Palladium-mediated ring closure reactions. Facile syntheses of enantiopure bicyclic and tricyclic alkenones

Article abstract of DOI:10.1016/S0040-4020(00)00658-X

(R)-Carvone was used as a chiral building block. Regio- and stereoselective alkylations at C6 and C2 of (R)-carvone and (R)-5-isopropyl-2-methyl-2-cyclohexenone [derived from the hydrogenation of (R)-carvone] followed by palladium-mediated ring closures a

Full text of DOI:10.1016/S0040-4020(00)00658-X

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 7389–7398
Palladium-Mediated Ring Closure Reactions. Facile Syntheses
of Enantiopure Bicyclic and Tricyclic Alkenones
†
‡
§
*
Duy H. Hua, Kiyosei Takasu, Xiaodong Huang, Gail S. Millward, Yi Chen and Jingmei Fan
Department of Chemistry, Kansas State University, Manhattan, KS 66506, USA
Received 6 June 2000; accepted 25 July 2000
Abstract—(R)-Carvone was used as a chiral building block. Regio- and stereoselective alkylations at C6 and C2 of (R)-carvone and (R)-5-
isopropyl-2-methyl-2-cyclohexenone [derived from the hydrogenation of (R)-carvone] followed by palladium-mediated ring closures
afforded various enantiopure bicyclic and tricyclic alkenones. Hence, cyclization of (5S,6S)-2,6-dimethyl-6-(cis-3-iodo-2-propenyl)-5-iso-
propenyl-2-cyclohexenone (3) gave (4aS,5S,8aS)-1,4,4a,5,8,8a-hexahydro-5-(methoxycarbonylmethyl)-2,5,8a-trimethylnaphthalen-1-one
(7) as the major product, cyclization of (5S,6S)-2,6-dimethyl-6-(cis-3-iodo-2-propenyl)-5-isopropyl-2-cyclohexenone (22) produced
(1S,5R,6S)-1,5-dimethyl-6-isopropyltricyclo[3.3.1.02,8]-3-nonen-9-one (23), and cyclization of (2R,5S,6S)-2,6-dimethyl-2-(cis-3-iodo-2-
propenyl)-5-isopropenyl-3-cyclohexen-1-one (25) afforded (3aR,6S,7aR)-6,7a-dimethyl-5-isopropenyl-3a,6,7,7a-tetrahydro-1H-inden-7-
one (26). A 1,2-rearrangement reaction of bromide 16 gave hexahydro-1H-benzocycloheptene 17. ᭧ 2000 Elsevier Science Ltd. All rights
reserved.
Introduction
construction of various useful enantiopure bicyclic and
tricyclic intermediates for natural-product synthesis.
In the studies of chiral syntheses of biologically active
natural products, pyripyropenes1 (acyl-CoA: cholesterol
O-acyltransferase inhibitors),2 arisugacin (acetylcholine-
sterase inhibitor),3 and chloropuupehenone and its deriva-
tives4 (cholesteryl ester transfer protein inhibitors); various
enantiopure and substituted trans-bicyclo[4.4.0]-decanes
were needed for the syntheses. Herein, we report the
regio- and stereoselective propenylation of 6-methylcar-
vones followed by a modified intramolecular Heck reaction5
in facile syntheses of enantiopure substituted trans-bicyclo-
[4.4.0]decanones, bicyclo[5.4.0]undecenones, cis-hydro-
indans, and tricyclic alkenones starting from (R)-carvone
(2). These methods, not previously reported, allow a rapid
Results and Discussion
From our initial retrosynthetic analysis of pyripyropene A
and other diterpenes, the A–B ring fragment, such as func-
tionalized trans-bicyclo[4.4.0]decane 1, can be synthesized
from (R)-(Ϫ)-carvone (2) via intermediate 3 (Scheme 1).
Hence, intermediate 3 was prepared from selective a-mono-
methylation6 followed by a-propenylation of (R)-carvone.
Treatment of (R)-carvone (2) with LDA in THF followed by
methyl iodide gave a 79% yield of a mixture (3:1) of 4 and 5
(Scheme 2). Epimers 4 and 5, although separable by silica
Scheme 1.
Keywords: bicyclic aliphatic compounds; cyclization; palladium and compounds; stereocontrol.
* Corresponding author. E-mail: duy@ksu.edu
†
E-mail: xhu7786@ksu.edu
E-mail: ychen2@nd.edu
E-mail: jfan@corr.com
‡
§
0040–4020/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00658-X

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D. H. Hua et al. / Tetrahedron 56 (2000) 7389–7398
Scheme 2.
gel flash column chromatography, were treated together
with 2 equiv. of LDA in THF at Ϫ78ЊC, followed by
1 equiv. of HMPA at 0ЊC and then cis-3-iodo-2-propenyl
methanesulfonate (6)7 to give a 78% yield of pure iodide
3 after column chromatography (along with 14% of
recovered 4 and 5) as a single stereoisomer. When
1 equiv. of LDA was used, only 51% yield of 3 was
obtained. No NOE was observed between C6–Me and
C5–H in the 2D NOESY spectrum of 3. First, when iodide
3 was treated with catalytic amounts of Pd(OAc)2
(0.1 equiv.) and Ph3P (0.2 equiv.), 1 equiv. of Ag2CO3, in
DMF and MeOH under 1 atm of CO at 60ЊC, only a 6%
yield of 7 and 8 was obtained along with 46% yield of
unsaturated ester 10. The results indicate that reaction of
the intermediate vinylpalladium complex with CO and
MeOH is faster than the intramolecular cyclization.
Hence, a stoichiometric amount of palladium acetate was
used to effect complete cyclization. Various reaction con-
ditions were examined for the palladium-mediated cycliza-
tion of 3; the results are summarized in Table 1. It was found
that when CO and MeOH were added (after 30 min reaction
time) prior to the addition of silver carbonate (after 1.5 h
reaction time), the hexahydro-1H-cyclopropa[a]naphtha-
lene 9 was obtained as the predominant product (64%
yield; Entry 1). This implies that the relative rate of intra-
molecular cyclopropanation (leading to 9) increases at
higher temperature (60ЊC) from the same vinylic palladium
intermediate (12A; vide infra). When silver carbonate was
added at the beginning of the reaction (Entries 2–4) and CO
was added after 0.7–1.5 h, although the percent yield of 8
remains similar, the percent yield of desired product 7
increases and that of 9 decreases. At lower temperatures
(50 and 35ЊC; Entries 5 and 6) and when silver carbonate,
MeOH, and CO were added after 0.5 h, 7 was formed as the
major product and 9 was not detected (at 35ЊC); although
the amount of 8 remains the same.
Based on the literature5 and our own results, a proposed
mechanism is depicted in Scheme 3. Presumably, Pd(0),8a
derived from palladium acetate and triphenylphosphine,
undergoes insertion into the vinylic iodide of 3 to give the
s-Pd complex 11 which can cyclize via the ‘exo-type’
mode8b to provide 12A (major) and the ‘endo-type’
mode8b to afford 12B (minor), as illustrated. At 35ЊC, the
formation of 9 from 12A is slow, and the addition of silver
carbonate generates 13A and 13B which react with CO and
MeOH to give 7 and 8.
Apparently, intermediate 12B does not undergo cyclo-
propanation (leading to the stereoisomer of 9), which may
be explained as follows: in the transition state, the syn-
addition of the palladium moiety of 13B onto C6,7-double
bond (palladium is resulted at the C-7 axial position) under-
goes a 1,3-diaxial interaction with C-8a axial methyl and,
therefore, the activation energy would be expected to be
higher than that from 12A to 9 as well as that of the con-
version to 8. Fortunately, these different products are
separable by silica gel column chromatography.
The stereochemistry is elucidated by 2D NOESY spectro-
scopy. The 2D spectra (NOESY) revealed NOE between
C10–Me and C13–Me for 7, C11–CH2 and C13–Me
(axial), C10–Me and C4a–H (axial) for 8, and C10–
Me and C1a–H, and C7a–H and C1a–H for 9, but no
NOE between C10– and C13–Me with C4a–H for 7
(Fig. 1).
