Synthesis of (+/-) mappicine and mappicine ketone

Article abstract of DOI:10.1002/jhet.5570400407

Mappicine and mappicine ketone are camptothecin analogs of interest as antiviral agents. A novel synthesis of these compounds is described using a Friedlander condensation. The requisite ketone is prepared via a regioselective ortho-directed metallation/a

Full text of DOI:10.1002/jhet.5570400407

Jul-Aug 2003
601
Synthesis of (+/-) Mappicine and Mappicine Ketone
Kevin E. Henegar* and Ted A. Baughman
Chemical Research and Development, 1500-91-201, Pfizer, 7000 Portage Road, Kalamazoo, Michigan 49001
Received March 3, 2003
Mappicine and mappicine ketone are camptothecin analogs of interest as antiviral agents. A novel
synthesis of these compounds is described using a Friedlander condensation. The requisite ketone is
prepared via a regioselective ortho-directed metallation/alkylation of a trisubstituted pyridine. This is
condensed with N-t-butyloxycarbonyl-o-aminobenzaldehyde as a convenient, stable o-aminobenzaldehyde
equivalent in the Friedlander condensation.
J. Heterocyclic Chem., 40, 601(2003).
Mappicine is an analog of camptothecin originally iso-
benzyl bromide. The carbonylation reaction of the
chloropyridine 5 proceeded readily at 90 °C in a mixture
of DMF and n-propanol with atmospheric pressure CO
lated from Mapia Foetida [1]. The closely related map-
picine ketone (nothapodyne A) was isolated from
Nothapodytes foetida, and is of interest due the antiviral
properties of it and some of its analogs [2,3]. A number of
syntheses of mappicine and mappicine ketone have been
reported [4] and these two compounds are readily inter-
converted through oxidation and reduction. Both map-
picine ketone and mappicine have been prepared by degra-
dation of camptothecin [5,6].
in the presence of Pd(OAc) and 1,3-bis(diphenylphos-
2
phino)propane (DPPP) to give the ester 6. The
methoxypyridine was then converted to the pyridone 7
by demethylation with in situ generated trimethylsilyl
iodide (TMS-I) [8]. Reaction of the pyridone 7 with
Cs CO in DMSO under carefully defined conditions
2
3
yielded the cyclized keto ester 8, which according to
spectral data exists entirely in the enol form.
We report a total synthesis of mappicine and mappicine
ketone which was developed in conjunction with our work
on the synthesis of the camptothecin analog irinotecan [7].
The starting material for the synthesis is 1 (Scheme 1),
which is readily available and has been prepared on a ton
scale [7]. Deprotonation of 1 with n-BuLi in heptane
followed by reaction of the resultant anion with methyl
iodide proceeded poorly, presumably due to competitive
transmetallation between the alkyl iodide and the aryl
anion. However, reaction of the anion with dimethyl sul-
fate proceeded smoothly to give the methylated product 2
in 66 % yield after chromatography to remove unreacted
starting material and the small amount of the regioisomer
formed. Deketalization with trifluoroacetic acid cleanly
yielded the ketone 3, which was then reduced with sodium
borohydride to give the racemic alcohol 4. Due to time
constraints, enantioselective reduction of the ketone was
not examined but this compound should be a good sub-
strate for this type of reduction. To avoid the formation of
intermolecular esters in the subsequent palladium cat-
alyzed carbonylation, the alcohol 4 was then converted to
the benzyl ether 5 by reaction with sodium hydride and
Deesterification-decarboxylation of 8 under acidic
conditions yielded the tricyclic ketone 9 as a relatively
unstable gum or amorphous foam.
