Facile synthesis of (-)-ascochlorin using palladium-catalyzed three component coupling reaction

Article abstract of DOI:10.1246/cl.2007.654

(-)-Ascochlorin was synthesized using palladium-catalyzed three component coupling reaction. Reaction of the aryl iodide 3, isoprene, and sodium p-toluenesulfinate in the presence of Pd₂(dba)₃CHCl ₃ catalyst and NaHCO

Full text of DOI:10.1246/cl.2007.654

654
Chemistry Letters Vol.36, No.5 (2007)
Facile Synthesis of (À)-Ascochlorin
Using Palladium-catalyzed Three Component Coupling Reaction
Makoto Aoki, Kenji Kawashima, Hirohisa Fujihara, and Isao Shimizuꢀ
Department of Applied Chemistry, School of Science and Engineering, Waseda University,
3-4-1 Okubo, Shinjuku-ku, Tokyo 169-8555
(Received February 8, 2007; CL-070154; E-mail: shimizui@waseda.jp)
(ꢁ)-Ascochlorin was synthesized using palladium-cata-
OMe
3
I
lyzed three component coupling reaction. Reaction of the aryl
iodide 3, isoprene, and sodium p-toluenesulfinate in the presence
of Pd2(dba)3CHCl3 catalyst and NaHCO3 gave the 4-aryl-2-
methyl-2-butenylsulfone 5 selectively in 68% yield. The allylic
sulfone 5 was converted into the useful intermediate 2 in 5 steps,
which was subjected to Julia olefination with the aldehyde 4 and
deprotection gave (ꢁ)-ascochlorin.
O
OMOM
Pd cat.
Ts
O
OMe
OMOM
Cl
2
p-TsNa
1
O
O
H
O
4
In the course of studies on development of transition metal-
catalyzed reactions toward organic synthesis, we have synthe-
sized mycophenolic acid by a palladium-catalyzed three compo-
nent coupling reaction, in which the requisite carbon framework
was prepared in one pot (Scheme 1).1
Scheme 2. Retrosynthetic analysis of (ꢁ)-ascochlorin (1).
phenols on the basis of organo-sulfone chemistry.4 In this paper,
we have realized a facile synthesis of (ꢁ)-ascochlorin by means
of the palladium-catalyzed three component coupling reaction.
Our retrosynthetic approach is shown in Scheme 2. (ꢁ)-
Ascochlorin is synthesized by Julia olefination4b of the allylic
sulfone segment 2 and the aldehyde segment 4. The allylic
sulfone 2 is accessible from three components, aryl halide 3,
isoprene, and sulfinate by the palladium-catalyzed reaction.
Actually the key intermediate 5 was prepared form the aryl
halide 3, which was prepared from 5-methyl resorcinol in two
steps (NIS in CH3CN at 0 ꢂC, 91%, then, MeI in DMF at r.t.
quant.). Reaction of aryl halide 3, isoprene, and sodium p-tolu-
enesulfinate was carried out under various conditions. Excess
isoprene was necessary because of its volatility. The reaction
proceeded without phosphines or phosphites, which are normal-
ly used as ligand of the catalysts to prevent precipitating the met-
al. Reaction without adding base did not proceed smoothly, and
addition of bases is necessary for the reaction. The reactions
at 80 ꢂC with various bases are summarized in Table 1. The
choice of base was important for the three component coupling,
thus, Et3N, NaOAc, and K2CO3 did not give satisfactory results,
but NaHCO3 was found to be suitable, and the best result was
obtained (Entry 4).
The method is applicable to other biologically active phe-
nols having functionalized isoprenoid chains such as (ꢁ)-asco-
chlorin (1) and a related compound, ascofuranone. These natural
prenyl phenols exhibit important biological activities as antivi-
ral, antibiotic, and antitumor activities.2 The relationship of
these activities and the unique structures as multi-substituted ar-
omatic ring connecting with functionalized isoprenoid chains
prompts chemists to synthesize the ascochlorin family (Figure 1).
Several synthetic methods are known for these functional-
ized prenyl phenols, however, the syntheses require many steps.3
To extend the palladium-catalyzed three component coupling re-
action to the synthesis of various prenyl phenols we have studied
the reaction with sodium p-toluenesulfinate as a nucleophile to
synthesize 4-sulfonylprenyl phenols, from which (ꢁ)-ascochlo-
rin and related compounds can be synthesized by furnishing
the requisite carbon frameworks of the biologically active prenyl
OMe
O
OR2
E
O
Pd cat.
I
CO2R1
O
O
CO2Me
CO2Me
OMe
OMe
R1 = R2 = CH3, E = CO2Me
Mycophenolic acid R1 = R2 = E = H
3 steps
Table 1. Palladium-catalyzed reaction of aryl halide 3, isoprene
and sodium p-toluenesulfinate5
Scheme 1. Synthesis of mycophenolic acid.
Pd2(dba)3CHCl3 (5 mol %)
Base (1.5 equiv.)
OMe
OMe
Ts
I
n-Bu4NI (1.1 equiv.)
OH
OH
DMSO
80 °C, 96 h
OMe
OMe
p-TsNa (2.2 equiv.)
O
OHC
O
OHC
3
5
Entry
Base
Yield (%)
OH
OH
O
R1
R2
Cl
1
2
3
4
Et3N
NaOAc
K2CO3
NaHCO3
49
34
29
68
R1 = Cl R2 = H
R1 = H R2 = H
1 = H R2 = OCOCH3
(−)-Ascochlorin (1)
Cylindrol B
Cylindrol B1
Ascofuranone
R
Figure 1. Ascochlorin family of sesquiterpenyl phenol.
Copyright Ó 2007 The Chemical Society of Japan

