Total synthesis of terprenin, a novel immunosuppressive p-terphenyl derivative

Article abstract of DOI:10.1021/jo980349t

We achieved a total synthesis of terprenin, a novel potent immunoglobulin E antibody suppressant which was obtained from the fermentation broth of Aspergillus candidus RF-5672 and has a highly oxygenated p-terphenyl skeleton with a prenyloxy side chain. The key steps relied on the Suzuki reaction to construct the terphenyl skeleton and on regioselective halogenations to selectively combine the aromatic rings. The highly efficient and practical production of this important natural product offers promise for the development of a new type of antiallergic drug.

Full text of DOI:10.1021/jo980349t

J . Org. Chem. 1998, 63, 5831-5837
5831
Tota l Syn th esis of Ter p r en in , a Novel Im m u n osu p p r essive
p-Ter p h en yl Der iva tive
Shuji Yonezawa, Tadafumi Komurasaki, Kenji Kawada,* Tatsuo Tsuri, Masahiro Fuji,
Akira Kugimiya, Nobuhiro Haga, Susumu Mitsumori, Masanao Inagaki, Takuji Nakatani,
Yoshinori Tamura, Shozo Takechi, Teruhiko Taishi, and Mitsuaki Ohtani*
Shionogi Research Laboratories, Shionogi & Co., Ltd., Fukushima-ku, Osaka 553-0002, J apan
Received February 24, 1998
We achieved a total synthesis of terprenin, a novel potent immunoglobulin E antibody suppressant
which was obtained from the fermentation broth of Aspergillus candidus RF-5672 and has a highly
oxygenated p-terphenyl skeleton with a prenyloxy side chain. The key steps relied on the Suzuki
reaction to construct the terphenyl skeleton and on regioselective halogenations to selectively
combine the aromatic rings. The highly efficient and practical production of this important natural
product offers promise for the development of a new type of antiallergic drug.
Sch em e 1
In tr od u ction
Terprenin (1, Scheme 1) was discovered in the fermen-
tation broth of Aspergillus candidus RF-5672 during our
screening of natural products aimed at discovering new
immunosuppressants from natural products.1,2 Terpre-
nin has a novel highly oxygenated p-terphenyl structure
with a prenyloxy side chain.3 Although several natural
cytotoxic p-terphenyl compounds have been isolated from
fungi, no derivative with an alkenyl side chain has been
reported.4 The impressive feature of immunosuppressive
activities of terprenin is its highly potent in vitro and in
vivo suppressive effect on immunoglobulin E (IgE) anti-
body production without any toxicological signs.5 IgE is
known to play a central role in a variety of allergic
diseases including atopic dermatitis, bronchial asthma,
allergic rhinitis, allergic conjunctivitis, and anaphylaxis.6
Although FK506 and cyclosporin A, which are known to
be strong immunosuppressants, are established drugs in
the management of human organ transplantation, they
have been reported to potentiate IgE production in mice.7
(1) Kamigauchi, T.; Sakazaki, R.; Nagashima, K.; Kawamura, Y.;
Yasuda, Y.; Matsushima, K.; Tani, H.; Takahashi, Y.; Ishii, K.; Suzuki,
R.; Koizumi, K.; Nakai, H.; Ikenishi, Y.; Terui, Y. J . Antibiot. 1998,
51, 445.
(2) For our previous work in this field, see: (a) Yasui, K.; Tamura,
Y.; Nakatani, T.; Kawada, K.; Ohtani, M. J . Org. Chem. 1995, 60, 7567.
(b) Yasui, K.; Tamura, Y.; Nakatani, T.; Horibe, I.; Kawada, K.;
Koizumi, K.; Suzuki, R.; Ohtani, M. J . Antibiot. 1996, 49, 173.
(3) Only 70 mg of terprenin was isolated from 2 L of the fermentation
broth.
(4) For natural p-terphenyl compounds, see: (a) Marchell, R.; Vining,
L. C. J . Chem. Soc. Chem. Commun. 1973, 555. (b) Takahashi, C.;
Yoshihira, K.; Natori, S.; Umeda, M. Chem. Pharm. Bull. 1976, 24,
613. (c) Cutler, H. G.; LeFiles, J . H.; Crumley, F. G.; Cox, R. H. J .
Agric. Food Chem. 1978, 26, 632. (d) Kurobane, I.; Vining, L. C.;
McInnes, A. G.; Smith, D. G. J . Antibiot. 1979, 32, 559. (e) Kobayashi,
A.; Takemoto, A.; Koshimizu, K.; Kawazu, K. Agric. Biol. Chem. 1985,
49, 867. (f) Tringali, C.; Piattelli, M.; Geraci, C.; Nicolosi, G.; Rocco, C.
Can. J . Chem. 1987, 65, 2369.
To develop a new type of immunosuppressive drug for
use against allergic diseases, we first sought to develop
a total synthesis of terprenin. Here, we report the highly
efficient and practical total synthesis of terprenin with
significant new results.5
(5) For a preliminary account of the biological activities and total
syntheses of terprenin, see: Kawada, K.; Arimura, A.; Tsuri, T.; Fuji,
M.; Komurasaki, T.; Yonezawa, S.; Kugimiya, A.; Haga, N.; Mitsumori,
S.; Inagaki, M.; Nakatani, T.; Tamura, Y.; Takechi, S.; Taishi, T.;
Kishino, J .; Ohtani, M. Angew. Chem., Int. Ed. Engl. 1998, 37, 973.
(6) For a general review, see: Plant, M.; Zimmerman, E. M. Allergy
and Mechanisms of Hypersensitivity. In Fundamental Immunology,
3rd ed; Pawl, W. E., Ed.; Raven Press: New York, 1993; pp 1399-
1425.
Resu lts a n d Discu ssion
Since biaryls are important core components in natural
products, organic materials, and molecules of medicinal
interest, a number of procedures have been developed for
the formation of an aryl-aryl linkage,8 including modern
catalytic cross-coupling reactions such as the Negishi,9
Stille,10 Hiyama,11 and Suzuki reactions.12 Among them,
(7) Nagai, H.; Hiyama, H.; Matsuo, A.; Ueda, Y.; Inagaki, N.;
Kawada, K. J . Pharmacol. Exp. Ther. 1997, 283, 321.
S0022-3263(98)00349-1 CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/06/1998

5832 J . Org. Chem., Vol. 63, No. 17, 1998
Yonezawa et al.
Sch em e 2a
Sch em e 3a
the Suzuki reaction, which is based on the palladium-
catalyzed cross-coupling of aryl halides or triflates with
boronic acids, offers several advantages, such as being
unaffected by the presence of water and tolerating a
variety of functional groups, which have led to its
increased use for a wide range of molecules.13 We chose
the Suzuki reaction to construct the terphenyl skeleton.
