A Total Synthesis of the Racemic Sesquiterpene Parvifoline

Article abstract of DOI:10.1021/jo972092p

A total synthesis of the sesquiterpene (±)-parvifoline 1 from the symmetrical naphthalene 4 is reported. The key step of the synthesis was a Stork-Landesman two-carbon ring expansion of β-tetralone 5, which affords 9a with the complete framework of the target. Although many reactions are involved in the sequence, the whole synthesis can be executed in only five synthetic operations and in ≈18% overall yield.

Full text of DOI:10.1021/jo972092p

2918
J . Org. Chem. 1998, 63, 2918-2921
A Tota l Syn th esis of th e Ra cem ic Sesqu iter p en e P a r vifolin e†
Adria´n Covarrubias-Zu´n˜iga, Fernando Cantu´, and Luis A. Maldonado*
Instituto de Quı´mica and Divisio´n de Estudios de Posgrado, Facultad de Qu´ımica, Universidad Nacional
Auto´noma de Me´xico, Circuito Exterior, Ciudad Universitaria, Coyoaca´n 04510, Me´xico D. F., Me´xico
Received November 14, 1997
A total synthesis of the sesquiterpene (()-parvifoline 1 from the symmetrical naphthalene 4 is
reported. The key step of the synthesis was a Stork-Landesman two-carbon ring expansion of
â-tetralone 5, which affords 9a with the complete framework of the target. Although many reactions
are involved in the sequence, the whole synthesis can be executed in only five synthetic operations
and in ≈18% overall yield.
Sch em e 1
The benzocyclooctene parvifoline (1) is a phenolic
sesquiterpene isolated from Coreopsis parvifolia, Pereziae
carpholepsis, Pereziae alamani var. oolepis, and Pereziae
longifolia Blake.1 Its structure was proposed from
spectral data1a and the absolute configuration established
by conversion (via isoparvifoline 2) to curcuquinone (3),
a natural product of known absolute configuration2
(Scheme 1).
It has been suggested that 1 is formed biogenetically,
by cyclization of an activated phenolic bisabolene precur-
sor such as a hydroxylated xanthorrizol, although its
attempted synthesis along this biomimetically modeled
route failed.3 To our knowledge, two total syntheses of
1 have been described, one in which the cyclooctane ring
was constructed by a Dieckmann-type intramolecular
cyclization of an ester sulfone4 and the other employing
a Grob fragmentation of a bicyclo[3.3.0]octane γ-hy-
droxymesylate.5 In both cases, a product with a C14
skeleton was obtained which was conveniently handled
to introduce the lacking CH3 group.
Sch em e 2
In this paper we wish to report another Grob fragmen-
tation-based total synthesis of 16 which has as the salient
features: (1) the starting material contains 80% (C12) of
the carbon atoms of the target skeleton and is readily
available, (2) in the cyclooctene ring formation, the
complete framework of 1 is delivered, and (3) though it
involves 12 chemical steps, it can be executed in only five
synthetic operations.
ring expansion7). From the recognition of this system in
the B ring of 1, it follows that by appropriate substitution
in the starting cyclohexanone a simple synthesis of 1 via
the Stork-Landesman two-carbon ring expansion would
be at hand.8 Our retrosynthetic analysis is depicted in
Scheme 2.
â-Tetralone 5 was easily obtained from the known
symmetrical naphthalene 49 by Na/EtOH reduction,
followed by acid-catalyzed hydrolysis of the intermediate
enol ether in 95% yield (Scheme 3). Due to the sensitive
nature of the intermediates involved in the Stork-
Landesman ring expansion sequence (as has been re-
ported for other substrates10), the conversion 5 f 9a was
first attempted without the isolation of intermediates.
By careful spectroscopic monitoring of the reaction steps,
Cyclohexanones can be converted into 4-cyclooctene
carboxylic acids via Grob fragmentation of a bicyclo[3.3.1]-
nonane intermediate (the Stork-Landesman two-carbon
† Contribution no. 1635 of Instituto de Qu´ımica, UNAM.
