Total synthesis of mappicine ketone (nothapodytine B) by means of sulfur-directed 5-exo-selective aryl radical cyclization onto enamides

Article abstract of DOI:10.1021/jo030177m

Enamides 5, on treatment with Bu₃SnH-AIBN, underwent aryl radical cyclization in a 5-exo manner to give 1-[bis(phenylthio)methyl]dihydroisoindoles 6, which were partially desulfurized with Bu₃SnH-AIBN to give 1-mono(phenylthio)methyl

Full text of DOI:10.1021/jo030177m

Tota l Syn th esis of Ma p p icin e Keton e (Noth a p od ytin e B) by Mea n s
of Su lfu r -Dir ected 5-exo-Selective Ar yl Ra d ica l Cycliza tion on to
En a m id es
Issei Kato, Masayuki Higashimoto, Osamu Tamura, and Hiroyuki Ishibashi*
Faculty of Pharmaceutical Sciences, Kanazawa University, Takara-machi, Kanazawa 920-0934, J apan
isibasi@p.kanazawa-u.ac.jp
Received May 21, 2003
Enamides 5, on treatment with Bu3SnH-AIBN, underwent aryl radical cyclization in a 5-exo manner
to give 1-[bis(phenylthio)methyl]dihydroisoindoles 6, which were partially desulfurized with
Bu3SnH-AIBN to give 1-mono(phenylthio)methyl congeners 7. Formation of 6 from 5 may be
explained by the presence of two phenylthio groups at the terminus of the N-vinylic bond of 5,
since enamide 8a having no phenylthio group underwent aryl radical cyclization in a 6-endo manner.
Compound 7d (R ) CF3) was transformed into sulfoxide 16, which was treated with (CF3CO)2O
and then with 10% NaOH to give a model compound 20 of mappicine ketone (MPK) (1) through
aldol condensation of aldehyde 18. An attempt to synthesize MPK using this method with sulfoxide
28 prepared from 25, however, was unsuccessful, and, instead, photochemical cyclization of enamide
38 prepared from 25 furnished MPK.
In tr od u ction
that intramolecular aldol condensation of aldehyde 18
derived from aryl radical cyclization product 7d afforded
a model compound 20 of MPK (Scheme 4). We attempted
the synthesis of MPK using this method with 25, but,
unfortunately, the crucial aldol condensation of 29 gave
an unexpected result (Scheme 5). We then devised an
alternative method for the synthesis of MPK and found
that photochemical cyclization of enamide 38 prepared
from 25 furnished MPK via oxidation of the intermediate
39 (Scheme 7). In this paper, we describe these results
Mappicine ketone (MPK) (1) has recently been identi-
fied as an antiviral lead compound with selective activi-
ties against herpesviruses HSV-1 and HSV-2 and hu-
man cytomegalovirus (HCMV).1 MPK is an oxidized
derivative of mappicine (2) and an E ring decarboxy-
lated analogue of camptothecin (3)2 that exhibits po-
tent cytotoxic activity against a wide range of tumor cell
lines. Camptothecin is now obtained easily in large
quantity from natural sources, but MPK has not been
isolated in sufficient amounts for further studies. Many
efforts have therefore been made recently to improve
the degradation3 of camptothecin as well as to develop
new methods for synthesizing MPK and related com-
pounds.4,5
(2) For total and formal total syntheses of camptothecin or its
derivatives, see: Tagami, K.; Nakazawa, N.; Sano, S.; Nagao, Y.
Heterocycles 2000, 53, 771. Brown, R. T.; J ianli, L.; Santos, C. A. M.
Tetrahedron Lett. 2000, 41, 859. Bennasar, M.-L.; J uan, C.; Bosch, J .
Chem. Commun. 2000, 2459. Comins, D. L.; Nolan, J . M. Org. Lett.
2001, 3, 4255. Gabarda, A. E.; Du, W.; Isarno, T.; Tangirala, R. S.;
Curran, D. P. Tetrahedron 2002, 58, 6329. Blagg, B. S. J .; Boger, D.
L. Tetrahedron 2002, 58, 6343. Thomas, O. P.; Zaparucha, A.; Husson,
H.-P. Eur. J . Org. Chem. 2002, 157. Curran, D. P.; Du, W. Org. Lett.
2002, 4, 3215. See also references therein.
(3) For transformation of camptothecin to MPK, see: Kingsbury,
W. D. Tetrahedron Lett. 1988, 29, 6847. Fortunak, J . M. D.; Mastrocola,
A. R.; Mellinger, M.; Wood, J . L. Tetrahedron Lett. 1994, 35, 5763. Das,
B.; Madhusudhan, P.; Kashinatham, A. Bioorg. Med. Chem. Lett. 1998,
8, 1403. Das, B.; Madhusudhan, P. Tetrahedron 1999, 55, 7875.
(4) For total and formal total syntheses of mappicine or mappicine
ketone (MPK), see: (a) Boger, D. L.; Hong, J . J . Am. Chem. Soc. 1998,
120, 1218. (b) Mekouar, K.; Ge´nisson, Y.; Leue, S.; Greene, A. E. J .
Org. Chem. 2000, 65, 5212. (c) Toyota, M.; Komori, C.; Ihara, M. J .
Org. Chem. 2000, 65, 7110. (d) Zhang, Q.; Rivkin, A.; Curran, D. P. J .
Am. Chem. Soc. 2002, 124, 5774. (e) Carles, L.; Narkunan, K.; Penlou,
S.; Rousset, L.; Bouchu, D.; Ciufolini, M. A. J . Org. Chem. 2002, 67,
4304. See also references therein.
(5) For recent synthetic studies on camptothecin, MPK, and related
compounds, see: Toyota, M.; Komori, C.; Ihara, M. Heterocycles 2000,
52, 591. Bowman, W. R.; Bridge, C. F.; Brookes, P.; Cloonan, M. O.;
Leach, D. C. J . Chem. Soc., Perkin Trans. 1 2002, 58. Yabu, K.;
Masumoto, S.; Kanai, M.; Curran, D. P.; Shibasaki, M. Tetrahedron
Lett. 2002, 43, 2923. Perzyna, A.; Houssin, R.; Barbry, D.; He´nichart,
J .-P. Synlett 2002, 2077.
In a previous communication,6 we reported that treat-
ment of enamides 5 with Bu3SnH-AIBN resulted in aryl
radical cyclization in a 5-exo manner to give 1-(phenylthio-
methyl)dihydroisoindoles 7 through partial desulfuriza-
tion of the initial products 6 (Scheme 1). We also reported
* To whom correspondence should be addressed. Fax: +81(76)-234-
4476.
(1) Pendrak, I.; Barney, S.; Wittrock, R.; Lambert, D. M.; Kingsbury,
W. D. J . Org. Chem. 1994, 59, 2623. Pendrak, I.; Wittrock, R.;
Kingsbury, W. D. J . Org. Chem. 1995, 60, 2912.
(6) Ishibashi, H.; Kato, I.; Takeda, Y.; Tamura, O. Tetrahedron Lett.
2001, 42, 931.
10.1021/jo030177m CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/20/2003
J . Org. Chem. 2003, 68, 7983-7989
7983

Kato et al.
