,
H-1b), 4.74 (1H, m, H-5), 4.92, 4.93 (1H, each t, J ) 9.5 Hz,
H-10), 5.16 (1H, t, J ) 9.5 Hz, H-11), 5.58 (1H, m, H-2), 5.79
(2H, m, H-3, H-4); 13C NMR (75.4 MHz, CDCl3) δ 20.6, 20.8,
24.8, 26.97, 27.01, 27.02, 28.9, 35.2, 35.7, 38.67, 38.73, 38.8,
57.15, 57.21, 64.7, 67.8, 70.51, 70.54, 72.5, 73.8, 73.9, 75.0, 76.4,
87.7, 79.2, 81.1, 81.4, 92.4, 93.1, 97.2, 97.9, 126.5, 127.3, 132.9,
133.2, 170.20, 170.23, 170.7, 177.2, 178.1, 199.7(br); IR (KBr)
2977, 2939, 2912, 2865, 2092, 2053, 2029, 1751, 1735, 1482,
1367, 1284, 1241, 1141, 520 cm-1; MS(FAB) m/z 849 (M + H
- MeOH), 796 (M - 3×CO), 768 (M - 4×CO), 712 (M -
6×CO); HRMS(FAB) calcd for C36H43O16Co2 849.1214, found
849.1214.
Acetylen e 58. To a solution of 57 (577 mg, 1.57 mmol) and
di-O-pivaloyl-D-xylal (668 mg, 2.36 mmol) in 25 mL of CH2Cl2
was added SnCl4 (265 µL, 2.28 mmol) at -20 °C. After stirring
for 30 min at -20 °C, another di-O-pivaloyl-D-xylal (446 mg,
1.57 mmol) was added. After additional 30 min at -20 °C, the
reaction mixture was poured into cooled sat. aq NaHCO3 and
sat. aq NaK(CH(OH)COO)2 (1:1) and extracted with CH2Cl2
(×3). The extracts were dried over Na2SO4, concentrated in
vacuo, and purified by silica gel column chromatography

Synthesis of Left Ends of Ciguatoxin and Gambiertoxin 4b
J . Org. Chem., Vol. 64, No. 1, 1999 47
en d o-Acet ylen ecob a lt h exa ca r b on yl Cyclic E t h er 60.
To a solution of 59 (930 mg, 1.06 mmol) in 40 mL of degassed
MeOH was added K2CO3 (176 mg, 1.27 mmol). After being
stirred for 45 min at room temperature, the reaction mixture
was poured into cooled sat. aq NH4Cl and extracted with Ac-
OEt (×2). The extracts were washed with brine, dried over
Na2SO4, concentrated, and purified by silica gel column chro-
matography (ethyl acetate/hexane ) 50:50) to give a dark red
diol 59′ (685 mg, 81%). To a solution of 59′ (21.3 mg, 26.7 µmol)
in degassed 26.0 mL of CH2Cl2 was added a solution of BF3‚
OEt2 (0.27 M in 1,2-dichloromethane, 100 µL, 27.2 µmol) at 0
°C. After being stirred for 20 min at 0 °C, the reaction mixture
was poured into cooled sat. aq NaHCO3 and extracted with
AcOEt (×2). The extracts were washed with brine, dried over
Na2SO4, concentrated, and purified by silica gel column chro-
