Synthesis of a fully functionalized 7-methoxyaziridinomitosene

Full text of DOI:10.1021/jo981143v

2520
J . Org. Chem. 1999, 64, 2520-2523
Sch em e 1
Syn th esis of a F u lly F u n ction a lized
7-Meth oxya zir id in om itosen e
Weitong Dong and Leslie S. J imenez*
Department of Chemistry, Rutgers University,
Piscataway, New J ersey 08854-8087
Received J une 15, 1998
Mitomycin C (1) is a potent antitumor agent whose
mode of action requires activation by either enzymatic
or chemical reduction1 or mild acidic treatment.2 The
active intermediate generated by reduction of mitomycin
C is believed to be either 7-aminoleucoaziridinomitosene3
(2) or the corresponding semiquinone 3.1b This active
intermediate binds to the minor groove of DNA4 where
alkylation of the 2-amino group of guanine results in the
formation of both monoalkylated adducts and DNA cross-
links.5 Several 7-substituted 1,2-aziridinomitosenes 4
have shown activity comparable to mitomycin C against
various tumor model systems.6
A number of aziridinomitosenes (4) have been prepared
by careful reduction of natural mitomycins, followed by
reoxidation of the intermediate hydroquinone.7 Synthetic
approaches have resulted in mitosenes with various
leaving groups at C-1 and C-108 and in cyclopropamito-
senes.9 An efficient synthesis of an aziridinomitosene
with an ester group at C-9 has been recently reported.10
This paper describes the preparation of a fully function-
alized aziridinomitosene with a carbamate side chain at
C-9 in 16 steps (3.4% overall yield) from 2,5-dimethyl-
anisole.
To synthesize significant quantities of the azido me-
sylate 5, it was necessary to improve our earlier synthesis
of the intermediate 4-aminoindole 6 (Scheme 1). This
compound had been previously prepared in a single
operation (47% yield) from 3,6-dimethyl-2,4-dinitroani-
sole.11 However, the yields fell dramatically when this
reaction was attempted on more than a 0.5 g scale. Also
our previous preparation of 3,6-dimethyl-2,4-dinitroani-
sole on a multigram scale became prohibitively expensive
using nitronium tetrafluoroborate as the nitrating agent.11
An improved procedure was developed in which 2,5-
dimethylanisole could be nitrated on a 50 g scale with
sodium nitrite in trifluoroacetic acid (Scheme 1).12 The
R-keto ester 7 was prepared in a 63% yield from 3,6-
dimethyl-2,4-dinitroanisole and dimethyl oxalate in the
presence of potassium tert-butoxide.13 Reaction of 7 with
3 equiv of stannous chloride in methanol resulted in a
60% yield of the hydroxyindole 8.14 Catalytic hydrogena-
(1) (a) Tomasz, M.; Lipman, R.; Chowdary, D.; Pawlik, J .; Verdine,
G.; Nakanishi, K. Science 1987, 235, 1204-1208. (b) Cera, C.; Egbert-
son, M.; Teng, S.; Crothers, D.; Danishefsky, S. Biochemistry 1989,
28, 5665-5669. (c) Giulivi, C.; Cadenas, E. Biochem. J . 1994, 301, 21-
30. (d) Sartorelli, A.; Hodnick, W.; Belcourt, M.; Tomasz, M.; Haffty,
B.; Fischer, J .; Rockwell, S. Oncol. Res. 1994, 6, 501-508. (e) Pan, S.;
Forrest, G.; Hu, L. Cancer Res. 1995, 55, 330-335.
(2) (a) Tomasz, M.; Lipman, R. J . Am. Chem. Soc. 1979, 101, 6063-
6067. (b) Yu, F.; Pan, S. Mol. Pharmacol. 1993, 43, 863-869. (c) Pan,
S.; Yu, F.; Hipsher, C. Ibid. 870-877.
(3) (a) Han, I.; Kohn, H. J . Org. Chem. 1991, 56, 4648-4653. (b)
Iyer, V.; Szybalski, W. Science 1964, 145, 55-58, 870-877. (c)
Maliepaard, M.; De Mol, N.; J anssen, L.; Goeptar, A.; Te Koppele, J .;
Vermeulen, N.; Verboom, W.; Reinhoudt, D. Free Rad. Res. 1995, 22,
109-121.
(4) Kumar, G.; He, Q.; Behr-Ventura, D.; Tomasz, M. Biochemistry
1995, 34, 2662-2671.
(5) (a) Tomasz, M.; Lipman, R.; Chowdary, D.; Pawlik, J .; Verdine,
G.; Nakanishi, K. Science 1987, 235, 1204-1028. (b) Cera, C.; Egbert-
son, M.; Teng, S.; Crothers, D.; Danishefsky, S. Biochemistry, 1989,
28, 5665-5669. (c) Iyer, V.; Szybalski, W. Proc. Natl. Acad. Sci. U.S.A.
1963, 50, 355-362. (c) Maliepaard, M.; De Mol, N.; Tomasz, M.;
Gargiulo, D.; J annssen, L.; van Duynhoven, J .; van Velzen, E.;
Verboom, W.; Reinhoudt, D. Biochemistry 1997, 36, 9211-9220.
(6) (a) Orlemans, E.; Verboom, W.; Scheltinga, M.; Reinhoudt, D.;
Lelieveld, P.; Fiebig, H.; Winterhalter, B.; Double, J .; Bibby, M. J . Med.
Chem. 1989, 32, 1612-1620. (b) Iyengar, B.; Remers, W.; Bradner, W.
J . Med. Chem. 1986, 29, 1864-1868. (c) Iyengar, B.; Dorr, R.; Remers,
W. J . Med. Chem. 1991, 34, 1947-1951.
(8) (a) Hodges, J .; Remers, W.; Bradner, W. J . Med. Chem. 1981,
24, 1184-1191. (b) Wender, P.; Cooper, C. Tetrahedron Lett. 1987, 28,
6125-6128. (c) Luly, J .; Rappoport, H. J . Org. Chem. 1982, 47, 2404-
2413.
(9) Cotterill, A.; Hartopp, P.; J ones, G.; Moody, C.; Norton, C.;
O’Sullivan, N.; Swann, E. Tetrahedron 1994, 50, 7657-7674.
(10) Edstrom, E.; Yu, T. Tetrahedron 1997, 53, 4549-4560.
(11) Wang, Z.; J imenez, L. J . Org. Chem. 1996, 61, 816-818.
(12) Uemura, S.; Toshimitsu, A.; Okano, M. J . Chem. Soc., Perkin
Trans. 1 1978, 1076-1079. We gratefully acknowledge Vince Colan-
drea, Rutgers University, for being the first to nitrate 2,5-dimeth-
ylanisole using sodium nitrite in trifluoroacetic acid.
(13) Allen, G., J r.; Poletto, J .; Weiss, M. J . Org. Chem. 1965, 30,
2897-2904.
(7) (a) Danishefsky, S.; Egbertson, M. J . Am. Chem. Soc. 1986, 108,
4648-50. (b) Cheng, L.; Remers, W. J . Med. Chem. 1977, 20, 767-
770. (c) Patrick, J .; Williams, R.; Meyer, W.; Fulmor, W.; Cosulich, D.;
Broschard, R.; Webb, J . J . Am. Chem. Soc. 1964, 86, 1889-1890.
(14) Bellamy, F.; Ou, K. Tetrahedron Lett. 1984, 25, 839-842.
10.1021/jo981143v CCC: $18.00 © 1999 American Chemical Society
Published on Web 03/12/1999