SCHEME 1
SCHEME 4 a
SCHEME 2
a
Reagents and conditions: (a) K2CO3, MeOH-H2O (15:1), room
temperature; (b) 11, EDC, DMAP, HOBt, CH2Cl2, room temper-
ature, 64% from 7d ; (c) MCPBA, CH2Cl2, 0 °C, 73%; (d) (CF3CO)2O,
CH2Cl2, 0 °C; (e) 10% NaOH, MeOH, reflux, 45% from 16.
N-vinylic bond underwent aryl radical cyclization in a
6-endo manner exclusively to give a tetrahydroisoquino-
line derivative 9 (Scheme 2),8 whereas enamide 8b having
a (Z)-PhS group afforded a 5-exo cyclization product 7a .
On the other hand, enamide 8c having an (E)-PhS group
showed an intermediate behavior to give 7a and 10.9 The
difference between the modes of cyclization of 8a -c can
be explained by the difference between the conformers
of their enamide double bonds, and the exclusive forma-
tion of the 5-exo cyclization product 6 from 5 may
therefore be ascribed to the presence of a (Z)-phenylthio
group in 5 as in the case of 8b.10 Another reason for the
preference for 5-exo closure of 5 to 6 may be that the
presence of two PhS groups greatly stabilizes the result-
ing radical.
SCHEME 3
together with a full account of preliminary works in this
area.
Resu lts a n d Discu ssion
The exclusive formation of 7 from 5 seems to be
promising for the construction of B-C-D rings of MPK,
since the sulfur atom incorporated into 7 would serve as
a handle for elaboration of the D ring. For this purpose,
enamide 13 would be the most suitable precursor for the
synthesis of a model compound 20 via the radical cycliza-
tion product 15. However, acylation of 4 with carboxyclic
acid 11 or with the corresponding acid chloride 12 using
conventional means was unsuccessful. Therefore, we
decided to prepare compound 15 from 7b, 7c, or 7d .
The alkaline hydrolysis of 7b,c giving amine 14
required rather drastic conditions and a long reaction
time. For example, heating 7b with 40% aqueous KOH
in boiling ethylene glycol for 3 h gave only a 51% yield of
Condensation of o-bromobenzylamine with bis(phen-
ylthio)acetaldehyde7 gave enamine 4 in 69% yield. Com-
pound 4 was then treated with propionyl chloride in the
presence of diethylaniline in boiling benzene to give
enamide 5a in 78% yield. Similar treatment of 4 with
alkoxycarbonyl chlorides gave 5b and 5c in 72 and 51%
yields, respectively. On the other hand, treatment of 4
with (CF3CO)2O in the presence of triethylamine gave
trifluoroacetyl compound 5d in 92% yield.
When enamide 5a was treated with 1.1 equiv of
Bu3SnH in the presence of AIBN in boiling benzene, the
5-exo aryl radical cyclization product 6a was obtained in
38% yield along with the partially desulfurized compound
7a (27% yield). On the other hand, treatment of 5a with
5 equiv of Bu3SnH gave only 7a in 68% yield. Similar
treatment of 5b, 5c, and 5d afforded 7b, 7c, and 7d in
84, 68, and 85% yields, respectively.
(8) Ishibashi, H.; Kato, I.; Takeda, Y.; Kogure, M.; Tamura, O. Chem.
Commun. 2000, 1527.
(9) Formation of 10 might be a result of a consecutive 6-endo aryl
radical cyclization of 8c and an elimination of benzenethiyl radical from
the resulting radical intermediate.
(10) For other sulfur-directed exo-selective radical cyclizations,
see: Ishibashi, H.; Kawanami, H.; Nakagawa, H.; Ikeda, M. J . Chem.
A previous study in our laboratory revealed that
enamide 8a having no PhS group at the terminus of its
(7) Ishibashi, H.; Kameoka, C.; Iriyama, H.; Kodama, K.; Sato, T.;
Ikeda, M. J . Org. Chem. 1995, 60, 1276.
Soc., Perkin Trans.
Takamasu, D. Synlett 1999, 1286. See also ref 7.
1 1997, 2291. Ishibashi, H.; Kobayashi, T.;
7984 J . Org. Chem., Vol. 68, No. 21, 2003

Total Synthesis of Mappicine Ketone
SCHEME 5 a
SCHEME 7 a
a
Reagents and conditions: (a) EDC, CH2Cl2, room temperature
16 h, 75%; (b) MCPBA, CH2Cl2, 0 °C, 98%; (c) CaCO3, toluene,
reflux 13 h, 63%; (d) hν, MeOH, 1.5 h; (e) 10% Pd/C, CH3CO2H,
80 °C, 3 h, 28% from 38.
was completely consumed, but no desired amine 14 could
be obtained. The amine 14 was best prepared by treating
trifluoroacetamide 7d with K2CO3 in MeOH-H2O (15:1)
at room temperature. This amine was then acylated with
carboxylic acid 11 in the presence of 1-(3-dimethylami-
nopropyl)-3-ethylcarbodiimide (EDC), DMAP, and 1-hy-
droxybenzotriazole (HOBt) to give amide 15 in 64% yield
(based on 7d ).
a
Oxidation of 15 with MCPBA (73%) followed by treat-
ment of the resulting sulfoxide 16 with trifluoroacetic
anhydride (TFAA) gave a Pummerer rearrangement
product 17. This compound, without purification, was
then treated with 10% aqueous NaOH in boiling MeOH
to give the target compound 20 in 45% yield (based on
16). Formation of 20 from 17 can be explained by a three-
step sequence of the reactions that involve alkaline
hydrolysis of trifluoroacetate 17, intramolecular aldol
condensation of the resulting aldehyde 18, and autoxi-
dation of the six-membered unsaturated lactam 19. It
should be noted that no specific oxidizing agent such as
DDQ was required in the final step. It is not clear at
present whether compound 20 was formed from 19 or
from its regioisomer with respect to the double bond.
Encouraged by the success of obtaining a model
compound 20 for MPK, we next examined the cyclization
of enamide 24 and the elaboration of the resulting
product 25 to MPK (Scheme 5).
Reagents and conditions: (a) aq NH4OH, room temperature,
5 days, 91%. (b) (PhS)2CHCHO, MgSO4, Et2O, room temperature,
10 h, 82%. (c) (CF3CO)2O, Et3N, CH2Cl2, room temperature, 30
min, 84%. (d) Bu3SnH, AIBN, benzene, reflux, 85%. (e) NaBH4,
EtOH, room temperature, 30 min. (f) 12, Et3N, CH2Cl2, room
temperature, 13 h, 75% from 25. (g) MCPBA, CH2Cl2, 0 °C, 72%.
(h) (1) (CF3CO)2O, CH2Cl2, 0 °C; (2) 10% NaOH, MeOH, reflux,
62% from 28 for 30, 5% from 28 for 31.
SCHEME 6
Synthesis of the requisite radical precursor 24 was
begun by amination of 2-bromo-3-(bromomethyl)quinoline
(21)13 with NH3 followed by condensation of the resulting
amine 224b with bis(phenylthio)acetaldehyde to give
enamine 23. Acylation of 23 with (CF3CO)2O gave 24 in
84% yield. Treatment of 24 with 5 equiv of Bu3SnH and
14. On the other hand, hydrolysis of 7c with 40% aqueous
KOH in boiling MeOH required a 43 h period of heating
to give 14 in 78% yield. Compound 7c was therefore
subjected to hydrogenolysis with a Willkinson’s catalyst
[RhCl(PPh3)3] in benzene11 or treated with trimethylsilyl
iodide in acetonitrile, whereupon the starting material
(11) It has been reported that catalytic hydrogenation of sulfur-
containing compounds such as allyl phenyl sulfide is effected with a
Willkinson catalyst in benzene. See: Birch, A. J .; Walker, K. A. M.
