Total Syntheses of (-)-Methyl Atis-16-en-19-oate, (-)-Methyl Kaur-16-en-19-oate, and (-)-Methyl Trachyloban-19-oate by a Combination of Palladium-Catalyzed Cycloalkenylation and Homoallyl-Homoallyl Radical Rearrangement

Article abstract of DOI:10.1021/jo000142b

Asymmetric total syntheses of (-)-methyl atis-16-en-19-oate (1c), (-)-methyl kaur-16-en-19-oate (2c), and (-)-methyl trachyloban-19-oate (3c) have been achieved by employing a hybrid strategy of palladium-catalyzed cycloalkenylation and homoallyl-homoallyl radical rearrangement. The common synthetic intermediate 5 was prepared from 2-allylcyclohexanone (4) with 98% ee using d'Angelo's asymmetric Michael addition. A series of functional group modifications in 5 via palladium-catalyzed cycloalkenylation led to (+)-14, which had already been prepared by us as racemate. (-)-Methyl atis-16-ene-19-oate (1c) was generated via homoallyl-homoallyl radical rearrangement. On the other hand, Wolff-Kishner reduction of 18 followed by esterification yielded (-)-methyl kaur-16-en-19-oate (2c) together with (-)-methyl trachyloban-19-oate (3c).

Full text of DOI:10.1021/jo000142b

J . Org. Chem. 2000, 65, 4565-4570
4565
Tota l Syn th eses of (-)-Meth yl Atis-16-en -19-oa te, (-)-Meth yl
Ka u r -16-en -19-oa te, a n d (-)-Meth yl Tr a ch yloba n -19-oa te by a
Com bin a tion of P a lla d iu m -Ca ta lyzed Cycloa lk en yla tion a n d
Hom oa llyl-Hom oa llyl Ra d ica l Rea r r a n gem en t
Masahiro Toyota,* Toshihiro Wada, and Masataka Ihara*
Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences,
Tohoku University, Aobayama, Sendai 980-8578, J apan
mihara@mail.pharm.tohoku.ac.jp
Received February 2, 2000
Asymmetric total syntheses of (-)-methyl atis-16-en-19-oate (1c), (-)-methyl kaur-16-en-19-oate
(2c), and (-)-methyl trachyloban-19-oate (3c) have been achieved by employing a hybrid strategy
of palladium-catalyzed cycloalkenylation and homoallyl-homoallyl radical rearrangement. The
common synthetic intermediate 5 was prepared from 2-allylcyclohexanone (4) with 98% ee using
d’Angelo’s asymmetric Michael addition. A series of functional group modifications in 5 via
palladium-catalyzed cycloalkenylation led to (+)-14, which had already been prepared by us as
racemate. (-)-Methyl atis-16-ene-19-oate (1c) was generated via homoallyl-homoallyl radical
rearrangement. On the other hand, Wolff-Kishner reduction of 18 followed by esterification yielded
(-)-methyl kaur-16-en-19-oate (2c) together with (-)-methyl trachyloban-19-oate (3c).
Sch em e 1
1. In tr od u ction
Although diterpenes belonging to atisirene (1a ), kau-
rene (2a ), and trachylobane (3a ) families arise biogeneti-
cally from (-)-copalyl pyrophosphate,1 each family has
a unique tetra- or pentacyclic carbon framework, com-
prising a number of contiguous stereogenic centers, as
shown in Scheme 1.
In our own quest for a diastereoselective avenue
toward tetra- and pentacyclic diterpenoids such as (()-
1c, (()-2c, and (()-3c, we already demonstrated the total
synthesis of these compounds by a combination of pal-
ladium-catalyzed cycloalkenylation and homoallyl-
homoallyl radical rearrangement.2 This success prompted
us to extend the strategy for the syntheses of optically
active 1c, 2c, and 3c via the same key intermediate 14
in the case of racemate.
Sch em e 2
2. Syn th esis of th e Ch ir a l Key In ter m ed ia te (+)-5
Among a number of methodologies for the enantio-
selective construction of quaternary stereogenic center,3
we adopted the asymmetric Michael reaction, developed
by d’Angelo,4 for the following reasons: (i) cyclohexanone
derivatives are easily obtained with high enantioselec-
tivity, (ii) both enantiomers of the chiral auxiliary,
1-phenylethylamine, are commercially available in high
purity and at moderate price, and (iii) the C3 carbon unit
can be introduced in a single step (in the previous
racemate synthesis, the C2 alkyl side chain was homolo-
gated).
We planned an alternative strategy for the synthesis
of chiral 1c, 2c, and 3c as shown in Scheme 2, in which
1,3-transcarbonylation of the chiral keto ester 5 could
give the enone ester 6. Although the present synthetic
strategy is a modification of our racemate synthesis, we
focused on the minimization of purification steps by
chromatography to make this synthesis practically viable.
The synthesis started with the generation of chiral
quaternary center next to the carbonyl group of cyclo-
hexanone by applying asymmetric Michael reaction.
Thus, 2-allylcyclohexanone 45 was condensed with (-)-
(S)-1-phenylethylamine (>98% ee) in the presence of 5
Å molecular sieves in refluxing toluene,6 and the result-
(1) (a) Wenkert, E. Chem. Ind. (London) 1955, 282. (b) Coates, B.
