Total synthesis of the pyralomicinones

Full text of DOI:10.1021/jo972340h

J . Org. Chem. 1998, 63, 3147-3150
3147
Sch em e 1
Tota l Syn th esis of th e P yr a lom icin on es
T. Ross Kelly* and Rimma L. Moiseyeva
Department of Chemistry, E. F. Merkert Chemistry Center,
Boston College, Chestnut Hill, Massachusetts 02167
Received December 31, 1997
The structures of the pyralomicins, typified by 1 and
2, were recently reported.1 These heterocycles, which
were isolated from the microorganism Microtetraspora
spiralis, exhibit antimicrobial and antitumor activities.1
Because of their unusual benzopyranopyrrole ring sys-
tem2 and our continuing interest in the synthesis of
heterocyclic natural products,3 we undertook the synthe-
sis of pyralomicinones 3 and 4, which are the “aglycones”
of the pyralomicins. We now report the first synthesis
of the pyralomicinones.
In planning the syntheses of 3 and 4, we envisioned
preparing them from a common intermediate already
containing the pyrrole and benzene rings, as in I, and
precursors. To that end, the tosylated pyrrole aldehyde
5 (Scheme 1) was prepared from commercially available
pyrrole in four steps according to the procedure of
Demopoulos.4a-c It was necessary to protect the pyrrole
NH for the coupling reaction with 8 due to the former’s
acidity. Chloride 7 was made in one step from com-
mercially available 2,4-dimethoxytoluene by chlorinating
it with N-chlorosuccinimide (NCS). Addition of the
lithium anion 8 derived from 7 to aldehyde 5 produced
9. Unexpectedly, reaction of chlorinated aldehyde 6 with
8 failed to form alcohol 10 under an analogous procedure.
Alcohol 9 was then oxidized to ketone 11 with pyridinium
chlorochromate (PCC) and deprotected with BBr3 to
afford ketone 13. To our surprise, attempts to chlorinate
forming the pyranone ring in the final major constructive
step. Intermediate I, in turn, was expected to be as-
sembled from suitably protected phenyl and pyrrolyl
(1) (a) Kawamura, N.; Sawa, R.; Takahashi, Y.; Isshiki, T.; Sawa,
T.; Kinoshita, N.; Naganawa, H.; Hamada, M.; Takeuchi, T. J . Antibiot.
1995, 48, 435. (b) Kawamura, N.; Sawa, R.; Takahashi, Y.; Isshiki, T.;
Sawa, T.; Naganawa, H.; Takeuchi, T. J . Antibiot. 1996, 49, 651. (c)
Kawamura, N.; Sawa, R.; Takahashi, Y.; Sawa, T.; Naganawa, H.;
Takeuchi, T. J . Antibiot. 1996, 49, 657. (d) Kawamura, N.; Kinoshita,
N.; Sawa, R.; Takahashi, Y.; Sawa, T.; Naganawa, H.; Hamada, M.;
Takeuchi, T. J . Antibiot. 1996, 49, 706. (e) Kawamura, N.; Nakamura,
H.; Sawa, R.; Takahashi, Y.; Sawa, T.; Naganawa, H.; Takeuchi, T. J .
Antibiot. 1997, 50, 147.
5
ketone 13 with NCS or SO2Cl2 were unsuccessful, even
though we had previously chlorinated pyrrole-3-carbox-
aldehyde6 and 5 using NCS. Therefore, we chlorinated
alcohol 9 with NCS and oxidized the resulting 10 to 12
(2) The benzopyranopyrrole ring system has also been reported
recently in TAN-876A: Funabashi, Y.; Takizawa, M.; Tsubotani, S.;
Tanida, S.; Harada, S. Takeda Kenkyushoho 1992, 51, 73; Chem. Abstr.
