Total synthesis of cleomiscosin C via a regioselective cycloaddition reaction of o-quinone

Article abstract of DOI:10.1016/j.tetlet.2008.05.051

We have achieved total synthesis of cleomiscosin C (aquillochin) through regioselective cycloaddition of o-quinone and protected sinapyl alcohol as a key step. During preparation of o-quinone from phenol by IBX oxidation, silyl substituents adjacent to the phenolic hydroxyl group afforded effective inhibition of an undesired oxidative elimination.

Full text of DOI:10.1016/j.tetlet.2008.05.051

Tetrahedron Letters 49 (2008) 4516–4518
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Tetrahedron Letters
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Total synthesis of cleomiscosin C via a regioselective cycloaddition
reaction of o-quinone
*
*
Atsuhito Kuboki , Chie Maeda, Tetsuya Arishige, Kohei Kuyama, Mami Hamabata, Susumu Ohira
Department of Biochemistry, Okayama University of Science, 1-1 Ridai-cho, Okayama 700-0005, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
We have achieved total synthesis of cleomiscosin C (aquillochin) through regioselective cycloaddition of
o-quinone and protected sinapyl alcohol as a key step. During preparation of o-quinone from phenol by
IBX oxidation, silyl substituents adjacent to the phenolic hydroxyl group afforded effective inhibition of
an undesired oxidative elimination.
Received 4 April 2008
Revised 6 May 2008
Accepted 12 May 2008
Available online 15 May 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
o-Quinone
1,4-Benzodioxane
Regioselective cycloaddition
Natural product synthesis
Recently we developed a novel procedure for regioselective
cycloaddition of o-quinone 1 and a sinapyl alcohol unit 2 to con-
struct 1,4-benzodioxanes 3 (from 1a,b) and 30 (from 10a,b).1,2 The
position of the alkoxy substituent on the o-quinone ring could
effectively control the regioselectivity of the cycloaddition (Fig. 1).
The results prompted us to apply this cycloaddition to the syn-
thesis of natural products. Here, we describe total synthesis of cle-
omiscosin C (aquillochin, 4, Fig. 2), a coumarinolignan isolated
from many groups of plants.3–8 It exhibits a vasorelaxant effect5
and inhibitory activity against tyrosinase,6 monoamine oxidase,7
lipid peroxidation,7 and LDL oxidation.8 The synthesis of 4 has been
accomplished by oxidative coupling between catechol and sinapyl
alcohol using silver oxide9 or diphenyl selonoxide10 in low yield,
accompanied by its regioisomer, cleomiscosin D. In the case of
horseradish peroxidase or tyrosinase, the cyclization proceeded
selectively but slowly in low yield.9,11 As an alternative route,
OR
OR
O
O
O
OTBS
OMe
O
OMe
OH
OMe
O
O
O
O
OH
OH
OMe
OH
OMe
O
TBS
OBn
OH
OMe
OMe
3
O
O
O
(R = Me)
(R = Bn)
1a
1b
OMe
OMe
OMe
OTBS
O
O
O
OH
5
OTBS
O
2
RO
O
O
cleomiscosin C
(aquillochin, 4)
RO
O
OMe
OTBS
cycloaddition
O
O
O
O
O
TBS
TBS
1'a (R = Me)
(R = Bn)
3'
OTBS
OH
O
O
1'b
+
2
Figure 1. Regioselective cycloaddition of o-quinone 1 (10) and sinapyl alcohol unit 2
to afford 1,4-benzodioxane 3 (30).
O
O
O
O
O
OBn
OBn
OBn
82
7a
6a
* Corresponding authors. Tel./fax: +81 86 2569489 (A.K.).
E-mail address: kuboki@dbc.ous.ac.jp (A. Kuboki).
Figure 2. Retrosynthetic strategy for cleomiscosin C (4).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.051

A. Kuboki et al. / Tetrahedron Letters 49 (2008) 4516–4518
4517
successive nucleophilic substitution and dehydrated condensation
OMe
have been used to form the 1,4-benzodioxane skeleton.12
Our approach to the synthesis of 4 is summarized in Figure 2.