E.; Norton, K. J . Org. Chem. 1971, 36, 3722, and references therein.
(c) Recent syntheses of the atisirene family: Berettoni, M.; Chiara, G.
D.; Iacoangeli, T.; Surdo, P. L.; Bettolo, M.; di Mirabello, L. M.; Nicolini,
L.; Scarpelli, R. Helv. Chim. Acta 1996, 79, 2035 and references therein.
(d) Our own synthetic study: Ihara, M.; Toyota, M.; Fukumoto, K.;
Kametani, T. J . Chem. Soc., Perkin Trans. 1 1986, 2151 and references
therein.
(2) Toyota, M.; Wada, T.; Fukumoto, K.; Ihara, M. J . Am. Chem.
Soc. 1998, 120, 4916.
(3) For a recent review: Corey, E. J .; Gunzman-Perez, A. Angew.
Chem., Int. Ed. Engl. 1998, 37, 389.
(4) A review: d'Angelo. J . D.; Desmaele, D.; Dumas, F.; Guingant,
A. Tetrahedron: Asymmetry 1992, 3, 459, and references therein.
(5) Conia, J . M.; Leydendecker, F. Bull. Soc. Chim. Fr. 1967, 830.
(6) Taguchi, K.; Westheimer, F. H. J . Org. Chem. 1971, 36, 1570.
10.1021/jo000142b CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/28/2000

4566 J . Org. Chem., Vol. 65, No. 15, 2000
Toyota et al.
Sch em e 3
was carried out using catalytic amounts of chromic acid
in the presence of 70% aqueous tert-butyl hydroperoxide
as reoxidant7 to furnish the enone 10 in 64% yield.8
Palladium-catalyzed cycloalkenylation reaction of 10
via the corresponding TBDMS enol ether gave rise to the
bicyclo[3.2.1]octenone 11 (72% overall yield from 10),
which was subjected to stereoselective introduction of
isopropenyl group (88% yield), followed by hydrolysis of
the pivaloate moiety (79% yield) and protection of the
carbonyl group (96% yield), to afford the alcohol 13.
Successive oxidation of 13, Wittig olefination (76% overall
yield from 13) and DIBALH reduction (76% yield) led to
the allylic alcohol (+)-14 (Scheme 4). The spectral data
of synthetic (+)-14 were identical with those of the
racemic compound.2
With an efficient access to (+)-14 and our previous
experience with the transformation of (()-14 into (()-
1c, 2c and 3c, the completion of syntheses of chiral target
natural products seemed imminent. Oxidation of 14 with
MnO2 followed by Wittig olefination provided the tetraene
15 (70% overall yield for 2 steps), which was subjected
to intramolecular Diels-Alder reaction at 200 °C in a
sealed tube to give the cycloadducts (16a and 16b, 70%)
as an 85:15 stereoisomeric mixture. Without separation
of the stereoisomers, the mixture was carbomethoxylated
(82% yield) and then reduced with magnesium in MeOH
to yield the desired ester 17 (63% yield). Subsequent
methylation of 17 and hydrolysis furnished the keto ester
18 (Scheme 5).
ing crude imine was subjected to Michael reaction with
methyl acrylate, followed by hydrolysis with acetic acid
to afford the keto ester 5 in 68% yield. To determine the
ee, the compound 5 was converted to the corresponding
pentafluorophenyl ester 7 by sequential alkaline hydroly-
sis and reesterification with pentafluorophenol in the
presence of 1-ethyl-3-(3′-dimethylaminopropyl)carbodi-
imide hydrochloride and DMAP. The chromatographic
analysis of 7 with chiral HPLC (SUMICHIRAL OA-4600)
showed that the above asymmetric Michael reaction
proceeded in 98% ee (Scheme 3).
With the convenient access to the keto ester 5 secure,
1,3-transcarbonylation of 5 was next investigated as
depicted in Scheme 4. Thus, the compound 5 was reduced
with LiAlH4 followed by treatment with 1 equiv of
pivaloyl chloride. The reaction mixture was quenched
with methanesulfonyl chloride to provide the crude
mesylate 8, which was then heated at 110 °C with 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) without additional
solvents. The desired cyclohexene 9 was eventually
obtained in 78% overall yield. The allylic oxidation of 9
3. Com p letion of Tota l Syn th eses of (-)-Meth yl
Atis-16-en -19-oa te (1c), (-)-Meth yl
Ka u r -16-en -19-oa te (2c), a n d (-)-Meth yl
Tr a ch yloba n -19-oa te (3c)
Transformation of 18 into structurally different natural
products, such as atisirene, kaurene, and trachylobane,
is shown in Scheme 6. First, 18 was reduced with NaBH4
Sch em e 4

Synthesis of (-)-Methyl Atis-16-en-19-oate
J . Org. Chem., Vol. 65, No. 15, 2000 4567
Sch em e 5
drofuran (THF) and dichloromethane (CH2Cl2) were purchased
from Kanto Chemical Co., Inc. Toluene, pyridine, and diiso-
propylamine (i-Pr2NH) were distilled from CaH2. Hexameth-
ylphosphoramide (HMPA) and dimethyl sulfoxide (DMSO)
were distilled from CaH2 under reduced pressure. Benzene
(C6H6) and methanol (MeOH) were distilled under argon
immediately prior to use. Unless otherwise mentioned, materi-
als were obtained from commercial suppliers and used without
further purification. Organic extracts were dried by being
stirred over anhydrous MgSO4, filtered through Celite, and
concentrated under reduced pressure with the aid of a rotary
evaporator. Flash chromatography was carried out using
Merck 60 (230-400 mesh) or Cica 60 (spherical/40-100 µm)
silica gel. Reactions and chromatography fractions were
analyzed employing precoated silica gel 60 F254 plates (Merck).
