A facile synthesis of telisatin A via microwave-promoted annulation and reformatsky reaction

Article abstract of DOI:10.1055/s-2008-1042764

A facile one-pot synthesis of 2,3-dioxopyrrolo[2,1-a]isoquinolines is reported involving the ring formation of aryl pyruvate derivatives with 3,4-dihydroisoquinolines under basic conditions and utilizing the Reformatsky reaction. Using microwave irradiation, the required compounds were obtained in moderate to good yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1042764

LETTER
505
A Facile Synthesis of Telisatin A via Microwave-Promoted Annulation and
Reformatsky Reaction
F
acile Synthesis of
o
Telisatin
A
pporn Thasana,*a,b Ben Bjerke-Kroll,b Somsak Ruchirawat*a–c
a
Chulabhorn Graduate Institute, Vipavadee Rangsit Highway, Bangkok 10210, Thailand
Fax +66(2)5742027; E-mail: nopporn@cri.or.th
b
c
Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, Vipavadee Rangsit Highway, Bangkok 10210, Thailand
Programme on Research and Development of Synthetic Drugs, Institute of Science and Technology for Research and Development,
Mahidol University, Salaya Campus, Nakhonpathom 73170, Thailand
Received 15 August 2007
R1
Abstract: A facile one-pot synthesis of 2,3-dioxopyrrolo[2,1-a]iso-
quinolines is reported involving the ring formation of aryl pyruvate
derivatives with 3,4-dihydroisoquinolines under basic conditions
and utilizing the Reformatsky reaction. Using microwave irradia-
tion, the required compounds were obtained in moderate to good
yields.
R2
N 6
O
O
R3
R4
1
12
7
11
13
8
R5
Key words: microwave, annulation, Reformatsky reaction, dioxo-
pyrrolo[2,1-a]isoquinoline, dioxoaporphine
R6
telisatin A (1a) R2 = R3 = OMe, R1 = R4 = R5 = R6 = H
telisatin B (1b) R1 = R2 = R3 = OMe, R4 = R5 = R6 = H
laurodionine (1c) R3 = R5 = OMe, R2 = R6 = OH, R1 = R4 = H
lettowianthine (1d) R2–R3 = OCH2O, R1 = R4 = R5 = R6 = H
11-methoxylettowianthine (1e) R2–R3 = OCH2O, R4 = OMe, R1 = R5 = R6 = H
12,13-Dioxoaporphine is a new subclass of aporphine al-
kaloids which possesses a 1,2-dione group linking N-6
and C-7 of aporphine and can be classified as an oxalyl-
fused aporphine.1 Up till now, five 12,13-dioxoapor-
phines have been found in nature (Figure 1). Telisatin A
(1a) and telisatin B (1b), isolated from Telitoxicum peru-
vianum, were the first two representatives. The plant has
been used as an ingredient of curare by the Huitoto Indi-
ans in Peru.2 Laurodionine (1c) was isolated from the
stems of Phoebe formosana, Hayata (Lauraceae) which is
abundantly available in Taiwan.3 The last two com-
pounds, lettowianthine (1d) and 11-methoxylettowian-
thine (1e), were isolated from the root bark of
Lettowianthus stellatus, a plant growing in coastal rain
forests of Kenya and Tanzania. The root bark extracts of
this plant have been shown to exhibit weak antimalarial
activity.4 Lettowianthine (1d) was also isolated from the
fruits and stems of Annona glabra, a tropical plant in Tai-
wan, and was given another name, annobraine, by Wu.5
Figure 1 Structure of natural 12,13-dioxoaporphine alkaloids
R1
MeO
R1
N4
MeO
10b
O
MeO
ref. 9
N
N
2
MeO
Y
X
1
O
O
4
Ph
X
O
Br
N
O
6
7
Ph
OR2
R1
O
5
R1
MeO
MeO
MeO
N4
10b
N
3
O
O
MeO
X
X
Telisatin A (1a) was previously synthesized by Cava6 us-
ing dehydroaporphine with oxalyl chloride. It was also
obtained as a [4+2]-cycloadduct in low yield as reported
by Castedo.7 Most isatins were prepared as the key inter-
mediate for the synthesis of various alkaloids using oxalyl
chloride as the source of the dioxo synthon.8
2
1
O
O
3
2
Scheme 1 Retrosynthetic analysis of 2,3-dioxopyrrolo[2,1-a]iso-
quinoline 2
Recently, we reported the ring closure of dihydroisoquin-
oline 4 with azlactone 6 under neutral conditions to give
the imidazoloisoquinolin-3-one 7 by simultaneous forma-
tion of two C–N bonds.9 Herein, we report a facile synthe-
sis of isatin skeleton 2. Our new method is based on the
construction of C1–C10b and N4–C3 bonds by condensing
3,4-dihydroisoquinoline 4 with aryl pyruvate derivative 5
via dihydroisatin 3 which could be further oxidized to pro-
vide the desired 2,3-dioxopyrrolo[2,1-a]isoquinolines 2
as shown in Scheme 1.
