Total synthesis of natural dysidiolide

Article abstract of DOI:10.1021/jo0015772

Dysidiolide (1), a novel sesterterpenoid previously isolated from the Caribbean sponge Dysidea etheria de Laubenfels, inhibits the action of the protein phosphatase, cdc25A. The authors establish a novel total synthesis of natural dysidiolide (1) using intramolecular Diels - Alder reaction as the key step from optically active cyclohexenone 3. Decalin, the core structure of 1, was constructed by intramolecular Diels - Alder reaction of the diene ester generated by elimination of the phenyl sulfoxide group from sulfoxide ester 6 prepared from cyclohexenone 3. Diastereoselective methylation at C-7, alkylation at C-6, and deoxygenation of C-12 and C-24 positions gave the fully substituted bicyclic core of 1. The two side chains of the bicyclic core were further extended so as to afford natural dysidiolide (1). The total yield of this synthesis exceeds that of previous syntheses of 1.

Full text of DOI:10.1021/jo0015772

J . Org. Chem. 2001, 66, 1429-1435
1429
Tota l Syn th esis of Na tu r a l Dysid iolid e
Hiroaki Miyaoka, Yasuhiro Kajiwara, Yoshinori Hara, and Yasuji Yamada*
School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji,
Tokyo 192-0392, J apan
yamaday@ps.toyaku.ac.jp
Received November 6, 2000
Dysidiolide (1), a novel sesterterpenoid previously isolated from the Caribbean sponge Dysidea
etheria de Laubenfels, inhibits the action of the protein phosphatase, cdc25A. The authors establish
a novel total synthesis of natural dysidiolide (1) using intramolecular Diels-Alder reaction as the
key step from optically active cyclohexenone 3. Decalin, the core structure of 1, was constructed by
intramolecular Diels-Alder reaction of the diene ester generated by elimination of the phenyl
sulfoxide group from sulfoxide ester 6 prepared from cyclohexenone 3. Diastereoselective methylation
at C-7, alkylation at C-6, and deoxygenation of C-12 and C-24 positions gave the fully substituted
bicyclic core of 1. The two side chains of the bicyclic core were further extended so as to afford
natural dysidiolide (1). The total yield of this synthesis exceeds that of previous syntheses of 1.
Dysidiolide (1, Figure 1), isolated from the Caribbean
sponge Dysidea etheria de Laubenfels by Gunasekera et
al. in 1996, is a novel sesterterpenoid possessing a unique
new carbon skeleton.1,2 Dysidiolide is the first compound
noted to be a natural inhibitor of protein phosphatase
cdc25A (IC50 ) 9.4 µM), which is essential for cell
proliferation. Dysidiolide inhibits the growth of A-549
human lung carcinoma (IC50 ) 4.7 µM) and P388 murine
leukemia cells (IC50 ) 1.5 µM). The relative configuration
of 1 was determined by single-crystal X-ray diffraction,
and its conformation includes two large side chains that
occupy axial and pseudoaxial positions on the same side
F igu r e 1.
of the decalin ring. These chains may possibly be impor-
tantly involved in the expression of biological activity.
The inhibitory activity of the enantiomer and racemate
of dysidiolide (1) toward protein phosphatase cdc25A has
been investigated and found to be weak.12 For detailed
pharmacological reseach on dysidiolide, an efficient total
synthesis of natural dysidiolide would be required. The
authors thus undertook the total synthesis of natural
dysidiolide. The stereoselective total synthesis of natural
dysidiolide from an optically active cyclohexenone deriva-
tive is presented in this paper.
Thus, many efforts have been made to establish a mode
of synthesis for 1 in consideration of its unique structure
features and potential biological significance. The first
total synthesis of natural dysidiolide (1) was reported by
Corey et al. in 1997, and its absolute configuration was
determined by this total synthesis.3 Total syntheses of
enantiomeric,4 racemic,5-8 and natural9 dysidiolide (1)
and synthetic studies10,11 have subsequently been re-
ported. The authors previously reported the total syn-
thesis of (()-dysidiolide using intramolecular Diels-
Alder reaction as the key reaction.6
The route for the synthesis of natural dysidiolide (1)
is presented in Scheme 1. The total synthesis of natural
dysidiolide may be conducted essentially in accordance
with the method for synthesizing (()-dysidiolide, as
previously reported.6 Optically active enone E may be
used instead of enone 2, the starting material for the
synthesis of (()-dysidiolide, since the efficient synthesis
of optically active enone E was reported by the authors13
and the optically active form of enone 2 is not accessible.
The decalin framework, the core structure of dysidiolide,
was constructed in such a way that lactone C would be
obtained by intramolecular Diels-Alder reaction of diene
ester D produced from cyclohexenone E via vinylation
and esterification. Stereoselective methylation at C-714
(1) Gunasekera, S. P.; McCarthy, P. J .; Kelly-Borges, M.; Lobkovsky,
E.; Clardy, J . J . Am. Chem. Soc. 1996, 118, 8759-8780.
(2) Recently, cladocorans A and B, having the same carbon skeleton,
were reported. Fontana, A.; Ciavatta, M. L.; Cimino, G. J . Org. Chem.
1998, 63, 2845-2849.
(3) Corey, E. J .; Roberts, B. E. J . Am. Chem. Soc. 1997, 119, 12425-
12431.
(4) Boukouvalas, J .; Cheng, Y.-X.; Robichaud, J . J . Org. Chem. 1998,
63, 228-229.
(5) Magnuson, S. R.; Sepp-Lorenzino, L.; Rosen, N.; Danishefsky,
S. J . J . Am. Chem. Soc. 1998, 120, 1615-1616.
(6) Miyaoka, H.; Kajiwara, Y.; Yamada, Y. Tetrahedron Lett. 2000,
41, 911-914.
