New construction of the bicyclo[3.3.1]nonane system via Lewis acid promoted regioselective ring-opening reaction of the tricyclo[4.4.0.05,7]dec-2-ene derivative

Article abstract of DOI:10.1016/j.tetlet.2006.07.010

A new access to the bicyclo[3.3.1]nonane system, which is a common structure in a number of polyisoprenylated phloroglucinol derivatives (phloroglucins), has been developed via the Lewis acid promoted regioselective ring-opening reaction of the cyclopropa

Full text of DOI:10.1016/j.tetlet.2006.07.010

Tetrahedron Letters 47 (2006) 6347–6351
New construction of the bicyclo[3.3.1]nonane system via Lewis
acid promoted regioselective ring-opening reaction of the
tricyclo[4.4.0.05,7]dec-2-ene derivative
Masahito Abe and Masahisa Nakada*
Department of Chemistry, Faculty of Science and Engineering, Waseda University, 3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan
Received 19 June 2006; revised 4 July 2006; accepted 6 July 2006
Abstract—A new access to the bicyclo[3.3.1]nonane system, which is a common structure in a number of polyisoprenylated phloro-
glucinol derivatives (phloroglucins), has been developed via the Lewis acid promoted regioselective ring-opening reaction of the
cyclopropane, a tricyclo[4.4.0.05,7]dec-2-ene derivative.
Ó 2006 Elsevier Ltd. All rights reserved.
Hyperforin (Fig. 1) was isolated as a metabolite from
St. John’s wort (Hypericum perforatum L.), a medicinal
plant traditionally used to treat depression and super-
ficial wounds, burns, and dermatitis.1 To date it has
been reported that hyperforin shows antibacterial,1a,2
antitumor,3 apoptotic,4 and some other interesting
biological activities.5–7 Recently, a number of polyiso-
prenylated phloroglucinol derivatives (phloroglucins)
from diverse plant sources have been reported,8 and
synthetic studies on members of this class of natural
products have been carried out.9,10
and an isobutyryl function at the bridgehead C5, giving
us a synthetic challenge.
The potent bioactivity and complex structural features
make hyperforin an attractive synthetic target; hence,
we commenced synthetic studies on hyperforin, and
report herein a new construction of the bicyclo-
[3.3.1]nonane system, a core structure of hyperforin.
As outlined in Scheme 1, we expected that Lewis acid
promoted regioselective ring-opening reaction of the
cyclopropane 1, a tricyclo[4.4.0.05,7]dec-2-ene derivative,
via the intramolecular attack of the benzyl carbonate
would afford the cyclic carbonate 2,12 which was a
potentially viable intermediate for the synthesis of
phloroglucins because 2 was oxygenated at its C9
In addition to its wide-ranging biological activities,
hyperforin possesses a trioxygenated bicyclo[3.3.1]non-
ane system, bearing a homoprenyl group and a methyl
group at C6, three prenyl groups at C1, C3, and C7,
Figure 1.
*
Corresponding author. Tel./fax: +81 3 5286 3240; e-mail: mnakada@
waseda.jp
Scheme 1. Retrosynthetic analysis of 1.11
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.07.010