Compounds were visualized using a ultraviolet lamp (254 nm)
and/or by staining with p-anisaldehyde (in EtOH), phospho-
molybdic acid (in EtOH), or ammonium molybdate (in 10%
H2SO4). IR spectra were recorded as films on NaCl plates
unless otherwise noted. 1H NMR spectra were measured as
CDCl3 solutions at 300 MHz. Chemical shifts are expressed
in ppm downfield from internal tetramethylsilane or relative
internal CHCl3. J values are reported in hertz.
Sch em e 6
to give the alcohols, which were acylated with 1,1′-
thiocarbonyldiimidazole and DMAP. The resulting thio-
imidazolides were subjected to deoxygenation with Bu3-
SnH and AIBN to provide (-)-methyl atis-16-en-19-oate
(1c)9 in 71% yield. On the other hand, Wolff-Kishner
reduction of 18 followed by esterification afforded (-)-
methyl kaur-16-en-19-oate (2c, 59%)9 and (-)-methyl
trachyloban-19-oate (3c, 16%).9 The spectral data (1H
NMR, IR, MS) of synthetic (-)-1c, (-)-2c, and (-)-3c
were identical with those of the racemates synthesized
by us.2
In conclusion, asymmetric total syntheses of atisirane,
kaurane, and trachylobane diterpenes have been achieved
from a common chiral intermediate. Since the common
intermediate was easily obtainable by applying d’Angelo’s
aymmetric Michael reaction with high enantiomeric
excess, the present synthetic route would be suitable for
the other members of atisirene, kaurene, and trachylo-
bane family and also the related diterpene alkaloids.
(+)-Met h yl 3-[(1R)-2-Oxo-1-(2-p r op en yl)cycloh exyl]-
p r op a n oa te (5). A mixture of 2-allylcyclohexanone (4)5 (20.1
g, 145 mmol), (S)-(-)-phenylethylamine (22.0 mL, 172 mmol)
and 5 Å molecular sieves (60 g) in toluene (60 mL) was refluxed
for 20 h, and then cooled to room temperature. [The reaction
was monitored by IR and 1H NMR.] Molecular sieves were
filtered off and toluene was mostly evaporated. To the residue
was added freshly distilled methyl acrylate (20.0 mL, 222
mmol) and the resulting viscous mixture was stirred at room
temperature for a week. After evaporation of excess methyl
acrylate, MeOH (30 mL), water (60 mL) and AcOH (12.0 mL,
210 mmol) were added, and then the resulting mixture was
vigorously stirred at room temperature for 1 h, and saturated
with NaCl. Hexane (100 mL) was added to the reaction
mixture and the layers were separated. The aqueous layer was
extracted with hexane, and the combined organic layers were
washed with 10% HCl, saturated aqueous NaHCO3, and
saturated aqueous NaCl, and then dried. Removal of the
solvent and flash chromatography of the residue on silica gel
with hexanes-EtOAc (9:1 v/v) as an eluent furnished the
Michael adduct 5 (22.2 g, 68% from 4) as a colorless oil. IR
1
1720 and 1715 cm-1. H NMR δ 1.66-1.88 (7H, m), 1.19 (1H,
Exp er im en ta l Section
dd, J ) 5.0 and 10.5), 2.00-2.44 (6H, m), 3.66 (3H, s), 5.02-
5.11 (2H, m) and 5.66 (1H, ddt, J ) 6.5, 10.5 and 15.0). 13C
NMR δ 20.52, 26.85, 28.44, 29.53, 36.00 38.84, 38.98, 50.68,
Gen er a l Meth od s. Unless otherwise noted, all reactions
were performed in oven-dried glassware, sealed with a rubber
septum under an atmosphere of argon. Anhydrous tetrahy-
51.50, 118.37 133.27, 174.01 and 214.18. [R]25 +3.6 (c 3.5,
D
CHCl3). MS m/z 224 (M+). Anal. Calcd for C13H20O3: C, 69.61;
H, 8.99. Found: C, 69.39; H, 9.07.
(7) Muzart, J . Tetrahedron Lett. 1987, 28, 4665.
(-)-P en t a flu or op h en yl 3-[(1R)-2-Oxo-1-(2-p r op en yl)-
cycloh exyl]p r op a n oa te (7). A mixture of the ester 5 (64.5
mg, 0.288 mmol) and lithium hydroxide monohydrate (23.5 mg,
(8) Although the TBDMS analogue of 9 was also synthesized, the
TBDMS group was susceptible to Cr(VI)-catalyzed allylic oxidation.
(9) Pyrek, J . S. Tetrahedron 1970, 26, 5029.

4568 J . Org. Chem., Vol. 65, No. 15, 2000
Toyota et al.