(7) Piers, E.; Caille´, S.; Chen, G. Org. Lett. 2000, 2, 2483-2486.
(8) Demeke, D.; Forsyth, C. J . Org. Lett. 2000, 2, 3177-3179.
(9) Takahashi, M.; Dodo, K.; Hashimoto, Y.; Shirai, R. Tetrahedron
Lett. 2000, 41, 2111-2114.
(10) Brohm, D.; Waldmann, H. Tetrahedron Lett. 1998. 39, 3995-
3998.
(12) Blanchard, J . L.; Epstein, D. M.; Boisclair, M. D.; Rudolph, J .;
Pal, K. Bioorg. Med. Chem. Lett. 1999, 9, 2537-2538.
(13) Miyaoka, H.; Kajiwara, Y.; Hara, M.; Suma, A.; Yamada, Y.
Tetrahedron: Asymmetry 1999, 10, 3189-3196.
(11) J ung, M. E.; Nishimura, N. J . Am. Chem. Soc. 1999, 121, 3529-
3530.
10.1021/jo0015772 CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/27/2001

1430 J . Org. Chem., Vol. 66, No. 4, 2001
Miyaoka et al.
Sch em e 1
F igu r e 2. NOESY correlations of compound 7.
Protection of the conjugated dienone moiety in 4 with
thiophenol in the presence of Et3N gave R,â-unsaturated
ketone in 93% yield, which was subsequently reduced
with diisobutylaluminum hydride (DIBAL-H) at -78 °C
to give a diastereomeric mixture of allylic alcohols 5a and
5b (5a /5b ) 1:1) in 96% yield. After separation of alcohols
5a and 5b, absolute configurations of the secondary
hydroxy groups in 5a and 5b were determined as R and
S, respectively, by the modified Mosher method.15 Oxida-
tion of the sulfide in 5a with m-chloroperbenzoic acid (m-
CPBA) gave sulfoxide in 99% yield, and the secondary
hydroxy group of sulfoxide was acylated with propiolic
acid, 1,3-dicyclohexylcarbodiimide (DCC), and 4-(dimeth-
ylamino)pyridine (DMAP) in toluene to afford ester 6 in
quantitative yield. Allylic alcohol 5b was converted to
ester 6 via oxidation of the sulfide with m-CPBA (97%
yield) and Mitsunobu reaction16 using propiolic acid,
DEAD, and Ph3P (98% yield).17 A solution of ester 6 in
toluene was refluxed in the presence of ethyl propiolate
and pyridine to regenerate the diene by elimination of
phenyl sulfoxide followed by intramolecular Diels-Alder
reaction to give decalin 7, which corresponds to lactone
C in the synthetic strategy, as the sole product in 89%
yield. In the absence of pyridine, no decalin 7 was
obtained. In the absence of ethyl propiolate, a mixture
of decalin 7, the addition product of 7 with phenylsulfenic
acid (structure not determined) and the addition product
of reaction intermediate diene with phenylsulfenic acid
(structure not determined) was obtained.
Sch em e 2a
a
Reagents and conditions: (a) (i) TBDMS-Cl, imidazole, DMF,
rt, 94%; (ii) vinylmagnesium bromide, THF, 0 °C, then silica gel,
92%; (b) (i) PhSH, Et3N, benzene, rt, 93%, (ii) DIBAL-H, toluene,
-78 °C, 96%; (c) (i) m-CPBA, CHCl3, -42 °C, 99%, (ii) propiolic
acid, DCC, DMAP, toluene, rt, quant; (d) i) m-CPBA, CHCl3, -42
°C, 97%, (ii) propiolic acid, DEAD, Ph3P, THF, rt, 98%; (e) pyridine,
ethyl propiolate, toluene, reflux, 89%.
The relative configuration of 7 was confirmed on the
basis of the NOESY spectrum (Figure 2). NOESY cor-
relations were noted between the methine proton at C-11
and both methylene protons at C-16, between the
methine proton at C-12 and both methylene protons at
C-16, and between the olefinic proton at C-9 and methyl
and alkylation at C-6 of lactone C may occur to provide
lactone B since the R-face of lactone C is the less hindered
side. Lactone B was converted to aldehyde A by deoxy-
genation at C-12 and C-24 and elongation of the side
chain. The highly functional γ-hydroxybutenolide was
obtained by addition of 3-lithiofuran to aldehyde A and
photochemical oxidation of the furan moiety gave natural
dysidiolide (1).
Construction of decalin, the core structure of dysid-
iolide, was investigated via intramolecular Diels-Alder
reaction (Scheme 2). The synthesis of dysidiolide (1) was
initiated from optically active cyclohexenone 3 (99%ee)
readily obtained by the lipase-catalyzed kinetic resolution
of racemic 3 in the presence of vinyl acetate.13 The
hydroxy group of cyclohexenone 3 was protected by
treatment with tert-butyldimethylsilyl chloride (TBDMS-
Cl) and imidazole to give TBDMS ether in 94% yield. The
cyclohexenone was vinylated with vinylmagnesium bro-
mide and then treated with silica gel to afford conjugated
dienone 4 in 92% yield.
(15) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J . Am.
Chem. Soc. 1991, 113, 4092-4096.
(16) Mitsunobu, O. Synthesis 1981, 1-28.
(17) In the synthesis of racemic 1, diene alcohol 8a , which was
derived from enone 2 by a similar method, was treated with propiolic
acid and N,N-bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl)18
in benzene to give decalin 9 and SN2′-type adduct 10 (9/10 ) 4:17).6
Diene alcohol 8b was treated with propiolic acid, diethyl azodicar-
boxylate (DEAD), and Ph3P16 in tetrahydrofuran (THF) to give SN2′
type adduct 10 as the sole product (eq 1). Acylation of diene alcohol
8a and Mitsunobu reaction of diene alcohol 8b were not successful
and these reactions gave SN2′ type adduct 10 as the major product.
