Synthesis of a model compound of mappicine ketone based on sulfur-directed 5-exo selective aryl radical cyclization onto enamides

Article abstract of DOI:10.1016/S0040-4039(00)02138-9

Enamides 10, upon treatment with Bu₃SnH-AIBN, gave 5-exo aryl radical cyclization products 11, which were partially dusulfurized to give 1-substituted dihydroisoindoles 7 and 12. This method was applied to the synthesis of a model compound 4 of

Full text of DOI:10.1016/S0040-4039(00)02138-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 931–933
Synthesis of a model compound of mappicine ketone based on
sulfur-directed 5-exo selective aryl radical cyclization onto
enamides
Hiroyuki Ishibashi,* Issei Kato, Yoshifumi Takeda and Osamu Tamura
Faculty of Pharmaceutical Sciences, Kanazawa University, Takara-machi, Kanazawa 920-0934, Japan
Received 18 October 2000; revised 13 November 2000; accepted 17 November 2000
Abstract—Enamides 10, upon treatment with Bu3SnH–AIBN, gave 5-exo aryl radical cyclization products 11, which were partially
desulfurized to give 1-substituted dihydroisoindoles 7 and 12. This method was applied to the synthesis of a model compound 4
of mappicine ketone (1). © 2001 Elsevier Science Ltd. All rights reserved.
Mappicine ketone (MPK) (1) is an oxidized derivative of
mappicine (2) and an E ring decarboxylated analogue of
camptothecin (3), the parent member of an important
family of anticancer agents. MPK has recently been
identified as an antiviral lead compound with selective
activities against herpesviruses HSV-1 and HSV-2 and
human cytomegalovirus (HCMV).1 While camptothecin
is now available from natural sources in quantity,2 MPK
has only been isolated in low content which prohibits
isolation of useful amounts for further studies. There-
fore, efforts have been made recently to improve the
degradation3 of camptothecin as well as to develop new
synthetic methods of MPK and related compounds.4 In
the present paper, we describe a novel approach to MPK,
exemplified by the synthesis of a model compound 4,
using sulfur-directed 5-exo selective aryl radical cycliza-
tion onto enamides as a key step.
A previous study in our laboratory revealed that
enamide 5a, upon treatment with Bu3SnH in the pres-
ence of azobiscyclohexanecarbonitrile (ACN), under-
went aryl radical cyclization in a 6-endo manner to
give a tetrahydroisoquinoline derivative 6, whereas
enamide 5b having a (Z)-phenylthio group at the ter-
minus of the N-vinylic bond afforded a 5-exo cycliza-
tion product 7.5 On the other hand, enamide 5c
having an (E)-phenylthio group showed an intermedi-
ate behavior to give approximately equal amounts of
a 6-endo cyclization product 8 and 5-exo cyclization
product 7. The difference between the modes of cy-
clization of 5a–c can be explained in terms of the
difference between the conformers of their enamide
double bonds.
O
O
O
C
A
B
N
C
N
N
A
B
D
D
N
N
E
O
X
Y
O
OH
O
3: Camptothecin
4
1: X ,Y = O (Mappicine Ketone)
2: X = OH, Y = H (Mappicine)
Keywords: antivirals; aryl halides; enamides; isoindoles; radicals and radical reactions.
* Corresponding author. Fax: +81 76 234 4476; e-mail: isibasi@dbs.p.kanazawa-u.ac.jp
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02138-9