1992, 118, 55722. (b) For a very recent synthesis of the ring system
(by a different route) see Alberola, A.; AÄ lvaro, R.; Ortega, A. G.; San˜udo,
C. Tetrahedron 1997, 53, 16185.
(4) (a) Demopoulos, V. J . J . Heterocycl. Chem. 1988, 25, 635. (b)
Demopoulos, V. J . Org. Prep. Proced. Int. 1986, 18, 278. (c) Demopoulos,
B. J .; Anderson, H. J .; Loader, C. E.; Faber, K. Can. J . Chem., 1983,
61, 2415.
(5) Artico, M. In Pyrroles; J ones, R. A., Ed.; Wiley: New York, 1990;
Part 1, pp 349-371.
(6) Unpublished results of R. L. Moiseyeva and T. R. Kelly.
(3) Kelly, T. R.; Lang, F. J . Org. Chem. 1996, 61, 4623 and earlier
work cited therein.
S0022-3263(97)02340-2 CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/04/1998

3148 J . Org. Chem., Vol. 63, No. 9, 1998
Notes
Sch em e 2
Sch em e 3
Ta ble 1
conditions
ratio 3:4
LiOMe, MeOH
Na OMe, MeOH
TlOEt, EtOH
Mg(OMe)2, MeOH
Sr(Oi-Pr)2, MeOH
Ba(Oi-Pr)2, MeOH
Al(Oi-Pr)3, MeOH
Sm(Oi-Pr)3, MeOH
1:1
1:2.5
1:2
3:1
1:1
1:2
2:1
1:1
Ta ble 2
1
3
2
4
1H NMR (δ)
with PCC. Deprotection of ketone 12 with BBr3 fur-
nished the pyralomicinones’ anticipated precursor 14.
Now what remained were to form the tricyclic system
by an intramolecular, base-promoted, nucleophilic aro-
matic substitution and to remove the tosyl protecting
group. 2-Halopyrroles are usually inert to nucleophilic
aromatic substitution,7 but we believed that the presence
on the pyrrole of two strongly electron-withdrawing
groups, and the use of an intramolecular reaction,
nonetheless augured well for success. Since the two
possible regioisomers that might be produced in the
cyclization were both desired products, we had chosen
to avoid the complication of a protecting-group or other
strategy to form an individual regioisomer separate from
the other one. Rather, we anticipated that different
reaction conditions might be developed to favor produc-
tion of first one and then the other regioisomer. That
expectation proved justified, as use of a variety of metal
alkoxides for the base-induced cyclizations resulted in
different regioselectivities (Scheme 2; Table 1). More-
over, cleavage of the tosyl group also occurred during the
reaction to give the desired 3 and 4 directly. The
variation in regiochemistry may be due to different
associations of the metal ions between the carbonyl and
one of the phenolic oxygens. The best regioselectivities
(Table 1) were obtained with magnesium and sodium
methoxides. Finally, the mixtures of 3 and 4 were
separated using preparative reverse phase HPLC to
afford the pure pyralomicinones.
2.38
6.74
7.71
2.38
6.55
7.64
2.27
6.80
7.77
2.25
6.57
7.69
13.81
14.04
13.40
13.82
13C NMR (δ)
14.8
99.7
14.7
99.8
14.4
14.7
100.8
105.6
109.9
109.9
119.0
122.2
136.0
148.3
149.9
158.8
177.8
100.7
106.3
109.9
110.5
116.6
122.4
136.1
148.8
150.9
159.6
178.3
105.2
110.1
114.2
117.8
119.8
135.6
150.2
151.4
155.5
177.5
105.8
110.3
114.0
117.5
117.6
135.4
151.6
151.7
155.8
177.7
the methoxy group. Authentic samples of naturally
derived aglycones 3 and 4 were not available (the
pyralomicins have not been hydrolyzed to their agly-
cones8), but the spectra of the synthetic aglycones are in
excellent agreement with the spectra for the correspond-
ing components of the natural products (Table 2).