In considering the palladium-catalyzed elimination reac-
tion of allylic phenyl ethers14 as well as the instability of
the prenyloxy group under acidic and hydrogenous condi-
tions,15 we decided to construct a C-4 side chain moiety
at the last step in the synthetic sequence. Additional
consideration of a conveniently available starting mate-
rial, 3-bromo-2,5-dimethoxybenzaldehyde (2), guided the
design of our retrosynthetic analysis as shown in Scheme
1. The crucial step in the synthesis was the regioselective
functionalization of the aromatic ring. We also needed
to be able to discriminate the six oxygen functions using
an appropriate protection method.
methoxybenzaldehyde according to a known proced-
ure.16 The Suzuki reaction of 2 with boronic acid 317
(Scheme 3) proceeded almost quantitatively to afford the
biphenyl compound 4. In this reaction, the tert-bu-
tyldimethylsilyl (TBDMS)-protected group of 3 was cleaved
to give the corresponding phenol 4 in the presence of
water. A similar palladium-catalyzed desilylation of
phenolic silyl ethers has been reported recently by Wilson
and Keay.18
After protection of the C-4′′ hydroxyl group of 4 as the
mesylate, bromination of 5 with molecular bromine led
exclusively to regioselective functionalization to give the
desired bromide 6. In this bromination, the C-2′ formyl
group seems to play an important role in the regioselec-
tivity, since the desired C-1′ brominated compound could
not be obtained selectively by using the C-2′ phenol or
mesylate as a substrate. Next, the formyl group of 6 was
converted to the hydroxyl group by Baeyer-Villiger
oxidation followed by acidic hydrolysis. Catechol-type
boronic acid 8 was prepared from 5-bromosalicylaldehyde
The first synthesis (route A in Scheme 1) relied upon
the stepwise Suzuki reaction as shown in Scheme 2. The
starting material 2 was prepared from 2-hydroxy-5-
(8) For general reviews, see: (a) Sainsbury, M. Tetrahedron 1980,
36, 3359. (b) Bringmann, G.; Walte, R.; Weirich, R. Angew. Chem., Int.
Ed. Engl. 1990, 29, 977. (c) Stanforth, S. P. Tetrahedron 1998, 54, 263.
(9) Negishi, E. Acc. Chem. Res. 1982, 15, 340.
(10) (a) Stille, J . K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508. (b)
Farina, V.; Krishnamurthy, V.; Scott, W. Org. React. 1997, 50, 1.
(11) Hatanaka, Y.; Hiyama, T. Synlett 1991, 845.
(12) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(13) For the synthesis of terphenyl compounds, see: (a) Iwema
Bakker, W. I.; Haas, M.; den Hertog, H. J ., J r.; Verboom, W.; de Zeeuv,
D.; Bruins, A. P.; Reinhoudt, D. N. J . Org. Chem. 1994, 59, 972. (b)
Todd, M. H.; Balasubramanian, S.; Abell, C. Tetrahedron Lett. 1997,
38, 6781. For recent works in this area, see: (c) Charette, A. B.; Giroux,
A. J . Org. Chem. 1996, 61, 8718. (d) Anderson, N. G.; Maddaford, S.
P.; Keay, B. A. J . Org. Chem. 1996, 61, 9556. (e) Sengupta, S.;
Bhattacharyya, S. J . Org. Chem. 1997, 62, 3405. (f) Su, D. S.; Meng,
D.; Bertinato, P.; Balog, A.; Sorenson, E. J .; Danishefsky, S. J . Angew.
Chem., Int. Ed. Engl. 1997, 36, 757. (g) Ruhland, B.; Bombrun, A.;
Gallop, M. A. J . Org. Chem. 1997, 62, 7820.
(14) For a palladium-catalyzed hydrogenolysis of allylic compounds,
see: Tsuji, J .; Mandai, T. Synthesis 1996, 1.
(15) About 50% of the prenyl group of terprenin was cleaved when
treated with 3% TFA-MeOH-H2O for 1 h at 25 °C.
(16) Rubenstein, L. J . Chem. Soc. 1925, 1998.
(17) Oxford, A. W.; Clitherow, J . W. UK Patent GB 2276162 A, 1994;
Chem. Abstr. 1994, 121, 300771z.
(18) Wilson, N. S.; Keay, B. A. Tetrahedron Lett. 1996, 37, 153.

Total Synthesis of Terprenin
J . Org. Chem., Vol. 63, No. 17, 1998 5833
Sch em e 4a
Sch em e 5a
(14), as shown in Scheme 3, through a sequence involving
conversion of 14 to the phenol 15,19 protection of the
hydroxyl group of 15 as the TBDMS ether 16, and
borylation of 16 using triisopropyl borate. Although aryl
halides or triflates containing electron-withdrawing func-
tional groups have been known to be more favorable for
the Suzuki reaction,12 the reaction of the highly oxygen-
ated, electron-donating, and sterically hindered bromide
7 with 8 proceeded smoothly to afford the expected
terphenyl compound 9.
Sch em e 6a
Formation of the terphenyl skeleton set the stage for
the introduction of the side chain at the C-4 position.
Since employing acetyl or silyl protecting group at the
C-3 hydroxyl group caused migration of the protecting
group to the C-4 free hydroxyl group produced at the next
hydrogenolysis step, the free hydroxyl groups of 9 were
protected as mesylates which would be sensitive to basic
deprotection. After deprotection of the benzyl ether of
10 by hydrogenolysis, the prenyl group was introduced
to the desired position of terphenyl compound 11 using
prenyl bromide. Finally, deprotection of the mesyl groups
of 12 by potassium hydroxide led to completion of the
total synthesis of terprenin. Spectroscopic data and
biological activities of the synthetic compound were
identical in all respects to the natural product from A.
candidus.
In this first total synthesis, the yield of each step was
quite high and the overall yield from 2 was 40%.
Moreover, since the purification of each product was
performed by simple crystallization, no chromatography
was needed throughout the manipulation. Therefore,
this procedure would be suitable for large-scale and
practical production of terprenin.
ment of 17 with iodine in the presence of tert-butylamine
for 48 h led to regioselective iodination to give the desired
C-1′ iodide 18 in 92% yield.21 A small amount of C-5′
iodide 22 (Scheme 5) was also obtained, and the regiose-
lectivity was 15:1. The success of this reaction was
attributed to tert-butylamine, without which no iodina-
tion occurred. Employing other amines such as diiso-
propylamine and triethylamine led to lower regioselec-
tivity. We also observed that the isolated 22, which was
obtained as the major product after the reaction of 15
min, was converted to 18 under the above reaction
conditions for 48 h as shown in Scheme 5. Namely, the
reaction is thermodynamically controlled, and 18 becomes
the predominant product when the reaction reaches
equilibrium.
