Synthesis of the first 'inside-outside' eight-membered ring via ringclosing metathesis: A total synthesis of (+/-)-asteriscanolide

Article abstract of DOI:10.1055/s-2000-6302

A total synthesis of (+/-)-asteriscanolide which features two transition metal-mediated carbocyclic ring forming reactions as key elements of our strategy (Scheme 1) is described. The highly functionalized cyclopentenone 4, the product of a cobalt-mediated Pauson-Khand [2+2+l]cycloaddition, is the key starting point for the synthesis. Excellent regiocontrol was obtained in the intermolecular Pauson-Khand reaction. Further synthetic manipulations of 4 led to diene 16 which underwent ring-closing metathesis using (PPh₃)₂Cl₂Ru(CHPh)] to provide the desired 'inside-outside' tricycle 17. Conversion of 17 to 1 was achieved in a minimal number of steps. The synthesis of asteriscanolide has been achieved in 19 steps and 12% overall yield.

Full text of DOI:10.1055/s-2000-6302

1020
PAPER
Synthesis of the First "Inside-Outside" Eight-Membered Ring via Ring-
Closing Metathesis: A Total Synthesis of (+/-)-Asteriscanolide
Marie E. Krafft,* Yiu-Yin Cheung, Carmelinda A. Juliano-Capucao
Department of Chemistry, Florida State University, Tallahassee, FL 32306, USA
Received 20 January 2000; revised 1 March 2000
Abstract: A total synthesis of (+/-)-asteriscanolide which features
two transition metal-mediated carbocyclic ring forming reactions as
key elements of our strategy (Scheme 1) is described. The highly
functionalized cyclopentenone 4, the product of a cobalt-mediated
Pauson-Khand [2+2+1]cycloaddition, is the key starting point for
the synthesis. Excellent regiocontrol was obtained in the intermo-
lecular Pauson-Khand reaction. Further synthetic manipulations of
4 led to diene 16 which underwent ring-closing metathesis using
(PPh3)2Cl2Ru(CHPh)] to provide the desired ’inside-outside’ tricy-
cle 17. Conversion of 17 to 1 was achieved in a minimal number of
steps. The synthesis of asteriscanolide has been achieved in 19 steps
and 12 % overall yield.
Key words: ring-closing, metathesis, total synthesis, Pauson-
Khand cycloaddition, transition metal mediated reactions
Scheme 1
In our retrosynthetic analysis we envisaged that the for-
mation of the bridging eight-membered ring could be
achieved through ring-closing metathesis of diene 2.13
This would enable stereoselective incorporation of the
C-7 methyl prior to cyclooctane ring formation. Further
disconnection leads to the [3.3.0] oxabicyclooctane 3 as a
key intermediate, which could be derived from the highly
functionalized cyclopentenone 4, the product of a cobalt-
mediated Pauson-Khand [2+2+1] cycloaddition.14
Asteriscanolide, 1, is a cyclooctane sesquiterpene lactone
which was isolated from the hexane extract of Asteriscus
aquaticus in 1985.1 The structure was determined by
spectroscopic means and confirmed by X-ray analysis.
One total synthesis of asteriscanolide2 and three synthetic
approaches have been reported.3-5 The structure exhibits a
number of challenging features which include the [6.3.0]
carbocyclic system and a bridging butyrolactone and any
synthetic strategy would need to accomodate three contig-
uous stereocenters in a cis orientation on a cyclopentane
ring. More importantly, it has been reported that introduc-
tion of the C-7 methyl was not possible via alkylation of
the corresponding des-methyl cyclooctane. Thus, the ste-
reocenter must be established prior to eight-membered
ring formation.4
The strategy that we used for the construction of 4 takes
advantage of our recent successes with the Pauson-
Khand reaction of alkynoates. These results have shown
that excellent regiocontrol in the cycloaddition can be
achieved in the reaction of unsymmetrically substituted
alkenes with alkynoates to give 1,4 dicarbonyl products.
The regioselectivity observed in the cycloaddition across
the alkyne has been rationalized on electronic grounds.15
In addition, intermolecular reactions between internal
alkynes and terminal alkenes give rise to 2,3,5-trisubsti-
tuted cyclopentenones in preference to the 2,3,4-trisubsti-
tuted isomer. A steric argument has been invoked to
explain this regioselectivity.16
We now report a total synthesis of (+/-)-asteriscanolide
which features two transition metal-mediated carbocyclic
ring forming reactions, the Pauson-Khand cycloaddition
and a ring-closing metathesis, as key elements of our strat-
egy (Scheme 1). The latter of these resulted in the first ste-
reoselective synthesis of an ‘inside-outside’6 eight-
membered ring by RCM.7 The significance of this result
lies in its potential application for the synthesis of natural
products with skeletons that exhibit the ‘in-out’ intra-
bridgehead stereochemistry as exemplified by the in-
genane diterpenes.8 The research efforts of Rigby,9
Winkler,10 Funk,11 and Kuwajima12 provide four funda-
mentally different approaches to the ‘in-out’ ingenane tri-
cyclic system. However, these strategies require multi-
step transformations or isomerization of the correspond-
ing ‘out-out’ epimer. This work provides an example of a
direct carbocyclization to give exclusively an ‘in-out’
bridging ring system.
Our initial goal was establishment of the three stereogenic
centers on the cyclopentane ring. Toward this end, protec-
tion of 3-butyn-1-ol (6) as the corresponding tert-bu-
tyldimethylsilyl (TBS) ether, generation of the lithio
alkyne with s-BuLi in THF at -78 °C followed by its ad-
dition to ethyl chloroformate in THF at -78 °C gave the
corresponding alkynoate which was then treated with di-
cobalt octacarbonyl to give the hexacarbonyldicobalt
complexed alkyne 5 (Scheme 2). Pauson-Khand cycload-
dition of 5 with excess propene in methylene chloride pro-
ceeded via incremental addition of N-methylmorpholine-
N-oxide monohydrate (NMO) to give the highly function-
Synthesis 2000, No. 7, 1020–1026 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of the First "Inside-Outside" Eight-Membered Ring via Ring-Closing Metathesis
1021
alized cyclopentenone 7 bearing functionality appropri- moallylic alcohol 15 was treated with triethylsilyl trifluo-
ately positioned for further manipulation of the romethanesulfonate (TESOTf) in pyridine to give the
sidechains. No efficient cycloaddition was obtained with corresponding TES ether. Lactone deprotonation using
isobutene or allylic thioalkyl derivatives17 of isobutene. LiHMDS/HMPA in THF at -78 °C followed by quench-
Deprotonation of 7 using LiHMDS/HMPA followed by ing the enolate with allyl bromide at -78 °C gave diene 16
quenching with methyl iodide gave the gem-dimethylated (90%). At this point, we envisioned that the key formation
ketone 4. All attempts to reduce the tetrasubstituted dou- of the bridging eight-membered ring would be more facile
ble bond of 4 by catalytic hydrogenation gave recovered from the C-3 epimer of 16. However, we were unable to
starting material. Desilylation of 4 with HF/pyridine achieve efficient epimerization of the allyl side chain. In
yielded hydroxy ketone 8. Subsequent reduction of ketone spite of the many recent advances in ring-closing metathe-
8 with NaBH4/CeCl3.7H2O in ethanol gave the corre- sis there was no literature precedent to suggest that diene
sponding allylic alcohol which yielded hydroxy lactone 9 16 would cyclize. We proceeded with reaction of diene
after quenching with water and stirring for 12 h in the 16, even though, conformational analyses indicated that
presence of 2 N HCl. Although hydrogenation of enone 9 the alkene moieties were far removed from one another.