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M. Abe, M. Nakada / Tetrahedron Letters 47 (2006) 6347–6351
position. Hence, 2 was suitable for preparing the bi-
cyclo[3.3.1]nonane-9-one system, which had been
successfully alkylated at its bridgehead position.13
4 was replaced with a readily removable TBDPS group.
The benzyl group was easily removed by Birch reduc-
tion, and the resulting diol was converted to TBDPS
ether 5 under carefully controlled conditions to avoid
formation of the bis-TBDPS ether (80%, 2 steps). Swern
oxidation of 5 cleanly afforded aldehyde 6 (94%), which
was reacted with methoxymethylidene phosphorane,
followed by acidic hydrolysis to afford the one-carbon
homologated aldehyde 7 (93%, 2 steps). Aldol reaction
of a lithium enolate of ethyl acetate with 7 proceeded
smoothly to produce 8 as a mixture of diastereomers;
hence, this mixture was used for the next step without
purification. Dess–Martin oxidation of 8 cleanly pro-
duced the corresponding ketone, which was successfully
converted to the a-diazo-b-keto ester 317 (83%, 3 steps).
The Lewis acid promoted ring-opening reaction of
cyclopropane 1 was challenging because no precedent
for this type of ring-opening reaction forming cyclic
carbonate had been reported so far as we know. In
addition, two diastereomers could be produced by the
possible bond cleavage between either C1 and C8 or
C8 and C9 of 1. We expected that, however, this ring-
opening reaction would take place because the Lewis
acid promoted ring-opening reaction of cyclopropyl
ketone with oxygen nucleophile had been reported.12
Furthermore, formation of cyclic carbonate by the
Lewis acid promoted ring-opening reaction of the epox-
ide of allylic benzyl carbonate had been reported, too.14
We also expected that the bicyclo[3.3.1]nonane deriva-
tive 2 would be the major product, because the intramo-
lecular attack of the benzyl carbonate group at C9 would
be favorable due to the limited length of the carbonate.
The intramolecular cyclopropanation of 3 with CuOTf
(10 mol %) was sluggish, but the reaction using the cat-
alyst in situ formed from CuOTf (10 mol %) and ligand
9
18 (15 mol %) affected to produce the desired 1019 (88%)
(Scheme 3). The TBDPS group in 10 was removed
with TBAF (93%) to afford the alcohol 11, which was
converted to 120 (quantitative) under conventional
conditions.
Since we have succeeded in preparing some chiral tri-
cyclo[4.4.0.05,7]dec-2-ene derivatives via the catalytic
asymmetric intramolecular cyclopropanation,15 we ex-
pected that 1 would be easily prepared according to
the similar procedure, that is, the intramolecular cyclo-
propanation of a-diazo-b-keto ester 3.
Now, the stage was set for the Lewis acid promoted
ring-opening reaction of 1. Among various Lewis acids
screened, we found that TESOTf promoted the ring-
opening reaction of 1 (Table 1, entries 1–3), however,
use of TESOTf (1.0 equiv) produced the desired product
2 in only 33% yield (at 50% conversion) (entry 1).
Although an excess amount of TESOTf slightly
increased the yield (entries 2 and 3), the starting material
remained under these reaction conditions. Furthermore,
the reaction carried out at elevated reaction temperature
resulted in decreased yield, so another Lewis acid effec-
tive for this ring-opening reaction was investigated.
Thus, we commenced the preparation of 3 from alcohol
415b,16 as shown in Scheme 2. To introduce a benzyl
carbonate group at the later stage, the benzyl group in
Fortunately, BF3ÆOEt2 was found to be most suitable
for this ring-opening reaction. Thus, 1 equiv of
BF3ÆOEt2 produced 2 in rather low yield (quantitative
at 34% conversion), but use of 6 equiv of BF3ÆOEt2
Scheme 2. Synthesis of 3.
Scheme 3. Synthesis of 1.

M. Abe, M. Nakada / Tetrahedron Letters 47 (2006) 6347–6351
Table 1. Lewis acid promoted ring-opening reaction of cyclopropane 1
6349
Entry
Lewis acid (equiv)
Temperature (°C)
Timea (h)
Yieldb (%)
1
2
3
4
5
6
TESOTf (1.0)
TESOTf (3.0)
TESOTf (6.0)
BF3ÆOEt2 (1.0)
BF3ÆOEt2 (6.0)
BF3ÆOEt2 (6.0)
ꢀ78, ꢀ78 to ꢀ10
ꢀ78, ꢀ60, ꢀ60 to ꢀ20
ꢀ78, ꢀ20
4, 11.5
0.75, 1, 13
0.2, 36
4, 11.5
0.2, 1.5, 6.5
0.2, 47
33 (at 50% conv)
44 (at 14% conv)
73 (at 29% conv)
Quantitative (at 34% conv)
61 (at 84% conv)
93
ꢀ78, ꢀ78 to ꢀ10
ꢀ78, ꢀ50, ꢀ20
ꢀ78, ꢀ20
a Time at the corresponding reaction temperature. That is, 4 h for ꢀ78 °C (entry 1) is the reaction time at ꢀ78 °C, and 11.5 h for ꢀ78 to ꢀ10 °C
(entry 1) is the time required for raising the reaction temperature from ꢀ78 to ꢀ10 °C.
b Isolated yields.
Acknowledgments
This work was financially supported in part by a Wase-
da University Grant for Special Research Projects and a
Grant-in-Aid for Scientific Research on Priority Areas
(Creation of Biologically Functional Molecules (No.
17035082)) from The Ministry of Education, Culture,
Sports, Science and Technology (MEXT), Japan. We
are also indebted to 21COE ‘Practical Nano-Chemistry’.
Figure 2.
increased the yield to 61% (at 84% conversion), and,
finally, prolonged reaction time (47 h) at ꢀ20 °C
successfully increased the yield up to 93% without recov-
ering the starting material. It should be noted that no
formation of 20 (Fig. 2), which could be produced via
another bond-cleavage of the cyclopropane 1, was
observed in all entries in Table 1.
References and notes
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In summary, a new access to the bicyclo[3.3.1]nonane
system, which is a common structure in a number of
polyisoprenylated phloroglucinol derivatives (phloro-
glucins), has been developed. The key reaction is the
Lewis acid promoted regioselective ring-opening reac-
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17. Compound 3: Rf 0.28 (hexane/ethyl acetate = 10/1);
mp = 45–47 °C; 1H NMR (400 MHz, CDCl3): d = 7.67
(4H, m), 7.38 (6H, m), 5.80 (2H, m), 5.75 (2H, d,
J = 10.5 Hz), 4.28 (2H, q, J = 7.1 Hz), 3.59 (2H, s), 3.17
(2H, s), 2.60 (2H, m), 1.32 (3H, t, J = 7.1 Hz), 1.07 (9H, s);
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26.9, 26.6, 19.5, 14.4; IR (neat) mmax: 2848, 2129, 1707,
1656, 1335, 1316, 1177, 1140, 1114, 1051, 833, 744,
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18. Asymmetric catalysis of this reaction using a chiral
bisoxazoline ligand was not pursued at this point because
we thought that the key ring-opening reaction of 1 should
be examined first.
19. Compound 10: Rf 0.30 (hexane/ethyl acetate = 4/1); 1H
NMR (400 MHz, CDCl3): d = 7.66 (4H, m), 7.41 (6H, m),
5.79 (1H, m), 5.68 (1H, dd, J = 9.7, 2.9 Hz), 4.20 (2H, q,