Con clu sion
In summary, the first synthesis of the two tricyclic
aglycones (3 and 4) of the pyralomicins has been achieved.
The spectra of 3 and 4 strongly support the structures
assigned to the chromophore units of the natural prod-
ucts.
Exp er im en ta l Section 9
Assignment of which regioisomer was which was
1-[(4-Meth ylp h en yl)su lfon yl]-1H-p yr r ole-3-ca r boxa ld e-
h yd e (5). This compound was prepared as a light beige solid
in four steps from pyrrole (Acros) according to the procedure of
Demopoulos:4a-c mp 53-55 °C (lit.4a mp 61-62 °C); 1H NMR
(CDCl3) δ 2.35 (s, 3H), 6.64 (dd, 1H, J ) 3.2, 1.6 Hz), 7.13-7.15
(m, 1H), 7.29 (d, 2H, J ) 8.4 Hz), 7.76-7.78 (m, 3H), 9.76 (s,
1H); 13C NMR (CDCl3) δ 21.7, 110.8, 122.3, 127.3, 128.2, 129.5,
130.4, 134.7, 146.3, 185.2; IR (CDCl3) ν 3125, 1677 cm-1. Anal.
Calcd for C12H11NO3S: C, 57.82; H, 4.45; N, 5.62. Found: C,
57.64; H, 4.28; N, 5.38.
2,5-Dich lor o-1-[(4-m eth ylp h en yl)su lfon yl]-1H-p yr r ole-3-
ca r boxa ld eh yd e (6). Aldehyde 5 (5.15 g, 20.7 mmol) was
placed with N-chlorosuccinimide (13.8 g, 103 mmol, 5.0 equiv)
in a 250 mL round-bottomed flask under a nitrogen atmosphere.
Anhydrous THF (150 mL) was added all at once, and the solution
was refluxed with stirring overnight. After cooling to room
temperature, the solution was poured into a saturated aqueous
solution of NaCl (200 mL) and extracted with diethyl ether (3
1
initially tentatively made by comparing the H and 13C
NMR spectra of 3 and 4 with spectra of the regioisomeric
chromophores of 1 and 2 (see Table 2), but a rigorous
1
assignment was achieved by H-1H NOESY 2D NMR
experiments (see Supporting Information for spectra) on
derivatives of 3 and 4. Accordingly, pyralomicinones 3
and 4 were separately methylated with iodomethane to
afford the two dimethylated derivatives 15 and 16,
respectively, and the expected crossover peaks were
observed (Scheme 3). In particular, in 3-derived 15 the
aromatic CH3 group displayed a crossover peak with the
aromatic hydrogen, but not with the methoxy group; in
contrast, in 4-derived 16 the aromatic CH3 group exhib-
ited crossover peaks with both the aromatic hydrogen and
(7) (a) Dennis, N. In Pyrroles; J ones, R. A., Ed.; Wiley: New York,
1990; Part 1, pp 537-548. (b) J oule, J . A.; Smith, G. F. Heterocyclic
Chemistry; Van Nostrand Reinhold: London, 1972; p 211.
(8) Personal communication from Dr. T. Takeuchi.1
(9) For general experimental procedures, see ref 3.

Notes
J . Org. Chem., Vol. 63, No. 9, 1998 3149
× 100 mL). The combined extracts were washed with
a
61.1, 61.3, 63.7, 112.9, 113.7, 117.3, 122.7, 127.7, 128.3, 128.4,
129.5, 130.1, 132.2, 135.4, 146.1, 152.3, 155.5; IR (CDCl3) ν 3471,
2942, 1469, 1394 cm-1. An analytical sample was obtained as
beige plates, mp 150-152 °C, after crystallization from CH2Cl2/
petroleum ether. Anal. Calcd for C21H20Cl3NO5S: C, 49.97; H,
3.99; N, 2.77. Found: C, 49.89; H, 3.80; N, 2.65.