matography (ether/hexane ) 30:70) to give a dark red oil 60
(14.5 mg, 71%). 59′: 1H NMR (300 MHz, CDCl3) δ 1.19, 1,20
(9H, each s, Piv), 1.21 (9H, brs, Piv), 1.40-1.53 (1H, m, H-14a),
1.69 (2H, m, H-15), 2.02-2.12 (1H, m, H-14b), 2.60-2.86 (2H,
m, H-8), 2.94 (1h, t, J ) 9 Hz, H-12), 3.04-3.14(1H, m, H-13),
3.32-3.45 (3H, m, H-10, H-11, H-16a), 3.39, 3.43 (total 3H,
each s, OMe), 3.59 (1H, m, H-9), 3.96 (1H, m, H-16b), 4.06 (1H,
ddd, J ) 12, 8, 3 Hz, H-1a), 4.29 (1H, dd, J ) 12, 3.5 Hz, H-1b),
4.78 (1H, m, H-5), 5,56 (1H, m, H-2), 5.80 (2H, m, H-3, H-4);
13C NMR (75.4 MHz, CDCl3), δ 25.0, 26.98, 27.01, 27.03, 28.79,
28.84, 28.86, 35.7, 36.0, 38.70, 38.72, 38.77, 38.79, 57.1, 57.2,
64.8, 64.9, 67.8, 70.6, 70.8, 74.6, 76.1, 76.5, 80.2, 80.3, 81.2,
81.4, 81.7, 93.6, 93.9, 96.7, 97.6, 126.3, 127.2, 133.2, 177.4,
177.5, 178.20, 178.23, 178.3, 199.9(br); IR (KBr) 3467 (br),
2968, 2948, 2881, 2870, 2090, 2048, 2027, 1739, 1733, 1482,
1280, 1163, 1153, 1084 cm-1; MS(FAB) m/z 765 (M + H -
MeOH), 712 (M - 3×CO), 684 (M - 4×CO), 656 (M - 5×CO),
628 (M - 6×CO); HRMS(FAB) calcd for C32H39O14Co2 765.1003,
found 765.1003. 60: [R]29D -266 (c 0.12, CHCl3); 1H NMR (300
MHz, CDCl3) δ 1.18, 1.20 (each 9H, each s, OPiv), 1.40-1.53
(1H, m, H-14a), 1.72 (2H, m, H-15), 2.04-2.11 (1H, m, H-14b),
2.87 (1H, bs, -OH), 2.91 (1H, dd, J ) 16, 10 Hz, H-8a), 3.05
(1H, t, J ) 9 Hz, H-12), 3.13 (1H, td, J ) 9, 4 Hz, H-13), 3.38
(1H, m, H-16a), 3.41 (1H, t, J ) 9 Hz, H-10), 3.47 (1H, ddd, J
) 10, 9, 4 Hz, H-9), 3.51 (1H, m, H-16a), 3.60 (1H, dd, J ) 16,
4 Hz, H-8b), 3.68 (1H, t, J ) 9 Hz, H-11), 4.00 (1H, m, H-16b),
4.12 (1H, dd, J ) 11.6, 7 Hz, H-1a), 4.27 (1H, dd, J ) 11.6, 3.5
Hz, H-1b), 5.07 (1H, d, J ) 4.7 Hz, H-5), 5,63 (1H, m, H-2),
5.88 (1H, dd, J ) 16, 5 Hz, H-3), 5.92 (1H, dd, J ) 16, 4.7 Hz,
H-4); 13C NMR (75.4 MHz, CDCl3) δ 24.9, 26.95, 27.04, 28.9,
38.67, 38.72, 38.8, 54.7, 67.6, 70.7, 74.3, 74.7, 75.8, 76.4, 80.0,
81.37, 87.6, 91.7, 99.8, 125.8, 131.9, 198.9(br); IR (KBr)
3503(br), 2958, 2932, 2873, 2093, 2054, 2025, 1733, 1482, 1282,
1146, 1097, 519 cm-1; MS(FAB) m/z 765 (M + H), 680 (M -
3×CO), 653 (M + H - 4×CO), 624 (M - 5×CO), 596 (M -
6×CO); HRMS(FAB) calcd for C26H38O8Co2, 596.1230, found
596.1224.