M. Abe, M. Nakada / Tetrahedron Letters 47 (2006) 6347–6351
J = 7.1 Hz), 3.78 (2H, s), 3.03 (1H, d, J = 17.1 Hz), 2.65
6351
61.5, 54.1, 43.7, 38.3, 36.0, 30.6, 20.8, 14.1; IR (neat) mmax
:
(3H, m), 2.10 (1H, m), 1.99 (1H, d, J = 17.1 Hz), 1.28 (3H,
t, J = 7.1 Hz), 1.07 (9H, s); 13C NMR (100 MHz, CDCl3):
d = 207.0, 168.8, 135.5, 135.4, 132.9, 132.8, 131.7, 129.8,
129.7, 127.7, 126.6, 68.5, 61.3, 53.7, 44.2, 39.6, 38.5, 30.5,
26.8, 21.2, 19.3, 14.2; IR (neat) mmax: 2860, 1738, 1266,
1238, 1114, 736, 704 cmꢀ1; FAB HRMS [M+H]+ calcd for
C29H35O4Si: 475.2305, found: 475.2295.
2980, 1750, 1398, 1266, 1040, 952, 734, 700 cmꢀ1; FAB
MS [M+H]+ calcd for C21H23O6: 371.1495, found:
371.1495.
21. Compound 2: Rf 0.33 (hexane/ethyl acetate = 1/1);
mp = 134–136 °C; 1H NMR (400 MHz, CDCl3):
d = 12.4 (1H, s), 5.98 (1H, dd, 10.0, 4.9 Hz), 5.45 (1H, d,
10.0 Hz), 4.54 (1H, d, 4.4 Hz), 4.27 (4H, m), 3.22 (1H, dd,
4.4, 2.2 Hz), 2.54 (1H, dd, 18.6, 2.2 Hz), 2.36 (1H, d,
17.8 Hz), 2.27 (1H, d, 17.8 Hz), 2.04 (1H, dd, 18.6,
4.9 Hz), 1.33 (3H, t, 7.1 Hz); 13C NMR (100 MHz,
CDCl3): d = 171.1, 168.8, 147.7, 130.6, 124.9, 99.5, 77.7,
74.0, 60.8, 36.1, 31.5, 30.2, 25.7, 14.1; IR (neat) mmax: 3446,
2908, 1750, 1643, 1608, 1231, 742 cmꢀ1; FAB HRMS
[M+H]+ calcd for C14H17O6: 281.1025, found: 281.1062.
20. Compound 1: Rf 0.70 (hexane/ethyl acetate = 1/1);1H
NMR (400 MHz, CDCl3) d = 7.38 (5H, m), 5.86 (1H, m),
5.75 (1H, dd, 9.9, 2.7 Hz), 5.19 (2H, s), 4.39 (1H, d,
10.5 Hz), 4.31 (1H, d, 10.5 Hz), 4.19 (2H, q, 7.1 Hz), 2.66
(4H, m), 2.10 (1H, m), 2.08 (1H, d, 17.1 Hz), 1.27 (3H, t,
7.1 Hz); 13C NMR (100 MHz, CDCl3): d = 205.1, 168.4,
154.9, 134.7, 130.9, 128.6, 128.5, 128.3, 127.2, 72.5, 70.0,