Tetrahedron Lett. 1967, 1935.
J . Org. Chem, Vol. 68, No. 21, 2003 7985

Kato et al.
dried (MgSO4). The solvent was evaporated off, and the residue
was chromatographed on silica gel (hexane/AcOEt, 6:1) to
AIBN gave the expected radical cyclzation product 25 in
85% yield. Deprotection of 25 with K2CO3 in aquoues
MeOH required a longer reaction time than 7d . Com-
pound 25 was treated with NaBH4 in EtOH for 30 min
to give amine 26. Acylation of 26 with acid chloride 12
gave amide 27 in 75% yield. Oxidation of 27 with MCPBA
gave sulfoxide 28 (72%), which was treated with
(CF3CO)2O and then with 10% NaOH to give tetracyclic
compound 30 in 62% yield along with a trace amount (5%
yield) of its oxidized compound 31. Unfortunately, no
expected MPK was obtained from 29.
The spectral data of compound 30 indicated it to be a
product in which CO was eliminated from MPK. Forma-
tion of 30 may be explained as follows. Alkaline hydroly-
sis of the Pummerer rearrangement product derived from
sulfoxide 28 gives aldehyde 29, whose hydrate 32 elimi-
nates HCO2H with the aid of a nitrogen atom of the
quinoline ring as shown in Scheme 6. Then the resulting
enamine 33 attacks the internal carbonyl group to give
34, whose elimination of water gives 30.
On the basis of these results, we envisioned that the
photochemical cyclization of enamide 38 would provide
the D ring of MPK. Compound 38 was prepared by
thermal elimination of benzenesulfenic acid of sulfoxide
37, which, in turn, was prepared from amine 26 by
acylation with unsaturated carboxylic acid 35 followed
by oxidation of the resulting amide 36 with MCPBA. The
thermal elimination of benzenesulfenic acid of sulfoxide
37 in boiling toluene in the presence of NaHCO3 gave an
unsatisfactory result, but the use of CaCO3 in place of
NaHCO3 gave 38 in 63% yield. Compound 38 was
irradiated with a low-pressure Hg lamp in a quartz tube,
and then the reaction mixture containing 39 was treated
with 10% Pd/C in acetic acid12 to give MPK (1) in 28%
yield with recovery of the starting material 38 (38%). The
melting point (235-237 °C) and spectral data of MPK
herein obtained were identical with the reported values
(mp 236-237 °C).4a Other attempts to synthesize MPK
(1) from 39 by treating with oxygen gas in MeOH, MnO2
in benzene, DDQ in benzene, and FeCl3 in MeOH failed.
1
give 5a (265 mg, 78%) as an oil: IR ν 1665 cm-1; H NMR δ
1.17 (t, J ) 7.3 Hz, 3H), 2.40 (q, J ) 7.3 Hz, 2H), 5.01 (s, 2H),
7.04-7.28 (m, 14H), 7.54 (d, J ) 7.9 Hz, 1H). Anal. Calcd for
C
24H22BrNOS2: C, 59.50; H, 4.58; N, 2.89. Found: C, 59.66;
H, 4.58; N, 2.91.
Eth yl N-(o-Br om oben zyl)-N-[2,2-bis(p h en ylth io)eth e-
n yl]ca r ba m a te (5b). Using a procedure similar to that
described above for 5a , enamine 4 (224 mg, 0.52 mmol) was
treated with ethoxycarbonyl chloride (170 mg, 1.56 mmol) in
the presence of N,N-diethylaniline (312 mg, 2.10 mmol) in
boiling benzene (10 mL) for 20 h. After workup, the crude
material was chromatographed on silica gel (hexane/AcOEt,
50:1 to 30:1) to give 5b (187 mg, 72%) as an oil: IR ν 1710
cm-1; 1H NMR δ 1.30 (t, J ) 7.0 Hz, 3H), 4.23 (q, J ) 7.0 Hz,
2H), 5.06 (s, 2H), 6.90-7.40 (m, 14H), 7.49 (d, J ) 7.9 Hz,
1H). Anal. Calcd for C24H22BrNO2S2: C, 57.60; H, 4.43; N, 2.80.
Found: C, 57.32; H, 4.41; N, 3.00.
Ben zyl N-(o-Br om oben zyl)-N-[2,2-bis(p h en ylth io)eth e-
n yl]ca r ba m a te (5c). Using a procedure similar to that
described above for 5a , enamine 4 (208 mg, 0.49 mmol) was
treated with benzyloxycarbonyl chloride (248 mg, 1.46 mmol)
in the presence of N,N-diethylaniline (290 mg, 1.94 mmol) in
boiling benzene (10 mL) for 20 h. After workup, the crude
material was chromatographed on silica gel (hexane/AcOEt,
50:1 to 30:1) to give 5c (187 mg, 72%) as an oil: IR ν 1710
cm-1; 1H NMR δ 5.08 (s, 2H), 5.24 (s, 2H), 6.95-7.35 (m, 19H),
7.51 (d, J ) 7.9 Hz, 1H). Anal. Calcd for C29H24BrNO2S2: C,
61.92; H, 4.30; N, 2.49. Found: C, 61.80; H, 4.41; N, 2.46.
N-(o-Br om oben zyl)-N-[2,2-bis(p h en ylth io)eth en yl]tr i-
flu or oa ceta m id e (5d ). To a solution of enamine 4 (946 mg,
2.21 mmol) and Et3N (671 mg, 6.63 mmol) in toluene (10
mL) was added (CF3CO)2O (928 mg, 4.42 mmol) at 0 °C, and
the mixture was stirred at room temperature for 1 h. After
workup, the crude material was chromatographed on silica gel
(hexane/AcOEt, 10:1) to give 5d (1.06 g, 92%) as an oil: IR ν
1705 cm-1; 1H NMR δ 5.06 (s, 2H), 6.48 (s, 1H), 7.03-7.34 (m,
13H), 7.59 (d, J ) 7.6 Hz, 1H). Anal. Calcd for C23H17BrF3-
NOS2: C, 52.68; H, 3.27; N, 2.67. Found: C, 52.44; H, 3.26;
N, 2.53.
Ra d ica l Cycliza tion of 5a w ith 1.1 Equ iv of Bu 3Sn H.
