A novel and efficient route to the construction of the 4-oxa-tricyclo[4.3.1.0]decan-2-one scaffold

Article abstract of DOI:10.1016/j.tetlet.2007.07.005

A short and efficient route to the synthesis of 4-oxa-tricyclo[4.3.1.0]decan-2-one scaffold 12 in good yield is reported. Essential to the synthesis was the implementation of selective protection of the catechol system in xanthone 2 with Ph₂CCl

Full text of DOI:10.1016/j.tetlet.2007.07.005

Tetrahedron Letters 48 (2007) 6586–6589
A novel and efficient route to the construction of the
4-oxa-tricyclo[4.3.1.0]decan-2-one scaffold
Nian-Guang Li,a Jin-Xin Wang,a Xiao-Rong Liu,a Chang-Jun Lin,a Qi-Dong Youa,* and
Qing-Long Guob
aDepartment of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China
bDepartment of Physiology, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China
Received 9 May 2007; revised 30 June 2007; accepted 3 July 2007
Available online 7 July 2007
Abstract—A short and efficient route to the synthesis of 4-oxa-tricyclo[4.3.1.0]decan-2-one scaffold 12 in good yield is reported.
Essential to the synthesis was the implementation of selective protection of the catechol system in xanthone 2 with Ph2CCl2 and
MOM groups. Subsequently, a biomimetic tandem Claisen/Diels–Alder reaction occurred to produce the desired tricyclic scaffold
11a as a single isomer. A rationalization of the excellent region and stereoselectivity of this transformation was also proposed.
Ó 2007 Elsevier Ltd. All rights reserved.
The intriguing 4-oxa-tricyclo[4.3.1.03,7]decan-2-one scaf-
fold 12 is found in a growing class of biologically active
natural products isolated from plants of the genus
Garcinia. These compounds, including forbesione,1 gam-
bogic acid,2 morellin,3 lateriflorone,4 and gaudichaudi-
ones,5 exhibit interesting antibacterial activity and
cytotoxicity. Possibly, the 4-oxa-tricyclo[4.3.1.03,7]-
decan-2-one moiety is responsible for the bioactivity
since the planar xanthones alone do not show a marked
biological profile.6 This caged scaffold was first pro-
posed and experimentally tested by Quillinan and
Scheinwam in 1971 by means of a tandem Claisen/
Diels–Alder rearrangement7 and was further developed
by Nicolaou and Li during their synthesis of 1-O-meth-
ylforbesione8 in 2001.
leaving the 1-hydroxy unaffected. Thus, only in 9 steps,
the caged scaffold is obtained with just one isomer 11a.
The cascade precursor 9 was synthesized as summarized
in Scheme 1. Xanthone 2 was obtained in 52% yield
through a ZnCl2-mediated condensation of phloroglu-
cinol 1 with 2,3,4-trihydroxybenzoic acid in POCl3.10
Then, compound 2 was treated with a variety of protect-
ing agents under several conditions to selectively protect
the 5,6-dihydroxy, but with the 1,3-dihydroxy unaf-
fected. Firstly, attempt to form the acetonide of the cat-
echol system of 2 through reaction with acetone/TsOH
was completely ineffective. The use of triphosgene as a
protecting group yielded a product that was highly
unstable at room temperature. Fortunately, Ph2CCl2
effectively protected the 5,6-dihydroxy of xanthone 2,
giving the desired intermediate 3. However, following
the literature procedure,11 the yield was very low when
xanthone 2 reacted with Ph2CCl2 without any solvent.
After several experimental attempts, we found that the
best conditions, which involved treatment of 2 with
Ph2CCl2 in diphenyl ether at 175 °C, could produce 3
in 85% yield. Then, various protecting groups and con-
ditions, such as TBDMSCl, Ac2O and MOMCl, were
used to protect the 3-hydroxy group in 3. MOMCl12
was found to give optimum results when used in con-
junction with NaH in DMF to afford 4 in 90% yield.
