Cyclopropane ring-opening of tricyclo[3.3.0.02,8]octan-3-ones: a quick access to bicyclo[3.2.1]octanones from 2-methoxyphenols

Article abstract of DOI:10.1016/j.tetlet.2009.02.150

We herein report an efficient and rapid strategy for the synthesis of highly functionalized bicyclo[3.2.1]octanones via sequential reactions: Diels-Alder reaction of MOB-ODPM rearrangement-reductive cleavage of cyclopropane, and its application to synthes

Full text of DOI:10.1016/j.tetlet.2009.02.150

Tetrahedron Letters 50 (2009) 3414–3417
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
2,8
Cyclopropane ring-opening of tricyclo[3.3.0.0 ]octan-3-ones: a quick access to
bicyclo[3.2.1]octanones from 2-methoxyphenols
a
a
a
a,b,*
Chun-Ping Chang , Ching-Hsien Chen , Gary Jing Chuang , Chun-Chen Liao
a
Department of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan
Department of Chemistry, Chung Yuan Christian University, Chungli 32023, Taiwan
b
a r t i c l e i n f o
a b s t r a c t
Article history:
We herein report an efficient and rapid strategy for the synthesis of highly functionalized bicy-
clo[3.2.1]octanones via sequential reactions: Diels–Alder reaction of MOB—ODPM rearrangement—
reductive cleavage of cyclopropane, and its application to synthesize the core structure of drechslerine D.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 13 January 2009
Revised 16 February 2009
Accepted 19 February 2009
Available online 25 February 2009
Bicyclic structures have been one of the main spotlights in
synthetic chemistry over the years owing to their presence in a
continuation of our efforts to develop new and efficient methodolo-
gies for the syntheses of natural products starting from 2-methoxy-
1
large number of natural products and synthetic challenges.
2
Among the derivatives of bicyclo[3.2.1] skeleton, drechslerine,
a
HO
O
small and rare family of sesquiterpenoids (Fig. 1), has drawn our
attention with its structural uniqueness. Although there have been
quite a few synthetic approaches developed over the years for the
construction of bicyclo[3.2.1] skeletons through diverse chemical
O
O
O
R
O
O
3
methodologies, synthesis of the drechslerine family natural prod-
OH
ucts is yet to be reported. The installations of the fused lactone ring
and the quaternary bridgehead on this bicyclic structure post a
great challenge for synthetic chemists.
drechslerine B drechslerine D (R = O)
drechslerine F
In the past, we have successfully demonstrated the power and
potential of the chemistry of masked o-benzoquinones (MOBs) in
organic syntheses to construct highly functionalized bicy-
drechslerine E (R = H, β-OMe)
Figure 1. The drechslerine family natural products.
4
cis-decalins,5 bicyclo[4.2.2]- and bicy-
clo[2.2.2]octenones,
6
7
clo[3.2.2]-skeletons, linear and angular triquinanes skeletons
from the Diels–Alder adducts of MOBs, and applied these synthetic
strategies to the syntheses of natural products with diverse struc-
X
O
X
O
hυ
8
OMe
OMe
OMe
OMe
tural nature. The strategy that we have employed for the syntheses
R
ODPM
R
8d
9
of triquinane/diquinane cores of capnellene, magellanine, and
forsythide aglucone dimethyl ester10 is the oxa-di-
-methane
ODPM) rearrangements of bicyclo[2.2.2]octenones, adducts from
X
p
MeO
cleavage of
OMe
(
OMe
OMe
"
a-bond"
the Diels–Alder reactions of MOBs, followed by the reductive cleav-
age of the tricyclo[3.3.0.02 ]octan-3-ones (Scheme 1). As the cleav-
age of ‘a-bond’ yielded the diquinane skeleton, we foresee the
cleavage of ‘b-bond’ of the ODPM rearrangement products would
give an access to the corresponding bicyclo[3.2.1] skeletons. Though
it has beenreported that the cleavage of thecyclopropane ring in this
X
O
b
,8
R
a
R
O
diquinanes
cleavage of
b-bond"
X
"
R
7
,11
OMe
OMe
tricyclic system typically took place at ‘a-bond’,
examples of
OMe
OMe
O
12
usingnucleophilicaddition orfunctionalgroupdirectingreductive
cleavage to generate bicyclo[3.2.1]octanones from compounds of
tricyclo[3.3.0.0 ] skeleton have also been reported. Thus as the
R
O
X
1
3
2
,8
bicyclo[3.2.1]octan-3-ones
*
Corresponding author. Tel.: +886 3 5715131 33388; fax: +888 3 5728123.
Scheme 1. Approach to diquinanes and bicyclo[3.2.1]octan-3ones starting from
E-mail addresses: ccliao@mx.nthu.edu.tw, ccliao@cycu.edu.tw (C.-C. Liao).
MOBs.
0
040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.150