After obtaining compound 18 which had different
halogen functionality at the desired C-1′ and C-4′ posi-
tions, we examined the various conditions of the one-pot
Suzuki reaction. Although the iodo group was located
at a more sterically hindered position than the bromo
group, as shown in Scheme 6, the catechol-type boronic
acid 8 reacted preferentially with the iodo-substituted
position using Pd(PPh3)4 as a catalyst. Without isolation
The second synthesis (route B in Scheme 1) was based
on the one-pot Suzuki reaction starting from the same
bromobenzaldehyde 2 as shown in Scheme 4. To perform
the Suzuki reaction regioselectively, we tried to introduce
an iodo group to the C-1′ position of the aryl bromide 2.
First, since the iodination of 2 did not proceed selec-
tively,20 the aldehyde was converted to phenol 17. Treat-
(19) (a) Schmidt, U.; Meyer, R.; Leitenberger, V.; Griesser, H.;
Lieberknecht, A. Synthesis 1992, 1025. (b) Suzuki, K.; Satake, N.;
Sugiura, A.; Fujii, T. J apan Patent Kokai 5-213930, 1993; Chem. Abstr.
1994, 120, 134493t.
(20) Efforts to effect the iododethallation of 2 were unrewarding.
For related iodination reactions, see: (a) Taylor, E. C.; Kienzle, F.;
Robey, R. L.; McKillop, A.; Hunt, J . D. J . Am. Chem. Soc. 1971, 93,
4845. (b) Merkushev, E. B. Synthesis 1988, 923. (c) Noda, Y.; Kashima,
M. Tetrahedron Lett. 1997, 38, 6225. (d) Zupan, M.; Iskra, J .; Stavber,
S. Tetrahedron Lett. 1997, 38, 6305.
(21) For the iodination of phenols with iodine and amines, see: (a)
Chabrier, P.; Seyden-Penne, J .; Fouace, A. C. R. Acad. Sci. 1957, 245,
174. For related ortho-bromination of phenols, see: (b) Pearson, D. E.;
Wysong, R. D.; Breder, C. V. J . Org. Chem. 1967, 32, 2358. (c) Fujisaki,
S.; Eguchi, H.; Omura, A.; Okamoto, A.; Nishida, A. Bull. Chem. Soc.
J pn. 1993, 66, 1576.

5834 J . Org. Chem., Vol. 63, No. 17, 1998
Yonezawa et al.
Sch em e 7a
Suzuki reaction can be useful for the construction of these
highly oxygenated aromatic molecules.
Exp er im en ta l Section
Melting points are uncorrected. 1H NMR spectra were
determined at 200 or 300 MHz. 13C NMR spectra were
determined at 50.3 or 75.5 MHz. High-resolution liquid
secondary ion mass spectra (HR-LSIMS) or fast atom bom-
bardment mass spectra (HR-FABMS) were determined using
m-nitrobenzyl alcohol as a matrix. Fractional moles of water
found in some of the analytical samples could not be prevented
despite drying in vacuo and were confirmed by their presence
in the Karl Fischer method. Unless otherwise stated, all
reactions were carried out under a nitrogen atmosphere with
anhydrous solvents that had been dried over type 4A molecular
sieves. Drying of an organic phase over anhydrous sodium
sulfate is simply indicated by the word “dried”. Column
chromatography using Merck Silica gel 60 or a Merck Lobar
column is referred to as “chromatography on silica gel”.
4′-Hydr oxy-2,5-dim eth oxy-[1,1′]biph en yl-3-aldeh yde (4).
To a solution of 18.3 g (74.8 mmol) of 216 in 300 mL of DME
and 75 mL of EtOH were added 20.7 g (82.2 mmol) of 3, 150
mL of 2 M Na2CO3 solution, and 4.23 g (3.74 mmol) of Pd-
(PPh3)4 under an argon atmosphere. The mixture was refluxed
for 20 h. After cooling to 0 °C, the mixture was diluted with
2 N HCl solution and EtOAc and then filtered through a Celite
pad. The filtrate was extracted with EtOAc, and then the
organic solution was washed with 2 N HCl solution, saturated
NaHCO3 solution, and brine. The organic solution was dried
and concentrated. The residue was crystallized from (i-Pr)2O-
hexane to afford 19.3 g (100%) of 4 as colorless crystals: mp
120-122 °C; IR (KBr) 3410, 3256, 1683 cm-1; 1H NMR (CDCl3)
δ 3.48 (s, 3H), 3.85 (s, 3H), 5.24 (s, 1H), 6.94 (m, 2H), 7.16 (d,
J ) 3.3 Hz, 1H), 7.28 (d, J ) 3.3 Hz, 1H), 7.48 (m, 2H), 10.43
(s, 1H); 13C NMR (CDCl3) δ 55.83, 62.77, 108.52, 115.54 (2C),
124.73, 129.21, 130.02, 130.30 (2C), 136.90, 155.47, 155.60,
156.00, 190.50. Anal. Calcd for C15H14O4: C, 69.76; H, 5.46.
Found: C, 69.82; H, 5.55.
4′-(Meth a n esu lfon yloxy)-2,5-d im eth oxy-[1,1′]bip h en yl-
3-a ld eh yd e (5). To a solution of 19.3 g (74.8 mmol) of 4 in
320 mL of CH2Cl2 were added 13.1 mL (93.7 mmol) of Et3N
and 6.6 mL (85.9 mmol) of methanesulfonyl chloride at 0 °C.
The mixture was stirred for 18 h at 20 °C and diluted with 1
N HCl solution. The mixture was extracted with CHCl3, and
then the organic solution was washed with saturated NaHCO3
solution and brine and then dried and concentrated. The
crystalline residue was washed with (i-Pr)2O-hexane to afford
23.7 g (94%) of 5 as colorless crystals: mp 129-130 °C; IR
(KBr) 1676 cm-1; 1H NMR (CDCl3) δ 3.22 (s, 3H), 3.48 (s, 3H),
3.86 (s, 3H), 7.15 (d, J ) 3.5 Hz, 1H), 7.34 (d, J ) 3.5 Hz, 1H),
7.39 (m, 2H), 7.65 (m, 2H), 10.43 (s, 1H); 13C NMR (CDCl3) δ
37.68, 55.88, 63.27, 109.64, 122.19 (2C), 124.53, 130.24, 130.59
(2C), 135.75, 136.05, 148.80, 155.13, 156.08, 189.83. Anal.
Calcd for C16H16O6S: C, 57.13; H, 4.79; S, 9.53. Found: C,
57.32; H, 4.84; S, 9.53.
of the biphenyl compound, the phenol-type boronic acid
3 and Pd(PPh3)4 were added to the reaction mixture, and
the expected terphenyl compound 23 was obtained in 67%
yield. Since the phenol 23 was converted to the mesylate
10, terprenin could be prepared efficiently using this one-
pot Suzuki reaction. We next tried to find a more
convenient procedure without using protection-depro-
tection of the hydroxyl groups at the final stage of
introducing the C-4 side chain.