saturated aqueous solution of NaCl (2 × 100 mL), dried over
Na2SO4, and concentrated in vacuo to afford a brown oil. Flash
chromatography on a 6 × 25 cm SiO2 column eluting with 50:
50 diethyl ether/petroleum ether afforded 6 (2.17 g, 33%) as a
light yellow solid. Recrystallization from ether/petroleum ether
produced a white solid: mp 105-106.5 °C; 1H NMR (CDCl3) δ
2.37 (s, 3H), 6.44 (s, 1H), 7.33 (d, 2H, J ) 8.4 Hz), 7.87 (d, 2H,
J ) 8.4 Hz), 9.75 (s, 1H); 13C NMR (CDCl3) δ 21.7, 109.8, 119.9,
123.3, 125.5, 127.8, 130.4, 134.3, 147.1, 182.8; IR (CDCl3) ν 1681
cm-1. Anal. Calcd for C12H9Cl2NO3S: C, 45.30; H, 2.85; N, 4.40.
Found: C, 45.05; H, 2.78; N, 4.33.
3-Ch lor o-2,6-dim eth oxy-5-m eth ylph en yl 1-[(4-Meth ylph e-
n yl)su lfon yl]-1H-p yr r ol-3-yl Keton e (11). Ketone 11 (65%)
was prepared as off-white prisms, mp 130-132 °C, in a manner
analogous to the preparation of ketone 12: 1H NMR (CDCl3) δ
2.25 (s, 3H), 2.41 (s, 3H), 3.61 (s, 3H), 3.69 (s, 3H), 6.69 (dd, 1H,
J ) 3.2, 1.6 Hz), 7.12-7.14 (m, 1H), 7.27 (s, 1H), 7.32 (d, 2H, J
) 8.4 Hz), 7.50-7.51 (m, 1H), 7.77 (d, 2H, J ) 8.4 Hz); 13C NMR
(CDCl3) δ 15.6, 21.8, 62.1, 62.4, 112.8, 121.8, 122.6, 126.9, 127.4,
128.8, 129.6, 130.1, 130.4, 132.9, 134.9, 146.2, 151.3, 154.4, 188.1;
1-Ch lor o-2,4-d im et h oxy-5-m et h ylb en zen e (7).10 2,4-
Dimethoxytoluene (Aldrich, 4.98 g, 32.8 mmol) was placed with
N-chlorosuccinimide (6.56 g, 49.2 mmol, 1.5 equiv) in a 100 mL
round-bottomed flask under a nitrogen atmosphere. Anhydrous
DMF (50 mL) was added, and the solution was refluxed with
stirring for 2 h. After cooling to room temperature, the solution
was poured into a saturated aqueous solution of NaCl (200 mL)
and extracted with CH2Cl2 (3 × 100 mL). The combined extracts
were washed with a saturated solution of NaCl (2 × 100 mL),
dried over Na2SO4, and concentrated in vacuo. The resulting
brown-orange oil was purified using flash column chromatog-
raphy (6 × 20 cm SiO2 column, CH2Cl2) to afford 7 (4.67 g, 76%)
as a white fluffy solid: mp 89-90 °C (lit.10 mp 74-75 °C); 1H
NMR (CDCl3) δ 2.10 (s, 3H), 3.80 (s, 3H), 3.85 (s, 3H), 6.42 (s,
1H), 7.05 (s, 1H); 13C NMR (CDCl3) δ 15.2, 55.7, 56.4, 96.5, 112.7,
119.5, 131.1, 153.7, 157.1; IR (CDCl3) ν 1604, 1504, 1302, 1210,
1168, 1035, 808 cm-1. Anal. Calcd for C9H11ClO2: C, 57.92; H,
5.94. Found: C, 57.68; H, 5.73.
IR (CDCl3) ν 1659, 1469, 1377, 1173 cm-1
21H20ClNO5S: C, 58.13; H, 4.65; N, 3.23. Found: C, 57.95; H,
4.55; N, 3.05.