C.-P. Chang et al. / Tetrahedron Letters 50 (2009) 3414–3417
3415
phenols via the corresponding MOBs, we report herein our results of
the constructions of bicyclo[3.2.1]octanones from 2-methoxyphe-
nols via sequential reactions: Diels–Alder reaction of MOB—ODPM
rearrangement—reductive cleavage of cyclopropane.
clo[3.3.0.02,8]octan-3-ones, precursors for the next stage
cyclopropane ring-opening reaction. The detailed experimental pro-
cedures and structural determinations with spectral data assign-
ment are available in the Supplementary data. After having
compounds 5 and 6 in hand, we tried a number of reducing condi-
tions. Messy mixtures were obtained from reactions using
In order to induce the desire selectivity of cleaving ‘b-bond’ over
2
,8
‘
3
a-bond’ in the forthcoming reductions of tricyclo[3.3.0.0 ]octan-
-ones obtained from the photoreaction,13 we deliberated to uti-
lize MOBs with electron-withdrawing groups (R = CO Me, COMe,
15
7a,16
Li/NH
3
and SmI
2
asreducingagents. Treatmentsof 5and6with
1
7
2
Zn/AcOH were found unreactive.
However, reduction using
1
3a,13b
13c
7b,9
or CN), thus making the b-bond, connecting to the keto group of
cyclopentanone and the R—substituent on the cyclopropane ring
to be especially electron deficient and prone for the reduction to
take place. The installation of the electron-withdrawing R-groups
could also avoid the possibility of unwanted decarbonylation or
other types of rearrangements during the triplet sensitized photo-
3
n-Bu SnH, reported by Enholm,
Lahiri, and us,
was found
to give the ring-opening reaction in clean and good yields (Table 2).
The reductive cleavage reactions were directed by the adjacent car-
bonyl and electron-withdrawing R-groups and found to be com-
pletely chemoselective for the cleavage of ‘b-bond’. The desired
bicyclo[3.2.1]octanones were obtained in moderate to good yields.
As we examined closely the stereochemistry of the reduced
products, an inversion of configuration at the carbon center of the
cyclopropane where the R-group is attached was found during the
bond-breaking process (Fig. 2). This stereo-chemical outcome is
presumably due to steric effect. In which during the cyclopropane
ring-opening reaction, the late stage hydrogen abstraction of inter-
1
4
reactions. The results of the Diels–Alder reactions of selected
8
c,8d
MOBs
and the following irradiation with 300 nm UV light in
acetone with acetophenone as the sensitizer in a Rayonet reactor
to give the ODPM rearrangement products are shown in Table 1.
The cycloadditions of MOBs and the subsequent photorearrange-
ments gave moderate to excellent yields to the tricy-
Table 1
Construction of tricyclo[3.3.0.02,8]octan-3-ones from MOBs
X
OMe
OMe
X
OH
O
DAIBa
MeOH
hυ b
O
X
O
OMe
OMe
OMe
OMe
R
R
R
OMe
R
1
1
1
a: R = CO Me
b: R = COMe
c: R = CN
2
X = COMe, 5
X = Ph, 6
MOB 2
X = COMe, 3
X = Ph, 4
Entry
MOB
X
D–A adduct (%)
ODPM product (%)
1
2
3
4
5
6
2a
2b
2c
2a
2b
2c
COMe
COMe
COMe
Ph
Ph
Ph
3a/87
3b/85
3c/44
4a/95
4b/93
4c/90
5a/83
5b/93
5c/86
6a/90
6b/95
6c/96
aDiacetoxyiodobenzene. bPhotolysis condition: h
m = 300 nm, 10 equiv acetophenone, substrate as 1% solution in acetone.
Table 2
Reductive cleavage to yield bicyclo[3.2.1]octanones
OMe
OMe
R
OMe
OMe
4
eq of n-Bu SnH, AIBN
3
X
O
o
benzene, 80 C
X
R
O
5
a-c
a-c
7a-c
8a-c
6
n-Bu3Sn
n-Bu3Sn
H
H O
2
R
"more hindered
MeO
OMe
side"
OMe
-
δ
+
X
O
δ
OMe
SnBu3
X
-
δ
R
O
+
δ
SnBu3
I
II
Entry
R
X
Product (%)
1
2
3
4
5
6
(5a)
(5b)
(5c)
(6a)
(6b)
(6c)
CO
COMe
CN
CO Me
2
COMe
CN
2
Me
COMe
COMe
COMe
Ph
Ph
Ph
7a/59
7b/64
7c/51
8a/65
8b/83
8c/40