Friedlander condensations to give A-ring unsubsituted
quinolines have been reported with o-aminobenzaldehyde
or the Borsche imine [9]. o-Aminobenzaldehyde itself is
unstable and difficult to prepare and store [10], and the
preparation of the Borsche imine is troublesome [11]. We
found that N-BOC-o-aminobenzaldehyde 10 is an excellent
reactant in the Friedlander condensation. This material is
prepared without difficulty from N-BOC-aniline via an
orthometallation procedure [12] and is isolated as a stable
crystalline solid that can be stored for extended periods
without decomposition. Reaction of the ketone 9 with
N-BOC-o-aminobenzaldehyde 10 (Scheme 2) smoothly
gave O-benzyl mappicine 11 in 80% yield. The condensa-
tion can also be done directly with the ketoester 8 but this
reaction is not nearly as clean as with the ketone 9.
Debenzylation of 11 by catalytic hydrogenation over palla-
dium catalysts was sluggish. However, reaction of 11 with
BBr in the presence of tetra-n-butylammonium iodide as a
3
soluble iodide source proceeded rapidly to give mappicine

602
Vol. 40
K. E. Henegar and T. A. Baughman
6-Chloro-4-(2-ethyl-1,3-dioxolan-2-yl)-2-methoxy-3-methyl-
pyridine (2).
in 88 % yield [13]. Isolation of mappicine was complicated
by the poor solubility properties of this material. Oxidation
of mappicine to the ketone proceeded cleanly with Jones
reagent but the isolated yield was low. Oxidation with PCC
[4d] gave mappicine ketone in 62% yield.
Compound 1 (10.0 g, 41.0 mmol) was dissolved in 500 mL of
heptane. The solution was cooled to 0 °C and 24.4 mL of a
solution of n-BuLi in hexanes (51.2 mmol) was added while
maintaining reaction temperature at 0 °C. The bright-orange
slurry was stirred at 0 °C for 1.75 hours. Dimethyl sulfate
(4.8 mL, 51.2 mmol) was added keeping the temperature below
10 °C. The reaction was stirred at 0 °C for 2 hours, and then
1.5 mL of conc. ammonium hydroxide was added and the
mixture stirred for 1 hour. Water (40 mL) and EtOAc (75 mL)
were added. After 15 minutes, the phases were partitioned and
the aqueous extracted with EtOAc (3 x 50 mL). The organic
extracts were combined, dried over sodium sulfate, filtered, and
concentrated to a red oil. Chromatography on silica (methylene
chloride) gave 2 (6.97 g, 66%) as a clear, colorless oil, IR (film)
EXPERIMENTAL
Materials were used as received from commercial suppliers.
Melting points were determined on a Buchi automatic melting
point determination instrument. Infrared spectra were recorded,
as noted, in potassium bromide for solid samples (2 mg sam-
ple/200 mg potassium bromide) or as thin films for oils.
Microanalyses and high resolution mass spectra were performed
by Structural and Medicinal Chemistry (Pfizer). All silica used
was 230-400 mesh Merck silica 60.

Jul-Aug 2003
Synthesis of (+/-) Mappicine and Mappicine Ketone
603
1
1580, 1550, 1405, 1040 cm-1; H NMR (300.14 MHz, deuteri-
ochloroform): d 7.08 (s, 1H), 4.05-4.01 (m, 2H), 3.97 (s, 3H),
3.80-3.75 (m, 2H), 2.28 (s, 3H), 1.93 (dd, J = 7.4, 14.9 Hz, 2H),
0.91 (t, J = 7.4 Hz, 3H); 13C NMR (75.47 MHz, deuteriochloro-
form): d 162.9, 153.3, 144.9, 116.9, 114.4, 110.1, 64.5, 54.2,
chloride (3 x 20 mL). The organic phases were combined, dried
(sodium sulfate), filtered, and concentrated to a yellow oil.
