The first total synthesis and structural determination of TMC-264

Article abstract of DOI:10.1016/j.tetlet.2008.04.074

The first total synthesis and structural determination of TMC-264 has been accomplished. Regioselective bromination, regioselective methoxymethylation, and nickel(0)-Lewis acid-mediated cyclization afforded multi-functionalized 1-methyl-dibenzo[b,d]-pyran

Full text of DOI:10.1016/j.tetlet.2008.04.074

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Tetrahedron Letters 49 (2008) 4036–4039
The first total synthesis and structural determination of TMC-264
Kuniaki Tatsuta *, Akiho Furuyama, Tomoe Yano, Yasuaki Suzuki,
Takashi Ogura, Seijiro Hosokawa *
Department of Applied Chemistry, Faculty of Science and Engineering, Waseda University 3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan
Received 25 March 2008; revised 10 April 2008; accepted 11 April 2008
Available online 15 April 2008
Abstract
The first total synthesis and structural determination of TMC-264 has been accomplished. Regioselective bromination, regioselective
methoxymethylation, and nickel(0)-Lewis acid-mediated cyclization afforded multi-functionalized 1-methyl-dibenzo[b,d]-pyran skeleton.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Total synthesis; Absolute configuration; TMC-264; Antiallergic agent; Regioselective methoxymethylation; Biaryl coupling
TMC-264 (1) was isolated as an inhibitor of IL-4 signal-
ing from the fermentation broth of a fungus Phoma sp. TC
1674 by Tanabe Seiyaku group in 2003.1 This compound
has been found to inhibit selectively both tyrosine
phosphorylation of STAT6 and the complex formation of
phosphorylated STAT6 with its recognition sequence.
TMC-264 has been expected as an antiallergic agent.1,2
The structure of TMC-264 was elucidated to be the tricyclic
structure including chloro-1H-dibenzo[b,d]pyran-4,6-dione
skeleton (Fig. 1). However, the absolute configuration
has not been determined yet. The unique structure and
remarkable bioactivity stimulated us to synthesize TMC-
264 (1).
The synthetic plan of TMC-264 (1) is shown in Scheme
1. Compound 1 would be synthesized from bis(aryl halide)
2 by intramolecular aryl–aryl coupling followed by oxida-
tion. Compound 2 should be provided by esterification
with 3 and 4. The per-substituted phenol 3 might be
derived from the commercially available 5 by successive
regioselective functionalization.
Regioselective synthesis of 3 was achieved as shown in
Scheme 2 and Table 1. Selective de-O-methylation of 5 to
afford 6 was realized in high yield by the treatment of 5
with 1 equiv of boron tribromide. Regioselective bromina-
tion of 6 was accomplished with N-bromosuccinimide,
which promoted the reaction to give C6-brominated prod-
uct predominantly. The structure of the resulting monobr-
omide 7 was determined by the observation of NOE
between H4 and OMe. It is quite interesting that bromina-
tion proceeded at C6 position superior to C4, although the
electron density of C4 carbon was higher than C6 by 13C
NMR (dC4 104.0, dC6 109.2, Fig. 2). Catechol 7 was chlori-
nated to afford 8. The next regioselective methoxymethyla-
tion to yield 3 was problematic. The normal conditions
Cl
HO
OMe
1
Me
4
10a
MeO
10b
O
4a
O
OH
O
including methoxymethyl chloride and Hunig base pro-
¨
TMC-264 (1)
moted non-selective methoxymethylation (Table 1, entries
1 and 2). The structure of 3 was confirmed by NOE
between C3–OMe and CH2 in MOM ether, while 9 showed
NOE between C3–OMe and OH (Fig. 3). After numerous
examinations, we found that the addition of zinc(II) salt
Fig. 1. Structure of TMC-264 (1).
*
Corresponding authors. Tel./fax: +81 3 3200 3203 (K.T.).
E-mail address: tatsuta@waseda.jp (K. Tatsuta).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.04.074