Thus, to prevent generation of the SN2′ type adduct, the conjugated
diene moiety of 4 was initially protected as phenyl sulfide, which was
then converted to the ester (reagents and conditions: (a) propiolic acid,
BOP-Cl, benzene, rt, 79%; (b) propiolic acid, DEAD, Ph3P, THF, rt,
92%).
(14) Numbering of compounds is in accordance with that for
dysidiolide in this paper.

Total Synthesis of Natural Dysidiolide
J . Org. Chem., Vol. 66, No. 4, 2001 1431
F igu r e 4. NOESY correlations of compound 16a .
F igu r e 3. NOESY correlations of compound 11a .
Sch em e 4a
Sch em e 3
protons at C-22. The relative configuration of 7 thus
determined is shown in Figure 2.
The stereoselective methylation of 7 was carried out.
R,â-Unsaturated lactone 7 was treated with Me2CuLi at
0 °C in Et2O to afford diastereoselectively 7R-methyl
lactone 11a with a small amount of 7â-methyl lactone
11b (11a /11b ) 30:1) in 91% yield (Scheme 3). After
separation of the mixture, the relative configurations of
C-6 and C-7 in 11a were determined on the basis of
NOESY correlations between H-6 and H-12, between
H-11 and Me-23, and between H-6 and Me-23 (Figure
3). The stereoselectivity of methylation of 7 with Me2-
CuLi may be explained as due to approach of the reagent
from the less hindered side (convex face) of 7. The
stereoselectivity of methylation of 7 was greater than the
stereoselectivity of methylation of 9.6 Greater selectivity
in methylation was observed by shortening the length of
the R-side chain at C-15 and as was also confirmed by
the finding that enone 13 possessing geminal methyl
groups at the C-15 position, reacted with Me2CuLi to give
7R-methyl lactone 14 as the sole product in 89% yield.
Attention was then directed to stereoselective alkyla-
tion at C-6 (Scheme 4). TBDMS ether 11a was converted
to benzyl ether 15 in two steps: (1) removal of the
TBDMS group with excess tetrabutylammonium fluoride
(TBAF) (quantitative yield) and (2) protection of the
hydroxy group as its benzyl ether with benzyl bromide
(Bn-Br), NaH and n-Bu4NI (93% yield). Lactone 15 was
treated with lithium diisopropylamide (LDA) and then
1-iodo-2-(tetrahydro-2-pyranyloxy)ethane to give lactone
16, which corresponds to lactone B in the synthetic
strategy, in 92% yield as the sole product. The relative
configuration at C-6 in 16 was determined from the
NOESY spectrum of alcohol 16a , which was prepared
from 16 by methanolysis of the tetrahydropyranyl (THP)
group (Figure 4). NOESY correlations were observed
between both methylene protons at C-5 and methyl
protons at C-23 methyl, between one of the methylene
protons at C-5 and the methine proton at C-11 and
between one of the methylene protons at C-5 and the
methine proton at C-12.
a
Reagents and conditions: (a) (i) TBAF, THF, rt, quant, (ii) Bn-
Br, NaH, n-Bu4NI, THF-DMF, rt, 93%; (b) LDA, THPOCH2CH2I,
THF, 0 °C, 92%; (c) (i) DIBAL-H, toluene, -78 °C, (ii) LiBH4,
MeOH-THF, 0 °C, quant (two steps), (iii) TBDMS-Cl, imidazole,
DMF, rt, 96%; (d) (i) PON-Cl, MeLi, TMEDA, THF, 0 °C to rt,
93%, (ii) Li, MeNH2, t-BuOH, 2-methyl-2-butene, reflux, 92%; (e)
(i) N-phenylthiosuccinimide, n-Bu3P, pyridine, 60 °C, then H2O2,
(ii) TPAP, NMO, CH2Cl2, rt, 88% (two steps); (f) (i) n-BuLi, 4-iodo-
2-methyl-1-butene, THF, 50 °C, 92%, (ii) Na-Hg, Na2HPO4,
MeOH, rt, 96%; (g) (i) TBAF, THF, 50 °C, 93%, (ii) TPAP, NMO,
CH2Cl2, rt, 95%, (iii) H2NNH2, KOH, diethylene glycol, 200 °C,
95%; (h) (i) PPTS, MeOH, rt, 97%, (ii) TPAP, NMO, CH2Cl2, rt,
90%; (i) 3-bromofuran, n-BuLi, THF, -78 °C, 93%; (j) O2, hν, Rose
Bengal, i-Pr2NEt, CH2Cl2, -78 °C, 88%.
Deoxygenation of the C-12 and C-24 positions was
carried out. Lactone 16 was reduced with DIBAL-H to
give hemiacetal followed by reduction with LiBH4 to
afford the diol in quantitative yield (two steps). Selective
protection of the primary hydroxy group in the diol was
done by treatment with TBDMS-Cl and imidazole to give
TBDMS ether 17 as the sole product in 96% yield.
Deoxygenation of the secondary hydroxy group at C-12
in 17 was conducted in two steps: (1) conversion to
phosphoramidate with (Me2N)2P(O)Cl (PON-Cl), MeLi,
and N,N,N′,N′-tetramethylethylenediamine (TMEDA)
(93% yield) and (2) Benkeser reduction19 using Li in CH3-
NH2 in the presence of t-BuOH and 2-methyl-2-butene
(92% yield) to afford alcohol 18, which possesses the

1432 J . Org. Chem., Vol. 66, No. 4, 2001
Miyaoka et al.
requisite chiral centers at C-6, C-7, C-11, and C-15 of
dysidiolide. In the absence of 2-methyl-2-butene, a mix-
ture of alcohol 18 and its reduction product of the double
bond at C-9 was obtained.