Chromatography on silica (4:1 hexane/EtOAc) gave 5 (5.09 g,
90%) as a clear oil: IR (film) 1738, 1717, 1454, 1369, 1227 cm-1;
1H NMR (300.14 MHz, deuteriochloroform): d 7.38-7.32 (m,
5H), 7.07 (s, 1H), 4.53-4.46 (m, 2H), 4.26 (d, J = 11.7 Hz, 1H),
4.00 (s, 3H), 2.09 (s, 3H), 1.83-1.62 (m, 2H), 0.98 (t, J=7.3 Hz,
3H); 13C NMR (75.47 MHz, deuteriochloroform): d 162.0,
154.0, 145.6, 137.9, 128.4, 127.8, 127.7, 116.3, 113.8, 78.0, 71.0,
54.2, 29.5, 10.5, 10.1;MS (EI) m/z 305, 307; MS (CI) m/z (-
NH3+) 306, 308; HRMS calcd for C17H20NO2Cl; m/z 305.1183;
Found m/z 305.1166.
+
31.5, 12.0, 7.4;MS (EI) m/z 257, 259; MS (CI) m/z (-NH3 ) 258,
260; HRMS calcd for C12H16ClNO3; m/z 257.0818; Found m/z
257.0815.
Anal. Calcd. for C12H16ClNO3: C, 55.93; H, 6.26; N, 5.43.
Found: C, 55.77; H, 6.30; N, 5.45.
6-Chloro-2-methoxy-3-methyl-4-(1-oxopropyl)pyridine (3).
Compound 2 (12.0 g, 46 mmol) was dissolved in 25 mL of
aqueous TFA (64% v/v) and heated to 40 °C. After 4 hours, the
mixture was cooled and quenched with water (50 mL) and 2:1
EtOAc/heptane (75 mL). The phases were separated and the
aqueous phase extracted with 2:1 EtOAc/heptane (3 x 40 mL).
The organic extracts were combined and neutralized with 200 mL
of saturated aqueous sodium bicarbonate solution. The phases
were partitioned and the aqueous phase was extracted with
EtOAc (3 x 50 mL). The organic phases were combined, dried
(sodium sulfate), filtered, and concentrated under vacuum to give
9.9 g of 3 as a slightly yellow oil (99%), IR (film) 1706 cm-1; 1H
NMR (300.14 MHz, deuteriochloroform): d 6.88 (s, 1H), 3.99 (s,
3H), 2.82 (dd, J = 7.2, 14.5 Hz, 2H), 2.16 (s, 3H), 1.19 (t, J = 7.2
Hz, 3H); 13C NMR (75.47 MHz, deuteriochloroform): d 204.2,
162.6, 150.5, 145.5, 116.3, 113.0, 54.4, 35.9, 11.8, 7.6; MS (EI)
Anal. Calcd. for C17H20ClNO2: C, 66.77; H, 6.59; N, 4.58;Cl,
11.59. Found: C, 66.76; H, 6.58; N, 5.03; Cl, 11.56.
6-Methoxy-5-methyl-4-[1-(phenylmethoxy)propyl)pyridine-2-
carboxylic Acid, Propyl Ester (6).
Compound 5 (4.00 g, 13.1 mmol), potassium acetate (1.92 g,
19.6 mmol), palladium acetate (0.147 g, 0.65 mmol), and DPPP
(0.268 g, 0.65 mmol), were stirred with 80 mL of DMF and 40
mL of n-PrOH. The flask was purged with carbon monoxide and
then heated to 85 °C under carbon monoxide (15 PSI). After 25
hours the mixture was cooled to room temperature and purged
with nitrogen. The solution was filtered over celite and the filtrate
was concentrated and then partitioned between 80 mL of water
and 160 mL methyl t-butyl ether. The aqueous phase was
extracted with methyl t-butyl ether (3 x 50 mL). The organic
extracts were combined, washed with water (4 x 25 mL), dried
(sodium sulfate), filtered, and concentrated to a brown oil. The
oil was chromatographed on silica (methylene chloride) to give 6
(4.14 g, 89%) as a colorless oil, IR (film) 1717, 1739 cm-1; 1H
NMR (300.14 MHz, deuteriochloroform): d 7.88 (s, 1H), 7.38-
7.28 (m, 5H), 4.57-4.53 (m, 1H), 4.48 (d, J = 11.6 Hz, 1H), 4.36-
4.32 (m, 2H), 4.25 (d, J = 11.6 Hz, 1H), 4.09 (s, 3H), 2.18 (s, 3H),
1.90-1.80 (m, 3H), 1.78-1.64 (m, 1H), 1.06 (t, J = 7.4 Hz, 3H),
0.97 (t, J = 7.4 Hz, 3H); 13C NMR (75.47 MHz, deuteriochloro-
form): d 165.5, 162.3, 151.5, 142.8, 138.0, 128.3, 127.8, 127.7,
122.9, 116.5, 78.1, 70.9, 66.8, 53.8, 29.5, 22.0, 11.3, 10.4, 10.2;
MS (EI) m/z 358; MS (CI) m/z (-NH3+) 358, 360; HRMS calcd
for C21H27NO4; m/z 357.1940; Found m/z 357.1932.