(1) (a) Bohlmann, F.; Zdero, Ch. Chem. Ber. 1977, 110, 468. (b)
J oseph-Nathan, P.; Herna´ndez, J . D.; Roma´n, L. U.; Garc´ıa, E.;
Mendoza, V. Phytochemistry 1982, 21, 669. (c) J oseph-Nathan, P.;
Herna´ndez, J . D.; Roma´n, L. U.; Garc´ıa, E.; Mendoza, V.; Mendoza, S.
Phytochemistry 1982, 21, 1129. (d) Garc´ıa, E.; Mendoza, V.; Guzma´n,
J . A. J . Nat. Prod. 1988, 51, 150.
(2) (a) Garc´ıa, E.; Mendoza, V.; Guzma´n, J . A. J . Nat. Prod. 1987,
50, 1055. (b) J oseph-Nathan, P.; Herna´ndez-Medel, M. del R.; Mart´ınez,
E.; Rojas-Gardida, M.; Cerda, C. M. J . Nat. Prod. 1988, 51, 675.
(3) Krause, W.; Bohlmann, F. Tetrahedron Lett. 1987, 28, 2575.
(4) Grimm, E. L.; Levac, S.; Coutu, M. L. Tetrahedron Lett. 1994,
35, 5369.
(5) (a) Villago´mez-Ibarra, R.; J oseph-Nathan, P. Tetrahedron Lett.
1994, 35, 4771. (b) Villago´mez-Ibarra, R.; Alvarez-Cisneros, C.; J oseph-
Nathan, P. Tetrahedron 1995, 51, 9285.
(7) (a) Stork, G.; Landesman, H. K. J . Am. Chem. Soc. 1956, 78,
5129. (b) Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis;
Wiley: New York, 1967; Vol. 1, p 555.
(8) For a review on the syntheses of cyclooctanes, which includes
fragmentation reactions of bicyclic systems, see: Petasis, N. A.; Patane,
M. A. Tetrahedron 1992, 48, 5757.
(9) J ohansson, A. M.; Mellin, Ch.; Hacksell, U. J . Org. Chem. 1986,
51, 5252.
(10) For a reference in which a bicyclo[3.3.1]nonane pyrrolidinoke-
tone closely related to 7 was isolated, but not characterized, see:
Mitsuhashi, K.; Shiotani, S. Chem. Pharm. Bull. 1970, 18, 75.
(6) Covarrubias, A.; Maldonado, L. A. 4th Chemical Congress of
North America 1991, Abs. Org. 176.
S0022-3263(97)02092-6 CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/14/1998

A Total Synthesis of Parvifoline
J . Org. Chem., Vol. 63, No. 9, 1998 2919
Sch em e 3
Sch em e 4
reaction conditions, the isomeric derived mesylate 11b
from the axial ketol 11a gave also carboxylic acid 9a but
only in 41% yield.16
1
At this point, it was gratifying to find that the H NMR
spectrum of 9a matched very closely with that of parvi-
foline methyl ether 13, with the exception of the chemical
shift and splitting pattern of the benzylic methine. Thus,
the CO2H substituent in 9a induces a low field shift of
the CH signal as compared with 13 and is seen at δ 4.11
as a doublet of doublets (J ) 4.8, 13.5) due to coupling
with the vicinal CH2. In 13, the benzylic CH is observed
as a complex signal (additional coupling with the CH3
substituent) at δ 3.20. The structure of 9a was confirmed
later unambiguously, by single-crystal X-ray analysis.17
For practical purposes, the â-tetralone 5 could be
converted into 9a by consecutive (1) enamine formation
(pyrrolidine, C6H6, reflux with H2O separator), (2) treat-
ment of a dioxane solution of crude 6 with 3 equiv of
acrolein, (3) shaking of the ethereal solution of crude 7
with 10% aqueous HCl, (4) after column chromatography
purification, mesylation of the mixture of ketols 10a and
11a (1.3 equiv of MsCl, Et3N, CH2Cl2, 0 °C, 1.5 h), and
(5) fragmentation of the derived mesylates 10b and 11b
with 15% aqueous NaOH solution. In this way, consis-
tent yields of 9a were obtained in ≈40% overall yield from
5.
In completing the synthesis of 1, the apparently trivial
CO2H f CH3 conversion was not an uncomplicated event.
