First total synthesis of (-)-ichthyothereol and its acetate

Article abstract of DOI:10.1021/jo0104532

The first and stereoselective total syntheses of (-)-ichthyothereol (1) and its acetate ((+)-2) were achieved by incorporation of the two chiral centers of diethyl L-tartrate. The starting diethyl L-tartrate was converted into trans-2-ethynyl-3-hydroxytetrahydropyran 14 in a stereoselective manner via the endo mode cyclization of the epoxy-alkyne derivative 12. The alcohol 12 was then transformed into (E)-iodoolefin derivative 15, which was exposed to a coupling reaction with 1-tributylstannyl-1,3,5-heptyne (19), derived from the corresponding 1-trimethylsilyl-1,3,5-heptyne (18), under Stille conditions to produce the all-carbon framework of the target natural products. Chemical modification of the coupled product 20 under conventional conditions completed the first total synthesis of (-)-ichthyothereol (1) and its acetate ((+)-2).

Full text of DOI:10.1021/jo0104532

J . Org. Chem. 2001, 66, 5875-5880
5875
F ir st Tota l Syn th esis of (-)-Ich th yoth er eol a n d Its Aceta te
Chisato Mukai,*,† Naoki Miyakoshi, and Miyoji Hanaoka*
Faculty of Pharmaceutical Sciences, Kanazawa University, Takara-machi 13-1,
Kanazawa 920-0934, J apan
cmukai@kenroku.kanazawa-u.ac.jp
Received May 2, 2001
The first and stereoselective total syntheses of (-)-ichthyothereol (1) and its acetate ((+)-2) were
achieved by incorporation of the two chiral centers of diethyl L-tartrate. The starting diethyl
L-tartrate was converted into trans-2-ethynyl-3-hydroxytetrahydropyran 14 in a stereoselective
manner via the endo mode cyclization of the epoxy-alkyne derivative 12. The alcohol 12 was then
transformed into (E)-iodoolefin derivative 15, which was exposed to a coupling reaction with
1-tributylstannyl-1,3,5-heptyne (19), derived from the corresponding 1-trimethylsilyl-1,3,5-heptyne
(18), under Stille conditions to produce the all-carbon framework of the target natural products.
Chemical modification of the coupled product 20 under conventional conditions completed the first
total synthesis of (-)-ichthyothereol (1) and its acetate ((+)-2).
Sch em e 1
In tr od u ction
In 1965, (-)-ichthyothereol (1) and its acetate (2)1,2
were isolated from the leaves and flowers of Dahlia
coccinea as well as from the leaves of Ichthyother
terminals, the latter of which have long been known to
be used as a fish poison by the natives of the Lower
Amazon Basin.1,3 The crude extracts of the leaves of I.
terminals had been found to be extremely poisonous not
only to fish but also to mammals.3 The effects in dogs
were typically convulsant, similar to those of picrotoxin,
indicating bulbar action. Minute quantities of either
ichthyothereol (1) or its acetate (2) were extremely toxic
to the fish Lebistes reticulatus, confirming that these
triyne derivatives should be at least in part responsible
for the toxicity of the leaves of I. terminals.1,3 These two
compounds were also shown to kill mice1 when injected
intraperitoneally in doses of 1 mg in olive oil. The gross
structure1,3 including the relative stereochemistry of
compounds 1 and 2 was determined by 1H NMR analysis.
The absolute configuration of two chiral centers of 1 and
2 was first tentatively deduced on the basis of the optical
rotatory dispersion curve1 of the substituted tetrahydro-
pyran-3-one derivatives prepared by oxidation of perhy-
droichthyothereol. Finally, the absolute configuration of
1 and 2 was unambiguously established by chemical
transformation of 1 into the (-)-bis(2,4-dinitrobenzoate)
of trans-3-hydroxy-2-hydroxymethyltetahydropyran.4
Surprisingly, no publication dealing with the total
synthesis of toxic ichthyothereol (1) and/or its acetate (2)
has so far been available notwithstanding the fact that
more than 30 years have now elapsed since their first
isolation in 1965. In this paper, we describe the first total
synthesis of (-)-ichthyothereol (l) and its acetate (2)
starting from L-tartrate in a highly stereoselective man-
ner.
Our retrosynthetic analysis is outlined in Scheme 1.
The first carbon-carbon bond disconnection of 1 would
be made between the triyne moiety and the (E)-olefin part
leading to the triyne species 3 and the trans-3-hydroxy-
2-vinyltetrahydropyran derivative 4. The latter should
be prepared from the optically active cis-epoxide 5
through the dicobalt octacarbonyl [Co2(CO)8]-mediated
endo mode cyclization5 of the cis-epoxy-alkyne species
† Tel: +81-76-234-4411. Fax: +81-76-234-4410.
(1) Chin, C.; J ones, E. R. H.; Thaller, V.; Aplin, R. T.; Durham, L.
J .; Cascon, S. C.; Mors, W. B.; Tursch, B. M. Chem. Commun. 1965,
152.
(2) Several reports on isolation of ichthyothereol and its acetate were
also recorded: (a) Gorinsky, C.; Templeton, W.; Zaidi, S. A. H. Lloydia
1973, 36, 352. (b) Czerson, H.; Bohlmann, F.; Stuessy, T. F.; Fischer,
N. H. Phytochemistry 1979, 18, 257. (c) Bohlmann, F.; Borthakur, N.;
King, R. M.; Robinson, H. Phytochemistry 1982, 21, 1793. (d) Lam, J .;
Christensen, L. P.; Thomasen, T. Phytochemistry 1991, 30, 515.
