Construction of the adamantane core of plukenetione-type polycyclic polyprenylated acylphloroglucinols

Article abstract of DOI:10.1021/jo801595y

(Chemical Equation Presented) The construction of a highly functionalized adamantane core of plukenetione-type polycyclic polyprenylated acylphloroglucinols (PPAPs) is described. The method features the construction of the bicyclo[3.3.1]nonane core (3) by successive Michael reactions and the construction of the adamantane core of plukenetione-type PPAPs by acid-catalyzed cyclization of a bicyclo[3.3.1]nonane precursor (2).

Full text of DOI:10.1021/jo801595y

Construction of the Adamantane Core of Plukenetione-Type
Polycyclic Polyprenylated Acylphloroglucinols
Ryukichi Takagi,* Yuta Inoue, and Katsuo Ohkata
Department of Chemistry, Graduate School of Science, Hiroshima UniVersity, 1-3-1 Kagamiyama,
Higashi-Hiroshima 739-8526, Japan
rtakagi@hiroshima-u.ac.jp
ReceiVed July 18, 2008
The construction of a highly functionalized adamantane core of plukenetione-type polycyclic polyprenylated
acylphloroglucinols (PPAPs) is described. The method features the construction of the bicyclo[3.3.1]nonane
core (3) by successive Michael reactions and the construction of the adamantane core of plukenetione-
type PPAPs by acid-catalyzed cyclization of a bicyclo[3.3.1]nonane precursor (2).
Introduction
Polycyclic polyprenylated acylphloroglucinols (PPAPs) are
secondary metabolites isolated from Guttiferous plants and are
biosynthetically generated from monocyclic polyprenylated
acyphloroglucinols.1 PPAPs feature a highly oxygenated and
densely substituted bicyclo[3.3.1]nonane, bicyclo[3.2.1]octane,
adamantane, or homoadamantane core. PPAPs are classified into
three types (types A-C), depending on the relative position of
the acyl group on the bicyclic core structure (Figure 1).1a,2 The
less common PPAPs bearing an adamantane core are also
classified accordingly (Figure 2).3
PPAPs have attracted attention as synthetic targets due to
their significant biological activity1,4 and their synthetically
challenging structure, and a number of synthetic efforts toward
the bicyclo[3.3.1]nonane core have been reported.5,6 We have
recently developed a method for the construction of polyfunc-
* To whom correspondence should be addressed. Tel: +81-82-424-7434. Fax:
+81-82-424-0727.
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FIGURE 1. PPAPs with a bicyclo[3.3.1]nonane core.
tionalized bicyclo[3.3.1]nonanes by successive Michael reactions
of 2-cyclohexenone derivatives with acrylates.7 In the course
of the examination, we found that adamantane derivatives could
be constructed by the one-pot reaction of ethyl 2,4-dioxocy-
clohexanecarboxylate with 2-phenylethyl 2-(acetoxymethyl)-
acrylate or 2-(acetoxymethyl)-1-phenyl-2-propen-1-one via a
domino reaction involving inter- and intramolecular Michael
ˇ
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9320 J. Org. Chem. 2008, 73, 9320–9325
10.1021/jo801595y CCC: $40.75 2008 American Chemical Society
Published on Web 11/04/2008

Construction of the Adamantane Core of Acylphloroglucinols
SCHEME 1. Synthetic Plan for the Model Adamantane
Compound 1 of Plukenetione
FIGURE 2. PPAPs with an adamantane core.
reactions and a Dieckmann condensation or an aldol-type
reaction in succession.8 Although the constructions of
bicyclo[3.3.1]nonanes9 and adamantanes10 via Michael reactions
have been reported, the Michael donors have mostly been
limited to enamines derived from cyclohexanones. The method
we developed using successive Michael reactions is able to
directly afford poly functionalized bicyclo[3.3.1]nonenones and
adamantanones from cyclohexenones. Porco and co-workers
have recently reported a similar approach to properly function-
alized clusianone-type bicyclo[3.3.1]nonanes via an alkylative
dearomatization-annulation process involving acylphlorogluci-
nols and in the course of their investigation, they found that a
partially functionalized adamantane core for the type B hyperi-
bone could also be prepared.6h However, probably due to the
increased complexity accompanying adamantane cored PPAPs,
so far, no total synthesis of adamantane cored natural PPAPs
have been reported, and this is the only report we are aware of
involving the synthesis of adamantanes with an advanced
structure toward PPAP. We have succeeded in the construction
of an advanced model compound of a type A adamantane cored
PPAP, plukenetione. Our compound differs with the natural
product only in the precise identity of three alkyl substituents
(methyls in the place of prenyls). Herein we describe the
synthetic details.