+
m/z 213, 215; MS (CI) m/z (-NH3 ) 214, 216; HRMS calcd for
C10H12ClNO2; m/z 213.0556; Found m/z 213.0547.
Anal. Calcd. for C10H12ClNO2: C, 56.21; H, 5.66; N, 6.56.
Found: C, 56.30; H, 5.67; N, 6.43.
6-Chloro-4-[1-hydroxypropyl]-2-methoxy-5-methylpyridine (4).
Compound 3 (9.9 g, 46 mmol) was dissolved in 100 mL of
MeOH and cooled to 0°C. A freshly-prepared solution of 2.18 g of
sodium borohydride (58 mmol) in 20 mL of 50% aqueous MeOH
was added all at once. After 20 minutes, the reaction was quenched
with 50 mL of 1 M hydrochloric acid and then diluted with 100 mL
of methylene chloride and 10 mL of water. The phases were sepa-
rated and the aqueous phase was extracted with methylene chloride
(3 x 50 mL). The organic extracts were concentrated to a white
solid. The solid material was recrystallized from hexane to give 4
(8.54 g, 85%) as long needles, mp 97.0-97.5 °C; IR (film) 3127,
Anal. Calcd. for C21H27NO4: C, 70.56; H, 7.61; N, 3.92.
Found: C, 70.40; H, 7.62; N, 4.40.
1,6-Dihydro-5-methyl-6-oxo-4-[1-(phenylmethoxy)propyl]-2-
pyridinecarboxylic Acid, Propyl Ester (7).
-1 1
3224 cm ; H NMR (300.14 MHz, deuteriochloroform): d 7.05 (s,
1H), 4.85 - 4.81 (m, 1H), 3.95 (s, 3H), 2.08 (s, 3H), 1.76-1.63 (m,
2H), 0.98 (t, J = 7.4 Hz. 3H); 13C NMR (75.47 MHz, deuteriochlo-
roform):d 161.8, 155.6, 145.4, 115.0, 113.1, 71.0, 54.1, 30.4, 10.5,
A solution of sodium iodide (1.89 g, 12.6 mmol) and 6 (3.00 g,
8.4 mmol) in 30 mL of acetonitrile was cooled to 0° C and
trimethylsilyl chloride (1.6 mL, 12.6 mmol) was added. After 15
minutes the reaction mixture was allowed to warm to room tem-
perature. After 24 hours the reaction was quenched by adding
sequentially 4.2 mL of 6 M hydrochloric acid, 5.3 mL of satu-
rated aqueous sodium chloride solution, 10.6 mL of water, 0.4
mL of 38% aqueous sodium bisulfite solution, and 20 mL of
EtOAc. After stirring at room temperature for 30 minutes, the
phases were separated and the aqueous phase was extracted with
EtOAc (3 x 10 mL). The organic solutions were combined and
washed with 7 mL of saturated aqueous sodium bicarbonate solu-
tion containing 0.25 mL of 38% aqueous sodium bisulfite solu-
tion. After stirring for 15 minutes, the phases were separated and
the organic solution was washed with saturated aqueous sodium
chloride solution (2 x 10 mL). The solution was dried over
+
9.8; MS (EI)m/z 215, 217; MS (CI) m/z (-NH3 ) 216, 218;
Anal. Calcd. for C10H14NO2Cl: C, 55.69; H, 6.49; N, 6.49.
