A total synthesis of a new type of furo[3,2-h]isoquinoline alkaloid, TMC-120B

Article abstract of DOI:10.3987/com-03-s19

A total synthesis of a new furo[3,2-h]isoquinoline alkaloid, TMC-120B (2) has been completed in sixteen steps. The key step is the synthesis of 7,8-disubstituted isoquinoline (17) based on the thermal electrocyclic reaction of 1-azahexatriene system invol

Full text of DOI:10.3987/com-03-s19

HETEROCYCLES, Vol. 61, 2003
13
HETEROCYCLES, Vol. 61, 2003, pp. 13 - 17
Received, 22nd May, 2003, Accepted, 19th June, 2003, Published online, 24th June, 2003
A
TOTAL SYNTHESIS OF
A
NEW TYPE OF FURO[3,2-
h]ISOQUINOLINE ALKALOID, TMC-120B
Teppei Kumemura, Tominari Choshi, Aki Hirata, Mitsuko Sera, Yohhei
Takahashi, Junko Nobuhiro, and Satoshi Hibino*
Graduate School of Pharmacy and Pharmaceutical Sciences, Faculty of
Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama,
Hiroshima 729-0292, Japan
hibino@fupharm.fukuyama-u.ac.jp
Abstract – A total synthesis of a new furo[3,2-h]isoquinoline alkaloid, TMC-
120B (2) has been completed in sixteen steps. The key step is the synthesis of
7,8-disubstituted isoquinoline (17) based on the thermal electrocyclic reaction of
1-azahexatriene system involving the benzene 1,2-bond.
Three new furo[3,2-h]isoquinoline alkaloids, TMC-120A (1), B (2), and C (3) were isolated from a
fermentation broth of Aspergillus ustus TC 1118 (Chart 1).1 Their structures have been determined by
extensive spectroscopic and chemical analyses. TMC-120C (3) is the racemic compound, and an absolute
configuration of the chiral compound (1) has not yet been ascertained. In addition, the structure of TMC-
120B (2) has been also elucidated by X-Ray analysis. TMC-120B (2) shows moderate inhibitory activity
against the interleukin-5 mediated prolongation of eosinophil survival (IC50=2.0mM).
Me
Me
OH
Me
Me
O
Me
O
Me
O
O
O
O
N
N
N
Me
Me
Me
1 : TMC-120A
2 : TMC-120B
Chart 1
3 : TMC-120C
We have been performing synthetic studies of biologically active condensed heteroaromatic compounds
including natural products through the construction of functionalized frameworks based on the thermal
electrocyclic reaction2 of either a 6p-electron3,4 or an aza 6p-electron3,5 system incorporating the
heteroaromatic or aromatic portion. In our research program, we planned a total synthesis of TMC-120A
(1), B (2), and C (3).

