Total Synthesis of Natural Bicyclic Lactones (+)-Dihydrocanadensolide, (±)-Avenociolide, and (±)-Isoavenociolide via Tungsten-π-Allyl Complexes

Article abstract of DOI:10.1021/jo991077c

A synthetic method using tungsten-π-allyl compounds is developed for total syntheses of natural bislactones including (+)-dihydrocanadensaolide (2), (±)-avenociolide (3), and (±)-isoavenociolide (4). Syntheses of these natural compounds are based on a com

Full text of DOI:10.1021/jo991077c

J . Org. Chem. 1999, 64, 8311-8318
8311
Tota l Syn th esis of Na tu r a l Bicyclic La cton es
(+)-Dih yd r oca n a d en solid e, (()-Aven ociolid e, a n d
(()-Isoa ven ociolid e via Tu n gsten -π-Allyl Com p lexes
Ming-J ung Chen, Kesavaram Narkunan, and Rai-Shung Liu*
Department of Chemistry, National Tsing-Hua University, Hsinchu, 30043, Taiwan, ROC
Received J uly 6, 1999
A synthetic method using tungsten-π-allyl compounds is developed for total syntheses of natural
bislactones including (+)-dihydrocanadensaolide (2), (()-avenociolide (3), and (()-isoavenociolide
(4). Syntheses of these natural compounds are based on a common intermediate, trans-R-methylene
butyrolactones bearing an anti-homoallylic alcohol. The kep steps in the syntheses involve an
intramolecular alkoxycarbonylation of propargyltungsten complexes to yield tungsten-π,γ-lactonyl
species, followed by condensation of their CpW(NO)I(π-allyl) derivatives with suitable aldehydes.
This new method is very efficient for the synthesis of (()-avenociolide (3) and (()-isoavenociolide
(4). Total syntheses of compounds 3 and 4 require only six and three steps, respectively, on the
basis of chloropropargyl derivatives.
Sch em e 1
In tr od u ction s
Allylation of organic carbonyl compounds with allyl-
metal complexes is a very important tool in organic
synthesis.1,2 Faller reported3 that CpMo(NO)Cl(π-allyl)
complexes condensed with aldehyde via a chairlike
transition state, yielding homoallylic alcohol with excel-
lent diastereoselectivities (Scheme 1, eq 1). We applied
this method to the syntheses of trans-R-methylene bu-
tyrolactones4 via alkoxycarbonylation of propargyltung-
sten compounds (eq 2) to yield tungsten-π-allyl com-
plexes, followed by condensation of their CpW(NO)I(π-
ally) derivatives with aldehydes. We extended this
synthetic sequence to intramolecular alkoxycarbonyla-
tion5 of propargyltungsten compounds as shown in eq 3,
ultimately proceeding to trans-R-methylene butyro-
lactones bearing an anti-homoallylic alcohol 1. Recently,
we reported that compound 1 serves as an useful inter-
mediate for total synthesis of natural monocyclic R-me-
thylene butyrolactones including (-)-methylenolactocin,6
(()-protolichesterinic acid, and (()-rocellaric acid.7 In this
paper, we demonstrate the use of compound 1 as an
intermediate for total syntheses of natural bislactones8
including (+)-dihydrocanadensolide 2, (()-avenociolide 3,
and (()-isoavenociolide 4. Dihydrocanadensolides 2 was
isolated as a mold metabolite of Penicillum canadense9,10
* e-mail: rsliu@faculty.nthu.edu.tw.
(1) Yamamoto, Y.; Asao, N. Chem. Rev. 1993, 93, 2207.
(2) Rousch W. R. In Comprehensive Organic Synthesis; Trost, B. M.,
Ed.; Pergamon Press: Oxford, 1991; Vol. 2, pp 1-53.
(3) (a) Faller, J . W.; Linebarrier, D. L. J . Am. Chem. Soc.. 1989,
111, 1939. (b) Faller, J . W.; J ohn, J . A.; Mazzier, M. R. Tetrahedron
Lett. 1989, 31, 1769.
(4) Lin, S.-H.; Vong, W.-J .: Liu, R.-S. Organometallics 1995, 14,
1619.
(5) (a) Chen, C.-H.; Fan, J .-S.; Lee, G.-H.; Shieh, S.-J .; Wang, S.-L.;
Peng S.-M.; Liu, R.-S. J . Am. Chem. Soc. 1996, 118, 9279. (b) Shiu, L.
H.; Wang S.-L.; Wu M.-J .; Liu R. S. J . Chem. Soc., Chem. Commun.
1997, 2055.
with biological activity, and a first total synthesis was
described by Mulzer.11,12 Avenaciolide (3) and isoavena-
ciolide (4) are secondary metabolites isolated from As-
(6) Chandrasekharam, M.; Liu, R.-S. J . Org. Chem. 1998, 63, 9122.
(7) Chen, M.-J .; Liu, R.-S. Tetrahedron Lett, 1998, 39, 9465.
(8) Among these three natural bislactones, synthesis of racemic
avenociolide and isoavenociolide has appeared in an earlier com-
munication; see: Narkunan K.; Liu, R.-S. J . Chem. Soc., Chem.
Commun. 1998, 1521.
(10) Kato, M.; Kageyama, M.; Tanaka, R.; Kuwahara, K.; Yoshiko-
shi, A. J . Org. Chem. 1975, 40, 423.
(11) Mulzer, J .; Kattner, L. Angew. Chem., Int. Ed. Engl. 1990, 29,
679.
(12) Papers concerning total synthesis of dihydrocanadensaolide,
only two reports have appeared; see ref 11 for the (+) and (-)-froms.
For the (+)-form, see: Nubbemeyer, U. J . Org. Chem. 1996, 61, 3677
(9) Mccorkindale, N. J .; Wright, J . L.; Brian, P. W.; Chlarke, S. M.;
Hutchinson, S. A. Tetrahedron Lett. 1968, 727.
10.1021/jo991077c CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/14/1999

8312 J . Org. Chem., Vol. 64, No. 22, 1999
Chen et al.
Sch em e 2
Sch em e 3
pergillus and Penicillium;13 total syntheses of these two
compounds have attracted considerable attention14 be-
cause of their diverse and potent biological activities. In
this paper, we report total syntheses of these three
bislactones based on tungsten-π-allyl complexes; this
synthetic protocol is highly efficient, particularly for
avenociolide 3 and isoavenociolide 4, because it requires
only a few steps from the starting chloropropargyl
derivative.
Tota l Syn th esis of (+)-Dih yd r oca n a d ein solid e.
Shown in Scheme 2 are the syntheses of organic sub-
strates designed for organotungsten compounds. Treat-
ment of 1-hexyne 5 with DIBAL, followed by I2-oxidation,
gave the iodoalkene derivative 6 in 74% yield. Palladium-
catalyzed coupling of the propargyl alcohol and 6 in
pyrrolidine15 in the presence of CuI catalyst yielded the
alcohol 7 in 93%. Chlorination of the alcohol 7 with
thionyl chloride in HMPA gave a 96% yield of chloropro-
pargyl derivative 8. Asymmetric cis-dihydroxylation of
8 over AD-mix-R catalysts16 produced the (+)-diol 9 in
96% yield. The enantiomeric excess of the diol was
determined to be 97% by analysis of its cyclic ketal (-)-
10 on a chiral HPLC column (Merck, Chiraspher).
Protection of the diol group of 9 with CH(OMe)3, followed
by DIBAL-treatment to induce asymmetric ring cleav-
age,17 afforded the (+)-methoxymethyl ether 11 in 98%
yield. Metalation of (+)-chloropropargyl compound 11
with NaCpW(CO)3 gave a 98% yield of (-)-propargyl-
tungsten compound 12. Treatment of 12 with triflic acid
catalyst (20 mol %) induced an intramolecular alkoxy-
carbonylation reaction12 to yield an 85% yield of tungsten-
π-allyl complex 13 as a mixture of syn and anti isomers
(syn/anti ) 2.2). The two isomers are distinguishable by
the magnitude of the J 34 coupling constant; the value is
3.0 Hz for the syn isomer and 0 Hz for the anti isomer.5a
It is unnecessary to separate the two diastereomers 13-
syn and 13-a n ti because their CpW(NO)I derivatives will
give the same diastereomeric product12 in condensation
with aldehydes.