It was originally anticipated that cleavage of the C10b–N1
bond of imidazoloisoquinolin-3-one 7 and subsequent hy-
drolysis of the corresponding enamide could furnish 2,3-
SYNLETT 2008, No. 4, pp 0505–0508
Advanced online publication: 12.02.2008
DOI: 10.1055/s-2008-1042764; Art ID: D25207ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
0
8

506
N. Thasana et al.
LETTER
Table 1 Synthesis of 2,3-Dioxopyrrolo[2,1-a]isoquinolines 214
R1
R2O
O
R1
Y
X
MeO
MeO
O
MeO
MeO
conditions
N
X
O
N
2a R1 = X = H
5a R2 = Et, X = Y = H
4a R1 = H
4b R1 = OMe
2b R1 = H, X = Br
2c R1 = OMe, X = H
2d R1 = OMe, X = Br
5b R2 = Me, X = Br, Y = H
5c R2 = Et, X = H, Y = Cl
5d R2 = Et, X = Br, Y = Cl
O
Entry
1
Imines
Phenyl pyruvates
Conditionsa
Yield (%) 2b
4a
4a
4a
4b
4b
4a
4a
4b
4b
4a
4a
4b
4b
5a
5a
5b
5a
5b
5a
5b
5a
5b
5c
5d
5c
5d
A
B
B
B
B
C
C
C
C
D
D
D
D
57
69
53
40
38
75
78
58c
54c
82d
77d
69
60
2
3
4
5
6
7
8
9
10
11
12
13
a Conditions A: NaOMe, MeOH, reflux, 12 h; B: NaOMe, DMF, reflux, 2 h; C: NaOMe, DMF, MW, 150 °C, 300 W, 100 psi, 10 min; D: Zn/
Cu, benzene, MW, 150 °C, 300 W, 100 psi, 10 min.
b Isolated yields of pure product after column chromatography on silica.
c The C-2 demethylated by-product was observed in poor yields (5% and 8%, respectively).
d On using conventional heating for 14 h, yields of the desired products were 59% and 47%, respectively.
dioxopyrrolo[2,1-a]isoquinoline 2. With this idea in furnishing the desired product 2a in moderate yield and
mind, various hydrolysis conditions were studied. How- also the penultimate target compound 3a albeit in poor
ever, all conditions afforded mixtures of varying amount yield. Better yield of the target compound could be ob-
of the recovered compound 7 together with the target tained by increasing the reaction time to 12 hours. The
compound 2 in disappointing yields.
yield was improved to a moderate 57% yield using condi-
tions A (entry 1). Changing to a higher boiling-point sol-
vent such as DMF under conditions B, the reaction was
complete in only two hours and gave compounds 2a–d in
moderate 38–69% yields (entries 2–5).
We then envisioned an alternative method for the synthe-
sis of compound 2 using our developed methodology. The
required 3,4-dihydroisoquinolines 4 were synthesized by
the well-established Bischler–Napieralski reaction start-
ing from the aryl ethylamine derivative which was con- Interestingly, by using microwave heating in conditions
verted into the corresponding formamide derivative and C,15 the reaction time could be reduced from two hours to
then cyclized to imine 4 using POCl3.10 The aryl pyruvate only a few minutes and compounds 2a–d were obtained in
esters 5a and 5b were obtained by the Grignard reaction moderate to good yields (entries 6–9). Under these condi-
of different benzyl magnesium bromides with diethyl tions, however, the C-2 demethylation adducts were also
oxalate11 as well as by the esterification of aryl pyruvic observed in low yields (5–8%).