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Results and Discussion
The reports on both the construction of the adamantane
skeleton from bicyclo[3.3.1]nonanes8,11 and the speculated
biosynthetic pathway of sampsoniones3b-e encouraged us to
attempt the construction of adamantane 1, as a highly function-
alized model compound of plukenetione, by the acid-catalyzed
cyclization of bicyclo[3.3.1]nonane 2 (Scheme 1).12 We envi-
sioned that bicyclo[3.3.1]nonane 3, which was generated from
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Takagi et al.
SCHEME 2. Successive Michael Reactions of 4 with 5
SCHEME 3. Introduction of the C10-gem-Dimethyl Groups
and the C2-Carbonyl Group
TABLE 1. Optimization of the Intramolecular Michael Reaction
of 6
Scheme 3. To prevent nucleophilic attack during introduction
of the C10-gem-dimethyl groups, the C9-carbonyl group was
reduced with LiBH4 to give 7 as a single isomer (100%). The
product stereochemistry of 7 was determined on the basis of
1H NMR dif-NOE experiments, in which NOE enhancement
between H2 and H9 was observed (Figure 3). The steric
hindrance of the pseudoaxial C6-methyl group probably played
an important role in bringing about the high stereoselectivity.17
The C10-gem-dimethyl groups were introduced by the reaction
of 7 with MeLi in the presence of CeCl3 (74%).18,19 The X-ray
structure of 8 confirmed the stereochemical assignment in the
reduction of 3. The C2-carbonyl group was introduced by the
Pd(OH)2/C-catalyzed allylic oxidation of 8.20 Compared with
typical literature conditions, a large amount of base and/or
catalyst and long reaction time were necessary for optimum
yields [Pd(OH)2/C (5 mol%), Cs2CO3 (10 equiv), 0 °C, 1 week:
60%; Pd(OH)2/C (5 mol%), Cs2CO3 (5.0 equiv), 0 °C, 1.5 days
then Pd(OH)2/C (5 mol%), 0 °C, 1.5 days: 58%].
successive Michael reactions of cyclohexenone 513 with acrylate
4,14 would serve as a moderately substituted synthetic interme-
diate for adamantane 1.
Our synthetic effort commenced with successive Michael
reactions of cyclohexenone 5 with acrylate 4 (Scheme 2). The
annulation precursor 6 was obtained in 92% yield by the
intermolecular Michael reaction of cyclohexenone 5 with
acrylate 4 (E/Z 25:1).15 The stereoselectivity in the intermo-
lecular Michael reaction was similar to that observed by
Buchholz and Hoffmann.16 Results of the optimization of the
intramolecular Michael reaction of 6 are summarized in Table
1. Treatment of the annulation precursor 6 with K2CO3 (3.0
equiv) and tetrabutylammonium bromide (TBAB) (1.0 equiv)
at 90 °C for 3 days gave R-annulation product 3 in 41% yield
(entry 1).7b When Cs2CO3 was used as the base instead of
K2CO3, a diastereomeric mixture of R-annulation product 3 and
γ-annulation product γ-3 was obtained (entry 2). This result
suggested that decomposition and/or isomerization of the
annulation products under the reaction conditions had occurred.
When the reaction was carried out at 110 °C for 31 h, the yield
of the annulation products improved (3: 55% plus a diastere-
omeric mixture of the γ-annulation product γ-3: 25%, entry 3).
The introduction of the C10-gem-dimethyl groups and the
C2-carbonyl group to bicyclo[3.3.1]nonane 3 is depicted in
FIGURE 3. 1H NMR NOE experiment of 7.
With bicyclo[3.3.1]nonane 9 in hand, we shifted our attention
to the introduction of the C3-benzoyl group. We initially planned
the introduction of the C3 benzoyl group via diketone 106d,21
and attempted acid-catalyzed deprotection of ethyl enol ether 9
with concd HCl (10 equiv) in THF at 40 °C. However,
dehydration product 11 and adamantane 12 were obtained
(17) In the reduction of 7-endo-tert-butoxycarbonyl-1,5-dimethylbicyclo[3.3.1]-
non-2-en-9-one with NaBH4, practically no diastereoselectivity was observed
(dr 44:56).
(18) (a) Imamoto, T.; Kusumoto, T.; Tawarayama, Y.; Sugiura, Y.; Mita,
T.; Hatanaka, Y.; Yokoyama, M. J. Org. Chem. 1984, 49, 3904–3912. (b)
Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.; Kamiya, Y. J. Am.
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(19) In initial studies, the C7-tert-butoxy ester was used as the substituent.
However, the organocerium reaction did not proceed with this ester. Therefore,
the less bulky ethyl ester 3 was used instead for the ensuing synthetic stu-
dies.
(14) (a) Hayashi, N.; Yanagihara, K.; Tsuboi, S. Tetrahedron: Asymmetry
1998, 9, 3825–3830. (b) Trost, B. M.; Machacek, M. R.; Tsui, H. C. J. Am.