(13) (a) Brookes, D.; Tidd, B. K.; Turner, W. B. J . Chem. Soc. 1963,
5385. (b) Ellis, J . J .; Stodola, F. H.; Vesonder, R. F.; Glass, C. A. Nature
1964, 203, 1382.
(14) Examples for total syntheses of avenociolide and isoaveno-
ciolide, see: (a) Tsuboi, S.; Sakamoto J .-I.; Yamashita H.; Sakai, T.
Utaka, M. J . Org. Chem. 1998, 63, 1102. (b) Parker, W. L.; J ohnson,
F. J . Org. Chem. 1973, 38, 2489. (c) Rodriguez, C. M.; Martin, T.;
Martin, V. S. J . Org. Chem. 1996, 61, 8448. (d) Burke, S. D.; Pacofsky,
G. J .; Piscopio, A. D. J . Org. Chem. 1992, 57, 2228. (e) Udding, J . H.;
Tuijp, K. J . M.; Van Zanden, M. N. A.; Hiemstra, H.; Speckamp, W.
N. J . Org. Chem. 1994, 59, 1993. (f) Herrmann, J . F.; Berger, M. T. J .
Am. Chem. Soc. 1979, 101, 1544. (g) Schreiber, S. L.; Hoveyda, A. H.
J . Am. Chem. Soc. 1984, 106, 7200. (h) Sakai, T.; Horikawa, H.;
Takeda, A. J . Org. Chem. 1980, 45, 2040. (i) Kallmerten, J .; Gould, T.
J . J . Org. Chem. 1985, 50, 1128. (j) Anderson, R. C.; Fraser-Reid B. J .
Org. Chem. 1985. 50, 4781. (k) Kido, F.; Tooyama, Y.; Noda, Y.;
Yoshikoshi, A. Chem. Lett. 1983, 881.
Scheme 3 shows a synthetic protocol to use tungsten-
π-allyl complex 13 for enantiomeric synthesis of (+)-
dihydrocanadensolide 2. Sequential treatment of the syn
and anti mixtures (syn/ anti ) 2.2) of 13 with NOBF4
(1.0 equiv), NaI, and NaOAc yielded the CpW(NO)I(π-
allyl) derivative3 of 13 that reacted in situ with TBSOCH2-
CHO to afford trans-R-methylene butyrolactone 14 in
(16) Honda, T.; Horiuchi, S.; Mizutani, H.; Kanai, K. J . Org. Chem.
1996, 61, 4944.
(17) Friesen, R. W.; Vanderwal, C. J . Org. Chem. 1996, 61, 9103.
(15) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 4467.

Total Synthesis of Natural Bicyclic Lactones
J . Org. Chem., Vol. 64, No. 22, 1999 8313
Sch em e 4
Sch em e 5
73% yield. After removal of the siloxy group, the diol
group of 14 was oxidatively cleaved by NaIO4/SiO2 to give
the aldehyde 15. The trans configuration of 15 seems to
be a problem to achieve a 5,5-bislactone structure.
Compound 15 was thus treated with pyridine to give a
furanone 16 in 88% yield. Reduction of the aldehyde 15
with NaBH4/CeCl3 afforded the alcohol 17 in 86% yield.
Hydrogenation (1.0 atm) of 17 over PtO2 catalyst deliv-
ered the trisubstituted γ-lactone 18 in 91% yield. The
stereochemistry of 18 is established by proton NOE
spectra that show a cis arrangement for the three
substituents. PCC-oxidation of the alcohol 18 afforded
an aldehyde that was subsequently heated in a HCl/
MeOH mixture to give a tetrahydrofuranyl ether 19 in
overall 54% yield. The stereochemistry of 19 is again
confirmed by proton NOE-difference spectra. Epimeriza-
tion of 19 with t-BuOK in THF gave the more stable
isomer 20 in 86% yield. Finally, J ones oxidation of
compound 20 afforded a 91% yield of the desired (+)-
dihydrocanadensolide 2. Spectral data of 2 [[R]25D ) +29.8
(c ) 0.1, CHCl3)] in this synthesis is virtually identical
situ with C8H17CHO to yield trans-R-methylene butyro-
lactone 25 in 62% isolated yield. For compound 25, the
anti configuration at the secondary alcohol is inferred
from the structure of its transacylation product 26 that
has a trans configuration (vide infra). We first aim at
the synthesis of isoavenociolide 4 because it can be easily
achieved from γ-lactone 25 via epimerization at its C(5)
carbon. Compound 25 was thus heated in toluene for 7
h with the DBU catalyst (0.30 equiv), but to induce an
unexpected transacylation reaction, yielding a new R-me-
thylene butyrolactone 26 in 86% yield. Compound 26 also
has a trans configuration on the lactonyl ring according
to the proton NOE effect. Under the same conditions,
p-TSA catalyst (0.20 equiv) also gave compound 26 in
91% yield. If tBuOK (0.15 equiv) was used in the reaction,
compound 26 and a mixture of unknown species were
formed upon heating in THF (60 °C) for 6 h. Hence, we
sought to invert the configuration at the CH(OH) carbon
of 26 since it is a more stable form than its transacylation
isomer 25. Epimerization of this secondary alcohol pro-
ceeded smoothly according to Mitsunobu reaction,19
sequentially giving 27 and 28 in 90% and 89%, respec-
tively. We envision that isoavenociolide 4 is readily
achieved from 28 via a base-catalyzed transacylation
equilibrium. To our disappointment, heating a mixture
of DBU (0.2-2.0 equiv) and 28 in toluene at reflux for
72 h did not show any sign of chemical reaction, and the
starting material 28 was recovered exclusively. We then
attempt to achieve this transacylation with acid catalyst
but to give surprising results. Heating 28 with excess
p-TSA‚H2O (2.0 equiv) in toluene in a sealed tube (150
°C, 4 h) produced the desired avenaciolide 3 in 65% yield
together with isoavenaciolide 2 in 5% yield. Formation
of avenaciolide 3 from 28 indicates an inversion of
to those reported in the literature9,10 [[R]25 ) +30.1
D
(c ) 0.1, CHCl3)]. A similar oxidation on bicyclic furanyl
ether 19 delivered the (-)-3-epi-dihydrocanadensolide 21
[[R]D ) -20.3 (c ) 0.50, CHCl3)] in 92% yield. Spectral
data of the 3-epimer 21 are also identical to those
reported in the literature12 ([R]D ) -20.6 (c ) 1.3,
CHCl3)].
Tota l Syn th esis of Aven ociolid e a n d Isoa ven o-
ciolid e. Avenociolide (3) and isoavenociolide (4) have
distinct bislactone structures from that of dihydroca-
nadensolide (2). Total synthesis of 3 and 4 in racemic
forms can also be achieved from tungsten-π-allyl com-
plexes according to the retrosynthesis in Scheme 4. A
major task here is that it requires to complete two
inversions of stereochemistries at the C1′ and C5 carbons
for avenociolide (3) and an inversion of stereochemistry
at the C5 carbon for isoavenociolide (4).
As shown in Scheme 5, the starting chloropropargyl
derivative 22 is readily available from chloropropargyl
anion and n-butyl glyoxalate.18 Metalation of 22 with
CpW(CO)3Na (1.3 equiv) yielded propargyltungsten com-
plex 23, which was not isolated because of its chemical
reactivity. Elution of this tungsten species through a
silica column led to intramolecular alkoxycarbonylation,
giving tungsten-syn-π-allyl complex 24 in a overall 70%
yield. The syn configuration of 24 is indicated by the
coupling constant J 34 ) 3.1 Hz.5a,b Sequential addition
of NOBF4 (1.0 equiv) and LiCl (2.0 equiv) to 4 in CH3CN
generated its CpW(NO)Cl derivative,3 which reacted in
(19) (a) Overman, L. E.; Bell, K. L.; Ito, F. J . Am. Chem. Soc. 1984,
106, 4192. (b) Okabe, M.; Sun, R. C.; Zenchoff G. B. J . Org. Chem.
1991, 56, 4392.
(18) Brandsma, L. In Preparative Acetylenic Chemistry; Elsevier:
Amsterdam, 1988.

8314 J . Org. Chem., Vol. 64, No. 22, 1999
Chen et al.