As shown in Scheme 7, we converted 14 to a bicyclic
acetal 26 through a sequence involving condensation of
the hydroxyl group of 14 with 2-bromo-1,1-dimethoxy-
ethane, Baeyer-Villiger oxidation of 24 followed by
alkaline hydrolysis, and acetal formation of 25 by treat-
ment with p-toluenesulfonic acid. Borylation of 26
furnished the desired boronic acid 19. Although the
Suzuki reaction of 18 with this acetal-type boronic acid
19 proceeded rather sluggishly and unselectively with Pd-
(PPh3)4 as the catalyst, employing Pd2(dba)3 as the
catalyst led to regioselective cross-coupling at the iodo-
substituted position to give the biphenyl compound. As
a result, the one-pot Suzuki reaction proceeded smoothly
on the following addition of the phenol-type boronic acid
3 and Pd(PPh3)4 to afford the expected terphenyl com-
pound 20 in 70% yield as shown in Scheme 4.22
The second total synthesis of terprenin was completed
by hydrolysis of the acetal 20 using p-toluenesulfonic acid
in aqueous acetone and the Wittig reaction of 21 with
excess isopropyltriphenylphosphonium iodide without
protection of the C-2′ and C-4′′ hydroxyl groups. Since
this second synthesis needed no protection-deprotection
procedure of the hydroxyl groups, the synthetic sequence
could be minimized for efficient production of terprenin.
4-Br om o-4′-(m eth a n esu lfon yloxy)-2,5-d im eth oxy-[1,1′]-
bip h en yl-3-a ld eh yd e (6). To a solution of 12.3 g (36.6 mmol)
of 5 and 6.0 g (73.3 mmol) of NaOAc in 150 mL of HOAc was
added 3.77 mL (73.3 mmol) of bromine. After the mixture was
stirred for 18 h at 20 °C, 6.0 g (73.3 mmol) of NaOAc and 3.77
mL (73.3 mmol) of bromine were added. The mixture was
stirred for 5 h at 50 °C and then poured into 1 L of ice-water.
The mixture was diluted with 50 mL of 1 N Na2S2O3 solution
and stirred for 30 min. The resulting precipitate was filtered
and dissolved in CHCl3, and then the organic solution was
washed with saturated NaHCO3 solution and brine and then
dried and concentrated. The residue was crystallized from
CHCl3-hexane to afford 12.3 g (81%) of 6 as colorless
These highly efficient and practical syntheses of ter-
prenin, a potent IgE antibody suppressant, can offer
sufficient supplies of this important natural product in
order to develop a new type of antiallergic drug as well
as to clarify its interesting mechanism of action. These
syntheses also provide a convenient method of preparing
compounds of this type and suggest that employing the
crystals: mp 179-180 °C; IR (KBr) 1700 cm-1 1H NMR
;
(CDCl3) δ 3.22 (s, 3H), 3.45 (s, 3H), 3.94 (s, 3H), 7.04 (s, 1H),
7.39 (m, 2H), 7.64 (m, 2H), 10.42 (s, 1H); 13C NMR (CDCl3) δ
37.73, 57.03, 62.82, 113.07, 117.52, 122.23 (2C), 130.38, 130.64
(2C), 134.49, 135.92, 148.81, 152.34, 152.86, 191.03. Anal.
(22) The second coupling did not proceed with the use of Pd2(dba)3
as the catalyst.

Total Synthesis of Terprenin
J . Org. Chem., Vol. 63, No. 17, 1998 5835
Calcd for C16H15BrO6S: C, 46.28; H, 3.64; Br, 19.24; S, 7.72.
Found: C, 46.62; H, 3.73; Br, 18.89; S, 8.00.
Meth a n esu lfon ic Acid 4,3′-Bis(m eth a n esu lfon yloxy)-
2′,5′-d im eth oxy-4-(3-m eth yl-2-bu ten yloxy)-[1,1′:4′,1′′]ter -
p h en yl-3′′-yl Ester (12). To a solution of 7.75 g (13.2 mmol)