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(15) The diastereomer mixture was used for the next intramolecular Michael
reaction without separation.
(16) (a) Buchholz, R.; Hoffmann, H. M. R. HelV. Chim. Acta 1991, 74, 1213–
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8361. (d) Chandrasekhar, S.; Chandrashekar, G.; Vijeender, K.; Reddy, M. S.
Tetrahedron Lett. 2006, 47, 3475–3478.
(20) (a) Yu, J.-Q.; Corey, E. J. Org. Lett. 2002, 4, 2727–2730. (b) Yu, J.-Q.;
Corey, E. J. J. Am. Chem. Soc. 2003, 125, 3232–3233. (c) Yu, J.-Q.; Wu, H.-C.;
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9322 J. Org. Chem. Vol. 73, No. 23, 2008

Construction of the Adamantane Core of Acylphloroglucinols
SCHEME 4. Attempted Acid-Catalyzed Deprotection of the
Ethoxy Enol Ether
SCHEME 6. C3-Benzoylation via a Vinyl Anion
zole (3,5-DMP).22,23 Exposure of 9 to Swern oxidation condi-
tions was unsatisfactory, furnishing a complex mixture also
containing 11 and 12 among others. The benzoylation of 13
with benzoyl chloride via the intramolecular hetero-Michael
reaction gave O-benzoylation product 14 (39%, two steps).
Attempted cyanide catalyzed isomerization of 14 to C-benzoy-
lation product 2 with KCN and Et3N failed.21a,24 A switch to
benzoyl cyanide25 for the reaction with 13 enabled us to obtain
C-benzoylation products 2 (12%, two steps) and 15 (5%, two
steps) along with protonated product 16 (1%, two steps).
However, the separation of the products 2, 15, and 16 proved
to be troublesome.
SCHEME 5. Attempted C3-Benzoylation via an
Intramolecular Hetero-Michael Reaction
Although 2 and 15 could be envisioned as precursors to the
benzoylated adamantane product, the total yield of the two was
not acceptable. Thus, in order to develop a more practical
method, C3-benzoylation via the vinyl anion was examined
(Scheme 6).6c,e,f To prevent the hetero-Michael pathway, the
C10-alcohol of 9 was protected with a trimethylsilyl (TMS)
group (85%, two steps from 9). Treatment of 17 with lithium
2,2,6,6-tetramethylpiperidide (LTMP), followed by benzoyl
chloride gave C3-benzoylation product 2, in which the TMS
group incidentally hydrolyzed off during workup (88%).
The acid-catalyzed cyclization of 2 is summarized in Scheme
7. In the acid-catalyzed cyclization of 9, decomposition of THF
by acids had been observed to accompany adamantane formation
(Scheme 4). Therefore, to overcome this side reaction, several
acidic reaction conditions were examined for the cyclization of
2. The attempted acid-catalyzed cyclization of 2 in DMSO and
toluene accompanied decomposition of the solvent (entries
1-3).26 However, when 2 was treated with TfOH (1.0 equiv)
in CH2Cl2, decomposition of the solvent could be avoided and
adamantane 2 was obtained in 59% yield (entry 4).
instead of diketone 10 (Scheme 4). The adamantane skeleton
of 12 was confirmed by X-ray structural analysis. Treatment of
11 with concd HCl in THF at 60 °C quantitatively gave
adamantane 12. Thus, deprotection of the enol ether and
cyclization to the adamantane skeleton could be achieved in an
elegant tandem manner by acid catalysis. Unfortunately, intro-
duction of the C3-benzoyl group to adamantane 12 could not
be effected in spite of extensive efforts and we had to abandon
this route.
Since C3-benzoylation had to be carried out before the
formation of the adamantane framework, we decided to attempt
C3-benzoylation by reacting the enolate involving C3 position
generated by the intramolecular hetero-Michael addition of the
oxide from the C10-alcohol to the C4 position (Scheme 5). This
strategy seemed favorable since the C10-alcohol could also be
protected during the process. Before carrying out the intramo-
lecular hetero-Michael reaction, the C9-carbonyl group was
regenerated by the oxidation of 9 with CrO3 ·3,5-dimethylpyra-
In summary, we have developed an efficient method for
the construction of the adamantane core of plukenetione-type
PPAPs. The method features the construction of bicyclo[3.3.1]-
nonane 3 by successive Michael reactions and the construc-
tion of the adamantane core by acid-catalyzed cyclization of
bicyclo[3.3.1]nonane 2. This report is the first on the cons-
(22) Salmond, W. G.; Barta, M. A.; Havens, J. L. J. Org. Chem. 1978, 43,
2057–2059.