(3) Cascon, S. C.; Mors, W. B.; Tursch, B. M.; Aplin, R. T.; Durham,
L. J . J . Am. Chem. Soc. 1965, 87, 5237.
(5) (a) Mukai, C.; Ikeda, Y.; Sugimoto, Y.; Hanaoka, M. Tetrahedron
Lett. 1994, 35, 2179. (b) Mukai, C.; Sugimoto, Y.; Ikeda, Y.; Hanaoka,
M. Tetrahedron Lett. 1994, 35, 2183. (c) Mukai, C.; Sugimoto, Y. Ikeda,
Y.; Hanaoka, M. J . Chem. Soc., Chem. Commun. 1994, 1161. (d) Mukai,
C.; Sugimoto, Y.; Ikeda, Y.; Hanaoka, M. Tetrahedron 1998, 54, 823.
(e) Mukai, C.; Sugimoto, Y.; Miyazawa, K.; Yamaguchi, S.; Hanaoka,
M. J . Org. Chem. 1998, 63, 6281. (f) Mukai, C.; Yamaguchi, S.;
Sugimoto, Y.; Miyakoshi, N.; Kasamatsu, E.; Hanaoka, M. J . Org.
Chem. 2000, 65, 6761. (g) Mukai, C.; Yamaguchi, S.; Kim, I. J .;
Hanaoka, M. Chem. Pharm. Bull. 2001, 49, 613.
(4) Chin, C.; Cutler, M. C.; J ones, E. R. H.; Lee, J .; Safe, S.; Thaller,
V. J . Chem. Soc. C 1970, 314.
10.1021/jo0104532 CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/25/2001

5876 J . Org. Chem., Vol. 66, No. 17, 2001
Mukai et al.
Sch em e 2a
a
Reaction conditions: (a) TsCl, pyridine, 0 °C; (b) K2CO3, MeOH, rt; (c) TMS-≡, nBuLi,BF3‚OEt2, THF, -78 °C; (d) TBDPSCl, imidazole,
DMF, rt; (e) Lindlar cataltst, H2, rt; (f) BH3‚THF, then H2O2, NaOH, 0 °C; (g) PivCl, DMAP, CH2Cl2, 0 °C; (h) PPTS, MeOH, rt; (i) Swern
oxidation, -78 °C; (j) CBr4, PPh3, CH2Cl2, 0 °C; (k) EtMgBr, THF, -20 °C; (l) TBAF, THF, rt; (m) TsCl, DMAP, CH2Cl2, rt; (n) BBr3,
CH2Cl2, -78 °C; (o) DIBAL-H, epoxypropane, CH2Cl2, -78 °C; (p) Co2(CO)8, CH2Cl2, rt; (q) BF3‚OEt2, -78 °C; (r) CAN, MeOH, rt; (s)
TBDMSCl, imidazole, DMF, rt; (t) Bu3SnH, PdCl2(PPh3)2, THF, -78 °C; (u) I2, CH2Cl2, rt.
5, which would be obtained by taking advantage of the
two contiguous chiral centers of diethyl L-tartrate. Thus,
diethyl L-tartrate became the starting material for this
program. The triyne counterpart 3 (X ) SnBu3) for the
coupling reaction would be anticipated to be obtained
from hex-1,4-diyn-3-one by combination of Tykwinski’s
triyne synthesis6 and transformation of the silyl group
to a stannyl one by Buchwald’s procedure.7
mide11 to produce, after n-tetrabutylammonium fluoride
(TBAF) treatment, the alkyne derivative 10 in 61% yield.
Treatment of 10 with tosyl chloride (TsCl) at room
temperature and debenzylation with BBr3 at -78 °C
afforded the hydroxy compound, epoxidation of which was
then accomplished by exposure to K2CO3 in MeOH,
yielding the epoxy derivative 11 in 81% overall yield.
Conversion of 11 into 12 was somewhat troublesome.
Treatment of 11 with ethylmagnesium bromide or meth-
ylmagnesium bromide in several kinds of solvents gave
an intractable mixture including the desired 12. A similar
behavior was observed on exposure of 11 to methyl-
lithium. When 2 equiv of diisobutylaluminum hydride
(DIBAL-H) in THF was employed, 11 gave a rather clear
mixture mainly consisting of 12 and the epoxy ring-
opened products arising from 12 along with the starting
11. We envisaged that DIBAL-H might have reacted with
the pivaloyl group faster than with the epoxy moiety of
11, leading to the production of 12. However, 12 seems
susceptible to further reduction by DIBAL-H. Thus, the
addition of another epoxy compound in the reaction
mixture would avoid the over-reaction of 12. The epoxy
derivative that would be used for the above purpose must
be one with less steric hindrance compared to the epoxy
moiety of 11 and 12. In other words, epoxy derivatives
more reactive than 11 and 12 toward DIBAL-H would
be favorable for this aim. Therefore, we selected propyl-
ene oxide as a scavenger of excess of DIBAL-H. As a
result, reaction of 11 with DIBAL-H (5.0 equiv) in the
presence of excess propylene oxide (20 equiv)12 at -78
°C proceeded very clearly to provide 12 as the sole
isolable product in 91% yield. The substrate for the endo
mode cyclization was thus obtained. According to the
procedure5 for the endo mode cyclization of the racemic
epoxy-alkyne derivatives, 12 was converted to the cor-
responding dicobalthexacarbonyl species, which was then
Resu lts a n d Discu ssion
(2S,3R)-3-(tert-Butyldimethylsiloxy)-2-[(E)-2-iodovinyl]-
tetrahydropyran (15), the key compound of the coupling
reaction for construction of the carbon framework of 1
and 2, was prepared as depicted in Scheme 2. Diol 6 was
easily obtained from diethyl L-tartrate according to
Saito’s procedure.8 Activation of the primary hydroxy
group of 6 by tosylation was followed by base treatment,
affording epoxide 7 in 63% yield. Transformation of 7 into
vinyl derivative 8 was realized as follows. Addition of the
acetylide, prepared from trimethylsilylacetylene and
9
n-BuLi, to 7 in the presence of BF3‚OEt2 furnished the
homopropynyl alcohol, which was protected with a tert-
butyldiphenyl (TBDPS) group, and then the terminal
trimethylsilyl (TMS) group was removed. The resulting
alkyne derivative was half-hydrogenated over a Lindlar
catalyst to give 8 in 94% overall yield. Upon successive
exposure to BH3‚THF and hydrogen peroxide, compound
8 underwent hydroboration-oxidation to produce the
primary alcohol. Protection of the primary hydroxy
moiety with a pivaloyl group and desilylation under acidic
conditions provided 9 in 85% yield. Compound 9 was
oxidized under Swern conditions to give the labile alde-
hyde, which was subsequently exposed to Corey’s dibro-
moolefination conditions10 and ethylmagnesium bro-
(6) Eisler, S.; Tykwinski, R. R. J . Am. Chem. Soc. 2000, 122, 10737.