of 11 in 65 mL of DMF were added 2.73 g (19.8 mmol) of K2-
CO3 and 1.82 mL (15.8 mmol) of prenyl bromide at 0 °C. The
mixture was stirred for 18 h at 20 °C and then diluted with
0.2 N HCl solution at 0 °C. The mixture was extracted with
EtOAc, and then the organic solution was washed with 10%
citric acid solution, saturated NaHCO3 solution, and brine and
then dried and concentrated. The crystalline residue was
washed with (i-Pr)2O to afford 8.54 g (99%) of 12 as colorless
crystals: mp 155-157 °C; 1H NMR (CDCl3) δ 1.76 (d, J ) 0.9
Hz, 3H), 1.81 (s, 3H), 2.71 (s, 3H), 3.21 (s, 3H), 3.23 (s, 3H),
3.56 (s, 3H), 3.78 (s, 3H), 4.64 (d, J ) 6.6 Hz, 2H), 5.49 (dd, J
) 0.9 and 6.6 Hz, 1H), 6.84 (s, 1H), 7.09 (d, J ) 8.4 Hz, 1H),
7.32-7.40 (m, 4H), 7.69 (m, 2H); 13C NMR (CDCl3) δ 18.32,
25.81, 37.65, 38.68, 39.61, 56.32, 61.39, 65.94, 111.41, 113.60,
118.78, 122.16 (2C), 124.15, 125.16, 127.31, 130.80 (3C),
134.15, 136.74, 138.37, 139.28, 142.10, 144.87, 148.86, 150.61,
153.20. Anal. Calcd for C28H32O12S3: C, 51.21; H, 4.91; S,
14.65. Found: C, 50.92; H, 4.92; S, 14.39.
3′,6′-Dim eth oxy-4-(3-m eth yl-2-bu ten yloxy)-[1,1′:4′,1′′]-
ter p h en yl-3,2′,4′′-tr iol (ter p r en in , 1). To a solution of 8.54
g (13.0 mmol) of 12 in 130 mL of 1:1 dioxane-MeOH was
added 260 mL of 3 N KOH solution. The mixture was stirred
for 18 h at 50 °C and then diluted with 2 N HCl solution at 0
°C. The mixture was extracted with CHCl3, and then the
organic solution was washed with 10% citric acid solution,
saturated NaHCO3 solution, and brine and then dried and
concentrated. The residue was crystallized from (i-Pr)2O to
afford 5.33 g (97%) of 1 as colorless crystals: mp 155.5-156
°C; IR (KBr) 3393 cm-1;1H NMR (acetone-d6, 600 MHz) δ 1.77
(br s, 3H), 1.79 (br s, 3H), 3.37 (s, 3H), 3.73 (s, 3H), 4.63 (br d,
J ) 6.6 Hz, 2H), 5.52 (m, 1H), 6.49 (s, 1H), 6.83 (dd, J ) 2.2
and 8.2 Hz, 1H), 6.92 (d, J ) 2.2 Hz, 1H), 6.94 (m, 2H), 6.96
(d, J ) 8.2 Hz, 1H), 7.54 (m, 2H), 7.62 (br s, 1H), 7.78 (s, 1H),
8.64 (br s, 1H); 13C NMR (acetone-d6, 150 MHz) δ 18.31, 26.00,
56.04, 60.67, 66.18, 103.85, 112.75, 116.06 (2C), 117.61, 118.97,
121.44, 123.15, 127.91, 130.48, 130.85 (2C), 133.54, 137.50,
140.04, 146.23, 146.79, 149.24, 154.51, 157.79; HR-LSIMS m/z
422.1730 (M)+ (calcd for C25H26O6 m/z 422.1728). Anal. Calcd
for C25H26O6‚0.6H2O: C, 69.30; H, 6.33. Found: C, 69.40; H,
6.41. Karl Fischer Calcd for C25H26O6‚0.6H2O: H2O, 2.50.
Found: H2O, 2.53.
4-Br om o-4′-(m eth a n esu lfon yloxy)-2,5-d im eth oxy-[1,1′]-
bip h en yl-3-ol (7). To a solution of 10.6 g (25.6 mmol) of 6 in
200 mL of CH2Cl2 was added 8.28 g (38.4 mmol) of 80%
m-CPBA at 0 °C. The mixture was stirred for 18 h at 20 °C
and then refluxed for 4 h. The mixture was diluted with 1 N
Na2S2O3 and saturated NaHCO3 solution and extracted with
CHCl3. The organic solution was washed with saturated
NaHCO3 solution and brine and then dried and concentrated.
The residue was dissolved in 200 mL of dioxane, and then 100
mL of 4 N HCl solution was added. The mixture was stirred
for 18 h at 50 °C. After cooling to 20 °C, the mixture was
diluted with water and extracted with EtOAc, and then the
organic solution was washed with saturated NaHCO3 solution
and brine and then dried and concentrated. The crystalline
residue was washed with 1:1 (i-Pr)2O-hexane to afford 8.81 g
(85%) of 7 as colorless crystals: mp 172-174 °C; IR (KBr) 3410
cm-1 1H NMR (CDCl3) δ 3.21 (s, 3H), 3.47 (s, 3H), 3.89 (s,
;
3H), 6.15 (s, 1H), 6.42 (s, 1H), 7.36 (m, 2H), 7.63 (m, 2H); 13C
NMR (CDCl3) δ 37.64, 56.57, 61.19, 98.79, 104.07, 122.14 (2C),
130.42 (2C), 131.88, 136.79, 138.98, 147.83, 148.66, 153.02.
Anal. Calcd for C15H15BrO6S: C, 44.68; H, 3.75; Br, 19.81; S,
7.95. Found: C, 44.58; H, 3.79; Br, 19.59; S, 8.07.
4-Ben zyloxy-4′′-(m eth a n esu lfon yloxy)-3′,6′-d im eth oxy-
[1,1′:4′,1′′]ter p h en yl-3,2′-d iol (9). The procedure described
for the preparation of 4 was repeated using 8.79 g (21.8 mmol)
of 7, 110 mL of DME, 23 mL of EtOH, 9.37 g (26.2 mmol) of 8,
55 mL of 2 M Na2CO3 solution, and 1.26 g (1.09 mmol) of Pd-
(PPh3)4 to afford 9, which was used for the next reaction
without further purification. Crystallization from EtOAc-
hexane afforded pure 9 as colorless crystals: mp 183-185 °C;
IR (KBr) 3496, 3465 cm-1 1H NMR (CDCl3) δ 3.21 (s, 3H),
;
3.47 (s, 3H), 3.75 (s, 3H), 5.16 (s, 2H), 5.70 (s, 1H), 5.87 (s,
1H), 6.45 (s, 1H), 6.95 (dd, J ) 1.8 and 8.4 Hz, 1H), 7.03 (d, J
) 8.4 Hz, 1H), 7.08 (d, J ) 1.8 Hz, 1H), 7.35-7.47 (m, 7H),
7.71 (m, 2H); 13C NMR (CDCl3) δ 37.57, 56.05, 61.08, 71.11,
103.78, 111.81, 117.21, 117.32, 122.07 (2C), 122.40, 126.22,
127.92 (2C), 128.47, 128.79 (2C), 130.47 (2C), 131.49, 136.43,
137.48, 138.88, 145.37, 145.59, 147.42, 148.54, 153.64. Anal.
Calcd for C28H26O8S: C, 64.36; H, 5.01; S, 6.14. Found: C,
64.22; H, 5.09; S, 6.07.
Meth an esu lfon ic Acid 4′′-(ben zyloxy)-4,3′-bis(m eth an e-
su lfon yloxy)-2′,5′-dim eth oxy-[1,1′:4′,1′′]ter ph en yl-3′′-yl Es-
ter (10). The procedure described for the preparation of 5 was
repeated using the above product, 100 mL of CH2Cl2 15.2 mL
(109 mmol) of Et3N, and 6.75 mL (87.2 mmol) of methane-
sulfonyl chloride to afford, after crystallization from MeOH,
10.1 g (68% from 7) of 10 as colorless crystals: mp 163-165
1-(Ben zyloxy)-4-br om o-2-(ter t-bu tyld im eth ylsilyloxy)-
ben zen e (16). To a solution of 85.0 g (305 mmol) of 1519 in
500 mL of DMF were added 27.0 g (397 mmol) of imidazole
and 55.1 g (365 mmol) of tert-butyldimethylsilyl chloride. The
mixture was stirred for 18 h at 20 °C and then concentrated
in vacuo. The residue was diluted with 1 L of EtOAc, 500 mL
of water, and 200 mL of 1 N HCl solution. The organic layer
was separated and washed with water, saturated NaHCO3
solution, and brine and then dried and concentrated. The
crystalline residue was washed with hexane to afford 108 g
(90%) of 16 as colorless crystals: mp 34-36 °C; 1H NMR
(CDCl3) δ 0.11 (s, 6H), 0.95 (s, 9H), 5.01 (s, 2H), 6.53 (d, J )
9.0 Hz, 1H), 6.95-7.00 (m, 2H), 7.30-7.45 (m, 5H); 13C NMR
(CDCl3) δ -4.64 (2C), 18.35, 25.63 (3C), 71.02, 112.84, 115.24,
124.27, 124.42, 127.83 (2C), 128.08, 128.49 (2C), 136.61,
146.40, 149.69. Anal. Calcd for C19H25BrO2Si: C, 58.01; H,
6.41; Br, 20.31. Found: C, 57.98; H, 6.39; Br, 20.16.