Table 1. Cyclization of iodide 3 under various conditions. In all cases, 1 equiv. of Pd(OAc)2 and 2 equiv. of PPh3 were used prior to the addition of silver
carbonate (1 equiv.) and CO and methanol
MeOHa (h)
COa (h)
Reaction time (h)
7 (% yield)
8 (% yield)
9 (% yield)
a
Entry
Solvent
Temp. (ЊC)
Ag2CO3 (h)
1
2
3
4
5
6
DMF
DMF
DMF
CH3CN
DMF
DMF
60
50
40
50
50
35
0.5
0
0
0
0.5
0.5
0.5
0
0
0
0.5
0.5
0.5
0.7
1.5
1.5
0.5
0.5
30
10
5
4.5
4
0
36
17
15
40
50
18
18
17
15
20
23
64
7
17
15
5
3.5
0
a The addition time from initial reaction.

D. H. Hua et al. / Tetrahedron 56 (2000) 7389–7398
7391
Scheme 3.
The conversion of ester 7 to alcohol 1 was carried out
following Barton’s decarboxylation–hydroxylation pro-
cedure.9a Treatment of carboxylic acid 14, derived from
basic hydrolysis of 7, with NaH and oxalyl chloride in
benzene followed by N-hydroxy-2-thiopyridinone, NaH,
t-BuSH, oxygen, and then trimethyl phosphite, gave a
45% yield of alcohol 1 (Scheme 4). Similarly, isomer 8
was converted into the b-hydroxymethyl isomer 15 under
these conditions.
During the studies of the conversion of 7 into 1, the dis-
placement of bromomethyl derivative 16 with hydroxyl
nucleophile was also investigated (Scheme 5). Hence,
bromide 16 was obtained from basic hydrolysis of 7 with
KOH in MeOH–H2O at 25ЊC (96% yield) followed by free-
radical decarboxylation–bromination9b with NaH–oxalyl
chloride and then CBrCl3-DMAP and 3-hydroxy-4-methyl-
2(3H)-thiazolethione at 25ЊC (68% yield). An interesting
1,2-rearrangement was found when 16 was treated with
Figure 1.
Scheme 4. (a) KOH, MeOH, H2O. (b) (i) NaH, (COCl)2; (ii) N-hydroxy-2-thiopyridinone, NaH, t-BuSH, O2; (iii) P(OMe)3.

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D. H. Hua et al. / Tetrahedron 56 (2000) 7389–7398
Scheme 5.
Scheme 6.
K2CO3–H2O–dioxane under reflux for 10 h; hexahydro-
benzocycloheptenone 17 (55% yield) was isolated as a
single stereoisomer (Scheme 5). The stereochemistry was
established by 2D NOESY in which C11 and C12 methyls
exhibit an NOE, while C4a–H shows no NOE with either
the C11- or C12-methyl. Presumably, the C6 vinylic carbon
of 16 undergoes a 1,2-migration from C5 to C10, thereby
displacing the bromide. Water or hydroxide ion attacks the
resulting tertiary carbocation from the a face (opposite the
C12–Me) to give 17.
of the A-B ring fragment of chloropuupehenone via a cata-
lytic process. It was predicted that the rate of the reaction of
s-palladium complexes 12 with a hydride donor such as
sodium formate is slow compared with that of ring closure
(i.e. 3 to 12). Moreover, reaction of hydride with either 12A
or 12B provides the same product, 18. Hence, cyclization of
3 with 0.1 equiv. of Pd(OAc)2–0.2 equiv. of Ph3P–2 equiv.
of HCO2Na11–1 equiv. of Et4NBr in DMF at 35ЊC for 5 days
gave 18 (41% yield), 19A and 19B (40% yield; inseparable;
2:1), and 9 (9% yield) (Scheme 6). The 2D NOESY spec-
trum of 18 shows no NOE between the C8a angular methyl
and C4a–H. Scheme 7 proposes the formation of these
products. Likely, the relative rates for the reactions of 12
Next, we investigated the trapping of the s-palladium
complexes 12 with hydride donor10 to effect the construction
Scheme 7.

D. H. Hua et al. / Tetrahedron 56 (2000) 7389–7398
7393
Scheme 8.
Scheme 9.
with sodium formate and intramolecular ring closure are
similar. Product 18 and intermediates 20A and 20B (from
the addition of s-Pd complex with C-6,7 double bond),
respectively, are formed from Pd complexes 12A and 12B
by either reacting with hydride from sodium formate or
undergoing syn-addition with the C-6,7 double bond. Pd
complex 20A either reacts with sodium formate to give
by-product 19A or undergoes elimination to give cyclo-
alkene 9. The fact that the stereoisomer of 9 did not form
implies that the relative rate of the elimination of 20B is
slow compared with that of the reaction with sodium
formate.
the C6 isopropyl group of 24, slowing down the syn-elimi-
nation reaction of Pd(PPh3)2 and C7–H.
If the 3-iodo-2-propenylation of 4 could be effected at C2,
then subsequent cyclization would provide hydroindene 26.
Fortunately, propenylation of 4 with lithium hexamethyl-
disilazide, HMPA, and mesylate 6 in THF afforded
iodide 25 (60% yield) (Scheme 9). The stereochemistry
of 25 was supported by 2D NOESY spectroscopy in
which C6 hydrogen shows NOE with C2 methyl and
the methyl group of the isopropenyl group at C5. Cycli-
zation of 25 with 0.2 equiv. of Pd(OAc)2–0.4 equiv. of
Ph3P–1 equiv. of Ag2CO3–2 equiv. of Et3N in DMF at
60ЊC for 20 h gave 26 (65% yield). NOESY spectrum of 26
shows NOE between C3a–H and C7a–Me. Table 2
Based on these results, other catalytic cyclizations within
the carvone skeleton were investigated to fully explore the
use of (R)-carvone as a chiral building block. Hence, we
envisioned ring formation between C2 and C6, and C2
and C3, of the carvone skeleton. To examine these possi-
bilities, selective hydrogenation of the isopropenyl side
chain followed by alkylations to provide vinylic iodide 22,
and selective alkylation at C2 of carvone to give iodide 25
should be studied (Schemes 8 and 9).
Table 2. NOE correlations of compounds 7, 8, 9, 17, 18, 25, and 26
Compound
Proton
NOE correlations
H-13 (Me)
Compound 7
Compound 8
H-10 (Me)
H-11
H-4a
H-13 (Me)
H-10 (Me)
The reported selective hydrogenation procedure by Ireland12
was followed. Treatment of (R)-carvone (2) with H2–
(Ph3P)3RhCl in benzene gave cyclohexenone 21 (85%
yield). Methylation of 21 with LDA–MeI in THF followed
by propenylation with LDA–HMPA–6 in THF gave iodide
22 (60% yield; 2 steps). Cyclization of 22 with 0.2 equiv. of
Pd(OAc)2, 0.4 equiv. of Ph3P, 1 equiv. of Et3N and silver
carbonate in DMF at 70ЊC for 20 h afforded a 67% yield of
23. It is interesting to note that the intermediate s-Pd
complex 24 does not undergo syn-elimination but, instead,
undergoes cyclopropanation followed by elimination to give
23. This may be due to the steric hindrance, generated from
Compound 9
Compound 17
H-1a
H-7a
H-10 (Me)
H-1a
H-4b
H-4a
H-11 (Me)
H-11 (Me)
H-4a
H-12 (Me)
Compound 18
Compound 25
H-4a
H-4a
H-10 (a-Me)
H-4a
H-5
H-6
H-13 (Me)
H-12 (cis to C5)
H-13 (Me), H-10 (Me)
H-12 (trans to C5)
Compound 26
H-3a
H-12 (Me)

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D. H. Hua et al. / Tetrahedron 56 (2000) 7389–7398
summarizes the NOE correlations of compounds 7, 8, 9, 17,
18, 25, and 26 from 2D NOESY.
column chromatographed on silica gel using a mixture of
hexane and ether (10:1) as eluant to give 6.23 g (59% yield)
4 and 2.08 g (20% yield) of 5. Compound 4: [a]2D2ˆϩ19.7Њ
(cˆ1, CHCl3); 1H NMR (CDCl3) d 6.70 (m, 1H, C3H), 4.80
(m, 2H, vCH2), 2.22–2.53 (m, 4H), 1.78 (d, Jˆ1.2 Hz, 3H,
C2 Me), 1.70 (dd, Jˆ1.6, 0.8 Hz, 3H, vCMe), 1.04 (d, Jˆ
7.0 Hz, 3H, C6Me); 13C NMR 201.8 (s, CvO), 145.6 (s,
C2), 143.3 (d, C3), 134.7 (s, Cv), 113.2 (t, vCH2), 50.5,
44.2, 31.1, 18.1, 16.1, 12.5. Compound 5: [a]2D2ˆϩ36.2Њ
Conclusion
Three types of Pd-catalyzed cyclization reactions are illus-
trated starting from (R)-carvone which produced useful
enantiopure bicyclic and tricyclic alkenones. The cyclic
intermediates can be used in the synthesis of natural and
other products, and will be reported in due course. An unex-
pected stereoselective 1,2-rearrangement of bromide 16 led
to benzocycloheptenone 17 was observed.