Thus, LiAlH4 reduction of both carboxylic acid 9a , as well
as its derived methyl ester 9b (CH2N2, Et2O), gave
appreciable amounts of overreduced (saturated) products.
Since transannular reactions in the cyclooctane ring are
common,18 very probably intramolecular hydroalumina-
tion from an alkoxy organoaluminum hydride intermedi-
ate explains this unusual reduction of an isolated CdC
double bond.
we could tentatively identify the following: enamine 6
[IR 1610 cm-1 (CdCN), no absorption for CdO], bridged
amino ketone 711 [IR 1715 cm-1 (CdO); 1H NMR (CDCl3)
δ ppm 1.15 (s, CCH3)], and the quaternary ammonium
salt 8 [1H NMR (CDCl3) δ 3.56 (s, N+CH3)]. However,
treatment of 8 with 15% aqueous NaOH solution to
induce cleavage of the bicyclo[3.3.1]nonane ring system
gave only traces of acidic material; the main product was
extracted into the organic solvent from the original
alkaline solution and identified as impure 7.11
Since NaOH apparently induced the N-demethylation
of 8 to give back amino ketone 7,12 an alternative plan
became necessary. Mild acid treatment of 7 gave a
mixture of ketols13 that could be separated by column
chromatography and characterized by spectroscopy and
(in the case of 11a ) by single-crystal X-ray analysis14 as
the equatorial and axial isomers 10a and 11a in a 3:2
ratio (57% combined yield, Scheme 4). The MS (EI)
spectra of the ketols are also in accord with the assigned
structures, since an important (41% of relative intensity)
M+ - 18 peak is observed in the axial isomer, but is
almost absent (10%) in the equatorial isomer.
As expected from stereoelectronic considerations, the
mesylate 10b derived from the equatorial ketol 10a , upon
treatment with refluxing 15% aqueous NaOH solution15
under a N2 atmosphere, gave cleanly (82% yield) the
benzocyclooctene carboxylic acid 9a . Under the same
Fortunately, this undesirable side reaction could be
avoided by NaBH4 reduction of either the methyl ester
9b in t-BuOH-MeOH19 or the mixed ethyl carbonic
anhydride 9c (prepared in situ from 9a with ClCO2Et
(11) Although isolated in ≈90% yield, crude 7 was unstable on
attempted purification by column chromatography. The complete 1H
NMR data for the crude product is (CDCl3) δ 1.15 (s, 3H), 2.15 (s, 3H),
3.78 (s, 3H), 6.35 (s, 1H), 6.78 (s, 3H). The aliphatic CH2 and CH
protons are shown in the range of δ ≈1.0-4.0.
(12) As a referee has pointed out, since the conversion 7 f 8 was
followed only by TLC, an incomplete N-methylation reaction can also
(partially) explain the observed results.
(16) Low-polarity compounds (unidentified) were also formed in this
experiment. The successful (although modest yielding) formation of
carboxylic acid 9a from the axial isomer 11a , very probably involves a
nonconcerted carbonium ion initiated fragmentation. The alternative,
concerted fragmentation of mesylate 11b from a boat ring C conforma-
tion is ruled out, since a strained (E)-cyclooctene double bond should
be obtained.
(17) Soriano-Garc´ıa, M.; Villena Iribe, R.; Covarrubias, A.; Cantu´,
F.; Maldonado, L. A. Anal. Sci. 1993, 9, 439.
(18) Harrowven, D. C.; Pattenden, G. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford,
1991; Vol. 3 pp 379-385 and references therein.
(19) Soai, K.; Oyamada, H.; Takase, M.; Ookawa, A. Bull. Chem.
Soc. J pn. 1984, 57, 1948.
(13) Aqueous acid treatment of bridged â-amino ketones gives
bridged ketols by a reaction mechanism involving (1) acid-catalyzed
opening of the bridged system, (2) hydrolysis of the immonium salt
intermediate, and (3) acid-catalyzed aldol recyclization of the 1,5-keto
aldehyde. See, for instance: (a) Allan, R. D.; Cordiner, B. G.; Wells, R.