14
HETEROCYCLES, Vol. 61, 2003
In this paper, we here describe the first total synthesis of TMC-120B (2) through the synthesis of 7,8-
disubstituted isoquinoline nucleus by an application of an aza 6p-electrocyclic reaction3,4 of a 1-
azahexatriene system, involving the benzene 1,2-bond. We chose the known 2,4-dimethoxymethyl(di-
MOM)oxybenzaldehyde (4)6 as a starting material. As shown in Scheme 1, reduction of benzaldehyde (4)
with sodium borohydride in EtOH, followed by treatment of the resulting alcohol (5: 90%)7 with tert-
butyldimethylsilyl chloride (TBDMSCl) in the presence of imidazole in DMF gave the TBDMS ether (6)
(85%). The ether (6) was treated with n-BuLi in THF, and the resulting lithio compound8 was then
OMOM
OMOM
OMOM
ii
i
OHC
HO
TBDMSO
OMOM
OMOM
OMOM
4
5
6
OMOM
OMOM
iv
iii
v
CHO
TBDMSO
TBDMSO
NOMe
OMOM
OMOM
7
8
OMOM
OH
12
x
OMOM
vi
vii
R
OHC
HO
NOMe
NOMe
OMOM
NOMe
OMOM
OMOM
10 : R = CHO
11 : R = COOMe
9
OCH COOMe
OCH COOMe
2
2
viii
ix
OHC
OHC
NOMe
NOMe
OH
14
OMOM
13
OCH COOMe
2
OCH COOMe
OCH COOMe
2
2
xi
xii
OHC
OHC
OHC
N
NOMe
OTf
NOMe
Me
17
Me
15
16
Scheme 1. Reagent and conditions : (i) NaBH , EtOH, rt, 2 h (90%), (ii) TBDMSCl,
4
o
imidazole, DMF, rt, 12 h (85%), (iii) n-BuLi, THF, 40 min and then DMF, 0 C, 20 min
o
(75%), (iv) MeONH ・HCl, AcONa, EtOH, 80 C, 12 h (89%), (v) TBAF, THF, rt, 1.5 h
2
o
(92%), (vi) act. MnO , CH Cl , rt, 24 h (89%), (vii) conc. HCl, MeOH, 0 C, 3 h (92%),
2
2
2
o
(viii) NaH, DMF, BrCH COOMe, rt, 12 h (93%), (ix) AcOH, 90 C, 12 h (80%), (x) Tf O,
2
2
o
pyridine, CH Cl , 0 C, 4 h (85%), (xi) Me-CH=CH-SnBu , Et NCl, PdCl (PPh ) , DMF,
2
2
3
4
2
3 2
o
o
80 C, 4 h (83%), (xii) 180 C, o-dichlorobenzene, 30 min (44%).

HETEROCYCLES, Vol. 61, 2003
15
quenched with DMF to yield the benzaldehyde derivative (7) (75%). The reaction of the aldehyde (7)
tetrabutylammonium fluoride (TBAF) in THF to give benzyl alcohol (9) (92%). Oxidation of 9 with with
hydroxylamine methyl ether in EtOH gave oxime methyl ether (8) (89%), which was treated with
activated manganese dioxide (MnO2) in CH2Cl2 afforded the benzaldehyde derivative (10) (89%), but a
direct conversion of a formyl group of 10 into the methyl ester (11) failed. On the other hand, treatment
of 10 with conc. HCl in MeOH at 0oC selectively produced 2-hydroxybenzaldehyde derivative (12)
(92%), which was converted into the ether (13) by means of methyl bromoacetate with sodium hydride
(93%). The cleavage of MOM-ether (13) in acetic acid at 90oC successfully provided the 4-
hydroxybenzaldehyde (14) (80%), and sequential treatment of 14 with trifluoromethanesulfonic
anhydride (Tf2O) and pyridine at 0oC then gave the triflate (15) (85%). The palladium-catalyzed cross-
coupling reaction of 15 with tributyl 1-propenyltin in the presence of PdCl2(PPh3)2 in DMF at 80oC
afforded the appropriate o-propenyl aldoxime methyl ether (16) (83%) as a 1-aza 6p-electron system.
The thermal electrocyclic reaction of 16 was carried out in o-dichlorobenzene at 180oC3,5 to produce the
desired 7,8-disubstituted isoquinoline (17) in a somewhat low yield (44%).
For the formation of the furanone ring by Dieckmann condensation (Scheme 2), 7-formylisoquinoline
(17) was converted into the methyl ester (18) using sodium cyanide, MnO2, and acetic acid in MeOH
according to Corey’s procedure9 (83%). The cyclization of 18 with sodium methoxide in MeOH at 80oC
gave the b-keto ester (19) (66%), which was treated with lithium hydroxide in aqueous DMSO at 70oC10
to yield the expected furanone (20) (75%). Finally, the reaction of 20 with acetone in the presence of
lithium diisopropylamide (LDA), followed by treatment with methanesulfonyl chloride (MsCl) and
dimethylaminopyridine (DMAP) in pyridine11 provided TMC-120B (2) (33%). The physical and
spectroscopic data of synthetic TMC-120B (2) agreed with those of natural TMC-120B (2) in all
respects.12
MeOOC
OCH COOMe
2
OCH COOMe
2
O
OHC
MeOOC
HO
i
ii
N
N
N
Me
Me
Me
18
17
19
Me
Me
O
O
O
O
iii
iv
N
N
Me
Me
2
20
Scheme 2. Reagent and conditions : (i) NaCN, AcOH, MnO , MeOH, rt, 4 h (83%), (ii) NaOEt,
2
o
o
MeOH, 80 C, 12 h (66%), (iii) LiOH・H O, DMSO-H O, 70 C, 2 h (75%), (iv) LDA, Me CO,
2
2
2
o
o
THF, -78 C, 4 h; MeSO Cl, DMAP, pyridine, 0 C, 2 h (33%).
2