(23) The product could not be freed of small quanitities of impurities upon
purification. Therefore, the product was used for the next reaction after only
simple purification.
(24) Tabuchi, H.; Hamamoto, T.; Ichihara, A. Synlett 1993, 651–652.
(25) Wiles, C.; Watts, P.; Haswell, S. J.; Pombo-Villar, E. Tetrahedron Lett.
2002, 43, 2945–2948.
J. Org. Chem. Vol. 73, No. 23, 2008 9323

Takagi et al.
SCHEME 7. Acid-Catalyzed Cyclization of 2 to the
Adamantane Core of Plukenetione
1 H), 2.66 (dt, J ) 14.5, 1.7 Hz, 1 H), 2.52 (dd, J ) 16.2, 4.8 Hz,
1 H), 2.24 (dt, J ) 7.4, 1.7 Hz, 1 H), 2.12 (dt, J ) 16.2, 2.0 Hz,
1 H), 1.89 (ddd, J ) 14.5, 7.4, 2.0 Hz, 1 H), 1.30 (t, J ) 7.2 Hz,
3 H), 1.28 (t, J ) 7.0 Hz, 3 H), 1.12 (s, 3 H), 1.02 (s, 3 H), 0.92
(d, J ) 7.4 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ 214.0, 173.1,
154.9, 94.2, 62.6, 60.6, 52.9, 45.4, 44.5, 42.4, 38.1, 37.8, 23.8, 16.1,
15.3, 14.5, 14.1; EI-HRMS m/z calcd for C17H26O4 [M+] 294.1831,
found 294.1838. Anal. Calcd for C17H26O4: C, 69.36; H, 8.90.
Found: C, 69.40; H, 8.60.
2-Ethoxy-7-endo-ethoxycarbonyl-9-hydroxy-1,5,8-exo-trimethy-
lbicyclo[3.3.1]non-2-ene (7). To a solution of 3 (123.3 mg, 0.42
mmol) at 0 °C was added LiBH4 (27.4 mg, 1.26 mmol). After the
mixture was stirred at 0 °C for 3.5 h, the reaction was quenched
with satd NH4Cl, and the mixture was extracted with CH2Cl2. The
combined organic layer was washed with H2O and brine, dried over
Na2SO4, and evaporated. The resulting residue was purified by
column chromatography (silica gel, hexane/EtOAc 5:1) to give 7
1
(130.2 mg, 100%) as a yellow oil: H NMR (500 MHz, C6D6) δ
truction of the adamantane core of plukenetione and the
product differs with the actual natural product only in the
exact identity of three alkyl groups (methyls in the place of
prenyls). Synthetic studies toward plukenetione A using the
newly developed methodology are now in progress.
4.14 (dd, J ) 4.9, 2.3 Hz, 1 H), 3.99 (dq, J ) 10.8, 7.2 Hz, 1 H),
3.83 (dq, J ) 10.8, 7.2 Hz, 1 H), 3.39-3.32 (m, 2 H), 3.08 (s, 1
H), 2.90 (q, J ) 7.6 Hz, 1 H), 2.31 (dd, J ) 16.2, 4.9 Hz, 1 H),
2.27 (dt, J ) 7.0, 2.4 Hz, 1 H), 2.12 (ddt, J ) 14.0, 2.4, 1.0 Hz, 1
H), 1.92 (ddd, J ) 16.2, 2.3, 1.4 Hz, 1 H), 1.88 (ddd, J ) 14.0,
7.0, 1.4 Hz, 1 H), 1.31 (s, 3 H), 1.27 (d, J ) 7.6 Hz, 3 H), 1.18 (t,
J ) 7.0 Hz, 3 H), 1.01 (t, J ) 7.2 Hz, 3 H), 0.93 (s, 3 H); 13C
NMR (125 MHz, C6D6) δ 174.1, 157.6, 92.8, 79.4, 62.1, 60.0, 46.0,
42.3, 36.9, 34.9, 33.7, 28.9, 27.8, 19.3, 18.2, 14.8, 14.2; EI-HRMS
m/z calcd for C17H28O4 [M+] 296.1988, found 296.2000.
Experimental Section
3-Ethoxy-6-(2′-ethoxycarbonyl-2′Z-butenyl)-2,6-dimethyl-2-cy-
clohexenone (6). To a stirred solution of LDA, prepared from
i-Pr2NH (2.10 mL, 16.0 mmol) in THF (13 mL) and n-BuLi (1.60
M in hexane, 8.20 mL, 13.1 mmol), was added a solution of
cyclohexenone 5 (1.44 g, 8.59 mmol) in THF (3.0 mL) at -78 °C.