0.560 mmol) in water-THF (2:1 v/v, 3 mL) was stirred at room
temperature for 13 h. After evaporation of the solvent, the
residue was acidified with 10% HCl (0.5 mL) and extracted
with CHCl3. After being dried, evaporation of the solvent gave
the crude acid, which was dissolved in CH2Cl2 (2.0 mL). To
the resulting solution were added 1-ethyl-3-(3′-dimethyl-
aminopropyl)carbodiimide hydrochloride (67.0 mg, 0.350 mmol),
DMAP (46.8 mg, 0.383 mmol), and pentafluorophenol (2.4 mg,
0.393 mmol) at 0 °C, and then the resulting mixture was
stirred at room temperature for 7 h. After evaporation of the
solvent, to the residue were added hexane (20 mL) and water
(10 mL), and the layers were separated. The aqueous layer
was extracted with hexane, and the combined organic layers
were washed with saturated aqueous NaCl and dried. Removal
of the solvent and chromatography of the residue on silica gel
with hexanes-EtOAc (5:1 v/v) as an eluent afforded the
pentafluoroester 7 (66 mg, 61% from 5) as a colorless oil. The
analysis of 7 by chiral HPLC [SUMICHIRAL OA-4600, hex-
ane-CHCl3 (100:1 v/v as an eluent)] revealed that the ee of 7
was more than 98%: IR 1720 and 1715 cm-1; 1H NMR δ 1.65-
1.95 (7H, m), 2.00 (1H, ddd, J ) 2.0, 6.5 and 8.5), 2.25-2.76
(6H, m), 5.11 (1H, dq, J ) 1.0 and 15.0), 5.10-5.16 (1H, m)
and 5.67 (1H, ddt, J ) 6.5, 10.5 and 15.0); 13C NMR δ 20.65,
26.94, 28.11, 29.49, 35.88, 39.15, 39.18, 50.87, 119.02, 132.79,
of CrO3 (723 mg, 7.23 mmol) in CH2Cl2 (72 mL) cooled to 0 °C
was added dropwise a 70% aqueous solution of tert-butyl
hydroperoxide (20.0 mL, 146 mmol). The resulting red solution
was stirred at the same temperature for 10 min, and then a
solution of 9 (9.52 g, 36.0 mmol) in CH2Cl2 (17 mL) was added
dropwise to the mixture at such a rate as to keep the internal
temperature below 6 °C. The reaction mixture was stirred at
0 °C for 2 h, and then the ice-water bath was replaced with
a water bath (10 °C) and stirring was continued for 18 h. The
reaction was quenched by the dropwise addition of 10%
aqueous solution of NaHSO3 (50 mL) at 0 °C, and the resulting
greenish mixture was diluted with Et2O (150 mL). After 1.5 h
of vigorous stirring at room temperature, the layers were
separated. The aqueous layer was extracted with Et2O, and
the combined organic layers were washed with saturated
NaHCO3 and brine and dried. Removal of the solvent and
chromatography of the residue on silica gel with hexanes-
EtOAc (5:1 v/v) as an eluent afforded the starting material
(581 mg, 6%) followed by the enone 10 (6.43 g, 64%), each as
1
a colorless oil: IR 1720 and 1675 cm-1; H NMR δ 1.20 (9H,
s), 1.48-1.73 (4H, m), 1.90 (2H, t, J ) 6.5), 2.25 (2H, d, J )
6.5), 2.46 (2H, dt, J ) 4.0 and 6.5), 4.06 (2H, t, J ) 6.5), 5.08-
5.18 (2H, m), 5.77 (1H, ddt, J ) 6.5, 10.0 and 15.0), 5.96 (1H,
d, J ) 9.5) and (1H, d, J ) 9.5); 13C NMR δ 23.20, 26.97, 30.76,
33.62, 33.73, 37.95, 38.51, 42.05, 64.12, 118.85, 128.46, 133.11,
157.25, 178.40 and 199.10; [R]25D -9.9 (c 14.7, CHCl3); MS m/z
278 (M+). Anal. Calcd for C17H26O3: C, 73.35; H, 9.41. Found:
C, 73.36; H, 9.47.
169.83 and 214.09; [R]27 -14.1 (c 1.1, CHCl3); MS m/z 376
D
(M+); HRMS calcd for C18H17F5O3 376.1098, found 376.1081.
(-)-3-[(1R)-1-(2-P r op en yl)-2-cycloh exen yl]p r op yl 2,2-
Dim eth ylp r op a n oa te (9). To a stirred suspension of LiAlH4
(4.14 g, 109 mmol) in THF (600 mL) was added dropwise a
solution of the keto ester 5 (22.5 g 100 mmol) in THF (40 mL)
at 0 °C. Stirring was continued at the same temperature for
20 min, and then the reaction was quenched by successive
addition of water (4.1 mL), 15% NaOH (4.1 mL), and water
(12.3 mL). The mixture was stirred at room temperature for
30 min, and then MgSO4 (10 g) was added. The resulting
suspension was filtered through Celite. Removal of the solvent
provided an oil, and the solvent was completely removed with
toluene as an azeotropy. The residue was used without further
purification.