(7) Warner, B. P.; Buchwald, S. L. J . Org. Chem. 1994, 59, 5822.
(8) Saito, S.; Kuroda, A.; Tanaka, K.; Kimura, R. Synlett 1996, 231.
(9) Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391.
(10) Corey, E. J .; Fuchs, P. L. Tetrahedron Lett. 1972, 3769.
(11) n-BuLi was found to be ineffective in this case.
(12) An excess of propylene oxide (bp 34 °C) can be easily removed
by evaporation.

Total Synthesis of (-)-Ichthyothereol
J . Org. Chem., Vol. 66, No. 17, 2001 5877
Sch em e 3a
Sch em e 4a
a
Reaction conditions: (a) Me-≡-MgBr, THF, 0 °C; (b) MnO2,
CH2Cl2, rt; (c) CBr4, PPh3, CH2Cl2, 0 °C; (d) n-BuLi, hexane,
-78 °C.
treated with a catalytic amount of BF3‚OEt2 in CH2Cl2
at -78 °C to leave the trans-tetrahydropyran derivative
135d in 87% yield. Demetalation of 13 with cerium
ammoniun nitrate (CAN) was followed by protection of
the secondary hydroxy functionality with a silyl group
to afford 1413 in 87% yield. Upon consecutive treatment
with n-butyltin hydride in the presence of a palladium
catalyst at -78 °C and iodine at room temperature, 14
undertook hydrostannylation,14 followed by a tributyl-
stannyl moiety-iodine exchange reaction15 leading to the
(E)-iodovinyl derivative 15 in 83% yield.
a
Reaction conditions: (a) (Bu3Sn)2O, catalytic TBAF, THF, 60
°C; (b) 5 mol % of PdCl2(PPh3)2, rt; (c) TBAF, THF, rt; (d) Ac2O,
DMAP, CH2Cl2, rt.
In summary, we have completed the first total syn-
thesis of (-)-ichthyothereol and its acetate by a pal-
ladium-catalyzed coupling reaction between the iodoolefin
15 and the triyne derivative 19. The iodoolefin 15 was
prepared from commercially available diethyl L-tartrate
through the Co2(CO)8-mediated endo mode cyclization of
the optically active epoxy-alkyne derivative 12 in a
highly stereoselective manner. Further studies on the
preparation of the analogues of 1 and 2 using the
procedure described here as well as on the examination
of their biological activities are now in progress.
Our endeavors were then directed toward the prepara-
tion of counterpart 18 for the coupling reaction (Scheme
3). Trimethylsilylpropynal (16) was reacted with propyn-
ylmagnesium bromide to give the alcohol, which was
subsequently oxidized with manganese dioxide. The
resulting diynone derivative was then converted into the
dibromoolefin 17 in 45% overall yield under standard
conditions.10 By taking advantage of the method devel-
oped by Tykwinski,6 17 was exposed to n-BuLi in hexane
at -78 °C furnishing 1-trimethylsilyl-1,3,5-heptatriyne
(18) in 76% yield.
Exp er im en ta l Section
Melting points are uncorrected. IR spectra were measured
in CHCl3.1H NMR spectra were taken in CDCl3. CHCl3 (7.26
ppm) was used as an internal standard for silyl compounds.
13C NMR spectra were recorded in CDCl3 with CHCl3 (77.00
ppm) as an internal standard. Commercially available dry CH2-
With ready access to 18, we were ready to consider the
completion of the construction of the carbon skeleton of
1 and 2 by the palladium-catalyzed coupling reaction
under Stille conditions. Transmetalation of the silyl group
of 18 to the corresponding stannyl one was realized by
Buchwald’s procedure.7 Treatment of 18 with bis(tribu-
tyltin)oxide in THF in the presence of a catalytic amount
of TBAF at 60 °C for 2.5 h provided the crude stannyl
derivative 19, the Stille coupling of which with 15 in the
standard fashion (5 mol % of Pd2(PPh3)2 in THF at room
temperature)16 proceeded without difficulty to produce
the coupling product 20 in 95% yield (Scheme 4). The
final phase of this program is simple chemical modifica-
tions of 20. Desilylation of 20 with TBAF in THF at room
temperature afforded (-)-ichthyothereol (1) in a quanti-
tative yield. Acetylation of (-)-1 by conventional means
provided (+)-2 in 88% yield. The synthetic (-)-1 and (+)-2
were identical with the natural (-)-ichtyothereol and its
acetate, (+)-2, respectively, by comparison with their
spectral as well as physical data.
i
Cl2 and THF were employed for reactions. Et3N and Pr2NH
were distilled from CaH2 prior to use. All reactions were
carried out under a nitrogen atmosphere unless otherwise
stated. Silica gel (silica gel 60, 230-400 mesh, Merck) was used
for chromatography. Organic extracts were dried over anhy-
drous Na2SO4.