1
(cˆ1, CHCl3); H NMR (CDCl3) d 6.72 (m, 1H, C3H),
4.93 (s, 1H, vCH), 4.74 (s, 1H, vCH), 2.70 (m, 2H),
2.50 (m, 1H), 2.30 (m, 1H), 1.79 (s, 3H, C2Me), 1.71 (s,
3H, Me), 0.93 (d, Jˆ7.0 Hz, 3H, C6Me); 13C NMR 202.8 (s,
CvO), 144.9 (s, C2), 144.0 (d, C3), 133.6 (s, Cv), 111.4 (t,
vCH2), 44.7, 42.9, 26.2, 21.9, 16.0, 10.4.
Experimental
(5S,6S)-2,6-Dimethyl-6-(cis-3-iodo-2-propenyl)-5-isopro-
penyl-2-cyclohexenone (3). To a cold (Ϫ40ЊC) solution of
21 mmol of LDA (prepared as described above) in THF
(30 mL) and hexane (13 mL) under argon, a solution of
1.69 g (10.3 mmol) of 4 and 5 in 30 mL of ether was
added slowly via cannula. The solution was stirred for
45 min at 0ЊC, 1.8 mL (10 mmol) of HMPA was added,
the resulting solution was stirred for 4 h at 0ЊC, and 5.68 g
(22 mmol) of cis-3-iodo-2-propenyl methanesulfonate (6)7
was added. The reaction was stirred at 0–25ЊC for 12 h,
poured into aqueous NaHCO3, and extracted three times
with diethyl ether. The combined extracts were washed
with brine, dried (MgSO4), concentrated, and column chro-
matographed on silica gel using a mixture (3:2) of hexane
and methylene chloride as eluant to give 2.48 g (73% yield)
of 3 and 0.24 g (14% recovery) of 4 and 5. Compound 3:
General methods
All non-aqueous reactions were carried out under argon
atmosphere unless specified otherwise. Nuclear magnetic
1
resonance spectra were obtained at 400 MHz for H and
100 MHz for 13C in deuteriochloroform. H NMR spectra
1
are reported in ppm (d units) downfield of internal reference
tetramethylsilane (TMS), 13C NMR spectra are reported in
ppm (d units) using chloroform (CHCl3) as the standard
(77 ppm). Infrared spectra are reported in wavenumbers
(cmϪ1). Mass spectra were obtained from a Hewlett Packard
GC/HPLC 5989A mass spectrometer using either EI, CI or
FAB (m-nitrobenzyl alcohol was used as the matrix).
Rotations of optically active compounds were determined
with a Perkin–Elmer 241 polarimeter. Davisil silica gel,
grade 643 (200–425 mesh), was used for the flash chro-
matographic separations. E. Merck precoated TLC plates
silica gel 60F-254 were used in preparative TLC plates.
Solvents such as THF and diethyl ether for organometallic
reactions were distilled over sodium and benzophenone
under argon, and diisopropylamine and hexamethyldisila-
zane were freshly distilled from CaH2. (R)-Carvone,
2-propynol, palladium acetate, silver carbonate, triphenyl-
phosphine, N-hydroxy-2-thiopyridinone, and 3-hydroxy-4-
methyl-2(3H)-thiazolethione were purchased from Aldrich.
1
[a]2D2ˆϪ31.9Њ (cˆ1.5, CHCl3); H NMR (CDCl3) d 6.62
(m, 1H, C3H) 6.31 (dt, Jˆ7.6, 1.6 Hz, 1H, vCHI), 6.13
(dt, Jˆ7.6, 6.8 Hz, 1H, CHvCI), 4.83 (m, 1H, vCH),
4.74 (s, 1H, vCH), 2.72–2.62 (m, 2H), 2.46 (ddd Jˆ15.2,
6.4, 1.6 Hz, 1H), 2.42–2.32 (m, 2H), 1.80 (m, 3H, C2Me),
1.65 (s, 3H, C6Me). 13C NMR 203.4 (s, C1), 145.8 (s, C2),
142.4 (d, C3), 137.7 (d, Cv), 134.2 (s, Cv), 114.8 (t,
vCH2), 84.9 (d, vCHI), 50.5 (d), 48.0 (s, C6), 42.8 (t),
29.2 (t), 22.5 (q), 19.3 (q), 16.6 (q). 2D COSY and NOESY
spectra confirm the assigned stereochemistry. MS m/z CI
331 (Mϩ1). Anal. Calcd for C14H19IO: C, 50.92; H, 5.80.
Found: C, 50.77; H, 5.63.
1
All new compounds displayed satisfactory H (400 MHz)
and 13C (100 MHz) NMR, UV, IR, mass spectra (FAB or
CI), and elemental analysis or high resolution mass spectra.
The stereochemistry was determined by 2D COSY and
NOESY spectroscopy as noted in the experiments.
(4aS,5S,8aS)-1,4,4a,5,8,8a-Hexahydro-5-(methoxycarbon-
ylmethyl)-2,5,8a-trimethylnaphthalen-1-one (7) and
(4aS,5R,8aS)-1,4,4a,5,8,8a-hexahydro-5-(methoxycarbon-
ylmethyl)-2,5,8a-trimethylnaphthalen-1-one (8). (Entry 6
in Table 1). To a dried flask, 0.387 g (1.7 mmol) of
Pd(OAc)2 and 0.904 g (3.4 mmol) of Ph3P were added.
The compounds were dried under vacuum and maintained
under argon, 20 mL of DMF was added, and the solution
was stirred at 25ЊC for 1 h. A solution of 0.569 g
(1.74 mmol) of 3 in 20 mL of DMF was added via cannula,
the mixture was stirred at 32ЊC for 30 min, 0.476 g
(1.7 mmol) of Ag2CO3 was added followed by CO gas
which was introduced into the reaction mixture via a
balloon, and then 10 mL of MeOH was added. After being
stirred at 35ЊC for 15 h, the mixture was filtered, rinsed with
ether, and the filtrate was diluted with 50 mL of water. The
mixture was extracted three times with ether, the combined
extracts were washed with water, and brine, dried (MgSO4),
(6S,5R)-2,6-Dimethyl-5-(1-methylethenyl)-2-cyclohexen-
1-one (4) and (6R,5R)-2,6-dimethyl-5-(1-methylethenyl)-
2-cyclohexen-1-one (5).6 To a cold (Ϫ78ЊC) solution of
10 mL (71.4 mmol) of diisopropylamine in 200 mL of
THF under argon was added dropwise 46 mL (73.6 mmol)
of n-BuLi (1.6 M in hexane). After being stirred at 0ЊC for
1 h, the solution was cooled to Ϫ78ЊC, and 10 mL
(63.8 mmol) of (R)-(Ϫ)-carvone was added dropwise via
syringe. The solution was stirred at 0ЊC for 1 h, cooled to
Ϫ40ЊC, and 5.2 mL (82.9 mmol) of methyl iodide was
added. The resulting solution was stirred at Ϫ40ЊC for 3 h
and 25ЊC for 4 h, poured onto aqueous NH4Cl, and extracted
three times with diethyl ether (200 mL each). The ether
extracts were combined and washed with aqueous
NaHCO3, and brine, dried (MgSO4), concentrated, and

D. H. Hua et al. / Tetrahedron 56 (2000) 7389–7398
7395
concentrated, and column chromatographed on silica gel
using a gradient mixture of hexane and ether to give
0.228 g (50% yield) of 7 and 0.104 g (23% yield) of 8.