Sch em e 6
was 96%. Subsequent treatment of propargyltungsten
species 30 with p-TSA‚H2O (1.0 equiv) in a MeOH/CH2-
Cl2 mixture (volume ratio ) 1/10) to effect intramolecular
alkoxycarbonylation,5a,b yielding tungsten-π-allyl com-
plex 31 in 65% yield. Further conversion of 31 to its CpW-
(NO)I derivative is achieved through sequential treat-
ment with NOBF4 (1.0 equiv) and NaI (2.0 equiv).
Reaction of this species in situ with C8H17CHO gave a
62% yield of bislactone species 33 which was presumbly
produced via lactonization of the primary compound 32.
Decarboxylation of 33 proceeded smoothly through heat-
ing its dimethylacetamide solution (150 °C, 3 h) contain-
ing MgCl2‚6H2O (5.0 equiv)21 to yield the desired iso-
avenaciolide 4 in 59% yield. 1H and 13C NMR data of
isoavenociolide 4 in this synthesis were identical to those
of authentic sample.14
We reported here an extented work on the synthetic
utility of tungsten-π-allyl complexes. Previously, we
demonstrated the use of these organotungsten com-
pounds for the synthesis of natural monocyclic R-meth-
ylene butyrolactone.6,7 In this paper, these allyl complexes
are proved useful for total syntheses of naturally occur-
ring bislactones such as (+)-dihydrocanadensolide (2),
(()-avenociolide (3), and (()-isoavenociolide (4). The
overall synthetic sequence for racemic avenociolide and
isoavenociolide is considered to be the most efficient one
among the known methods.14
Sch em e 7
Exp er im en ta l Section
General procedures and spectroscopic methods are described
elsewhere.5a,b NaCpW(CO)3 was prepared by stirring of [CpW-
(CO)3]2 with sodium amalgam in THF for 8 h, and it was used
in situ.
Syn th esis of 1-Iod o-1-h exen e (6). To a hexane solution
of 1-hexyne (13.1 g, 160 mmol) was added DIBAL (1.0 M, 160
mL, 160 mmol) at -40 °C, and the solution was stirred for 20
min and gradually warmed to 23 °C in a period of 4 h. After
an additional stirring for 2 h at 23 °C, the solution was heated
at 50 °C for 4 h and then cooled to -40 °C. To this cooled
solution was added dropwise a THF solution of I2 (41.0 g, 160
mmol), the solution was warmed to 23 °C and stirred for 12 h.
To the resulting solution was added 20% H2SO4 (72 mL), and
the organic layer was extracted with hexane. The extract was
washed sequentially with an aqueous solution of Na2S2O3 (2.0
M, 10 mL), NaHCO3 (1.5 M, 10 mL) and NaCl (10 mL). The
extract was dried over MgSO4, and eluted through a silica
column to give iodo compound 6 as an oil (25 g, 119 mmol,
74.4%): IR (neat, cm-1) ν(CdC) 1610 (w); 1H NMR (CDCl3,
300 MHz) δ 0.86 (t, J ) 6.9 Hz, 3H), 1.31 (m, 4H), 2.02 (m,
2H), 5.94 (d, J ) 13.3 Hz, 1H), 6.46 (dt, J ) 13.3, 7.1 Hz, 1H);
13C NMR (CDCl3, 100 MHz) δ 13.7, 21.85, 30.34, 35.59, 74.28,
146.37; HRMS calcd for C6H11I, 209.9905, found 209.9900.
Syn th esis of Non -4-en -2-yn -1-ol (7). To a pyrrolidine
solution (30 mL) of iodo compound 1 (6.73 g, 32.1 mmol) were
added PdCl2(PPh3)2 (0.90 g, 1.28 mmol) and CuI (0.44 g, 2.56
mmol), and the mixture was stirred for 10 min before addition
of propargyl alcohol (3.73 mL, 64.1 mmol) at 0 °C. The mixture
was stirred for 2 h and quenched with a saturated solution of
NH4Cl (60 mL) and HCl (2.0 N, 60 mL). The organic layer was
extracted with ethyl acetate, dried over MgSO4, and eluted
through a silica column to afford alkynol 7 (4.10 g, 29.7 mmol,
stereochemistry at the CH(C8H17) carbon of 28. According
to an early Burk’s work,14d formation of 3 can be rational-
ized to proceed from intramolecular attack of the acid
group of intermediate B at its C(5)-carbon to invert its
stereoconfiguration,14c-d ultimately yielding avenaciolide
3 (Scheme 6). Spectral data of avenociolide 3 were
consistent with those reported in the literature.13,14
Although we were unsuccessful in obtaining isoaveno-
ciolide 4 in the preceding synthesis, we sought to find
an alternative approach to the synthesis of isoavenaci-
olide 4 using tungsten-π-allyl complexes. The whole
synthesis shown in Scheme 7 requires only three steps
from chloropropargyl species 9.20 Treatment of 9 with
CpW(CO)3Na (2.0 equiv) in THF at 23 °C gave the
expected propargyltungsten species 30, which was puri-
fied on a deactivated alumina column; the overall yield
1
92.7%): IR (neat, cm-1) ν(OH) 3328(vs), ν(CtC) 2245(m); H
NMR (CDCl3, 300 MHz) δ 0.78 (t, J ) 7.0 Hz, 3 H), 1.24 (m, 4
H), 1.98 (m, 2 H), 3.56 (bs, 1 H), 4.24 (d, J ) 3.4 Hz, 2H), 5.38
(dt, J ) 16.1, 1.6 Hz, 1H), 6.03 (dt, J ) 16.1, 6.9 Hz, 1H); 13C
NMR (CDCl3, 100 MHz) δ 13.5, 21.9, 30.5, 32.4, 50.8, 83.9,
85.6, 108.7, 145.0; HRMS calcd for C9H14O 138.1045, found
138.1047.
(20) Nagao, Y.; Kim, K.; Sano, S.; Kakegawa, H.; Lee, W. S.;
Shimizu, H.; Shiro, M.; Katunuma, N. Tetrahedron Lett. 1996, 37, 861.
(21) Vekemans, J . A. J . M.; Dapperens, C. W. M.; Laessen, R. C.;
Koten, A. M.; Chittenden, E. J . F. J . Org. Chem. 1990, 55, 5336.

Total Synthesis of Natural Bicyclic Lactones
J . Org. Chem., Vol. 64, No. 22, 1999 8315
Syn th esis of 1-Ch lor o-n on -4-en -2-yn e (8). To a diethyl
ether solution (11 mL) of alkynol 2 (3.70 g, 26.8 mmol) and
HMPA (11.0 mL) was added SOCl2 (32.1 mL) at 0 °C, and the
mixture was stirred for 3 h before addition of water (10 mL).
To this solution was added NaHCO3 solution, and the organic
layer was extracted with diethyl ether, dried over MgSO4, and
eluted through a silica column to give chloropropargyl com-
pound 8 as a colorless oil (4.05 g, 23.9 mmol, 96.6%): IR (neat,
cm-1) ν(CtC) 2221(w), ν(CdC) 1624(w); 1H NMR (CDCl3, 400
MHz) δ 0.87 (t, J ) 7.2 Hz, 3H), 1.33 (m, 4H), 2.10 (m, 2H),
4.24 (d, J ) 2.0 Hz, 2H), 5.49(dt, J ) 16.0, 0.8 Hz, 1H), 6.19
(dt, J ) 16.0, 7.2 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 13.7,
22.0, 30.6, 31.2, 32.7, 82.0, 85.2, 108.4, 146.7; HRMS calcd for
C9H13Cl 156.0706, found 156.0705.
Syn th esis of (+)-(4S,5S)-1-Ch lor on on -2-yn e-4,5-d iol (9).