(+)-3-[(1R,5S)-7-Meth ylid en e-2-oxobicyclo[3.2.1]octa n -
2-en -5-yl]p r op yl 2,2-Dim eth ylp r op a n oa te (11). To a stirred
i
solution of LDA [prepared in situ from Pr2NH (3.6 mL, 25.7
mmol) and 1.54 M hexane solution of BuLi (15.0 mL, 23.4
mmol) at 0 °C] in THF (50 mL) cooled to -78 °C was added
dropwise a solution of 10 (4.40 g, 15.8 mmol) in THF (8 mL).
After 50 min, a solution of TBDMSCl (3.81 g, 24.5 mmol) and
HMPA (3.3 mL, 19.0 mmol) in THF (3 mL) was added, and
the resulting mixture was allowed to warm to 0 °C. After
removal of the solvent, the residue was diluted with hexane,
washed with H2O and brine, and dried over K2CO3. Removal
of the solvent and chromatography of the residue on silica gel
with hexanes-EtOAc (25:1 v/v) as an eluent provided a
colorless oil, which was heated to 80 °C under 1 mmHg for 30
min to furnish the analytically pure TBDMS enol ether (6.20
g, 100%) as a colorless oil: 1H NMR δ 0.13 (6H, s), 0.93 (9H,
s), 1.19 (9H, s), 1.28-1.49 (2H, m), 1.54-1.71 (2H, m), 4.01
(2H, t, J ) 6.0), 4.75 (1H, dt, J ) 1.5 and 4.0), 4.97-5.08 (2H,
m), 5.49 (1H, d, J ) 9.5), 5.66 (1H, dd, J ) 2.0 and 9.5) and
5.76 (1H, ddt, J ) 6.5, 10.0 and 15.5); 13C NMR δ -4.50, 18.01,
23.77, 25.69, 27.21, 32.31, 34.50, 36.81, 38.75, 42.88, 64.91,
101.38, 117.52, 125.64, 134.97, 136.54, 147.58 and 178.81;
To a stirred solution of the above crude diol (16.7 g, 84.2
mmol) and pyridine (34.0 mL, 420 mmol) in CH2Cl2 (300 mL)
was added dropwise freshly distilled pivaloyl chloride (11.0 mL,
89.9 mmol) at 0 °C, and the resulting mixture was stirred at
the same temperature for 2 h, and then warmed to room
temperature. After 2 h, the reaction mixture was cooled to 0
°C and Et3N (23 mL, 165 mmol) and freshly distilled meth-
anesulfonyl chloride were successively added dropwise to the
mixture. Stirring was continued at room temperature for 1 h,
and water (100 mL) and Et2O (300 mL) were added at 0 °C.
The resulting layers were separated, and then the aqueous
layer was extracted with Et2O. The combined organic layers
were washed with saturated aqueous NaHCO3 and saturated
aqueous NaCl and dried. After removal of the solvent, residual
pyridine was removed with toluene as an azeotropy, and then
to the residue was added DBU (50.0 mL, 334.3 mmol). The
resulting mixture was heated at 110 °C for 7 h and cooled to
room temperature. Water (150 mL) and Et2O (150 mL) were
added to the reaction mixture and the layers were separated.
The aqueous layer was extracted with Et2O, and the combined
organic layers were washed with 10% HCl, saturated aqueous
NaHCO3 and saturated aqueous NaCl and dried. Removal of
the solvent and chromatography of the residue on silica gel
with hexanes-EtOAc (20:1 v/v) as an eluent furnished the
olefin 9 (20.6 g, 78% from 5) as a colorless oil: IR 1720, 1670
[R]25 -1.1 (c 11.2, CHCl3). Anal. Calcd for C23H38SiO3: C,
D
70.36; H, 10.27. Found: C, 70.31; H, 10.27.
A mixture of the TBDMS enol ether (5.83 g, 14.9 mmol) and
Pd(OAc)2 (104 mg, 0.461 mmol, 3 mol %) in DMSO (150 mL,
0.1 M) was stirred under O2 (1 atm) for 15 h. The reaction
mixture was diluted with Et2O and filtered through Celite to
remove Pd black. Water (300 mL) was added to the filtrate,
and the layers were separated. The aqueous layer was
extracted with Et2O, and the combined organic layers were
washed with ice-cold 10% HCl, saturated aqueous NaHCO3
and saturated aqueous NaCl and dried. Removal of the solvent
and flash chromatography of the residue on silica gel with
hexanes-EtOAc (6:1 v/v) as an eluent furnished the bicyclic
enone 11 (3.13 g, 72%) as a colorless oil: IR 1720 and 1715
and 1630 cm-1
;
1H NMR δ 1.20 (9H, s), 1.28-1.49 (4H, m),
cm-1 1H NMR δ 1.56-1.84 (5H, m), 2.13 (1H, d, J ) 10.5),
;
1.53-1.66 (4H, m), 1.89-1.98 (2H, m), 2.07 (2H, dd, J ) 1.0
and 6.5), 4.01 (2H, t, J ) 6.5) 5.01 (1H, dt, J ) 1.0 and 15.0),
5.00-5.07 (1H, m) 5.41 (1H, dt, J ) 2.0 and 9.5), 5.68 (1H, dt,
2.39 (1H, t, J ) 2.0), 3.47 (1H, br d, J ) 5.0), 4.11 (1H, t, J )
6.0), 5.05 (1H, br s), 5.28 (1H, br s), 5.84 (1H, dd, J ) 1.5 and
9.0) and 5.99 (1H, dd, J ) 2.0 and 9.0); 13C NMR δ 24.92, 27.11,
33.83, 38.66, 42.11, 44.53, 46.33, 58.59, 64.18, 112.35, 126.96,
145.36, 157.94, 178.65 and 198.75; [R]25D +87.0 (c 21.4, CHCl3);
MS m/z 276 (M+). Anal. Calcd for C17H24O3: C, 63.14; H, 8.83.