Compound 7: [a]2D2ˆϪ15Њ (cˆ1, CHCl3); 1H NMR
(CDCl3) d 6.77 (m, 1H, C3H), 5.69 (ddd, Jˆ10.4, 6.4,
2.4 Hz, 1H, C7H), 5.53 (dd, Jˆ10.4, 3.2 Hz, 1H, C6H),
3.62 (s, 3H, OMe), 2.42–2.07 (series of m, 7H), 1.77 (s,
3H, C2–Me), 1.12 (s, 3H, Me), 1.08 (s, 3H, Me); 13C
NMR (CDCl3) d 204.5 (s, CO), 171.7 (s, CO), 143.6 (d),
133.6 (s), 133.2 (d), 123.6 (d), 51.3 (q, CO), 46.7, 44.1, 43.4,
38.0, 32.9, 24.1, 23.7, 17.8, 16.3. MS m/z CI 263 (Mϩ1).
Anal. Calcd for C16H22O3: C, 73.25; H, 8.45. Found: C,
73.47; H, 8.21. Compound 8: [a]2D2ˆϩ80.6Њ (cˆ1,
of iodide 3 in 1 mL of DMF and 0.7 mL of MeOH was
added via cannula. This mixture was stirred at 25ЊC for
5 min, 46 mg (0.17 mmol) of Ag2CO3 was added, and
carbon monoxide was introduced via a balloon. This
mixture was maintained under CO at 60ЊC for 40 h, filtered,
rinsed with ether, the filtrate was diluted with water, and the
mixture was extracted three times with ether. The combined
extracts were washed with brine, dried (MgSO4), concen-
trated, and column chromatographed on silica gel using a
mixture (10:1) of hexane and ether as eluant to give 20 mg
(46% yield) of 10 and 3 mg (6% yield) of a mixture (1:1.5)
of 7 and 8. Compound 10: [a]2D2ˆϪ48.6Њ (cˆ0.7, CHCl3);
1H NMR (CDCl3) d 6.62 (m, 1H, C3H), 6.20 (ddd, Jˆ11.5,
7.0, 6.9 Hz, 1H, vCH), 5.84 (dt, Jˆ11.5, 2.0 Hz, 1H,
vCHCO), 4.80 (s, 1H, vCH), 4.72 (s, 1H, vCH), 3.70
(s, 3H, OMe), 3.11 (ddd, Jˆ16.0, 7.0, 2.0 Hz, 1H,
CH2Cv), 2.87 (ddd, Jˆ16.0, 6.7, 2.0 Hz, 1H, CH2Cv),
2.70 (t, Jˆ6.0 Hz, 1H, CH–Cv), 2.64 (m, 1H, C4H),
2.36 (m, 1H, C4H), 1.78 (s, 3H, C2Me), 1.64 (s, 3H, Me–
Cv), 1.18 (s, 3H, C6Me); 13C NMR (CDCl3) d 203.6 (s,
CO), 166.9 (s, CO), 146.8 (d, vCH), 145.9 (s), 142.5
(d), 134.3 (s), 120.9 (d), 114.6 (t), 51.2 (q, Me), 50.7
(d), 48.0 (s), 36.6 (t), 29.1 (t), 22.5 (q), 19.1 (q), 16.5
(q); Anal. Calcd for C16H22O3: C, 73.25; H, 8.45. Found: C,
73.01; H, 8.72.
1
CHCl3); H NMR (CDCl3) d 6.78 (m, 1H, C3H), 5.68
(ddd, Jˆ10.4, 6.4, 2.4 Hz, 1H, C7H), 5.56 (dd, Jˆ10.4,
3.2 Hz, 1H, C6H), 3.68 (s, 3H, OMe), 2.63 (d, Jˆ12.8 Hz,
1H, C11H), 2.31 (d, Jˆ12.8 Hz, 1H, C11H), 2.40–2.26
(series of m, 3H, C8, C4Hs), 2.14 (d, Jˆ18 Hz, 1H, C8H),
2.02 (dd, Jˆ11.0, 5.0 Hz, 1H, C4aH), 1.77 (s, 3H, C2–Me),
1.21 (s, 3H, C10–Me), 1.11 (s, 3H, C13–Me); 13C NMR
(CDCl3) d 204.5 (s, CO), 172.5 (s, CO), 143.6 (d), 134.8 (s),
132.5 (d), 123.5 (d), 51.4 (q, CO), 47.8, 41.6, 38.8, 36.5,
33.5, 28.3, 23.7, 17.9, 16.3. MS m/z CI 263 (Mϩ1). Anal.
Calcd for C16H22O3: C, 73.25; H, 8.45. Found: C, 73.12; H,
8.33. The stereochemistry of 7 and 8 were determined by 2D
COSY and NOESY spectroscopy.
(4aS,5S,8aS)-1,4,4a,5,8,8a-Hexahydro-1-oxo-2,5,8a-tri-
methylnaphthalen-5-acetic acid (14). To a solution of
0.127 g (0.48 mmol) of methyl ester 7 in 2 mL of MeOH
and 0.5 mL of H2O was added 90 mg (1.6 mmol) of KOH.
The solution was stirred at 25ЊC for 22 h, acidified with 1N
HCl, extracted with methylene chloride three times, and the
combined organic extract was washed with brine, dried
(MgSO4), concentrated, and column chromatographed on
silica gel using hexanes and ether (1:1) as eluant to give
0.116 g (96% yield) of acid 14. [a]2D2ˆϪ6.2Њ (cˆ0.3,
(1aR,3aS,7aS,7bR)-1a,3a,4,7,7a,7b-Hexahydro-3a,5,7b-
trimethyl-1H-cyclopropa[a]naphthalen-4-one (9). (Entry
1 in Table 1). A solution of 38.6 mg (0.17 mmol) of
Pd(OAc)2 and 90.2 mg (0.34 mmol) of Ph3P in 2 mL of
DMF was stirred at 25ЊC under argon for 30 min. A solution
of 56.8 mg (0.17 mmol) of iodide 3 in 2 mL of DMF was
then added via cannula. This mixture was stirred at 60ЊC for
30 min, 0.476 g (1.7 mmol) of Ag2CO3 and 0.5 mL of
MeOH were added, and carbon monoxide was introduced
into the reaction mixture using a balloon filled with CO and
maintained under CO for 30 h. The mixture was filtered, the
residual solids rinsed with ether, and the filtrate with ether
washings was diluted with water, and this mixture was
extracted three times with ether. The combined extracts
were washed with brine, dried (MgSO4), concentrated, and
column chromatographed on silica gel using a mixture
(10:1) of hexane and ether as eluant to give 22.2 mg (64%
yield) of 9 and 8 mg (18% yield) of 8. Compound 9:
1
CHCl3); H NMR (CDCl3) d 6.76 (m, 1H, C3H), 5.70
(ddd, Jˆ10.5, 6.4, 2.0 Hz, 1H, vCH), 5.56 (dd, Jˆ10.5,
2.8 Hz, 1H, vCH), 2.40–2.08 (series of m, 7H), 1.78 (s,
3H, C2Me), 1.15 (s, 3H, Me), 1.08 (s, 3H, Me); 13C NMR
(CDCl3) d 204.8 (s, CO), 177.5 (s, CO), 143.9 (d, vC),
133.8 (s, vC), 133.0 (d, vC), 124.2 (d, vC), 46.8, 44.4,
43.6, 38.2, 33.1, 24.4, 23.9, 18.1, 16.5. MS m/z CI 249
(Mϩ1). Anal. Calcd for C15H20O3: C, 72.55; H, 8.12.
Found: C, 72.37; H, 8.40.
1
[a]2D2ˆϪ26.7Њ (cˆ1.1, CHCl3); H NMR (CDCl3) d 6.72
(m, 1H, C6H), 6.48 (d, Jˆ10.0 Hz, 1H, C3H), 5.88 (dd,
Jˆ10.0, 2.8 Hz, 1H, C2H), 2.52 (m, 2H, C7H), 1.92 (dd,
Jˆ11.2, 6.0 Hz, 1H, C7aH), 1.76 (m, 1H, C9Me), 1.19 (s,
3H, Me), 1.18 (s, 3H, Me), 1.02 (m, 1H, C1aH), 0.72 (dd,
Jˆ8.8, 3.6 Hz, C1bH), 0.22 (t, Jˆ4.4 Hz, 1H, C1aH); 13C
NMR (CDCl3) d 193.8 (s, CO), 146.3 (s), 143.6 (d), 134.1
(d), 127.8 (d), 47.5, 46.5, 28.5, 26.7, 23.2, 20.2, 19.2, 16.7,
16.4. MS m/z CI 203 (Mϩ1). Anal. Calcd for C14H18O: C,
83.12; H, 8.97. Found: C, 82.91; H, 9.16. The stereo-
chemistry was determined from 2D COSY and NOESY
spectroscopy.