To a tert-butyl alcohol solution (46 mL) of AD-mix-R (12.25 g)
was added an aqueous solution (46 mL) of MeSO2NH2 (0.97 g,
10.2 mmol) and chloropropargyl compound 9 (1.60 g, 10.2
mmol), and the mixture was stirred for 27 h in the absence of
light. To this solution was added Na2SO3 (13.2 g) at 0 °C, and
the mixture was stirred for 2 h before it was concentrated in
vacuo. The organic layer was extracted with ethyl acetate, and
the extract was washed with an aqueous NaCl solution, dried
over MgSO4, and eluted through a short silica bed to yield the
diol 4 (1.87 g, 9.80 mmol, 96%): [R]D ) +15.5 (c ) 0.35, CHCl3);
IR (neat, cm-1) ν(OH) 3443(vs), ν(CtC) 2214 (w); 1H NMR
(CDCl3, 300 MHz) δ 0.88 (t, J ) 7.3 Hz, 3H), 1.27-1.64 (m,
6H), 3.22 (bs, 2H), 3.59 (m, 1H), 4.19 (d, J ) 1.7 Hz, 2H), 4.27
(dt, J ) 6.6, 1.7 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 13.8,
22.6, 27.5, 30.2, 32.1, 66.0, 74.6, 80.8, 84.9; HRMS calcd for
C9H15ClO2 190.0761, found 190.0761.
afford 12 as a viscous yellow oil (4.20 g, 7.56 mmol, 98%): [R]D
) -41.3; IR (neat, cm-1) ν(OH) 3444(vs), ν(CO) 2022(s), 1931-
(s); 1H NMR (CDCl3, 400 MHz) δ 0.91 (t, J ) 6.8 Hz, 3H), 1.34
(m, 4H), 1.59 (m, 1H), 1.78 (m, 1H), 1.99 (d, J ) 2.4 Hz, 2H),
3.09 (bs, 1H), 3.43 (s, 3H), 3.50 (m, 1H), 4.37 (dt, J ) 5.5, 2.4
Hz, 1H), 4.70(d, J ) 6.8 Hz, 1H), 4.82 (d, J ) 6.8 Hz, 1H),
5.51 (s, 5H); 13C NMR (CDCl3, 100 MHz) δ -33.1, 13.8, 22.6,
27.2, 30.9, 55.6, 65.4, 78.1, 83.5, 92.4, 95.7, 97.3, 216.5, 228.5.
Anal. Calcd for C19H24WO6: C, 42.88; H, 4.53. Found: C, 42.85;
H, 4.51.
Syn th esis of Tu n gsten -π-Allyl Com p lex (13). To a CH2-
Cl2 solution (80 mL) of propargyltungsten complex (4.20 g, 7.56
mmol) was added triflic acid (0.133 mL, 1.51 mmol) at -60
°C, and the mixture was stirred for 30 min before treatment
with a saturated NaHCO3 solution The organic layer was
extracted with CH2Cl2, dried over MgSO4, and eluted through
a silica column to give allyltungsten compound 13 as a mixture
of syn and anti isomers (3.57 g, 6.71 mmol, 85%):. IR (neat,
cm-1) ν(CO) 1953(s), 1874(s), 1700(s); 1H NMR (CDCl3, 400
MHz) syn form, δ, 0.92 (t, J ) 7.6 Hz, 3H), 1.20-1.90 (m, 6H),
1.50 (d, J ) 3.6 Hz, 1H), 3.22 (d, J ) 4.0 Hz, 1H), 3.42 (d, J )
3.6 Hz, 1H), 3.43 (s, 3H), 3.73 (m, 1H), 4.70 (t, J ) 7.2 Hz,
2H), 4.95 (dd, J ) 8.8, 4.0 Hz, 5.39 (s, 5H), anti form, δ, 0.91
(t, J ) 7.6 Hz, 3H), 1.20-1.90 (m, 6H), 1.50 (d, J ) 3.6 Hz,
3H), 3.11-3.16 (m, 2H), 3.37 (s, 3H), 3.46 (s, 1H), 4.69 (d, J )
4.4 Hz, 1H), 4.70 (s, 2H), 5.34 (s, 5H); 13C NMR (CDCl3, 100
MHz) syn-form, 13.8, 21.3, 22.5, 27.2, 30.8, 55.7, 63.2, 69.4,
81.9, 83.2, 93.8, 96.4, 175.2, 219.8, 224.4, anti form, 13.8, 21.0,
22.6, 27.2, 29.6, 55.9, 63.2, 68.7, 79.3, 83.8, 93.8, 96.8, 175.6,
219.2, 225.2. Anal. Calcd for C19H24WO6: C, 42.88; H, 4.54.
Found: C, 42.67; H, 4.66.
Syn t h esis of (-)-(4S,5S)-4-Bu t yl-5-(3-ch lor op r op -1-
yn yl)-2,2-d im eth yl[1,3]d ioxola n e (10). To an acetone solu-
tion (7.0 mL) of the diol 9 (0.381 g, 2.0 mmol) were added
p-toluenesulfonic acid (30 mg, 0.16 mmol) and 2,2-dimethox-
propane (7 mL), and the mixtures were heated under reflux.
To this mixture was added a saturated NaHCO3 (10 mL)
solution, and the solution was extracted with diethyl ether.
The extract was dried over MgSO4 and eluted through a silica
Syn th esis of (+)-tr a n s-r-Meth ylen ebu tyr ola cton e 14.
To a CH3CN solution of tungsten-π-allyl complex 13 (2,60 g,
4.89 mmol) was added NOBF4 (571 mg, 4.89 mmol) at 0 °C,
and the mixture was stirred for 20 min before addition of LiCl
(415 mg, 9.78 mmol). After being stirred for 20 min at 0 °C,
this solution was added to NaOAc (802 mg, 9.78 mmol) and
CHOCH2OTBS (2.54 g, 14.7 mmol), and the mixture was
stirred for 8 h at 23 °C. To this solution was added MeOH
(1.0 mL), and the mixture was stirred for 30 min. Diethyl ether
(200 mL) was added to the solution to precipitate the undesired
salt, and the filtrate was dried over MaSO4, concentrated, and
eluted through a silica column to yield compound 14 as an oil
(1.39 g, 3.59 mmol, 73.3%): [R]D ) + 20.0 (c ) 1.0, CHCl3); IR
column to obtain compound 10 as a colorless oil (0.41 g, 1.76
-1
mmol, 88%): [R]D ) -41.3 (c ) 1.0, CHCl3); IR (neat, cm
)
ν(CtC) 2260(w), ν(CdC) 1624(w); 1H NMR (CDCl3, 400 MHz)
δ, 0.90 (t, J ) 7.2 Hz, 3H), 1.37 (s, 3H), 1.39 (s, 3H), 1.35-
1.62 (m, 6H), 3.99 (dt, J ) 8.0, 6.0 Hz, 1H), 4.15 (d, J ) 1.6
Hz, 1H), 4.23 (dt, J ) 8.0, 1.6 Hz, 1H); 13C NMR (CDCl3, 100
Hz) δ 13.8, 22.6, 26.1, 27.0, 27.7, 30.1, 32.0, 70.4, 81.2, 81.3,
83.2, 109.8; HRMS calcd for C12H19ClO2 230.1074, found
230.1072.
1
(neat, cm-1) ν(OH) 3358, ν(CO) 1751 cm-1; H NMR (CDCl3,
400 MHz) δ 0.05 (s, 6 H), 0.87-0.91 (bs, 12 H), 1.31 (m, 4 H),
1.59 (m, 2H), 2.62 (bs, 1H), 3.32 (m, 1H), 3.52 (s, 3H), 3.54 (m,
1H), 3.63 (dd, J ) 10.4, 4.0 Hz, 1H), 3.77 (m, 1H), 4.56 (t, J )
2.8 Hz, 1H), 4.57 (d, J ) 7.6 Hz, 1H), 4.67 (d, J ) 7.6 Hz, 1H),
5.67 (d, J ) 2.0 Hz, 1H), 6.29 (d, J ) 2.0 Hz, 1H); 13C NMR
(CDCl3, 100 MHz) δ -5.6, 13.8, 18.3, 22.6, 25.7, 27.5, 30.1,
43.6, 59.9, 63.4, 72.8, 78.8, 79.3, 96.1, 123.2, 135.4, 170.2;
HRMS calcd for C20H38SiO6 402.2438, found 402.2435.