(2S,3S)-2-Ben zyloxy-3,4-ep oxy-1-(ter t-bu tyld im eth ylsi-
loxy)bu ta n e ((-)-7). A solution of TsCl (620 mg, 3.00 mmol)
in pyridine (4 mL) was added to a solution of diol 6 (890 mg,
2.73 mmol) in pyridine (5.00 mL) at 0 °C. After stirring for 8
h, the solution was concentrated and the residue was diluted
with Et2O. The Et2O solution was washed with water and
brine, dried, and concentrated to leave the crude tosylate. The
crude tosylate was used directly for the next reaction. To a
solution of the residue in MeOH (15.0 mL) was added K2CO3
(530 mg 3.82 mmol), and the reaction mixture was stirred for
1 h. MeOH was evaporated off, and the residue was taken up
in AcOEt, which was washed with saturated aqueous NH4Cl,
water, and brine, dried, and concentrated to dryness. Chro-
matography of the residue with hexane-AcOEt (10:1) afforded
25
(-)-7 (532 mg, 63%) as a colorless oil: [R]D -7.3 (c 0.50,
CHCl3); H NMR δ 7.29-7.22 (m, 5H), 4.82, 4.65 (AB-q, 2H,
(13) Mart´ın et al. reported an alternative method for the preparation
of 2-ethynyl-3-hydroxytetrahydropyrane derivatives: Alvarez, E.; Pe´rez,
R.; Rico, M.; Rodr´ıguez, R. M.; Sua´rez, M. C.; Mart´ın, J . D. Synlett
1996, 1082.
(14) Zhang, H. X.; Guibe´, F.; Balavoine, G. J . Org. Chem. 1990, 55,
1857.
(15) Barth, W.; Paquette, L. A. J . Org. Chem. 1985, 50, 2438, and
references therein.
(16) Stille, J . K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508, and
references therein.
1
J ) 11.9 Hz), 3.81-3.67 (m, 2H), 3.20 (dt, 1H, J ) 6.6, 5.6
Hz), 3.08 (ddd, 1H, J ) 6.6, 3.9, 2.6, Hz), 2.80 (dd, 1H, J )
4.9, 3.9 Hz), 2.63 (dd, 1H, J ) 4.9, 2.6 Hz), 0.89 (s, 9H), 0.05
(s, 6H); 13C NMR δ 138.37, 128.25, 127.69, 127.49, 80.68, 71.99,
63.38, 53.25, 43.38, 25.77, 18.15, -5.51, -5.57; MS m/z 308
(M+, 0.1). Anal. Calcd for C17H28O3Si: C, 66.19; H, 9.15.
Found: C, 65.94; H, 9.25.

5878 J . Org. Chem., Vol. 66, No. 17, 2001
Mukai et al.
(2S,3S)-2-Ben zyloxy-1-(ter t-bu tyldim eth ylsiloxy)-3-(ter t-
bu tyld ip h en ylsiloxy)h ex-5-en e ((-)-8). A solution of n-BuLi
in hexane (1.14 M, 10.0 mL, 11.4 mmol) was added to a
solution of (trimethylsilyl)acetylene (1.60 mL, 11.4 mmol) in
THF (30.0 mL) at -78 °C. After being stirred for 10 min, BF3‚
OEt2 in THF (1.00 M, 11.4 mL, 11.4 mmol) was added to the
reaction mixture and stirring was continued for 10 min at the
same temperature. A solution of (-)-7 (1.39 g, 4.54 mmol) in
THF (15.0 mL) was then added to the reaction mixture, which
was further stirred for 5 min, quenched by addition of
saturated aqueous NaHCO3, and extracted with AcOEt. The
extract was washed with water and brine, dried, and concen-
trated to dryness. The residue was passed through a short pad
of silica gel with hexane-AcOEt (4:1) to give the crude alcohol.
The crude alcohol was taken up in DMF (3.50 mL), to which
imidazole (1.23 g, 18.2 mmol) and TBDPSCl (2.36 mL, 9.08
mmol) were added at room temperature. The reaction mixture
was stirred at room temperature for 4.5 h, quenched by
addition of water, and extracted with Et2O. The extract was
washed with water and brine, dried, and concentrated to
dryness. The residue was passed through a short pad of silica
gel with hexane-AcOEt (4:1) to afford the crude TBDPS-
protected product. To the solution of the crude product thus
obtained in MeOH (30.0 mL) was added K2CO3 (1.25 g, 9.08
mmol), and the reaction mixture was stirred for 1 h. MeOH
was evaporated off, and the residue was taken up in AcOEt,
which was washed with saturated aqueous NH4Cl, water, and
brine, dried, and concentrated to dryness. The residue was
passed through a short pad of silica gel with hexane-AcOEt
(4:1) to provide the terminal alkyne derivative. A solution of
this alkyne and pyridine (2.75 mL, 34.1 mmol) in AcOEt (45.0
mL) was hydrogenated for 4.5 h under a hydrogen atmosphere
in the presence of Pd-BaCO3 (260 mg) at room temperature.
The catalyst was filtered off, and the filtrate was concentrated
to dryness. Chromatography of the residual oil with hexane-
AcOEt (100:1) afforded (-)-8 (2.44 g, 94%) as a colorless oil:
δ 7.61-7.57 (m, 4H), 7.38-7.30 (m, 6H), 7.28-7.18 (m, 3H),
7.07-7.04 (m, 2H), 4.19 (s, 2H), 3.84-3.72 (m, 4H), 3.63 (dd,
1H, J ) 11.6, 6.9 Hz), 3.45-3.39 (m, 1H), 2.01-1.91 (s, 1H),
1.62-1.20 (m, 4H), 1.07 (s, 9H), 0.99 (s, 9H); 13C NMR δ 178.36,
138.24, 135.97, 135.93, 133.61, 133.45, 129.88, 129.82, 128.34,
127.71, 127.65, 127.62, 127.59, 81.65, 77.20, 72.27, 64.05,
61.28, 38.64, 28.33, 27.13, 27.02, 25.27, 19.31; FABMS m/z 561
(M+, 4.7). Anal. Calcd for C34H46O5Si: C, 72.56; H,8.24.