932
H. Ishibashi et al. / Tetrahedron Letters 42 (2001) 931–933
O
X
Bu3SnH
ACN
COEt
COEt
COEt
N
Et
N
N
N
+
+
SPh
toluene
reflux
Br
5a: X = H
6
7
8
5b: X = (Z)-SPh
5c: X = (E)-SPh
The exclusive formation of 7 from 5b seems to be
highly promising for the construction of BꢀCꢀD rings
of MPK, since the sulfur atom incorporated into 7
would serve as a handle for elaboration of the CꢀC
bond of the D ring. The (Z)-phenylthio-substituted
enamide 5b, however, could be obtained only as a
minor product during the course of the preparation of
the corresponding (E)-isomer 5c. Therefore, our atten-
tion was turned to an alternative synthesis of 7 by aryl
radical cyclization of 10a having two phenylthio groups
at the terminus of the N-vinylic bond.
equiv. of Bu3SnH, compound 7 was obtained as a sole
product in 68% yield. The exclusive formation of the
5-exo cyclization product 7 from 10a via 11a may be
ascribed to the presence of a (Z)-phenylthio group in
10a as in the case of 5b.5,7 Similar treatment of 10b–d
afforded 12b–d in 84, 68 and 85% yields, respectively.
Enamide 15 would be the most suitable precursor for
the synthesis of 4 via the radical cyclization product 17.
However, acylation of 9 with acid chloride 138 or with
the parent acid 148 was unsuccessful. Therefore, we
decided to prepare compound 17 from 12b–d.
O
acylating
agents
PhNEt2
H
SPh
SPh
MgSO4
N
R
NH2
N
+
OHC
SPh
ether
r. t.
SPh
Br
10a-d
Br
Br
SPh
SPh
O
9
Bu3SnH
O
(5 eq.)
AIBN
N
R
N
R
a: R = Et, b: R = OEt
benzene
reflux
SPh
c: R = OCH2Ph, d: R = CF3
SPh
SPh
7, 12b-d
11a-d
O
O
Et
N
Et
9
+
X
SPh
O
Br
O
PhS
13: X = Cl
14: X = OH
15
The requisite radical precursors 10a–d were readily
prepared as follows. Condensation of o-bromobenzyl-
amine with bis(phenylthio)acetaldehyde gave enamine
96 in 69% yield, which was then treated with acid
chlorides in the presence of diethylaniline in boiling
benzene [except for 10d: (CF3CO)2O, toluene, room
temp.] to give enamides 10a–d in 78, 72, 51 and 92%
yields, respectively.
When compound 12c was subjected to hydrogenolysis
with a Wilkinson catalyst [RhCl(PPh3)3] in benzene9 or
treated with trimethylsilyl iodide in acetonitrile, the
starting material was completely consumed, but no
desired amine 16 could be obtained. The preparation of
amine 16 was best achieved by treating trifluoro-
acetamide 12d with K2CO3 in MeOH–H2O (15:1) at
room temp.10 This amine was then acylated with car-
boxylic acid 14 in the presence of 1-(3-dimethyl-
aminopropyl)-3-ethylcarbodiimide (EDC), DMAP and
1-hydroxybenzotriazole (HOBt) to give the desired
amide 17 in 64% yield (based on 12d). Oxidation of 17
with MCPBA (73%) followed by treatment of the
resulting sulfoxide 18 with trifluoroacetic anhydride
(TFAA) gave a Pummerer rearrangement product 19.
Treatment of 10a with 1.1 equiv. of Bu3SnH in the
presence of AIBN in boiling benzene gave a mixture of
the 5-exo cyclization product 11a and the correspond-
ing partially desulfurized compound 7 in 38 and 27%
yields, respectively, along with the recovered starting
material 10a. When enamide 10a was treated with 5

