Synthesis of acuminolide and 17-O-acetylacuminolide from (+)-sclareolide

Article abstract of DOI:10.1021/jo971631n

The synthesis of natural acuminolide and 17-O-acetylacuminolide is reported. Commercially available (+)-sclareolide was converted to epoxy alcohol 3, which upon acid-catalyzed cyclization afforded tricycle 14. Reaction of 14 with ¹O₂ in the presence of a hindered base gave an inseparable mixture of acuminolide 1a and 16-epiacuminolide 1b in a 70:30 ratio. Chromatographic separation of the diacetates of 1a and 1b afforded pure 18a and 18b. An analogous reaction sequence was used in the synthesis of 17-O-acetylacuminolide (2a) and 16-epi-17-O-acetylacuminolide (2b).

Full text of DOI:10.1021/jo971631n

1156
J . Org. Chem. 1998, 63, 1156-1161
Syn th esis of Acu m in olid e a n d 17-O-Acetyla cu m in olid e fr om
(+)-Scla r eolid e
Phillip A. Zoretic* and Haiquan Fang
Department of Chemistry, East Carolina University, Greenville, North Carolina 27858
Anthony A. Ribeiro† and George Dubay‡
Duke NMR Spectroscopy Center, Department of Radiology, Duke University Medical Center,
Durham, North Carolina 27710, and Department of Chemistry, Duke University, P. M. Gross Chemical
Laboratories, Durham, North Carolina 27708
Received September 3, 1997
The synthesis of natural acuminolide and 17-O-acetylacuminolide is reported. Commerically
available (+)-sclareolide was converted to epoxy alcohol 3, which upon acid-catalyzed cyclization
1
afforded tricycle 14. Reaction of 14 with O2 in the presence of a hindered base gave an inseparable
mixture of acuminolide 1a and 16-epiacuminolide 1b in a 70:30 ratio. Chromatographic separation
of the diacetates of 1a and 1b afforded pure 18a and 18b. An analogous reaction sequence was
used in the synthesis of 17-O-acetylacuminolide (2a ) and 16-epi-17-O-acetylacuminolide (2b).
Sch em e 1a
In tr od u ction
Acuminolide (1) and 17-O-acetylacuminolide (2) are
novel cytotoxic labdane diterpenoids recently isolated1
from the stem bark of Neouvaria acuminatissima. Both
compounds were shown to possess cytotoxic activity in
human cancer cell lines. Compound 1 displayed activity
against melanoma (Me12), and 2 was active against
prostate (LNCaP) cells. These compounds contain both
a â-substituted γ-hydroxybutenolide group and an 8R,-
12-epoxy moiety as key components in their structures.
The control of the crucial stereogenic centers at C-8 and
C-12 in these labdanoids coupled with the timely intro-
duction of the incorporated functional groups, and the
potential biological applications of these compounds make
them interesting synthetic targets.
a
Key: (a) LAH; THF, ∆; (b) TBDMSCl, Et3N, 4-DMAP, CH2CL2;
(c) 12-crown-4, n-BuLi, -78 °C; then CF3SO2Cl; followed by
4-DMAP, -78 °C to rt (overnight); (d) n-Bu4NF, THF, 0 °C to rt;
(e) m-CPBA, CH2Cl2, 0 °C to rt.
Following this approach, the synthesis of the key
synthon 3 is detailed below. Hydride reduction of (+)-
sclareolide with LAH (Scheme 1) gave diol 52 in quanti-
tative yield. Selective protection of the less hindered
primary alcohol in the presence of the tertiary alcohol
was effected with TBDMSCl3 in the presence of Et3N and
4-DMAP4 to afford 65 (98%). Treatment of 6 with n-BuLi
in the presence of 12-crown-4 followed by reaction of the
intermediate alkoxide with trifluoromethanesulfonyl chlo-
ride and subsequent reaction of the intermediate sul-
fonate with 4-DMAP (-78 °C f rt) afforded a 42% yield
of an inseparable mixture of exo and endo silyl ethers
7 along with an inseparable mixture of alcohols 8 in
38% yield, after chromatography. Desilylation of 7 with
Resu lts a n d Discu ssion
In considering an optically active approach to acumi-
nolide (1), it was anticipated that commercially available
(+)-sclareolide (4) would be used to construct the chiral
centers at C-5, -9, and -10 and that 4 would also serve
as an entry to the desired epoxy alcohol 3, which in turn
would be converted to the acuminolide skeleton. The
crucial γ-hydroxybutenolide group would then be intro-
duced in the last step of the synthesis via a singlet
photooxygenation reaction.
† Duke NMR Spectroscopy Center.
(2) Hinder, M.; Stoll, M. Helv. Chem. Acta 1950, 33, 1308.
(3) Corey, E. J .; Venkateswarlu, A. J . Am. Chem. Soc. 1972, 94,
6190.
(4) Chaudhary, S. K.; Hernandez, O. Tetrahedron Lett. 1979, 99.
(5) Chackalamannil, S.; Wang, Y.; Xia, Y.; Czarniecki, M. Tetrahe-
dron Lett. 1995, 36, 5315.
‡ Department of Chemistry.
(1) Lee, I.-S.; Ma, X.; Chai, H.-B.; Madulid, D. A.; Lamont, R. B.;
O’Neill, M. J .; Besterman, J . M.; Farnsworth, N. R.; Soejarto, D. D.;
Cordell, G. A.; Pezzuto, J . M.; Kinghorn, A. D. Tetrahedron 1995, 51,
21.
S0022-3263(97)01631-9 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/30/1998

Synthesis of Acuminolide and 17-O-Acetylacuminolide
J . Org. Chem., Vol. 63, No. 4, 1998 1157
Sch em e 2a
Sch em e 3
diastereotopic protons at δ 3.57 and 3.40. Additional
enhancements were also observed to the axial protons
at H-2 and H-6, the pseudoaxial proton at H-11, the H-1
equatorial proton, and the 19-Me. Irradiation of the H-17
diastereotopic proton at δ 3.57 showed an enhancement
of the H-6 axial proton (δ 1.33) and a weaker enhance-
ment of the H-11 pseudoaxial proton (δ ∼1.86). A recip-
a
Key: (a) CrO3‚2py, CH2Cl2, rt; (b) furyllithium, THF, -78
°C; then aqueous NH4Cl; (c) p-TsOH‚H2O, MeNO2, -20 °C.
n-Bu4NF6 gave the bicyclohomofarnesols 87 in 96% yield.