(4aS,5R,8aS)-1,4,4a,5,8,8a-Hexahydro-1-oxo-2,5,8a-tri-
methylnaphthalen-5-acetic acid (14B). To a solution of
0.12 g (0.46 mmol) of methyl ester 8 in 2 mL of MeOH
and 0.5 mL of H2O was added 90 mg (1.6 mmol) of KOH.
The solution was stirred at 25ЊC for 22 h, acidified with 1N
HCl, extracted with methylene chloride three times, and the
combined organic extract was washed with brine, dried
(MgSO4), concentrated, and column chromatographed on
silica gel using hexanes and ether (1:1) as eluant to give
0.110 g (97% yield) of acid 14B. [a]2D2ˆϩ65Њ (cˆ0.4,
1
CHCl3); H NMR (CDCl3) d 6.78 (m, 1H, C3H), 5.74–
5.62 (m, 2H, vCH), 2.64 (d, Jˆ13.0 Hz, 1H), 2.44–2.10
(series of m, 5H), 2.03 (dd, Jˆ11.4, 5.0 Hz, 1H), 1.78 (s, 3H,
Me), 1.24 (s, 3H, Me), 1.10 (s, 3H, Me); 13C NMR (CDCl3)
d 204.7 (s, CO), 178.4 (s, CO), 143.8 (d, vC), 133.9 (s,
vC), 132.2 (d, vC), 123.9 (d, vC), 48.1, 44.2, 41.8, 36.7,
33.8, 28.4, 24.0, 18.1, 16.5. MS m/z CI 249 (Mϩ1). Anal.
(5S,6S)-2,6-dimethyl-5-Isopropenyl-6-(3-methoxycarbo-
nyl-2-propenyl)-2-cyclohexenone (10). After a solution of
11.2 mg (0.05 mmol) of Pd(OAc)2 and 26.2 mg
(0.10 mmol) of Ph3P in 1 mL of DMF was stirred at 25ЊC
under argon for 30 min, a solution of 54.9 mg (0.17 mmol)

7396
D. H. Hua et al. / Tetrahedron 56 (2000) 7389–7398
Calcd for C15H20O3: C, 72.55; H, 8.12. Found: C, 72.73; H,
7.98.
(4aS,5S,8aS)-1,4,4a,5,8,8a-Hexahydro-5-(bromomethyl)-
2,5,8a-trimethylnaphthalen-1-one (16). To 1 mmol of
(4aS,5S,8aS)-1,4,4a,5,8,8a-hexahydro-1-oxo-2,5,8a-trimethyl-
naphthalen-5-acetyl chloride in 20 mL of CBrCl3 under
argon at 25ЊC were added 0.163 g (1.1 mmol) of 3-hydroxy-
4-methyl-2(3H)-thiazolethione and 0.136 g (1.1 mmol) of
4-dimethylaminopyridine. The solution was heated to reflux
for 10 h, cooled to 25ЊC, poured into 1N HCl solution, and
extracted three times with ether. The combined extracts
were washed with brine, dried (MgSO4), concentrated, and
column chromatographed on silica gel using hexane–
etherˆ5:1 as eluant to give 0.195 g (68% yield) of bromide
16 as a colorless oil. 1H NMR (CDCl3) d 6.74 (m, 1H, C3H),
5.80 (ddd, Jˆ10.0, 6.0, 2.0 Hz, 1H, C7H), 5.36 (dd, Jˆ10.0,
2.8 Hz, 1H, C6H), 3.34 (ABq, Jˆ10.4 Hz, 1H, CH2O), 3.27
(ABq, Jˆ10.4 Hz, 1H, CH2O), 2.44–2.10 (a series of m,
5H), 1.78 (s, 3H, C2–Me), 1.18 (s, 3H, Me), 1.09 (s, 3H,
Me); 13C NMR (CDCl3) d 204.4 (s, CO), 143.5, 132.4,
132.0, 125.7, 45.3, 44.2, 42.3, 39.5, 33.2, 24.5, 22.3, 18.0,
16.5. MS (FAB) m/z 283, 285 (Mϩ1), 203, 142. Anal. Calcd
for C14H19BrO: C, 59.37; H, 6.76. Found: C, 59.11; H, 6.55.
(4aS,5S,8aS)-1,4,4a,5,8,8a-Hexahydro-1-oxo-2,5,8a-tri-
methylnaphthalen-5-acetyl chloride. To a suspension of
NaH (60 mg; 50% oil, 1.25 mmol) in 10 mL of benzene
under argon was added a solution of 0.25 g (1 mmol) of
acid 14 in 10 mL of benzene via cannula. After stirring at
25ЊC for 30 min, 0.26 mL (3 mmol) of oxalyl chloride was
added, and the mixture was heated to reflux for 3 h. The
solvent and excess of reagent were removed under vacuum
to give the crude acid chloride which was used in the next
step without purification. 1H NMR (CDCl3) d 6.76 (m, 1H,
C3H), 5.77 (dd, Jˆ10.0, 2.0 Hz, 1H, vCH), 5.55 (dd,
Jˆ10.0, 2.4 Hz, 1H, vCH), 2.94 (ABq, Jˆ16.0 Hz, 2H),
2.44–2.12 (series of m, 5H), 1.78 (s, 3H, Me), 1.16 (s, 3H,
Me), 1.07 (s, 3H, Me).
(4aS,5S,8aS)-1,4,4a,5,8,8a-Hexahydro-5-(hydroxymethyl)-
2,5,8a-trimethylnaphthalen-1-one (1). To a solution of the
above acid chloride in 10 mL of toluene under argon was
added a solution of 0.162 g (1.1 mmol) of N-hydroxy-2-
thiopyridinone in 1 mL of t-butanethiol and 10 mL of
toluene via cannula. The solution was stirred, and 60 mg
(1.25 mmol) of sodium hydride (50% oil) was added. The
argon gas inlet was removed, oxygen gas was introduced
into the reaction vessel, and the mixture was kept under an
oxygen atmosphere and stirred at 80ЊC for 1 h. After cooling
to room temperature, 0.25 mL (2.1 mmol) of trimethyl
phosphite was added, and the mixture was stirred for 2 h
at 25ЊC. The mixture was diluted with ether and washed
with aqueous ammonium chloride, and then brine, dried
(MgSO4), concentrated, and column chromatographed on
silica gel using hexane–ether (1:1) as eluant to give
99 mg (45% overall yield) of alcohol 1. [a]2D2ˆϩ3.4Њ
(cˆ0.5, CHCl3); 1H NMR (CDCl3) d 6.75 (m, 1H,
C3H), 5.93 (ddd, Jˆ10.4, 6.4, 2.4 Hz, 1H, C7H), 5.30
(dd, Jˆ10.4, 2.8 Hz, 1H, C6H), 3.35 (d, Jˆ10.8 Hz, 1H,
CH2O), 3.21 (d, Jˆ10.8 Hz, 1H, CH2O), 2.47 (dd, Jˆ
11.2, 4.8 Hz, 1H), 2.42–2.25 (a series of m, 3H), 2.13
(d, Jˆ17.2 Hz, 1H), 1.77 (s, 3H, C2–Me), 1.56 (bs, 1H,
OH), 1.09 (s, 3H, Me), 0.98 (s, 3H, Me); 13C NMR
(CDCl3) d 205.0 (s, CO), 144.6, 132, 127.8, 119.8,
69.7 (CO), 41.1, 39.9, 36.7, 33.6, 24.4, 20.0, 17.8, 16.5.
MS m/z FAB (in NBA) 221 (Mϩ1), 219, 203, 189, 179,
167. Anal. Calcd for C14H20O2: C, 76.33; H, 9.15. Found:
C, 76.51; H, 8.93.