Subsequent hydrogenolysis13 of the two benzyl groups
in this new product, followed by a reaction with 2-
chloro-2-methylbutyne in the presence of K2CO3, KI
Recently, Nicolaou and co-workers obtained two iso-
mers of this caged scaffold in 16 steps by protecting
the 1,3-dihydroxy of xanthone 9 with the MOM group
during their total synthesis of gambogin.9 In the present
Letter, a new and convenient method is reported by
using Ph2CCl2 first to protect the 5,6-dihydroxy func-
tionality in xanthone 2 and then using the MOM group
to selectively protect the 3-hydroxy in xanthone 3,
Keywords: Xanthone; Tandem Claisen/Diels–Alder reaction; 4-Oxa-
tricyclo[4.3.1.0]decan-2-one scaffold.
*
Corresponding author. Tel./fax: +86 25 83271351; e-mail:
youqidong@gmail.com
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.005

N.-G. Li et al. / Tetrahedron Letters 48 (2007) 6586–6589
6587
OH
1
O
OH
O
OH
OH
1
O
OH
1
O
1
a
c
b
d
6
6
O
6
6
HO
3
O
OH
3
HO
O
HO
e
OH
MOMO
3
O
4
O
5
OH
5
3
MOMO
O
OH
5
O
5
OH
2
O
1
3
Ph
5
Ph
Ph
Ph
OH
1
O
OH
O
OH
O
OH
1
O
21 22
f
g
h
6
6
19
3
CH3OCH2O
O
O
20
18 MOMO
O
O
MOMO
O
O
3
5
OH
MOMO
O
O
5
O
12
11
6
OH
O
8
7
9
O
Scheme 1. Reagents and conditions: (a) 2,3,4-trihydroxybenzoic acid, ZnCl2, POCl3, 70 °C, 3 h, 52%; (b) Ph2CCl2, Ph2O, 175 °C, 30 min, 85%; (c)
MOMCl, NaH, DMF, 25 °C, 8 h, 90%; (d) Pd/C (10 wt %), H2 (1 atm), THF/Et2OH, 6 h, 95%; (e) 2-chloro-2-methylbutyne, KI, K2CO3, CuI,
acetone, reflux, microwave irradiation, 20 min, 80%; (f) 10% Pd/BaSO4, quinoline, EtOAc, 25 °C, 30 min, 95%; (g) t-BuOK, THF, 0 °C; then
concentrated and suspended in MeCN; then 18[crown]-6, 15 min, bromoisobutyraldehyde, 0–25 °C, 1 h, 85%; (h) CH3P+Ph3BrÀ, NaHMDS, THF,
0–25 °C, 2 h, 85%.
and catalytic CuI in refluxing acetone under microwave
irradiation resulted in the formation of propargylic ether
6 in 76% overall yield. The propargylic ether group at C-
6 instead of C-5 in compound 6 could be supported by
NOE studies,14 and the regioselectivity observed during
this etherification of xanthone 5 could be explained as
the C6–OH is para to the electronically deficient C9
carbonyl group of 5, so that the C6–OH is much more
active than C5–OH. Selective reduction (H2, Lindlar
catalyst) of the acetylenic group in compound 6 gave
the corresponding olefin 7 in 95% yield. The potassium
salt of 7, generated by addition of t-BuOK, was sus-
pended in CH3CN and treated with a-bromoisobutyral-
dehyde in the presence of [18]crown-6 to afford 8 in
85% yield. Then, dialkene 9was obtained in 85%
yield by reaÀction of 8 with methylene phosphorane
(MeP+Ph3Br , NaHMDS).8
by HMBC studies.15 Removal of the MOM group from
the desired compound 11a was smoothly effected
through the action of HCl (1.0 M in CH2Cl2/Et2O
(1:1)), which generated the caged scaffold 12 in 90%
yield.