Found: C, 63.10; H, 8.88.
(+)-3-[(1R,4S,5S)-5-(2-Meth oxym eth oxyeth yl)-4-m eth -
yleth en yl-7-m eth ylid en e-2-oxobicyclo[3.2.1]octa n -5-yl]-
p r op yl 2,2-Dim eth ylp r op a n oa te (12). To a stirred solution
J ) 3.5 and 9.5) and 5.77 (1H, ddt, J ) 6.5, 10.0 and 15.0); 13
C
NMR δ 18.79, 23.13, 24.97, 27.11, 32.12, 35.59, 36.61, 38.61,
44.32, 64.91, 117.11, 126.87, 134.82, 135.10 and 178.59; [R]26
D
-3.4 (c 8.8, CHCl3); MS m/z 264 (M+). Anal. Calcd for
C
17H28O2: C, 77.22; H, 10.67. Found: C, 77.08; H, 10.86.
(-)-3-[(1S)-4-Oxo-1-(2-p r op en yl)-2-cycloh exen yl]p r o-
p yl 2,2-Dim eth ylp r op a n oa te (10). To a stirred suspension

Synthesis of (-)-Methyl Atis-16-en-19-oate
J . Org. Chem., Vol. 65, No. 15, 2000 4569
of isopropenylmagnesium bromide [from 2-bromopropene (3.5
mL, 39.4 mmol) and Mg (1.02 mg, 42.0 mmol)] and HMPA (8.9
mL, 51.2 mmol) in THF (80 mL) was added CuBr‚SMe2 (710
mg, 3.42 mmol) at -78 °C. After 5 min, a solution of the enone
11 (7.08 g, 25.6 mmol) and TMSCl (6.5 mL, 51.2 mmol) in THF
(25 mL) was added dropwise at the same temperature, and
stirring was continued for a further 30 min, and then 10% HCl
was added at -78 °C. The resulting mixture was allowed to
warm to 0 °C and then diluted with Et2O. The aqueous layer
was further extracted with Et2O, and the combined organic
layers were washed with water, saturated aqueous NaHCO3,
and saturated aqueous NaCl and dried. Removal of the solvent
and flash chromatography of the residue on silica gel with
hexanes-EtOAc (8:1 v/v) as an eluent afforded the ketone 12
with water, 10% aqueous CuSO4, water, saturated aqueous
NaHCO3, and saturated aqueous NaCl, dried, and evaporated
to provide an oil, which was dissolved in toluene (27 mL), and
to the solution was added the bromo-containing Wittig reagent
(9.73 g, 22.8 mmol). The resulting mixture was heated at 80
°C for 3 h and then cooled to room temperature. The solvent
was evaporated, and to the residue was added hexane and
triturated. The mixture was filtered through Celite. Removal
of the solvent and flash chromatography of the residue on silica
gel with hexanes-EtOAc (12:1 v/v) as an eluent furnished the
chiral nonracemic ester (5.85 g, 76%) as a colorless oil.
Following the procedure for the racemic compound, the
above ester (3.19 g, 7.49 mmol) was reduced with DIBALH
(0.94 M in hexane, 17.5 mL, 16.5 mmol) in toluene (50 mL) at
0 °C to give rise to the (Z)-allylic alcohol 14 (2.11 g, 76%) as a
colorless oil. Spectral data of 14 were consistent with those of
(7.19 g, 88%) as a colorless oil: IR 1720 and 1715 cm-1 1H
;
NMR δ 1.20 (9H, s), 1.29-1.41 (1H, m), 1.59-1.72 (3H, m),
1.77 (3H, br t, J ) 0.5), 1.78-1.87 (1H, m), 2.12 (1H, dd, J )
1.0 and 15.0), 2.27 (1H, d, J ) 12.0), 2.50 (2H, br t, J ) 2.0),
2.73 (1H, dd, J ) 2.0 and 9.0), 2.91 (1H, dd, J ) 9.0 and 15.0),
3.26 (1H, br d, J ) 5.0), 4.05 (2H, dt, J ) 2.0 and 5.5), 4.71
(1H, br s), 4.88 (1H, br d, J ) 1.5), 4.94 (1H, br s) and 5.05
(1H, br t, J ) 2.5); 13C NMR δ 23.08, 24.46, 27.14, 33.98, 38.71,
39.42, 40.83, 43.64, 45.49, 50.81, 60.16, 64.16, 108.66, 115.06,
147.56, 148.68, 178.73 and 210.78; [R]25D +82.3 (c 1.7, CHCl3);
MS m/z 318 (M+). Anal. Calcd for C20H30O3: C, 75.43; H, 9.49.
Found: C, 75.51; H, 9.49.
the corresponding racemate: [R]25 +3.61 (c 3.5, CHCl3); MS
D
m/z 382 (M+). Anal. Calcd for C19H27BrO3: C, 59.53; H, 7.10;
Br, 20.85. Found: C, 59.52; H, 7.17; Br, 20.79.