The hydroxy group of 18 was protected by treatment
with Bn-Br, NaH, and n-Bu4NI to give benzyl ether and
deprotection of the TBDMS group afforded the alcohol
in 92% yield (two steps) (eq 1; reagents and conditions:
(a) (i) Bn-Br, NaH, n-Bu4NI, THF-DMF, rt; (ii) TBAF,
THF, reflux, 92% (two steps); (iii) PON-Cl, MeLi, TME-
DA, THF, 0 °C to rt, 99%; (b) Li, MeNH2, t-BuOH,
2-methyl-2-butene, reflux, 90%). The alcohol was then
ment of aldehyde 26 with 3-lithiofuran, prepared from
3-bromofuran and n-BuLi, gave a mixture of epimeric
alcohols 27a and 27b (27a /27b ) 1:1). Chemical conver-
sion of the R-alcohol 27b to the â-alcohol 27a has been
previously reported by Corey.3 Photochemical oxidation21
of 27a afforded dysidiolide (1) ([R]28 ) -10.8 (c 0.51,
D
CH2Cl2/MeOH ) 1:1). Spectral data and the sign of
optical rotation of synthetic 1 were identical to those of
reported natural dysidiolide, [R]24 ) -11.1 (c 0.6,
D
CH2Cl2/MeOH ) 1:1).1
The asymmetric synthesis of natural dysidiolide was
achieved in 27 steps and 9.7% overall yield (from 3). The
overall yield of the present synthesis exceeds that of any
other method reported to date.
Exp er im en ta l Section
(R)-4-ter t-Bu t yld im et h ylsilyloxym et h yl-4-m et h yl-3-
vin yl-2-cycloh exen on e (4). Imidazole (33.3 g, 489 mmol) and
TBDMS-Cl (36.9 g, 245 mmol) were added sequentially to a
solution of alcohol 3 (44.5 g, 222 mmol) in DMF (222 mL) at
room temperature under an argon atmosphere. After the
mixture was stirred at room temperature for 10 h, the reaction
mixture was diluted with Et2O, washed with saturated aque-
ous NaHCO3, water, and saturated aqueous NaCl, dried over
MgSO4, and concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (hexane/
EtOAc ) 1:1) to give silyl ether (65.6 g, 209 mmol, 94% yield)
as a colorless oil.
To a solution of the above silyl ether (18.9 g, 60.1 mmol) in
THF (300 mL) was added vinylmagnesium bromide in THF
(1.26 M, 95.4 mL, 118 mmol), followed by stirring for 6 h at 0
°C. The reaction mixture was diluted with Et2O, washed with
saturated aqueous NH4Cl, water, and saturated aqueous NaCl,
dried over MgSO4, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography
(hexane/EtOAc ) 5:1) to give dienone 4 (21.6 g, 55.3 mmol,
92% yield) as a colorless oil.
(1R,4R)-4-ter t-Bu tyld im eth ylsilyloxym eth yl-4-m eth yl-
3-(2-p h en ylt h ioet h yl)-2-cycloh exen ol (5a ) a n d (1S,4R)-
4-ter t-Bu tyld im eth ylsilyloxym eth yl-4-m eth yl-3-(2-p h en -
ylth ioeth yl)-2-cycloh exen on e (5b). To a solution of dienone
4 (56.5 g, 202 mmol) in benzene (400 mL) were added PhSH
(22.9 mL, 243 mmol) and Et3N (8.4 mL, 60.3 mmol) sequen-
tially, followed by stirring for 1 h at room temperature. The
reaction mixture was diluted with Et2O, washed with 3 N
NaOH, water, and saturated aqueous NaCl, dried over MgSO4,
and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (hexane/
EtOAc ) 5:1) to give enone (73.5 g, 188 mmol, 93% yield) as a
colorless oil.
A solution of DIBAL-H in hexane (0.95 M, 64.2 mL, 61.0
mmol) was added to a cold (-78 °C) solution of the above enone
(18.3 g, 46.9 mmol) in toluene (235 mL) under an argon
atmosphere. After the mixture was stirred for 30 min at -78
°C, MeOH was added, the mixture was diluted with Et2O, and
saturated aqueous NaCl was added. The mixture was stirred
for 10 h, dried over MgSO4, and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (hexane/EtOAc ) 3:1) to give alcohol 5a (8.76
g, 22.3 mmol, 48% yield) and alcohol 5b (8.75 g, 22.3 mmol,
48% yield), each as a colorless oil.
(1R,4R)-4-ter t-Bu tyld im eth ylsilyloxym eth yl-4-m eth yl-
3-(2-p h en ylsu lfin yleth yl)-2-cycloh exen yl P r op iola te (6)
fr om â-Alcoh ol 5a . A solution of m-CPBA (730 mg, 2.96 mmol
(70%)) in CHCl3 (7.4 mL) was added to a suspension of
â-alcohol 5a (1.16 g, 2.96 mmol) and Na2HPO4 (420 mg, 2.96
mmol) in CHCl3 (7.4 mL) at -42 °C. After 30 min, the
suspension was poured into saturated aqueous NaHCO3. The
organic layer was washed sequentially with saturated aqueous
converted to phosphoramidate 19 with PON-Cl, MeLi,
and TMEDA in 99% yield. Benkeser reduction of phos-
phoramidate 19 in the presence of t-BuOH and 2-methyl-
2-butene gave a mixture of two olefin-reduced products
21 and 22 in 90% yield (21/22 ) 7:2). The desired
reduction product 20 could not be produced, regardless
of what reduction conditions implemented. Deoxygen-
ation of C-24 was thus conducted by a different method
after elongation of the side chain.