(4aR,5R,9aS)-5-Hydroxy-2,5,9a-trimethyl-4,4a,5,6,9,9a-
hexahydro-[1H]-benzocyclohepten-1-one (17). To a solu-
tion of 27 mg (0.096 mmol) of bromide 16 in 0.5 mL of 1,4-
dioxane and 0.5 mL of H2O was added 27 mg (0.2 mmol) of
K2CO3 at 25ЊC. The solution was then stirred at 100ЊC for
10 h, cooled to 25ЊC, diluted with aqueous NH4Cl, and
extracted three times with ether. The combined extracts
were washed with brine, dried (MgSO4), concentrated, and
column chromatographed on silica gel using hexane–
etherˆ1:1 as eluant to give 11.6 mg (55% yield) of 17.
1
[a]2D2ˆϪ168Њ (cˆ0.5, CHCl3); H NMR (CDCl3) d 6.73
(m, 1H, C3H), 5.88 (m, 2H, C7,8Hs), 2.88 (dd, Jˆ14.4,
8.4 Hz, 1H, C6H), 2.68 (dt, Jˆ20.0, 4.0 Hz, 1H, C4H),
2.55 (dd, Jˆ13.0, 5.0 Hz, 1H, C9H), 2.35 (dt, Jˆ20.0,
3.0 Hz, 1H, C4H), 2.28 (m, 1H, C6H), 2.20 (dd, Jˆ13.0,
8.0 Hz, 1H, C9H), 2.12 (dd, Jˆ12.0, 4.0 Hz, 1H, C4aH),
1.73 (m, 3H, C10Me), 1.23 (s, 3H, C11Me), 0.98 (s, 3H,
C12Me); 13C NMR (CDCl3) d 196, 144.0, 131.3, 128.9,
128.3, 71.8, 69.8, 56.6, 46.9, 43.4, 33.0, 25.0, 24.0, 16.7.
MS (FAB), m/z 221 (Mϩ1), 203, 185, 175, 161, 133. Anal.
Calcd for C14H20O2: C, 76.33; H, 9.15. Found: C, 76.23; H,
9.41.
(4aS,8aS)-1,4,4a,5,8,8a-Hexahydro-2,5,5,8a-tetramethyl-
naphthalen-1-one (18) and (3aS,7aS)-1a,2,33a,4,7,7a,7b-
octahydro-3a,5,7b-trimethyl-1H-cyclopropa[a]naphthalen-
4-one (19A and 19B). A mixture of 0.042 g (0.19 mmol) of
Pd(OAc)2 and 0.105 g (0.38 mmol) of PPh3 in 10 mL of
DMF was stirred under argon for 45 min at 25ЊC. To it
were added a solution of 0.64 g (1.94 mmol) of iodide 3
in 10 mL of DMF via cannula, followed by 0.264 g
(3.9 mmol) of HCO2Na and 0.4 g (1.94 mmol) of Et4NBr.
The mixture was stirred at 35ЊC for five days, cooled to
25ЊC, diluted with aqueous NH4Cl, and extracted twice
with ether. The combined extracts were washed with
water, then brine, dried (MgSO4), concentrated, and column
chromatographed on silica gel using a gradient mixture of
hexane and ether as eluant to give 0.162 g (41% yield) of 18,
0.160 (40% yield) of a mixture of 19A and 19B (insepar-
able; 2:1), and 35 mg (9% yield) of 9. Compound 18:
(4aS,5R,8aS)-1,4,4a,5,8,8a-Hexahydro-5-(hydroxymethyl)-
2,5,8a-trimethylnaphthalen-1-one (15). By following a
similar sequence of reactions as that from 14 to 1, stereo-
isomer 14B was converted into 15 in 46% yield.
1
[a]2D2ˆϩ1.2Њ (cˆ0.5, CHCl3); H NMR (CDCl3) d 6.77
(m, 1H, C3H), 5.76 (ddd, Jˆ10.4, 6.0, 2.0 Hz, 1H, C7H),
5.49 (dd, Jˆ10.4, 2.8 Hz, 1H, C6H), 3.65 (d, Jˆ11.2 Hz,
1H, CH2O), 3.59 (d, Jˆ11.2 Hz, 1H, CH2O), 2.42 (m, 2H),
2.28 (dd, Jˆ18.4, 6.0 Hz, 1H), 2.16 (d, Jˆ18.4 Hz, 1H),
2.05 (t, Jˆ8.0 Hz, 1H), 1.77 (q, Jˆ1.6 Hz, 3H, C2–Me),
1.54 (bs, 1H, OH), 1.08 (s, 6H, Me); 13C NMR (CDCl3) d
204.0 (s, CO), 144.2, 137.6, 132.0, 121.3, 67.9 (CO), 46.9,
44.0, 39.6, 33.4, 31.6, 25.8, 18.5, 16.5. MS m/z FAB (in
NBA) 221 (Mϩ1). Anal. Calcd for C14H20O2: C, 76.33;
H, 9.15. Found: C, 75.98; H, 9.35.
1
[a]2D2ˆϩ14Њ (cˆ0.22, CHCl3); H NMR (CDCl3) d 6.76

D. H. Hua et al. / Tetrahedron 56 (2000) 7389–7398
7397
(m, 1H, C3H), 5.58 (ddd, Jˆ10.0, 5.6, 2.0 Hz, 1H C7H),
5.38 (dd, Jˆ10.0, 2.0 Hz, 1H, C6H), 2.36 (m, 2H, C4H),
2.23 (dd, Jˆ18.0, 6.0 Hz, 1H, C8H), 2.12 (d, Jˆ18.0 Hz,
1H, C8H), 1.96 (dd, Jˆ10.8, 5.2 Hz, 1H, 4aH), 1.76 (m, 3H,
vCMe), 1.07 (s, 3H, C8a–Me), 1.02 (s, 3H, C5–Me), 1.00
(s, 3H, C5–Me); 13C NMR (CDCl3) d 203.2, 144.1, 143.1,
136.7, 121.3, 46.7, 44.2, 34.9, 33.4, 31.4, 24.5, 24.3, 17.6,
16.3. Anal. Calcd for C14H20O: C, 82.30; H, 9.87. Found: C,
82.19; H, 9.66.
isopropyl group). Anal. Calcd for C11H18O: C, 79.47; H,
10.91. Found: C, 79.25; H, 10.67.
(5S,6S)-2,6-Dimethyl-6-(cis-3-iodo-2-propenyl)-5-iso-
propyl-2-cyclohexenone (22). To a cold (Ϫ40ЊC) solution
of 0.71 mmol of LDA in 1 mL of THF under argon was
added a solution of 0.06 g (0.36 mmol) of (5R,6S)-2,6-
dimethyl-5-(isopropyl)-2-cyclohexen-1-one in 1 mL of
THF. After being stirred the solution at 0ЊC for 30 min,
70 mL (0.4 mmol) of HMPA was added, stirred at the
same temperature for 4 h, and a solution of 0.2 g
(0.76 mmol) of 6 in 1 mL of THF. The solution was stirred
at 25ЊC for 18 h, diluted with aqueous sodium bicarbonate,
and extracted three times with diethyl ether. The combined
extracts were washed with brine, dried (MgSO4), concen-
trated, and column chromatographed on silica gel using a
mixture of methylene chloride and hexane (1:2) as eluant to
give 91 mg (76% yield) of 22. [a]2D2ˆϩ36.1Њ (cˆ0.8,
Compounds 19A and 19B: A 2:1 ratio was determined by 1H
NMR and the relative stereochemistry was tentatively
1
determined based on 2D NOESY spectroscopy. H NMR
(CDCl3) d 6.69 (m, 1H, vCH), 2.60–2.50 (m, 1H,
vC–CH, 19A), 2.50–2.40 (m, 1H,vC–CH, 19B), 2.18
(dt, Jˆ11.0, 2.4 Hz, 1H, vC–CH, 19A), 2.10 (m, 2H,
C2H), 1.99 (dd, Jˆ11.0, 3.6 Hz, 1H, C7aH), 1.90 (m, 2H,
C2H), 1.76 (m, 3H, Me–Cv), 1.74 (m, 3H, Me–Cv),
1.65–1.53 (m, 1H, C3H), 1.26–1.15 (m, 1H, C3H), 1.06,
(s, 3H, Me of 19B), 1.03 (s, 3H, C12–Me of 19A), 1.00 (s,
3H, Me of 19B), 0.87 (s, 3H, C3a–Me of 19A), 0.76–0.66
(m, 1H, C1aH of 19A and 19B), 0.49 (t, Jˆ4.8 Hz, 1H,
C1bH of 19A; showed NOE between C3a–Me at d 0.87),
0.45 (dd, Jˆ9.6, 4.4 Hz, 1H, C1H of 19B), 0.32 (dd, Jˆ9.2,
4.8 Hz, 1H, C1aH of 19A), 0.06 (dd, Jˆ5.6, 4.4 Hz, 1H,
C1H of 19B). 13C NMR (CDCl3) d 203.0 (s, CvO), 146.0
(s, vC), 143.1 (d, vCH, 19A), 133.5 (d, vCH, 19B), 45.7,
44.1, 43.8, 32.0, 29.0, 27.5, 27.2, 26.9, 26.8, 24.2, 23.0,
20.8, 20.0, 19.5, 19.3, 18.6, 18.5, 18.2, 16.6, 16.4, 15.0,
14.7. Anal. Calcd for C14H20O: C, 82.30; H, 9.87. Found:
C, 82.54; H, 10.03.