(Pd/C, 40 psi of H2) gave a 1.6:1 ratio of diastereoisomers Remarkably, ring-closing metathesis of 16 was achieved
favoring the all-cis diastereoisomer, the corresponding using 50 mol% of the ruthenium catalyst 2022 in refluxing
TBS ether 10 underwent hydrogenation (Pd/C, 20 psi of methylene chloride (0.007M) for 24 h to give the ‘inside-
H2) to give the desired all-cis diastereoisomer 12 (90%) in outside’ tricycle 17 (92%). The relative stereochemistry
addition to isomer 11 (10%).
of 17 was confirmed by 1H NMR nOe experiments. To our
knowledge this is the first example of an eight-membered
ring bearing an ‘in-out’-intrabridgehead stereochemical
relationship6,23 to be synthesized by ring-closing metathe-
sis.
OTBS
OH
O
O
OH
a, b, c
d
OTBS
e, f
Co2(CO)6
CO2Et
CO2Et
CO2Et
8
6
5
7
g
OR
OTBS
TBSO
H
H
i
O
O
O
O
9 R=H
10 R=TBS
h
O
O
12
11
a, TBSCl, Et3N, DMAP (99%); b, s-BuLi, THF -78 °C; EtOCOCl
(94%); c, Co2(CO)8, 0 °C, low boiling petroleum ether (99%); d, pro-
pene:CH2Cl2 (1:1), 6 equiv NMO.H2O (89%); e, i. LiHMDS, -78 °C
THF, ii. MeI (92%); f, HF/pyridine, CH3CN (93%); g, i. NaBH4/
CeCl3.7H2O, EtOH, ii. 2N HCl, (89%); h, TBSOTf, pyridine 0 °C
(99%); i, 10 mol% Pd/C, EtOH, 20 psi H2 (12, 90%; 11, 10%).
Scheme 2
Having established the requisite cis stereochemistry of all
three substituents on the cyclopentane ring we proceeded
to convert bicyclic lactone 12 to diene 16 for the key met-
athesis step (Scheme 3). Lactone 12 was reduced with
DIBAL-H in toluene18 at -78 °C to give a mixture of lac-
tols which were treated with 10 equivalents of CH2PPh3 in
refluxing THF to give the corresponding alkene. The large
excess of ylide was required to avoid epimerization of the
stereocenter adjacent to the aldehyde prior to the Wittig
olefination. The carboxylic acid resulting from Jones oxi-
dation of the primary alcohol was refluxed with 2 N HCl
(1:1) for 2 h to give bicyclic lactone 13 (89%, 2 steps).
Ozonolysis of 13 followed by a reductive work-up gave
aldehyde 3 which was treated in situ with (E)-crotyl tri-n-
butyl stannane19 and BF3∑OEt2 at -78 °C20 to give a 1:8
ratio of the homoallylic alcohols 14 and 15 (correct C-7
configuration) in 74% overall yield. Crotylboration of al-
dehyde 3, using (Z)-2-butenylboronic acid pinacol cyclic
ester,21 gave a 2:1 ratio of 14 and 15, respectively. Ho-
a, DIBAL-H, toluene, -78 °C (96%); b, MePPh3Br (10 equiv), n-Bu-
Li, THF, reflux, 20 min (89%); c, i. Jones’ reagent/acetone,
ii. i-PrOH, 2 N HCl, reflux, 2 h (89%); d, i. O3/CH2Cl2, -78 °C, ii.
Me2S, iii. (E)-crotyl SnnBu3, CH2Cl2, -78 °C, BF3∑Et2O (74%; 15/14,
8:1); e, TESOTf, pyridine, 0 °C (87%); f, i. LiHMDS/HMPA, -
78 °C, THF, ii. allyl bromide (90%); g, 50 mol% [20,
(PPh3)2Cl2Ru(CHPh)], 0.007M CH2Cl2, reflux, 24 h (92%); h, TBAT,
CH3CN, reflux, 29 h (62% of 19); (i) H2, 10 mol% Pd/C, EtOH (93%);
j, nPr4NRuO4/NMO, CH2Cl2 (100%).
Scheme 3
Desilylation of 17 with tetrabutylammonium (triphenylsi-
lyl)difluorosilicate24 (TBAT) (6 equivalents) in refluxing
acetonitrile for 29 hours gave alcohols 18 (30%) and 19
(62%). When alcohols 18 and 19 were individually re-
subjected to reaction with TBAT in refluxing acetonitrile
a 2:1 equilibrium mixture of 19: 18 was obtained. All at-
tempts to deprotonate/reprotonate lactone 18 under kinet-
Synthesis 2000, No. 7, 1020–1026 ISSN 0039-7881 © Thieme Stuttgart · New York

1022
M. E. Krafft et al.
PAPER
ic conditions failed. Molecular Mechanics calculations25
for 18 and 19 showed a 0.5 Kkcal difference in energy in
favor of alcohol 19. Tricycle 19 was hydrogenated over
Pd/C in EtOH to give the corresponding saturated tricyclic
lactone in quantitative yield. Oxidation of the secondary
alcohol with tetrapropylammonium perruthenate and
NMO in methylene chloride26 gave asteriscanolide (1),
bonyl-5-methyl-2-cyclopentenone (7), and 2-[2-(t-butyldimethyl-
silyloxy)ethyl]-3-ethoxycarbonyl-4-methyl-2-cyclopentenone in
89% yield (50 mg) and >30:1 ratio by integration of resonances in
the 1H NMR (500 MHz) spectrum. When the reaction was scaled up
(1.3 g expected yield using 45 mL capacity tube and 2.5 g expected
yield using the 100 mL capacity tube), NMO.H2O (a total of 8
equiv) was added to the reaction mixtures (2 equiv added for every
30 min of reaction time) and the reaction was worked up after total
reaction times not exceeding 12 h.
1
which was identical to the natural product1 by H NMR
analysis (satisfactory spectral data: IR, MS, 13C, 1H NMR
nOe comparison and combustion analysis were also ob-
tained).
IR (film): n = 1704, 1457, 1092 cm-1.
1H NMR (300 MHz, CDCl3): d = -0.03 (s, 6H, Si(CH3)2), +0.03 (s,
9H, Si-C(CH3)3), 1.18 (d, 3H, J = 7.1 Hz, 5-C-CH3), 1.33 (t, 3H,
J = 7.1 Hz, OCH2CH3), 2.34 (br dt, 1H, J = 18.7, 2.7 Hz, 4-CHH),
2.42 (ddq, 1H, J = 2.8, 7.1, 7.1 Hz, 5-CH), 2.79 (br t, 2H, J = 6.6
Hz, 2-C-CH2), 3.01 (br dd, 1H, J = 18.7, 7.1 Hz, 4-CHH), 3.67 (t,
2H, J = 6.6 Hz, CH2-OSi), 4.29 (q, 2H, J = 7.1 Hz, OCH2CH3).