Syn th esis of Com p ou n d 15. To a THF solution (30 mL)
of compound 14 was added a THF solution of Bu4NF (1.0 M,
1.86 mL), and the solution was stirred for 3 h. To this solution
was added a saturated NH4Cl solution (0.6 mL) to form a
precipitate that was removed by filtration, and the filtrate was
dried over MgSO, and eluted through a silica column to yield
a colorless oil (380 mg, 1.32 mmol, 85% yield). To a CH2Cl2
(50 mL) solution of this diol (300 mg, 1.04 mmol) was added
NaIO4/silica (3.00 g, 20 wt %, 1.50 mmol), and the mixture
was stirred for 1 h before filtration through a short MgSO4
bed. The silica bed was washed twice with CH2Cl2, and the
CH2Cl2 layer was combined with the filtrate and concentrated
in vacuo to give the aldehyde 15 in 94% yield (250 mg, 0.98
mmol): [R]D ) -14.5 (c ) 0.5, CHCl3); IR (neat, cm-1) ν(CO)
1767(s), 1708(s); 1H NMR (CDCl3, 300 MHz) δ 0.87 (t, J ) 6.9
Hz, 3H), 1.32 (m, 4H), 1.58 (m, 2H), 3.30 (s, 3H), 3.60 (dt, J )
9.9, 3.3 Hz, 1H), 3.86 (dd, J ) 6.2, 3.3 Hz, 1H) 4.60 (dd, J )
6.9 Hz, 2H), 5.01 (t, J ) 3.4 Hz, 1 H), 5.86 (d, J ) 2.7 Hz, 1H),
6.43 (d, J ) 2.7 Hz, 1H), 9.60 (s, 1H); 13C NMR (CDCl3, 100
MHz) δ, 13.8, 22.6, 27.5, 29.8, 56.1, 75.7, 78.3, 96.5, 124.6,
131.1, 168.2, 194.9; HRMS calcd for C13H20O5 256.1311, found
256.1308.
Syn t h esis of (+)-(4S,5S)-1-Ch lor o-5-m et h oxym et h -
oxyn on -2-yn -4-ol (11). To a CH2Cl2 solution of the diol 9 (1.50
g, 7.87 mmol) and camphorsulfonic acid (72 mg, 0.31 mmol)
was added CH(OMe)3 (1.72 mL, 15.6 mmol), and the mixture
was stirred for 1 h before it was cooled to -78 °C. To this
solution was added DIBAL-H (1.0 M in hexane, 78.4 mL, 78.4
mmol), and the mixture was stirred for 1 h before it was
warmed to 0 °C. To this solution was added an aqueous HCl
solution (1 N, 60 mL), and the organic layer was extracted
ethyl acetate. The extract was washed with HCl (1.0 N, 20
mL) and NaCl (2.0 M, 20 mL), dried over MgSO4, and
concentrated. Elution of the residues through a silica column
afforded compound 11 as a colorless oil (1.81 g, 7.72 mmol,
98%): [R]D ) +17.5 (c ) 0.7, CHCl3); IR (neat, cm-1) ν(OH)
1
3412(w), ν(CtC) 2260(w); H NMR (CDCl3, 400 MHz) δ 0.90
(t, J ) 7.2 Hz, 3H), 1.32 (m, 4H), 1.57 (m, 1H), 1.70 (m, 1H),
3.42 (s, 3H), 3.55 (m, 1H), 4.15 (d, J ) 1.6 Hz, 2H), 4.32(dt, J
) 5.6, 1.6 Hz, 1H), 4.67(d, J ) 7.6 Hz), 4.79(d, J ) 7.6 Hz,
1H); 13C NMR (CDCl3, 100 MHz) δ 13.5, 22.2, 27.0, 29.9, 30.1,
55.3, 64.2, 79.9, 81.3, 85.1, 96.6; HRMS calcd for C11H19ClO3
234.1023, found 234.1021.
Syn th esis of (-)-P r op a r gyltu n gsten Com p ou n d 12.
[CpW(CO)3]2 (4.62 g, 6.94 mmol) was stirred with Na/Hg (8.30
g, 20% Na content) in THF (60 mL) for 6 h, and to this solution
was added chloroalkynol 11 (1.81 g, 7.72 mmol) at 0 °C. The
mixture was stirred for 23 °C for 9 h, and the solution was
concentrated and filtered through a basic alumina column to

8316 J . Org. Chem., Vol. 64, No. 22, 1999
Chen et al.
Syn th esis of Com p ou n d 16. To a CHCl3 solution (20 mL)
of the aldehyde 15 (250 mg, 0.98 mmol) was added pyridine
(0.60 mL), and the mixtures were stirred at 0 °C for 2 h before
addition of a saturated NH4Cl solution. The organic layer was
extracted with CH2Cl2, dried over MgSO4, and eluted through
a short silica bed to give the unsaturated aldehyde 16 (220
mg, 0.86 mmol, 88%): [R]D ) +20.1 (c ) 0.8, CHCl3); IR (neat,
cm-1) ν(CO) 1767(s), 1688(s); 1H NMR (CDCl3, 400 MHz) δ 0.89
(t, J ) 6.8 Hz, 3 H), 1.33 (m, 4 H), 1.70 (m, 2H), 2.25 (d, J )
2.4 Hz, 3 H), 3.16 (s, 3H), 3.95 (dt, J ) 7.2, 1.2 Hz, 1 H), 4.43
(dd, J ) 7.6, 2H), 5.13 (dd, J ) 2.4, 1.2 Hz, 1H), 10.14(s, 1H);
13C NMR (CDCl3, 100 MHz) δ 9.4, 13.9, 22.6, 27.7, 31.9, 55.6,
76.8, 81.5, 97.0, 139.9, 149.8, 173.0, 186.2; HRMS calcd for
solution, dried over MgSO4, and concentrated. Elution of the
residues through a preparative SiO2-TLC afford compound 20
in 86% yield (25.8 mg, 0.113 mmol): [R]D ) -38.8 (c ) 0.25,
CHCl3); IR (CHCl3, cm-1) ν(CO) 1778(vs); 1H NMR (CDCl3, 600
MHz) δ 0.85 (t, J ) 7.2 Hz, 3H), 1.29-1.36 (m, 7H), 1.62 (m,
2H), 2.49 (dq, J ) 7.2, 4.4 Hz, 1H), 2.61 (dd, J ) 7.2, 4.4 Hz,
1H), 3.30 (s, 3H), 3.92 (dt, J ) 6.8, 3.6 Hz, 1H), 4.81 (s, 1H),
4.85(dd, J ) 6.8, 3.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ
13.9, 17.2, 22.6, 28.2, 28.2, 38.4, 55.9, 54.4, 79.4, 81.4, 108.6,
179.22; HRMS calcd for C12H20O4 228.1362, found 228.1361.
Syn th esis of (+)-Dih yd r oca n a d en solid e (3). To an ac-
etone solution of bicyclic tetrahydrofuranyl ether 20 (30 mg,
0.13 mmol) was added J ones reagent (ca. 0.20 mmol) at 23
°C, and the resulting solution was stirred for 2 h before
quenching with 2-propanol. To this mixture was added water
(2.0 mL), and the solution was concentrated and extracted with
CH2Cl2. The extract was dried over MgSO4 and eluted through
a preparative SiO2 plate to afford (+)-dihydrocanadensolide 3
as a colorless solid (25.1 mg, 0.12 mmol, 91%): mp 93-94 °C
(lit.9,10 mp 94 °C); [R]D ) +29.8 (c ) 0.35, CHCl3); IR (CHCl3,
cm-1) ν(CO) 1779(s); 1H NMR (CDCl3, 400 MHz) δ 0.90 (t, J )
7.60 Hz, 3H), 1.36-1.46 (m,7H), 1.80 (m, 2H), 3.04 (dq, J )
7.6, 1.2 Hz, 1H), 3.12(dd, J ) 6.4, 1.2 Hz, 1H), 4.53 (m, 1H),
5.09 (dd, J ) 6.4, 4.0 Hz, 1 H); 13C NMR (CDCl3, 100 MHz) δ
13.8, 17.1, 22.4, 27.4, 28.5, 38.3, 48.9, 78.3, 82.4, 174.7, 176.8;
HRMS calcd for C11H16O4 212.1049, found 212.1047.