Epoxidation of 8 with m-CPBA afforded the ∆8,17-epoxide
98a in 49% yield along with the isomeric epoxides 10 and
11 in 23% and 27% yields, respectively, after chroma-
tography.
With the desired epoxy alcohol 9 in hand, the introduc-
tion of the 12S center and the furan group in 3, which
would ultimately serve as an entry to the γ-hydroxy-
butenolide moiety, was addressed. Reaction of 9 (Scheme
2) with Collins reagent gave crude aldehyde 128b in
essentially quantitative yield. The unstable aldehyde
was directly treated with 3-furyllithium at -78 °C, and
subsequent acidification with aqueous NH4Cl followed by
chromatography gave the 12S-alcohol 3 in 45% yield
along with the 12R-alcohol 13 in 32% yield. The major
alcohol 3 resulted from attack of the lithium reagent on
12 from the slightly less hindered re-face.
At this stage, the stereochemistry of the 12S and 12R
products could not be elucidated. The stereochemistry
was actually determined indirectly at the tricyclic stage
resulting from acid-catalyzed cyclization of the 12S- and
12R-alcohols. Reaction of 3 with p-TsOH‚H2O in ni-
tromethane at -20 °C gave exclusively tricycle 14 (90%).
The assignments of the individual protons in 14 were
obtained from a series of COSY, HMQC, and HMBC 2D
NMR studies. The stereochemistry depicted in 14 was
proven from NOE observations. The assignment of the
â-disposition of the C-17 hydroxymethyl substituent in
14 was based on the following NOE result. Irradiation
of the 20-Me at δ 0.82 in 14 gave an enhancement of the
rocal enhancement to the 20-Me, and an enhancement
of the second diastereotopic proton at H-17 (δ 3.40), was
also observed. Irradiation of the latter diastereotopic
H-17 proton at δ 3.40 showed no enhancement of the H-6
axial proton but showed a strong enhancement to the
H-11 pseudoaxial proton along with a weaker enhance-
ment to the 20-Me. These results are consistent with
the stereochemical assignments shown in 14, thus es-
tablishing indirectly that the stereogenic center at C-12
in 3, resulting from 1,2-addition, must be 12S.
The exclusive formation of the 12S,8R-isomer 14 from
the cyclization of 3, opposed to the formation of the
12S,8S-isomer 15, might be rationalized from the follow-
ing considerations as detailed in Scheme 3. Reaction of
3 with acid would lead to two transition states i and ii
assuming that the cyclization would occur via a carboca-
tion intermediate or a protonated epoxide having an
elongated C-8-O bond in which the C-8 tertiary carbon
would have considerable carbocation-like character. Tran-
sition state ii should be favored over transition state i
due to the severe steric interaction between the 20-Me
and the C-12 center and the additional steric interaction
between the 20-Me and the furan ring system. Thus,
transition state ii would lead to the 12S,8R-tricycle 14,
a kinetically derived product.
An identical cyclization of the 12R-alcohol 13 with
p-TsOH‚H2O in nitromethane (eq 1) gave a 60:40 ratio
of a mixture of (12R,8S)-16 and (12R,8R)-17 in 94% yield.
The two diastereomers were readily separated by chro-
matography and the relative stereochemistry shown in
each compound was corroborated from NOE difference
spectra (NOEDS).
(6) Corey, E. J .; Chaykovsky, M. J . Am. Chem. Soc. 1962, 84, 3782.
Corey, E. J .; Chaykovsky, M. J . Am. Chem. Soc. 1965, 87, 1353.
(7) Cambie, R. C.; J oblin, K. N.; Preston, A. F. Aust. J . Chem. 1971,
24, 583 and references within.
(8) (a) Mori, K.; Tamura, H. Liebigs Ann. Chem. 1990, 361. (b)
Chauvet, F.; Coste-Maniere, I.; Martres, P.; Perfetti, P.; Waegell, B.;
Zahra, J .-P. Tetrahedron Lett. 1996, 37, 3695.

1158 J . Org. Chem., Vol. 63, No. 4, 1998
Zoretic et al.
Sch em e 4
Irradiation of the 20-Me (δ 0.79) in (12R,8R)-17 gave
an enhancement of the H-17, H-2ax, H-6ax, H-11ax, and
H-1eq protons and the 19-Me. While irradiation of the
H-12 proton (δ 5.10) showed an enhancement of the H-17,
H-11ax, H-14, and H-16 protons, irradiation of the H-17
protons (δ 3.55) showed a reciprocal enhancement to H-12
and the 20-Me and additional enhancements of the H-6ax,
H-11ax, and H-7eq protons. A similar NOE study with
(12R,8S)-16 showed that irradiation of the C-20 Me (δ
1.03) gave a strong enhancement to the 19-Me and the
H-12 proton and a weaker enhancement to the H-2ax,
H-6ax, H-11ax, H-12eq, and H-1eq protons, but no enhance-
ment of the H-17 protons was observed. Thus, these
studies confirm the relative stereochemistry depicted in
16 and 17 and indirectly corroborated the assignment of
the 12R center in 13.
Sch em e 5a
The formation of diastereomers (12R,8S)-16 and
(12R,8R)-17 from the cyclization of 13 might be rational-
ized from the following considerations. It might be
assumed here that the kinetically derived diastereomer
17 (Scheme 4) is obtained via TS iv and that this step is
reversible, leading to TS iii, which upon cyclization would
give rise to the more stable thermodynamic product,
(12R,8S)-16.