acid obtained from the hydrolysis of the azlactones 6.12
We have also investigated another procedure employing
The a-chlorophenyl pyruvates 5c and 5d were obtained
the Reformatsky reaction16 to synthesize 2,3-dioxopyrro-
via the Darzens condensation.13
lo[2,1-a]isoquinoline 2. Reaction of a-chloroaryl pyru-
A model experiment for constructing the isatin framework vates 5c and 5d with Cu/Zn metals and
was performed by reacting compound 4a with 5a in the dihydroisoquinoline 4a in refluxing benzene for 14 hours
presence of NaOMe in refluxing MeOH for four hours, gave compounds 2a and 2b in 59% and 47%, yields re-
Synlett 2008, No. 4, 505–508 © Thieme Stuttgart · New York

LETTER
Facile Synthesis of Telisatin A
507
R1
Science Foundation. Grant from NSF-REU (INT-0123857, Re-
search Fellowship) for B.B.-K. is gratefully acknowledged.
R2O
O
A
MeO
MeO
O
R1
MeO
N
X
X
O
OR2
References and Notes
N
conditions A–C
R2O
MeO
(1) Bentley, K. W. The Isoquinoline Alkaloids; Ravindranath,
B., Ed.; Harwood Academic Publishers: Amsterdam, 1998,
158.
4
O
ClZn
O
conditions D
(2) Menachery, M. D.; Blake, G. W.; Gourley, R. C. J. Nat.
Prod. 1995, 58, 1945.
(3) Chen, C.-C.; Huang, Y.-L.; Lee, S.-S.; Ou, J.-C. J. Nat.
Prod. 1997, 60, 826.
(4) Nkunya, M. H. H.; Jonker, S. A.; Makangara, J. J.; Waibel,
R.; Achenbach, H. Phytochemistry 2000, 53, 1067.
(5) Chang, F.-R.; Chen, C.-Y.; Hsieh, T.-J.; Cho, C.-P.; Wu, Y.-
C. J. Chin. Chem. Soc. 2000, 47, 913.
O
B
X
R1
R1
MeO
MeO
MeO
N
N
O
MeO
O
OR2
O
O
(6) Saá, J. M.; Cava, M. P. J. Org. Chem. 1978, 43, 1096.
(7) (a) Saá, C.; Guitián, E.; Castedo, L. J. Org. Chem. 1986, 51,
2781. (b) See also: Cobas, A.; Guitián, E.; Castedo, L.; Saá,
J. M. Tetrahedron Lett. 1988, 29, 2491.
(8) (a) Castedo, L.; Saá, C.; Saá, J. M.; Suau, R. J. Org. Chem.
1982, 47, 513. (b) Cheng, Y.; Ye, H.-L.; Zhan, Y.-H.; Meth-
Cohn, O. Synthesis 2001, 904. (c) Suau, R.; López-Romero,
J. M.; Ruiz, A.; Rico, R. Tetrahedron 2000, 56, 993.
(d) Sano, T.; Toda, J.; Kashiwaba, N.; Tsuda, Y.; Iitaka, Y.
Heterocycles 1981, 16, 1151.
(9) Worayuthakarn, R.; Thasana, N.; Ruchirawat, S. Org. Lett.
2006, 8, 5845.
(10) Barbier, D.; Marazano, C.; Das, B. C.; Potier, P. J. Org.
Chem. 1996, 61, 9596.
(11) (a) Weinstock, L. M.; Currie, R. B.; Lovell, A. V. Synth.
Commun. 1981, 11, 943. (b) Creary, X. J. Org. Chem. 1987,
52, 5026.
X
X
3
[O]
R1
MeO
MeO
N
X
O
O
2
Scheme 2 Proposed mechanism of the annulation of 2,3-dioxopyr-
rolo[2,1-a]isoquinoline 2
spectively. Using microwave irradiation (conditions D)
instead of conventional heating led to a better yield of 2,3-
dioxopyrrolo[2,1-a]isoquinolines 2 (entries 10–13).
(12) (a) Peschko, C.; Winklhofer, C.; Steglich, W. Chem. Eur. J.
2000, 6, 1147. (b) Weber, V.; Coudert, P.; Rubat, C.;
Duroux, E.; Vallée-Goyet, D.; Gardette, D.; Bria, M.;
Albuisson, E.; Leal, F.; Gramain, J.-C.; Couquelet, J.;
Madesclaire, M. Bioorg. Med. Chem. 2002, 10, 1647.