1
°C; H NMR (CDCl3) δ 2.68 (s, 3H), 3.13 (s, 3H), 3.21 (s, 3H),
3.56 (s, 3H), 3.78 (s, 3H), 5.19 (s, 2H), 6.84 (s, 1H), 7.15 (d, J
) 8.7 Hz, 1H), 7.32-7.49 (m, 9H), 7.69 (m, 2H); 13C NMR
(CDCl3) δ 37.62, 38.70, 39.57, 56.31, 61.37, 71.14, 111.38,
113.87, 122.13 (2C), 123.97, 125.59, 127.25, 127.75 (2C),
128.54, 128.81 (2C), 130.75 (2C), 130.82, 134.18, 135.75,
136.66, 138.27, 142.04, 144.79, 148.82, 150.41, 153.13; HR-
LSIMS m/z 701.0793 (M + Na)+ (calcd for C30H30NaO12S3 m/z
701.0795).
3,2′′,4′′-Tr is(m eth a n esu lfon yloxy)-3′,6′-d im eth oxy-[1,1′:
4′,1′′]ter p h en yl-4-ol (11). A solution of 9.94 g (14.6 mmol)
of 10 in 200 mL of dioxane was hydrogenated at ordinary
pressure using 2.98 g of 20% palladium hydroxide on carbon
for 18 h at 20 °C. The mixture was filtered through a Celite
pad, and the filtrate was concentrated. The crystalline residue
was washed with (i-Pr)2O to afford 7.94 g (92%) of 11 as
4-(Ben zyloxy)-3-(ter t-bu tyld im eth ylsilyloxy)ben zen e-
bor on ic Acid (8). To a solution of 56.9 g (145 mmol) of 16 in
500 mL of THF was added 100 mL (159 mmol) of 1.59 N
n-BuLi in hexane dropwise over a 10-min period at -78 °C.
The mixture was stirred for 30 min, and then 100 mL (433
mmol) of triisopropyl borate was added. The mixture was
allowed to warm to -20 °C and diluted with 30 mL of water.
After stirring for 18 h, the mixture was extracted with EtOAc.
The organic solution was washed with water and brine and
then dried and concentrated. The crystalline residue was
washed with hexane to afford 32.9 g (64%) of 8 as colorless
colorless crystals: mp 185-187 °C; IR (KBr) 3503 cm-1 1H
;
NMR (CDCl3) δ 2.83 (s, 3H), 3.22 (s, 3H), 3.28 (s, 3H), 3.55 (s,
3H), 3.77 (s, 3H), 6.32 (s, 1H), 6.85 (s, 1H), 7.16 (m, 1H), 7.27-
7.31 (m, 2H), 7.39 (m, 2H), 7.68 (m, 2H); 13C NMR (CDCl3) δ
37.46, 38.03, 39.35, 56.18, 60.87, 111.53, 117.03, 122.18 (2C),
122.91, 123.99, 126.12, 130.45, 130.53 (2C), 133.19, 135.90,
136.40, 141.49, 144.02, 148.53, 149.23, 152.65. Anal. Calcd
for C23H24O12S3: C, 46.93; H, 4.11; S, 16.34. Found: C, 46.63;
H, 4.11; S, 16.29.
crystals: mp 125-126 °C; IR (KBr) 3433 cm-1 1H NMR
;
(CDCl3) δ 0.17 (s, 6H), 1.01 (s, 9H), 5.14 (s, 2H), 7.04 (d, J )
8.2 Hz, 1H), 7.30-7.50 (m, 5H), 7.67 (d, J ) 1.4 Hz, 1H), 7.77

5836 J . Org. Chem., Vol. 63, No. 17, 1998
Yonezawa et al.
(dd, J ) 1.4 and 8.2 Hz, 1H); 13C NMR (CDCl3) δ -4.48 (2C),
18.42, 25.79 (3C), 70.51, 113.00, 123.00, 127.61, 127.86 (2C),
128.03, 128.48 (2C), 130.19, 136.74, 144.84, 154.12; HR-
FABMS m/z 651.2314 (bis(m-nitrobenzyl) ester)+ (calcd for
C33H3711BN2NaO8Si m/z 651.2316).
chromatographed on silica gel using 1:1 EtOAc-hexane to
afford 2.00 g (83%) of 21 as colorless crystals: mp 183-185
°C; IR (CHCl3) 3691, 3596, 3510 cm-1; 1H NMR (CDCl3) δ 3.45
(s, 3H), 3.57 (d, J ) 7.8 Hz, 1H), 3.75 (s, 3H), 4.11-4.19 (m,
2H), 5.39 (s, 1H), 5.58 (m, 1H), 5.96 (d, J ) 0.6 Hz, 1H), 6.45
(s, 1H), 6.89-6.95 (m, 2H), 6.97-7.06 (m, 3H), 7.50-7.55 (m,
2H); 13C NMR (DMSO-d6) δ 55.47, 59.95, 66.82, 88.54, 102.82,
115.10 (2C), 115.37, 116.29, 119.51, 123.72, 127.36, 128.60,
129.65 (2C), 132.63, 139.20, 140.60, 141.33, 148.10, 152.92,
156.70; HR-FABMS m/z 396.1211 (M)+ (calcd for C22H29O7
m/z 396.1209).
3′,6′-Dim eth oxy-4-(3-m eth yl-2-bu ten yloxy)-[1,1′:4′,1′′]-
ter p h en yl-3,2′,4′′-tr iol (ter p r en in , 1). To a solution of 818
mg (1.90 mmol) of isopropyltriphenylphosphonium iodide in
5 mL of THF was added 1.20 mL (1.90 mmol) of 1.57 N n-BuLi
in hexane dropwise over a 1-min period at 0 °C. The mixture
was stirred for 30 min at 25 °C, and then 50.0 mg (0.130 mmol)
of 21 in 3 mL of THF was added at -78 °C. The mixture was
stirred for 30 min at the same temperature and then allowed
to warm to 25 °C and stirred for 7 h. The mixture was diluted
with saturated NH4Cl solution and then extracted with EtOAc.
The organic solution was washed with water and brine and
then dried and concentrated. The residue was chromato-
graphed on silica gel using 2:3 EtOAc-hexane to afford 47.0
mg (87%) of 1, which was identical in all respects with the
natural product.