H. Ishibashi et al. / Tetrahedron Letters 42 (2001) 931–933
933
This compound, without purification, was then heated
in MeOH containing 10% aq. NaOH to give the target
compound 4 in 45% yield (based on 18). Formation of
4 from 19 can be explained by a three-step sequence of
the reactions involving alkaline hydrolysis of trifl-
uoroacetate 19, intramolecular aldol condensation of
the resulting aldehyde 20, and auto-oxidation of the
six-membered unsaturated lactam 21. Although it is not
clear presently whether the compound 4 was formed
from 21 or from its regioisomer with respect to the
double bond, it should be noted that no specific oxidiz-
ing agent such as DDQ was required in the final step.
4. For total syntheses of MPK and related compounds,
see: (a) Kametani, T.; Takeda, H.; Nemoto, H.;
Fukumoto, K. J. Chem. Soc., Perkin Trans. 1 1975, 1825;
(b) Comins, D. L.; Saha, J. K. J. Org. Chem. 1996, 61,
9623; (c) Josien, H.; Curran, D. P. Tetrahedron 1997, 53,
8881; (d) Boger, D. L.; Hong, J. J. Am. Chem. Soc. 1998,
120, 1218; (e) Yadav, J. S.; Sarkar, S.; Chandrasekhar, S.
Tetrahedron 1999, 55, 5449; (f) Toyota, M.; Komori, C.;
Ihara, M. Heterocycles 2000, 52, 591; (g) Mekouar, K.;
Ge´nisson, Y.; Leue, S.; Green, A. E. J. Org. Chem. 2000,
65, 5212. See also Ref. 1.
O
O
i
ii
iv
N
v
N
12d
N
H
CF3COO
PhS
PhS
O
O
PhS
Et
Et
(O)n
19
16
17: n = 0
iii
18: n = 1
O
O
O
N
N
N
[O]
H
O
O
O
O
Et
Et
Et
20
4
21
i) K2CO3, MeOH-H2O (15:1), room temp.; ii) 14, EDC, DMAP, HOBt, CH2Cl2, room temp.; iii) MCPBA, CH2Cl2,
0 ˚C; iv) (CF3CO)2O, CH2Cl2, 0 ˚C; v) 10% NaOH, MeOH, reflux.
Thus, we demonstrated the feasibility of using sulfur-
directed 5-exo selective aryl radical cyclization of o-bro-
5. Ishibashi, H.; Kato, I.; Takeda, Y.; Kogure, M.; Tamura,
O. Chem. Commun. 2000, 1527.
mobenzyl enamides 10 for the synthesis of a model
6. 1H NMR for 9 (diagnostic data only): l 4.29 (d, J=6.3
compound 4 of MPK. An application of this method to
Hz, 2 H, ArCH2), 5.43 (dt, J=13.2, 6.6 Hz, 1 H, NH).
7. For other sulfur-directed exo selective radical cycliza-
the synthesis of MPK is now under investigation, and
the results will be reported in due course.
tions, see: (a) Ishibashi, H.; Kameoka, C.; Iriyama, H.;
Kodama, K.; Sato, T.; Ikeda, M. J. Org. Chem. 1995, 60,
1276; (b) Ishibashi, H.; Kawanami, H.; Nakagawa, H.;
Ikeda, M. J. Chem. Soc., Perkin Trans. 1 1997, 2291; (c)
References
Ishibashi, H.; Kobayashi, T.; Takamasu, D. Synlett 1999,
1286.
8. Carboxylic acid 14 was prepared by alkylation of methyl
1. (a) Pendrak, I.; Barney, S.; Wittrock, R.; Lambert, D.
M.; Kingsbury, W. D. J. Org. Chem. 1994, 59, 2623; (b)
Pendrak, I.; Wittrock, R.; Kingsbury, W. D. J. Org.
Chem. 1995, 60, 2912.
3-oxopentanoate with methyl 2-bromopropionate
(K2CO3, Bu4NI, acetone, 77%) followed by decar-
boxylative hydrolysis (AcOH, conc. HCl, 89%). Acid
chloride 13 was prepared from 14 [(COCl)2, pyridine,
benzene].
2. For recent works on the synthesis of camptothecin, see:
(a) Tagami, K.; Nakazawa, N.; Sano, S.; Nagao, Y.
Heterocycles 2000, 53, 771; (b) Brown, R. T.; Jianli, L.;
Santos, C. A. M. Tetrahedron Lett. 2000, 41, 859.
3. For transformation of camptothecin to MPK, see: (a)
Kingsbury, W. D. Tetrahedron Lett. 1988, 29, 6847; (b)
Fortunak, J. M. D.; Mastrocola, A. R.; Mellinger, M.;
Wood, J. L. Tetrahedron Lett. 1994, 35, 5763; (c) Das, B.;
Madhusudhan, P. Tetrahedron 1999, 55, 7875; (d) Das,
B.; Madhusudhan, P.; Kashinatham, A. Bioorg. Med.
Chem. Lett. 1998, 8, 1403.
9. It has been reported that catalytic hydrogenation of
sulfur-containing compounds such as allyl phenyl sulfide
is effected with a Wilkinson catalyst in benzene. See:
Birch, A. J.; Walker, K. A. M. Tetrahedron Lett. 1967,
1935.
10. Alkaline hydrolysis of 12b,c required rather drastic condi-
tions and long reaction times.
.
.