1
CHCl3). H NMR (CDCl3) d 6.66 (m, 1H, C3H), 6.26
(ddd, Jˆ7.2, 1.6, 1.2 Hz, 1H, CHI), 6.01 (dt, Jˆ7.6,
5.6 Hz, 1H, vCH), 2.64 (ddd, Jˆ15.0, 6.0, 2.0 Hz, 1H,
CH2Cv), 2.45–2.37 (m, 2H), 2.34–2.25 (m, 1H, C4H),
2.03 (heptd, Jˆ6.8, 2.4 Hz, 1H, CHMe2), 1.86 (ddd, Jˆ
7.6, 5.6, 2.0 Hz, 1H, C5H), 1.75 (s, 3H, C2 Me), 1.11 (s,
3H, C6 Me), 0.91 (d, Jˆ6.8 Hz, 3H, Me), 0.80 (d, Jˆ6.8 Hz,
3H, Me); 13C NMR (CDCl3) d 204.0 (s, CvO), 143.9 (d,
C3), 138.1 (d), 134.0 (s, C2), 84.3 (d, vCI), 49.6 (s), 46.7,
42.5, 27.1, 23.5, 23.1, 19.4, 19.0, 16.6. The proton assign-
ment was based on 2D COSY. Anal. Calcd for C14H21IO: C,
50.61; H, 6.37. Found: C, 50.47; H, 6.10.
(1S,5R,6S)-1,5-Dimethyl-6-isopropyltricyclo[3.3.1.02,8]-
3-nonen-9-one (23). A solution of 3.6 mg (0.016 mmol) of
palladium acetate and 8.4 mg (0.032 mmol) of triphenyl-
phosphine in 1 mL of DMF was stirred under argon at
25ЊC for 1 h. To it, were added 22 mg (0.08 mmol) of silver
carbonate, a solution of 26.5 mg (0.08 mmol) of iodide 22 in
1 mL of DMF, and then 45 mL (0.32 mmol) of triethyl-
amine. The mixture was stirred at 70ЊC for 20 h, poured
into water, and extracted three times with ether. The
combined extracts were washed with brine, dried
(MgSO4), concentrated, and column chromatographed on
silica gel using a mixture of hexane and ether (30:1) as
eluant to give 11 mg (67% yield) of 23: [a]2D2ˆϩ5.1Њ
(cˆ0.5, CHCl3); 1H NMR (CDCl3) d 5.76 (dd, Jˆ9.0,
5.0 Hz, 1H, C3H), 5.42 (dd, Jˆ9.0, 2.4 Hz, 1H, C4H),
2.05 (dd, Jˆ14.0, 8.0 Hz, 1H, C7H), 1.94 (d, Jˆ14.0 Hz,
1H, C7H), 1.91 (d, Jˆ7.0 Hz, 1H, C2H), 1.88 (m, 1H, C6H),
1.81 (d, Jˆ7.0 Hz, 1H, C8H), 1.80 (m, 1H, C12H), 1.23 (s,
3H, C10Me), 1.04 (s, 3H, C11Me), 0.82 (d, Jˆ7.0 Hz, 3H,
C13Me), 0.70 (d, Jˆ7.0 Hz, 3H, C14Me); 13C NMR
(CDCl3) d 208.8, 133.8, 122.8, 59.5, 56.9, 51.4, 46.8,
45.0, 41.3, 37.5, 34.9, 32.8, 23.1, 22.1. MS (FAB) m/z 205
(Mϩ1), 192, 165. Anal. Calcd for C14H20O: C, 82.30; H,
9.87. Found: C, 82.11; H, 10.01. The stereochemistry was
verified by 2D COSY and 2D NOESY spectroscopy.
(R)-5-Isopropyl-2-methyl-2-cyclohexen-1-one (21).12 This
compound was prepared by following the reported pro-
1
cedure12 in 85% yield. H NMR (CDCl3) d 6.74 (m, 1H,
C3H), 2.60–1.60 (a series of m, 6H), 1.76 (s, 3H, Me), 0.91
(d, Jˆ7.0 Hz, 6H, Me).
(5R,6S)-2,6-Dimethyl-5-(isopropyl)-2-cyclohexen-1-one.
To a cold (Ϫ78ЊC) solution of 2 mL (12.6 mmol) of diiso-
propylamine in 50 mL of THF under argon was added drop-
wise 9 mL (14.4 mmol) of n-BuLi (1.6 M in hexane). After
being stirred at 0ЊC for 1 h, the solution was cooled to
Ϫ78ЊC, and added into a cold (Ϫ78ЊC) solution of 1.74 g
(11.4 mmol) of 21 in 20 mL was added via cannula. The
solution was stirred for 30 min at Ϫ78ЊC and 30 min at 0ЊC.
To it, was added 1.4 mL (22.9 mmol) of methyl iodide and
the solution was stirred for 2 h at 0ЊC and 30 min at 25ЊC.
The solution was poured onto aqueous NH4Cl, and extracted
three times with diethyl ether (100 mL each). The combined
extracts were washed with brine, dried (MgSO4), concen-
trated, and column chromatographed on silica gel using a
gradient mixture of hexane and ether as eluant to give 1.62 g
(85% yield) of (5R,6S)-2,6-dimethyl-5-(isopropyl)-2-cyclo-
hexen-1-one. [a]D22ˆϪ37Њ (cˆ0.55, CHCl3). 1H NMR
(CDCl3) d 6.67 (m, 1H, C3H), 2.30 (m, 2H), 2.17 (m,
1H), 1.90 (m, 1H), 1.75 (s, 3H, C2 Me), 1.69 (m, 3H),
1.13 (d, Jˆ6.8 Hz, 3H, Me), 0.93 (d, Jˆ6.9 Hz, 3H, Me),
0.83 (d, Jˆ6.9 Hz, 3H, Me); 13C NMR (CDCl3) d 202.5 (s,
CvO), 143.4 (d, C3), 134.3 (s, C2), 46.3 (d), 44.7 (d), 27.6
(d), 24.7 (t), 20.6 (q), 16.0 (q), 15.8 (q), 12.0 (q). The stereo-
chemistry is supported by 2D COSY and 2D NOESY (no
NOE was observed between C6 methyl and the CH of the
(2R,5S,6S)-2,6-Dimethyl-2-(cis-3-iodo-2-propenyl)-5-iso-
propenyl-3-cyclohexen-1-one (25). To a cold (Ϫ78ЊC)
solution of 0.3 mL (1.4 mmol) of hexamethyldisilazane
(HMDS) in 2 mL of THF under argon was added 0.9 mL
(1.4 mmol) of n-BuLi (1.6 M in hexane). After being stirred
at 0ЊC for 1 h, a solution of 0.21 g (1.28 mmol) of ketone 4

7398
D. H. Hua et al. / Tetrahedron 56 (2000) 7389–7398
in 2 mL of THF was added via cannula at Ϫ40ЊC, the
solution was then stirred at 25ЊC for 30 min, and 0.44 mL
(2.8 mmol) of HMPA was added. The resulting solution was
stirred at 25ЊC for 30 min, a solution of 0.47 g (1.8 mmol) of
mesylate 6 in 2 mL of THF was added, stirred for 15 h,
poured into aqueous sodium bicarbonate, and extracted
three times with diethyl ether. The combined extracts
were washed with brine, dried (MgSO4), concentrated, and
column chromatographed on silica gel using a mixture of
hexane and methylene chloride (3:2) as eluant to give
from Kansas State University, NSF-REU (CHE-9732103),
and NSF-ILI (DUE-985167).