13C NMR (75 MHz): d = 13.9, 15.9, 18.0, 25.7, 27.6, 35.6, 39.4,
61.0, 146.8, 155.1, 165.8, 212.3, 216.3.
EIMS: m/z = 326 (M+), 269 (100), 75.
Our strategy for the synthesis of asteriscanolide allows for
the stereocontrolled introduction of the C-7 methyl group
and takes advantage of two transition metal-mediated car-
bocyclic ring forming reactions as key elements. In these
investigations, we have further developed the applications
of the intermolecular Pauson-Khand reaction with polar-
ized alkynes. Furthermore, we have shown that ring-clos-
ing metathesis can be used to form an eight-membered
ring with ‘in-out’-intrabridgehead stereochemistry. The
synthesis of asteriscanolide has been achieved in 19 steps
and 12% overall yield. Investigations into the synthesis of
other medium-sized rings with ‘in-out’-intrabridgehead
stereochemistry are underway and these results will be re-
ported in due course.
Anal. Calcd for C17H30O4Si: C, 62.54; H, 9.27. Found: C, 62.72; H,
9.37.
2-[2-(tert-Butyldimethylsilyloxy)ethyl]-3-ethoxycarbonyl-5,5-
dimethyl-2-cyclopentenone (4)
IR (film): n = 1704, 1248 cm-1.
1H NMR (300 MHz, CDCl3): d = 0.00 (s, 6H, Si(CH3)2), 0.83 (s, 9H,
SiC(CH3)3), 1.11 (s, 6H, 5-C(CH3)2), 1.35 (t, 3H, J = 7.1 Hz,
OCH2CH3), 2.63 (t, 2H, J = 1.1 Hz, 4-CH2), 2.81 (tt, 2H, J = 6.6, 1.1
Hz, 2-C-CH2CH2-O), 2.81 (t, 2H, J = 6.6 Hz, 2-C-CH2CH2-O), 4.30
(q, 2H, J = 7.1 Hz, OCH2CH3).
13C NMR (75 MHz): d = 13.40, 17.97, 24.75, 25.66, 27.62, 42.82,
43.61, 60.99, 145.43, 153.68, 165.78, 214.19.
(Ethyl 5-tert-butyldimethylsilyloxy-2-pentynoate)hexacarbon-
yldicobalt (5)
IR: n = 2096, 2058, 2034, 1999, 1701 cm-1.
1H NMR (300 MHz, CDCl3): d = 0.08 (s, 6H, Si(CH3)2), 0.90 (s, 9H,
Si-C(CH3)3), 1.31 (t, 3H, J = 7.1 Hz, CO2CH2CH3), 3.07 (t, 2H,
J = 7.1 Hz, C∫C-CH2), 3.90 (t, 2H, J = 7.1 Hz, CH2-OSi), 4.40 (q,
2H, J = 7.1 Hz, CO2CH2CH3).
EIMS: m/z = 340 (M+), 283 (100).
Anal. Calcd for C18H32O4Si: C, 63.49; H, 9.48. Found: C, 63.21; H,
9.45.
13C NMR (75 MHz): d = -5.7, 13.8, 18.1, 25.6, 36.4, 60.1, 61.6,
63.3, 79.2, 94.9, 169.9, 198.0-200.0 (m).
2-[2-Hydroxyethyl]-3-ethoxycarbonyl-5,5-dimethyl-2-cyclo-
pentenone (8)
IR (film): n = 3604, 2872, 1714, 1704 cm-1.
(Ethyl 5-hydroxy-2-pentynoate)hexacarbonyldicobalt
1H NMR (300 MHz, CDCl3): d = 1.34 (t, 3H, J = 6.0 Hz,
OCH2CH3), 3.18 (t, 2H, J = 5.4 Hz, C∫C-CH2), 3.23 (br t, 1H,
J = 6.0 Hz, CH2OH), 3.89 (dq, 2H, J = 6.0, 5.4 Hz, CH2CH2OH),
4.33 (q, 2H, J = 6.0 Hz, OCH2CH3).
1H NMR (500 MHz, CDCl3): d = 1.15 (s, 6H, 2 ¥ CH3), 1.36 (t, 3H,
J = 7.2 Hz, CH2CH3), 2.33 (br t, 1H, J = 5.4 Hz, CH2OH), 2.67 [t,
2H, J = 1.3 Hz, CH2C(CH3)2], 2.86 (tt, 2H, J = 6.0, 1.3 Hz,
CH2CH2OH), 3.75 (q, 2H, J = 5.6 Hz, CH2OH), 4.32 (q, 2H, J = 7.2
Hz, CH2CH3).
13C NMR (75 MHz, CDCl3): d = 13.9, 24.7, 27.8, 43.1, 43.6, 61.3,
2-[2-(tert-Butyldimethylsilyloxy)ethyl]-3-ethoxycarbonyl-5-me-
thyl-2-cyclopentenone (7)
61.4, 146.1, 154.2, 166.0, 215.1.
MS (CI isobutane): m/z = 226 (M+).
To
a
solution of (ethyl 5-t-butyldimethylsilyloxy-2-pen-
tynoate)hexacarbonyldicobalt (5, 101 mg, 0.19 mmol) in CH2Cl2
(1.0 mL) in a 15 mL capacity resealable tube cooled to -78 °C was
condensed propene (~1.0 mL, bp -50 °C) resulting in a 0.2 M solu-
tion of (ethyl 5-t-butyldimethylsilyloxy-2-pentynoate)hexacarbon-
yldicobalt in 1:1 propene/CH2Cl2. N-methylmorpholine N-oxide
monohydrate (NMO.H2O, obtained from 15% aq solution (Aldrich)
and recrystallized twice from acetone, 2 equiv, 50 mg, 0.37 mmol)
was added to the mixture, after which the tube was sealed and al-
lowed to warm to r.t. The mixture was stirred at r.t. for 15 min after
which it was cooled to -78 °C and NMO.H2O (2 equiv) were added,
a total of 6 equiv were added. The reaction was complete after a to-
tal time of 2.5 h. The mixture was cooled to -78 °C, CH2Cl2 (1 mL)
was added and the tube was loosely capped to allow propene to
evaporate. The mixture was then run through a plug of silica gel
(EtOAc/hexane, 1:6). Flash chromatography (EtOAc/hexane, 1:15)
yielded enones 2-[2-(t-butyldimethylsilyloxy)ethyl]-3-ethoxycar-
Anal. Calcd for C12H18O4.0.2 H2O: C, 62.70, H, 8.07. Found C,
62.53, H, 7.93.
Bicyclic Hydroxy Lactone 9
To a stirred solution of hydroxy ketone 8 (1.95 g, 8.62 mmol) and
cerium trichloride heptahydrate (6.42 g; 17.24 mmol) in absolute
EtOH (45 mL) at 0 °C was carefully added NaBH4 (655 mg, 17.24
mmol). After the reaction was complete according to TLC, 2 N HCl
(50 mL) was carefully added to the solution and the reaction was
stirred overnight. The reaction mixture was poured into a separatory
funnel and extracted with CH2Cl2 (2 x 100 mL). The organic layers
were combined and dried (MgSO4). Removal of solvent in vacuo
gave the crude product which was chromatographed on silica gel
(hexane/EtOAc, 1:4) to give the product 9 as a colorless oil (1.40 g;
89%).