16
HETEROCYCLES, Vol. 61, 2003
Thus, a first total synthesis of TMC-120B (2) was completed in sixteen steps through the construction of
the appropriate 7,8-disubstituted isoquinoline framework based on the thermal electrocyclic reaction of
the 1-azatriene system, followed by the formation of a furanone ring. Further studies of the total
syntheses of TMC-120A (1) and C (3) are now in progress.
ACKNOWLEDGEMENT
This work was supported in part by Grant-in-Aid for Sientific Research (C) (No. 15590033) from the
Ministry of Education, Science, Sports and Culture of Japan.
REFERENCES AND NOTES
1.
2.
(a) J. Kohno, H. Hiramatsu, M. Nishio, M. Sakurai, T. Okuda, and S. Komatsubara, Tetrahedron,
1999, 55, 11247. (b) J. Kohno, M. Sakurai, N. Kameda, M. Nishio, K. Kawano, N. Kishi, T. Okuda,
and S. Komatsubara, J. Antibiotics, 1999, 52, 913.
For reviews see: (a) R. B. Woodward and R. Hoffmann, The Conservation of Orbital Symmetry,
Verlag Chemie, Weinheim, 1970, Chapter 5. (b) E. N. Marvel, Thermal Electrocyclic Reactions,
Academic Press, New York, 1980, Chapter 2. (c) W. H. Okamura and A. R. de Lera, In
Comprehensive Organic Synthesis, ed. by B. M. Trost, I. Fleming, and L. A. Paquette, Pergamon
Press, New York, 1991, Vol. 5, pp. 699-750.
3.
4.
(a) S. Hibino and E. Sugino, In Advances in Nitrogen Heterocycles, ed. by C. J. Moody, JAI Press,
Greenwich, CT, 1995, Vol. 1, pp. 205-227. (b) T. Choshi, Yakugaku Zasshi, 2001, 121, 487.
(a) T. Choshi, T. Sada, H. Fujimoto, C. Nagayama, E. Sugino, and S. Hibino, Tetrahedron Lett.,
1996, 37, 2593. (b) T. Choshi, H. Fujimoto, E. Sugino, and S. Hibino, Heterocycles, 1996, 43, 1847.
(c) T. Choshi, T. Sada, H. Fujimoto, C. Nagayama, E. Sugino, and S. Hibino, J. Org. Chem., 1997,
62, 2535. (d) H. Hagiwara, T. Choshi, H. Fujimoto, E. Sugino, and S. Hibino, Chem. Pharm. Bull.,
1998, 46, 1948. (e) H. Hagiwara, T. Choshi, H. Fujimoto, E. Sugino, and S. Hibino, Tetrahedron,
2000, 56, 5807. (f) H. Hagiwara, T. Choshi, J. Nobuhiro, H. Fujimoto, and S. Hibino, Chem. Pharm.
Bull., 2001, 49, 881.
5.
(a) T. Choshi, S. Yamada, E. Sugino, T. Kuwada, and S. Hibino, J. Org. Chem., 1995, 60, 5899. (b)
H. Yoshioka, T. Choshi, E. Sugino, and S. Hibino, Heterocycles, 1995, 41, 161. (c) H. Yoshioka, Y.
Matsuya, T. Choshi, E. Sugino, and S. Hibino, Chem. Pharm. Bull., 1996, 44, 709. (d) T. Choshi, S.
Yamada, J. Nobuhiro, Y. Mihara, E. Sugino, and S. Hibino, Heterocycles, 1998, 48, 11. (e) T.
Choshi, Y. Matsuya, M. Okida, K. Inada, E. Sugino, and S. Hibino, Tetrahedron Lett., 1998, 39,
2341. (f) E. Sugino, T. Choshi, and S. Hibino, Heterocycles, 1999, 50, 543. (g) N. Kuwabara, H.
Hayashi, N. Hiramatsu, T. Choshi, E. Sugino, and S. Hibino, Chem. Pharm. Bull., 1999, 47, 1805.

