Concise synthesis of mappicine ketone and (±)-mappicine

Full text of DOI:10.1021/jo961698v

J . Org. Chem. 1996, 61, 9623-9624
9623
Sch em e 1
Con cise Syn th esis of Ma p p icin e Keton e
a n d (()-Ma p p icin e
Daniel L. Comins* and J ayanta K. Saha
Department of Chemistry, North Carolina State University,
Raleigh, North Carolina 27695-8204
Received September 4, 1996
Mappicine ketone (1) is a derivative of a natural
alkaloid mappicine (2), isolated from Mapia foetida
Miers.1 It has been reported that 1 possesses potent
activity against the herpes viruses HSV-1 and HSV-2 and
human cytomegalovirus (HCMV).2 Mappicine ketone has
been prepared by partial synthesis (three steps) from
natural camptothecin,1c by reaction of camptothecin with
sodium azide in hot DMF,3 and by total synthesis (13
steps).4 Recognizing that these preparations are not well-
suited for general analog preparation, Pendrak and co-
workers2 developed synthetic routes to mappicine ketone
derivatives for antiviral evaluation. Their approaches
were based on the Friedlander condensation strategy
used by Wall and co-workers5 for the synthesis of camp-
tothecin alkaloids and on Sugasawa’s6 methods for the
total synthesis of camptothecin. Their syntheses of
analogs required 12-15 steps.
yield of intermediate 7 as a light yellow solid. The Heck
reaction was used to convert 7 to mappicine ketone (1)
in 57% yield.7,9 As reported,4 reduction of 1 with sodium
borohydride provided (()-mappicine in 77% yield.
In summary, mappicine ketone and mappicine have
been prepared from readily available 2-fluoro-4-iodo-3-
methylpyridine using five and six steps in yields of 30
and 23%, respectively.
On the basis of our own work in the camptothecin
area,7 we have developed a short, convergent route to
mappicine ketone and (()-mappicine as shown in Scheme
1. Treatment of 2-fluoro-3-iodopyridine with LDA and
methyl iodide provided 2-fluoro-4-iodo-3-methylpyridine
(3) via a halogen-dance reaction.8 Lithium-iodine ex-
change and addition of propionaldehyde gave alcohol 4
in 84% yield, which was oxidized to ketone 5 with
pyridinium chlorochromate (84%). Hydrolysis of 5 with
aqueous hydrochloric acid provided ketopyridone 6 in
92% yield. N-Alkylation of 6 with potassium tert-butox-
ide and 2-bromo-3-(bromomethyl)quinoline7a gave an 81%
Exp er im en ta l Section
1-(2′-F lu or o-3′-m eth yl-4′-p yr id yl)p r op a n -1-ol (4). To a
stirred solution of 2-fluoro-4-iodo-3-methylpyridine8 (100 mg,
0.422 mmol) in 3 mL of THF at -78 °C under argon was added
n-BuLi in hexane (2.13 M, 0.21 mL, 0.443 mmol). After 1 min,
propionaldehyde (40 µL, 0.554 mmol) was added, and the
mixture was stirred for 15 min. The reaction mixture was
quenched with saturated aqueous NaHCO3 at -78 °C and then
extracted with ether. The combined ether extracts were dried
(MgSO4) and concentrated in vacuo. The residual yellow oil (434
mg) was purified by radial PLC (silica gel, 20-30% ethyl acetate/
hexanes) to give 60 mg (84%) of alcohol 4 as a colorless oil: 1H
NMR (300 MHz, CDCl3) δ 7.99 (d, l H, J ) 5 Hz), 7.31 (d, l H,
J ) 5 Hz), 4.89 (m, l H), 2.21 (s, 3 H), 1.72 (m, 2 H), 0.99 (t, 3 H,
J ) 7 Hz); 13C NMR (75 MHz, CDCl3) δ 161.8 (d, J CF ) 236 Hz),
157.8, (d, J CF ) 4 Hz), 143.5 (d, J CF ) 15 Hz), 118.5, 115.8 (d,
J CF ) 30 Hz), 70.4, 30.2, 9.8, 9.7; IR (CHCl3) 3688, 3606, 1602
cm-1; HRMS calcd for (C9H12FNO + H) 170.0981 [(M + H)+],
found 170.0978.