To complete the synthesis of natural acuminolide 1a
and 17-O-acetylacuminolide (2a ), it was assumed that the
crucial γ-hydroxybutenolide moiety would be introduced
in the last step of the reaction sequence via a photooxy-
genation reaction with regiospecific removal of the less
hindered hydrogen from the intermediate endoperoxide
with a hindered base. A molecular model study sug-
gested that the reaction should occur mainly from the
less hindered R-face of the molecule. Thus, reaction of
14 with 1O2 in the presence of excess ethyldiisopropy-
lamine9 and a catalytic amount of rose bengal at -78 °C
followed by chromatography gave an inseparable mixture
of 1a and 1b (90%) in a 70:30 ratio as determined
indirectly from the corresponding diacetates. The mix-
ture of 1a and 1b appeared as a single spot on TLC
analysis. The 1H NMR spectrum (major chemical shifts)
was identical with that reported for 1a ; however, the
melting point was lower than that of natural 1a , sug-
gesting that a mixture of C-16 epimers was obtained from
a
Key: (a) 1O2, rose bengal, ethyldiisopropylamine, CH2Cl2, -78
°C to rt; (b) Ac2O, py, 4-DMAP, CH2Cl2.
singlet oxygen in the presence of ethyldiisopropylamine
(-78 °C f rt) followed by chromatography afforded an
87% yield of an inseparable mixture of 2a and 2b in an
approximate 66:34 ratio. Acylation of 2a and 2b followed
by chromatography of the diacetate mixture gave 18a
(60%) and 18b (32%). The 13C NMR spectrum of the
faster moving diastereomer 18a was identical to the 13C
NMR spectrum of the known diacetate1 of 1a . The 13C
NMR spectrum of the slower moving diastereomer 18b
was identical to the spectrum derived from diacylation
of 1b.
Con clu sion
1
the O2 reaction. Subsequent diacylation of the mixture
of 1a and 1b (Scheme 5) in the presence of base gave
diacetates 18a and 18b in an approximate 70:30 ratio
as determined by NMR analysis of the reaction mixture.
Fortunately, the diacetates were readily separated by
chromatography to afford 18a (64%, faster moving dias-
tereomer) and 18b (23%, slower moving diastereomer).
The 13C NMR spectrum of 18a was identical with that
reported for the known diacetate1 derived from acumi-
nolide 1a .
An asymmetric route to natural acuminolides has been
demonstrated. In addition, the route provides an entry
to several epimeric analogues that might provide some
insight between structure and antitumor activity.
Exp er im en ta l Section
Gen er a l P r oced u r es. NMR spectra were obtained at 200,
500, and 600 MHz. C and H microanalyses were obtained from
Galbraith Laboratories. HRMS analyses were obtained from
the Mass Spectroscopy Facility at Duke. All melting points
are uncorrected. Preparative chromatography was performed
on Merck silica gel G 60 (70-230 mesh) and Merck silica gel
G (230-400 mesh, for pressure chromatography). TLC was
performed with Sybron/Brinkmann silica gel G/UV 254 plates,
An analogous reaction sequence was used in an ap-
proach to 17-O-acetylacuminolide 2a . Acylation of 14
afforded acetate 19 in 96% yield. Reaction of 19 with
(9) Kernan, M. R.; Faulkner, D. J . J . Org. Chem. 1988, 53, 2773.

Synthesis of Acuminolide and 17-O-Acetylacuminolide
J . Org. Chem., Vol. 63, No. 4, 1998 1159
0.25 mm (analytical). Compounds on chromatography plates
were visualized by spraying with 4% phosphomolybdic acid
in isopropyl alcohol followed by heating. THF was distilled
from sodium benzophenone ketyl. Commercial reagent-grade
solvents and chemicals were used as obtained unless otherwise
noted.
(1R,2R,4a S,8a S)-2-(Ep oxym eth ylen e)-5,5,8a -tr im eth yl-
1,2,3,4,4a ,5,6,7,8,8a -d eca h yd r o-1-n a p h th a len eeth a n ol (9),
(1R,2S,3R,4aS,8aS)-2,3-Epoxy-2,5,5,8a-tetr am eth yl-1,2,3,4,-
4a ,5,6,7,8,8a -d eca h yd r o-1-n a p h th a len eeth a n ol (10), a n d
(1S,2R,4a S,8a S)-1,2-E p oxy-2,5,5,8a -t et r a m et h yl-1,2,3,4,-
4a ,5,6,7,8,8a -d eca h yd r o-1-n a p h th a len eeth a n ol (11). m-
CPBA (80-90%, 15.2 g, 74.9 mmol) was added in several
portions to isomeric alcohols 8 (6.8 g, 28.8 mmol) in dry CH2-
Cl2 (280 mL) at 0 °C. The reaction mixture was allowed to
warm to rt, stirred for 2 h, and then neutralized with 1%
NaOH. The resulting mixture was washed with H2O and
brine, dried (Na2SO4), and concentrated in vacuo to afford an
oil. Chromatography on silica gel (100 g, 230-400 mesh)
eluting with 10% ethyl acetate-hexanes gave 2.0 g (27%) of
11, 3.6 g (49%) of 9,8a and 1.6 g (23%) of 10. For 11: 1H NMR
(CDCl3) δ 3.74-3.89 (m, 1H), 3.54-3.73 (m, 1H), 2.79 (br s,
1H), 1.67-2.08 (m, 5H), 1.07-1.62 (m) and 1.30 (s) [11H], 0.99
(s, 3H), 0.84 (s, 3H), 0.81 (s, 3H); 13C NMR (CDCl3, 77.00) δ
72.21, 62.82, 61.56, 42.06, 41.31, 38.28, 34.63, 33.43, 32.79,
28.88, 27.65, 21.72, 21.37, 18.24, 17.05, 16.96. For 10: 1H
NMR (CDCl3) δ 3.81 (ddd, 1H, J ) 4.9, 8.8, 10.3 Hz), 3.62 (dt,
1H, J ) 7.6, 10.3 Hz), 3.00 (br dd, 1H, J ) 1.3, 2.5 Hz), 2.31
(br s, 1H), 2.12 (dd, 1H, J ) 4.5, 15.0 Hz), 1.25-1.86 (m) and
1.33 (s) [12H], 1.08-1.20 (m) and 1.05 (dd, J ) 4.7, 12.6 Hz)
[2H], 0.87 (s) and 0.85 (s) [6H], 0.76 (s, 3H); 13C NMR (CDCl3,
77.00) δ 63.76, 61.02, 58.72, 51.11, 45.73, 41.91, 38.68, 35.55,
32.95, 32.58, 29.02, 22.99, 22.81, 21.85, 18.54, 14.15. Epoxides
10 and 11 were not characterized further. For 9:8a 1H NMR
(CDCl3) δ 3.54-3.71 (m, 1H), 3.35-3.52 (m, 1H), 2.97 (br s,
1H), 2.87 (dd, 1H, J ) 1.9, 4.0 Hz), 2.58 (d, 1H, J ) 3.8 Hz),
1.32-2.02 (m, 10H), 1.20 (dd, 1H, J ) 4.8, 13.1 Hz), 0.87-
1.14 (m) and 0.90 (s) [6H], 0.83 (s, 3H), 0.80 (s, 3H); 13C NMR
(CDCl3, 77.00) δ 63.61, 59.58, 54.78, 52.45, 50.92, 41.76, 40.12,
38.70, 36.19, 33.42, 33.36, 25.20, 21.68, 21.52, 18.58, 14.58.