The excellent regioselectivity observed during this
tandem Claisen/Diels–Alder reaction deserves some
comments. In principle, as in the case of diolefin 13
(Scheme 3), upon heating in DMF at 120 °C, the xan-
thone derivative 13 should smoothly undergo two differ-
ent expected ortho-Claisen rearrangements, to afford
OR
1
O
9
6
10
O
3
20
13
19
18
MOMO
O
5
Upon heating in DMF at 120 °C, the bis-(a,a-dimethyl-
allyl) aryl ether 9 smoothly underwent the expected
Claisen/Diels–Alder cascade sequence through the pre-
sumed intermediate 10a to furnish 11a in 85% yield
(Scheme 2). The desired connectivity across the central
tetrahydrofuran core of this compound was supported
O
15
14
9: R=H
13: R=MOM
Claisen
OR
1
O
9
OR
1
O
9
6
5
6
OH
A
O
O
10
O
5
MOMO
O
O
MOMO
O
10
18
19
18
O
13
O
19
20
14
a
MOMO
O
13
9
10a: R=H
14a: R=MOM
10b: R=H
14b: R=MOM
O
10a
Diels-Alder
Diels-Alder
21
22
20
O
6
OR
1
O
OR
1
O
O
6
O
O
6
19
OH
A
O
OH
O
18
8
1
5
b
O
3
9a
9b
5
13
O
9
3
7
MOMO
O
14
4
19
O
MOMO
A
5
12
11
O
O 13
4
18
10aO10b
3
HO
O
O
O
4
14
11a: R=H
(85%)
11b: R=H
(ND)
10
15
17
12
15a: R=MOM (69%)
16
11a
15b: R=MOM (23%)
Scheme 2. Reagents and conditions: (a) DMF, 120 °C, 45 min, 85%;
(b) HCl (1.0 M) in Et2O/CH2Cl2 (1:1), 25 °C, 6 h, 90%.
Scheme 3. Possible isomers anticipated from the tandem Claisen/
Diels–Alder reaction of compounds 4 and 13.

6588
N.-G. Li et al. / Tetrahedron Letters 48 (2007) 6586–6589
structures 14a and 14b, which after the subsequent
Diels–Alder reaction can produces adducts 15a and
15b in 69% and 23% yields, respectively.9 However, in
xanthone 9, the absence of intermediate 10b and the
complete conversion of 9 to the desired regioisomer
10a were observed. This preferential reaction path may
be attributed to the C9 carbonyl group, the xanthone
oxygen (O10), and the nature of the C1 functionality16
in 9.
Acknowledgments
The authors thank the 863 High-Tech Project of China
(2002AA2Z3112) (2004AA2Z3A10), the Key Projects of
Science and Technology Research of Ministry of Educa-
tion of PRC (2006-106094) and the Projects of Natural
Science Foundation of Jiangsu Province (BK2006149),
for financial support.
The electronically deficient C9 carbonyl group of 9 is
para to the C6 allyloxy unit. Thus, C9 can accept elec-
tron density from the C6 oxygen, which contributes to
a weakening of the ether bond and facilitates rupture
of the bond, yielding the C20 alkyl fragment, leading
to intermediate 10a (Scheme 3). In addition, as shown
in the structure of 10a, the xanthone oxygen (O10) is
meta to the C6 carbonyl group, thereby stabilizing it
by resonance. Such a stabilization effect cannot be
achieved at the C5 carbonyl group of intermediate
10b. Furthermore, in the case of 9 (R@H), the C9 car-
bonyl group is bound to the C1 OH by a hydrogen
bond,16 which increases its electronic deficiency. This
leads to high selectivity of the Claisen rearrangement
that produces intermediate 10a exclusively and, follow-
ing Diels–Alder reaction with the pendant C13-C14
dienophile, affords only11aas the regular caged scaffold.
However, a partial loss of the site selectivity is observed
with the 1,3-dimethoxymethoxy xanthone 13. Appar-
ently, the presence of the C1 methylene ether in 13
attenuates the electron withdrawing effect of the C9 car-
bonyl group, which reduces the preference for cleavage
of the O–C20 bond and allows a competing rearrange-
ment using the C5 allyloxy ether to take place. So, in
the case of 13, competition of these processes produces
a mixture of Claisen adducts 14a and 14b and thereby
a mixture of final products 15a (regular caged scaffold)
and 15b (neo caged scaffold) in an approximate ratio
of 3:1.
References and notes
1. Leong, Y.-W.; Harrison, L. J.; Bennett, G. J.; Tan,
H. T.-W. J. Chem. Res., Synop. 1996, 392–393.
2. Ollis, W. D.; Ramsay, M. V. J.; Sutherland, I. O.;
Mongkolsuk, S. Tetrahedron 1965, 21, 1453–1470.