Found: C, 55.61; H, 6.55; N, 6.56.
6-Chloro-2-methoxy-3-methyl-4-[1-(phenylmethoxy)propyl]-
pyridine.(5).
A solution of 4 (4.00 g, 18.5 mmol) in 40 mL of THF was
stirred with sodium hydride (1.55 g, 64.6 mmol) for 30 minutes at
room temperature. Benzyl bromide (2.3 mL, 18.9 mmol) was
added and the mixture was stirred for 8 hours at room tempera-
ture. Saturated aqueous ammonium chloride solution (10 mL),
water (10 mL), and methylene chloride (20 mL) were added. The
phases were separated and the aqueous phase was adjusted to pH
7 with 1 M hydrochloric acid, then extracted with methylene

604
Vol. 40
K. E. Henegar and T. A. Baughman
sodium sulfate, then filtered and concentrated to give 2.80 g
(97%) of 7 as a waxy yellow-white solid, mp 91.0-92.0 °C; IR
(potassium bromide) 1721 cm-1 1H NMR (300.14 MHz,
;
uum to dryness. The residue was chromatographed on silica
(EtOAc) to give 0.51 g (80%) of 11 as a light tan solid, mp 175.0
°C; IR (potassium bromide) 1658, 1605 cm -1; 1H NMR (300.14
MHz, deuteriochloroform): d 8.33 (s, 1H), 8.22 (d, J = 8.5 Hz,
1H), 7.90 (d, J = 8.1 Hz, 1H), 7.80 (t, J = 7 Hz, 1H), 7.64-7.57 (m,
2H), 7.38 - 7.29 (m, 5H), 5.28 (s, 2H), 4.64-4.54 (m, 2H), 4.32 (d,
J = 12 Hz, 1H), 2.25 (s, 3H), 1.94-1.65 (m, 2H), 1.02 (t, J = 7.3
Hz, 3H); 13C NMR (75.47 MHz, deuteriochloroform): d 161.51,
153.51, 151.30, 148.78, 142.67, 138.12, 130.67, 130.12, 129.56,
128.64, 128.33, 127.98, 127.76, 127.60, 127.29, 126.87, 99.51,
78.18, 70.81, 49.91, 29.08, 11.99, 10.19; MS (CI) m/z 397;
HRMS calcd for C26H24N2O2 (M+H+); m/z 397.1917; Found m/z
397.1919.
deuteriochloroform): d 9.82 (br s), 7.39-7.29 (m, 6H), 4.51-4.46
(m, 1H), 4.35-4.26 (m, 2H), 2.14 (s, 3H), 1.87-1.75 (m, 3H),
1.71-1.57 (m, 1H), 1.05-0.95 (m, 6H); 13C NMR (75.47 MHz,
deuteriochloroform): d 162.42, 161.28, 150.41, 137.63, 133.04,
130.54, 128.40, 127.87, 108.01, 77.76, 71.13, 67.95, 28.80,
21.84, 12.04, 10.29, 10.06; MS (EI) m/z 343, 344; MS (CI) m/z
(-NH3+) 344, 345; HRMS calcd for C20H25NO4; m/z 343.1783;
Found m/z 343.1781.
Anal. Calcd. for C20H25NO4: C, 69.95; H, 7.34; N, 4.08.
Found: C, 69.94; H, 7.30; N, 4.08.
Anal. Calcd. for C26H24N2O: C, 78.76; H, 6.10; N, 7.07.
Found: C, 79.08; H, 5.95; N, 7.06.
2,3-Dihydro-6-methyl-7-[1-(phenylmethoxy)-propyl]-1,5-
indolizinedione-2-carboxylic Acid 1,1-Dimethylethyl Ester (8).
(+/-)-Mappicine.