K. Tatsuta et al. / Tetrahedron Letters 49 (2008) 4036–4039
4037
Cl
Me
OMe
OMe
Me
Br
OMe
4
Cl
O
10b
OMOM
Me
10b
OMe
Cl
OMe
OH
3
HO
OMe
O
5
1
Me
Br
OMOM
4
10a
10b
MeO
X
MeO
+
10a
4a
O
10a
MeO
X
OH
OMe O
OH
O
TMC-264 (1)
2
OMe O
4: X = halogen
Scheme 1. Retrosynthetic analysis of TMC-264 (1).
8.3%
10.0%
OMe
δC4 104.0
H
4
H
Me
4
Me
OMe
Me
6
OMe
OH
Me
Br
OMe
OH
a
b
H
6
OH
nOe
HMQC
OMe
6
δC6 109.2
OH
OMe
OH
OH
6
5
6
7
Fig. 2.
Cl
Cl
Me
Br
OMe
OH
Me
OMe
c
Table 1
Cl
Cl
Br
OMOM
Me
Br
OMe
O
Me
Br
OMe
3
OH
OH
3
1.6%
OMe
8
3
0.9%
2
OH
1
OH
OMOM
Scheme 2. Reagents and conditions: (a) BBr3, CH2Cl2, 0 °C, 5 min, 87%;
(b) NBS, CCl4, 0 °C, 1 day, 80% (7); (c) NCS, THF, rt, 1 h, 61%.
3
9
Fig. 3.
Table 1
DMF (entry 4). The best result was provided with 1 equiv
of zinc chloride to give desired 3 in 83% yield (entry 5).
Zinc chloride worked as catalyst to promote methoxyme-
thylation in regioselective manner (entry 6), however, the
isolated yield of 3 was decreased in comparison with the
stoichiometric reaction. Therefore, per-substituted phenol
3 was synthesized in four steps from commercially avail-
able 5.
The halogenated carboxylic acid 4 was prepared in two
steps from the commercially available 11 (Scheme 3).
5-Chloro-1,3-dimethoxybenzene (11) was brominated
regioselectively to provide 12, which was converted to
carboxylic acid 13 (4: X = Cl) by lithiation followed by
the addition of CO2.
Regioselective methoxymethylation with diol 8
MOMCl
Cl
i-Pr2NEt
Me
Br
OMe
OH
additive
solvent
−40 ºC
OH
8
Cl
Cl
Cl
Me
Br
OMe
Me
+
OMe
OH
Me
Br
OMe
3
+
OMOM
Br
OMOM
OH
OMOM
OMOM
3
9
10
Entry
Additive (equiv)
Solvent
Isolated yield (%)
The first total synthesis of TMC-264 was accomplished
as shown in Scheme 4. Carboxylic acid 13 was converted
3
9
10
1
2
3
4
5
6
—
—
CH2Cl2
DMF
CH2Cl2
DMF
DMF
DMF
24
16
27
62
83
64
20
34
20
21
13
15
30
13
41
16
2
Zn(OAc)2ꢀ2H2O (1.0)
Zn(OAc)2ꢀ2H2O (1.0)
ZnCl2(1.0)
MeO
Cl
MeO
Cl
Br
MeO
Cl
a
b
OH
ZnCl2(0.2)
12
OMe
OMe
OMe O
11
12
13
was effective for the regioselective alkylation. Zinc acetate
preformed the regioselective methoxymethylation in
Scheme 3. Reagents and conditions: (a) NBS, (CH2Cl2)2, 60 °C, 5 h, 90%;
(b) s-BuLi, PhMe, ꢁ78 °C, 10 min, then CO2 (gas), rt, 30 min, 87%.