. Anal. Calcd for
C
3-Ch lor o-2,6-d im eth oxy-5-m eth ylp h en yl 2,5-Dich lor o-1-
[(4-m eth ylp h en yl)su lfon yl]-1H-p yr r ol-3-yl Keton e (12). Al-
cohol 10 (2.15 g, 4.26 mmol) was placed with PCC (2.76 g, 12.8
mmol, 3.0 equiv) in a 250 mL round-bottomed flask under a
nitrogen atmosphere. Anhydrous CH2Cl2 (150 mL) was added,
and the mixture was stirred at room temperature overnight. The
solvent was evaporated, and the black residue was extracted (30:
70 ethyl acetate/petroleum ether, 3 × 100 mL) and filtered off
in order to eliminate the insoluble impurities. The combined
filtrates were concentrated in vacuo, and the resulting yellow
oil was purified using flash column chromatography (3 × 25 cm
SiO2 column, 30:70 ethyl acetate/petroleum ether) to afford
ketone 12 (1.48 g, 69%) as a light yellow oil: 1H NMR (CDCl3)
δ 2.22 (s, 3H), 2.46 (s, 3H), 3.62 (s, 3H), 3.71 (s, 3H), 6.39 (s,
1H), 7.25 (s, 1H), 7.38 (d, 2H, J ) 8.4 Hz), 7.93 (d, 2H, J ) 8.4
Hz); 13C NMR (CDCl3) δ 15.7, 22.0, 62.1, 62.3, 113.1, 118.8, 121.9,
122.7, 123.8, 128.2, 128.9, 130.2, 130.4, 133.2, 134.8, 147.0, 151.1,
154.2, 186.7; IR (CDCl3) ν 2942, 1662, 1475 cm-1. Anal. Calcd
for C21H18Cl3NO5S: C, 50.17; H, 3.61; N, 2.79. Found: C, 49.98;
H, 3.43; N, 2.68.
r-(3-Ch lor o-2,6-d im eth oxy-5-m eth ylp h en yl)-1-[(4-m eth -
ylp h en yl)su lfon yl]-1H -p yr r ole-3-m et h a n ol (9). Chloro-
dimethoxytoluene 7 (2.11 g, 11.3 mmol) was dissolved in 100
mL of anhydrous diethyl ether in a 250 mL round-bottomed flask
under a nitrogen atmosphere, and n-butyllithium (6.36 mL of a
2.31 M solution in hexanes, 14.7 mmol, 1.3 equiv) was added at
room temperature all at once. After 40 min of stirring at room
temperature, the resulting yellow suspension was cooled in an
ice bath and added dropwise over 30 min via cannula to a
vigorously stirred solution of aldehyde 5 (2.81 g, 11.3 mmol) in
100 mL of anhydrous diethyl ether in a 500 mL round-bottomed
flask cooled in an ice/salt bath. The cooling bath was removed,
and the mixture was stirred for an additional 10 min. The
solvent was evaporated to afford a brown oil, which was
dissolved in a minimum amount of methanol (∼ 20 mL), and
mixed with SiO2 (∼2 g); volatiles were removed in vacuo, and
the solid residue was applied to the top of a 6 × 20 cm SiO2
column. Elution with 30:70 ethyl acetate/petroleum ether
afforded 9 (3.39 g, 69%) as a pale pink glass: mp 87-89 °C; 1H
NMR (CDCl3) δ 2.22 (s, 3H), 2.40 (s, 3H), 3.43 (s, 3H), 3.49 (s,
3H), 4.13 (d, 1H, J ) 11.0 Hz), 5.95 (d, 1H, J ) 11.0 Hz), 6.16