After 30 min, a solution of acrylate 4 (1.85 g, 9.94 mmol) in THF
(3.0 mL) was added. The mixture was stirred at -78 °C for 4 h
and quenched with satd NH4Cl. The resulting mixture was extracted
with Et2O. The combined organic layer was washed with water
and brine, dried over Na2SO4, and evaporated. The resulting residue
was purified by column chromatography (silica gel, hexane/EtOAc
5:1) to give a mixture of E- and Z-6 (2.33 g, 92%, E/Z 25:1) as a
yellow oil. E-6: IR (thin film) 2981, 2938, 1709, 1618, 1449, 1381,
1256, 1052, 1025 cm-1; 1H NMR (500 MHz, CDCl3) δ 6.94 (q, J
) 7.2 Hz, 1 H), 4.19-4.12 (m, 2 H), 4.06 (q, J ) 6.9 Hz, 2 H),
2.80 (d, J ) 13.8 Hz, 1 H), 2.78-2.69 (m, 1 H), 2.55-2.42 (m, 1
H), 2.52 (d, J ) 13.8 Hz, 1 H), 1.84 (dt, J ) 13.9, 5.8 Hz, 1 H),
1.79 (d, J ) 7.2 Hz, 3 H), 1.75-1.67 (m, 1 H), 1.69 (t, J ) 1.6
Hz, 3 H), 1.35 (t, J ) 6.9 Hz, 3 H), 1.28 (t, J ) 7.2 Hz, 3 H), 1.00
(s, 3 H); 13C NMR (125 MHz, CDCl3) δ 202.2, 169.2, 168.8, 139.8,
130.2, 113.2, 63.1, 60.4, 43.9, 32.5, 32.0, 22.2, 22.3, 15.3, 15.2,
14.2, 8.0; EI-HRMS m/z calcd for C17H26O4 [M+] 294.1831, found
294.1819. Anal. Calcd for C17H26O4: C, 69.36; H, 8.90. Found: C,
69.07; H, 9.16.
2-Ethoxy-7-endo-(2′-hydroxy-2′-propyl)-9-hydroxy-1,5,8-exo-
trimethylbicyclo[3.3.1]non-2-ene (8). THF (2.0 mL) was added to
anhydrous CeCl3 (256.3 mg, 1.04 mmol), and the mixture was
stirred at room temperature for 11 h. To the mixture at -78 °C
was added MeLi (1.20 M in Et2O, 0.90 mL, 1.08 mmol) and stirring
was continued at the same temperature for 1.5 h. A solution of 7
(34.4 mg, 0.12 mmol) in THF (1.0 mL) was added to the reaction
mixture. After the resulting mixture was stirred at -78 °C to room
temperature for 7 h, the reaction was quenched with satd NH4Cl
and extracted with EtOAc. The combined organic layer was washed
with H2O and brine, dried over Na2SO4, and evaporated. The
resulting residue was purified by column chromatography (silica
gel, hexane/EtOAc 3:1) to give 8 (21.6 mg, 74%) as a white solid:
mp 116-119 °C; IR (thin film) 3475, 3348, 2974, 2933, 2881, 1705,
1
1643, 1454, 1370, 1264, 1215, 1174, 1060 cm-1; H NMR (500
MHz, C6D6) δ 4.19 (dd, J ) 5.9, 1.7 Hz, 1 H), 3.48-3.35 (m, 2
H), 2.99 (d, J ) 4.3 Hz, 1 H), 2.11 (dq, J ) 7.5, 7.0 Hz, 1 H), 1.89
(dt, J ) 12.0, 7.5 Hz, 1 H), 1.83 (dd, J ) 15.6, 1.7 Hz, 1 H), 1.70
(d, J ) 15.6, 5.9 Hz, 1 H), 1.52 (dd, J ) 14.1, 7.5 Hz, 1 H), 1.46
(d, J ) 7.0 Hz, 3 H), 1.41 (dd, J ) 14.1, 12.0 Hz, 1 H), 1.38 (s,
3 H), 1.11 (s, 3 H), 1.09 (s, 3 H), 1.08 (t, J ) 7.0 Hz, 3 H), 0.99
(s, 3 H); 13C NMR (125 MHz, C6D6) δ 161.6, 90.8, 81.9, 62.4,
48.8, 43.8, 41.2, 34.8, 34.1, 33.3, 29.8, 26.9, 26.7, 21.9, 21.5, 20.0,
14.7; EI-HRMS m/z calcd for C17H30O3 [M+] 282.2195, found
282.2204. Anal. Calcd for C17H30O3: C, 72.30; H, 10.71. Found:
C, 72.37; H, 10.59.