3
416
C.-P. Chang et al. / Tetrahedron Letters 50 (2009) 3414–3417
Figure 2. ORTEP drawing for 7b at 50% probability thermal ellipsoids.
Figure 3. ORTEP drawing for 7d at 50% probability thermal ellipsoids.
mediate II took place from the less hindered side of the tertiary rad-
7d. Thus within only four chemical transformations, a bicy-
ical center to avoid steric interaction to the dimethoxy ketal and
bulky enol connected SnBu group as shown in Table 2’s drawing.
3
After successfully obtaining bicyclo[3.2.1]octanones from the
Diels–Alder reaction of MOB—ODPM rearrangement—reductive cleav-
age of cyclopropane sequence, we then applied this methodology to
the synthesis of the core structure of drechslerine D (Scheme 2). As
clo[3.2.1]octanone with 3 (the fused carbons on lactone ring and the
quaternary carbon on the bridgehead of the bicyclo[3.2.1]octanone)
of the 4 stereocenters of drechslerine D was synthesized (Fig. 3).
In summary, we have successfully developed an efficient meth-
odology for the syntheses of highly functionalized bicyclo
[3.2.1]octanone systems. Several bicyclo[3.2.1]octanone derivatives
were obtained rapidly in good to excellent yields starting from com-
mercially available or easily accessible 2-methoxyphenols. In addi-
tion, the efficacy of our strategy has been demonstrated by
utilizing it as a key step for the synthesis drechslerine D framework.
a contrast to high yielding Diels–Alder reactions mentioned in Table
c
1
and in our previous results,8 initial Diels–Alder reaction of
MOB 2d with furanone 9 was found sluggish under conventional
heating method. However, using microwave reactor significantly
shortens the reaction time and gave a moderate yield of the cyc-
loadducts. Unfortunately, a 1: 1 ratio of regioselectivity was found
Acknowledgments
0
from the cycloaddition to give isomeric compounds 3d and 3d .
0
We gratefully acknowledge the financial supports from
National Science Council of Taiwan (NSCT). C.C.L. thanks Chung
Yuan Christian University for the support under Grant CYCU-97-
CR-CH and G.J.C. thanks NSCT for a postdoctoral fellowship.
Carrying the desired regiochemistry, adduct 3d was hydrolyzed
to give aldehyde 10, which was then irradiated accordingly to the
previously mentioned condition to produce compound 5d in good
3
yield. The following reductive cleavage with n-Bu SnH furnished
O
O
O
O
O
O
O
O
O
O
OMe
OMe
9
+
OMe
OMe
O
4 h, toluene,
mw 150 C,
Acetal
Acetal
o
OMe
OMe
2d
7
1%
3d
1 : 1
3d'
O
O
H
O
O
acetone / 1N HClaq(1:1)
rt, 5 h, 85%
O
hυ
1%
O
O
8
OMe
OMe
OMe
OMe
OHC
5
d
10
H
O
O
n-Bu SnH, AIBN
3
O
Benzene
O
OMe
72%
MeO
7
d
Scheme 2. Synthesis of the core structure of drechslerine.

C.-P. Chang et al. / Tetrahedron Letters 50 (2009) 3414–3417
3417
4
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