Gen er a l P r oced u r e. To a boiling solution of 5a (212 mg, 0.45
mmol) in benzene (60 mL) was added dropwise a solution of
Bu3SnH (144 mg, 0.495 mmol) and AIBN (14.8 mg, 0.09 mmol)
in benzene (60 mL) via syringe over a period of 3 h, and the
mixture was further heated under reflux for 4 h. After
evaporation of the solvent, Et2O (50 mL) and 8% aqueous KF
(20 mL) were added to the residue, and the whole was
vigorously stirred at room temperature for 1 h. The organic
phase was separated and the aqueous layer was further
extracted with Et2O. The combined organic phase was dried
(MgSO4) and concentrated, and the residue was chromato-
graphed on silica gel (hexane/AcOEt, 3:1). The first fraction
gave 1-bis(phenylthio)methyl-2-propionyldihydroisoindole (6a )
Exp er im en ta l Section
N-(o-Br om oben zyl)-N-[2,2-bis(p h en ylth io)eth en yl]p r o-
p a n a m id e (5a ). To a solution of o-bromobenzylamine (1.29
g, 6.91 mmol) in Et2O (10 mL) were added bis(phenylthio)-
acetaldehyde7 (1.50 g, 5.76 mmol) and MgSO4 (2 g), and the
mixture was stirred at room temperature for 15 h. MgSO4 was
removed by filtration; the filtrate was concentrated, and the
residue was chromatographed on silica gel (hexane/AcOEt, 16:
1) to give enamine 4 (2.39 g, 97%) as an oil: 1H NMR δ 4.41
(d, J ) 6.3 Hz, 2H), 5.48-5.62 (m, 1H), 7.07-7.32 (m, 14H),
7.56 (d, J ) 7.9 Hz, 1H). This enamine was used immediately
in the next step. Propionyl chloride (260 mg, 2.81 mmol) was
added to a boiling solution of enamine 4 (300 mg, 0.70 mmol)
and N,N-diethylaniline (524 mg, 3.51 mmol) in benzene (15
mL), and the mixture was further heated under reflux for 2.5
h. After the mixture was cooled, water (15 mL) was added and
the organic phase was separated. The aqueous phase was
further extracted with AcOEt, and the combined organic phase
was washed successively with a saturated aqueous NaHCO3
solution, a saturated aqueous NH4Cl solution, and brine and
1
(69 mg, 38%): mp 122-124 °C (hexane); IR ν 1640 cm-1; H
NMR δ 1.12 (t, J ) 7.3 Hz, 3H), 2.02-2.36 (m, 2H), 4.68 (d, J
) 13.5 Hz, 1H), 4.83 (d, J ) 13.5 Hz, 1H), 5.78 (s, 2H), 7.10-
7.40 (m, 12H), 7.66 (d, J ) 7.3 Hz, 1H), 7.88 (d, J ) 6.6 Hz,
1H). Anal. Calcd for C24H23NOS2: C, 71.08; H, 5.72; N, 3.45.
Found: C, 71.04; H, 5.75; N, 3.37. The second fraction gave
1-phenylthiomethyl-2-propionyldihydroisoindole (7a ) (36 mg,
27%) as an oil: IR ν 1645 cm-1; 1H NMR δ 1.08 (t, J ) 7.3 Hz,
3H), 1.99 (dq, J ) 16.2, 7.6 Hz, 1H), 2.22 (dq, J ) 16.2, 7.6
Hz, 1H), 3.50 (dd, J ) 13.9, 2.5 Hz, 1H), 3.85 (dd, J ) 13.9,
5.6 Hz, 1H), 4.67 (s, 2 H), 5.59 (dd, J ) 5.6, 2.5 Hz, 1H), 7.08-
7.36 (m, 9H); 13C NMR δ 9.0, 28.1, 38.0, 53.3, 62.6, 122.7, 123.7,
126.2, 128.1, 128.5, 129.1, 129.4, 136.8, 137.2, 139.4, 173.1;
HRMS calcd for C18H19NOS (M+) 297.1187, found 297.1183.
(12) Nakamichi, N.; Kawashita, Y.; Hayashi, M. Org. Lett. 2002, 4,
3955. For a similar reaction, see: ref 4b.
(13) Comins, D. L.; Baevsky, M. F.; Hong, H. J . Am. Chem. Soc.
1992, 114, 10971.
Ra d ica l Cycliza tion of 5a w ith 5 Equ iv of Bu 3Sn H.
Following the general procedure, a solution of 5a (120 mg, 0.25
mmol) in boiling benzene (30 mL) was treated with a solution
7986 J . Org. Chem., Vol. 68, No. 21, 2003

Total Synthesis of Mappicine Ketone
of Bu3SnH (361 mg, 1.24 mmol) and AIBN (20 mg, 0.12 mmol)
in benzene (50 mL). After workup, the crude material was
chromatographed on silica gel (hexane/AcOEt, 2:1) to give 7a
(51 mg, 69%).
2-(2-Meth yl-4-oxoh exa n oyl)-1-(ph en ylth iom eth yl)d ih y-
d r oisoin ole (15). A mixture of 7d (50.0 mg, 1.15 mmol) and
K2CO3 (50 mg) in MeOH/H2O (15:1) (1.6 mL) was stirred at
room temperature for 6 h. After removal of MeOH, water was
added to the residue and the whole was extracted with CHCl3.
The organic phase was washed with brine, dried (MgSO4), and
concentrated. The residue containing 1-(phenylthiomethyl)-
dihydroisoindole (14) was dissolved in CH2Cl2 (2 mL), and to
this solution were added carboxylic acid 11 (43 mg, 0.297
mmol), EDC (57 mg, 0.287 mmol), and HOBt (40 mg, 0.297
mmol). The mixture was stirred at room temperature for 1.5
h; water was added to the reaction mixture, and the whole
was extracted with AcOEt. The organic phase was washed
successively with 1 N HCl, 1 N NaOH, and brine, dried
(MgSO4), and concentrated. The residue was chromatographed
on silica gel (hexane/AcOEt, 5:1) to give 15 (35 mg, 64%) as
Ra d ica l Cycliza tion of 5b. Following the general proce-
dure, a solution of 5b (193 mg, 0.39 mmol) in boiling benzene
(40 mL) was treated with a solution of Bu3SnH (560 mg, 1.93
mmol) and AIBN (32 mg, 0.19 mmol) in benzene (40 mL). After
workup, the crude material was chromatographed on silica gel
(hexane/AcOEt, 8:1) to give 2-ethoxycarbonyl-1-(phenylthiom-
ethyl)dihydroisoindole (7b) (101 mg, 84%) as an oil: IR ν 1690
cm-1 1H NMR δ 1.23-1.32 (m, 3H), 3.33 (dd, J ) 13.5, 7.3
;
Hz, 3/7H), 3.52-3.72 (m, 1H + 4/7H), 4.01-4.20 (m, 2H), 4.57-
4.83 (m, 2H), 5.25 (m, 3/7H), 5.38 (m, 4/7H), 7.09-7.43 (m,
9H). Anal. Calcd for C18H19NO2S: C, 68.98; H, 6.11 N, 4.47.
Found: C, 68.93; H, 6.22; N, 4.22.