J . Tetrahedron Lett. 1968, 6055. (b) Momose, T.; Kinoshita, M.;
Imanishi, T. Heterocycles 1979, 12, 243. (c) Boucher, R. J .; Campbell,
M. M.; Rae, D. Tetrahedron 1990, 46, 6839.
(14) Soriano-Garc´ıa, M.; Villena, R.; Covarrubias, A.; Olguin, J . S.;
Maldonado, L. A. Acta Crystallogr. 1993, C49, 2140.
(15) Hendrickson, J . B.; Boeckman, R. K., J r. J . Am. Chem. Soc.
1971, 93, 1307.

2920 J . Org. Chem., Vol. 63, No. 9, 1998
Covarrubias-Zu´n˜iga et al.
10-(eq u a t or ia l a n d a xia l)-H yd r oxy-40-m et h oxy-5,9-
d im eth yltr icyclo[7.3.1.02,7]tr id ec-2,4,6-tr ien e-13-on e (10a
a n d 11a ). A mixture of 5 (5.50 g, 0.027 mol) and pyrrolidine
(5 mL, 0.058 mol) in benzene (75 mL) was refluxed under a
water separator for 2.25 h. After removal of solvent and excess
pyrrolidine in vacuo, the crude crystalline enamine was
dissolved in dioxane (45 mL). To this solution was added
freshly distilled acrolein (2.0 g, 0.0357 mol) in dioxane (5 mL)
with ice cooling and stirring; the cooling bath was removed
and stirring was continued for 12 h at room temperature. After
evaporation of the solvent, the residual syrup was dissolved
in ether (100 mL). The ethereal extract was washed with 50
mL each of 10% aqueous HCl and water, dried over Na2SO4,
filtered, and concentrated to give 4.70 g of residue which was
purified by column chromatography with ethyl acetate/hexanes
1:6 as eluent to give 2.25 g of ketol 10a (equatorial isomer)
and 1.73 g of ketol 11a (axial isomer) in 57% combined yield.
Sch em e 5
and Et3N in dry THF) in THF-H2O. The primary alcohol
12 was thus obtained in 87 and 78% yields, respectively
(Scheme 5).
10a (equ a tor ia l isom er ): IR (neat) 3450, 1715 cm-1 1H
;
NMR δ 1.17 (s, 3H), 1.50-1.90 (m, 4H), 2.05-2.20 (m, 1H),
2.13 (s, 3H), 3.45 (t, 1H, J ) 3.3), 3.63 (br d, 1H, J ) 6), 2.60
and 3.55 (AB system, 2H, J ) 16.8), 3.79 (s, 3H), 6.37 (s, 1H),
6.86 (s, 1H); 13C NMR δ 15.87, 19.97, 26.89, 31.14, 37.16, 51.26,
52.70, 55.42, 78.66, 108.76, 125.23, 127.23, 129.09, 136.25,
156.79, 213.57; MS m/z (relative intensity) 260 (M+, 100), 216
(88), 203 (95), 188 (45); HRMS calcd for C16H20O3 260.1412,
found 260.1395. Anal. Calcd for C16H20O3: C, 73.84; H, 7.69.
Found: C, 73.92; H, 7.76.
11a (a xia l isom er ): mp 164.5-166.5 °C; IR (KBr) 3400,
1710 cm-1; 1H NMR δ 1.21 (s, 3H), 1.63 (dm, 1H, J ) 14), 1.75-
1.95 (m, 3H), 2.17 (s, 3H), 2.48 (tt, 1H, J ) 4, 13), 2.95 and
3.15 (AB system, 2H, J ) 17.4), 3.46 (br t, 1H, J ) 3.3), 3.80
(s, 3H), 4.00 (br dd, 1H, J ) 2.7, 2.4), 6.41 (s, 1H), 6.83 (s,
1H); 13C NMR δ 15.84, 19.73, 25.64, 31.66, 43.14, 50.73, 53.39,
55.38, 81.69, 108.87, 125.68, 126.29, 128.88, 136.79,156.78,
213.91; MS m/z (relative intensity) 260 (M+, 62), 242 (41), 203
(43), 186 (100); HRMS calcd for C16H20O3 260.1412, found
Mesylation of alcohol 12 (1.3 equiv of MsCl, Et3N, CH2-
Cl2), followed by reduction of the crude mesylate with
LiEt3BH gave racemic 13 in 55% overall yield. The
synthetic material was spectroscopically identical with
an authentic sample prepared (Me2SO4, K2CO3, Me2CO)
from natural 1.20 Finally, cleavage of the methyl ether
in 13 with EtSLi in dry DMF (105 °C, 48 h) gave racemic
1 (97%) whose spectroscopic properties were identical
with those reported for the natural product.20
Since the easily obtained carboxylic acid 9a should be
amenable to enantiomeric resolution, a total synthesis
of natural 1 by the approach described in this paper is
in principle conceivable. Work along this way is being
pursued at present in our laboratory and will be reported
in due course.