Elongation of the side chains and deoxygenation of the
C-24 position were carried out so as to obtain natural
dysidiolide (1). Alcohol 18 was treated with N-phenyl-
thiosuccinimide, n-Bu3P, and pyridine and then with
H2O2 to give a sulfoxide that was then oxidized with
tetrapropylammonium perruthenate (TPAP) and 4-me-
thylmorpholine N-oxide (NMO) to afford sulfone 23 in
88% yield (two steps). Coupling of lithio derivative of
sulfone 23 with 4-iodo-2-methyl-1-butene at 50 °C in 92%
yield followed by removal of the phenylsulfonyl group
with Na-Hg provided silyl ether 24 (96% yield). Deoxy-
genation of 24 at C-24 was conducted in three steps: (1)
removal of the TBDMS group in 24 with excess TBAF
(93% yield), (2) TPAP-oxidation of hydroxy group to
provide aldehyde (95% yield), and (3) Wolff-Kishner
reduction20 of the formyl group with H2NNH2 and KOH
in diethylene glycol at 200 °C to give compound 25 (95%
yield). Methanolysis of the THP group with pyridinuim
p-toluenesulfonate (PPTS) in 25 followed by oxidation
with TPAP and NMO gave aldehyde 263 which corre-
sponds to aldehyde A in the synthetic strategy. Treat-
(18) Diago-Meseguer, J .; Palomo-Coll, A. L.; Ferna´ndez-Lizarbe, J .
R.; Zugaza-Bilbao, A. Synthesis 1980, 547-551.
(19) Ireland, R. E.; Muchmore, D. C.; Hengartner, U. J . Am. Chem.
Soc. 1972, 94, 5098-5100. See also: Trost, B. M.; Renaut, P. J . Am.
Chem. Soc. 1982, 104, 6668-6672. Wender, P. A.; von Geldern, T. W.;
Levine, B. H. J . Am. Chem. Soc. 1988, 110, 4858-4860.
(20) Cram, D. J .; Sahyum, M. R. V.; Knox, G. R. J . Am. Chem. Soc.
1962, 84, 1734-1735.
(21) Kernan, M. R.; Faulkner, D. J . J . Org. Chem. 1988, 53, 2773-
2776.

Total Synthesis of Natural Dysidiolide
J . Org. Chem., Vol. 66, No. 4, 2001 1433
NaHCO3, water, and saturated aqueous NaCl, dried over
MgSO4, and concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (hexane/
EtOAc ) 1:2) to give sulfoxide alcohol (1.20 g, 2.93 mmol, 99%
yield) as a colorless oil.
alcohol (4.40 mg, 18.6 mmol, quantitative yield) as a white
solid. An analytical sample was obtained by recrystallization
of the solid from Et2O-hexane as colorless needles.
NaH (2.15 g, 53.8 mmol (60%)), n-Bu4NI (4.97 g, 13.5 mmol),
and BnBr (8.22 mL, 67.3 mmol) were added sequentially to a
solution of the above alcohol (6.36 g, 26.9 mmol) in THF/
DMF ) 4:1 (270 mL) at room temperature. The mixture was
stirred for 24 h at this temperature. The reaction mixture was
diluted with Et2O, washed with water and saturated aqueous
NaCl, dried over MgSO4, and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (hexane/EtOAc ) 10:1) to give benzyl ether
15 (8.17 g, 25.0 mmol, 93% yield) as a colorless oil.
(2aS,3R,6R,8aR,8bS)-2a,3,4,6,7,8,8a,8b-Octah ydr o-6-ben -
zyloxym eth yl-3,6-d im eth yl-2a -[2-(tetr a h yd r o-2-p yr a n yl-
oxy)eth yl][1,8-bc]n a p h th o-2-fu r a n on e (16). A solution of
n-BuLi in hexane (1.54 M, 4.18 mL, 6.47 mmol) was added to
a cold (0 °C) solution of diisopropylamine (1.09 mL, 7.76 mmol)
in THF (22 mL) under an argon atmosphere. The mixture was
stirred for 30 min at 0 °C. A solution of lactone 15 (1.05 g,
3.22 mmol) in THF (10 mL) was added to the mixture and
stirred for 30 min at 0 °C. 2-Tetrahydropyranyloxy-1-iodoeth-
ane (2.89 g, 11.3 mmol) was added to this mixture at 0 °C.
After stirring at 0 °C for 2 h, the reaction mixture was diluted
with Et2O, washed with saturated aqueous NH4Cl, water and
saturated aqueous NaCl, dried over MgSO4, and concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (hexane/EtOAc ) 6:1) to give lactone
16 (1.35 g, 2.96 mmol, 92% yield) as a colorless oil.
(1R,4R,7R,8S,8a R)-1,2,3,4,6,7,8,8a -Octa h yd r o-4-ben zyl-
oxym et h yl-4,7-d im et h yl-8-ter t-b u t yld im et h ylsilyloxy-
m eth yl-8-[2-(tetr a h yd r o-2-p yr a n yloxy)eth yl]-1-n a p h th a l-
en ol (17). A solution of DIBAL-H in hexane (0.95 M, 47.1 mL,
49.6 mmol) was added to a cold (-78 °C) solution of lactone
16 (13.6 g, 29.8 mmol) in toluene (150 mL) under an argon
atmosphere. The mixture was stirred for 30 min at -78 °C,
MeOH was added, the mixture was diluted with Et2O, and
saturated aqueous NaCl was added. The mixture was stirred
for 10 h,dried over MgSO4, and concentrated under reduced
pressure. The crude product was used for next reaction without
purification.
LiBH4 (1.30 g, 59.7 mmol) was added to the crude product
in MeOH (150 mL) at 0 °C. The mixture was stirred for 2 h at
0 °C. The reaction mixture was diluted with EtOAc, washed
with saturated aqueous NH4Cl, water, and saturated aqueous
NaCl, dried over MgSO4, and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (hexane/EtOAc ) 1:1) to give diol (13.7 g, 29.8
mmol, quantitative yield, two steps) as a colorless oil.