(dd, 1H, J ) 3.2, 1.6 Hz), 6.98-6.99 (m, 1H), 7.11-7.12 (m, 1H),
7.15 (s, 1H), 7.27 (d, 2H, J ) 8.4 Hz), 7.73 (d, 2H, J ) 8.4 Hz);
13C NMR (CDCl3) δ 15.7, 21.5, 60.9, 61.0, 65.0, 112.7, 116.6,
121.2, 122.6, 126.8, 128.4, 129.9, 131.2, 131.6, 134.8, 135.9, 145.1,
3-Ch lor o-2,6-dih ydr oxy-5-m eth ylph en yl 1-[(4-Meth ylph e-
n yl)su lfon yl]-1H-p yr r ol-3-yl Keton e (13). Ketone 13 (30%)
was prepared as a bright yellow oil in a manner analogous to
the preparation of ketone 14: 1H NMR (CDCl3) δ 2.17 (s, 3H),
2.43 (s, 3H), 6.16 (br s, 1H), 6.71 (dd, 1H, J ) 3.2, 1.6 Hz), 7.11-
7.13 (m, 1H), 7.24 (s, 1H), 7.34 (d, 2H, J ) 8.4 Hz), 7.76-7.80
(m, 3H), 10.20 (s, 1H); 13C NMR (CDCl3) δ 15.3, 21.9, 110.3,
111.5, 114.0, 119.9, 120.9, 126.7, 127.5, 129.2, 130.6, 134.5, 135.3,
146.2, 149.1, 157.8, 191.5; IR (CDCl3) ν 3427, 2923, 1643, 1614,
1453, 1338, 1170 cm-1
. Anal. Calcd for C19H16ClNO5S: C,
56.23; H, 3.97; N, 3.45. Found: C, 55.93; H, 3.79; N, 3.24.
3-Ch lor o-2,6-d ih yd r oxy-5-m eth ylp h en yl 2,5-Dich lor o-1-
[(4-m eth ylp h en yl)su lfon yl]-1H-p yr r ol-3-yl Keton e (14). Ke-
tone 12 (0.25 g, 0.50 mmol) was dissolved in 15 mL of anhydrous
CH2Cl2 under a nitrogen atmosphere. BBr3 (3.0 mL of a 1.0 M
solution in heptanes, 3.0 mmol, 6.0 equiv) was added dropwise
at room temperature over 1 min, and the resulting brown-orange
solution was stirred at room temperature for 24 h. The solution
was washed with water (3 × 50 mL), dried over Na2SO4, and
concentrated in vacuo to afford a brown oil, which was purified
by preparative TLC (Analtech, catalog no. 81013, SiO2 UNI-
PLATE-T Taper Plate, 10:90 ethyl acetate/petroleum ether) to
give 14 (0.156 g, 66%) as a bright yellow oil: 1H NMR (CDCl3)
δ 2.16 (s, 3H), 2.46 (s, 3H), 5.98 (s, 1H), 6.38 (s, 1H), 7.25 (s,
1H), 7.38 (d, 2H, J ) 8.4 Hz), 7.93 (d, 2H, J ) 8.4 Hz), 10.88 (s,
1H); 13C NMR (CDCl3) δ 15.2, 22.0, 109.8, 111.0, 113.2, 118.2,
119.5, 119.8, 125.8, 128.1, 130.4, 135.1, 136.0, 146.8, 149.9, 158.9,
191.1; IR (CDCl3) ν 3502, 1612, 1480, 1403 cm-1. Anal. Calcd
for C19H14Cl3NO5S: C, 48.07; H, 2.97; N, 2.95. Found: C, 48.45;
H, 2.81; N, 2.97.
2,6-Dich lor o-5-h yd r oxy-8-m eth yl-[1]ben zop yr a n o[2,3-b]-
p yr r ol-4(1H)-on e (3) a n d 2,8-Dich lor o-5-h yd r oxy-6-m eth yl-
[1]ben zop yr a n o[2,3-b]p yr r ol-4(1H)-on e (4). Meth od A. To
a stirred solution of 14 (60 mg, 0.13 mmol) at room temperature
in anhydrous methanol (5 mL) under a nitrogen atmosphere was
added 7.4% methanolic Mg(OCH3)2 (Aldrich, 0.30 mL, 2.0 equiv).