1
an oil: IR ν 1710, 1640 cm-1; H NMR δ 0.89-1.40 (m, 6H),
Ra d ica l Cycliza tion of 5c. Following the general proce-
dure, a solution of 5c (329 mg, 0.59 mmol) in boiling benzene
(60 mL) was treated with a solution of Bu3SnH (853 mg, 2.93
mmol) and AIBN (48 mg, 0.29 mmol) in benzene (60 mL). After
workup, the crude material was chromatographed on silica gel
(hexane/AcOEt, 10:1) to give 2-benzyloxycarbonyl-1-(phenylth-
iomethyl)dihydroisoindole (7c) (375 mg, 68%) as an oil: IR ν
2.42-2.52 (m, 3H), 2.84-3.13 (m, 2H), 3.32-3.72 (m, 2H),
4.80-5.18 (m, 2H), 5.49 (br d, J ) 6.9 Hz, 2/3 H), 5.59 (m,
1/3H), 7.10-7.43 (m, 9H); 13C NMR δ 8.0 (8.1), 17.3 (17.5), 33.6
(33.8), 36.3 (36.5), 37.4 (38.6), 46.4 (46.7), 53.0 (53.5), 62.2
(62.6), 122.7 (127.9), 123.6 (128.0), 124.2 (128.5), 125.9 (129.1),
129.2 (129.5), 136.9 (136.9), 139.1 (139.8), 175.9 (175.5), 210.4
(210.9) (the values in parentheses are probably due to the
diasteroisomer); HRMS calcd for C22H25NO2S (M+) 367.1606,
found 367.1602.
2-(2-Meth yl-4-oxoh exa n oyl)-1-(p h en ylsu lfin ylm eth yl)-
d ih yd r oisoin d ole (16). To a solution of 15 (17 mg, 0.046
mmol) in CH2Cl2 (5 mL) was added dropwise a solution of
MCPBA (9.6 mg, 0.056 mmol) in CH2Cl2 (5 mL) at 0 °C over
a period of 30 min. An aqueous Na2S2O3 solution (5 mL) was
added to the reaction mixture, and the whole was extracted
with CHCl3. The extract was washed successively with a
saturated aqueous NaHCO3 solution and brine, dried (MgSO4),
and concentrated. The residue was chromatographed on silica
gel (hexane/AcOEt, 1:5) to give 16 (13 mg, 73%): 1H NMR δ
0.99-1.29 (m, 6H), 2.42-2.58 (m, 3H), 3.06-3.19 (m, 2H),
3.34-3.74 (m, 2H), 4.86-5.30 (m, 2H), 5.61 (brd, 1/2H), 5.79
(brd, 1/2H), 7.28-7.70 (m, 9H). This compound was used
immediately in the next step.
1
1700 cm-1; H NMR δ 3.30 (dd, J ) 13.7, 7.1 Hz, 1/3H), 3.52
(dd, J ) 13.5, 2.6 Hz, 1/3H), 3.56 (dd, J ) 13.7, 2.8 Hz, 2/3H),
3.68 (dd, J ) 13.9, 5.9 Hz, 2/3H), 4.64 (d, J ) 14.5 Hz, 1/3H),
4.69 (d, J ) 14.8 Hz, 1/3H), 4.73 (d, J ) 14.5 Hz, 2/3H), 4.82
(d, J ) 14.8 Hz, 2/3H), 5.00 (d, J ) 12.5 Hz, 2/3H), 5.13 (s,
2/3H), 5.15 (d, J ) 12.2 Hz, 2/3H), 5.24 (br d, J ) 6.9 Hz, 1/3H),
5.38 (m, 2/3H), 7.09-7.32 (m, 14H). Anal. Calcd for C23H21
-
NO2S: C, 73.57; H, 5.64; N, 3.73. Found: C, 73.49; H, 5.71;
N, 3.71.
Ra d ica l Cycliza tion of 5d . Following the general proce-
dure, a solution of 5d (289 mg, 0.553 mmol) in boilng benzene
(60 mL) was treated with a solution of Bu3SnH (804 mg, 2.76
mmol) and AIBN (45 mg, 0.286 mmol) in benzene (60 mL).
After workup, the crude material was chromatographed on
silica gel (hexane/AcOEt, 15:1) to give 1-phenylthiomethyl-2-
(trifluoroacetyl)dihydroisoindole (7d ) (159 mg, 85%) as an oil:
IR ν 1690 cm-1 1H NMR δ 3.55 (dd, J ) 14.2, 2.6 Hz, 1H),
;
4,6-Dih yd r o-3-m eth yl-2-p r op a n oylisoin d olo[1,2-a ]p y-
r id in -4-on e (20). To a solution of sufloxide 16 (10 mg, 0.026
mmol) in CH2Cl2 (5 mL) was added (CF3CO)2O (78 mg, 0.37
mmol) at 0 °C, and the mixture was stirred at the same
temperature for 3 h. The reaction mixture was concentrated;
MeOH (2 mL) and 10% NaOH (0.2 mL) were added to the
residue, and the mixture was heated under reflux for 30 min.
Water was added to the reaction mixture, and the whole was
extracted with CHCl3. The organic phase was washed with
brine, dried (MgSO4), and concentrated. The residue was
chromatographed on silica gel (hexane/AcOEt, 1:1 to 1:2) to
give 20 (3 mg, 45%): IR ν 1705, 1655 cm-1; 1H NMR δ 1.23 (t,
J ) 7.3 Hz, 3H), 2.23 (s, 3H), 2.85 (q, J ) 7.3 Hz, 2H), 5.14 (s,
3.73 (dd, J ) 14.2, 5.9 Hz, 1H), 4.92 (d, J ) 13.9 Hz, 1H), 4.98
(d, J ) 13.9 Hz, 1H), 5.65 (dd, J ) 5.9, 2.6 Hz, 1H), 7.12-7.37
(m, 9H). Anal. Calcd for C17H14F3NOS: C, 60.53; H, 4.18; N,
4.15. Found: C, 60.60; H, 4.24; N, 4.15.
2-Meth yl-4-oxoh exa n oic Acid (11). A mixture of methyl
3-oxopentanoate (6.51 g, 50 mmol), methyl 2-bromopropionate
(7.55 g, 50 mmol), K2CO3 (35.0 g), and tetrabutylammonium
iodide (3.70 g, 10 mmol) in acetone (200 mL) was stirred
vigorously at room temperature for 3 h. Inorganic materials
were filtered off; the solvent was evaporated off, and AcOEt
was added to the residue. The organic phase was washed
successively with water and brine, dried (MgSO4), and con-
centrated. The residue was chromatographed on silica gel
(hexane/AcOEt, 8:1) to give alkylation product (9.90 g, 92%).
This compound was dissolved in a mixed solvent of AcOH (100
mL), concentrated HCl (50 mL), and water (25 mL), and the
mixture was heated under reflux for 4 h. AcOH was removed
by evaporation; water was added to the residue, and the whole
was extracted with Et2O. The organic phase was dried
(MgSO4), and the solvent was evaporated off to give carboxylic
2H), 6.64 (s, 1H), 7.45-7.78 (m, 4H); HRMS calcd for C16H15
-
NO2 (M+) 253.1103, found 253.1106.
(2-Br om oqu in olin -3-yl)m eth yla m in e (22). A solution of
2-bromo-3-(bromomethyl)quinoline (21)13 (500 mg, 1.67 mmol)
in 28% aqueous NH4OH (150 mL) was stirred at room
temperature for 5 days. The reaction mixture was extracted
with CHCl3, and the extract was washed with brine, dried
(NaOH), and concentrated to give amine 224b (360 mg, 91%):
acid 11 (5.87 g, 89%) as an oil: IR ν 1715 cm-1 1H NMR δ
;
1.06 (t, J ) 7.3 Hz, 3H), 1.22 (d, J ) 6.9 Hz, 3H), 2.41-2.52
(m, 3H), 2.84-3.06 (m, 2H), 9.8-10.6 (br, 1H). Anal. Calcd for
C7H12O3: C, 58.32; H, 8.39. Found: C, 58.17; H, 8.41.