(2S,5S)-ABC Segm en t 40. To the solution of dipivalate 61
(9.4 mg, 19.6 µmol) in MeOH (1.5 mL) was added NaOMe (28%
in MeOH, 30 µL). After being stirred for 4 h at room
temperature, the reaction was quenched by AcOH (10% in
MeOH, 50 µL) at 0 °C. The resulting mixture was concentrated
in vacuo. The residue was purified by silica gel column
chromatography to obtain (2S,5S)-ABC segment 40 (5.2 mg,
85%). Mp 144.5-145 °C; [R]28 -52.7 (c 0.045, MeOH); 1H
D
NMR (400 MHz, CD3OD) δ 1.38-1.47 (1H, m, H-14a), 1.65-
1.72 (2H, m, H-15), 2.01-2.05 (1H, m, H-14b), 2.33-2.41 (1H,
m, H-8a), 2.55-2.61 (1H, m, H-8b), 2.89 (1H, t, J ) 9 Hz, H-12),
3.09 (1H, ddd, J ) 11, 9, 4.5 Hz, H-13), 3.21 (1H, td, J ) 9, 4
Hz, H-9), 3.30 (1H, t, J ) 9 Hz, H-10), 3.32-3.39 (1H, m,
H-16a), 3.47 (1H, dd, J ) 11, 6 Hz, H-1a), 3.51 (1H, dd, J )
11, 5 Hz, H-1b), 3.51 (1H, t, J ) 9 Hz, H-11), 3.89-2.94 (1H,
m, H-16b), 4.08-4.13 (1H, m, H-2), 4.55-4.58 (1H, m, H-5),
5.75-5.82 (3H, m, H-3*, 6, 7), 5.85 (1H, dd, J ) 15.5, 5 Hz,
H-4*); IR (KBr) 3356, 3195, 1101, 1042 cm-1. Anal. Calcd for
C
16H24O6: C, 61.52; H, 7.74. Found: C, 61.51; H, 7.72.
(2R,5S)-ABC Segm en t 41. (2R,5S)-ABC segment 41 was
prepared as (2S,5S)-ABC segment 40. Mp 167.5-168 °C; [R]28
D
1
-45.4 (c 0.045, MeOH); H NMR (400 MHz, CD3OD) δ 1.39-
1.47 (1H, m, H-14a), 1.65-1.72 (2H, m, H-15), 2.00-2.05 (1H,
m, H-14b), 2.33-2.41 (1H, m, H-8a), 2.54-2.62 (1H, m, H-8b),
2.89 (1H, t, J ) 9 Hz, H-12), 3.09 (1H, ddd, J ) 11, 9, 4.5 Hz,
H-13), 3.21 (1H, td, J ) 9, 4 Hz, H-9), 3.31 (1H, t, J ) 9 Hz,
H-10), 3.35-3.39 (1H, m, H-16a), 3.46 (1H, dd, J ) 11, 4 Hz,
H-1a), 3.50 (1H, dd, J ) 11, 5.5 Hz, H-1b), 3.50 (1H, t, J ) 9
Hz, H-11), 3.89-2.94 (1H, m, H-16b), 4.09-4.14 (1H, m, H-2),
4.55-4.58 (1H, m, H-5), 5.77-5.82 (2H, m, H-6, 7), 5.81 (1H,
dd, J ) 15.5, 5 Hz, H-3*), 5.86 (1H, dd, J ) 15.5, 4.5 Hz, H-4*);
IR (KBr) 3314 (br), 3232, 1098, 1047 cm-1. Anal. Calcd for
C
16H24O6: C, 61.52; H, 7.74. Found: C, 61.51; H, 7.72.
(2S,5S)-Tr is(p-br om oben zoyl)-ABC Segm en t 42. To the
solution of (2S,5S)-ABC fragment 40 (2.8 mg, 8.96 µmol) in
the mixture of CH2Cl2 (1.0 mL) and triethylamine (50 µL) was
added p-bromobenzoyl chloride (9.4 mg, 45.7 µmol) at 0 °C.