260.1397. Anal. Calcd for
Found: C, 73.89; H, 7.73.
C16H20O3: C, 73.84; H, 7.69.
Exp er im en ta l Section
10-Ca r boxy-5,8,9,10-tetr a h yd r o-2-m eth oxy-3,6-d im eth -
ylben zocycloocten e (9a ). To a mixture of 10a (0.18 g, 0.69
mmol) and anhydrous Et3N (0.15 mL, 1.04 mmol) in dry CH2-
Cl2 (10 mL) was added MsCl (0.10 mL, 0.865 mmol). The
solution was stirred at 25 °C for 1.5 h and then poured into
ice-water (20 mL) and extracted with ether. Drying, filtra-
tion, and concentration of the ether layer gave a residue which
was boiled for 2.5 h with 15% aqueous NaOH solution (10 mL)
under a N2 atmosphere. The reaction mixture was poured into
ice-water (20 mL) and extracted with ether. The aqueous
layer was acidified with 15% HCl solution to pH 3, extracted
with ether, washed with water, and dried (Na2SO4). Concen-
tration of the ether layer gave a solid residue which was
recrystallized from ethyl acetate/hexanes to afford 148 mg
(82%) of 9a .
Melting points are uncorrected. Thin-layer chromatography
was performed on silica gel 60 F254 plates and visualized by
UV irradiation; column chromatography purifications were
carried out using silica gel (70-230 mesh). 1H NMR spectra
were recorded at either 200 or 300 MHz, while 13C NMR were
run at 75 MHz. Low- and high-resolution mass spectra were
measured at 70 eV (EI). Elemental analyses were performed
by Galbraith Laboratories, Inc.
1,4-Dih yd r o-2,7-d im et h oxy-3,6-d im et h yln a p h t h a len e
(4a ) was prepared as indicated in ref 9 for the synthesis of
other 1,4-dihydronaphthalenes: mp 103-105 °C; yield 95%;
1H NMR δ 1.59 (s, 3H), 2.01 (s, 3H), 3.05-3.18 (m, 2H), 3.24-
3.42 (m, 2H), 3.43 (s, 3H), 3.63 (s, 3H), 6.40 (s, 1H), 6.72 (s,
1H); 13C NMR δ 14.98, 15.82, 29.56, 35.03, 55.30, 56.50, 109.27,
112.38, 124.58, 125.33, 129.83, 131.85, 145.21, 155.92; MS m/z
(relative intensity) 218 (M+, 72), 203 (43), 187 (100), 172 (38);
HRMS calcd for C14H18O2 218.1307, found 218.1303. Anal.
Calcd for C14H18O2: C, 77.06; H, 8,25. Found: C, 76.87; H,
8.12.