Found: C, 72.28; H, 8.37.
(3S,4S)-3-Ben zyloxy-6-(p iva loyloxy)-1-h ep tyn -4-ol ((+)-
10). A solution of DMSO (0.18 mL, 2.53 mmol) in CH2Cl2 (6.00
mL) was added to a solution of oxalyl chloride (0.11 mL, 1.27
mmol) in CH2Cl2 (4.00 mL) at -78 °C over a period of 5 min.
After the mixture was stirred for 15 min, a solution of the
alcohol (-)-9 (650 mg, 1.15 mmol) in CH2Cl2 (4.00 mL) was
added to the CH2Cl2 solution, and the reaction mixture was
stirred at the same temperature for an additional 1 h. Et3N
(0.80 mL 5.75 mmol) was then added to the reaction mixture,
which was gradually warmed to room temperature and diluted
with CH2Cl2. The CH2Cl2 solution was washed with water and
brine, dried, and concentrated to leave the crude aldehyde. The
crude aldehyde was used directly for the next reaction. To a
solution of PPh3 (1.80 g, 6.90 mmol) in CH2Cl2 (4.00 mL) was
added CBr4 (1.14 g, 3.45 mmol) in CH2Cl2 (4.00 mL) at 0 °C,
and the reaction mixture was stirred for 30 min. A solution of
crude aldehyde in CH2Cl2 (6.00 mL) was then added to a
solution of the ylide in CH2Cl2 solution thus adjusted 0 °C,
and stirring was continued for 5 min at the same temperature.
The reaction mixture was quenched by addition of saturated
aqueous NaHCO3, and the CH2Cl2 solution was washed with
water and brine, dried, and concentrated to dryness. The
residue was passed through a short pad of silica gel with
hexane-AcOEt (5:1) to give the dibromoolefin derivative. To
a solution of the dibromoolefin derivative in THF (12.0 mL)
was added EtMgBr in THF (0.96 M, 5.99 mL, 5.75 mmol) at
-20 °C, and the reaction mixture was stirred for 10 min at
the same temperature. The reaction mixture was quenched
by addition of water and extracted with Et2O, which was
washed with water and brine, dried, and concentrated to
dryness. The residue was passed through a short pad of silica
gel with hexane-AcOEt (5:1) to afford the alkyne derivative.
To a solution of residue in THF (12.0 mL) was added TBAF in
THF (1.00 M, 1.60 mL, 1.60 mmol), and the reaction mixture
was stirred for 12 h at room temperature, quenched by
addition of water, and extracted with AcOEt. The extract was
washed with water and brine, dried, and concentrated to
dryness. The residual oil was chromatographed with hexane-
24
1
[R]D -3.4 (c 0.50, CHCl3); IR 1639 cm-1; H NMR δ 7.69-
7.66 (m, 4H), 7.40-7.21 (m, 11H), 5.67-5.51 (m, 1H), 4.88-
4.81 (m, 2H), 4.56, 4.37 (AB-q, 2H, J ) 11.9 Hz), 3.97-3.87
(m, 2H), 3.78 (dd, 1H, J ) 10.7, 7.1 Hz), 3.46-3.41 (m, 1H),
2.46-2.35 (m, 1H), 2.15-2.03 (m, 1H), 1.04 (s, 9H), 0.88 (s,
9H), 0.03 (s, 6H); 13C NMR δ 139.23, 136.08, 135.98, 135.53,
134.16, 133.93, 129.58, 129.52, 128.07, 127.49, 127.39, 127.13,
116.69, 82.19, 72.99, 72.63, 63.36, 37.06, 27.05, 25.90, 19.41,
18.19, -5.35, -5.46; FABMS m/z 575 (M++ 1, 0.1). Anal. Calcd
for C35H50O3Si: C, 73.12; H, 8.77. Found: C, 73.01; H, 8.89.
(2S,3S)-2-Ben zyloxy-3-(ter t-bu tyldiph en ylsiloxy)-6-(piv-
a loyloxy)h exa n -1-ol ((-)-9). To a solution of (-)-8 (510 mg,
0.89 mmol) in THF (9.00 mL) was added BH3‚THF complex
in THF (0.90 M, 1.50 mL, 1.33 mmol) at 0 °C. The resulting
solution was stirred for 1 h at room temperature. Then 5%
aqueous NaOH (5.50 mL) and 30% aqueous H2O2 (5.50 mL)
were successively added to the reaction mixture, and stirring
was continued for an additional hour at room temperature.
The mixture was extracted with AcOEt, which was washed
with water and brine, dried, and concentrated to dryness. The
residue was passed through a short pad of silica gel with
hexane-AcOEt (4:1) to give the alcohol. Pivaloyl chloride (0.22
mL, 1.78 mmol) was added to a mixture of the alcohol, Et3N
(0.50 mL, 3.56 mmol), and DMAP (22.0 mg, 0.18 mmol) in CH2-
Cl2 (9.00 mL) at 0 °C. After being stirred for 4 h at room
temperature, the reaction was quenched by addition of water
and extracted with CH2Cl2. The extract was washed with
water and brine, dried, and concentrated to dryness. The
residue was passed through a short pad of silica gel with
hexane-AcOEt (4:1) to leave the acylated product. To the
residue in MeOH (6.00 mL) was added PPTS (25.0 mg, 0.01
mmol) at room temperature, and the reaction mixture was
stirred for 24 h. MeOH was evaporated off, and the residue
was taken up in AcOEt, which was washed with saturated
aqueous NaHCO3, water and brine, dried, and concentrated
to dryness. Chromatography of the residue with hexane-
AcOEt (5:1) afforded (-)-9 (426 mg, 85%) as a colorless oil:
[R]D26 -12.2 (c 0.50, CHCl3); IR 3582, 3520, 1719 cm-1; 1H NMR
AcOEt (6:1) to afford (+)-10 (224 mg, 61%) as a colorless oil:
[R]D +68.8 (c 0.5, CHCl3); IR 3578, 3304, 2116, 1717 cm-1
;
24
1H NMR δ 7.36-7.33 (m, 5H), 4.86, 4.52 (AB-q, 2H, J ) 11.6
Hz), 4.09 (t, 2H, J ) 6.1 Hz), 3.93 (dd, 1H, J ) 7.3, 2.0 Hz),
3.77-3.70 (m, 1H), 2.55 (br s, 1H), 2.53 (d, 1H, J ) 2.0 Hz),
1.90-1.47 (m,4H), 1.19 (s, 9H); 13C NMR δ 178.47, 137.05,
128.45, 128.12, 127.98, 79.88, 75.90, 73.92, 72.63, 70.96, 64.03,
38.67, 28.59, 27.14, 24.69; MS m/z 318 (M+, 0.8). HRMS calcd
for C19H26O4 318.1841, found 318.1818.