A mixture of 7 (3.22 g, 9.4 mmol), cesium carbonate (6.12 g,
18.8 mmol), t-butyl acrylate (13.5 mL, 92.3 mmol), and 50 mL of
DMSO was heated to 65 °C. After 3 hours the reaction mixture
was cooled to 0 °C and 60 mL of 0.5 M hydrochloric acid was
added, maintaining the internal reaction temperature < 15°C. The
mixture was diluted with 30 mL of 4:1 toluene/EtOAc and parti-
tioned. The aqueous phase was extracted with 4:1 toluene/EtOAc
(2 x 30 mL). The organic extracts were combined and washed
with water (3 x 30 mL), dried over sodium sulfate, filtered, and
concentrated to 4.57 g of yellow oil. Chromatography on silica
(5% MeOH in methylene chloride) yielded 3.28 g of 8 as an off-
white solid (85%), IR (potassium bromide) 1690, 1720 cm -1; 1H
NMR (300.14 MHz, deuteriochloroform):d 9.91 (br s), 7.39-7.29
(m, 5H), 6.91 (s, 1H), 4.67 (s, 2H), 4.52-4.48 (m, 2H), 4.26 (d, J =
11.8 Hz, 1H), 2.18 (s, 3H), 1.87-1.78 (m, 1H), 1.70-1.53 (m, 1 H
), 1.59 (s, 9H), 0.97 (t, J = 7.4 Hz, 3H); 13C NMR (75.47 MHz,
deuteriochloroform): d 166.61, 160.77, 160.28, 150.69, 140.25,
137.89, 128.35, 127.77, 127.69, 126.63, 103.99, 99.13, 82.95,
78.02, 70.88, 49.08, 29.01, 28.25, 27.87, 11.84, 10.07; MS (EI)
To a dry, argon-purged flask equipped with magnetic stirring
and an internal temperature probe was charged 0.148 g of 11
(0.37 mmol), 0.54 g of tetra- n-butylammonium iodide
(1.5 mmol), and 20 mL of methylene chloride. The mixture was
stirred to dissolve the solids and then cooled to -40 °C. Boron
tribromide (0.4 mL, 4.4 mmol) was added and the mixture was
stirred for 30 minutes at -40 °C. Twenty mL of saturated sodium
bicarbonate solution was added. The mixture was filtered to
isolate crude mappicine as a light orange solid. This was dis-
solved off the filter with methanol. The methanol solution was
evaporated to yield an off-white solid (0.34 g) that was chro-
matographed on silica (95:5:1 methylene chloride-methanol-
acetic acid) to give 0.074 g of the product as a slightly yellow
solid. The two-phase filtrate from the isolation of crude map-
picine was separated and the organic phase was evaporated. The
residue was chromatographed on silica to give 0.026 g of (+/-)-
mappicine (total yield, 0.100 g, 88 %) as a slightly yellow solid,
mp 267.4 °C (lit. [4a] mp 271-273 °C, lit. [4b] mp 283-286 °C);
1H NMR (500 MHz, deuteriochloroform/methanol-d4): d 8.20
(s, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.70 (m, 2H), 7.54 (s, 1H), 7.50
(t, J = 7.5 Hz, 1H), 5.22 (d, J = 18.5, 1H), 5.14 (d, J = 18.5, 1H),
4.88 (t, J = 5.5 Hz, 1H), 2.21 (s, 3H), 1.8-1.70 (m, 2H), 1.02
(t, J = 7 Hz, 3H); 13C NMR (125.77 MHz, deuteriochloro-
form/methanol-d4): d 161.63, 154.80, 152.60, 148.01, 141.81,
131.05, 130.25, 128.56, 128.37, 127.94, 127.59, 127.37, 125.01,
100.19, 70.98, 49.99, 29.91, 11.84, 9.90; MS (EI) m/z 306, 307;
MS (CI) m/z (-NH3+) 307, 308.
+
m/z 411, 412; MS (CI) m/z (-NH3 ) 412, 413.
Anal. Calcd for C24H29NO5: C, 70.05; H, 7.10; N, 3.40.
Found: C, 69.69; H, 7.04; N, 3.47.