Synthesis 2000, No. 7, 1020–1026 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of the First "Inside-Outside" Eight-Membered Ring via Ring-Closing Metathesis
1023
IR (film): n = 3418, 2957, 1704, 1468, 1123, 1084 cm-1.
13C NMR (75 MHz, CDCl3): d = -4.6, -4.4, 17.9, 23.4, 23.8, 25.7,
26.8, 39.1, 39.7, 40.9, 43.2, 67.2, 80.9, 175.7.
1H NMR (500 MHz, C6D6): d = 0.78 (s, 3H, CH3), 0.82 (s, 3H, CH3),
1.60 (AB, dddd, 1H, JAB = 18.2, J = 9.6, 7.5, 3.9, 2.1 Hz,
CHHCH2O), 1.79 (AB, dddd, 1H, JAB = 18.2, J = 8.1, 5.7, 3.0, 0.9
Hz, CHHCH2O), 2.15 [AB, ddd, 1H, JAB = 15.8 Hz, J = 3.6, 1.8, 1.8
Hz, CHHC(CH3)2], 2.31 [AB, ddd, 1H, JAB = 15.8, J = 2.1, 2.1, 2.0,
CHHC(CH3)2], 3.67 (br s, 1H, CHOH), 3.71 (AB, dd, 1H,
JAB = 11.1, J = 9.3, 5.1 Hz, CHHOCO), 3.75 (AB, dd, 1H,
MS (CI, isobutane): m/z = 299 (MH+).
Anal. Calcd for C16H30O3Si: C, 64.38, H, 10.13. Found C, 64.62, H,
10.10.
Bicyclic Lactone 13
To a stirred solution of lactone 12 (1.55 g; 5.2 mmol) in dry toluene
(26 mL) at -78 °C was added dropwise DIBAL-H (6.9 mL, 10.4
mmol, 1.3 M solution in toluene). The resulting solution was stirred
at -78 °C for 20 min and monitored by TLC. Upon completion, the
reaction was quenched at -78 °C with sat. sodium potassium tar-
trate and warmed to r.t. The reaction mixture was partitioned be-
tween CH2Cl2 and H2O. The aqueous layer was extracted with
CH2Cl2 (3 x 100 mL) and the combined organic extracts were dried
(MgSO4). Removal of solvent in vacuo gave the crude lactol as a
mixture of diastereoisomers (1.52 g, 97%) which was used immedi-
ately for the next step without further purification.
J
AB = 11.1, J = 11.1, 5.4 Hz, CHHOCO).
13C NMR (75 MHz, CDCl3): d = 21.8, 22.8, 27.2, 42.5, 42.7, 67.2,
85.2, 129.0, 158.3, 164.7.
MS (CI, isobutane): m/z = 183 (MH+).
Anal. Calcd for C10H14O3: C, 65.91, H, 7.74. Found C, 65.99, H,
7.81.
Bicyclic Lactone 10
IR (CHCl3): n = 2958, 2859, 1716, 1213, 1115 cm-1.
1H NMR (500 MHz, C6D6): d = -0.11 (s, 3H, SiCH3), -0.05 (s, 3H,
SiCH3), 0.87 (s, 3H, CH3), 0.89 (s, 9H, SiC(CH3)3), 0.92 (s, 3H,
CH3), 1.67 (AB, dddd, 1H, JAB = 17.9, J = 9.6, 7.6, 4.0, 1.9 Hz,
CHHCH2OCO), 1.88 (AB, dddd, 1H, JAB = 17.9, J = 6.9, 4.6, 2.2,
1.0 Hz, CHHCH2OCO), 2.18 [AB, ddd, 1H, JAB = 15.8, J = 4.2, 2.1,
2.1 Hz, CHHC(CH3)2], 2.39 [AB, ddd, 1H, JAB = 15.7, J = 1.8, 1.8,
1.8 Hz, CHHC(CH3)2], 3.75 (AB, dd, 1H, JAB = 11.1, J = 9.9, 4.8
Hz, CHHOCO), 3.83 (AB, dd, 1H, JAB = 11.1, J = 5.7, 4.8 Hz,
CHHOCO), 3.94 (ddd, J = 3.0,1.9, 1.9, 1H,CHOTBS).
13C NMR (75 MHz, CDCl3): d = -4.7, -4.6, 17.9, 22.4, 23.3, 25.6,
To a suspension of MePPh3Br (12.73 g, 35.6 mmol) in dry THF
(71 mL) under N2 at 0 °C was added n-BuLi (21.14 mL, 33.82
mmol, 1.6 M solution in hexanes). The ice bath was removed and
the resulting orange solution was stirred for 15 min. A solution of
crude lactol (1.06 g, 3.56 mmol) in dry THF (17.8 mL) was added
and the reaction mixture was refluxed for 30 min. The reaction was
complete and the solution was cooled to r.t. The excess ylide was
quenched by dropwise addition of H2O and the reaction mixture was
partitioned between EtOAc and H2O. The aqueous layer was ex-
tracted with EtOAc (2 x 100 mL) and the combined organic extracts
were washed with brine and dried (MgSO4). Removal of solvent in
vacuo gave the crude product, which was filtered through a plug of
silica gel eluting with hexane/EtOAc (3:1). Final purification by
flash chromagraphy on silica gel using hexane/EtOAc (first 6:1 fol-
lowed by 3:1) gave the corresponding hydroxy alkene as a pale yel-
low oil (940 mg, 89%).
27.0, 42.6, 43.6, 67.0, 85.3, 128.0, 159.2, 164.7.
MS (CI, isobutane): m/z = 297 (MH+).
Anal. Calcd. for C16H28O3Si: C, 64.82, H, 9.52. Found C, 64.76, H,
9.56.
Lactones 11 and 12
11: mp 64-65 °C (hexane/EtOAc).
IR (film): n = 2956, 1740, 1472, 1389, 1257, 1162, 1096,
1073 cm-1.
1H NMR (500 MHz, C6D6): d = 0.04 (s, 3H, SiCH3), 0.06 (s, 3H,
SiCH3), 0.90 (s, 12H, SiC(CH3)3, a-CH3), 0.99 (s, 3H, b-CH3), 1.55
(dddd, 1H, J = 14.0, 10.6, 10.1, 3.4 Hz, H6b), 1.73 (dd, 1H, J = 13.5,
9.9 Hz, H3b), 1.96 (dd, 1H, J = 13.5, 9.3 Hz, H3a), 2.14 (dddd, 1H,
J = 14.0, 7.0, 4.7, 2.1 Hz, H6a), 2.42 (dddd, 1H, J = 12.4, 8.8, 8.3,
7.5 Hz, H5a), 2.96 (ddd, 1H, J = 12.2, 9.6, 9.6 Hz, H4a), 3.35 (d, 1H,
J = 8.6 Hz, H1b), 4.16 (ddd, 1H, J = 11.5, 10.4, 2.1 Hz, H7a), 4.36
(ddd, 1H, J = 11.2, 4.4, 3.6 Hz, H7b).
13C NMR (75 MHz, CDCl3): d = -4.5, -4.2, 17.8, 20.2, 25.6, 26.4,
28.2, 37.1, 40.0, 41.1, 41.4, 67.2, 86.2, 175.6.
MS (CI, isobutane): m/z = 299 (MH+).