1-(2′-F lu or o-3′-m eth yl-4′-p yr id yl)p r op a n -1-on e (5). To a
stirred solution of alcohol 4 (358 mg, 2.12 mmol) in 20 mL of
dichloromethane at 0 °C under nitrogen was added Celite,
pyridinium chlorochromate (481 mg, 2.23 mmol), and 4 Å
molecular sieves. The reaction mixture was warmed to rt and
stirred for 29 h. The mixture was filtered through Celite, and
the solid was washed with CH2Cl2. The filtrate was concen-
trated in vacuo, and the residual brown gum (560 mg) was
purified by radial PLC (silica gel, 10-30% ethyl acetate/hexanes)
to give 297 mg (84%) of ketone 5 as a colorless oil: 1H NMR
(300 MHz, CDCl3) δ 8.14 (d, 1 H, J ) 5 Hz), 7.21 (d, l H, J ) 5
Hz), 2.87 (q, 2 H, J ) 7 Hz), 2.32 (s, 3 H), 1.21 (t, 3 H, J ) 7 Hz);
(1) (a) Govindachari, T. R.; Viswranathan, N. Indian J . Chem. 1972,
10, 453. (b) Govindachari, T. R.; Viswanathan, N. Phytochemistry 1972,
11, 3529. (c) Govindachari, T. R.; Ravindranath, K. R.; Viswanathan,
N. J . Chem. Soc., Perkin Trans. 1 1974, 1215.
(2) (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) Kingsbury, W. D. Tetrahedron Lett. 1988, 29, 6847.
(4) (a) Kametani, T.; Takeda, H.; Nemoto, H.; Fukumoto, K.
Heterocycles 1975, 3, 167. (b) Kametani, T.; Takeda, H.; Nemoto, H.;
Fukumoto, K. J . Chem. Soc., Perkin Trans 1 1975, 1825.
(5) Wani, M. C.; Ronman, P. E.; Lindley, J . T.; Wall, M. E. J . Med.
Chem. 1980, 23, 554.
(6) Sugasawa, T.; Toyoda, T.; Sasukura, K. Tetrahedron Lett. 1972,
5109.
(7) (a) Comins, D. L.; Baevsky, M. F.; Hong, H. J . Am. Chem. Soc.
1992, 114, 10971. (b) Comins, D. L.; Hong, H.; J ianhua, G. Tetrahedron
Lett. 1994, 35, 5331. (c) Comins, D. L.; Hong, H.; Saha, J .; J ianhua,
G. J . Org. Chem. 1994, 59, 5120. (d) Comins, D. L.; Saha, J . K.
Tetrahedron Lett. 1995, 36, 7995.
(8) Rocca, P.; Cochennec, C.; Marsais, F.; Thomas-dit-Dumont, L.;
Mallet, M.; Godard, A.; Quequiner, G. J . Org. Chem. 1993, 58, 7832
and references cited therein.
(9) Grigg, R.; Sridharan, V.; Stevenson, P.; Sukirthalingam, S.;
Worakun, T. Tetrahedron 1990, 46, 4003.
S0022-3263(96)01698-2 CCC: $12.00 © 1996 American Chemical Society

9624 J . Org. Chem., Vol. 61, No. 26, 1996
Notes
13C NMR (75 MHz, CDCl3) δ 203.5, 162.9 (d, J CF ) 238 Hz), 150.5
(d, J CF ) 4 Hz), 144.9 (d, J CF ) 15 Hz), 118.6 (d, J CF ) 4 Hz),
117.6 (d, J CF ) 33 Hz), 35.7, 11.4, 7.7; IR (CHCl3) 2940, 1702,
1600, cm-1. Anal. Calcd for C9H10FNO: C, 64.66; H, 6.03; N,
8.38. Found: C, 64.70; H, 6.01; N, 8.31.
0.022 mmol) in acetonitrile (5 mL) was heated at reflux under
argon for 3 h. The hot reaction mixture was filtered through
Celite, and the residue was washed with hot 40% MeOH/CH2-
Cl2. The filtrate was concentrated in vacuo, and the residue was
purified by radial PLC (silica gel, CH2Cl2-2% MeOH/CH2Cl2)
to give 22 mg (57%) of mappicine ketone (1): mp 238-239 °C
1-(3′-Meth yl-2′-oxo-4′-p yr id yl)p r op a n -1-on e (6). A mix-
ture of ketone 5 (45 mg, 0.269 mmol) and 3 N HCl (2 mL) was
heated at reflux in air for 2 h. The reaction mixture was
concentrated in vacuo, and the residue was purified by radial
PLC (silica gel, CH2Cl2-5% MeOH/CH2Cl2) to give 41 mg (92%)
1
(lit.4a mp 237-238 °C); H NMR (300 MHz, CDCl3) δ 8.36 (s, 1
H), 8.19 (d, 1 H, J ) 8 Hz), 7.92 (d, 1 H, J ) 8 Hz), 7.81 (t, 1 H,
J ) 7 Hz), 7.64 (t, 1 H, J ) 7 Hz), 7.25 (s, 1 H), 5.29 (s, 2 H),
2.91 (q, 2 H, J ) 7 Hz), 2.30 (s, 3 H), 1.25 (t, 3 H, J ) 7 Hz).