Chemistry Letters Vol.36, No.5 (2007)
655
O
OMOM
OP
R
O
Ts
O
h
f, g
O
1
OMOM
OP
X
Cl
8
5
X = R = H, P = Me
a, b
6 X = Cl, R = CHO, P = Me
7 X = Cl, R = CHO, P = MOM
c, d
e
2 X = Cl, R = CH(OCH2
) 2, P = MOM
Scheme 3. Reagents and conditions; a) NCS, MeCN, reflux, quant.; b) CHCl2OCH3, TiCl4, CH2Cl2, 0 ꢂC to r.t., 65%; c) BBr3,
CH2Cl2, ꢁ78 to 0 ꢂC, 73%; d) MOMCl, DIPEA, r.t., quant.; e) ethylene glycol, PPTS cat., benzene, 75%; f) 4, LHMDS, Ac2O,
THF, ꢁ78 ꢂC to r.t., 88%; g) Na/Hg (10%), Na2HPO4, MeOH, 57%; h) 1 M HCl, THF, 81%.
3
Total synthesis of (ꢁ)-ascochlorin: a) K. Mori, S. Takechi,
Tetrahedron 1985, 41, 3049. b) G. B. Dudley, K. S. Takaki,
D. D. Cha, R. L. Danheiser, Org. Lett. 2000, 2, 3407. Total
synthesis of (ꢃ)-ascochlorin: c) J. E. Safaryn, J. Chiarello,
K. M. Chen, M. M. Joullie, Tetrahedron 1986, 42, 2635.
a) M. Julia, D. Arnould, Bull. Soc. Chim. Fr. 1973, 743. b) M.
Julia, J. M. Paris, Tetrahedron Lett. 1973, 14, 4833. c) H. Kotake,
T. Yamamoto, H. Kinoshita, Chem. Lett. 1982, 1331. d) M.
Julia, A. R. Tapif, J. N. Verpeaux, Tetrahedron 1983, 39,
3283. e) J. Clayden, M. Julia, J. Chem. Soc., Chem. Commun.
1994, 1905.
O
O
a
b, c
4
9
10
4
Scheme 4. Reagents and conditions; a) vinylmagnesium bro-
mide, CuI, THF, ꢁ25 ꢂC, 63%; b) ethylene glycol, PTSA cat.,
toluene, 91%; c) O3, Me2S, MeOH, ꢁ78 ꢂC to r.t., 85%.
Conversion of the allylic sulfone 5 to ascochlorin (1) was
shown in Scheme 3. Chlorination of 5 with NCS followed by for-
mylation of the aromatic ring with dichloromethyl methyl ether
using TiCl4 gave the aromatic aldehyde 6. After the protecting
group of the phenol 6 was changed from methyl to the methoxy
methyl ether 7 and the acetal protection of the aldehyde with
ethylene glycol, the allylic sulfone segment 2 was subjected to
Julia olefination with the aldehyde segment 46 to afford the diene
8. Finally, simultaneous deprotection of acetal and MOM ether
of 8 with 1 M HCl gave (ꢁ)-ascochlorin (1) (Scheme 3).
In summary, we have developed a novel method to synthe-
size (ꢁ)-ascochlorin (1) by means of the palladium-catalyzed
three component coupling reaction with the aryl halide, isoprene
and sodium p-toluenesulfinate, which provides a useful method-
ology, especially for biologically active phenols substituted
with functionalized prenyl groups. Synthesis of the other phenol
isoprenoid such as ascofuranone or related compounds for
structure–activity relationship study is in progress.
5
Preparation of 5 as a typical procedure for the palladium-
catalyzed three component coupling reactions in Table 1: A mix-
ture of 3,5-dimethoxy-4-iodotoluene (3) (55.6 mg, 0.200 mmol),
sodium p-toluenesulfinate (78.4 mg, 0.440 mmol), sodium hydro-
gen carbonate (26.2 mg, 0.312 mmol), tetra-n-butylammonium
iodide (77.6 mg, 0.210 mmol), Pd2(dba)3CHCl3 (10.4 mg,
5 mol %), isoprene (0.4 mL) in DMSO (0.606 mL) was stirred
at 80 ꢂC for 96 h in Pyrex tube. The mixture was quenched with