(3S,4R)-3,4-Ep oxy-6-(p iva loyloxy)h ep t-1-yn e ((+)-11).
TsCl (9.20 g, 48.1 mmol) was added to a solution of (+)-10 (1.53
g, 4.81 mmol), Et3N (13.7 mL, 96.2 mmol), and DMAP (580
mg, 4.81 mmol) in CH2Cl2 at 0 °C. After being stirred for 24 h
at room temperature, the reaction mixture was quenched by
addition of water and extracted with CH2Cl2. The extract was
washed with water and brine, dried, and concentrated to
dryness. The residue was passed through a short pad of silica
gel with hexane-AcOEt (4:1) to afford the crude tosylate. To
a solution of crude tosylate in CH2Cl2 (48 mL) was added BBr3
in CH2Cl2 solution (1.00 M, 4.81 mL, 4.81 mmol) at -78 °C.
The mixture was stirred for 5 min, quenched by addition of
saturated aqueous NaHCO3, and extracted with CH2Cl2. The
extract was washed with water and brine, dried, and concen-
trated to leave the crude alcohol. The crude alcohol was used
directly for the next reaction. A suspension of the crude alcohol
and K2CO3 (1.33 mg, 9.62 mmol) in MeOH (48.0 mL) was
stirred at room temperature for 30 min. MeOH was evaporated
off, and the residue was taken up in AcOEt, which was washed

Total Synthesis of (-)-Ichthyothereol
J . Org. Chem., Vol. 66, No. 17, 2001 5879
with saturated aqueous NH4Cl, water, and brine, dried, and
concentrated to dryness. Chromatography of the residue with
hexane-AcOEt (30:1) afforded (+)-11 (820 mg, 81%) as a
colorless oil: [R]D27 +26.0 (c 0.50, CHCl3); IR 3306, 2125, 1722
cm-1; 1H NMR δ 4.10-4.04 (m, 2H), 3.37 (dd, 1H, J ) 4.1, 1.7
Hz), 3.01 (td, 1H, J ) 5.6, 4.1 Hz), 2.32, (d, 1H, J ) 1.7 Hz),
1.82-1.72 (m, 4H), 1.14 (s, 9H); 13C NMR δ 178.20, 78.51,
73.68, 63.52, 56.95, 44.55, 38.55, 27.01, 25.88, 24.98; FABMS
m/z 211 (M+ + 1, 5.1). FABHRMS calcd for C12H18O3 211.1334,
found 211.1343.
M, 17.5 mL, 8.73 mmol) at 0 °C, and the reaction mixture was
stirred for 10 min, quenched by addition of water, extracted
with Et2O. The extract was washed with water and brine,
dried, and concentrated to dryness. The residue was passed
through a short pad of silica gel with hexane-AcOEt (4:1) to
give the crude alcohol. A mixture of crude alcohol and chemical
manganese dioxide17 (7.06 g, 79.4 mmol) in CH2Cl2 (40.0 mL)
was stirred at room temperature for 24 h. The mixture was
filtered off, and the filtrate was concentrated to leave the
diynone derivative. To a solution of PPh3 (8.30 g, 31.8 mmol)
in CH2Cl2 (20.0 mL) was added CBr4 (5.27 g, 15.9 mmol) in
CH2Cl2 (5.00 mL) at 0 °C, and the reaction mixture was stirred
for 5 min. A solution of the diynone derivative in CH2Cl2 was
then added to a solution of the ylide in CH2Cl2 solution thus
adjusted at 0 °C, and stirring was continued for 5 h at the
same temperature. The reaction mixture was quenched by
addition of saturated aqueous NaHCO3, and the CH2Cl2 layer
was washed with water and brine, dried, and concentrated to
dryness. Chromatography of the residue with hexane afforded
17 (1.14 g, 45%) as a colorless oil: IR 2230, 2147 cm-1; 1H NMR
δ 1.99 (s, 3H), 0.22 (s, 9H); 13C NMR δ 114.41, 107.78, 101.76,
100.69, 93.85, 76.60, 4.82, -0.44; MS m/z 320 (M+, 100). HRMS
calcd for C10H12Br2Si 319.9054, found 319.9081.
(3S,4R)-3,4-Ep oxy-1-h ep tyn -7-ol ((+)-12). A solution of
DIBAL-H in hexane (1.00 M, 3.88 mL, 3.88 mmol) was added
to a solution of (+)-11 (163 mg, 0.78 mmol) and propyleneoxide
(1.08 mL, 15.5 mmol) in CH2Cl2 (15.0 mL) at -78 °C. The
mixture was stirred for 5 min, quenched by addition of
saturated aqueous Na2SO4, and filtered through Celite. The
filtrate was concentrated to leave the residual oil which was
chromatographed with hexane-AcOEt (1:1) to afford (+)-12
27
(89.0 mg, 91%) as a colorless oil: [R]D +54.6 (c 0.20, CHCl3).
Anal. Calcd for C7H10O2: C, 66.65; H, 7.99. Found: C, 66.25;
H, 8.01. Spectral data of racemic 12 were already reported in
ref 5d.