2-Meth yl-4-oxoh exa n oyl Ch lor id e (12). To a solution of
carboxylic acid 11 (1.0 g, 6.94 mmol) and pyridine (1.1 g, 13.9
mmol) in benzene (1 mL) was added oxalyl chloride (2.63 g,
20. 8 mmol), and the mixture was stirred at room temperature
for 1 h. After the solvent was evaporated off, Et2O was added
to the residue, and the precipitated salts were removed by
filtration. The solvent was evaporated off to give acid chloride
12 (1.12 g, quant.).
1
mp 134-136 °C (Et2O) (mp was not indicated in ref 4a); H
NMR δ 1.64 (s, 2H), 4.08 (s, 2H), 7.57 (t, J ) 6.9 Hz, 1H), 7.71
(t, J ) 6.9 Hz, 1H), 7.82 (d, J ) 8.3 Hz, 1H), 8.04 (d, J ) 8.3
Hz, 1H), 8.15 (s, 1H); 13C NMR δ 46.3, 127.7, 127.9, 128.1,
128.7, 130.4, 136.1, 136.7, 144.0, 147.8.
N -(2-Br om oq u in olin -3-yl)m e t h yl-N -[2,2-b is(p h e n yl-
th io)eth en yl]a m in e (23). A mixture of amine 22 (342 mg,
1.45 mmol), bis(phenylthio)acetaldehyde7 (415 mg, 1.59 mmol),
and MgSO4 (2 g) in Et2O (10 mL) was stirred at room
temperature for 10 h. MgSO4 was removed by filtration; the
filtrate was concentrated, and the residue was chromato-
J . Org. Chem, Vol. 68, No. 21, 2003 7987

Kato et al.
graphed on silica gel (hexane/AcOEt, 16:1 to 6:1) to give
enamine 23 (565 mg, 82%) as an oil: 1H NMR δ 4.56 (d, J )
5.9 Hz, 2H), 5.55-5.70 (m, 1H), 7.10-7.39 (m, 11H), 7.55-
7.65 (m, 1H), 7.70-7.78 (m, 2H), 7.90 (s, 1H), 8.06 (d, J ) 9.3
Hz, 1H). This compound was used immediately in the next
step.
graphed on silica gel (AcOEt) to give 28 (12 mg, 72%): 1H NMR
δ 0.93-1.14 (m, 3H), 1.19-1.37 (m, 3H), 2.35-2.64 (m, 3H),
3.12-3.36 (m, 2H), 3.46-3.74 (m, 1H), 3.83-4.07 (m, 1H),
5.06-5.54 (m, 2H), 5.70-5.80 (m, 1H), 7.35-7.47 (m, 3H),
7.51-7.61 (m, 3H), 7.67-7.88 (m, 2H), 7.98-8.12 (m, 2H). This
compound was used immediately in the next step.
N -(2-Br om oq u in olin -3-yl)m e t h yl-N -[2,2-b is(p h e n yl-
th io)eth en yl]tr iflu or oa ceta m id e (24). To a solution of
enamine 23 (296 mg, 0.62 mmol) and Et3N (188 mg, 1.86
mmol) in CH2Cl2 (10 mL) was added (CF3CO)2O (260 mg, 1.24
mmol) at 0 °C, and the mixture was stirred at room temper-
ature for 30 min. After workup as described above for 5a , the
crude material was chromatographed on silica gel (hexane/
6-Eth yl-7,8-dih ydr o-8-m eth yl-11H-in dolidin o[1,2-b]qu in -
olin -9-on e (30) a n d 6-Eth yl-8-m eth yl-11H-in d olid in o[1,2-
b]qu in olin -9-on e (31). To a solution of 28 (27 mg, 0.062
mmol) in CH2Cl2 (5 mL) was added (CF3CO)2O (130 mg, 0.62
mmol) at 0 °C, and the mixture was stirred at the same
temperature for 2 h. A saturated aqueous NaHCO3 solution
(1 mL), 10% NaOH (0.5 mL), and MeOH (5 mL) were added
to the mixture, and the reaction mixture was heated under
reflux for 15 min. Water was added to the reaction mixture,
and the whole was extracted with CHCl3. The organic phase
was washed with brine, dried (MgSO4), and concentrated. The
residue was chromatographed on silica gel (hexane/AcOEt, 4:1
to 1:1). The first fraction gave 30 (11 mg, 62%): IR ν 1650
cm-1; 1H NMR δ 1.20 (t, J ) 7.6 Hz, 3 H), 1.31 (d, J ) 6.8 Hz,
3H), 2.37 (dd, J ) 19.0, 12.2 Hz, 1H), 2.6-2.9 (m, 2H), 3.11
(dq, J ) 15.1, 7.3 Hz, 1H), 3.28 (dq, J ) 14.7, 7.3 Hz, 1H),
4.92 (d, J ) 17.6 Hz, 1H), 4.97 (d, J ) 17.6 Hz, 1H), 7.51 (ddd,
J ) 7.8, 6.8, 1.0 Hz, 1H), 7.68 (ddd, J ) 8.3, 6.8, 1.5 Hz, 1H),
7.77 (br d, J ) 8.3 Hz, 1H), 8.02 (s, 1H), 8.08 (d, J ) 8.8 Hz,
1H); HRMS calcd for C18H18N2O (M+) 278.1419, found 278.1416.
The second fraction gave 31 (0.8 mg, 5%): IR ν 1720, 1580
cm-1; 1H NMR δ 1.34 (t, J ) 7.6 Hz, 3H), 2.31 (s, 3H), 3.41 (q,
J ) 7.5 Hz, 2H), 5.24 (s, 2H), 7.42 (s, 1H), 7.60 (br d, J ) 8.0
Hz, 1H), 7.76 (br t, J ) 8.0 Hz, 1H), 7.88 (br d, J ) 8.3 Hz,
1H), 8.19 (d, J ) 8.8 Hz, 1H), 8.28 (s, 1H); HRMS calcd for
AcOEt, 8:1) to give 24 (299 mg, 84%) as an oil: IR ν 1700 cm-1
;
1H NMR δ 5.17 (s, 2H), 6.56 (s, 1H), 7.03-7.23 (m, 10H), 7.61
(t, J ) 6.9 Hz, 1H), 7.72-7.83 (m, 2H), 8.06 (d, J ) 8.6 Hz,
1H), 8.11 (s, 1H); 13C NMR δ 52.2, 118.7, 125.2, 125.4, 127.1,
127.1, 127.5, 128.0, 128.1, 128.2, 128.8, 129.0, 129.2, 129.3,
129.5, 131.0, 131.0, 133.0, 133.9, 136.4, 139.3, 148.4; HRMS
calcd for C26H1879BrF3N2OS2 (M+) 573.9996, found 573.9991.
7-Tr iflu or oa cet yl-6,8-d ih yd r o-6-(p h en ylt h iom et h yl)-
p yr r olo[3,4-b]qu in olin e (25). Following the general proce-
dure, a solution of 24 (130 mg, 0.226 mmol) in boiling benzene
(50 mL) was treated with a solution of Bu3SnH (330 mg, 1.13
mmol) and AIBN (19 mg, 0.113 mmol) in benzene (30 mL).