(1R,2R,4a S,8a S)-2-(Ep oxym eth ylen e)-5,5,8a -tr im eth yl-
1,2,3,4,4a ,5,6,7,8,8a -d eca h yd r o-1-n a p h t h a len ea cet a ld e-
h yd e (12). CrO3 (7.9 g, 78.7 mmol) was added to pyridine
(12.4 g, 157 mmol) in dry CH2Cl2 (600 mL). The reaction
mixture was stirred at rt for 30 min and then cooled to 0 °C
under N2. Alcohol 9 (2.5 g, 9.84 mmol) in dry CH2Cl2 (50 mL)
was added over 15 min. The reaction mixture was allowed to
warm to rt, stirred for 3 h, and then passed through a short
column of silica gel (10 g, 230-400 mesh) eluting with CH2-
Cl2 (700 mL) to give 2.5 g (100%) of crude 12:8b 1H NMR
(CDCl3) δ 9.57 (dd, 1H, J ) 1.4, 3.0 Hz), 2.65 (dd, 1H, J ) 1.8,
4.0 Hz), 2.52 (d, 1H, J ) 4.1 Hz), 2.32 (dd, 1H, J ) 5.3, 8.1
Hz) 2.15 (ddd, 1H, J ) 1.3, 5.3, 16.6 Hz), 1.78-2.02 (m) and
1.99 (dd, J ) 3.1, 8.2 Hz) [3H], 1.37-1.62 (m, 6H), 1.01-1.29
(m, 3H), 0.92 (s, 3H), 0.85 (s, 6H); 13C NMR (CDCl3, 77.00) δ
200.77, 58.29, 54.21, 49.48, 48.24, 41.31, 38.89, 38.72, 36.62,
35.10, 33.08, 32.88, 21.26, 21.12, 18.16, 14.19. Crude 12
(> 95% pure via 13C NMR) was subjected directly to 1,2-addi-
tion, since it was relatively unstable.
(1R,2R,4aS,8aS)-2-Hydr oxy-2,5,5,8a-tetr am eth yl-1,2,3,4,-
4a ,5,6,7, 8,8a -d eca h yd r o-1-n a p h th a len eeth a n ol [(-)-(1R)-
5]. (+)-Sclareolide (4) (97%, 10.7 g, 42.8 mmol) in dry THF
(70 mL) was added dropwise to a suspension of LAH (2.44 g,
64.2 mmol) in dry THF (180 mL) under N2 at rt. The reaction
mixture was refluxed for 2 h, cooled to 0 °C, quenched with
saturated Na2SO4 (200 mL), and extracted with CH2Cl2. The
organic solution was washed with brine, dried (Na2SO4), and
concentrated in vacuo to give 10.9 g (100%) of 5:2 mp 132.2-
1
133.0 °C (50% CH2Cl2-hexanes); H NMR (CDCl3) δ 4.41 (br
s, 1H, OH), 3.65-3.82 (m, 2H, HCHOH and OH), 3.40 (dt, 1H,
HCHOH, J ) 6.9, 9.6 Hz), 1.87 (dt, 1H, J ) 2.9, 11.8 Hz), 1.15
(s, 3H, 2-Me), 0.85 (s, 3H, 8a-Me), 0.76 [s, 6H, 5-(Me)2]; 13C
NMR (CDCl3, 77.00) δ 72.73, 63.74, 59.27, 55.94, 43.96, 41.82,
39.27, 38.87, 33.35, 33.19, 27.74, 24.44, 21.42, 20.34, 18.35,
15.27.
(1R ,2R ,4a S ,8a S )-1-[2-[(t er t -B u t y ld i m e t h y ls i ly l)-
oxy]e t h yl]-2-h yd r oxy-2,5,5,8a -t e t r a m e t h yl-1,2,3,4,4a ,-
5,6,7,8,8a -d eca h yd r on a p h th a len e (6). To diol 5 (5.75 g,
22.6 mmol) in dry CH2Cl2 (50 mL) were added Et3N (2.51 g,
24.9 mmol), 4-DMAP (1.10 g, 9.02 mmol), and TBDMSCl (3.75
g, 24.9 mmol). The reaction mixture was stirred at rt for 1 h
and concentrated in vacuo to give an oil. Chromatography on
silica gel (50 g, 230-400 mesh) eluting with hexanes and ethyl
acetate-hexanes gave 8.2 g (98%) of 6:5 1H NMR (CDCl3) δ
3.89 (s, 1H), 3.75-3.86 (m, 1H), 3.47 (6 line ddd, 1H, J ) 4.1,
9.8, 9.8 Hz), 1.92 (distorted dt, 1H, J ) 3.0, 12.2 Hz), 1.19-
1.72 (m, 12H), 1.14 (s, 3H), 0.93 (m), 0.91 (s), and 0.88 (s) [13H],
0.79 (s, 6H), 0.087 (s, 6H); 13C NMR (CDCl3, 77.00) δ 71.64,
64.86, 59.00, 56.14, 43.88, 41.88, 39.47, 38.90, 33.34, 33.19,
27.68, 25.89, 25.89, 25.89, 24.52, 21.45, 20.36, 18.38, 18.22,
15.30, -5.49, -5.54.
Bicycloh om ofa r n esol Silyl Eth er s 7 a n d Bicycloh om o-
fa r n esols 8. n-Butyllithium (2.5 M in hexanes, 8.7 mL, 21.8
mmol) was added dropwise to alcohol 6 (6.70 g, 18.2 mmol)
and 12-crown-4 (3.84 g, 21.8 mmol) in dry THF (140 mL) under
Ar at -78 °C over 15 min. The reaction mixture was stirred
at -78 °C for 30 min. CF3SO2Cl (3.99 g, 2.52 mL, 23.7 mmol)
was added dropwise, and stirring was continued for 2 h.