3-Br om o-2,5-d im eth oxyp h en ol (17). To a solution of 2.45
g (10.0 mmol) of 2 in 25 mL of CH2Cl2 was added 3.24 g (15.0
mmol) of 80% m-CPBA at 0 °C. The mixture was allowed to
warm to 20 °C and stirred for 18 h. The mixture was diluted
with CHCl3 and 1 N Na2S2O3 solution. The organic solution
was washed with saturated NaHCO3 solution and brine and
then dried and concentrated. The residue was dissolved in
50 mL of MeOH, and then 1 mL of 1 N KOH solution was
added. The mixture was stirred for 1 h at 20 °C and then
diluted with 50 mL of EtOAc, 50 mL of water, and 2 mL of 1
N HCl solution. The organic solution was washed with water
and brine and then dried and concentrated. The residue was
dissolved in 1:2 EtOAc-hexane and filtered through a pad of
silica gel. The filtrate was concentrated, and the resulting
crystalline residue was washed with hexane to afford 1.89 g
(81%) of 17 as colorless crystals: mp 73-74 °C; IR (CHCl3)
1
3526 cm-1; H NMR (CDCl3) δ 3.74 (s, 3H), 3.85 (s, 3H), 5.72
(s, 1H), 6.50 (d, J ) 3.0 Hz, 1H), 6.62 (d, J ) 3.0 Hz, 1H); 13
C
NMR (CDCl3) δ 55.76, 61.36, 101.40, 109.81, 115.81, 138.71,
150.30, 157.06. Anal. Calcd for C8H9BrO3‚0.1H2O: C, 40.91;
H, 3.95; Br, 34.02. Found: C, 40.83; H, 3.93; Br, 33.78. Karl
Fischer Calcd for C8H9BrO3‚0.1H2O: H2O, 0.77. Found: H2O,
0.63.
3-Br om o-4-iod o-2,5-d im eth oxyp h en ol (22). The proce-
dure described for the preparation of 18 was repeated for the
reaction of 15 min to afford, after chromatography on silica
gel using 1:2 EtOAc-hexane, 22 (64%) as colorless crystals:
3-Br om o-6-iod o-2,5-d im eth oxyp h en ol (18). To a solu-
tion of 5.0 mL (47.6 mmol) of tert-butylamine in 160 mL of
toluene was added 5.94 g (23.4 mmol) of iodine. After stirring
for 1 h at 25 °C, 5.46 g (23.4 mmol) of 17 was added at 0 °C.
The mixture was allowed to warm to 25 °C, stirred for 48 h,
and then diluted with EtOAc. The organic solution was
washed with water, 1 N Na2S2O3 solution, and brine and then
dried and concentrated. The crystalline residue was washed
with hexane to afford 7.72 g (92%) of 18, as colorless crystals:
mp 163-165 °C; IR (CHCl3) 3527 cm-1 1H NMR (CDCl3) δ
;
3.83 (s, 3H), 3.84 (s, 3H), 5.79 (br s, 1H), 6.57 (br s, 1H); 13C
NMR (CDCl3) δ 57.36, 61.60, 82.92, 98.80, 128.03, 139.48,
150.72, 157.19. Anal. Calcd for C8H8BrIO3: C, 26.77; H, 2.25;
Br, 22.26, I, 35.35. Found: C, 26.87; H, 2.36; Br, 22.26, I,
35.13.
4-(Ben zyloxy)-3′,6′-dim eth oxy-[1,1′:4′,1′′]ter ph en yl-3,2′,4′′-
tr iol (23). To a solution of 1.08 g (3.0 mmol) of 18 in 12 mL
of DME and 3.0 mL of EtOH were added 1.13 g (3.15 mmol)
of 8, 6.0 mL of 2 M Na2CO3 solution, and 174 mg (0.15 mmol)
of Pd(PPh3)4 under an argon atmosphere. The mixture was
stirred for 6 h for 70 °C. After cooling to 20 °C, 984 mg (3.9
mmol) of 3, 6.0 mL of 2 M Na2CO3 solution, 12 mL of DME,
3.0 mL of EtOH, and 174 mg (0.15 mmol) of Pd(PPh3)4 were
added. The mixture was refluxed for 15 h. After cooling to
20 °C, the mixture was diluted with 10% citric acid solution
and then filtered through a Celite pad. The filtrate was
extracted with EtOAc, and then the organic solution was
washed with brine, dried, and concentrated. The residue was
chromatographed on silica gel using 1:2 EtOAc-hexane to
afford 893 mg (67%) of 23 as colorless crystals: mp 138-141
mp 135-136 °C; IR (CHCl3) 3507 cm-1 1H NMR (CDCl3) δ
;
3.84 (s, 3H), 3.87 (s, 3H), 6.13 (s, 1H), 6.59 (s, 1H); 13C NMR
(CDCl3) δ 57.44, 61.92, 74.85, 107.00, 116.51, 139.13, 151.26,
156.20. Anal. Calcd for C8H8BrIO3: C, 26.77; H, 2.25; Br,
22.26, I, 35.35. Found: C, 26.73; H, 2.28; Br, 22.04, I, 35.39.
2,5-Dim et h oxy-4-(3-m et h oxy-2,3-d ih yd r ob en zo[1,4]-
d ioxin -6-yl)-bip h en yl-3,4′-d iol (20). To a solution of 500 mg
(1.40 mmol) of 18 in 20 mL of DME and 2.8 mL of EtOH were
added 292 mg (1.40 mmol) of 19, 2.8 mL of 2 M Na2CO3
solution, and 13.0 mg (0.0140 mmol) of Pd2(dba)3 under an
argon atmosphere. The mixture was refluxed for 2 h. After
cooling to 20 °C, 700 mg (2.80 mmol) of 3, 5.6 mL of 2 M Na2-
CO3 solution, 5 mL of EtOH, and 160 mg (0.14 mmol) of Pd-
(PPh3)4 were added. The mixture was refluxed for 18 h. After
cooling to 20 °C, the mixture was diluted with saturated NH4-
Cl solution and then extracted with EtOAc. The organic
solution was washed with saturated NaHCO3 solution and
brine and then dried and concentrated. The residue was
chromatographed on silica gel using 2:3 EtOAc-hexane to
afford 401 mg (70%) of 20 as colorless crystals: mp 103-105
1
°C; IR (KBr) 3367 cm-1; H NMR (CDCl3) δ 3.45 (s, 3H), 3.75
(s, 3H), 5.15 (s, 2H), 5.71 (s, 1H), 5.93 (s, 1H), 6.45 (s, 1H),
6.91-7.10 (m, 5H), 7.35-7.55 (m, 7H); 13C NMR (CDCl3) δ
55.99, 60.68, 71.07, 103.75, 111.75, 115.38 (2C), 116.16, 117.37,
122.48, 126.56, 127.88 (2C), 128.39, 128.73 (2C), 130.06 (2C),
130.45, 132.48, 136.45, 138.71, 145.21, 145.41, 147.23, 153.45,
155.22. Anal. Calcd for C27H24O6‚0.45H2O: C, 71.65; H, 5.55.
Found: C, 71.88; H, 5.63. Karl Fischer Calcd for C27H24O6‚
0.45H2O: H2O, 1.79. Found: H2O, 1.79.