4038
K. Tatsuta et al. / Tetrahedron Letters 49 (2008) 4036–4039
Table 2
the cyclization to afford 15 in high yield (entry 4). There-
fore, the role of aluminum reagents was not as reductant
but as Lewis acid to promote the oxidative addition of
nickel(0) in this reaction. Eventually, Ni(0)-Lewis acid-
mediated cyclization and successive selective de-O-methyl-
ation at C7 concomitant with de-O-methoxymethylation of
the crude 15 gave biphenol 16 in 70% yield (Scheme 4). The
tricyclic structure was confirmed with 16 by NOE between
H10 and Me as well as HMBC between H10 and C10b.
Finally, oxidation in the presence of [bis-(salicylidene)ethy-
lenediamine]cobalt (salcomine) under oxygen atmosphere
afforded ( )-TMC-264 (1).6 The synthetic 1 was identical
with natural product in all spectrometric aspects including
1H and 13C NMR, IR, and MS, completing the first total
synthesis.
Ni(0)-mediated cyclization with bis(arylhalide) 14
Cl
Cl
O
Me
10b
Br
OMe
Me
OMe
OMOM
Ni(cod)2
additive
10b
MeO
MeO
Cl
OMOM
10a
10a
O
DMF
40 ºC
OMe O
OMe O
14
15
Entry
Additive
14 (%)
15 (%)
Time (h)
1
2
3
4
None
Et3Al
Et2AlCl
EtAlCl2
No reaction
18
18
18
1
80
68
0
9
23
77
The absolute stereochemistry of (ꢁ)-TMC-264 [(ꢁ)-(1)],
the natural form, was determined by optical resolution and
X-ray crystallography (Scheme 5). Racemic TMC-264 [( )-
(1)] was submitted to esterification with N-Ts-L-phenylal-
anyl chloride. The resulting diastereo-mixture, including
L-phenylalanates 17 and 18, was separated by silica gel
column chromatography. Treatment of each diastereomer
with 4-dimethylaminopyridine in pyridine containing 5%
water provided optically pure TMC-264. Recrystallization
of optically pure (ꢁ)-(1) from toluene gave single crystals
to acid chloride to promote esterification with phenol 3.
10a-Chloro-10b-bromoester 14 was submitted to Ni(0)-
mediated cyclization (Table 2). Treatment of 14 with
Ni(cod)2 at 40 °C resulted in no reaction (entry 1).3 After
numerous experiments, we found that aluminum reagents
were effective for the coupling reaction (entries 2–4). Tri-
ethylaluminum, known as reductant for Ni(II) species,4
afforded the desired product in low yield, and 80% of start-
ing material was recovered (entry 2). Diethylaluminum
chloride also worked to give 15, but the reaction proceeded
slowly yet (entry 3).5 The best result was obtained by using
ethylaluminum dichloride, which dramatically promoted
22
25
(½aꢂD ꢁ40.9 (c 0.66, CHCl3) [natural ½aꢂD ꢁ43.8 (c 0.5,
CHCl3)]), which were suitable to perform X-ray crystallo-
graphy (Fig. 4).7 The Flack parameter8 obtained for
structure 1 was 0.01(2). Therefore, the natural form
(ꢁ)-TMC-264 was determined as 1R configuration. Opti-
cally pure (+)-(1) also provided single crystals to be deter-
mined as 1S configuration by X-ray crystallography.7–9
In conclusion, the first total synthesis of TMC-264 was
accomplished and the structural determination of
(ꢁ)-TMC-264 was achieved. Subsequent regioselective
transformation of phenols including de-O-methylation,
bromination, and O-methoxymethylation gave per-substi-
tuted phenol 3 in short steps. Intramolecular Ni(0)-medi-
Cl
Me
OMe
10b
Br
OMOM
MeO
Cl
MeO
Cl
10a
a,b
c
OH
O
OMe O
OMe O
14
13
Cl
O
10.0%
Cl
Me
OMe
Me
OMe
OH
Cl
Cl
O
H
HO
HO
10a
10b
10
OMe
O
OMe
O
10a
MeO
MeO
d
OMOM
10b
1
1
Me
Me
MeO
MeO
a
O
7
7OH
O
nOe
HMBC
O
OMe O
15
OH
O
OR O
16
17: 1
R
S
( )-TMC-264 (1)
Bn
18: 1
Cl
O
HO
Me
OMe
O
Cl
R =TsNH
HO
OMe
O
O
MeO
e
1
Me
MeO
b
O
OH
O
OH
O
TMC-264 (1)
(−)-TMC-264 [(−)-1]
Scheme 4. Reagents and conditions: (a) (COCl)2, DMF, CH2Cl2, 40 °C,
5 h, (b) 3, Py, 50 °C, 16 h, 82% (two steps), (c) Ni(cod)2, EtAlCl2, DMF,
40 °C, 1 h; (d) BCl3, CH2Cl2, ꢁ15 °C, 5 min, 70% (2 steps); (e) O2,
salcomine, MeCN, rt, 2.5 h, 62%.
Scheme 5. Reagents and conditions: (a) N-tosyl-L-phenylalanyl chloride,
pyridine, CH2Cl2, rt, 10 h, 58% (17:18 = 1:1); (b) DMAP, pyridine, rt,
1 day, 91% for (ꢁ)-1, 89% for (+)-1.