After the usual workup, the crude material was chromato-
graphed on silica gel (hexane/AcOEt, 6:1) to give 25 (159 mg,
1
85%): mp 134-136 °C (hexane); IR ν 1695 cm-1; H NMR δ
3.82 (dd, J ) 14.5, 2.3 Hz, 1H), 4.25 (dd, J ) 14.5, 4.1 Hz,
1H), 5.06 (d, J ) 14.9 Hz, 1H), 5.15 (d, J ) 14.9 Hz, 1H), 5.77
(dd, J ) 4.1, 2.3 Hz, 1H), 6.85-7.13 (m, 5H), 7.56 (t, J ) 6.9
Hz, 1H), 7.71 (t, J ) 6.9 Hz, 1H), 7.80 (d, J ) 7.9 Hz, 1H),
7.98 (s, 1H), 7.99 (d, J ) 9.2 Hz, 1H); 13C NMR δ 36.9, 51.8,
65.4, 126.8, 127.4, 128.2, 128.9, 129.6, 130.0, 130.1, 130.3,
135.3, 148.9, 158.8. Anal. Calcd for C20H15F3N2OS: C, 61.85;
H, 3.89; N, 7.21. Found: C, 62.00; H, 3.92; N, 7.21.
C
18H16N2O (M+) 276.1263, found 276.1263.
2-Meth yl-4-oxoh ex-2-en oic Acid (35). LiOH (1.94 g, 46.2
mmol) was added to a solution of methyl (E)-2-methyl-4-oxo-
2-hexenate (3.6 g, 23.1 mmol) in MeOH/H2O (2:1, 60 mL), and
the mixture was stirred at 0 °C for 2 h. The reaction mixture
was acidified with 10% HCl to pH 1-2, and the whole was
extracted with CHCl3. The organic phase was washed with
brine, dried (MgSO4), and concentrated. The residue was
chromatographed on silica gel (CHCl3/MeOH, 30:1) to give 35
(3.07 g, 94%) as an oil: 1H NMR δ 1.13 (t, J ) 7.3 Hz, 3H),
2.22 (d, J ) 1.7 Hz, 3H), 2.62 (q, J ) 7.3 Hz, 2H), 7.20 (q, J )
1.3 Hz, 1H), 10.00-12.00 (br, 1H); 13C NMR δ 8.1, 14.4, 38.5,
134.3, 139.7, 173.5, 202.8. Anal. Calcd for C7H10O3: C, 59.14;
H, 7.09. Found: C, 58.81; H, 7.16.
7-(2-Me t h yl-4-oxoh e xa n oyl)-6,8-d ih yd r o-6-(p h e n yl-
th iom eth yl)p yr r olo[3,4-b]qu in olin e (27). To a solution of
25 (285 mg, 0.735 mmol) in EtOH (50 mL) was added NaBH4
(55.6 mg, 1.47 mml) by portions, and the mixture was stirred
at room temperature for 30 min. EtOH was evaporated off;
water was added to the residue, and the whole was extracted
with CHCl3. The organic phase was washed with brine, dried
(MgSO4), and concentrated. The residue containing amine 26
was dissolved in CH2Cl2 (2 mL), and to the solution were added
Et3N (372 mg, 3.68 mmol) and acid chloride 12 (357 mg, 2.21
mmol). The mixture was stirred at room temperature for 13
h; water was added to the reaction mixture, and the whole
was extracted with CHCl3. The extract was washed succes-
sively with a saturated aqueous NaHCO3 solution and brine,
dried (MgSO4), and concentrated. The residue was chromato-
graphed on silica gel (hexane/AcOEt, 1:1) to give 27 (230 mg,
7-(2-Met h yl-4-oxoh ex-2-en oyl)-6,8-d ih yd r o-6-(p h en yl-
th iolm eth yl)p yr r olo[3,4-b]qu in olin e (36). According to a
procedure similar to that dscribed above for 27, amine 26 was
obtained from compound 25 (514.6 mg, 1.33 mmol) by reduc-
tion with NaBH4 (100.2 mg, 2.65 mmol) in EtOH (100 mL). A
solution containing the crude amine 26, EDC (506.7 mg, 2.65
mmol), and 35 in CH2Cl2 (15 mL) was stirred at room
temperature for 16 h. Water was added, and the whole was
extracted with CHCl3. The organic phase was washed succes-
sively with a saturated NaHCO3 solution and brine, dried
(MgSO4), and concentrated. The residue was chromatographed
on silica gel (hexane/AcOEt, 3:2) to give 36 (415.1 mg, 75%):
1
75%): IR ν 1710, 1645 cm-1; H NMR δ 0.98-1.25 (m, 3H),
2.34-2.53 (m, 2H + 4/5H), 2.75 (dd, J ) 17.8, 6.6 Hz, 1/5H),
3.12-3.25 (m, 2H), 3.71 (dd, J ) 13.9, 4.6 Hz, 1/5H), 3.81 (dd,
J ) 13.9, 2.0 Hz, 2/5H), 3.86 (dd, J ) 13.9, 2.0 Hz, 2/5H), 4.01-
4.05 (m, 1/5H), 4.17 (dd, J ) 13.9, 8.9 Hz, 2/5H), 4.19 (dd, J )
13.9, 7.9 Hz, 2/5H), 4.84 (d, J ) 16.8 Hz, 1/5H), 5.03 (br d, J
) 14.2 Hz, 4/5H), 5.19 (d, J ) 16.8 Hz, 1/5H), 5.22 (d, J )
14.2 Hz, 2/5H), 5.38 (d, J ) 14.5 Hz, 2/5H), 5.69 (m, 4/5H),
6.02 (m, 1/5H), 6.80-6.93 (m, 3H), 7.02-7.07 (m, 2H), 7.51
(br t, J ) 7.4 Hz, 1H), 7.66 (br t, J ) 7.8 Hz, 1H), 7.77 (d, J )
7.9 Hz, 1H), 7.94 (br s, 2H); HRMS calcd for C25H26N2O2S (M+)
418.1715, found 418.1697.
1
mp 162-163 °C (hexane/AcOEt); IR ν 1695 cm-1; H NMR δ
1.09 (t, J ) 7.3 Hz, 3H), 2.23 (s, 3H), 2.46 (q, J ) 7.3 Hz, 2H),
3.82 (dd, J ) 14.5, 1.7 Hz, 1H), 4.30 (dd, J ) 14.5, 4.0 Hz,
1H), 4.80 (d, J ) 14.8 Hz, 1H), 4.88 (d, J ) 14.8 Hz, 1H), 5.75
(s, 1H), 5.79 (br s, 1H), 6.97-7.20 (m, 5H), 7.54 (br t, J ) 7.6
Hz, 1H), 7.71 (br t, J ) 7.6 Hz, 1H), 7.80 (br d, J ) 7.9 Hz,
1H), 7.93 (s, 1H), 8.03 (d, J ) 8.3 Hz, 1H); 13C NMR δ 8.2,
16.5, 37.3, 38.3, 53.2, 63.5, 125.9, 126.3, 127.2, 128.0, 128.2,
129.1, 129.2, 129.5, 130.0, 130.1, 130.9, 136.5, 147.7, 148.8,
160.5, 171.2, 202.1. Anal. Calcd for C25H24N2O2S: C, 72.09;
H, 5.81; N, 6.73. Found: C, 72.16; H, 5.88; N, 6.66.