Con ver sion of (+)-14 to (-)-Meth yl Atisir en oa te by th e
Sa m e Rea ction Sequ en ce a s th e Ra cem a te (-)-Meth yl
20-Nor -12-oxok a u r -16-en -19-oa te 12-Eth ylen e Aceta l (17).
The alcohol (+)-14 (2.18 g, 5.70 mmol) was oxidized with MnO2
(2.15 g) in toluene (200 mL) for 17.5 h, followed by methyl-
enation with Ph3PdCH2 (7.85 mmol) in THF (40 mL) to afford
15 (1.52 g, 70%) as a colorless oil: MS m/z 378 (M+).
(+)-(1R,4S,5S)-5-(2-Hyd r oxyp r op yl)-4-m eth yleth en yl-
7-m eth ylid en ebicyclo[3.2.1]octa n -2-on e 2-Eth ylen e Ace-
ta l (13). To a stirred solution of the ester 12 (108 mg, 0.340
mmol) in THF (3 mL) was added a 40 w/w % aqueous solution
of tetrabutylammonium hydroxide (0.33 mL, 0.503 mmol).
After 10 h, tetrabutylammonium hydroxide (0.15 mL, 0 229
mmol) was added to the mixture, and stirring was continued
for an additional 4 h. The solvent was evaporated, and to the
residue was added saturated aqueous NaCl. The aqueous layer
was extracted with Et2O, and the combined organic layers were
washed with saturated aqueous NaCl and dried. Removal of
the solvent and flash chromatography of the residue on silica
gel with hexanes-EtOAc (1:1 v/v) as an eluent furnished the
hydroxy ketone (71.7 mg, 79%) as a colorless oil: IR 3400 and
Diels-Alder reaction of 15 (1.55 g, 4.01 mmol) furnished
1.08 g (70%) of 16a , MS m/z 378 (M+), and 16b (85:15 mixture
by 1H NMR) as a colorless oil. In contrast to the corresponding
racemate, 16a could not be crystallized. Therefore, the cyclo-
adducts were directly carbomethoxylated (82%), followed by
reduction with Mg (1.18 g, 48.5 mmol) in MeOH (12 mL) to
provide (-)-17 (472 mg, 63%) as a white solid. An analytical
sample was obtained by recrystallization of the solid from
Et2O-hexane as colorless needles: mp 170.0-172.0 °C; [R]28
D
-44.2 (c 2.1, CHCl3); MS m/z 360 (M+). Anal. Calcd for
C
22H32O4: C, 73.30; H, 8.95. Found: C, 73.39; H, 8.96.
(+)-Meth yl 12-Oxok a u r -16-en -19-oa te (18). The ester 17
(189 mg, 0.525 mmol) was methylated with MeI (1 mL, 16.1
mmol) in the presence of LDA (5.28 mmol) and HMPA (0.1
mL, 0.575 mmol). After extractive workup, the crude product
was treated with 15% HClO4 (5 mL) in THF (10 mL) to afford
the keto ester 18 (162 mg, 94% from 17) as a white solid. An
analytical sample was obtained by recrystallization of the solid
from Et2O-hexane as colorless prisms: mp 170.0-172.0 °C;
1
1715 cm-1; H NMR δ 1.19 (9H, s), 1.20-1.76 (5H, m), 1.91
(3H, s), 2.08 (1H, dd, J ) 9.0 and 14.5), 2.28 (1H, ddd, J )
2.0, 6.5 and 8.5), 2.41 (1H, br d, J ) 9.0), 2.59 (1H, br d, J )
5.0), 3.86-4.07 (6H, m), 4.75-4.79 (1H, m), 4.87-4.93 (2H,
m) and 5.00-5.05 (1H, m); 13C NMR δ 23.07, 28.05, 33.48,
39.19, 40.74, 43.35, 45.37, 50.62, 59.99, 62.74, 108.39, 114.68,
[R]26 +40.1 (c 4.1, CHCl3); MS m/z 330 (M+). Anal. Calcd for
D
147.59, 148.62 and 211.36; [R]25 +3.61 (c 3.5, CHCl3). Anal.
D
C
21H30O3: C, 76.33; H, 9.15. Found: C, 76.12; H, 9.29.
Calcd for C15H22O2: C, 76.88; H, 9.46. Found: C, 76.90; H,
8.89.
(-)-Meth yl Atis-16-en -19-oa te (1c). The ketone 18 (152
mg, 0.461 mmol) was reduced with NaBH4 (57.9 mg, 1.53
mmol) in MeOH (10 mL) to give the crude alcohol, which was
acylated with 1,1′-thiocarbonyldiimidazole (202 mg, 90%, 1.02
mmol) and DMAP (117 mg, 0.954 mmol) in CH2Cl2 (1.5 mL).