2,3-Dihydro-6-methyl-7-[1-(phenylmethoxy)-propyl]-1,5-indo-
lizinedione (9).
A solution of 8 (0.25 g, 0.61 mmol), trifluoroacetic acid (0.45
mL), and toluene (18 mL) was heated to 75 °C. After 24 hours,
the solution was concentrated to an oil. The oil was diluted with
20 mL of toluene and again concentrated to an oil. The oil was
chromatographed on silica (5% MeOH in methylene chloride) to
yield 0.138 g (73%) of 9 as a yellow foam, IR (potassium bro-
mide) 1737, 1650, 1606, 1198 cm-1; 1H NMR (300.14 MHz, deu-
teriochloroform): d 7.27-7.18 (m, 5H), 7.04 (s, 1H), 4.43- 4.38
(m, 2H), 4.23-4.13 (m, 3H), 2.80 (t, J = 6.9 Hz, 2H), 2.09 (s, 3H),
1.75-1.47 (m, 2H), 0.86 (t, J = 7.4 Hz, 3H); 13C NMR (75.47
MHz, deuteriochloroform): d 196.91, 161.48, 150.48, 137.67,
136.95, 132.94, 128.36, 127.71, 102.40, 77.77, 70.97, 41.92,
33.69, 28.90, 12.41, 9.98; MS (EI) m/z 311, 205; HRMS calcd for
C19H22NO3 (m+H+); m/z 312.1599; Found m/z 312.1597.
Mappicine Ketone.
(+/-)-Mappicine (0.050 g, 0.165 mmole) and 0.2 g of celite
were suspended in 5 mL of methylene chloride. Pyridinium
chlorochromate (PCC) (0.14 g, 0.66 mmole) was added and the
mixture stirred overnight at room temperature. Isopropyl alcohol
(1 mL) was added and the mixture was stirred at room
temperature for 1 hour. The solids were filtered over celite and
washed with 10 mL of methylene chloride. The filtrates were
evaporated to a dark residue. This was dissolved in chloroform
and chromatographed on silica, eluting with 97.5:2.5 methylene
chloride-methanol. Yield of product was 0.031 g (62%) as a light
yellow solid, mp 235 °C, (lit. [4a] mp 237-238 °C, lit. [4b] mp
(+/-) O-Benzylmappicine (11).
1
238-239 °C); H NMR (500 MHz, deuteriochloroform): d 1.25
A solution of 9 (0.50 g, 1.6 mmol), N-Boc-o-aminobenzalde-
hyde (0.47 g, 2.0 mmol), and AcOH (20 mL) was heated to 100
°C. After 4 hours the black solution was concentrated under vac-
(t, J=9.0 Hz, 3H), 2.29 (s, 3H), 2.91 (q, J=9Hz, 2H), 5.27 (s, 2H),
7.27 (s, 1H) 7.65 (t, J=9Hz, 1H), 7.80 (t, J=9 Hz, 1H), 7.90 (d,

Jul-Aug 2003
Synthesis of (+/-) Mappicine and Mappicine Ketone
605
Bouchu and M. A. Ciufolini, J. Org. Chem., 67, 4304 (2002).
J=10 Hz, 1H), 8.19 (d, J=10 Hz, 1H), 8.34, s, 1H); 13C NMR
(125.77 MHz, deuteriochloroform): d 7.74, 13.61, 35.96, 50.32,
97.80, 126.99, 127.65, 127.97, 128.10, 128.54, 129.52, 130.40,
130.96, 143.31, 148.08, 148.77, 152.84, 161.70, 205.42. MS
(electrospray) m/z 305.
[5] Mappicine ketone: [a] W. D. Kingsbury, Tetrahedron Lett., 29,
6847 (1988); [b] J. M. Fortunak, A. R. Mastrocola, M. Mellinger and
J. L. Wood, Tetrahedron Lett., 35, 5763 (1994); [c] B. Das and
P. Madhusudhan, Syn. Comm. , 30, 3321 (2000); [d] B. Das,
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3
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