IR (film): n = 3338.3, 2954.4, 1638.4, 1471.4, 1254.7 cm-1.
1H NMR (500 MHz, CDCl3): d = 0.059 (s, 3H, Si CH3), 0.062 (s,
3H, Si CH3), 0.94 (s, 9H, SiC(CH3), 0.98 (s, 3H, CH3), 0.99 (s, 3H,
CH3), 1.50 (dd, 1H, J = 13.2, 7.0 Hz, H3a), 1.62 (dddd, 1H, J = 13.9,
8.6, 7.0, 6.0 Hz, CHHCH2OH), 1.68 (obscured dd, 1H, J = 13.4, 8.2
Hz, H3b), 1.68 (obscured dddd, 1H, J = 14.5, 7.2, 7.2, 5.1 Hz,
CHHCH2OH), 2.24 (dddd, 1H, J = 8.5, 8.5, 4.8, 4.8 Hz, H5b), 2.66
(dddd, 1H, J = 8.2, 8.1, 8.2, 8.2 Hz, H4b), 3.58 (partly obscured ddd,
1H, J = 10.3, 7.0, 7.0 Hz, CHHOH), 3.59 (partly obscured d, 1H,
J = 4.2 Hz, H1b), 3.66 (ddd, 1H, J = 10.3, 7.3, 5.8 Hz, CHHOH),
4.87 (ddd, 1H, J = 16.7, 2.1, 0.9 Hz, CH = CHHtrans), 4.89 (ddd, 1H,
J = 10.5, 2.2, 0.4 Hz, CH = CHcisH), 5.91 (ddd, 1H, J = 16.7, 10.3,
9.4 Hz, CH = CH2).
Anal. Calcd for C16H30O3Si: C, 64.38, H, 10.13. Found C, 64.23, H,
10.05.
12: IR (film): n = 2955, 1740, 1471, 1388, 1255, 1161, 1095 cm-1.
1H NMR (500 MHz, C6D6): d = -0.11 (s, 3H, SiCH3), -0.06 (s, 3H,
SiCH3), 0.65 (s, 3H, a-CH3), 0.93 (s, 3H, b-CH3), 0.94 (s, 9H,
SiC(CH3)3), 1.08 (dddd, 1H, J = 14.0, 8.3, 2.8, 1.8 Hz, H6b), 1.47
(dd, 1H, J = 13.2, 6.7 Hz, H3b), 1.65 (dddd, 1H, J = 14.0, 12.5, 10.9,
3.6 Hz, H6a), 2.05 (dddd, 1H, J = 11.4, 11.2, 8.0, 4.9 Hz, H5b), 2.25
(ddd, 1H, J = 11.7, 9.3, 6.8 Hz, H4b), 2.40 (dd, 1H, J = 13.2, 6.7 Hz,
H3a), 3.13 (d, 1H, J = 4.9 Hz, H1b), 3.43 (ddd, 1H, J = 12.4, 10.6, 1.6
Hz, H7b), 3.79 (ddd, 1H, J = 10.9, 3.9, 3.1 Hz, H7a).
13C NMR (75 MHz, CDCl3): d = -4.3, -4.3, 18.1, 25.3, 26.0, 29.2,
29.5, 42.3, 43.5, 43.8, 45.2, 62.2, 84.2, 113.5, 143.2.
MS (CI, isobutane): m/z = 299 (MH+).
Anal. Calcd for C17H34O2Si: C, 68.39, H, 11.48. Found C, 68.34, H,
11.55.
Synthesis 2000, No. 7, 1020–1026 ISSN 0039-7881 © Thieme Stuttgart · New York

1024
M. E. Krafft et al.
PAPER
1H NMR (500 MHz, CDCl3): d = 0.98 (s, 3H, b-CH3), 1.06 (d,
J = 6.8 Hz, 3H, CHCH3), 1.15 (s, 3H, a-CH3), 1.49 (dd, 1H,
J = 12.6, 6.9 Hz, H3a), 1.51 (d, 1H, J = 5.3 Hz, CHOH), 1.66 (dd,
1H, J = 12.4, 12.4 Hz, H3b), 2.21 (ddq, 1H, J = 7.2, 7.1, 6.8 Hz,
CHCH3), 2.43 (dddd, 1H, J = 12.1, 9.5, 7.1, 4.7 Hz, H4b), 2.52 (dd,
1H, J = 18.0, 10.0 Hz, H6b), 2.68 (dd, 1H, J = 17.9, 3.1 Hz, H6a),
3.01 (dddd, 1H, J = 9.5, 9.5, 6.0, 3.1 Hz, H5b), 3.45 (ddd, 1H,
J = 5.3, 5 Hz, CHOH), 4.33 (d, 1H, J = 6.0 Hz, H1b), 5.07 (ddd, 1H,
J = 10.3, 0.8, 0.8 Hz, CH = CHHtrans), 5.09 (ddd, 1H, J = 17.3, 1.4,
1.4 Hz, CH = CHcisH), 5.72 (ddd, 1H, J = 17.3, 10.3, 7.9 Hz,
CH = CH2).
To a stirred solution of hydroxy alkene (784 mg, 2.63 mmol) in ac-
etone (26 mL) was added Jones’reagent (2.14 M) until there was a
persistent orange/red color. When the reaction was complete,
i-PrOH was added to quench the excess Jones’ reagent, 2 N HCl
(25 mL) was added, and the mixture was refluxed overnight. The re-
action mixture was poured into a separatory funnel and partitioned
between H2O and CH2Cl2. The aqueous layer was extracted with
CH2Cl2 (3 x 100 mL) and the combined organic extracts were dried
(MgSO4). Removal of the solvent in vacuo gave the crude product
which was chromatographed on silica gel eluting with hexane/
EtOAc (4:1) to give the product 13 as a colorless oil (419 mg; 89%).
13C NMR (75 MHz, CDCl3): d = 15.1, 23.2, 25.5, 31.2, 37.1, 40.4,
40.1, 41.3, 43.1, 74.1, 93.2, 115.3, 141.1, 178.4.
MS (CI, isobutane): m/z = 239 (MH+).
Anal. Calcd. for C14H22O3.0.4H2O: C, 68.48, H, 9.36. Found C,
68.36, H, 9.21.
IR (film): n = 3018, 2966, 1770, 1522, 1470, 1420 cm-1.
syn,anti Homoallylic Alcohol 14
Mp: 96-97 °C (hexane/EtOAc).
1H NMR (500 MHz, CDCl3): d = 1.02 (s, 3H, b-CH3), 1.15 (s, 3H,
a-CH3), 1.53 (obscured dd, 1H, J = 14.4, 4.8 Hz, H3a), 1.56 (dd, 1H,
J = 14.4, 7.9 Hz, H3b), 2.506 (d, 1H, J = 7.6 Hz, H6), 2.508 (d, 1H,
J = 6.3 Hz, H6’), 2.96 (ddddd, 1H, J = 12.1, 10.6, 8.4, 1.4, 1.4 Hz,
H4b), 3.09 (dddd, 1H, J = 12.1, 7.6, 6.3, 6.3 Hz, H5b), 4.40 (d, 1H,
J = 6.1 Hz, H1b), 5.05 (ddd, 1H, J = 17.2, 1.5, 1.5 Hz,
CH = CHHtrans), 5.12 (ddd, 1H, J = 10.5, 1.3, 1.3 Hz,
CH = CHcisH), 5.70 (ddd, 1H, J = 17.2, 10.3, 7.0 Hz, CH = CH2).