1
9a : mp 155-156 °C; IR (KBr) 3500, 1705 cm-1; H NMR δ
1.76 (s, 3H), 1.85-2.10 (m, 4H), 2.16 (s, 3H), 3.15 and 3.55
(AB system, 2H, J ) 18.3), 3.76 (s, 3H), 4.11 (dd, 1H, J ) 4.8,
13.5), 5.36 (br t, 1H, J ) 7.8), 6.69 (s, 1H), 6.93 (s, 1H), 9.80
(br signal, 1H, exchanges with D2O); 13C NMR δ 15.70, 22.28,
26.33, 32.89, 41.40, 46.15, 55.47, 108.21, 122.86, 125.08,
130.41, 132.22, 135.45, 138.07, 157.22, 180.15; MS m/z (relative
intensity) 260 (M+, 100), 245 (13), 215 (45), 173 (33); HRMS
calcd for C16H20O3 260.1412, found 260.1406. Anal. Calcd for
7-Meth oxy-3,6-d im eth yl-2-tetr a lon e (5) was prepared by
the same procedure of ref 9 for the synthesis of other tetra-
lones: mp 84-85 °C; yield quantitative; IR (KBr) 1708 cm-1
;
1H NMR δ 1.18 (d, 3H, J ) 6.9), 2.19 (s, 3H), 2.45-2.62 (m,
1H), 2.73 (dd, 1H, J ) 15.1, 10.7), 3.00 (dd, 1H, J ) 15.2, 5.7),
3.55 (s, 2H), 3.80 (s, 3H), 6.55 (s, 1H), 6.95 (s, 1H); 13C NMR
δ 14.90, 15.72, 36.12, 42.81, 43.96, 55.42, 109.67, 124.97,
127.48, 130.02, 131.57, 156.65, 212.05; MS m/z (relative
intensity) 204 (M+, 86), 175 (11), 161 (21), 148 (100); HRMS
calcd for C13H16O2 204.1150, found 204.1156. Anal. Calcd for
C
16H20O3: C, 73.84; H, 7.69. Found: C, 73.95; H, 7.76.
5,8,9,10-Tetr a h yd r o-10-h yd r oxym eth yl-2-m eth oxy-3,6-
d im eth ylben zocycloocten e (12). (a ) F r om 9b. A solution
of 9a (0.956 g, 3.68 mmol) in dry Et2O (25 mL) cooled in an
ice bath was treated with an ethereal solution of CH2N2
(prepared from 1.136 g, 0.011 mol, of N-nitroso-N-methylurea).
After allowing the mixture to stand for 2 h in the cooling bath,
excess CH2N2 was destroyed by dropwise addition of AcOH
(0.3 mL), the volatiles were removed in vacuo, and crude 9b
was kept at 50 °C for 1 h under reduced pressure (0.1 Torr).
C
13H16O2: C, 76.47; H, 7.84. Found: C, 76.40; H, 7.95.
(20) We thank M. Sc. J ose´ Agust´ın Guzma´n, Instituto de Investi-
gaciones Qu´ımico Biolo´gicas, Universidad Michoacana de San Nicola´s
Hidalgo, Morelia, Michoaca´n, Me´xico, for a generous gift of natural 1
and related spectral data.
To a refluxing mixture of crude methyl ester 9b (3.68 mmol)
and NaBH4 (0.35 g, 9.26 mmol) in dry t-BuOH (20 mL) was

A Total Synthesis of Parvifoline
J . Org. Chem., Vol. 63, No. 9, 1998 2921
added dry MeOH (2.9 mL) over a period of 1 h. The addition
of a fresh portion of NaBH4 and the slow addition of dry MeOH
were repeated twice, and the reflux was continued for an
additional 1 h (the total amounts of NaBH4 and MeOH were
1.05 g (27.78 mmol) and 7.8 mL, respectively). The reaction
mixture was cooled, water was added to quench the reaction,
and the MeOH and t-BuOH were removed under reduced
pressure. After extracting with ether, the combined extracts
were dried (Na2SO4), and the ether was evaporated. The
residue was purified by column chromatography using ethyl
acetate/hexanes (0.5:9.5) as eluent and 12 (0.79 g) was obtained
in 87% yield.
(b) F r om 9c. To acid 9a (0.1 g, 0.384 mmol) in dry THF (2
mL) and Et3N (0.06 mL, 0.403 mmol), cooled in an ice bath,
was added with stirring ClCO2Et (0.05 mL, 0.403 mmol). After
15 min the cooling bath was removed and stirring was
continued for 45 min at room temperature. The suspension
was filtered off and washed with dry THF (5 mL) and the
combined THF solution was added dropwise over a period of
30 min to a stirred solution of NaBH4 (0.0364 g, 0.963 mmol)
in H2O (0.4 mL) at room temperature. After 3.5 h the reaction
mixture was acidified with 5% HCl to pH 2, extracted with
ether, washed with brine, dried (Na2SO4), and evaporated. The
oily residue was purified by column chromatography using
ethyl acetate/hexanes (0.5:9.5) as eluent to give pure 12 (73.4
mg, 78%).