Syn th esis of (-)-3-epi-Dih yd r oca n a d en solid e (21). To
an acetone solution of bicyclic tetrahydrofuranyl ether 19 (30
mg, 0.13 mmol) was added J ones reagent (ca. 0.20 mmol) at
23 °C, and the resulting solution was stirred for 2 h before
quenching with 2-propanol. To this mixture was added water
(2.0 mL), and the solution was concentrated and extracted with
CH2Cl2. The extract was dried over MgSO4 and eluted through
a preparative SiO2 plate to afford (-)-3-epi-dihydrocanaden-
solide 21 (25.4 mg, 0.12 mmol, 92%): [R]D ) - 20.2 (c )0.50,
CHCl3); IR (CHCl3, cm-1) ν(CO) 1778(s), 1764(s); 1H NMR
(CDCl3, 400 MHz) δ 0.91 (t, J ) 7.2 Hz, 3H), 1.37-1.47 (m,-
7H), 1.84 (m, 2H), 3.04 (dq, J ) 10.4, 8.4 Hz, 1H), 3.43 (dd, J
) 10.4, 6.4 Hz, 1 H), 4.49 (m, 1 H), 5.00 (dd, J ) 6.4, 4.4 Hz,
1H); 13C NMR (CDCl3, 100 MHz) δ 10.8, 13.8, 22.4, 27.4, 28.4,
36.6, 44.6, 77.9, 81.57, 172.1, 176.2. Anal. Calcd for C11H16O4:
212.1049. Found 212.1043.
Syn th esis of 5-Ch lor o-2-h ydr oxypen t-3-yn oic Acid Bu t-
yl Ester (22). To a solution of propargyl chloride (1.74 mL,
24 mM) in ether (25 mL) at -78 °C under nitrogen was added
n-BuLi (1.6 M in hexane, 13.8 mL, 22.0 mmol) dropwise, and
the mixture was stirred at -78 °C for 15 min. To this acetylide
solution was added a freshly prepared butyl glyoxalate (2.6 g,
20 mmol) in ether (10 mL) dropwise over 10 min. at -78 °C.
The reaction mixture was stirred for further 1 h at -78 °C
and quenched with dropwise addition of acetic acid (1.5 mL,
26 mmol) at -78 °C. The resulting mixture was allowed to
warm to 0 °C, and 15 mL of brine was added. The organic layer
was extracted with ethyl acetate, dried over MgSO4, concen-
trated, and purified on a silica gel column (10% ethyl acetate
in hexane) to afford compound 22 as colorless oil (1.23 g, 6.7
mmol, 30%): IR (neat, cm-1) ν(OH) 3465(vs), ν(CO) 1746(s).;
1H NMR (CDCl3, 400 MHz) δ 0.93 (t, J ) 7.3 Hz, 3H), 1.41
(m, 2H), 1.67 (m, 2H), 4.14 (d, J ) 1.7 Hz, 1H), 4.24 (m, 2H),
4.86 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 13.7, 18.9, 29.9,
30.4, 61.4, 66.9, 80.3, 81.7, 169.9; HRMS calcd for C9H13ClO3
204.0553, found 204.0550.
Syn th esis of Tu n gsten -π-Allyl Com p lex (24). To an ice-
cold NaCpW(CO)3 solution (6.5 m M) in THF (30 mL) was
added a THF (5 mL) solution of the chloropropargyl derivative
22 (1.02 g, 5.0 mmol), and the mixture was stirred over 8 h at
23 °C. The solution was filtered through a short pad of basic
alumina with THF as a eluent. The combined filterate was
concentrated under reduced pressure and purified on a silica
gel column (1:1 ether-hexane) to yield tungsten-π-allyl
complex 24 as a yellow oil (1.76 g, 3.50 mmol, 70%): IR (neat,
cm-1) ν(CO) 1950(s), 1898(s), 1764(s), 1746(s); 1H NMR (CDCl3,
300 MHz) δ 0.92 (m, 3H), 1.37 (m, 2H), 1.48 (d, J ) 3.7 Hz,
1H), 1.67 (m, 2H), 3.08 (d, J ) 3.8 Hz, 1H), 3.62 (d, J ) 4.8
Hz, 1H), 4.12 (d, J ) 2.2 Hz, 1H), 4.25 (m, 2H), 5.36 (s, 5H),
C
13H20O5 256.1309, found 256.1311
Syn th esis of Com p ou n d 17. To a MeOH solution (2.0 mL)
of the aldehyde 16 (120 mg, 0.47 mmol) was added CeCl3.H2O
(174 mg, 0.47 mmol), and the mixture was stirred for 10 min.
To this solution was added NaBH4 (36 mg, 0.95 mmol) at 0
°C, and the mixture was stirred for 1 h before quenching with
water (3 mL). The solution was neutralized with HCl (2.0 N),
and the organic layer was extracted with CH2Cl2, dried over
MgSO4, and eluted through a short silica bed to yield the
alcohol 17 (103 mg, 0.40 mmol, 85.2%): [R]D ) -21.3 (c ) 1.3,
CHCl3); IR (neat, cm-1) ν(OH) 3398(vs), ν(CO) 1763(vs); 1H
NMR (CDCl3, 400 MHz) δ 0.87 (t, J ) 6.4 Hz, 3 H), 1.20-1.50
(m, 6 H), 1.87 (s, 3 H), 3.34 (s, 3 H), 4.01 (m, 1H), 4.49 (d, J )
14.8, 2H), 4.70 (d, J ) 6.4 Hz, 2H), 5.05 (s, 1H); 13C NMR
(CDCl3, 100 MHz) δ 8.7, 13.8, 22.4, 27.8, 30.3, 55.8, 57.3, 77.9,
82.0, 97.3, 125.5, 158.5, 173.9; HRMS calcd for C13H22O5
258.1467, found 258.1466.
Syn th esis of Tr isu bstitu ted γ-La cton e 18. To a prevacu-
ated two-neck vessel charged with MeOH (10 mL) were added
compound 17 (150 mg, 0.58 mmol) and PtO2 (13.2 mg, 0.058
mmol), and the solution was filled with hydrogen with a
balloon. The mixture was stirred for 48 h before it was filtered
through a Celite bed. The filtrate was concentrated to yield
compound 17 as a colorless oil (138 mg, 0.53 mmol, 91%): [R]D
) -8.1 (c ) 1.0, CHCl3); IR (neat, cm-1) ν(OH) 3459(s), ν(CO)
1761(s); 1H NMR (CDCl3, 400 MHz) δ 0.89 (t, J ) 7.6 Hz, 3H),
1.31 (d, J ) 7.2 Hz, 3H), 1.20-1.70 (m, 6H), 2.38 (m, 1H), 2.78
(dq, J ) 7.6, 7.2 Hz, 1H), 3.72 (dd, J ) 3.2, 1.6 Hz), 3.85 (dd,
J ) 12.0, 3.2 Hz, 1H), 3.93 (q, J ) 6.0 hz, 1H), 4.37 (t, J ) 5.6
Hz, 1H), 4.77 (t, J ) 7.2 Hz, 1H); 13C NMR (CDCl3, 100 MHz)
δ 9.3, 13.8, 22.6, 27.1, 31.1, 38.1, 42.9, 56.1, 57.3, 75.5, 82.3,
96.6, 179.1; HRMS calcd for C13H24O5 260.1624, found 260.1620.
Syn th esis of Tetr a h yd r ofu r a n yl Eth er 19. The PCC
reagent (183 mg, 0.85 mmol) was placed in vacuo for 3 h and
dissolved in CH2Cl2 (20 mL). To this solution was added
compound 18 (138 mg, 0.53 mmol), and the mixtures were
stirred for 3 h. The solution was filtered through a short silica
bed, and the bed was eluted with ethyl acetate to afford an
aldehyde (89 mg, 0.35 mmol, 65%). To a MeOH solution (3.0
mL) of this aldehyde (89 mg, 0.35 mmol) was added concen-
trated HCl solution (0.035 mL), and the mixture was heated
at 70 °C for 30 min. After removal of MeOH in vacuo, to the
solution was added water (3.0 mL), and the mixture was
neutralized with a saturated NaHCO3 solution. The organic
layer was extracted with CH2Cl2 (3 × 10 mL), dried over
MgSO4, and eluted through a silica column to give bicyclic
tetrahydrofuranyl ether 19 (66 mg, 0.29 mmol, 83%): [R]D
)
1
-48.3 (c ) 0.13, CHCl3); IR (CHCl3, cm-1) ν(CO) 1771(vs). H
NMR (CDCl3, 600 MHz) δ 0.90 (t, J ) 7.2 Hz, 3H), 1.31 (d, J
) 7.5 Hz, 3H), 1.37 (m, 4H), 1.70 (m, 2H), 2.86 (dq, J ) 11.2,
7.2 Hz, 1H), 2.99 (dd, J ) 11.2, 6.4 Hz, 1H), 3.31 (s, 3H), 4.00
(dt, J ) 6.4, 2.8 Hz, 1H), 4.81 (dd, J ) 6.4, 2.8 Hz, 1H), 4.96
(s, 1H); 13C NMR (CDCl3, 100 MHz) δ 11.7, 13.9, 22.7, 27.9,
28.3, 35.5, 50.3, 54.7, 79.9, 81.5, 103.3, 178.3; HRMS calcd for
C
12H20O4 228.1362, found 228.1359.