7-(2-Meth yl-4-oxoh exan oyl)-6,8-dih ydr o-6-(ph en ylsu lfi-
n ylm eth yl)p yr r olo[3,4-b]qu in olin e (28). A solution of 27
(16 mg, 0.038 mmol) in CH2Cl2 (2 mL) was added dropwise a
solution of MCPBA (80%) (9 mg, 0.041 mmol) in CH2Cl2 (2 mL)
at 0 °C over a period of 30 min. An aqueous Na2S2O3 solution
was added to the reaction mixture, and the whole was
extracted with CHCl3. The extract was washed with brine,
dried (MgSO4), and concenrated. The residue was chromato-
7-(2-Met h yl-4-oxoh ex-2-en oyl)-6,8-d ih yd r o-6-(p h en yl-
su lfin ylm eth yl)p yr r olo[3,4-b]qu in olin e (37). To a solution
of 36 (100 mg, 0.240 mmol) in CH2Cl2 (12 mL) was added
dropwise a solution of MCPBA (56.9 mg, 0.264 mmol) in
7988 J . Org. Chem., Vol. 68, No. 21, 2003

Total Synthesis of Mappicine Ketone
CH2Cl2 (12 mL) at 0 °C over a period of 30 min. An aqueous
Na2S2O3 solution (15 mL) was added to the reaction mixture,
and the whole was extracted with CHCl3. The extract was
washed with brine, dried (MgSO4), and concenrated. The
residue was chromatographed on silica gel (hexane/AcOEt, 1:4)
Ma p p icin e Keton e (1). A solution of 38 (10.0 mg, 0.033
mmol) in MeOH (6.5 mL) was irradiated with a low-pressure
mercury lamp (20 w) in a quartz vessel at room temperature
for 1.5 h. The reaction mixture was concentrated, and the
residue was chromatographed on silica gel (hexane/AcOEt, 1:2)
to remove the starting material 38 (3.8 mg). The crude
cyclization product 39 was dissolved in acetic acid (2.0 mL)
containing 10% Pd/C (1.0 mg), and the mixture was heated at
80 °C for 3 h. Pd/C was filtered off using Celite; the filtrate
was poured into a saturated aqueous NaHCO3 solution, and
the whole was extracted with AcOEt. The organic phase was
washed with brine, dried (MgSO4), and concentrated, and the
residue was chromatographed on silica gel (hexane/AcOEt, 1:2)
to give 1 (2.8 mg, 28%): mp 235-237 °C (MeOH) (lit.4a mp
1
to give 37 (101.8 mg, 98%): IR ν 1695, 1645 cm-1; H NMR
for one diasteromer δ 1.15 (t, J ) 7.3 Hz, 3H), 2.46 (d, J ) 1.3
Hz, 3H), 2.62 (q, J ) 7.3 Hz, 2H), 3.72 (dd, J ) 13.5, 3.0 Hz,
1H), 3.97 (dd, J ) 13.5, 6.6 Hz, 1H), 5.00 (d, J ) 14.5 Hz, 1H),
5.26 (d, J ) 14.5 Hz, 1H), 5.84 (dd, J ) 6.6, 3.0 Hz, 1H), 6.54
(br s, 1H), 7.42-7.58 (m, 6H), 7.71 (t, J ) 6.9 Hz, 1H), 7.82 (d,
J ) 7.6 Hz, 1H), 8.00 (d, J ) 9.6 Hz, 1H), 8.04 (s, 1H); 1H
NMR for the other diasteromer δ 1.14 (t, J ) 7.3 Hz, 3H), 2.41
(d, J ) 1.7 Hz, 3H), 2.62 (q, J ) 7.3 Hz, 2H), 3.49 (dd, J )
13.7, 3.5 Hz, 1H), 4.08 (dd, J ) 13.5, 3.0 Hz, 1H), 4.94 (d, J )
15.5 Hz, 1H), 5.26 (d, J ) 14.5 Hz, 1H), 5.91 (br t, J ) 3.0 Hz,
1H), 6.63 (br s, 1H), 7.41-7.85 (m, 11H). These sulfoxides were
used immediately in the next step.
1
236-237 °C); IR ν 1710, 1655, 1600 cm-1; H NMR δ 1.25 (t,
J ) 7.3 Hz, 3H), 2.30 (s, 3H), 2.91 (q, J ) 7.3 Hz, 2H), 5.30 (s,
2H), 7.25 (s, 1H), 7.64 (t, J ) 7.3 Hz, 1H), 7.81 (t, J ) 7.3 Hz,
1H), 7.91 (d, J ) 8.3 Hz, 1H), 8.18 (d, J ) 8.6 Hz, 1H), 8.35 (s,
1H); 13C NMR δ 7.8, 13.7, 36.0, 50.2, 97.9, 127.1, 127.7, 128.0,
128.2, 128.6, 129.6, 130.5, 131.0, 143.4, 148.2, 148.8, 152.9,
161.8, 205.5; HRMS calcd for C19H16N2O2 (M+) 304.1212, found
304.1217.
7-(2-Me t h yl-4-oxoh e x-2-e n oyl)-6,8-d ih yd r o-6-m e t h -
ylen ep yr r olo[3,4-b]qu in olin e (38). A mixtue of CaCO3 (58
mg) in toluene (20 mL) was heated under reflux with a Dean-
Stark water separator to remove water for 2 h. To this mixture
was added a solution of 37 (50.0 mg, 0.16 mmol) in toluene (5
mL), and the mixture was further heated under reflux for 13
h. After the reaction mixture was cooled, CaCO3 was filtered
off and the filtrate was washed with brine, dried (MgSO4), and
concentrated. The residue was chromatographed on silica gel
Ack n ow led gm en t. This work was supported by a
Grant-in-Aid for Scientific Research from the Ministry
of Education, Science, Sports, Culture and Technology
of J apan and Hoh-ansha Foundation (J apan).
(hexane/AcOEt, 3:1) to give 38 (17.8 mg, 63%): IR ν 1750 cm-1
;
1H NMR δ 1.13 (t, J ) 7.3 Hz, 3H), 2.42 (s, 3H), 2.58 (q, J )
7.3 Hz, 2H), 5.02 (s, 2H), 6.03 (br s, 1H), 6.35 (s, 1H), 7.55 (t,
J ) 7.3 Hz, 1H), 7.73 (br t, J ) 7.3 Hz, 1H), 7.81 (d, J ) 8.3
Hz, 1H), 8.05 (s, 1H), 8.12 (d, J ) 9.2 Hz, 1H) (the signal for
1H was not detected); 13C NMR δ 7.7, 16.1, 37.9, 51.2, 125.6,
125.7, 126.5, 126.9, 127.8, 128.2, 129.6, 129.9, 130.0, 142.2,
148.0, 148.7, 154.4, 170.2, 201.6; HRMS calcd for C19H18N2O2
(M+) 306.1369, found 306.1371.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra for
7a , 15, 20, 24, 27, 30, 31, 38, and mappicine ketone (1) and
13C NMR spectra for 7a , 15, 24, 38, and mappicine ketone (1).
This material is available free of charge via the Internet at
http://pubs.acs.org.
J O030177M
J . Org. Chem, Vol. 68, No. 21, 2003 7989