1
°C; IR (CHCl3) 3595, 3510 cm-1; H NMR (CDCl3) δ 3.45 (s,
3H), 3.58 (s, 3H), 3.75 (s, 3H), 4.12 (dd, J ) 1.8 and 11.4 Hz,
1H), 4.21 (dd, J ) 2.4 and 11.4 Hz, 1H), 4.87 (br s, 1H), 5.16
(dd, J ) 1.8 and 2.4 Hz, 1H), 5.93 (s, 1H), 6.45 (s, 1H), 6.89-
Meth a n esu lfon ic Acid 4′′-ben zyloxy-4,3′-bis(m eth a n e-
su lfon yloxy)-2′,5′-dim eth oxy-[1,1′:4′,1′′]ter ph en yl-3′′-yl Es-
ter (10). The procedure described for the preparation of 5 was
repeated using 893 mg (2.01 mmol) of 23, 10 mL of CH2Cl2,
1.68 mL (12.1 mmol) of Et3N, and 0.70 mL (9.05 mmol) of
methanesulfonyl chloride to afford 1.24 g (91%) of 10 which
was identical with the product from 9.
7.03 (m, 4H), 7.07 (d, J ) 1.8 Hz, 1H), 7.51-7.56 (m, 2H); 13
C
NMR (DMSO-d6) δ 55.19, 55.50, 59.96, 65.36, 94.46, 102.84,
115.12 (2C), 115.48, 116.13, 119.71, 124.34, 127.44, 128.59,
129.66 (2C), 132.69, 139.24, 139.57, 141.64, 148.10, 152.91,
156.74; HR-FABMS m/z 410.1352 (M)+ (calcd for C23H22O7
m/z 410.1366).
4-(3-H yd r oxy-2,3-d ih yd r ob en zo[1,4]d ioxin -6-yl)-2,5-
d im eth oxy-bip h en yl-3,4′-d iol (21). To a solution of 2.50 g
(6.10 mmol) of 20 in 20 mL of acetone and 20 mL of water
was added 3.50 g (18.3 mmol) of p-toluenesulfonic acid. The
mixture was refluxed for 18 h. After cooling to 20 °C, the
mixture was diluted with saturated NaHCO3 solution and
extracted with EtOAc. The organic solution was washed with
brine and then dried and concentrated. The residue was
5-Br om o-2-[2,2-(d im eth oxy)eth oxy]ben za ld eh yd e (24).
To a solution of 30.0 g (150 mmol) of 14 in 400 mL of DMF
were added 21.0 mL (178 mmol) of 2-bromo-1,1-dimethoxy-
ethane and 41.0 g (297 mmol) of K2CO3. The mixture was
refluxed for 3.5 h. After cooling to 20 °C, the mixture was
diluted with saturated NH4Cl solution and then extracted with
EtOAc. The organic solution was washed with water and brine
and then dried and concentrated. The residue was chromato-

Total Synthesis of Terprenin
J . Org. Chem., Vol. 63, No. 17, 1998 5837
graphed on silica gel using 1:2 EtOAc-hexane to afford 39.8
g (92%) of 24 as colorless crystals: mp 82-83 °C; IR (CHCl3)
Hz, 1H), 7.06 (d, J ) 2.3 Hz, 1H); 13C NMR (CDCl3) δ 56.08,
65.79, 94.94, 113.22, 118.44, 120.63, 124.85, 141.54, 142.55;
HR-FABMS m/z 243.9739 (M)+ (calcd for C9H979BrO3 m/z
243.9735).
1
1683 cm-1; H NMR (CDCl3) δ 3.48 (s, 6H), 4.10 (d, J ) 5.1
Hz, 2H), 4.75 (t, J ) 5.1 Hz, 1H), 6.90 (d, J ) 8.9 Hz, 1H),
7.62 (dd, J ) 2.5 and 8.9 Hz, 1H), 7.93 (d, J ) 2.5 Hz, 1H),
10.42 (s, 1H); 13C NMR (CDCl3) δ 54.65 (2C), 68.75, 102.13,
114.16, 115.00, 126.49, 131.05, 138.30, 159.84, 188.18; HR-
FABMS m/z 310.9911 (M + Na)+ (calcd for C11H1379BrNaO4
m/z 310.9895).
7-Br om o-2-m eth oxy-2,3-d ih yd r oben zo[1,4]d ioxin e (26).
The procedure described for the preparation of 17 was repeated
using 39.8 g (138 mmol) of 24, 400 mL of EtOAc, 59.4 g (275
mmol) of 80% m-CPBA, 140 mL of 1 N NaOH solution, and
280 mL of MeOH to afford 25, which was used for the next
reaction without further purification.
To a solution of the above product in 300 mL of CH2Cl2 was
added a solution of 13.5 g (71.0 mmol) of p-toluenesulfonic acid
in 10 mL of MeOH. The mixture was stirred for 3 h at 25 °C
and then diluted with saturated NaHCO3 solution and ex-
tracted with CH2Cl2. The organic solution was washed with
brine and then dried and concentrated. The residue was
chromatographed on silica gel using 1:10 EtOAc-hexane to
afford 23.5 g (70% from 24) of 26 as a colorless oil: 1H NMR
(CDCl3) δ 3.55 (s, 3H), 4.04 (dd, J ) 1.7 and 11.4 Hz, 1H),
4.19 (dd, J ) 2.0 and 11.4 Hz, 1H), 5.12 (dd, J ) 1.7 and 2.0
Hz, 1H), 6.77 (d, J ) 8.6 Hz, 1H), 6.98 (dd, J ) 2.3 and 8.6
2,3-Dih yd r oben zo[1,4]d ioxin e-7-bor on ic Acid (19). The
procedure described for the preparation of 8 was repeated
using 6.30 g (25.7 mmol) of 26, 120 mL of THF, 18.0 mL (28.3
mmol) of 1.57 N n-BuLi in hexane, and 8.90 mL (38.6 mmol)
of triisopropyl borate to afford, after chromatography on silica
gel using 2:1 EtOAc-hexane, 3.30 g (60%) of 19 as colorless
crystals: mp 94-97 °C; IR (CHCl3) 3684, 3608 cm-1; 1H NMR
(CDCl3) δ 3.60 (s, 3H), 4.17 (dd, J ) 1.7 and 11.3 Hz, 1H),
4.28 (dd, J ) 2.2 and 11.3 Hz, 1H), 5.21 (dd, J ) 1.7 and 2.2
Hz, 1H), 7.01 (d, J ) 8.4 Hz, 1H), 7.74-7.79 (m, 2H); 13C NMR
(CDCl3) δ 59.40, 69.48, 98.24, 120.34 (2C), 128.24, 133.40,
143.66, 150.59; HR-FABMS m/z 480.1345 (bis(m-nitrobenzyl)
ester)+ (calcd for C23H2111BN2O9 m/z 480.1340).
Ack n ow led gm en t. We thank Dr. H. Arita for his
encouragement and valuable advice throughout this
study. We also thank Dr. T. Konoike for the scale-up
production, and Drs. A. Arimura and R. Suzuki for the
biological evaluation.
J O980349T