H exa ca r b on yl-µ-[η4-(2R,3R)-2-et h yn yl-3-h yd r oxyt et -
r a h yd r op yr a n ]d icoba lt(Co-Co) (13). Compound 13 (93.0
mg, 87%) was obtained from (+)-12 (33.0 mg, 0.26 mmol)
according to the procedure described in ref 5d. Compound 13
was a reddish needle: mp 58-61 °C (hexane). Anal. Calcd for
1-Tr im eth ylsilylh ep t-1,3,5-tr iyn e (18). To a solution of
17 (500 mg, 1.56 mmol) in hexane was added a solution of
n-BuLi in hexane (1.36 M, 1.15 mL, 1.56 mmol) at -78 °C,
and the reaction mixture was stirred for 30 min at the same
temperature. The reaction mixture was gradually warmed to
0 °C, quenched by addition of saturated aqueous NH4Cl, and
extracted with Et2O. The extract was washed with water and
brine, dried, and concentrated to dryness. Chromatography of
the residue with hexane afforded 18 (190 mg, 76%) as colorless
C
13H10Co2O8: C, 37.89; H, 2.46. Found: C, 37.93; H, 2.45.
Specific rotation could not be determined because demetalation
occurred during measurement. Spectral data of racemic 13
were already reported in ref 5d.
(2S,3R)-3-(ter t-Bu tyld im eth ylsiloxy)-2-eth yn yltetr a h y-
d r op yr a n ((-)-14). To a solution of 13 (244 mg, 0.59 mmol)
in MeOH (6.00 mL) was added CAN (1.62 g, 2.96 mmol) at 0
°C. After being stirred for 30 min, the reaction mixture was
concentrated, diluted with water, and extracted with AcOEt.
The extract was washed with brine, dried, and concentrated
to dryness. The residue was dissolved in DMF (0.30 mL), to
which imidazole (120 mg, 1.77 mmol) and TBDMSCl (134 mg,
0.89 mmol) were added. The reaction mixture was stirred at
room temperature for 5 h, quenched by addition of water, and
extracted with Et2O. The extract was washed with water and
brine, dried, and concentrated to dryness. The residue was
chromatographed with hexane-AcOEt (50:1) to afford (-) 14
needles: mp 53.5-54 °C (hexane); IR 2218, 2168, 2081 cm-1
;
1H NMR δ 1.96 (s, 3H), 0.19 (s, 9H); 13C NMR δ 88.32, 85.21,
76.55, 64.74, 62.56, 59.33, 4.51, -0.52; MS m/z 160 (M+, 22.9).
Anal. Calcd for C10H12Si: C, 74.93; H, 7.55. Found: C, 74.76;
H, 7.75.
(2S,3R)-3-(ter t-Bu tyld im eth ylsiloxy)-2-[(1E)-n on -3,5,7-
tr iyn -1-en yl]tetr a h yd r op yr a n ((-)-20). To a solution of 18
(86.0 mg, 0.54 mmol) and (Bu3Sn)2O (0.14 mL, 0.27 mmol) in
THF (5.40 mL) was added TBAF in THF (1.00 M, 0.01 mL,
0.01 mmol) at room temperature. The reaction mixture was
stirred for 2.5 h at 60 °C, at which time the volatiles were
removed in vacuo. The residue was diluted with hexane and
filtered over Celite. The filtrate was concentrated to give the
crude 1-trimethylstannyl-1,3,5-heptatriyne (19). Crude 19 was
then added to a solution of (-)-15 (20.0 mg, 0.54 × 10-1 mmol)
and PdCl2(PPh3)2 (1.90 mg, 0.27 × 10-2 mmol) in THF (0.50
mL) at room temperature. After being stirred for 24 h, THF
was evaporated off and the residue was chromatographed with
24
(123 mg, 87%) as a colorless oil: [R]D -34.9 (c 0.50, CHCl3);
IR 3308, 2125 cm-1; 1H NMR δ 3.93-3.84 (m, 2H), 3.59 (ddd,
1H, J ) 8.9, 7.8, 4.2 Hz), 3.37 (ddd, 1H, J ) 11.5, 9.8, 2.9 Hz),
2.41 (d, 1H, J ) 2.3 Hz), 2.07-1.98 (m, 1H), 1.74-1.37 (m,
3H), 0.88 (s, 9H), 0.09 (s, 3H), 0.07 (s, 3H); 13C NMR δ 82.03,
73.68, 72.76, 70.24, 66.70, 32.08, 25.73, 23.96, 17.99, -4.51,
-4.63; MS m/z 240 (M+, 0.1). HRMS calcd for C13H24O2Si
240.1546, found 240.1523.
hexanes-Et2O (80:1) to afford (-)-20 (17.0 mg, 95%) as a pale
yellow oil: [R]D -65.5 (c 0.34, CHCl3); IR 2222, 2201 cm-1
;
26
(2S,3R)-3-(ter t-Bu tyldim eth ylsiloxy)-2-[(E)-2-iodovin yl]-
tetr a h yd r op yr a n ((-)-15). To a solution of (-)-14 (67.0 mg,
0.28 mmol) and PdCl2(PPh3)2 (3.90 mg, 0.56 × 10-2 mmol) in
THF (5.60 mL) was added tributyltin hydride (0.19 mL, 0.70
mmol) at -30 °C, and the reaction mixture was gradually
warmed to 0 °C over a period of 3 h. THF was evaporated off,
and the residue was used directry for the next reaction. To a
solution of the crude stanylated product in CH2Cl2 (5.60 mL)
was added iodine (140 mg, 0.56 mmol) at room temperature.