13C NMR (75 MHz, CDCl3): d = 23.3, 25.4, 30.4, 41.0, 41.8, 42.2,
42.9, 92.9, 116.6, 137.8, 177.5.
MS (CI, isobutane): m/z = 181 (MH+).
IR (CHCl3): n = 3569, 2967, 2874, 1767, 1637, 1469, 1371, 1194,
1161, 1042 cm-1.
1H NMR (500 MHz, CDCl3): d = 0.99 (d, J = 7.0 Hz, 3H, CHCH3),
1.00 (s, 3H, b-CH3), 1.14 (s, 3H, a-CH3), 1.34 (dd, J = 12.6, 12.6
Hz, 1H, H3a), 1.40 (dd, J = 12.4, 7.0 Hz, 1H, H3b), 1.51 (br. s, 1H,
OH), 2.33 (obscured dqdd, J = 6.6, 6.6, 6.6, 2.6, 1.5 Hz, 1H,
CHCH3), 2.36 (obscured dddd, J = 12.6, 9.9, 9.9, 7.1 Hz, 1H, H4b),
2.65 (dd, J = 18.9, 10.3 Hz, 1H, H6b), 2.89 (dd, J = 18.7, 2.8 Hz, 1H,
H6a), 3.15 (dddd, J = 9.3, 9.3, 6.0, 2.8 Hz, 1H, H5b), 3.46 (dd,
J = 12.6, 2.6 Hz, 1H, H1b), 4.39 (d, J = 5.9 Hz, 1H, H1b), 5.15 (ddd,
J = 17.4, 1.5, 1.5 Hz, 1H, CH = CHHtrans), 5.22 (ddd, J = 10.6, 1.5,
1.5 Hz, 1H, CH = CHcisH), 5.88 (ddd, J = 17.4, 10.6, 5.7 Hz, 1H,
CH = CH2).
Anal. Calcd. for C11H16O2: C, 73.30, H, 8.95. Found C, 73.17, H,
8.94.
13C NMR (75 MHz, CDCl3): d = 9.7, 23.2, 25.1, 30.4, 39.5, 39.7,
39.8, 41.5, 42.1, 73.6, 92.9, 116.3, 141.0, 178.2.
MS (CI, isobutane): m/z = 239 (MH+).
Anal. Calcd. for C14H22O3: C, 70.56, H, 9.30. Found C, 70.51, H,
9.24.
Diene 16
IR (film): n = 3079, 2958, 1770, 1640, 1460, 1416, 1371, 1182,
1111 cm-1.
syn,syn Homoallylic Alcohol 15
O3 was bubbled through a stirred solution of olefinic lactone 13
(51 mg, 0.28 mmol) in CH2Cl2 (4 mL) at -78 °C until a blue solu-
tion was obtained. O2 was bubbled through the solution to remove
excess O3 and N2 was then bubbled through the solution to remove
excess O2. Dimethyl sulfide (1 mL) was added at -78 °C and the re-
action was allowed to warm to r.t. and stirred for 15 h. The solvent
was removed in vacuo, the crude aldehyde was redissolved in
CH2Cl2 (3 mL), cooled to -78 °C, and (E)-crotyl-trinbutylstannane
(106 mg; 0.308 mmol) was added. To the resulting solution was
added BF3∑OEt2 (0.07 mL, 0.567 mmol) dropwise and the solution
was stirred at -78 °C for 40 min. When the reaction was complete,
sat. NaHCO3 was added and the solution was allowed to warm to r.t.
The reaction mixture was partitioned between CH2Cl2 and H2O. The
aqueous layer was extracted with CH2Cl2 (2 x 30 mL) and the or-
ganic extracts were combined and dried (MgSO4). The solvent was
removed in vacuo and the crude product was chromatographed on
silica gel (hexane/EtOAc, 4:1) to give the syn,syn homoallylic alco-
hol 15 as a white solid (44 mg, 66%) and the syn,anti alcohol 14 as
a white solid (5 mg; 8%).
1H NMR (500 MHz, CDCl3): d = 0.59 (q, 6H, J = 7.8 Hz,
Si(CH2CH3)3), 0.95 (t, 9H, J = 7.8 Hz, Si(CH2CH3)3), 0.98 (s, 3H,
b-CH3), 0.99 (d, 3H, J = 6.9 Hz, CHCH3), 1.10 (s, 3H, a-CH3), 1.38
(dd, 1H, J = 12.8, 12.8 Hz, H3a), 1.55 (dd, 1H, J = 12.8, 5.9 Hz,
H3b), 2.21 (dqd, 1H, J = 6.8, 6.8, 1.8 Hz, CHCH3), 2.36 (obscured
ddd, 1H, J = 13.7, 8.9, 6.1 Hz, CHHCH = CH2), 2.39 (obscured
ddd, 1H, J = 12.9, 9.1, 6.1 Hz, H4b), 2.50 (ddd, 1H, J = 13.7, 6.5, 6.5
Hz, CHHCH = CH2), 2.64 (ddd, 1H, J = 9.7, 5.6, 4.0 Hz, H6a), 2.69
(ddd, 1H, J = 10.2, 6.7, 3.8 Hz, H5b), 3.64 (dd, 1H, J = 8.9, 1.8 Hz,
CHOSi(CH2CH3)3), 4.30 (dd, 1H, J = 6.5, 0.8 Hz, H1b), 5.01 (ddd,
1H, J = 17.2, 1.6, 1.6 Hz, CHCH3CH = CHHtrans), 5.04 (ddd, 1H,
J = 9.6, 1.4, 1.4 Hz, CHCH3CH = CHcisH), 5.17 (ddd, 1H, J = 11.3,
0.6, 0.6 Hz, CH2CH = CHcisH), 5.17 (ddd, 1H, J = 17.2, 1.4, 1.4 Hz,
CH2CH = CHHtrans), 5.75 (dddd, 1H, J = 17.4, 9.7, 7.7, 7.2 Hz,
CH2CH = CH2), 5.88 (ddd, 1H, J = 17.4, 10.5, 7.0 Hz,
CHCH3CH = CH2).
13C NMR (75 MHz, CDCl3): d = 5.2, 5.3, 6.8, 6.9, 12.1, 23.7, 25.7,
36.4, 40.6, 41.36, 41.6, 42.7,44.3, 91.4, 114.2, 119.2, 133.0, 142.3,
179.3.
15: mp 108-110 °C (hexane/EtOAc).
IR (CHCl3): n = 3678, 3020, 1774, 1752, 1522, 1420 cm-1.
MS (CI, isobutane): m/z = 393 (MH+).
Synthesis 2000, No. 7, 1020–1026 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of the First "Inside-Outside" Eight-Membered Ring via Ring-Closing Metathesis
1025
Anal. Calcd. for C23H40O3Si: C, 70.36, H, 10.27. Found C, 70.61, H,
10.30.
Anal. Calcd. for C15H22O3: C, 71.97, H, 8.86. Found C, 71.71, H,
8.97.
5,6-Dehydro-8-dihydroasteriscanolide (19)
Mp: 130-132 °C (hexane/EtOAc).
IR (CHCl3): n = 3018, 1760, 1208 cm-1.