Ep im er iza tion of 19 to Com p ou n d 20. To a THF solution
t
(10 mL) was added BuOK (74 mg, 0.066 mmol), and 1.0 mL
of this solution was added to a THF solution (4.0 mL) of
compound 19 (30 mg, 0.13 mmol). The mixture was stirred
for 2.5 h, added to NaHSO3 (0.50 mL), and finally neutralized
with NaHCO3 solution. The organic layer was extracted with
CH2Cl2, and the extract was washed with a saturated NaCl

Total Synthesis of Natural Bicyclic Lactones
J . Org. Chem., Vol. 64, No. 22, 1999 8317
5.58 (d, J ) 4.8 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 13.7,
18.9, 19.1, 20.8, 30.5, 59.5, 65.9, 76.4, 86.7, 94.2, 167.4, 174.8,
219.3, 223.4. Anal. Calcd for C17H18WO6: C, 40.66; H, 3.61.
Found: C, 40.58; H, 3.77.
afford avenaciolide 3 (34 mg, 0.13 mmol 65%) and isoaveno-
ciolide 4 (2.8 mg, 1.05 × 10-2 mmol, 5%). Spectral data for 3:
1H NMR (CDCl3, 400 MHz) δ 0.86 (t, J ) 6.7 Hz, 3H), 1.20-
1.60 (m, 15 H), 1.70-1.90 (m, 2H), 3.55 (m, 1H), 4.40 (m, 1H),
5.04 (d, J ) 8.5 Hz, 1H), 5.86 (d, J ) 2.0 Hz, 1H), 6.45 (d, J )
2.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 14.1, 22.7, 24.9,
29.2, 29.4, 31.8, 36.3, 44.3, 74.4, 85.3, 126.3, 134.7, 167.6, 169.8;
HRMS calcd for C15H22O4 266.1518, found 266.1516.
Syn th esis of tr a n s-r-Meth ylen e Bu tyr ola cton e (25). To
a solution of the tungsten-π-allyl complex 24 (1.50 g, 3.00
mmol) in acetonitrile (15 mL) at 0 °C under nitrogen was added
NOBF4 (350 mg, 3.01 mmol), and the mixture was stirred at
0 °C for 30 min. LiCl (254 mg, 6 mmol) was then added to the
reaction mixture, and the solution was stirred for addition 30
min at 0 °C before addition of nonaldehyde (1.55 mL, 9.0 mmol)
at 0 °C. The reaction mixture was stirred at 23 °C for 8 h and
then quenched with MeOH (3 mL), concentrated, and purified
on a silica gel column (30% ethyl acetate in hexane) to afford
compound 25 as a colorless oil in 62% yield (633 mg, 1.86
mmol): IR (neat, cm-1) ν(OH) 3482(s), ν(CO) 1772(s), 1760(s);
1H NMR (CDCl3, 400 MHz) δ 0.83 (t, J ) 6.6 Hz, 3H), 0.88 (t,
J ) 7.4 Hz, 3H), 1.10-1.70 (m, 18 H), 3.07 (m, 1H), 3.72 (m,
1H), 4.14 (t, J ) 6.3 Hz, 2H), 4.83 (d, J ) 2.5 Hz, 1H), 5.73 (s,
1H), 6.35 (d, J ) 2 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ
13.6, 14.1, 18.9, 22.6, 25.7, 29.1, 29.2, 29.4, 29.5, 30.4, 31.8,
33.2, 49.0, 65.9, 72.9, 76.1, 125.7, 132.9, 169.6, 169.9; HRMS
calcd for C19H32O5 340.2250, found 340.2252.
Tr a n sa cyla tion of γ-La cton e 25 to γ-La cton e 26. A
mixture of R-methylene butyrolactone 25 (340 mg, 1.0 mmol)
and p-TSA (38 mg, 0.21 mmol) in toluene (15 mL) was heated
at 130 °C for 7 h. The reaction mixture was cooled to 23 °C,
concentrated, and purified on a silica gel column (30% ethyl
acetate) in hexane to afford the trans-acylation product 26 (310
mg, 0.91 mmol, 91%):. IR (neat, cm-1), ν(OH) 3482(vs), ν(CO)
1765(s), 1760(s); 1H NMR (CDCl3, 400 MHz) δ 0.85 (t, J ) 6.7
Hz, 3H), 0.92 (t, J ) 7.4 Hz, 3H), 1.10-1.70 (m, 18H), 3.06
(m, 2H), 4.17-4.30 (m, 3H), 4.45-4.50 (m, 1H), 5.50 (d, J )
2.3 Hz, 1H), 6.33 (d, J ) 2.4 Hz, 1H); 13C NMR (100 MHz) δ
13.6, 14.0, 19.0, 22.8, 24.8, 29.1, 29.3, 29.4, 30.4, 31.8, 36.1,
47.7, 66.4, 71.8, 79.8, 124.2, 134.3, 169.7, 172.5; HRMS calcd
for C19H32O5 340.2250, found 340.2255.
Syn th esis of γ-La cton e 27. To a solution of the substrate
26 (170 mg, 0.5 mM), triphenylphosphine (262 mg, 1.0 mmol),
and p-nitrobenzoic acid (167 mg, 1.0 mmol) in THF (4 mL) at
-78 °C under nitrogen was added DEAD (174 mg, 1.0 mmol)
dropwise, and the mixture was slowly warmed to 23 °C over 2
h. The mixture was stirred for 5 h. The reaction mixture was
concentrated and eluted on a silica gel column (10% ethyl
acetate in hexane) to afford γ-lactone 27 (220 mg, 0.90 mmol,
90%) as a colorless oil: IR (neat, cm-1) ν(CO) 1767(s), 1738(s);
1H NMR (CDCl3, 400 MHz) δ 0.85 (t, J ) 6.7 Hz, 3H), 0.90 (t,
J ) 7.4 Hz, 3H), 1.2-1.7 (m, 18H), 3.30-3.40 (m, 1H), 4.10-
4.30 (m, 2H), 4.66-4.72 (m, 1H), 5.42 (d, J ) 3.4 Hz, 1H), 5.85
(d, J ) 2.0 Hz, 1H), 6.42 (d, J ) 2.2 Hz, 1H), 8.13 (d, J ) 8.8
Hz, 2H), 8.28 (d, J ) 8.8 Hz, 2H); 13C NMR (CDCl3, 100 MHz)
δ 13.6, 14.1, 19.0, 22.1, 24.7, 29.2, 29.3, 29.5, 30.5, 31.7, 36.3,
45.4, 66.3, 74.7, 78.3, 123.7, 125.3, 131.1, 133.8, 134.6, 151.1,
163.8, 167.3, 168.9; HRMS calcd for C26H35O8N 489.2363, found
489.2367.
Syn th esis of γ-La cton e 28 A mixture of the p-nitroben-
zoate 28 (147 mg, 0.30 mmol) and freshly fused K2CO3 (21 mg,
0.15 mmol) in dry ethanol (3 mL) was stirred at 23 °C for 3
min and quenched with a saturated NH4Cl solution. The
organic layer was extracted with ethyl acetate. The extract
was dried over MgSO4, concentrated, and purified on a silica
gel column (30% ethyl acetate in hexane) to afford compound
28 (91 mg, 2.68 mmol, 89%): IR (neat, cm-1) ν(CO) 1770, 1760;
1H NMR (CDCl3, 400 MHz) δ 0.84 (t, J ) 6.7 Hz, 3H), 0.91 (t,
J ) 7.4 Hz, 3 H), 1.10-1.70 (m, 18 H), 3.08 (bs, 1 H), 3.20 (d,
J ) 3.2 Hz, 1H), 4.10-4.25 (m, 2 H), 4.33 (bs, 1H), 4.45-4.50
(m, 1H), 5.76 (d, J ) 2.2 Hz, 1H), 6.34 (d, J ) 2.5 Hz, 1H);
13CNMR (100 MHz) δ 13.6, 14.1, 19.1, 22.7, 24.7, 29.2, 29.3,
29.4, 30.47, 31.9, 36.2, 47.7, 66.5, 72.1, 78.3, 124.1, 135.4, 169.6,
172.7; HRMS calcd for C19H32O5 340.2250, found 340.2245.