4-Ethoxy-7-endo-(2′-hydroxy-2′-propyl)-9-hydroxy-1,5,6-exo-
trimethylbicyclo[3.3.1]non-3-en-2-one (9). To a solution of 8 (51.4
mg, 0.18 mmol) in CH2Cl2 (1.8 mL) at 0 °C were added Pd(OH)2/C
(20 wt % Pd on C, 6.39 mg, 0.91 mmol), Cs2CO3 (296.7 mg, 0.91
mmol), and tert-butyl hydroperoxide (70 wt % in H2O, 0.12 mL,
0.91 mmol). The resulting mixture was vigorously stirred at 0 °C
under an oxygen atmosphere. After 1.5 days, additional Pd(OH)2/C
(20 wt % Pd on C, 6.45 mg, 0.93 mmol) was added, and the mixture
was stirred for an additional 1.5 days under the same conditions.
The reaction was quenched with satd NH4Cl and the mixture was
extracted with CH2Cl2. The combined organic layer was washed
with H2O and brine, dried over Na2SO4, and evaporated. The
resulting residue was purified by recrystallization from MeOH to
give 9 (31.4 mg, 58%) as a white solid: mp 182-183 °C; IR (thin
film) 3326, 3267, 2986, 2968, 2936, 2887, 2473, 2429, 1627, 1598,
2-Ethoxy-7-endo-ethoxycarbonyl-1,5,8-exo-trimethylbicyclo[3.3.1]-
non-2-en-9-one (3). To a solution of 6 (101.0 mg, 0.34 mmol, E/Z
25:1) in toluene (1.5 mL) were added K2CO3 (142.2 mg, 1.03 mmol)
and TBAB (111.0 mg, 0.34 mmol). The resulting mixture was
stirred at 110 °C for 31 h. The mixture was quenched with satd.
NH4Cl and extracted with CH2Cl2. The combined organic layer
was washed with H2O and brine, dried over MgSO4, filtered, and
evaporated. The resulting residue was purified by preparative TLC
(silica gel, hexane/EtOAc 10:1) to give 3 (55.7 mg, 55%) as a
yellow oil and γ-3 (25.3 mg, 25%) as a white solid. 3: mp 73-75
°C; IR (thin film) 2973, 2943, 1714, 1665, 1455, 1369, 1232, 1207,
1
1144, 1033 cm-1; H NMR (500 MHz, CDCl3) δ 4.41 (dd, J )
4.8, 2.0 Hz, 1 H), 4.16 (dq, J ) 10.7, 7.2 Hz, 1 H), 4.03 (dq, J )
10.7, 7.16 Hz, 1 H), 3.57-3.50 (m, 2 H), 3.14 (qt, J ) 7.4, 1.7 Hz,
(26) When DMSO was used as a solvent, the stench like Me2S occurred and
a large amount of concd HCl and long reaction time were required. In the 1H
NMR of the crude product, which was obtained from the reaction in toluene,
some complicated signals were observed in the aromatic region.
9324 J. Org. Chem. Vol. 73, No. 23, 2008

Construction of the Adamantane Core of Acylphloroglucinols
1
1464, 1375, 1241, 1227, 1167, 1067 cm-1; H NMR (500 MHz,
for 30 min, a solution of benzoyl chloride (40 µL, 0.35 mmol) in
THF (1.1 mL) was added to the mixture at -78 °C. After the
mixture was stirred at -78 °C for 2.5 h, the reaction was quenched
with satd NH4Cl. The mixture was extracted with CH2Cl2. The
combined organic layer was washed with H2O and brine, dried over
Na2SO4, and evaporated. The resulting residue was purified by
column chromatography (silica gel, hexane/EtOAc 2:1) to give 2
(44.5 mg, 86%) as a yellow oil: IR (thin film) 3521, 2981, 2937,
1731, 1708, 1673, 1659, 1574, 1450, 1373, 1314, 1294, 1237, 1171,
CD3OD) δ 5.16 (s, 1 H), 3.96-3.82 (m, 2 H), 3.42 (s, 1 H), 1.92
(ddd, J ) 11.0, 6.6, 5.2 Hz, 1 H), 1.83 (dq, J ) 7.0, 6.2 Hz, 1 H),
1.66 (dd, J ) 15.2, 11.0 Hz, 1 H), 1.40 (dd, J ) 15.2, 6.6 Hz, 1
H), 1.37 (t, J ) 7.1 Hz, 3 H), 1.27 (s, 3 H), 1.25 (d, J ) 7.0 Hz,
3 H), 1.12 (s, 3 H), 1.02 (s, 3 H), 0.99 (s, 3 H); 13C NMR (125
MHz, CD3OD) δ 206.3, 184.0, 101.1, 78.4, 74.7, 66.1, 50.1, 46.6,
45.2, 32.5, 31.2, 28.3, 26.4, 22.6, 21.4, 20.6, 14.4; EI-HRMS m/z
calcd for C17H28O4 [M+] 296.1988, found 296.2005. Anal. Calcd
for C17H28O4: C, 68.89; H, 9.52. Found: C, 69.16; H, 9.37.