1H NMR (500 MHz, CDCl3): d = 0.96 (s, 3H, b-CH3), 1.16 (s, 3H,
a-CH3), 1.19 (d, 3H, J = 7.0 Hz, CHCH3), 1.66 (dd, 1H, J = 12.6,
12.6 Hz, H10a), 1.69 (d, 1H, J = 5.4 Hz, CHOH), 1.77 (dd, 1H,
J = 12.8, 7.2 Hz, H10b), 2.12 (ddq, 1H, J = 9.6, 7.0, 7.0 Hz, H7b),
2.35 (dd, 1H, J = 8.7, 3.5 Hz, H4b), 2.37 (dd, 1H, J = 8.7, 8.7 Hz,
H4a), 2.40 (ddd, 1H, J = 12.2, 10.9, 7.4 Hz, H9b), 2.97 (ddd, 1H,
J = 10.9, 8.7, 4.4 Hz, H2b), 3.09 (ddd, 1H, J = 10.9, 8.7, 8.7 Hz,
H3b), 3.99 (ddd, 1H, J = 10.7, 10.7, 5.0 Hz, H8a), 4.28 (dd, 1H,
J = 4.6, 0.9 Hz, H1b), 5.58 (ddd, 1H, J = 10.7, 9.4, 8.3 Hz, H5), 5.76
(dd, 1H, J = 10.7, 7.8 Hz, H6).
13C NMR (75 MHz, CDCl3): d = 18.9, 22.6, 23.7, 25.1, 40.2, 43.0,
43.7, 44.8, 45.2, 46.9, 77.7, 93.0, 126.3, 135.7, 178.2.
HRMS (CI, isobutane): Calcd for C15H23O3 (MH+) 251.1647.
Found: 251.1635.
3-epi-5,6-Dehydro-8-(dihydrotriethylsilyloxy)asteriscanolide
(17)
Bis(tricyclohexylphosphine)benzylidine ruthenium(IV) dichloride
(Ph3P)2Cl2Ru = CHPh (35 mg, 0.0423 mmol) was added to a stirred
solution of diene 16 (83 mg, 0.2117 mmol) in dry CH2Cl2 (32 mL)
and the reaction mixture was refluxed for 8 h under N2 after which
a further amount of the Grubbs’catalyst (35 mg, 0.0423 mmol) was
added and the solution was refluxed for another 8 h. A final 17 mg
(0.0211 mmol) was added and the reaction was refluxed for a fur-
ther 8 h. The reaction was complete according to TLC and the solu-
tion was allowed to cool to r.t. and then concentrated under vacuum.
The residue was loaded onto a plug of silica gel and eluted with hex-
ane/EtOAc (9:1) to remove excess ruthenium containing com-
pounds. The solvent was removed in vacuo and the residue was
chromatographed on silica gel (hexane/EtOAc, 19:1) to give the
product 17 as a pale yellow oil (70 mg, 92%).
Anal. Calcd. for C15H22O3: C, 71.97, H, 8.86. Found C, 71.81, H,
8.86.
(±)-Asteriscanolide (1)
To a solution of the unsaturated hydroxy tricycle 19 (13 mg,
0.052 mmol) in absolute EtOH (6 mL) was added palladium on car-
bon (4 mg) and the resulting mixture was subjected to 20 psi of H2
for 15 h. The reaction mixture was filtered through a plug of Celite,
and the solvent was removed in vacuo to give the crude product,
which was chromatographed on silica gel (hexane/EtOAc, 3:1) to
give 8-dihydroasteriscanolide as a white solid (12 mg, 93%), mp:
143-144 °C (hexane/EtOAc).
IR (film): n = 2958, 2878, 1760, 1470, 1462, 1454 cm-1.
1H NMR (500 MHz, CDCl3): d = 0.60 (q, 6H, J = 8.3 Hz,
Si(CH2CH3)3), 0.97 (t, 9H, J = 7.8 Hz, Si(CH2CH3)3), 0.99 (d, 3H,
J = 7.0 Hz, CHCH3), 1.04 (s, 3H, a-CH3), 1.07 [s, 3H, b-CH3)3],
1.36 (dd, 1H, J = 12.6, 12.6 Hz, H10a), 1.76 (dd, 1H, J = 12.8, 6.7
Hz, H10b), 2.10 (dddd, 1H, J = 16.3, 9.9, 3.4, 2.6 Hz, H4b), 2.41 (ddd,
1H, J = 9.7, 9.7, 1.6 Hz, H3a), 2.44 (dddd, 1H, J = 12.8, 9.1, 7.0, 6.1
Hz, H9b), 2.65 (dqdd, 1H, J = 13.4, 6.0, 1.0, 0.5 Hz, H7b), 2.77 (ddd,
1H, J = 15.8, 9.2, 1.6 Hz, H4a), 3.09 (br. ddd, 1H, J = 9.1, 7.9, 7.8
Hz, H2b), 3.47 (dd, 1H, J = 9.2, 4.9 Hz, H8a), 4.35 (dd, 1H, J = 8.0,
0.8 Hz, H1b), 5.59 (ddd, 1H, J = 10.5, 7.8, 2.6 Hz, H6), 5.69 (dddd,
1H, J = 10.7, 9.1, 4.2, 1.4 Hz, H5).
IR (CHCl3): n = 3850, 1760, 996 cm-1.
1H NMR (500 MHz, CDCl3): d = 1.00 (s, 3H, b-CH3), 1.11 (d, 3H,
J = 6.9 Hz, CHCH3), 1.17 (s, 3H, a-CH3), 1.53 (dd, 1H, J = 12.7,
12.7 Hz, H10a), 1.53-1.71 (m, 5H, H4a, H7b, H5, H6a, OH), 1.77 (dd,
1H, J = 12.7, 6.9 Hz, H10b), 1.94 (m, 2H, H6b, H5’), 2.08 (dddd, 1H,
J = 10.8, 7.7, 4.8, 4.8 Hz, H4b), 2.39 (dddd, 1H, J = 12.6, 10.6, 10.6,
6.8 Hz, H9b), 2.79 (ddd, 1H, J = 12.2, 9.5, 6.0 Hz, H3b), 3.33 (ddd,
1H, J = 9.8, 9.8, 5.2 Hz, H2b), 3.77 (dd, 1H, J = 11.0, 9.0 Hz, H8a),
4.26 (dd, 1H, J = 5.2, 1.0 Hz, H1b).
13C NMR (75 MHz, CDCl3): d = 15.7, 21.8, 22.90, 24.1, 25.4, 28.2,
40.3, 41.7, 42.9, 43.3, 44.7, 47.2, 78.6, 92.4, 179.5.
HRMS (CI, isobutane): Calcd for C15H25O3 (MH+) 253.1804.
Found: 253.1793.
13C NMR (75 MHz, CDCl3): d = 4.9, 6.8, 16.4, 24.4, 28.9, 30.4, 37.2,
41.2, 41.4, 44.6, 49.6, 50.6, 80.1, 80.1, 126.8, 141.7, 179.1.
MS (CI, isobutane): m/z = 365 (MH+).
Anal. Calcd. for C21H36O3Si.0.2H2O: C, 68.61, H, 9.98. Found C,
68.60, H, 9.95.