Syn th esis of Aven ociolid e 3. A mixture of γ-lactone 28
(68 mg, 0.20 mmol) and p-TSA‚H2O (76 mg, 0.40 mmol) in d8-
toluene (0.60 mL) in a sealed NMR tube was heated at 150 °C
for 4 h. The reaction mixture was concentrated and eluted on
a preparative silica plate (50% ethyl acetate in hexane) to
Syn th esis of Ch lor op r op a r gyl Com p ou n d 29. To a
solution of propargyl chloride (2.35 mL, 32.5 mmol) in 50 mL
of ether at -78 °C under nitrogen was added n-BuLi (1.6 M
in hexane, 18.7 mL, 30 mmol) dropwise at -78 °C over a period
of 30 min. To this stirring acetylide solution at -78 °C was
added a ether solution of diethyl ketomalonate (4.35 g, 25.0
mmol) in a period of 10 min. The mixture was slowly allowed
to warm to -60 °C over 3.0 h and quenched by a dropwise
addition of acetic acid (2 mL, 35 mmol) at -60 °C. The
resulting mixture was slowly warmed to 23 °C, and water (50
mL) was added. The organic layer was separated, and the
aqueous layer was extracted with ethyl acetate. The combined
organic solution was dried over MgSO4, concentrated, and
purified on a silica gel column (10% ethyl acetate in hexane)
to yield the alcohol 29 as a colorless oil (2.5 g, 10.1 mmol,
40%): IR (neat, cm-1) ν(OH) 3460(vs), ν(CO) 1747(s); 1H NMR
(CDCl3, 400 MHz) δ 1.31 (t, J ) 7.6 Hz, 6H), 4.18 (s, 2H), 4.32
(q, J ) 7.6 Hz, 4H); 13C NMR (75 MHz, CDCl3) δ 13.9, 29.8,
63.9, 72.6, 79.9, 81.6, 166.8; HRMS calcd for C10H13ClO5
248.0452, found 248.0448.
Syn th esis of P r op a r gyltu n gsten Com p lex 30. To a THF
solution (40 mL) of NaCpW(CO)3 (ca. 8.0 mmol) at 0 °C was
added dropwise a solution (THF, 5 mL) of chloropropargyl
derivative 29 (995 mg, 4.0 mmol), and the mixture was stirred
at 23 °C for 12 h. The reaction mixture was filtered through a
deactivated basic alumina with THF as a eluent, and concen-
tration of the filterate yielded propargyltungsten 30 as a yellow
viscous solid (2.10 g, 3.84 mmol, 96%): IR (neat, cm-1) ν(OH)
3391(vs), ν(CO) 2016(s), 1913(s), 1740(s); 1H NMR (CDCl3, 300
MHz) δ 1.31 (t, J ) 7.0 Hz, 6H), 1.95 (s, 2H), 4.31 (q, J ) 7.0
Hz, 4H), 5.56 (s, 5H); 13C NMR (CDCl3, 100 MHz) δ -33.4,
14.1, 63.4, 86.7, 90.7, 92.8, 98.2, 168.1, 191.2, 216.5, 228.9.
Anal. Calcd for C18H18WO8: C, 39.58; H, 3.32. Found: C, 39.55;
H, 3.40.
Syn th esis of Tu n gsten -π-Allyl Com p lex 31. To a CH2-
Cl2 (15 mL) solution of the propargyltungsten complex 30 (1.64
g, 3.00 mmol) were added p-TSA (570 mg, 3.00 mmol) and
methanol (2.43 mL) at 0 °C, and the mixture was stirred at 0
°C for 1 h. The reaction mixture was warmed to 23 °C and
stirred for an additional 2 h. The resulting reaction was
recooled to 0 °C and quenched with 25 mL of a saturated
NaHCO3 solution. The organic layers were separated, and the
aqueous layer was extracted with CH2Cl2. The combined
organic layers was dried, evaporated, and purified on a silica
gel column (1:1 ether/hexane) to afford tungsten-π-allyl
complex 31 in 65% yield (1.07 g, 1.95 mmol): IR (neat, cm-1),
ν(CO) 1962(s), 1885(s), 1775(s); 1H NMR (CDCl3, 300 MHz) δ
1.28-1.37 (m, 6H), 1.63 (d, J ) 3.72 Hz, 1H), 3.17 (d, J ) 3.78
Hz, 1H), 3.72 (s, 1H), 4.16-4.50 (m, 4H), 5.37 (s, 5H); 13C NMR
(100 MHz, CDCl3) δ 14.0, 22.2, 58.8, 62.8, 63.5, 85.1, 89.6, 94.5,
165.1, 165.9, 173.6, 216.9, 222.3. Anal. Calcd for C18H18WO8:
C, 39.58; H, 3.32. Found: C, 39.33; H, 3.45.
Syn th esis of Bisla cton e 33. To a solution of the tungsten-
π-allyl complex 32 (900 mg, 1.65 mmol) in acetonitrile (8.5 mL)
at 0 °C was added solid NOBF4 (193 mg, 1.65 mmol) under
nitrogen and the mixture stirred at 0 °C for 30 min. To this
mixture at 0 °C was added NaI (494 mg, 3.30 mmol), and the
solution was stirred for further 30 min at 0 °C. To the above
mixture was added nonaldehyde (703 mg, 4.94 mmol) at 0 °C,
and the mixture was allowed to warm to 23 °C and stirred for
24 h. The reaction was quenched with MeOH (1.6 mL) and
evaporated under reduced pressure. The crude product was
purified on a silica column (30% ethyl acetate in hexane) to
afford bislactone (346 mg, 1.02 mmol, 62%): IR (neat), ν(CO)
1
1790 cm-1; H NMR (CDCl3, 400 MHz) δ 0.86 (t, J ) 6.7 Hz,
3H), 1.20-1.80 (m, 17H), 4.01 (m, 1H), 4.34 (q, J ) 7.0 Hz,
2H), 4.87 (m, 1H), 5.90 (d, J ) 2.3 Hz, 1H), 6.63 (d, J ) 2.8

8318 J . Org. Chem., Vol. 64, No. 22, 1999
Chen et al.
Hz, 1H); 13C NMR (100 MHz) δ 13.7, 13.6, 22.4, 25.9, 28.9,
29.1, 31.5, 31.6, 46.6, 63.4, 80.6, 82.3, 129.6, 130.0, 164.9, 166.6,
167.7; HRMS calcd for C18H26O6 338.1729, found 338.1730.
Syn th esis of Isoa ven ociolid e 4. To a solution of bislactone
33 (68 mg, 0.2 mmol) in dimethylacetamide (0.6 mL) was
added MgCl2‚6H2O (203 mg, 1.0 mmol), and the solution was
heated at 150 °C for 3 h. After removal of solvent under
reduced pressure at 70 °C, to the residue was added water
(0.5 mL), and the organic product was extracted with ethyl
acetate. The extracts were dried over MgSO4 and concentrated.
Elution of the residue through a short silica bed yield isoave-
naciolide 4 as a colorless solid (mp 99 °C, 28 mg, 0.105 mmol,
52%): 1H NMR (CDCl3, 400 MHz) δ 0.86 (t, J ) 7 Hz, 3H),
1.20-1.80 (m, 14H), 3.98 (m, 1H), 4.74 (m, 1H), 5.10 (d, J )
8.8 Hz, 1H), 5.86 (d, J ) 2.2 Hz, 1H), 6.60 (d, J ) 2.8 Hz, 1H);
13C NMR (100 MHz) δ 14.1, 22.7, 26.1, 29.0, 29.2, 29.4, 31.8,
32.4, 41.8, 74.9, 80.6, 129.0, 130.9, 130.9, 167.9, 170.1; HRMS
calcd for C15H22O4 266.1518, found 266.1521.
Ackn owledgm en t. We thank National Science Coun-
cil, ROC (Taiwan), for financial support of this work.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra of compounds 2, 3, 4, and 6-33. This material
is available free of charge via the Internet at http://pubs.acs.org.
J O991077C