3. (a) Kartha, G.; Ramachandran, G. N.; Bhat, H. B.; Nair,
P. M.; Raghavan, V. K. V.; Venkataraman, K. Tetra-
hedron Lett. 1963, 4, 459–472; (b) Karanjgaonkar, C. G.;
Nair, P. M.; Venkataraman, K. Tetrahedron Lett. 1966, 7,
687–691.
4. Kosela, S.; Cao, S.-G.; Wu, X.-H.; Vittal, J. J.; Sukri, T.;
Masdianto,; Goh, S. H.; Sim, K.-Y. Tetrahedron Lett.
1999, 40, 157–160.
5. (a) Cao, S.-G.; Wu, X.-H.; Sim, K.-Y.; Tan, B. H. K.;
Pereira, J. T.; Wong, W. H.; Hew, N. F.; Goh, S. H.
Tetrahedron Lett. 1998, 39, 3353–3356; (b) Rukachaisir-
ikul, V.; Kaewnok, W.; Koysomboon, S.; Phongpaichit,
S.; Taylor, W. C. Tetrahedron 2000, 56, 8539–8543; (c) Xu,
Y. J.; Yip, S. C.; Kosela, S.; Fitri, E.; Hana, M.; Goh, S.
H.; Sim, K.-Y. Org. Lett. 2000, 2, 3945–3948.
6. Batova, A.; Lam, T.; Wascholowski, V.; Yu, A. L.;
Giannis, A.; Theodorakis, E. A. Org. Biomol. Chem. 2007,
5, 494–500.
7. Quillinan, A. J.; Scheinmann, F. J. Chem. Soc., Chem.
Commun 1971, 966–967.
8. Nicolaou, K. C.; Li, J. Angew. Chem. Int. Ed. 2001, 40,
4264–4268.
9. Nicolaou, K. C.; Xu, H.; Wartmann, M. Angew. Chem.
Int. Ed. 2005, 44, 756–761.
10. Burling, E. D.; Jefferson, A.; Scheinmann, F. Tetrahedron
1965, 21, 2653–2660.
11. Bengtsson, S.; Hogberg, T. J. Org. Chem. 1989, 54, 4549–
4553.
With this in mind, it appears that preinstalling all func-
tionalities at the correct oxidation state in compound 9
triggers the desired rearrangement, producing the caged
scaffold 11a exclusively. Such regiochemical preference
during this tandem rearrangement is also manifested in
the vast majority of the Garcinia natural products, the
structure of which is highlighted by the same homochiral
scaffold.
12. Susse, M.; Johne, S.; Hesse, M. Helv. Chim. Acta 1992, 75,
¨
457–470.
13. Feldman, K. S.; Ensel, S. M.; Minard, R. D. J. Am. Chem.
Soc. 1994, 116, 1742–1745.
14. Spectral data for xanthone 6. 1H NMR (300 MHz, CDCl3)
d 12.85 (s, 1H, C1–OH), 7.76 (d, J = 8.9 Hz, 1H, C8–H),
7.53 (d, J = 8.9 Hz, 1H, C7–H), 6.71 (d, J = 2.3 Hz, 1H,
C2–H), 6.46 (d, J = 2.3 Hz, 1H, C4–H), 5.80 (s, 1H,
C5–OH), 5.25 (s, 2H, C11–H), 3.50 (s, 3H, C12–H), 2.70
(s, 1H, C18–H), 1.79 (s, 6H, C21–H, C22–H); The position of
the MOM group at C3–O was determined by the ROESY
correlations between the signals at d 5.25 (H-11) with 6.46
(H-4)/6.71 (H-2), a cross-peak observed in the ROESY
spectrum between d 1.79 (H-21, H-22) with 7.53 (H-7)/7.76
(H-8) confirmed that the position of the propargylic ether
group was at C-6.
In conclusion, we have presented an efficient and conve-
nient synthesis of the caged scaffold 12, an important
intermediate for the total synthesis of many xanthone
and xanthonoid natural products isolated from the
Garcinia species of tropical plants. Our strategy high-
lights the use of selective protecting groups to form
the important intermediate 5, and the implementation
of a biomimetic and completely regioselective Claisen/
Diels–Alder cascade reaction to form the caged scaffold
11a as a single isomer. The good yields of all intermedi-
ates and final products and relatively easy experimental
procedures make this strategy a new and practical
pathway to a biomimetic synthesis of related natural
products.