The coumarin moiety of 4 should be formed from the cyclic acetal
part of 5. The 1,4-benzodioxane framework of 5 could be afforded
by cycloaddition of o-quinone 6a and 2.13 Preparation of 6a would
be carried out from 7a by regioselective oxidation with IBX.14,15
The TBS group was used as the methoxy group precursor16 after
a considerable investigation. Phenol 7a could be obtained from
known 8.2
Preparation of the o-quinone precursor 7a commenced with
bromination of 8 using NBS (97% yield), followed by protection of
the carbonyl moiety as a cyclic acetal to give 9 in 96% yield
(Scheme 1). The resulting 9 was converted to arylsilane 7a in
79% yield by intramolecular transposition of the TBS group with
nBuLi.
OH
TBS
O
O
a
b
OMe
6a
OTBS
O
O
OBn
OMe
5
H
H
H
OH
Si
O
OMe
OH
O
O
OBn
NOE
10
Oxidation of 7a with IBX afforded the target o-quinone 6a in
59% yield, together with the undesired 10b in 29% yield, which
was generated by oxidative elimination. o-Quinone 6a and 10b
could be separated readily by silica gel column chromatography.
The selectivity for 6a/10b was 2.0 (Table 1, entry 1). The selectivity
was influenced by the bulkiness of the silyl groups. Thus, the selec-
tivity was increased to 5.2 using the more bulky TIPS group17 (en-
try c), and decreased to 1.0 in the case of the less bulky TES group
(entry b). Preliminary experiments on the IBX oxidation step
revealed that each phenol 7d,18 7e, and 7f produces only 10b.
Cycloaddition of 6a and 2 proceeded regioselectively and
smoothly in the presence of triethylamine to provide the expected
adduct 5 in 51% yield (Scheme 2). The structure of the adduct was
confirmed by NOE experiments on 10, which was obtained after
deprotection of 5 under acidic conditions in 82% yield. NOEs were
observed for the tert-butyl proton of the TBS group to both protons
of the upper part of structure 10.
Scheme 2. Reagents and conditions: (a) 2, Et3N, THF, rt, 8 h (51%); (b) AcCl, MeOH–
CH2Cl2 (1/1), rt, 1 h (82%).
OMe
OBn
R
O
O
Ar
O
O
Ar
c
a
10
O
OMOM
O
OBn
OMOM
13
R = TBS: 11
R = I: 12
b
OMe
OMe
OH
O
O
Ar
O
O
Ar
d,e
f,g,h
OH
OHC
Protection of the hydroxyl and phenol groups of 10 as the MOM
ether gave 11 in 88% yield (Scheme 3). The TBS group of 11 was
O
OBn
OMOM
OMOM
14
15
OMe
OMe
Br
TBS
O
O
Ar
OMOM
OMe
i
j
OTBS
OH
4
Ar =
a,b
c
8
O
OMOM
O
O
O
O
OBn
OBn
16
O
9
7a
Scheme 3. Reagents and conditions: (a) MOMCl, iPr2NEt, CH2Cl2, 0 °C to rt, 3 h
(88%); (b) NIS, CH3CN, 80 °C, 3 h (66%); (c) NaOMe, CuCl, MeOH, DMF, 80 °C, 3 h
(quant.); (d) TBSCl, Et3N, NaI, CH3CN, 80 °C, 1 h; (e) OsO4, NMO, acetone–H2O (2/1),
rt, 2 h (60% in two steps); (f) NaBH4, EtOH–THF (1/1), rt, 5 h (51%); (g) NaIO4, THF–
H2O (2/1), rt, 1 h; (h) Pd/C, H2, EtOAc, rt, 0.5 h (quant. in two steps); (i) Ph3P@CH-
CO2Me, Et2NPh, 220 °C, 5 h (82%); (j) AcCl, MeOH, 0 °C to rt, 0.5 h (71%).
Scheme 1. Reagents and conditions: (a) NBS, CH3CN, rt, 3 h (97%); (b) ethylene
glycol, pTsOH, benzene, reflux, 3 h (96%); (c) nBuLi, THF, ꢀ78 °C, 3 h (79%).