4-DMAP (5.78 g, 47.4 mmol) was added, and the reaction
mixture was stirred at -78 °C for 1 h and then gradually
allowed to warm to rt and stirred overnight. Water (100 mL)
was added to the reaction mixture followed by neutralization
with 10% HCl. The resulting mixture was extracted with CH2-
Cl2. The organic solution was washed with saturated NaHCO3
and brine, dried (Na2SO4), and concentrated in vacuo to give
an oil. Chromatography on silica gel (65 g, 230-400 mesh)
eluting with hexanes and ethyl acetate-hexanes gave 2.68 g
(42%) of the three isomers of 7 and 1.65 g (38%) of the three
isomers of 8.7 For two isomers of 7: δ 5.34-5.42 (m, 3H), 4.78
(s, dCHH), 4.49 (s, dCHH). The three isomers of 7 on TLC
analysis appeared as one spot and could not be separated by
chromatography. Alcohols 8 also appeared as one spot on TLC
analysis and they could not be separated by chromatography
on silica gel. Hence, 7 was desilylated to give alcohols 8.
3-[1S-Hyd r oxy-2-[(4a S,5R,6R,8a S)-1,2,3,4,4a ,5,6,7,8,8a -
d eca h yd r o-1,1,4a -tr im eth yl-5-n a p h th yl]eth yl]fu r a n (3)
an d 3-[1(R)-Hydr oxy-2-[(4aS,5R,6R, 8aS)-1,2,3,4,4a,5,6,7,8,-
8a -d eca h yd r o-1,1,4a -t r im et h yl-5-n a p h t h yl]et h yl]fu r a n
(13). n-BuLi (2.5 M in hexane, 9.8 mL, 24.5 mmol) was added
dropwise to 3-bromofuran (3.62 g, 24.6 mmol) in dry THF (180
mL) at -78 °C under Ar over 15 min, and the reaction mixture
was stirred for 30 min. Aldehyde 12 (2.46 g, 9.84 mmol) in
dry THF (20 mL) was added dropwise over 20 s. The reaction
mixture was stirred at -78 °C for 1 h and then quenched with
a saturated NH4Cl solution. Water (50 mL) was added, and
the mixture was extracted with CH2Cl2. The organic solution
was washed with saturated NaHCO3 and brine, dried (Na2-
SO4), and concentrated in vacuo to give an oil. Chromatog-
raphy on silica gel (120 g, 230-400 mesh) eluting with 15%
ethyl acetate-hexanes gave 1.4 g (45%) of 3 and 1.0 g (32%)
Bicycloh om ofa r n esols 8 F r om Silyl Eth er s 7. n-Bu4-
NF (1 M in THF, 79.4 mL, 79.4 mmol) was added dropwise to
silyl ethers 7 (7.94 g, 22.7 mmol) in THF (180 mL) at 0 °C
under N2. The reaction mixture was allowed to warm to rt,
stirred for 2 h, and then diluted with CH2Cl2 (200 mL). The
organic solution was washed with water and brine, dried (Na2-
SO4), and concentrated in vacuo to give an oil. Chromatog-
raphy on silica gel (70 g, 230-400 mesh) eluting with 10%
ethyl acetate-hexanes gave 5.14 g (96%) of isomers 8:7 1H
NMR (CDCl3) δ 5.38-5.47 (m), 4.83 (s, dCHH), 4.54 (s,
dCHH), 3.65 (m), 0.95, 0.88, 0.86, 0.83, 0.81, 0.77, 0.69 (s,
angular methyls). Isomers 8 were directly submitted to an
epoxidation reaction.
1
of 13. For 3: mp 73.5-74.2 °C; H NMR (CDCl3) δ 7.37 (s)
and 7.36 (s) [2H], 6.35 (m, 1H), 4.47 (dt, 1H, J ) 3.7, 9.2 Hz),
3.77 (br d, 1H, J ) 4.1 Hz), 2.93 (dd, 1H, J ) 1.8, 3.6 Hz), 2.64
(d, 1H, J ) 3.6 Hz), 1.35-2.01 (m, 10H), 1.21 (dd, 1H, J ) 4.9,
13.0 Hz), 0.94-1.14 (m, 3H), 0.91 (s, 3H), 0.83 (s, 3H), 0.79 (s,
3H); 13C NMR (CDCl3, 77.00) δ 143.02, 138.82, 130.06, 108.38,

1160 J . Org. Chem., Vol. 63, No. 4, 1998
Zoretic et al.
68.11, 59.95, 54.80, 52.37, 51.05, 41.75, 40.34, 38.58, 36.08,
33.42, 31.60, 21.67, 21.53, 18.60, 14.60. Anal. Calcd for
3.0, 11.6 Hz), 2.17 (ddd, 1H, H11ax, J ) 9.3, 11.5, 13.5 Hz), 2.01
(br s, 1H), ∼1.81 (overlapping m, 2H, H9ax, H6eq), 1.71 (ddd,
1H, H11eq, J ) 2.5, 7.1, 11.5 Hz), 1.63 (m, 1H, H2ax), ∼1.42 (m,
3H, H1eq, H2eq, H3eq), ∼1.33 (H6ax) and ∼1.28 (H7ax) [overlapping
m, 2H], 1.18 (dt, 1H, H3ax, J ) 3.7, 13.4 Hz), 1.04 (dd, 1H,
C
20H30O3: C, 75.43; H, 9.50. Found: C, 75.55; H, 9.72. For
13: 1H NMR (CDCl3) δ 7.40 (m) and 7.37 (m) [2H], 6.31 (s,
1H), 4.79 (m, 1H), 3.32 (br d, 1H, J ) 4.1 Hz), 2.89 (dd, 1H, J
) 1.9, 3.7 Hz), 1.31-1.92 (m, 11H), 1.04-1.28 (m, 2H), 0.97
(dd, 1H, J ) 2.6, 12.2 Hz), 0.87 (s, 3H), 0.81 (s) and 0.79 (s)
[6H]; 13C NMR (CDCl3, 77.00) δ 142.90, 139.33, 129.22, 108.76,
66.24, 59.70, 54.63, 50.81, 48.14, 41.68, 39.86, 38.68, 36.24,
33.37, 29.82, 21.71, 21.55, 18.56, 14.75; IR (neat) 3423, 1501,
1460, 1445, 1390, 1366, 1158, 1061, 1024, 875, 732 cm-1. Anal.