(()-Ma p p icin e (2). To a stirred solution of mappicine ketone
7 (9 mg, 0.03 mmol) in 2 mL of 1:1 MeOH/CH2Cl2 was added
sodium borohydride (5 mg, 0.132 mmol) at rt, and the reaction
mixture was stirred for 3.5 h in air. The mixture was diluted
with 1 mL of water and then concentrated in vacuo. The residue
was purified by radial PLC (silica gel, CH2Cl2-5% MeOH/CH2-
Cl2) to give 7 mg (77%) of (()-mappicine as a yellow solid: mp
283-286 °C (lit.4a mp 271-273 °C); 1H NMR (300 MHz, CDCl3-
CD3OD) δ 8.25 (s, 1 H), 8.06 (d, 1 H, J ) 8 Hz), 7.74 (m, 2 H),
7.53 (m, 2 H), 5.22 (m, 2 H), 4.89 (t, 1 H, J ) 6 Hz), 2.22 (s, 3
H), 1.78 (m, 2 H), 1.03 (t, 3 H, J ) 7 Hz).
1
of pyridone 6 as a white solid: mp 128-129 °C; H NMR (300
MHz, CDCl3) δ 7.36 (d, l H, J ) 7 Hz), 6.21 (d, 1 H, J ) 7 Hz),
2.77 (q, 2 H, J ) 7 Hz), 2.14 (s, 3 H), 1.19 (t, 3 H, J ) 7 Hz); 13
C
NMR (75 MHz, CDCl3) δ 205.5, 165.6, 149.6, 132.0, 125.8, 103.9,
35.9, 13.0, 7.6; IR (CHCl3) 3690, 1706, 1646 cm-1; HRMS calcd
for C9H11NO2 165.0790 (M+), found 165.0797.
1-[1′-[(2′′-Br om o-3′′-qu in olyl)m eth yl]-3′-m eth yl-2′-oxo-4′-
p yr id yl]p r op a n -1-on e (7). To a stirred solution of the pyridone
6 (80 mg, 0.485 mmol) in DME (10 mL) was added potassium
tert-butoxide in THF (1M, 0.53 mL, 0.53 mmol) at rt under argon.
The yellow solution was stirred at rt for 30 min. Solid 2-bromo-
3-(bromomethyl)quinoline7a (190 mg, 0.631 mmol) was added,
and the heterogeneous reaction mixture was heated at reflux
for 4 d. The mixture was cooled to rt and then concentrated on
a rotary evaporator. The residue was purified by radial PLC
(silica gel, CH2Cl2-2% MeOH/CH2Cl2) to give 151 mg (81%) of
7 as a yellow solid: mp 242-244 °C dec; 1H NMR (300 MHz,
CDCl3) δ 8.02 (m, 2 H), 7.80 (d, 1 H, J ) 8 Hz), 7.73 (t, 1 H, J
) 8 Hz), 7.57 (t, 1 H, J ) 8 Hz), 7.46 (d, 1 H, J ) 7 Hz), 6.16 (d,
1 H, J ) 7 Hz), 5.37 (s, 2 H), 2.78 (q, 2 H, J ) 7 Hz), 2.18 (s, 3
H), 1.2 (t, 3 H, J ) 7 Hz); 13C NMR (75 MHz, CDCl3) δ 205.3,
163.0, 147.9, 147.6, 142.3, 138.2, 135.1, 130.8, 129.3, 128.3, 127.8,
127.5, 127.2, 127.0, 103.2, 52.4, 35.9, 13.9, 7.6; IR (CHCl3) 2993,
1701, 1646, 1600 cm-1; HRMS calcd for C19H17BrN2O2 (M+)
385.0552, found 385.0551.
Ack n ow led gm en t. We gratefully acknowledge the
support of this work by Glaxo Wellcome, Inc. NMR and
mass spectra were obtained at NCSU instrumentation
laboratories, which were established by grants from the
North Carolina Biotechnology Center and the National
Science Foundation (Grant CH#-9121380).
Su p p or tin g In for m a tion Ava ila ble: Comparison tables
1
of spectroscopic data for 1 and 2 and H and 13C NMR spectra
of 4, 6, and 7 (8 pages). This material is contained in libraries
on microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
Ma p p icin e Keton e (1). A mixture of 7 (49 mg, 0.127 mmol),
potassium acetate (41 mg, 0.42 mmol), tetrabutylammonium
bromide (66 mg, 0.205 mmol), and palladium acetate (5 mg,
J O961698V