After being stirred overnight at room temperature, to this
reaction mixture was added sat. NaHCO3, and it was extracted
with Et2O (×2). The extracts were washed with brine and dried
over Na2SO4. Evaporation and concentration gave a crude oil
which was purified by silica gel column chromatography (ether/
hexane ) 40:60) to obtain (2S,5S)-tris(p-bromobenzoyl)-ABC
segment 42 (2.9 mg, 3.34 µmol, 37%). Mp 174.5-175 °C; [R]27
D
-33.1 (c 0.42, CHCl3); 1H NMR (400 MHz, CDCl3) δ 1.50 (1H,
ddd, J ) 12, 11, 5 Hz, H-14a), 1.67-1.81 (2H, m, H-15), 2.14
(1H, m, H-14b), 2.44 (1H, ddtd, J ) 15.5, 10, 3, 2 Hz, H-8a),
2.68 (1H, ddd, J ) 15.5, 8.5, 3.5 Hz, H-8b), 3.19 (1H, t, J ) 9
Hz, H-12), 3.27 (1H, ddd, J ) 10.5, 9, 4.5 Hz, H-13), 3.31 (1H,
dd, J ) 11.5, 4 Hz, H-16a) 3.41 (1H, ddd, J ) 10, 9, 3.5 Hz,
H-9), 3.58 (1H, t. J ) 9 Hz, H-10), 3.92 (1H, m, H-16b), 4.22
(1H, dd, J ) 11.5, 7 Hz, H-1a), 4.33 (1H, dd, J ) 11.5, 3.5 Hz,
H-1b), 4.55 (1H, m, H-5), 5.42 (1H, t, J ) 9 Hz, H-11), 5.69-
5.90 (5H, m, H-2, H-3, H-4, H-6, H-7), 7.38, 7.55, 7.56, 7.68,
7.817, 7.822 (each 2H, each d, each J ) 8.5 Hz, O-p-BrBz);
13C NMR (75.4 MHz, CDCl3), δ 29.1, 29.6, 34.1, 65.5, 67.7, 72.5,
75.0, 75.6, 79.7, 85.6. 123.5, 128.0. 128.7, 129.3, 131.1, 131.3,
131.6, 131.85, 131.90, 134.8, 135.2, 164.9, 165.4, 165.6; IR
(KBr) 2952, 2867, 1724, 1590, 1484, 1399, 1267, 1174, 1101,
1013, 847, 754 cm-1. Anal. Calcd for C37H31O9Br3: C, 51.59;
H, 3.86. Found: C, 51.50; H, 3.85.
(2S,5S)-ABC Segm en t Dip iva la te 61. To a solution of 60
(10.2 mg, 13.3 µmol) in 2.0 mL of benzene was added Wilkinson
catalyst (0.6 mg, 0.67 µmol). After stirring for 5 h at 65-70
°C under 100 kg/cm2 hydrogen atmosphere, the pressure was
reduced to ambient pressure, and the temperature was turned
into room temperature. The resulting mixture was filtered,
concentrated, and purified by silica gel column chromatogra-
phy (ether/hexane ) 30:70) to give 61 (4.6 mg, 72%). Mp 88.5-
89 °C; [R]26D -17.2 (c 0.47, CHCl3); 1H NMR (300 MHz, CDCl3)
δ 1.19 (9H, s, Piv), 1.21 (9H, s, Piv), 1.45 (1H, m, H-14a), 1.72
(2H, m, H-15), 2.07 (1H, m, H-14b), 2.40 (1H, m, H-8a), 2.62
(1H, ddd, J ) 4, 8.5, 16.0 Hz, H-8b), 2.78 (1H, brs, -OH), 3.03
(1H, t, J ) 9.0 Hz, H-12), 3.13 (1H, ddd, J ) 11, 9, 6.5 Hz,
H-13), 3.24 (1H, ddd, J ) 9, 8.5, 4 Hz, H-9), 3.37 (1H, t, J ) 9
Hz, H-10), 3.43 (1H, m, H-16a), 3.67 (1H, t, J ) 9 Hz, H-11),
4.00 (1H, m, H-16b), 4.12 (1H, dd, J ) 6.5, 12 Hz, H-1a), 4.27
(1H, dd, J ) 4.0, 12 Hz, H-1b), 4.55 (1H, m, H-5), 5.52 (1H, m,
H-2), 5.73 (1H, ddd, J ) 15.5, 6, 1.5 Hz, H-3), 5.75 (1H, m,
H-7), 5.84 (1H, m, H-6), 5.89 (1H, ddd, J ) 15.5, 6, 1 Hz, H-4);
IR (KBr) 3470, 2971, 2871, 1732, 1482, 1281, 1144, 1098, 1040
cm-1. Anal. Calcd for C26H40O8: C, 64.98; H, 8.39. Found: C,
64.97; H, 8.41.