The thioimidazolde (190 mg, 93%) obtained was deoxygenated
with Bu3SnH (0.24 mL, 0.866 mol) and AIBN (5.5 mg, 0.0335
mmol) in degassed toluene (43 mL) to furnish (-)-1c (111 mg,
76%) as a white solid: mp 102.5-105.0 °C (needles, MeOH)
[lit.10 mp 126 °C]; [R]24D -58.6 (c 0.96, CHCl3) [lit.10 [R]20D -62.5
A solution of the above hydroxy ketone (4.27 g, 18.2 mmol),
ethylene glycol (20 mL, 210 mmol), and PPTS (59.3 mg, 0.236
mmol) in C6H6 (150 mL) was refluxed under a Dean-Stark
water separator for 6 h. The reaction mixture was cooled to
room temperature, and then water was added and the layers
were separated. The aqueous layer was extracted with Et2O,
and the combined organic layers were washed with saturated
aqueous NaHCO3, water, and saturated aqueous NaCl and
dried. Removal of the solvent and flash chromatography of the
residue on silica gel with hexanes-EtOAc (3:1 v/v) as an eluent
afforded the ethylene acetal 13 (4.89 g, 96%) as a colorless oil:
(c 0.96, CHCl3) and [R]20 -60.6 (c 0.64, CHCl3)11]; MS m/z
D
316 (M+). Anal. Calcd for C21H32O2: C, 79.70; H, 10.19.
Found: C, 79.43; H, 10.44.
1
IR 3400 cm-1; H NMR δ 1.20-1.81 (6H, m), 1.76 (3H, t, J )
The synthetic compound was in all respects (1H NMR, 13C
NMR, IR) indistinguishable from an authentic sample of (-)-
1c provided by Professor R. M. Coates.
0.7), 2.10 (1H, dd, J ) 1.2 and 14.5), 2.25 (1H, br d, J ) 12.0),
2.47-2.52 (2H, m), 2.73 (1H, dd, J ) 2.1 and 8.5), 2.80 (1H,
dd, J ) 8.5 and 14.5), 3.25 (1H, d, J ) 5.0), 3.63 (2H, t, J )
5.8), 4.70 (1H, s), 4.86 (1H, d, J ) 1.5), 4.92 (1H, br s) and
5.03 (1H, br t, J ) 2.3); [R]25D +7.2 (c 1.1, CHCl3); MS m/z 278
(M+). Anal. Calcd for C17H26O3: C, 73.35; H, 9.41. Found: C,
73.32; H, 9.55.
(-)-Meth yl Ka u r -16-en -19-oa te (2c) a n d (-)-Meth yl
Tr a ch yloba n -19-oa te (3c). The ketone 18 (94.9 mg, 0.287
mmol) was dissolved in di(ethylene glycol) (4 mL), and then
hydrazine monohydrate (1 mL, 20.6 mmol) was added. The
resulting mixture was refluxed at 135 °C for 2 h. After the
mixture was cooled to room temperature, KOH (172 mg, 2.61
mmol) was added at room temperature and the mixture was
(+)-(1R,4S,5S)-5[(Z)-4-Br om oh exa -3,5-d ien yl]-4-m eth -
yleth en yl-7-m eth yliden ebicyclo[3.2.1]octan e-2-on e 2-Eth -
ylen e Aceta l (14). To a stirred solution of the alcohol 13 (4.87
i
g, 17.5 mmol) and Pr2NEt (9.0 mL, 51.7 mmol) in DMSO-
(10) (a) Coates, R. M.; Bertram, E. F. J . Chem. Soc., Chem. Commun.
1969, 797. (b) Idem J . Org. Chem. 1971, 36, 2625.
(11) Bohlman, F.; Abraham, W.; Sherdlick, W. S. Phytochemistry
1980, 19, 869.
CH2Cl2 (1:5 v/v, 60 mL) was added SO3‚Py (5.61 g, 35.2 mmol).
Stirring was continued for 30 min, and then the reaction
mixture was diluted with Et2O. The organic layer was washed

4570 J . Org. Chem., Vol. 65, No. 15, 2000
Toyota et al.
allowed to warm to 200 °C over a period of 10 h. After 6.5 h of
heating, 5% HCl (4 mL) was added at room temperature, and
then the resulting mixture was extracted with EtOAc. The
organic layer was washed with water (2 mL) and saturated
aqueous NaCl and dried. Evaporation of the solvent left a
white solid, which was dissolved in Et2O (4 mL). The resulting
solution was treated with an ethereal solution of diazomethane
at room temperature. After 1 h of stirring at the same
temperature, AcOH was added until the evolution of nitrogen
gas ceased. Saturated aqueous K2CO3 (1 mL) was added, and
the mixture was extracted with Et2O. The ethereal layer was
washed with saturated aqueous NaCl and dried. Removal of
the solvent and chromatography of the residue on silica gel
impregnated with 30% silver nitrate with benzene-petroleum
ether (3:1 v/v) as an eluent provided (-)-methyl trachyloban-
19-oate (3c) (14.9 mg, 16%) [mp 96.5-98.0 °C [lit.9 mp 98-
100 °C]; [R] 24D -73.4 (c 0.89, CHCl3) [lit.9 [R]D -70.5 (CHCl3)];
MS m/z 316 (M+); HRMS calcd for C21H32O2 316.2402, found
316.2422] and (-)-methyl kaur-16-en-19-oate (2c) (53.3 mg,
24
59%): mp 72.0-73.5 °C [lit.9 mp 73.5-74.5 °C]; [R]
-96.4
D
(c 0.94, CHCl3) [lit.9 [R]D -104 (CHCl3)]; MS m/z 316 (M+);
HRMS calcd for C21H32O2 316.2402, found 316.2405.
J O000142B