Calcd for C20H30O3: C, 75.43; H, 9.50. Found: C, 75.48; H,
9.63.
H
5ax, J ) 2.5, 12.1 Hz) and ∼1.03 (H1ax) [overlapping m, 2H],
0.89 (s, 3H, 18-Me), 0.84 (s, 3H, 19-Me), 0.79 (s, 3H, 20-Me);
13C NMR (CDCl3, 150 MHz) δ 143.61 (C-15), 139.06 (C-16),
128.83 (C-13), 108.49 (C-14), 83.89 (C-8), 71.16 (C-12), 61.20
(C-17), 59.37 (C-9), 57.37 (C-5), 42.36 (C-3), 39.68 (C-1), 36.36
(C-10), 34.44 (C-7), 33.54 (C-18), 33.12 (C-4), 31.02 (C-11),
21.10 (C-19), 20.25 (C-6), 18.41 (C-2), 15.08 (C-20); HRMS calcd
for C20H30O3 (M+) 318.2195, found 318.2192.
(1S,3R,3a R,5a S,9a S)-1-(3-F u r yl)-3a -(h yd r oxym et h yl)-
6,6,9a -t r im et h yl-1,2,3, 3a ,4,5,5a ,6,7,8,9,9a -d od eca h yd r o-
n a p h th o[2,1-b]fu r a n (14). p-TsOH‚H2O (128 mg, 0.673
mmol) was added to epoxide alcohol 3 (756 mg, 2.38 mmol) in
CH3NO2 (45 mL) at -20 °C under N2. The reaction mixture
was stirred at -20 °C for 1 h and then poured into a 0.1 N
NaOH solution (30 mL). The mixture was extracted with CH2-
Cl2, and the organic solution was washed with brine, dried
(Na2SO4), and concentrated in vacuo to give an oil. Chroma-
tography on silica gel (35 g, 200-425 mesh, pH ) 7) eluting
with 12% ethyl acetate-hexanes gave 682 mg (90%) of 14: mp
103.2-103.6 °C (hexanes); 1H NMR (CDCl3, 600 MHz) δ 7.40
(s, 2H, H15, H16), 6.43 (s, 1H, H14), 5.02 (m, 1H, H12), 3.57 (d,
1H, H17, J ) 10.7 Hz), 3.40 (dd, 1H, H17, J ) 1.8, 10.7 Hz),
2.35 (dt, 1H, H7eq, J ) 3.0, 11.7 Hz), 2.13 (m, 1H, H11eq), ∼1.86
(m, H9ax, H11ax) and 1.80 (dq, H6eq, J ) 3.2, 14.1 Hz), 1.67 (qt,
Acu m in olid e (1a ) a n d 16-epi-Acu m in olid e (1b). Furan
14 (80 mg, 0.252 mmol), ethyldiisopropylamine (325 mg, 2.52
mmol), and rose bengal (2 mg) in dry CH2Cl2 was cooled to
-78 °C while passing a stream of anhydrous O2 through the
solution. The reaction mixture was then irradiated with a 200
W tungsten lamp placed 10 cm from the reaction vessel for 6
h at -78 °C. Chromatography on silica gel (8 g, 200-425
mesh, pH ) 7) eluting with ethyl acetate-hexanes gave 79
mg (90%) of an approximate 70:30 inseparable mixture of 1a
and 1b: mp 194.4-195.6 °C (ethyl acetate-hexanes); 1H NMR
(CDCl3) δ 6.22 (s, 1H), 6.03 (d, 1H, J ) 1.1 Hz), 4.94 (m, 1H),
3.68 (d, 1H, J ) 11 Hz), 3.34 (d, 1H, J ) 11 Hz), 2.39 (m, 1H),
2.23 (m, 1H), 0.89 (s, 3H), 0.83 (s, 3H), 0.80 (s, 3H); 13C NMR
(CDCl3, 50 MHz) δ 170.4 (C-15), 168.8 (C-13), 117.5 (C-14),
98.5 (C-16), 84.6 (C-8), 74.2 (C-12), 62.5 (C-17), 60.9 (C-9), 57.1
(C-5), 42.2 (C-3), 39.7 (C-1), 36.4 (C-10), 34.3 (C-7), 33.4 (C-
18), 33.1 (C-4), 29.1 (C-11), 21.0 (C-19), 20.3 (C-6), 18.4 (C-2),
15.5 (C-20). The ratio of 1a and 1b was determined indirectly
from the corresponding diacetates 18a and 18b.
1H, H2ax, J ) 3.4, 13.8 Hz), ∼1.47 (H1eq, H2eq) and ∼ 1.44 (H3eq
)
[3H, overlapping multiplets], 1.33 (8 line dddd, 1H, H6ax, J )
3.2, 3.2, 12.9, 12.9 Hz), ∼1.24 (H7ax) and 1.20 (partially resolved
dt, J ) 3.9, 13.5 Hz) [2H], 1.11 (dt, 1H, H1ax, J ) 2.8, 12.8
Hz), 1.04 (dd, H5ax, 1H, J ) 2.6, 12.5 Hz), 0.90 (s, 3H, 18-Me),
0.84 (s, 3H, 19-Me), 0.82 (s, 3H, 20-Me); 13C NMR (CDCl3, 150
MHz) δ 143.97 (C-15), 139.26 (C-16), 128.00 (C-13), 108.98 (C-
14), 83.35 (C-8), 73.09 (C-12), 63.01 (C-17), 61.27 (C-9), 57.25
(C-5), 42.40 (C-3), 39.86 (C-1), 36.53 (C-10), 34.86 (C-7), 33.52
(C-18), 33.14 (C-4), 30.25 (C-11), 21.06 (C-19), 20.42 (C-6),
18.47 (C-2), 15.46 (C-20). Anal. Calcd for C20H30O3: C, 75.43;
H, 9.50. Found: C, 75.55; H, 9.50.