Imidazole (4.87 g, 71.5 mmol) and TBDMS-Cl (5.39 g, 35.8
mmol) were added sequentially to a solution of the above diol
(13.7 g, 29.8 mmol) in DMF (150 mL) at room temperature
under an argon atmosphere. After the mixture was stirred at
room temperature for 10 h, the reaction mixture was diluted
with Et2O, washed with saturated aqueous NaHCO3, water,
and saturated aqueous NaCl, dried over MgSO4, and concen-
trated under reduced pressure. The residue was purified by
silica gel column chromatography (hexane/EtOAc ) 10:1) to
give silyl ether 17 (16.6 g, 28.6 mmol, 96% yield) as a colorless
oil.
DCC (15.1 g, 73.4 mmol) and DMAP (448 mg, 3.67 mmol)
were added sequentially to a stirred solution of the above
â-alcohol (15.0 g, 36.7 mmol) and propiolic acid (3.83 mL, 62.3
mmol) in toluene (367 mL) at 0 °C. After being stirred for 1 h
at 0 °C, the brownish suspension was filtered through a short
column on silica gel. The mixture was concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (hexane/EtOAc ) 5:1) to give sulfoxide ester
6 (16.9 g, 36.7 mmol, quantitative yield) as a colorless oil.
(1R,4R)-4-ter t-Bu tyld im eth ylsilyloxym eth yl-4-m eth yl-
3-(2-p h en ylsu lfin yleth yl)-2-cycloh exen yl P r op iola te (6)
fr om r-Alcoh ol 5b. A solution of m-CPBA (58.4 mg, 237 µmol
(70%)) in CHCl3 (2.4 mL) was added to a suspension of
R-alcohol 5b (105 mg, 237 µmol) and Na2HPO4 (33.6 mg, 237
µmol) in CHCl3 (2.4 mL) at -42 °C. After being stirred for 30
min, the suspension was poured into saturated aqueous
NaHCO3. The organic layer was washed sequentially with
saturated aqueous NaHCO3, water, and saturated aqueous
NaCl, dried over MgSO4, and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (hexane/EtOAc ) 1:2) to give sulfoxide alcohol
(106 mg, 230 µmol, 97% yield) as a colorless oil.
DEAD (159 µL, 1.03 mmol), propiolic acid (63.3 µL, 1.03
mmol), and a solution of the above R-alcohol (183 mg, 448
µmol) in THF (4.5 mL) were added sequentially to a stirred
solution of Ph3P (270 mg, 1.03 µmol) in THF (4.5 mL). The
mixture was followed by stirring for 1 h at room temperature
under an argon atmosphere. After dilution with hexane and
Et2O (1:1), the reaction mixture was filtered through a short
column on silica gel and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography
(hexane/EtOAc ) 5:1) to give sulfoxide ester 6 (201 mg, 437
µmol, 98% yield) as a colorless oil.
(6R,8a R,8b R)-4,6,7,8,8a ,8b -H exa h yd r o-6-ter t-b u t yld i-
m et h ylsilyloxym et h yl[1,8-bc]-6-m et h yln a p h t h o-2-fu r -
a n on e (7). Ethyl propiolate (290 mg, 2.96 mmol) was added
to a solution of sulfoxide ester 6 (680 mg, 1.48 mmol) in
toluene/pyridine ) 60:1 (150 mL) at room temperature under
an argon atmosphere. The mixture was refluxed for 8 h. The
mixture was diluted with hexane/Et2O ) 2:1, filtered through
a short column on silica gel, and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (hexane/EtOAc ) 5:1) to give decalin 7 (442
mg, 1.32 mmol, 89% yield) as a colorless oil.
(2aS,3R,6R,8aR,8bS)-2a,3,4,6,7,8,8a,8b-Octah ydr o-6-ter t-
bu tyld im eth ylsilyloxym eth yl[1,8-bc]-3,6-d im eth yln a p h -
th o-2-fu r a n on e (11a ). A solution of MeLi in Et2O (1.12 M,
1.26 mL, 1.41 mmol) was added to a cold (0 °C) suspension of
CuI (135 mg, 709 µmol) in Et2O (4.00 mL) under an argon
atmosphere. The mixture was stirred for 30 min at 0 °C. R,â-
Unsaturated lactone 7 (139 mg, 416 µmol) was added, and the
mixture was stirred for 15 min at 0 °C. The reaction mixture
was diluted with Et2O, washed with saturated aqueous NH4-
Cl, water, and saturated aqueous NaCl, dried over MgSO4, and
concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (hexane/EtOAc ) 6:1) to
give 7R-methyl lactone 11a (128 mg, 366 µmol, 88% yield) as
a white solid and 7â-methyl lactone 11b (4.4 mg, 12.5 µmol,
3% yield) as a colorless oil. An analytical sample was obtained
by recrystallization of the solid from Et2O-hexane as colorless
needles.
(1R,4a R,5S,6R)-1,2,3,4,4a ,5,6,7-Octa h yd r o-5-ter t-bu tyl-
d im eth ylsilyloxym eth yl-1,6-d im eth yl-1-h yd r oxym eth yl-
5-[2-(tetr ah ydr o-2-pyr an yloxy)eth yl]-1-n aph th alen ol (18).
To a solution of alcohol 17 (65.6 mg, 115 µmol) in THF (1.20
mL) were added TMEDA (60.5 µL, 401 mmol) and MeLi in
Et2O (1.13 M, 253 µL, 286 µmol), followed by stirring for 30
min at 0 °C. Tetramethylphosphorodiamidic chloride (34.0 µL,
230 µmol) was added to the mixture. After the mixture was
stirred for 30 min at 0 °C, saturated aqueous NaHCO3 was
added. The mixture was diluted with EtOAc and washed with
water and saturated aqueous NaCl. Organic layer was dried
over MgSO4, and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography
(hexane/EtOAc ) 1:1) to give phosphoramidate (69.3 mg, 107
mmol, 93% yield) as a colorless oil.