References
1. (a) Tomoda, H.; Nishida, H.; Kim, Y. K.; Obata, R.; Sunazuka,
T.; Omura, S.; Bordner, J.; Guadliana, M.; Dormer, P. G.; Smith,
A. B., III. J. Am. Chem. Soc. 1994, 116, 12097. (b) Tomoda, H.;
Kim, Y. K.; Nishida, H.; Masuma, R.; Omura, S. J. Antibiot. 1994,
47, 148. (c) Obata, R.; Sunazuka, T.; Li, Z.; Tomoda, H.; Omura, S.
J. Antibiot. 1995, 48, 749. (d) Omura, S.; Tomoda, H.; Kim, Y. K.;
Nishida, H. J. Antibiot. 1993, 46, 1168. (f) Tomoda, H.; Tabata, N.;
Yang, D.-J.; Takayangi, H.; Nishida, H.; Omura, S.; Kaneko, T.
J. Antibiot. 1995, 48, 495. (g) Tomoda, H.; Tabata, N.; Yang, D.-J.;
Takayangi, H.; Nishida, H.; Omura, S.; Kaneko, T. J. Antibiot.
1996, 49, 292.
1
0.253 g (60% yield) of 25. H NMR (CDCl3) d 6.25 (dt,
Jˆ7.2, 1.6 Hz, 1H, CHI) 6.01 (dt, Jˆ7.6, 6.0 Hz, 1H,
CHvCI), 5.60 (q, Jˆ10.0 Hz, 1H, CHv), 5.59 (q, Jˆ
10.0 Hz, 1H, vCH), 4.87 (m, 1H, vCH), 4.81 (s, 1H,
vCH), 2.77 (m, 1H), 2.73 (m, 1H), 2.66 (ddd Jˆ14.4,
6.4, 1.6 Hz, 1H, CH2CvCI), 2.22 (ddd Jˆ14.4, 7.2,
1.2 Hz, 1H, CH2CvCI), 1.71 (m, 3H, vCMe), 1.29 (s,
3H, C2Me), 0.99 (d, Jˆ6.0 Hz, 3H, C6Me); 13C NMR
(CDCl3) d 214.5 (s, CO), 145.0 (s), 137.8 (d), 134.5 (d),
130.4 (d), 113.9 (t, vCH2), 84.7 (d, vCHI), 53.8 (d), 48.9
(s), 42.8, 42.4 (t), 27.8 (q), 18.1 (q), 11.6 (q). 2D NOESY
spectra supports the assigned stereochemistry. MS m/z CI
331 (Mϩ1). Anal. Calcd for C14H19IO: C, 50.92; H, 5.80.
Found: C, 50.88; H, 5.92.
2. For a review of ACAT inhibitors: Sliskovic, D. R.; White, A. D.
Trends Pharmacol. Sci. 1991, 12 194.
3. Omura, S.; Kuno, F.; Otoguro, K.; Sunazuka, T.; Shiomi, K.;
Masuma, R.; Iwai, Y. J. Antibiot. 1995, 48, 745.
4. CETP inhibitors: (a) Coval, S. J.; Conover, M. A.; Mierzwa, R.;
King, A.; Puar, M. S.; Phife, D. W.; Pai, J. -K.; Burrier, R. E.; Ahn,
H.-S.; Boykow, G. C.; Patel, M.; Pomponi, S. A. Bioorg. Med.
Chem. Lett. 1995, 5, 605. Puupehenone and its derivatives: (b)
Ravi, B. N.; Perzanowski, H. P.; Ross, R. A.; Erdman, T. R.;
Scheuer, P. J.; Finer, J.; Clardy, J. Pure Appl. Chem. 1979, 51,
1893. (c) Hamann, M. T.; Scheuer, P. J. Tetrahedron Lett. 1991,
32, 5671. (d) Hamann, M. T.; Scheuer, P. J.; Kelly-Borges, M.
J. Org. Chem. 1993, 58, 6565.
5. For reviews of the Heck reactions in organic synthesis, see:
(a) Hegedus, L. S. J. Organomet. Chem. 1994, 477, 269. (b) de
Meijere, A.; Meyer, F. E. Angew. Chem., Int. Ed. Engl. 1994, 33,
2379. (c) Heumann, A.; Reglier, M. Tetrahedron 1996, 52, 9298.
(d) Toyota, M.; Masataka, I. Yuki Gosei Kagaku Kyokaishi 1998,
56, 818.
6. (a) Cory, R. M.; Renneboog, R. M. J. Org. Chem. 1984, 49,
3898. (b) Gesson, J. P.; Jacquesy, J. C.; Renoux B. Tetrahedron
Lett. 1986, 27, 4461.
7. Sata, Y.; Honda, T.; Shibasaki, M. Tetrahedron Lett. 1992, 33,
2593.
8. (a) Hayashi, T.; Kubo, A.; Ozawa, F. Pure Appl. Chem. 1992,
64, 421. (b) exo-Type refers to the orientation of the isopropenyl
double bond that is outside of the plane of the molecule, and endo-
type refers to the bond that is inside.
9. (a) Barton, D. H. R.; Crich, D.; Mothewell, W. B. Tetrahedron
1985, 41, 3901. (b) Barton, D. H. R.; Crich, D.; Motherwell, W. B.
Tetrahedron Lett. 1983, 24, 4979.
(3aR,6S,7aR)-6,7a-Dimethyl-5-isopropenyl-3a,6,7,7a-
tetrahydro-1H-inden-7-one (26). A solution of 5 mg
(0.022 mmol) of palladium acetate and 12 mg (0.044
mmol) of triphenylphosphine in 1 mL of DMF was stirred
under argon at 25ЊC for 1 h. To it, 31 mg (0.110 mmol) of
silver carbonate, a solution of 37 mg (0.110 mmol) of iodide
25 in 1 mL of DMF, and 32 mL (0.22 mmol) of triethyl-
amine were added. The resulting mixture was stirred at
60ЊC for 20 h, cooled to 25ЊC, poured into water, and
extracted three times with diethyl ether. The combined
extracts were washed with brine, dried (MgSO4), concen-
trated, and column chromatographed on silica gel using a
mixture of hexane and ether (20:1) as eluant to give 15 mg
(65% yield) of 26: [a]2D2ˆϩ158Њ (cˆ0.1, CHCl3); 1H NMR
(CDCl4) d 5.99 (d, Jˆ6.0 Hz, 1H, C4H), 5.66 (m, 2H,
C2&3Hs), 4.98 (s, 2H, C9Hs), 3.36 (m, 1H, C3aH), 3.27
(q, Jˆ7.6 Hz, 1H, C6H), 2.94 (dm, Jˆ17.0 Hz, 1H, C1H,
2.30 (dq, Jˆ17.0, 2.4 Hz, 1H, C1H), 1.93 (s, 3H, C10Me),
1.26 (s, 3H, C12Me), 1.24 (d, Jˆ7.6 Hz, 3H, C11Me); 13C
NMR (CDCl3) d 218.1, 141.3, 133.1, 128.8, 123.4, 123.3,
112.0, 55.6, 50.9, 45.7, 43.3, 24.8, 21.3, 20.0. Anal. Calcd
for C14H18O: C, 83.12; H, 8.97. Found: C, 82.86; H, 9.20.
10. Grigg, R.; Loganathan, V.; Sridharan, V.; Stevenson, P.;
Sukirthalingam, S.; Worakun, T. Tetrahedron 1996, 52, 11479
(and references cited therein).
Acknowledgements
We gratefully acknowledge financial support from
American Heart Association, Heartland Affiliate, BioServe
Space Technologies (NAGW-1197), Great Plains Diabetes
Inc., Wichita, KS, Special Group Incentive Research Award
11. Cacchi, S.; Morera, E.; Ortar, G. Tetrahedron Lett. 1984, 25,
4821.
12. Ireland, R.; Bey, P. Organic Synthesis Collective, Volume VI,
1988 (p 459).