16-O-17-O-Dia cetyla cu m in olid e (18a ) a n d 16-O-17-O-
Dia cetyl-16-ep ia cu m in olid e (18b). Acetic anhydride (20.5
mg, 0.201 mmol) in pyridine (0.5 mL) was added to a solution
of diols 1a and 1b (23.5 mg, 0.0671 mmol) and 4-DMAP (16.4
mg, 0.134 mmol) in pyridine (0.5 mL), and the reaction mixture
was stirred overnight at rt. The solvent was removed in vacuo,
and chromatography of the residue on silica gel (6 g, 200-
425 mesh, pH ) 7) with 7% ethyl acetate-hexanes gave 18.6
mg (64%) of 18a and 6.8 mg (23%) of 18b. Integration of the
resonance signals at δ 6.98 and 6.88 in the crude reaction
mixture gave an approximate 70:30 ratio of 18a and 18b. For
18a : 1H NMR (CDCl3) δ 6.88 (s, 1H), 6.21 (br s, 1H), 4.82 (m,
1H), 4.53 (d, 1H, J ) 11.8 Hz), 3.62 (d, 1H, J ) 11.8 Hz), 2.17
(1R,3R,3a S,5a S,9a S)-1-(3-F u r yl)-3a -(h yd r oxym et h yl)-
6,6,9a -t r im et h yl-1,2,3,3a ,4,5,5a ,6,7,8,9,9a -d od eca h yd r o-
n a p h th o[2,1-b]fu r a n (16) a n d (1R,3R,3a R,5a S,9a S)-1-(3-
F u r yl)-3a -(h yd r oxym eth yl)-6,6,9a -tr im eth yl-1,2,3,3a ,4,5,-
5a ,6,7,8,9,9a -d od eca h yd r on a p h t h o[2,1-b]fu r a n
(17).
(s, 3H), 2.11 (s, 3H), 0.88 (s, 3H), 0.87 (s, 3H), 0.84 (s, 3H); 13
C
p-TsOH‚H2O (61.7 mg, 0.324 mmol) was added to epoxide
alcohol 13 (430 mg, 1.35 mmol) in MeNO2 (26 mL) at -20 °C
under N2. The reaction mixture was stirred at -20 °C for 1 h
and then poured into a 0.1 N NaOH solution (20 mL). The
mixture was extracted with CH2Cl2, and the organic solution
was washed with brine, dried (Na2SO4), and concentrated in
vacuo to afford a 60:40 ratio of crude 16 (faster moving
diasteromer) and 17 (slower moving diastereomer). Chroma-
tography on silica gel (30 g, 230-400 mesh) eluting with 10%
ethyl acetate-hexanes (700 mL) gave 248 mg (58%) of 16 and
150 mg (35%) of 17. For 16: mp 84.5-85.6 °C (direct from
column); 1H NMR (CDCl3, 500 MHz) δ 7.38 (m, 2H, H15, H16),
6.39 (dd, 1H, H14, J ) 0.92, 1.4 Hz), 4.90 (dd, 1H, H12, J ) 6.6,
9.8 Hz), 3.38 (d, 1H, H17, J ) 11.0 Hz), 3.34 (d, 1H, H17, J )
11.0 Hz), 2.20 (4 line ddd, 1H, H11eq, J ) 6.5, 13.5 Hz), 2.01
(m, 2H, H11ax, H7eq), ∼1.75 (H9), ∼1.70 (H7ax), ∼1.66 (H1eq), and
OH [overlapping m, 4H], ∼1.54 (H6eq), ∼1.52 (H2ax), and ∼1.49
NMR (CDCl3, 50 Hz) δ 171.1 (C-15), 169.3 (OAc), 169.0 (OAc),
168.6 (C-13), 116.9 (C-14), 92.2 (C-16), 82.4 (C-8), 74.0 (C-12),
65.3 (C-17), 61.8 (C-9), 57.2 (C-5), 42.2 (C-3), 39.9 (C-1), 36.3
(C-10), 35.0 (C-7), 33.4 (C-18), 33.1 (C-3), 29.1 (C-11), 21.0 (CH3-
CO), 20.9 (C-19), 20.7 (CH3CO), 20.4 (C-6), 18.3 (C-2), 15.8 (C-
20). The 13C NMR spectrum of 18a was identical to the
spectrum of the known diacetate1 derived from diacylation of
natural 1a or acylation of 2a . For 18b: 1H NMR (CDCl3) δ
6.99 (s, 1H), 6.10 (br dd, 1H, J ) 0.9, 2.0 Hz), 4.83 (m, 1H),
4.45 (d, 1H, J ) 11.9 Hz), 3.70 (d, 1H, J ) 11.9 Hz), 2.17 (s,
3H), 2.11 (s, 3H), 2.08-2.24 (m, 1H), 0.89 (s, 3H), 0.87 (s, 3H),
0.84 (s, 3H); 13C NMR (CDCl3, 50 MHz) δ 171.0, 169.4, 168.9,
117.3, 93.1, 82.2, 73.8, 65.2, 61.6, 57.2, 42.2, 39.9, 36.3, 35.0,
33.4, 33.1, 29.1, 21.0, 21.0, 20.8, 20.4, 18.3, 15.74; HRMS calcd
for C24H34O7 (M - H)+ 433.2226, found 433.2225.