Table 1
Synthesis of 6 from precursor phenols (7)
R
O
R
replaced by iodide temporarily with NIS to afford 12 in 66% yield,
and introduction of a methoxy substituent by the Ulmann reaction
provided 13 in quantitative yield. The methyl ketone 13 was
converted to 14 in 60% yield by formation of the silyl enol ether
with TBSCl, followed by osmium-mediated dihydroxylation. The
resulting a-hydroxy ketone 14 was reduced to the diol in 51% yield,
which was subjected to successive oxidative cleavage and hydrog-
enolysis to give 15 in quantitative yield. To form the coumarin
structure from salicylaldehyde, we applied a procedure reported
by Harayama and co-workers.19 Thus, salicylaldehyde 15 was
treated with methyl (triphenylphosphoranylidene)acetate in N,N-
diethylaniline at 220 °C to afford protected cleomiscosin C 16 in
82% yield in a one-pot reaction. The MOM groups were removed
under acidic conditions to give 4 in 71% yield. Spectroscopic data
O
O
O
OH
IBX
+
DMSO
O
O
O
O
O
O
OBn
OBn
OBn
r.t., time
precursor
phenol (7)
6
1'b
Entry
R
Time (h)
6 (%)
10b
6/10b
b
c
d
e
f
TES
TIPS
Br
3
3
1
0.5
0.5
50
52
0
0
0
50
10
69
60
65
1.0
5.2
0
CHO
0
0
CH(SCH2)2

4518
A. Kuboki et al. / Tetrahedron Letters 49 (2008) 4516–4518
(1H, 13C NMR) for synthetic 420 were identical to those for natural
cleomiscosin C.4
12. Tanaka, H.; Ishihara, M.; Ichino, K.; Ito, K. Chem. Pharm. Bull. 1988, 36, 3833–
3837.
13. Kuboki, A.; Yamamoto, T.; Ohira, S. Chem. Lett. 2003, 32, 420–421.
14. Magdziak, D.; Rodriguez, A. A.; Water, R. W. V. D.; Pettus, T. R. R. Org. Lett. 2002,
4, 285–288.
In summary, a total synthesis of cleomiscosin C (15 steps from
8, 1.9% overall yield) has been achieved as an application of the
regioselective cycloaddition of o-quinone and 2. It is noteworthy
that silyl substituents were useful in avoiding the oxidative
elimination in the IBX-mediated oxidation of phenol for selective
formation of the target o-quinone 6. Further application of the
cycloaddition is currently under way.
15. Ozanne, A.; Pouysegu, L.; Depernet, D.; Francßois, B.; Quideau, S. Org. Lett. 2003,
5, 2903–2906.
16. From 17 with a methoxy substituent adjacent to the phenolic hydroxyl group,
10b was predominantly obtained instead of 1a in 78% yield by oxidative
elimination.14
OMe
OMe
O
OH
O
O
O
IBX
Acknowledgment
+
DMSO
r.t., 0.5 h
The authors thank Mr. Y. Fukuda of Okayama University of
Science for assistance with the NMR measurements.
O
O
O
O
O
O
17
1a
10%
18
78%
References and notes
17. Since cycloaddition of 6c with 2 did not proceed, the TBS substituent (6a) was
used in the procedure.
18. In a preliminary investigation, we found that the target o-quinone 20 was
generated selectively in 59% yield from 19 with no substituent at C-6 of 6d. On
the basis of this result, we initially planned the synthesis using 6d.
1. Kuboki, A.; Yamamoto, T.; Taira, M.; Arishige, T.; Ohira, S. Tetrahedron Lett.
2007, 48, 771–774.
2. Kuboki, A.; Yamamoto, T.; Taira, M.; Arishige, T.; Konishi, R.; Hamabata, M.;
Shirahama, M.; Hiramatsu, T.; Kuyama, K.; Ohira, S. Tetrahedron Lett. 2008, 49,
2558–2561.
3. (a) Bhandari, P.; Pant, P.; Rastogi, R. P. Phytochemistry 1982, 21, 2147–2149; (b)
Mizuno, M.; Kojima, H.; Tanaka, T.; Iinuma, M.; Kimura, R.; Min, Z. D.; Murata,
H. Phytochemistry 1987, 26, 2071–2074; (c) Hemlata; Kalidhar, S. B. J. Indian
Chem. Soc. 1994, 71, 213–214; (d) Cheng, X. F.; Chen, Z. L. Fitoterapia 2000, 71,
341–342; (e) Wu, P.-L.; Chuang, T.-H.; He, C.-X.; Wu, T.-S. Bioorg. Med. Chem.