(2a S,3R,6R,8a R,8bS)-2a ,3,4,6,7,8,8a ,8b-Octa h yd r on a p h -
t h o-6-b en zyloxym et h yl-3,6-d im et h yl[1,8-bc]n a p h t h o-2-
fu r a n on e (15). A solution of TBAF in THF (1.0 M, 28.0 mL,
28.0 mmol) was added to 7R-methyl lactone 11a (6.53 g, 18.6
mmol) at room temperature. After being stirred for 1 h, the
reaction mixture was diluted with Et2O, washed with water
and saturated aqueous NaCl, dried over MgSO4, and concen-
trated under reduced pressure. The residue was purified by
silica gel column chromatography (hexane/EtOAc ) 1:1) to give

1434 J . Org. Chem., Vol. 66, No. 4, 2001
Miyaoka et al.
Lithium (70.3 mg, 10.1 mmol) was added to a methylamine
(17.0 mL) at -78 °C under an argon atmosphere. After the
mixture was refluxed for 30 min, a solution of the above
phosphoramidate (358 mg, 507 µmol) in THF (500 µL) and
2-methyl-2-butene (851 µL, 10.1 mmol) were added. After the
resulting mixture was refluxed for 30 min, 2-methyl-2-propanol
(364 µL, 3.81 mmol) was added. After the resulting mixture
was refluxed for 30 min, the solid NH4Cl was carefully added
until the color disappeared. The reaction mixture was diluted
with Et2O and washed with saturated aqueous NH4Cl, water,
and saturated aqueous NaCl. The mixture was dried over
MgSO4 and concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (hexane/
EtOAc ) 4:1) to give alcohol 18 (218 mg, 466 µmol, 92% yield)
as a colorless oil.
(1S,2R,5R,8a R)-1,2,3,5,6,7,8,8a -Oct a h yd r o-5-b en zen e-
su lfon ylm eth yl-1-ter t-bu tyld im eth ylsilyloxym eth yl-2,5-
d im eth yl-1-[2-(tetr a h yd r o-2-p yr a n yloxy)eth yl]n a p h th a -
len e (23). A solution of N-thiophenylsuccinimide (3.39 g, 16.4
mmol) in pyridine (10.2 mL) and n-Bu3P (2.27 mL, 16.4 mmol)
were added sequentially to a solution of alcohol 18 (1.91 g,
4.09 mmol) in pyridine (10.2 mL) under an argon atmosphere
at room temperature. After being stirred for 6 h, the mixture
was diluted with Et2O and washed with water, 5% solution of
H2O2, water, and saturated aqueous NaCl. The organic layer
was dried over MgSO4 and concentrated under reduce pres-
sure. The brownish residue was filtered through a short
column on silica gel. The crude product was used for next
reaction without purification.
TPAP (410 mg, 1.17 mmol) was added to a stirred mixture
of the crude product, NMO (2.73 g, 23.3 mmol), and powdered
molecular sieves (1.95 g) in CH2Cl2 (19.5 mL) at room tem-
perature under an argon atmosphere. The reaction mixture
was stirred at room temperature for 2 h, passed through a
short pad of silica gel, and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (hexane/EtOAc ) 4:1) to give phenyl sulfone
23 (2.14 g, 3.63 mmol, 88% yield, two steps) as a colorless oil.
(1S,2R,5S,8a R)-1,2,3,5,6,7,8,8a -Octa h yr o-1-ter t-bu tyld i-
m et h ylsilyloxym et h yl-2,5-d im et h yl-5-(4-m et h yl-4-p en -
t e n yl)-1-[(2-t e t r a h yd r o-2-p yr a n yloxy)e t h yl]n a p h t h a -
len e (24). To a solution of sulfone 23 (291 mg, 0.493 mmol) in
THF (4.9 mL) was added a solution of n-BuLi in hexane (1.37
M, 720 µL, 986 µmol), and followed by stirring for 45 min at
50 °C. 4-Iodo-2-methylbutene (483 µL, 2.46 mmol) was added,
and the mixture was stirred for 2 h at 50 °C. The reaction
mixture was diluted with Et2O and washed with saturated
aqueous NH4Cl, water, and saturated aqueous NaCl. The
mixture was dried over MgSO4 and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (hexane/EtOAc ) 5:1) to give the diastereo-
meric mixture (292 mg, 453 µmol, 92% yield) as a colorless
oil.
at room temperature under an argon atmosphere. The reaction
mixture was stirred at room temperature for 2 h, passed
through a short pad of silica gel, and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (hexane/EtOAc ) 4:1) to give aldehyde (154
mg, 382 µmol, 95% yield) as a colorless oil.
KOH (322 mg, 5.74 mmol) and hydrazine monohydrate (391
µL, 7.66 µmol) were added sequentially to a solution of the
aldehyde (257 mg, 638 µmol) in diethylene glycol (12.8 mL)
under an argon atmosphere at room temperature. After the
mixture was stirred for 2 h at 200 °C, the reaction mixture
was cooled, diluted with Et2O, and washed with saturated
aqueous NH4Cl, water, and saturated aqueous NaCl. The
organic layer was dried over MgSO4 and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (hexane/EtOAc ) 6:1) to give 25 (235 mg, 605
µmol, 95% yield) as a colorless oil.