K. Tatsuta et al. / Tetrahedron Letters 49 (2008) 4036–4039
4039
Supplementary data
The spectrum data of compounds 3, 6, 7, 13, 14, 16–18,
(ꢁ)- 1 and (+)-1, 1H NMR spectrum (400 MHz in CDCl3),
and 13C NMR (100 MHz in CDCl3) spectrum of synthetic
( )-TMC-264 (1) are provided. The experimental proce-
dures of selective de-O-methylation to yield 6, selective
methoxymethylation to afford 3, and Ni(0)-Lewis acid-
mediated biaryl coupling followed by deprotection to give
16 were also disclosed. Supplementary data associated with
this article can be found, in the online version, at
doi:10.1016/j.tetlet.2008.04.074.
References and notes
1. (a) Sakurai, M.; Nishio, M.; Yamamoto, K.; Okuda, T.; Kawano, K.;
Ohnuki, T. J. Antibiot. 2003, 56, 513–519; (b) Sakurai, M.; Nishio, M.;
Yamamoto, K.; Okuda, T.; Kawano, K.; Ohnuki, T. Org. Lett. 2003,
5, 1083–1085.
Fig. 4. ORTEP drawing of (ꢁ)-TMC-264 (1), the natural form.
2. Arai, M.; Tomoda, H.; Matsumoto, A.; Takahashi, Y.; Woodruff, B.
H.; Ishiguro, N.; Kobayashi, S.; Omura, S. J. Antibiot. 2001, 54, 554–
561.
3. (a) Tsou, T. T.; Kochi, J. K. J. Am. Chem. Soc. 1979, 101, 7547–7560;
(b) Semmelhack, M. F.; Helquist, P.; Jones, L. D.; Keller, L.;
Mendelson, L.; Ryono, L. S.; Smith, J. G.; Stauffer, R. D. J. Am.
Chem. Soc. 1981, 103, 6460–6471.
4. (a) Yamamoto, T.; Yamamoto, A. J. Organomet. Chem. 1973, 57, 127–
137; (b) Fischer, K.; Jonas, K.; Misbach, P.; Stabba, R.; Wilke, G.
Angew. Chem., Int. Ed. Engl. 1973, 12, 943–1026.
ated biaryl coupling was achieved with 10a-chloro-10b-
bromoester 14 in the presence of ethylaluminum dichloride.
X-ray crystallography of each optically active TMC-264
confirmed the absolute structure of the natural product
to be 1R configuration.
5. Et2AlCl and EtAlCl2 were reported to promote the reductive elimina-
tion of dialkylnickel. Pennington, B. T.; Howell, J. E. J. Organomet.
Chem. 1977, 136, 95–102.
Acknowledgments
This work was financially supported by the Consoli-
dated Research Institute for Advanced Science and Medi-
cal Care, the Global COE program ‘Center for Practical
Chemical Wisdom’, and Scientific Research on Priority
Area ‘Creation of Biologically Functional Molecules’ from
the Ministry of Education, Culture, Sports, Science and
Technology.
6. Bozell, J. J.; Hames, B. R. J. Org. Chem. 1995, 60, 2398–2404.
7. Crystallographic data (excluding structure factors) for the structures of
(ꢁ)-1 and (+)-1 have been deposited with the Cambridge Crystallo-
graphic Data Center as supplementary publication numbers CCDC
680809 for (ꢁ)-1 and 680810 for (+)-1.
8. Flack, H. D. Acta Crystallogr., Sect. A 1983, 39 , 876–881.
9. The Flack parameter of (+)-1, obtained for the structure of the
enantiomer of 1, was 0.03(5).