HETEROCYCLES, Vol. 61, 2003
17
(h) T. Choshi, T. Kuwada, M. Fukui, Y. Matsuya, E. Sugino, and S. Hibino, Chem. Pharm. Bull.,
2000, 48, 108. (i) N. Kanekiyo, T. Choshi, T. Kuwada, E. Sugino, and S. Hibino, Heterocycles,
2000, 53, 1877. (j) N. Kanekiyo, T. Kuwada, T. Choshi, J. Nobuhiro, and S. Hibino, J. Org. Chem.,
2001, 66, 8793.
6.
(a) M. Miyake and Y. Fujimoto, Chem. Lett., 1993, 1683. (b) M. Miyake, Y. Hanaoka, Y. Fujimoto,
Y. Sato, N. Takemoto, I. Yokota, and Y. Yoshiyama, Heterocycles, 1996, 43, 665.
All new compounds provided satisfactory spectroscopic and analytical data.
M. Pocci, V. Bertini, F. Lucchesini, A. de Munno, N. Picci, F. Iemma, and S. Alfei, Tetrahedron
Lett., 2001, 42, 1351.
7.
8.
9.
(a) E. J. Corey, N. W. Gilman, and B. E. Ganem, J. Am. Chem. Soc., 1968, 90, 5616. (b) E. J. Corey,
J. A. Katzenellenbogen, N. W. Gilman, S. A. Roman, and B. W. Erickson, ibid., 1968, 90, 5618. (c)
G. Lai and W. K. Anderson, Synth. Commun., 1997, 27, 1281.
10. Y. Takeuchi, I. Watanabe, K. Misumi, M. Irea, Y. Hirose, K. Hirata, M. Yamato, and T. Harayama,
Chem. Pharm. Bull., 1997, 45, 2011.
11. S. Danishefsky and S. J. Etheredge, J. Org. Chem., 1978, 43, 4604.
1
12. Synthetic TMC-120B (2): mp 175-178oC (MeOH); H-NMR (300 MHz, CDCl3) d 2.26 (3H, s),
2.45 (3H, s), 2.76 (3H, s), 7.38 (1H, d, J=8.6 Hz), 7.56 (1H, s), 7.83 (1H, d, J=8.6 Hz), 9.57 (1H,
13
s); C-NMR (75 MHz, CDCl3) d 17.6, 20.4, 24.7, 114.6, 119.4, 119.6, 120.6, 124.2, 133.9, 141.4,
1
145.6, 146.2, 156.7, 164.0, 182.3. Natural TMC-120B (2): mp 176-177oC; H-NMR (400 MHz,
CDCl3) d 2.25 (3H, d, J=0.7 Hz), 2.43 (3H, d, J=0.7 Hz), 2.74 (3H, s), 7.35 (1H, d, J=8.5 Hz), 7.52
(1H, s), 7.80 (1H, d, J=8.5 Hz), 9.52 (1H, s); 13C-NMR (100 MHz, CDCl3) d 17.5, 20.4, 24.7, 114.6,
119.3, 119.5, 120.5, 124.1, 133.7, 141.3, 145.6, 146.2, 156.7, 164.0, 182.1.