3-epi-5,6-Dehydro-8-dihydroasteriscanolide (18)
Anal. Calcd. for C15H24O3: C, 71.39, H, 9.59. Found C, 71.23, H,
9.57.
Mp: 92-94 °C (hexane/EtOAc).
IR (CHCl3): n = 3627, 2964, 1764, 1465, 1372, 1190, 1032, 1004
Tetranpropyl ammonium perruthenate (2 mg, 0.0022 mmol) was
added to a stirred solution of 8-dihydroasteriscanolide (11 mg,
0.0436 mmol) and N-methylmorpholine-N-oxide monohydrate (9
mg, 0.0655 mmol) in dry CH2Cl2 (2 mL). After 2 h, the solution was
filtered through a short plug of silica gel eluting with hexane/EtOAc
(1:1) and the solvent was removed in vacuo to give the crude prod-
uct. Final purification by flash chromatography (hexane/EtOAc,
3:1) gave the racemic natural product 1 (11 mg; 100%), mp: 142-
143 °C (Et2O).
cm-1.
1H NMR (500 MHz, CDCl3): d = 1.05 (s, 3H, a-CH3), 1.08 (d, 3H,
J = 7.1 Hz, CHCH3), 1.08 (s, 3H, CH3), 1.48 (dd, 1H, J = 12.6, 12.6
Hz, H10a), 1.60 (br. s, 1H, OH), 1.90 (dd, 1H, J = 12.6, 6.0 Hz, H10b),
2.16 (dddd, 1H, J = 16.1, 9.3, 4.8, 1.8 Hz, H4b), 2.37 (dddd, 1H,
J = 12.8, 9.5, 6.6, 6.6 Hz, H9b), 2.47 (ddd, 1H, J = 9.7, 9.7, 3.1 Hz,
H3a), 2.58 (ddq, 1H, J = 14.1, 7.0, 7.0 Hz, H7b), 2.75 (ddd, 1H,
J = 15.9, 8.2, 3.1 Hz, H4a), 3.12 (br. ddd, 1H, J = 7.5, 7.5, 7.5 Hz,
H2b), 3.49 (dd, 1H, J = 9.3, 6.8 Hz, H8a), 4.37 (d, 1H, J = 8.1 Hz,
H1b), 5.58 (ddd, 1H, J = 11.5, 7.1, 2.2 Hz, H6), 5.66 (dddd, 1H,
J = 11.5, 8.2, 5.0, 1.5 Hz, H5).
IR (CHCl3): n = 2963, 2876, 1765, 1699, 1468, 1355, 1216, 1168
cm-1.
1H NMR (500 MHz, CDCl3): d = 1.00 (s, 3H, b-CH3), 1.13 (d, 3H,
J = 6.6 Hz, CHCH3), 1.20 (s, 3H, a-CH3), 1.35 (dddd, 1H, J = 13.0,
10.6, 3.1, 3.1 Hz, H4b), 1.39 (dd, 1H, J = 12.6, 6.8 Hz, H10b), 1.56
(obscured m, 1H, H5a), 1.80 (dddd, 1H, J = 14.5, 5.0, 5.0, 2.8 Hz,
13C NMR (75 MHz, CDCl3): d = 16.6, 24.3, 29.0, 29.7, 37.7, 40.6,
41.1, 44.4, 48.4, 49.6, 78.7, 89.35, 126.2, 140.1, 179.0.
MS (CI, isobutane): m/z = 251 (MH+).
Synthesis 2000, No. 7, 1020–1026 ISSN 0039-7881 © Thieme Stuttgart · New York

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M. E. Krafft et al.
PAPER
Funk, R. L.; Olmstead, J. A.; Parvez, M.; Stallman, J. B. J.
H6a), 1.93 (obscured m, 1H, H5b), 1.97 (obscured dddd, 1H,
J = 13.2, 8.1, 4.2, 4.2 Hz, H4a), 2.19 (dd, 1H, J = 13.0, 13.0 Hz,
Org. Chem. 1993, 58, 5873.
H
10a), 2.42 (dddd, 1H, J = 15.8, 12.4, 5.0, 3.7 Hz, H6b), 2.52 (ddq,
(12) Nakamura, T.; Matsui, T.; Tanino, K.; Kuwajima, I. J. Org.
Chem. 1997, 62, 3032.
(13) Miller, S. J.; Kim, S. H.; Chen, Z. R.; Grubbs, R. H. J. Am.
Chem. Soc. 1995, 117, 2108.
1H, J = 12.8, 10.4, 6.7 Hz, H7b), 2.71 (ddd, 1H, J = 12.4, 9.5, 4.6
Hz, H3b), 3.21 (ddd, 1H, J = 12.1, 12.1, 6.8 Hz, H9b), 3.73 (ddd, 1H,
J = 11.0, 9.7, 5.3 Hz, H2b),4.27(dd, 1H, J = 5.3, 0.9 Hz, H1b).
Schuster, S; Blechert, S. Angew. Chem., Int. Ed. Engl. 1997,
36, 2036.
Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413.
Alkene Metathesis in Organic Synthesis. In Topics in
Organometallic Chemistry, Vol. 1; Furstner, A., Ed.;
Springer-Verlag: Berlin, 1998.
13C NMR (75 MHz, CDCl3): d = 13.1, 22.3, 22.8, 22.8, 24.4, 27.9,
38.3, 40.7, 43.1, 45.6, 45.7, 50.2, 90.9, 178.0, 213.9.
MS (CI, isobutane): m/z = 251 (MH+).
Anal. Calcd. for C15H22O3: C, 71.97, H, 8.86. Found C, 71.71, H,
8.75.
(14) Schore, N. E. In Comprehensive Organic Synthesis, Vol. 5;
Trost, B. M., Ed.; Pergamon: Oxford, 1991; p 1037.
Schore, N. E. Org. Reactions 1991, 40, 1.
Schore, N. E. In Comprehensive Organometallic Chemistry-
II, Vol. 12; Hegedus, L. S., Ed.; Pergamon: Oxford, 1995; p
703.
Geis, O.; Schmalz, H. -G. Angew. Chem., Int. Ed. Engl. 1998,
37, 911.
(15) Krafft, M. E.; Romero, R. H.; Scott, I. L. J. Org. Chem. 1992,
57, 5277.
Acknowledgement
We thank the National Science Foundation and donors to the Krafft
Research Fund for financial support. We also thank Professor Ro-
bert H. Grubbs for helpful suggestions on the metathesis step, Pro-
fessor Paul A. Wender for providing H NMR spectral data of
synthetic and natural asteriscanolide and Professor James Panek for
suggestions on the aldehyde crotylation.
1
(16) Krafft, M. E. Tetrahedron Lett. 1988, 29, 999.
(17) Krafft, M. E. J. Am. Chem. Soc. 1988, 110, 968.
Krafft, M. E.; Juliano, C. A. J. Org. Chem. 1992, 57, 5106.
Krafft, M. E.; Juliano, C. A.; Scott, I. L.; Wright, C.;
McEachin, M. D. J. Am. Chem. Soc. 1991, 113, 1693.
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(19) Aoki, S.; Mikanmi, K.; Terado, M.; Nakai, T. Tetrahedron
1993, 49, 1783.
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Article Identifier:
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Synthesis 2000, No. 7, 1020–1026 ISSN 0039-7881 © Thieme Stuttgart · New York