2004, 12, 2193–2197; (f) Son, Y. K.; Lee, M. H.; Han, Y. Arch. Pharm. Res. 2005,
28, 34–38; (g) Wu, P.-L.; Wu, T.-S.; He, C.-X.; Su, C.-H.; Lee, K.-H. Chem. Pharm.
Bull. 2005, 53, 56–59; (h) Jin, W. Y.; Min, B. S.; Lee, J. P.; Thuong, P. T.; Lee, H.-K.;
Song, K.; Seong, Y. H.; Bae, K. Arch. Pharm. Res. 2007, 30, 172–176.
4. Ray, A. B.; Chattopadhyay, S. K.; Kumar, S.; Konno, C.; Kiso, Y.; Hikino, H.
Tetrahedron 1985, 41, 209–214.
Br
Br
OH
O
O
IBX
DMSO
r.t., 0.5 h
O
O
O
O
19
20
59%
5. Iizuka, T.; Nagumo, E.; Yotsumoto, H.; Moriyama, H.; Nagai, M. Biol. Pharm. Bull.
2007, 30, 1164–1166.
6. Ahmad, V. U.; Ullah, F.; Hussain, J.; Farooq, U.; Zubair, M.; Khan, M. T. H.;
Choudhary, M. I. Chem. Pharm. Bull. 2004, 52, 1458–1461.
7. Yun, B. S.; Lee, I. K.; Ryoo, I. J.; Yoo, I. D. J. Nat. Prod. 2001, 64, 1238–1240.
8. Jin, W. Y.; Thuong, P. T.; Nguyen, D.; Min, B. S.; Son, K. H.; Chang, H. W.; Kim, H.
P.; Kang, S. S.; Sok, D. E.; Bae, K. Arch. Pharm. Res. 2007, 30, 275–281.
9. (a) Lin, L.-J.; Cordell, G. A. J. Chem. Soc., Chem. Commun. 1984, 160–161; (b) Lin,
L.-J.; Cordell, G. A. J. Chem. Res. (S) 1988, 396–397; (c) Lin, L.-J.; Cordell, G. A. J.
Chem. Res. (M) 1988, 3052–3080.
10. Tanaka, H.; Ishihara, M.; Ichino, K.; Ito, K. Heterocycles 1988, 27, 2651–2658.
11. Matsumoto, K.; Takahashi, H.; Miyake, Y.; Fukuyama, Y. Tetrahedron Lett. 1999,
40, 3185–3186.
19. Ishi, H.; Kenmotsu, K.; Döpke, W.; Harayama, T. Chem. Pharm. Bull. 1992, 40,
1770–1772.
20. Spectral data for 4: 1H NMR (400 MHz, DMSO-d6): d 3.30 (ddd, J = 3.4, 4.9,
12.2 Hz, 1H), 3.65 (ddd, J = 2.4, 4.9, 12.2 Hz, 1H), 3.76 (s, 6H), 3.78 (s, 3H), 4.37
(ddd, J = 2.4, 3.4, 7.8 Hz, 1H), 4.95 (d, J = 7.8 Hz, 1H), 5.09 (t, J = 4.9 Hz, 1H), 6.34
(d, J = 9.3 Hz, 1H), 6.73 (s, 2H), 6.91 (s, 1H), 7.96 (d, J = 9.3 Hz, 1H), 8.60 (s, 1H);
(400 MHz, CDCl3): d 2.18 (dd, J = 4.8, 7.8 Hz, 1H), 3.59 (ddd, J = 3.4, 7.8, 12.2 Hz,
1H), 3.90 (s, 3H), 3.92 (s, 6H), 3.95 (ddd, J = 2.9, 4.8, 12.2 Hz, 1H), 4.11 (ddd,
J = 2.9, 3.4, 8.3 Hz, 1H), 5.04 (d, J = 8.3 Hz, 1H), 5.62 (s, 1H), 6.34 (d, J = 9.8 Hz,
1H), 6.55 (s, 1H), 6.68 (s, 2H), 7.64 (d, J = 9.8 Hz, 1H); 13C NMR (100 MHz,
pyridine-d5): d 56.1, 56.3, 60.8, 77.9, 79.9, 101.0, 106.3, 111.9, 113.8, 126.4,
133.0, 138.4, 139.3, 144.4, 146.3, 149.2, 160.7.