4-Ethoxy-7-endo-(2′-hydroxy-2′-propyl)-1,5,6-exo-trimethylbicy-
clo[3.3.1]non-3-ene-2,9-dione (13). To a solution of CrO3 (159.1
mg, 1.59 mmol) in CH2Cl2 (0.7 mL) at -20 °C was added 3,5-
dimethylpyrazole (3,5-DMP) (153.4 mg, 1.60 mmol). After the
reaction mixture was stirred for 20 min, a solution of 9 (47.1 mg,
0.16 mmol) in CH2Cl2 (0.8 mL) was added, and stirring was
continued at -20 °C for 2 h. The mixture was then diluted with
Et2O and passed through a pad of Celite. The filtrate was washed
with 1 M HCl, H2O, and brine, dried over Na2SO4, and evaporated.
The resulting residue was purified by column chromatography (silica
gel, hexane/EtOAc 1:1) to provide 13 (49.9 mg) as a yellow oil
with a small quantity of impurities. The product was used for the
next reaction without further purification: IR (thin film) 3534, 2984,
2933, 2895, 1719, 1666, 1597, 1478, 1454, 1372, 1249, 1218, 1162,
1
1015 cm-1; H NMR (500 MHz, CD3OD) δ 7.91-7.88 (m, 2 H),
7.64-7.59 (m, 1 H), 7.52-7.47 (m, 2 H), 3.94-3.84 (m, 2 H),
2.95 (dd, J ) 14.6, 12.5 Hz, 1 H), 2.81 (dq, J ) 7.4, 6.9 Hz, 1 H),
2.01 (dd, J ) 14.6, 7.4 Hz, 1 H), 1.55 (dt, J ) 12.5, 7.4 Hz, 1 H),
1.31 (s, 3 H), 1.26 (t, J ) 6.9 Hz, 3 H), 1.24 (s, 3 H), 1.23 (s, 3 H),
1.15 (s, 3 H), 1.05 (d, J ) 6.9 Hz, 3 H); 13C NMR (125 MHz,
CD3OD) δ 210.2, 197.8, 196.8, 180.5, 139.3, 135.0, 130.2 (×2),
130.0 (×2), 127.6, 73.1, 71.7, 60.0, 57.0, 50.0, 43.5, 41.8, 29.0,
27.1, 20.5, 17.2, 16.0, 15.3; EI-HRMS m/z calcd for C24H30O5 [M+]
398.2093, found 398.2089.
3-Benzoyl-1,5,6-exo-10,10-pentamethyltricyclo[3.3.1.13.7]deca-
2,4,9-trione (1). A solution of TfOH (0.1 M in CH2Cl2, 0.63 mL,
0.063 mmol) in CH2Cl2 was added to 2 (29.6 mg, 63.0 µmol), and
the reaction mixture was refluxed for 5.5 h. After the reaction
mixture was cooled to room temperature, the reaction was quenched
with satd K2CO3. The mixture was extracted with CH2Cl2. The
combined organic layer was washed with H2O and brine, dried over
Na2SO4, and evaporated. The resulting residue was purified by
column chromatography (silica gel, hexane/EtOAc 5:1) to give 1
(13.2 mg, 59%) as a white solid: mp 240-241 °C; IR (thin film)
2985, 2936, 1741, 1701, 1596, 1455, 1442, 1393, 1375, 1270, 1237,
1024 cm-1 1H NMR (500 MHz, CD3OD) δ 5.39 (s, 1 H),
;
4.07-4.01 (m, 2 H), 2.62 (dq, J ) 7.1, 6.9 Hz, 1 H), 2.46 (dd, J
) 14.6, 11.7 Hz, 1 H), 1.92 (dd, J ) 14.6, 7.7 Hz, 1 H), 1.52 (ddd,
J ) 11.7, 7.7, 7.1 Hz, 1 H), 1.41 (t, J ) 7.0 Hz, 3 H), 1.18 (s, 3
H), 1.15 (s, 3 H), 1.13 (s, 3 H), 1.12 (s, 3 H), 1.02 (d, J ) 6.9 Hz,
3 H); 13C NMR (125 MHz, CD3OD) δ 211.5, 199.3, 182.0, 100.2,
73.4, 67.1, 59.2, 55.0, 50.2, 44.1, 41.7, 28.7, 26.3, 20.7, 16.8, 16.1,
14.3; EI-HRMS m/z calcd for C17H26O4 [M+] 294.1831, found
294.1830. Anal. Calcd for C17H26O4: C, 69.36; H, 8.90. Found: C,
69.14; H, 8.83.