(1R,2R,5S,8a S)-1,2,3,5,6,7,8,8a -Octa h yd r o-1-(2-for m yl-
m eth yl)-5-(4-m eth yl-4-p en ten yl)-1,2,5-tr im eth yln a p h th a -
len e (26). A solution of PPTS in MeOH (1%, 3.40 mL, 0.17
M) was added to 25 (220 mg, 568 µmol) at room temperature.
After being stirred for 5 h, the reaction mixture was diluted
with Et2O, washed with saturated aqueous NaHCO3, water,
and saturated aqueous NaCl, dried over MgSO4, and concen-
trated under reduced pressure. The residue was purified by
silica gel column chromatography (hexane/EtOAc ) 3:1) to give
alcohol (168 mg, 551 mmol, 97% yield) as a colorless oil.
TPAP (1.7 mg, 4.86 µmol) was added to a stirred mixture of
the above alcohol (14.8 mg, 48.6 µmol), NMO (28.5 mg, 243
µmol), and powder molecular sieves (24.3 mg) in CH2Cl2 (972
µL) at room temperature under an argon atmosphere. The
reaction mixture was stirred at room temperature for 2 h,
passed through a short pad of silica gel, and concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (hexane/EtOAc ) 8:1) to give alde-
hyde 26 (13.2 mg, 43.7 µmol, 90% yield) as a colorless oil.
(1R,2R,5S,8a S)-1,2,3,5,6,7,8,8a -Octa h yd r o-1-[2R,S-2-h y-
d r oxy-2-(3-fu r yl)eth yl]-5-(4-m eth yl-4-p en ten yl)-1,2,5-tr i-
m eth yln a p h th a len e (27a a n d 27b). n-BuLi (1.53 M in
hexane, 1.16 mL, 1.77 mmol) was added to a solution of
3-bromofuran (178 µL, 1.98 mmol) in THF (4.00 mL) at -78
°C, and after 30 min, the yellow solution was treated with a
solution of aldehyde 26 (120 mg, 396 µmol) in THF (4.00 mL).
After the mixture was stirred for 30 min, saturated aqueous
NH4Cl was added, the mixture was warmed to room temper-
ature, and water and Et2O were added. The organic layer was
washed with saturated aqueous NH4Cl, water, and saturated
aqueous NaCl. The mixture was dried over MgSO4 and
concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (hexane/EtOAc ) 5:1) to
give alcohol 27a (67.4 mg, 182 µmol, 46% yield) and alcohol
27b (69.0 mg, 186 µmol, 47% yield) each as a colorless oil.
(-)-Dysid iolid e (1). Rose Bengal (0.4 mg) was added to a
solution of 27a (9.1 mg, 24.6 µmol) and diisopropylethylamine
(18 µL, 100 µmol) in CH2Cl2 (6.0 mL) at room temperature.
The suspension was cooled to -78 °C, saturated with anhy-
drous O2, and irradiated with a 270-W tungsten filament lamp
under an atmosphere of O2. After 6 h, irradiation was stopped,
the pink solution was warmed to room temperature, and
saturated aqueous oxalic acid (2 mL) was added. After 30 min
of vigorous stirring, water and CHCl3-EtOAc (1:2) were added
to the colorless mixture, and the aqueous portion was extracted
with CHCl3-EtOAc (1:2). The combined organic fractions were
dried over MgSO4 and concentrated in vacuo. The residue was
purified by silica gel column chromatography (hexane/
EtOAc ) 1:1) to give (-)-dysidiolide (1) (8.7 mg, 21.6 µmol,
88% yield) as a white solid. An analytical sample was obtained
by recrystallization of the solid from acetone-Et2O as colorless
needles.
To a solution of the above diastereomeric mixture (1.03 g,
1.57 mmol) in MeOH were added Na2HPO4 and Na-Hg (9.32
g, 5%), followed by stirring for 2 h at room temperature. The
reaction mixture was passed through a short pad of silica gel
and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (hexane/
EtOAc ) 14:1) to give desulfone compound 24 (777 mg, 1.50
mmol, 96% yield) as a colorless oil.
(1R,2R,5S,8a S)-1,2,3,5,6,7,8,8a -Octa h yd r o-5-(4-m eth yl-
4-p en t en yl)-1-[2-(t et r a h yd r o-2-p yr a n yloxy)et h yl]-1,2,5-
tr im eth yln a p h th a len e (25). A solution of TBAF in THF (1.0
M, 2.56 mL, 2.56 mmol) was added to 24 (133 mg, 256 µmol)
at room temperature. After being stirred for 10 h at 50 °C,
the reaction mixture was diluted with Et2O, washed with
water and saturated aqueous NaCl, dried over MgSO4, and
concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (hexane/EtOAc ) 1:1) to
give alcohol (96.7 mg, 239 µmol, 93% yield) as a colorless oil.
Ack n ow led gm en t. This work was supported in part
by a Grant-in-Aid for Scientific Research (Grant No.
09672165) from Ministry of Education, Science, Sports
TPAP (14.2 mg, 40.3 µmol) was added to a stirred mixture
of the alcohol (163 mg, 403 µmol), NMO (236 mg, 2.01 mmol),
and powdered molecular sieves (202 mg) in CH2Cl2 (4.0 mL)

Total Synthesis of Natural Dysidiolide
J . Org. Chem., Vol. 66, No. 4, 2001 1435
MTPA ester of 5b, 13, 14, and 16a . Spectroscopic data and
copies of 1H and 13C NMR spectra for compounds 4, 5a ,b, 6, 7,
11a , 15-18, 23-26, 27a ,b, and 1. This material is available
free of charge via the Internet at http://pubs.acs.org.
and Culture, and a Grant for private universities from
The Promotion and Mutual Aid Corporation for Private
Schools of J apan and Ministry of Education, Science,
Sports and Culture.
Su p p or tin g In for m a tion Ava ila ble: Details for the
preparation and spectroscopic data for MTPA ester of 5a ,
J O0015772