(2R,5S)-Tr is(p-br om oben zoyl)-ABC F r a gm en t 43. (2R,-
5S)-tris(p-bromobenzoyl)-ABC 43 segment was prepared as
(2S,5S)-tris(p-bromobenzoyl)-ABC segment 42. Mp 104.5-105
°C; [R]27 -79.9 (c 0.50, CHCl3); 1H NMR (400 MHz, CDCl3) δ
D
1.50 (1H, ddd, J ) 12, 11, 5 Hz, H-14a), 1.67-1.81 (2H, m,
H-15), 2.13 (1H, m, H-14b), 2.43 (1H, ddq, J ) 16, 10, 3 Hz,
H-8a), 2.68 (1H, ddd, J ) 16, 8.5, 1.5 Hz, H-8b), 3.20 (1H, t, J
) 9 Hz, H-12), 3.27 (1H, ddd, J ) 10.5, 9, 4 Hz, H-13), 3.31
(1H, td, J ) 11, 3.5 Hz, H-16a), 3.41 (1H, ddd, J ) 10, 9, 3.5
Hz, H-9), 3.59 (1H, t, J ) 9 Hz, H-10), 3.94 (1H, m, H-16b),
4.10 (1H, dd, J ) 10.5, 7 Hz, H-1a), 4.18 (1H, dd, J ) 10.5, 3.5
Hz, H-1b), 4.51 (1H, m, H-5), 5.42 (1H, t, J ) 9 Hz, H-11),
5.65-5.88 (5H, m, H-2, H-3, H-4, H-6, H-7), 7.54 (2H, d, J )

48 J . Org. Chem., Vol. 64, No. 1, 1999
Hosokawa and Isobe
8.5 Hz, O-p-BrBz), 7.55 (4H, d, J ) 8.5 Hz, O-p-BrBz), 7.55
(4H, d, J ) 8.5 Hz, O-p-BrBz), 7.99, 7.81, 7.90 (each 2H, each
d, each J ) 8.5 Hz, O-p-BrBz); 13C NMR (75.4 MHz, CDCl3), δ
29.1, 29.6, 34.1, 65.1, 67.7, 71.9, 75.0, 75.2, 75.6, 76.8, 79.7,
85.6, 123.6, 127.8, 128.2, 128.4, 129.3, 131.2, 131.8, 134.7,
135.0, 164.9, 165.3, 165.6; IR (KBr) 2951, 2855, 1725, 1591,
1484, 1399, 1267, 1174, 1013, 847, 754 cm-1. Anal. Calcd for
spectra and Mr. S. Kitamura in Nagoya University for
the measurement of elemental analysis and high reso-
lution mass spectra. We also thank Dr. Shigeyosi
Tanaka at Kao Co. Ltd. and Dr. Chavie Yenjai at Kohn
Kaen University, Thailand, for their preliminary studies
connected to this work.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR of spectra
of compounds 5, 11-13, 17, 20-25, 27, 35, 37, 40-43, 45-
47, 49-52, 54-61, the diastereomer of 61 at C-2 position, 62;
CD spectra of compounds 42 and 43 (38 pages). This material
is contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
C
37H31O9Br3: C, 51.59; H, 3.86. Found: C, 51.56; H, 3.93.
Ack n ow led gm en t. This research was financially
supported by a Grant-In-Aids for Scientific Research
from Ministry of Education, Science, Sports and Culture
and J SPS-RFTF. S.H. thanks to J SPS Research Fel-
lowships for Young Scientists. Special thanks are due
to Prof. Emeritus H. Nakata in Aichi Education Uni-
versity for the helpful discussion on assignment of mass
J O980088N