(1S,3R,3a R,5a S,9a S)-1-(3-F u r yl)-3a -(a cet oxym et h yl)-
6,6,9a -t r im et h yl-1,2,3,3a ,4,5,5a ,6,7,8,9,9a -d od eca h yd r o-
n a p h th o[2,1-b]fu r a n (19). Acetic anhydride (48.1 mg, 0.472
mmol) in dry pyridine (0.2 mL) was added to 14 (100 mg, 0.314
mmol) and 4-DMAP (38.3 mg, 0.314 mmol) in dry pyridine (0.8
mL) at rt. The reaction mixture was stirred for 24 h, and the
pyridine was removed in vacuo. The resulting mixture was
chromatographed on silica gel (6 g, 200-425 mesh, pH ) 7);
eluting with 3% ethyl acetate-hexanes gave 109 mg (96%) of
a colorless thick oil, which after standing at rt for several days
solidified to give 19: mp 66.0-67.0 °C (from column); 1H NMR
(CDCl3) δ 7.36 (m, 2H), 6.32 (s, 1H), 5.06 (dd, 1H, J ) 8.0,
10.7 Hz), 4.37 (d, 1H, J ) 11.6 Hz), 3.82 (d, 1H, J ) 11.6 Hz),
(H6ax) [overlapping m, 3H], ∼1.43 (H3eq), and ∼1.41 (H2eq
)
[overlapping m, 2H], 1.15 (dt, 1H, H3ax, J ) 3.5, 13.3 Hz), 1.03
(s, 3H, 20-Me), 0.95 (H1ax), 0.91 (s, 19-Me), 0.89 (H5ax) and 0.87
(s, 18-Me) [8H]; 13C NMR (CDCl3, 125.7 MHz) δ 143.55 (C-
15), 138.96 (C-16), 127.91 (C-13), 108.79 (C-14), 85.22 (C-8),
72.38 (C-12), 70.26 (C-17), 55.07 (C-9), 49.85 (C-5), 42.39 (C-
1), 42.14 (C-3), 36.11 (C-10), 34.94 (C-11), 33.26 (C-4), 33.13
(C-18), 28.93 (C-7), 21.78 (C-19), 18.43 (C-2), 17.82 (C-6), 16.15
(C-20). Anal. Calcd for C20H30O3: C, 75.43; H, 9.50. Found:
C, 75.11; H, 9.41. For 17: 1H NMR (CDCl3, 600 MHz) δ 7.39
(s, 1H, H15), 7.37 (s, 1H, H16), 6.34 (s, 1H, H14), 5.10 (dd, 1H,
H
12, J ) 2.2, 9.3 Hz), 3.55 (s, 2H, H17), 2.39 (dt, 1H, H7eq, J )

Synthesis of Acuminolide and 17-O-Acetylacuminolide
J . Org. Chem., Vol. 63, No. 4, 1998 1161
2.21 (m, 2H), 2.04 (s, 3H), 1.01-1.93 (m, 12H), 0.89 (s), 0.87
(s), and 0.83 (s) [9H]; 13C NMR (CDCl3, 50 MHz, 77.00) δ
171.45, 143.15, 138.43, 128.85, 108.64, 81.14, 73.68, 65.67,
61.97, 57.23, 42.28, 39.90, 36.20, 35.23, 33.42, 33.10, 30.88,
20.98, 20.37, 18.44, 15.87. Anal. Calcd for C22H32O4: C, 73.30;
H, 8.95. Found: C, 73.09; H, 9.11.
overnight at rt. The solvent was removed in vacuo, and
chromatography of the residue on silica gel (6 g, 200-425
mesh, pH ) 7) eluting with 7% ethyl acetate-hexanes gave
16.9 mg (60%) of 18a and 9.1 mg (32%) of 18b. The 13C NMR
spectrum of the faster moving diastereomer 18a was identical
to the 13C NMR spectrum of the known diacetate1 of 1a . The
13C NMR spectrum of the slower moving diastereomer 18b was
identical to the 13C NMR spectrum derived from diacylation
of 1b. Integration of the resonance signals at δ 6.99 and 6.88
in the crude reaction mixture gave an approximate 66:34 ratio
of 18a and 18b.
17-O-Acetyla cu m in olid e (2a ) a n d 17-O-Acetyl-16-epi-
a cu m in olid e (2b). A mixture of furan 19 (78.0 mg, 0.217
mmol), ethyldiisopropylamine (280 mg, 2.17 mmol), and rose
bengal (2 mg) in dry CH2Cl2 (8 mL) was cooled to -78 °C while
a stream of dry O2 was passed through the solution. The
reaction mixture was irradiated with a 200 W tungsten lamp
placed 10 cm from the reaction vessel for 5 h at -78 °C, allowed
to warm to rt after removal of the reaction tube from the -78
°C bath, and then allowed to stand at rt for an additional 30
min. The solvent was removed in vacuo, and chromatography
on silica gel (8 g, 200-425 mesh, pH ) 7) eluting with 50%
ethyl acetate-hexanes gave 73.7 mg (87%) of an approximate
66:34 inseparable mixture of 2a and 2b: mp 212.1-213.2 °C
(MeOH); 1H NMR (CDCl3) δ 6.11 (s, 1H), 6.06 (br s, 1H), 4.93
(m, 1H), 4.46 (d, 1H, J ) 11.8 Hz), 3.73 (d, 1H, J ) 11.8 Hz),
2.17-2.29 (m, 2H), 2.11 (s, 3H), 0.89 (s, 3H), 0.87 (s, 3H), 0.84
(s, 3H); 13C NMR (CDCl3, 50 MHz) δ 171.3, 170.3, 169.3, 116.9,
98.0, 82.4, 74.4, 65.1, 61.6, 57.1, 42.2, 39.8, 36.3, 34.9, 33.4,
33.1, 28.7, 21.0, 20.9, 20.3, 18.3, 15.8. The ratio of 2a and 2b
was determined indirectly from the corresponding diacetates
18a and 18b.
Ack n ow led gm en t. We are indebted to the donors
of the Petroleum Research Fund, administered by the
American Chemical Society, for partial support of this
research. One of us (H.F.) would like to thank the
Burroughs Wellcome Foundation for a research fellow-
ship. The Duke University NMR Spectroscopy Center
was established with grants from the NIH, the NSF,
and the North Carolina Biotechnology Center, which are
gratefully acknowledged. We are also grateful to Prof.
A. Douglas Kinghorn for the 13C NMR spectrum of 17-
O-acetylacuminolide.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of 10, 11, 17, and 18b (8 pages). This material
is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any
current masthead page for ordering information.
16-O-17-O-Dia cetyla cu m in olid e (18a ) a n d 16-O-17-O-
Dia cetyl-16-epi-a cu m in olid e (18b). F r om 2a a n d 2b.
Acetic anhydride (10.0 mg, 0.098 mmol) in pyridine (0.5 mL)
was added to a solution of hydroxy acetates 2a and 2b (25.6
mg, 0.0653 mmol) and 4-DMAP (8.0 mg, 0.065 mmol) in
pyridine (0.5 mL), and the reaction mixture was stirred
J O971631N