After 3 h the mixture was acidified with 2 M HCl to pH 2, and
the precipitate was collected by vacuum filtration to afford a
152.2, 155.3; IR (CDCl3) ν 3534, 2936, 1472, 1372, 1174 cm-1
.
An analytical sample was obtained as large, pale-pink crystals,
mp 94-96 °C, after recrystallization from CH2Cl2/petroleum
ether. Anal. Calcd for C21H22ClNO5S: C, 57.86; H, 5.09; N, 3.21.
Found: C, 58.04; H, 5.23; N, 3.27.
r-(3-Ch lor o-2,6-dim eth oxy-5-m eth ylph en yl)-2,5-dich lor o-
1-[(4-m eth ylp h en yl)su lfon yl]-1H-p yr r ole-3-m eth a n ol (10).
Alcohol 9 (3.75 g, 8.6 mmol) was placed with N-chlorosuccinimide
(2.87 g, 21.5 mmol, 2.5 equiv) in a 250 mL round-bottomed flask
under a nitrogen atmosphere. Anhydrous THF (150 mL) was
added, and the resulting solution was heated at reflux overnight
with stirring. After cooling to room temperature, the solution
was poured into a saturated aqueous solution of NaCl (200 mL)
and extracted with CH2Cl2 (2 × 200 mL). The combined extracts
were washed with a saturated aqueous solution of NaCl (200
mL), dried over Na2SO4, and concentrated in vacuo to afford a
dark yellow oil. Flash chromatography on a 6 × 25 cm SiO2
column, eluting with 10:40:50 ethyl acetate/petroleum ether/CH2-
Cl2, afforded 10 (2.60 g, 60%) as a beige oil: 1H NMR (CDCl3) δ
2.19 (s, 3H), 2.40 (s, 3H), 3.28 (br s, 1H), 3.53 (s, 3H), 3.62 (s,
3H), 5.97 (s, 1H), 6.27 (s, 1H), 7.12 (s, 1H), 7.29 (d, 2H, J ) 8.4
Hz), 7.84 (d, 2H, J ) 8.4 Hz); 13C NMR (CDCl3) δ 16.0, 21.8,

3150 J . Org. Chem., Vol. 63, No. 9, 1998
Notes
light yellow solid (25 mg, 70%), which was approximately (1H
NMR) a 3:1 mixture of 3 and 4, respectively.
2,6-Dich lor o-5-m et h oxy-1,8-d im et h yl-[1]b en zop yr a n o-
[2,3-b]p yr r ol-4(1H)-on e (15) a n d 2,8-Dich lor o-5-m eth oxy-
1,6-d im eth yl-[1]ben zop yr a n o[2,3-b]p yr r ol-4(1H)-on e (16).
Pyralomicinone 3 (8.0 mg, 0.028 mmol) was placed with NaH
(7.0 mg of a 60% dispersion in mineral oil, 0.17 mmol, 6.0 equiv)
under a nitrogen atmosphere. Anhydrous THF (5 mL) and CH3I
(178 µL, 2.8 mmol, 100 equiv) were added, and the mixture was
refluxed12 with stirring for 20 h. The solution was concentrated
Meth od B. To a stirred solution of 14 (60 mg, 0.13 mmol) at
room temperature in anhydrous methanol (7 mL) under a
nitrogen atmosphere was added 4.6 M methanolic NaOCH3
(Aldrich, 82 µL, 3.0 equiv). After 3 h the mixture was acidified
with 2 M HCl to pH 2, and the precipitate was collected by
vacuum filtration to afford a light yellow solid (28.6 mg, 80%),
which was approximately (1H NMR) a 1:2.5 mixture of 3 and 4,
respectively.
in vacuo to afford
a yellow solid, which was purified by
preparative TLC (Analtech, catalog no. 81013, SiO2 UNI-
PLATE-T Taper Plate, CH2Cl2) to give 15 (5.0 mg, 57%) as a
white solid: mp 202-204 °C; 1H NMR (CDCl3) δ 2.46 (s, 3H),
3.68 (s, 3H), 3.96 (s, 3H), 6.57 (s, 1H), 7.49 (s, 1H); HRMS (MH+)
calcd for C14H11Cl2NO3 312.0195, found 312.0195.