(13) (a) Coutrot, P.; Legris, C. Synthesis 1975, 118. (b) Coutrot,
P.; Grison, C.; Tabyaoui, M.; Czernecki, S.; Valery, J.-M. J.
Chem. Soc., Chem. Commun. 1988, 1515. (c) Coutrot, P.;
Grison, C.; Coutrot, F. Synlett 1998, 393.
(14) Synthesis of 2,3-Dioxopyrrolo[2,1-a]isoquinoline 2;
Typical Procedure (Conditions C): A mixture of imines 4
(0.1 mmol), aryl pyruvates 5 (0.1 mmol) and NaOMe (0.1
mmol) in DMF (1 mL) was irradiated using microwave. The
microwave run time was set to 2 min, with power at 300 W,
temperature at 150 °C, and pressure at 100 psi, and the
conditions were maintained for 10 min. The reaction was
quenched with H2O and extracted with EtOAc, dried
(Na2SO4) and evaporated in vacuo to yield a red residue. The
residue was purified by column chromatography, affording
crystals of 2 after recrystallization in moderate yields (54–
78%).
A proposed mechanism of the annulation of isatin 2 is
shown in Scheme 2. The reaction possibly proceeded
through a direct nucleophilic addition of either intermedi-
ate A or B to the dihydroisoquinoline 4 giving the dihy-
droisatin 3 which underwent further auto-oxidation to 2,3-
dioxopyrrolo[2,1-a]isoquinoline 2 as shown in Scheme 2.
The photocyclization of 2,3-dioxopyrrolo[2,1-a]isoquino-
line 2b in the presence of tert-butylamine by Hanovia 450
W high-pressure mercury lamp afforded the correspond-
ing product, telisatin A (1a), in 27% yield.8a
In conclusion, we have devised a facile route for the syn-
thesis of 2,3-dioxopyrrolo[2,1-a]isoquinolines 2 in one
step based on the ring formation of dihydroisoquinoline 4
with aryl pyruvate derivatives 5 under basic conditions
and the Reformatsky reaction. Both conditions were ex-
amined using microwave irradiation which gave better
yield than the conventional heating. The methodology
should be applicable to the synthesis of dioxoaporphine
and related alkaloids.
Conditions D: A mixture of imines 4 (0.1 mmol), aryl
pyruvates 5 (0.1 mmol), copper powder (0.1 mmol) and zinc
powder (0.1 mmol) in DMF (1 mL) was irradiated using
microwave. The microwave run time was set to 2 min, with
power at 300 W, temperature at 150 °C, and pressure at 100
psi, and the conditions were maintained for 10 min. The
reaction was quenched with H2O and extracted with EtOAc,
dried (Na2SO4) and evaporated in vacuo to yield a red
residue. The residue was purified by column chromatog
raphy, affording crystals of 2 after recrystallization in
moderate to good yields (60–82%). Compound 2a: deep-red
solid; mp 178–179 °C (EtOAc–hexane). IR (CHCl3): 3020,
1745, 1701, 1580, 1492, 1290 cm–1. 1H NMR (200 MHz,
Acknowledgment
We acknowledge the Thailand Research Fund for the TRF Research
Scholar Fellowship (RMU4980048) to N.T. This work was partially
supported by the Center for Toxicology, Environmental Health and
Management of Toxic Chemicals (TEM) and the Thailand Toray
Synlett 2008, No. 4, 505–508 © Thieme Stuttgart · New York

508
N. Thasana et al.
LETTER
CDCl3): d = 3.09 (t, J = 6.2 Hz, 2 H), 3.33 (s, 3 H), 3.85 (t,
J = 6.2 Hz, 2 H), 3.96 (s, 3 H), 6.77 (s, 1 H), 6.95 (s, 1 H),
7.37 (m, 5 H). 13C NMR (50 MHz, CDCl3): d = 28.6, 36.6,
55.3, 56.2, 111.2, 112.2, 116.8, 127.9, 128.9, 130.2, 130.3,
132.8, 147.9, 153.5, 157.4, 158.3, 165.9, 183.1. MS (EI):
m/z (%) = 263 (7), 306 (100), 307 (26), 335 (58) [M+].
HRMS (FAB): m/z [M + H+] calcd for C20H17NO4:
336.1236; found: 336.1234.