After being stirred for 1 h, THF was evaporated off and the
residue was chromatographed with hexanes-Et2O (85:1) to
1H NMR δ 6.45 (dd, 1H, J ) 16.1, 5.4 Hz), 5.77 (dd, 1H, J )
16.1, 1.5 Hz), 3.93-3.91 (m, 1H), 3.57 (ddd, 1H, J ) 8.8, 5.4,
1.5 Hz), 3.37-3.32 (m, 1H), 3.27 (ddd, 1H J ) 10.6, 8.8, 4.5
Hz), 2.04-2.00 (m, 1H), 1.98 (s, 3H), 1.68-1.35 (m, 3H), 0.88
(s, 9H), 0.04 (s, 6H); 13C NMR δ 146.76, 108.89, 81.91, 77.89,
74.76, 74.13, 71.27, 67.56, 66.88, 64.94, 59.26, 33.69, 25.74,
25.29, 17.93, 4.62, -4.27, -4.69; MS m/z 328 (M+, 4.3). HRMS
calcd for C20H28O2Si 328.1858, found 328.1860.
(-)-Ich th yoth er eol ((-)-1). To a solution of (-)-20 (17.0
mg, 0.52 × 10-1 mmol) in THF (0.50 mL) was added TBAF in
THF (1.00 M THF, 0.06 mL, 0.06 mmol) at room temperature.
After being stirred for 2 h, THF was evaporated off and the
residue was chromatographed with hexanes-Et2O (2:1) to
afford (-)-1 (11.0 mg, 100%) as white crystals: mp 86-87.5
24
afford (-)-15 (86.0 mg, 83%) as a pale yellow oil: [R]D -33.2
1
(c 0.50, CHCl3); IR 1614 cm-1; H NMR δ 6.63 (dd, 1H, J )
14.5, 5.9 Hz), 6.36 (dd, 1H, J ) 14.5, 1.0 Hz), 3.96-3.88 (m,
1H), 3.48 (ddd, 1H, J ) 8.8, 5.9, 1.0 Hz), 3.38-3.27 (m, 2H),
2.04-1.98 (m, 1H), 1.69-1.62 (m, 1H), 1.50-1.41 (m, 1H), 0.88
(s, 9H), 0.66 (s, 3H), 0.05 (s, 3H); 13C NMR δ 144.62, 84.55,
78.58, 70.95, 67.57, 33.50, 25.72, 25.33, 17.92, -4.36, -4.64;
FABMS m/z 369 (M+ + 1, 2.3). FABHRMS calcd for C13H26O2-
SiI 369.0746, found 369.0739.
24
°C (hexane) (lit.3 mp 89-90 °C); [R]D -40.2 (c 0.12, CHCl3)
(lit.3 [R]D -44); IR 3597, 2224, 2200 cm-1; 1H NMR δ 6.50 (dd,
1H, J ) 16.1, 5.9 Hz), 5.84 (d, 1H, J ) 16.1 Hz), 3.96-3.92
(m, 1H), 3.57 (ddd, 1H, J ) 9.3, 5.9, 1.5 Hz), 3.58-3.28 (m,
2H), 2.15-2.11 (m, 1H), 1.98 (s, 3H), 1.72-1.67 (m, 3H), 1.50-
3-(Dib r om om et h ylid en e)-1-t r im et h ylsilylh ex-1,4-d i-
yn e (17). To a solution of 16 (1.00 g, 7.94 mmol) in THF (60.0
mL) was added 1-propynylmagnesium bromide in THF (0.50
(17) Aoyama, T.; Sonoda, N.; Yamauchi, M.; Toriyama, K.; Anzai,
M.; Ando, A.; Shioiri, T. Synlett 1998, 35.

5880 J . Org. Chem., Vol. 66, No. 17, 2001
Mukai et al.
1.40 (m, 1H); 13C NMR δ 145.57, 110.24, 81.92, 78.18, 75.43,
73.59, 70.08, 67.42, 67.29, 64.90, 58.97, 32.42, 25.19, 4.64; MS
m/z 214 (M+, 26.7). HRMS calcd for C14H14O2 214.0994, found
214.0990.
(ddd, 1H, J ) 10.8, 9.3, 4.9 Hz), 3.99-3.93 (m, 1H), 3.77 (ddd,
1H, J ) 9.3, 5.4, 1.5 Hz), 3.40 (td, 1H, J ) 11.2, 3.3 Hz), 2.22-
2.18 (m, 1H), 2.04 (s, 3H), 1.98 (s, 3H), 1.76-1.67 (m, 2H); 13
C
NMR δ 169.83, 144.35, 110.25, 78.74, 78.21, 75.60, 73.46,
71.45, 67.46, 67.36, 64.87, 58.91, 29.24, 24.72, 21.05, 4.62; MS
m/z 256 (M+, 4.2). Anal. Calcd for C16H16O3: C, 74.98; H, 6.29.
Found: C, 74.87; H, 6.35.
(+)-Ich th yoth er eol Aceta te ((+)-2). Ac2O (0.13 × 10-1
mL, 0.13 mmol) was added to a solution of (-)-1 (14.0 mg, 0.67
× 10-1 mmol), Et3N (0.28 × 10-1 mL, 0.20 mmol), and DMAP
(0.80 mg, 0.67 × 10-2 mmol) in CH2Cl2 (0.67 mL) at 0 °C. After
being stirred for 5 min, CH2Cl2 was evaporated off and the
residue was chromatographed with hexanes-Et2O (5:1) to
afford (-)-2 (15.0 mg, 88%) as colorless needles: mp 59-61
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for compounds 1, 10, 11, 14, 15, 17, and 20. This
material is available free of charge via the Internet at
http://pubs.acs.org.
24
°C (hexane) (lit.3 mp 63-65 °C); [R]D +6.7 (c 0.29, CHCl3)
1
(lit.3 [R]D +7); IR 2224, 2202, 1738 cm-1; H NMR δ 6.30 (dd,
1H, J ) 16.1, 5.4 Hz), 5.79 (dd, 1H, J ) 16.1, 1.5 Hz), 4.49
J O0104532