1
1163, 1149, 1018, 1001 cm-1; H NMR (500 MHz, CDCl3) δ
7.44-7.40 (m, 1 H), 7.31-7.27 (m, 2 H), 7.17-7.14 (m, 2 H),
2.92-2.86 (m, 1 H), 2.53 (dt, J ) 13.8, 2.7 Hz, 1 H), 2.47 (dd, J
) 13.8, 2.7 Hz, 1 H), 1.58 (q, J ) 2.7 Hz, 1 H), 1.49 (s, 3 H), 1.48
4-Ethoxy-7-endo-(2′-trimethylsilyloxy-2′-propyl)-1,5,6-exo-
trimethylbicyclo[3.3.1]non-3-ene-2,9-dione (17). To a solution of
13 (51.7 mg, 0.18 mmol) in DMF (1.7 mL) at room temperature
were added imidazole (108.3 mg, 1.59 mmol) and TMSCl (70.0
µL, 0.55 mmol). After the mixture was stirred at room temperature
for 2 h, the reaction was quenched with H2O, and the mixture was
extracted with Et2O. The combined organic layer was washed with
brine, dried over Na2SO4, and evaporated. The resulting residue
was purified by column chromatography (silica gel, hexane/EtOAc
1:1) to give 17 (54.8 mg, 85% from 9) as a white solid: mp 51-52
°C; IR (thin film) 2976, 2931, 1727, 1676, 1591, 1460, 1378, 1250,
(s, 3 H), 1.30 (s, 3 H), 1.27 (s, 3 H), 1.08 (d, J ) 6.9 Hz, 3 H); 13
C
NMR (125 MHz, CDCl3) δ 203.7, 202.5, 202.4, 193.1, 135.0, 132.4,
128.8 (x2), 128.1 (x2), 81.6, 69.1, 65.0, 55.3, 49.1, 49.0, 41.8, 23.7,
23.1, 15.0, 14.8, 12.9; EI-HRMS m/z calcd for C22H24O4 [M+]
352.1675, found 352.1689. Anal. Calcd for C22H24O4: C, 74.98;
H, 6.86. Found: C, 74.92; H, 6.60.
Acknowledgment. This work was partly supported by a
Grant-in-Aid for Scientific Research on Priority Areas (No.
17035055) from the Ministry of Education, Culture, Sports,
Science and Technology (MEXT). NMR, MS, and elemental
analysis measurements were made at the Natural Science Center
for Basic Research and Development (N-BARD), Hiroshima
University. We express our gratitude toward Dr. Yoshikazu
Hiraga for NMR measurements at the Hiroshima Prefectural
Institute of Science and Technology. We thank Dr. Satoshi
Kojima for crystallographic analysis and suggestions. We thank
Dr. Manabu Abe for his helpful discussions.
1218, 1250, 1161 cm-1; H NMR (500 MHz, CD3OD) δ 5.38 (s,
1
1 H), 4.09-3.97 (m, 2 H), 2.62 (quin, J ) 7.0 Hz, 1 H), 2.51 (dd,
J ) 14.5, 12.2 Hz, 1 H), 1.89 (dd, J ) 14.5, 7.5 Hz, 1 H), 1.46
(ddd, J ) 12.2, 7.3, 7.0 Hz, 1 H), 1.41 (t, J ) 7.0 Hz, 3 H), 1.21
(s, 3 H), 1.17 (s, 6 H), 1.15 (s, 3 H), 0.99 (d, J ) 7.0 Hz, 3 H),
0.11 (s, 9 H); 13C NMR (125 MHz, CD3OD) δ 211.6, 199.4, 182.0,
99.9, 77.2, 67.1, 59.1, 55.1, 51.1, 44.1, 41.2, 29.7, 27.3, 20.9, 17.0,
16.1, 14.4, 2.6 (×3); EI-HRMS m/z calcd for C20H34O4Si [M+]
366.2266, found 366.2206. Anal. Calcd for C20H34O4Si: C, 65.53;
H, 9.35. Found: C, 65.41; H, 9.30.
Supporting Information Available: General experimental
methods, characterization data of γ-3, 11, 12, and 14-16, copies
of NMR spectra of new compounds, and X-ray crystallographic
files (CIF) for compounds 8 and 12. This material is available
free of charge via the Internet at http://pubs.acs.org.
3-Benzoyl-4-ethoxy-7-endo-(2′-hydroxy-2′-propyl)-1,5,6-exo-
trimethylbicyclo[3.3.1]non-3-ene-2,9-dione (2). To a solution of 17
(40.3 mg, 0.11 mmol) in THF (1.1 mL) at -78 °C was added
lithium 2,2,6,6-tetramethylpiperidide (LTMP) (0.50 M in THF, 0.50
mL, 0.25 mmol), prepared from n-BuLi and 2,2,6,6-tetramethylpi-
peridine in THF at -78 °C. After the reaction mixture was stirred
JO801595Y
J. Org. Chem. Vol. 73, No. 23, 2008 9325