NH4Cl aq. The organic layer was extracted with dichloro-
methane, washed with brine, dried over MgSO4 and filtered. The
filtrate was concentrated in vacuo. The residue was chromatogar-
aphed on silica gel (10% ethyl acetate in hexane) to give the
product 6 as a yellow oil (50.7 mg, 68%): 1H NMR (400 MHz
CDCl3) ꢀ 1.90 (s, 3H, CH3), 2.31 (s, 3H, CH3), 2.33 (s, 3H,
CH3), 3.20 (d, J ¼ 7:6 Hz, 2H, BnCH2), 3.61 (s, 2H, CH2),
3.72 (s, 6H, OCH3), 4.94 (t, J ¼ 7:5 Hz, 1H, CHCH2), 6.31 (s,
2H, aromatic H), 7.02 (d, J ¼ 8:1 Hz, 2H, aromatic H), 7.52
(d, J ¼ 8:2 Hz, 2H, aromatic H); 13C NMR (100 MHz CDCl3)
ꢀ 16.6, 21.5, 22.0, 22.3, 55.5, 66.3, 104.3, 113.1, 122.5, 128.4,
130.0, 134.5, 134.8, 136.9, 143.6, 157.6; IR (film) 2937, 2836,
1589, 1463, 1413, 1313, 1164, 1118, 1087 cmꢁ1; HRMS
(FAB) calcd for C21H27O4S [M + H]þ 375.1552, found
375.1636.
This research was supported by the program of Initiatives
for Attractive Education in Graduate Schools (2005 b043)
from the Ministry of Education, Culture, Sports, Science and
Technology and Waseda University Grant for Special Project
Research (No. 2006A-063). We thank the Materials Characteri-
zation Central Laboratory, Waseda University, for NMR, IR,
and HRMS measurement.
6
7
The segment 4 (97%ee) was prepared according to the procedure
reported3c from (4R)-(ꢁ)-2,3,4-trimethyl-2-cyclohexenone3b
(Scheme 4).
(ꢁ)-Ascochlorin (1): mp 172–174 ꢂC (lit:2b 172–173 ꢂC);
2b
25
25
½ꢁꢄD ꢁ 30:7 (c 0.69, MeOH) (lit: ½ꢁꢄD ꢁ 31 (c 0.99,
MeOH)); 1H NMR (400 MHz, CDCl3) ꢀ 0.69 (s, 3H, CH3),
0.80–0.84 (m, 6H), 1.60–1.67 (m, 1H), 1.89–1.96 (m, 2H),
1.92 (s, 3H, CH3), 2.33–2.46 (m, 3H), 2.60 (s, 3H, CH3), 3.53
(d, J ¼ 7:6 Hz, 2H, BnCH2), 5.38 (d, J ¼ 16:1 Hz, 1H), 5.52
(t, J ¼ 7:6 Hz, 1H, CHCH2), 5.90 (d, J ¼ 16:1 Hz, 1H), 6.39
(s, 1H, OH), 10.14 (s, 1H, CHO), 12.70 (s, 1H, OH); 13C NMR
(100 MHz CDCl3) ꢀ 8.99, 10.4, 12.7, 14.6, 16.4, 22.3, 31.2,
40.9, 41.6, 48.5, 53.6, 113.1, 113.6, 113.7, 127.4, 133.1, 134.0,
135.6, 137.7, 156.0, 162.1, 193.1, 212.6; IR (film) 3268, 2960,
2925, 2871, 1708, 1614, 1454, 1423, 1375, 1328, 1282, 1249,
1172, 1110, 1012, 970, 906, 798, 713, 590 cmꢁ1; HRMS
(FAB) calcd for C23H30ClO4 [M + H]þ 405.1754, found
405.1817.
References and Notes
1
2
a) I. Shimizu, Y. Lee, Y. Fujiwara, Synlett 2000, 1285. b) Y. Lee,
Y. Fujiwara, K. Ujita, M. Nagatomo, H. Ohta, I. Shimizu, Bull.
Chem. Soc. Jpn. 2001, 74, 1437.
a) G. Tamura, S. Suzuki, A. Takatsuki, K. Ando, K. Arima, J. An-
tibiot. 1968, 11, 539. b) G. A. Ellestad, R. H. Evans, M. P.
Kunstmann, Tetrahedron 1969, 25, 1323. c) S. B. Singh, R. G.
Ball, G. F. Bills, C. Cascales, J. B. Gibbs, M. A. Goetz, K.
Hoogsteen, R. G. Jenkins, J. M. Liesch, R. B. Lingham, K. C.
Silverman, J. Org. Chem. 1996, 61, 7727. d) H. Sasaki, T.
Okutomi, T. Hosokawa, Y. Nawata, K. Ando, Tetrahedron Lett.
1972, 13, 2541.
Published on the web (Advance View) April 14, 2007; doi:10.1246/cl.2007.654