Compound 2b: wine-red solid; mp 198–199 °C (EtOAc–
hexane; lit8c 176–178 °C). IR (KBr): 1746, 1692, 1575,
1514, 1396, 1290, 1223 cm–1. 1H NMR (200 MHz, CDCl3):
d = 3.11 (t, J = 6.2 Hz, 2 H), 3.30 (s, 3 H), 3.89 (t, J = 6.2 Hz,
2 H), 3.95 (s, 3 H), 6.65 (s, 1 H), 6.78 (s, 1 H), 7.31 (m, 3 H),
7.71 (d, J = 7.2 Hz, 1 H). 13C NMR (50 MHz, CDCl3): d =
28.4, 36.4, 55.2, 56.2, 107.9, 111.2, 111.5, 116.9, 125.9,
128.0, 129.9, 132.5, 132.8, 133.2, 148.3, 153.8, 158.1,
158.4, 181.6. MS (EI): m/z (%) = 306 (83), 334 (100), 384
(34), 386 (31), 413 (31) [M+], 415 (31) [M+ + 2]. HRMS
(FAB): m/z [M + H+] calcd for C20H16BrNO4: 414.0341;
found: 414.0343.
130.2, 147.1, 147.7, 150.5, 151.9, 157.1, 157.9, 183.4. MS
(EI): m/z (%) = 237 (37), 336 (100), 365 (60) [M+]. HRMS
(FAB): m/z [M + H+] calcd for C21H19NO5: 366.1341; found:
366.1338.
Compound 2d: wine-red solid; mp 153–155 °C (EtOAc–
hexane). IR (KBr): 1747, 1703, 1576, 1467, 1425, 1397,
1341, 1109, 1024 cm–1. 1H NMR (200 MHz, CDCl3): d =
3.11 (t, J = 6.6 Hz, 2 H), 3.20 (s, 3 H), 3.75 (t, J = 6.2 Hz, 2
H), 3.81 (s, 3 H), 3.87 (s, 3 H), 6.46 (s, 1 H), 7.20 (m, 2 H),
7.33 (t, J = 7.0 Hz, 1 H), 7.64 (d, J = 7.2 Hz, 1 H). 13C NMR
(50 MHz, CDCl3): d = 21.7, 36.2, 55.2, 61.0, 61.1, 108.6,
119.4, 125.4, 125.8, 128.0, 129.9, 132.3, 132.7, 133.2,
147.0, 150.6, 152.3, 157.9, 158.0, 182.0. MS (EI): m/z (%) =
336 (54), 364 (100), 414 (34), 416 (36), 443 (93) [M+], 445
(95) [M+ + 2]. HRMS (FAB): m/z [M + H+] calcd for
C21H18BrNO5: 444.0447; found: 444.0449.
(15) For microwave irradiation, see: (a)Kappe,C.O.;Stadler, A.
Microwaves in Organic and Medicinal Chemistry;
Mannhold, R.; Kubinyi, H.; Folkers, G., Eds.; Wiley-VCH:
Weinheim, 2005. (b) Hayes, B. L. Microwave Synthesis:
Chemistry at the Speed of Light; CEM Publishing:
Matthews, 2002.
(16) (a) Joshi, N. N.; Hoffmann, H. M. R. Tetrahedron Lett. 1986,
27, 687. (b) Petrier, C.; Dupuy, C.; Luche, J. L. Tetrahedron
Lett. 1986, 27, 3149. (c) Friedrich, E. C.; Domek, J. M.;
Pong, R. Y. J. Org. Chem. 1985, 50, 4640.
Compound 2c: deep-red solid; mp 178–179 °C (EtOAc–
hexane). IR (CHCl3): 2941, 1742, 1692, 1573, 1472, 1403,
1343, 1299, 1111, 1029 cm–1. 1H NMR (200 MHz, CDCl3):
d = 3.10 (t, J = 6.2 Hz, 2 H), 3.30 (s, 3 H), 3.81 (t, J = 6.2 Hz,
2 H), 3.89 (s, 3 H), 3.95 (s, 3 H), 6.82 (s, 1 H), 7.34 (m, 3 H),
7.37 (m, 2 H). 13C NMR (100 MHz, CDCl3): d = 21.7, 36.1,
55.2, 61.0, 61.1, 109.1, 119.3, 125.6, 128.0, 128.9, 130.1,
Synlett 2008, No. 4, 505–508 © Thieme Stuttgart · New York

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