25 °C for 2.5 h and then poured into water (10 mL) and
extracted with ether. The ether extract was dried (Na2SO4),
filtered, and concentrated to give a residue which was dissolved
under a N2 atmosphere in dry THF (5 mL) and cooled in an
ice bath. To this solution was added a 0.98 M solution of
LiBHEt3 in THF (1.05 mL, 1.03 mmol). The reaction mixture
was stirred for 10 h at 25 °C, poured into ice-water (10 mL),
and extracted with ether. Drying, filtration, and concentration
of the organic layer gave an oily residue which was purified
by column chromatography using ethyl acetate/hexanes (0.5:
9.5) as eluent. 13 (44 mg) was obtained in 55% yield.
13: The synthetic material was spectroscopically identical
with an authentic sample prepared (Me2SO4, K2CO3, Me2CO)
from natural 1.5,20
5 ,8 ,9 ,1 0 -T e t r a h y d r o -3 ,6 ,1 0 -t r i m e t h y l b e n z o c y -
cloocten e [(()-P a r vifolin e] (1). To a solution of EtSLi,
prepared by addition of n-BuLi (1.6 M in hexanes, 16 mmol,
10 mL) to a mixture of EtSH (3 mL, 39 mmol) and dry DMF
(10 mL) at -78 °C, was added 13 (186 mg, 0.81 mmol) in DMF
(5 mL). The mixture was stirred at 105 °C for 48 h, cooled to
room temperature, poured into dilute HCl (20 mL), and
extracted with EtOAc. After drying (Na2SO4), filtration, and
concentration of the organic layer, the crude product was
purified by column chromatography using ethyl acetate/
hexanes (0.5:9.5) as eluent. 1 (0.17 g) was obtained in 97%
yield, identical with the reported data for the natural prod-
uct.1,21
12: IR (neat) 3350 cm-1; 1H NMR δ 1.40-2.00 (m, 5H), 1.70
(s, 3H), 2.20 (s, 3H), 3.05-3.35 (X part of a ABX system, 1H),
3.15 and 3.50 (AB system, 2H, J ) 18), 3.80 (s, 3H), 3.70-
4.05 (AB part of a ABX system, 2H), 5.35 (br t, 1H, J ) 7),
6.60 (s, 1H), 6.90 (s, 1H); 13C NMR δ 15.73, 22.24, 26.35, 32.84,
38.79, 41.37, 55.44, 76.61, 108.06, 122.81, 125.00, 130.37,
132.20, 135.43, 138.04, 157.15; MS m/z (relative intensity) 246
(M+, 1), 55 (35), 43 (100), 41 (32). Anal. Calcd for C15H22O2:
C, 78.04; H, 8.94. Found C, 78.12; H, 8.97.
5,8,9,10-Tetr a h yd r o-2-m eth oxy-3,6,10-tr im eth ylben zo-
cycloocten e [(()-P a r vifolin e Meth yl Eth er ] (13). To
alcohol 12 (0.48 mmol) in dry CH2Cl2 (5 mL) cooled in an ice
bath was added with stirring dry Et3N (0.1 mL, 0.73 mmol)
and MsCl (0.05 mL, 0.61 mmol). The solution was stirred at
Ack n ow led gm en t. We are grateful to Q Alejandrina
Acosta, Q Marisela Gutie´rrez, QFB Graciela Cha´vez,
MC Claudia Contreras, Q Roc´ıo Patin˜o, IQ Luis Velasco,
MC J avier Pe´rez Flores, and MC Rube´n Gavin˜o, for
their assistance in acquiring spectral data. We also
thank a referee for the thorough and critical revision of
our manuscript which made this work readable.
J O972092P
(21) Interestingly, cleavage of 13 with n-BuSNa in dry DMF gave a
7:3 mixture of 1 and 2 (95%).