Compound 16 was prepared from pyralomicinone 4 in an
analogous manner: mp 210-211 °C; 1H NMR (CDCl3) δ 2.34
(s, 3H), 3.70 (s, 3H), 3.89 (s, 3H), 6.57 (s, 1H), 7.52 (s, 1H); HRMS
(MH+) calcd for C14H11Cl2NO3 312.0195, found 312.0196.
The mixtures were separated using preparative reverse phase
HPLC (Rainin Microsorb (8 µm particle size) C18 column: 21.4
mm × 250 mm, on a Rainin HPXL HPLC, equipped with a model
UV-D Dynamax absorbance detector) with a 60:40 acetone/water
mixture as the mobile phase at 21 mL/min flow rate. Retention
times: ∼ 12.4 min for 3 and 16.9 min for 4.
3: mp 330-332 °C (dec); UV-vis (DMF)11 274 (4.07), 306
(4.07), 368 (4.19) nm; 1H NMR (DMF-d7) δ 2.38 (s, 3H), 6.55 (s,
1H), 7.64 (s, 1H), 14.04 (s, 1H); 13C NMR (DMF-d7) δ 14.7, 99.8,
105.8, 110.3, 114.0, 117.5, 117.6, 135.4, 151.6, 151.7, 155.8, 177.7;
HRMS (MH+) calcd for C12H7Cl2NO3 283.9882, found 283.9879;
Ack n ow led gm en t. We thank Dr. Tomio Takeuchi1
for valuable exchange of information, Dr. Richard J .
Mears for helpful discussions, Dr. J ohn Boylan for help
with NMR experiments, and Mr. J effrey T. Sieglen for
assistance in the preparation of some intermediates.
IR (KBr) ν 3443, 3048, 2917, 1633, 1602, 1260 cm-1
. Anal.
Calcd for C12H7Cl2NO3: C, 50.73; H, 2.48; N, 4.93. Found: C,
50.62; H, 2.40; N, 4.85.
4: mp 334-336 °C (dec); UV-vis (DMF)11 272 (4.05), 306
(4.04), 368 (4.10) nm; 1H NMR (DMF-d7) δ 2.25 (s, 3H), 6.57 (s,
1H), 7.69 (s, 1H), 13.82 (s, 1H); 13C NMR (DMF-d7) δ 14.7, 100.7,
106.3, 109.9, 110.5, 116.6, 122.4, 136.1, 148.8, 150.9, 159.6, 178.3;
HRMS (MH+) calcd for C12H7Cl2NO3 283.9882, found 283.9876;
IR (CDCl3) ν 3437, 3043, 2913, 1609, 1299 cm-1. Anal. Calcd
for C12H7Cl2NO3: C, 50.73; H, 2.48; N, 4.93. Found: C, 50.50;
H, 2.52; N, 4.92.
Su p p or tin g In for m a tion Ava ila ble: 1H-1H NOESY 2D
NMR spectra of compounds 15 and 16 (2 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.
(10) For another procedure, see Bergquist, K.-E.; Nilsson, A.; Ronlan,
A. Acta Chem. Scand. Ser. B 1982, B36 (10), 675.
(11) Unlike the natural products, the pyralomicinones are not
soluble in methanol, which is why the UV-vis spectra are recorded in
DMF, not methanol.
J O972340H
(12) Stirring at room temperature affords methylation on nitrogen
only.