15. Spectral data for caged xanthone 11a. 1H NMR (300 MHz,
CDCl3) d 12.39 (s, 1H, C1–OH), 7.44 (d, J = 6.9 Hz, 1H,
C8–H), 6.21 (d, J = 2.0 Hz, 1H, C2–H), 6.18 (d, J = 2.0 Hz,
1H, C4–H), 5.20 (s, 2H, C11–H), 4.42–4.46 (m, 1H, C19–H),
3.50–3.52 (m, 2H, C13–H), 3.48 (s, 3H, C12–H), 2.60–2.63
(m, 2H, C18–H), 2.44 (d, J = 9.6 Hz, 1H, C14–H), 2.34 (dd,
J1 = 13.5, J2 = 4.5 Hz, 1H, C7–H), 1.69 (s, 3H, C17–H),
1.39 (s, 3H, C21–H), 1.29 (s, 3H, C16–H), 1.10 (s, 3H,

N.-G. Li et al. / Tetrahedron Letters 48 (2007) 6586–6589
6589
C22–H); 13C NMR (75 MHz, CDCl3) d 202.9 (C-6), 179.5
(C-9), 165.9 (C-3), 164.7 (C-9a), 160.9 (C-10a), 135.2 (C-8),
134.1 (C-20), 133.8 (C-9b), 118.3 (C-19), 101.7 (C-1), 97.0
(C-2), 95.5 (C-4), 94.0 (C-11), 90.3 (C-10b), 84.4 (C-5), 83.5
(C-15), 56.4 (C-12), 48.8 (C-14), 46.9 (C-13), 30.3 (C-17),
29.1 (C-18), 29.0 (C-16), 25.5 (C-21), 25.1 (C-7), 16.8
(C-22); The presence of phenol hydroxy group at d
12.39 ppm, 2 aromatic proton signals at d 6.21 (d,
J = 2.0 Hz, 1H, C2–H), d 6.18 (d, J = 2.0 Hz, 1H, C4–H),
one methylene signal at d 5.20 (s, 2H, C11–H), one methyl
signal at d 3.48 (s, 3H, C12–H) in the 1H NMR spectrum (in
at d 2.60–2.63 (H-18) with 118.3 (C-19), d 1.39 (H-21) with
16.8 (C-22)/118.3 (C-19)/134.1 (C-20) as well as the
correlated signals at d 1.10 (H-22) with 25.5 (C-21)/118.3
(C-19)/134.1 (C-20). The position of the prenyl group at C-
5 was determined by the HMBC correlations between the
signals at d 2.60–2.63 (H-18) with 84.4 (C-5)/90.3 (C-10b)/
202.9 (C-6). A cross-peak observed in the HMBC spectrum
between d 7.44 (H-8)/3.50–3.52 (H-13)/2.60–2.63 (H-18)
with 202.9 (C-6) confirmed the position of the carbonyl
group at carbon C-6. The connectivity between C-5 and C-
10b was determined by long-range correlation between the
signals at d 90.3 (C-10b) with 7.44 (H-8)/2.60–2.63 (H-18)
and 2.44 (H-14). Two methyl groups at C-15 were
determined by the signals d1.29 (H-16) with 30.3 (C-17)/
48.4 (C-14)/83.5 (C-15) as well as the signals at d 1.69 (H-
17) with 29.0 (C-16)/48.8 (C-14)/83.5 (C-15).
chloroform-d1) suggested that the
A ring remained
unchanged. One prenyl group was determined by the
geminal methyl protons signals at d 1.10 (s, 3H, C22–H), d
1.39 (s, 3H, C21–H), the alkene proton signal at d 4.42–4.46
(m, 1H, C19–H) and the methylene signal at d 2.60–2.63 (m,
2H, C18–H). The structure of this prenyl group was further
supported by the HMBC correlations between the signals
16. Tisdale, E. J.; Slobodov, I.; Theodorakis, E. A. Proc. Natl.
Acad. Sci. U.S.A. 2004, 101, 12030–12035.