Notes
J . Org. Chem., Vol. 64, No. 7, 1999 2521
12 with diisopropylvinylsulfonium triflate16 in the pres-
ence of sodium hydride, followed by the addition of
sodium azide. Use of dimethylvinylsulfonium iodide as
previously reported11 led to N-methylation of 12 among
other sideproducts. The mesylate 5 is obtained in a 90%
yield from 13.
Sch em e 2
The fully functionalized mitosene 14 has been synthe-
sized from the azido mesylate 5 (Scheme 2). The aldehyde
15 was obtained from 5 by Vilsmeier-Haack formylation
(96%), followed by oxidative cleavage of the TBS groups
with PCC (81%).17 Treatment of 15 with NaBH4 in
methanol for 5 min, followed by bubbling air through the
reaction solution (to reoxidize the hydroquinone) resulted
in a 74% yield of the alcohol 16. This was then converted
into the phenyl carbonate 17 by reaction with phenyl
chloroformate.8a Bubbling ammonia through a solution
of 17 dissolved in dichloromethane gave a 77% yield of
18, which was transformed into the mitosene 14 (70%)
in the presence of triphenylphosphine. Stirring 17 in 2
M ammonia in methanol for 2 days at room temperature
gave 19 (55%) plus a 21% yield of the alcohol 20. Reaction
of 19 with triphenylphosphine in the presence of triethy-
lamine did not result in the isolation of the mitosene 4
(R ) H, X ) NH2), although 19 was consumed. Mitosene
4 (R ) H, X ) NH2) appears to be quite labile under our
reaction conditions. These results are similar to those
reported earlier for optically pure 4 (R ) H, X ) NH2)
prepared from mitomycin C by electrolysis in MeOH, in
which HPLC analysis produced only the ring-opened
byproducts.7c
The synthesis of a fully functionalized mitosene 14 has
been achieved. Although this compound lacks the element
of methanol across the C9-9a double bond, it has the
two alkylating moieties, the carbamoyloxymethyl side
chain and the aziridine ring, necessary to form a DNA-
mitosene cross-link upon reduction of the quinone ring.
Such compounds have exhibited potent activity against
various tumor model systems.6
Exp er im en ta l Section
Gen er a l. Elemental analyses were processed by Quantitative
Technologies, Inc, Whitehouse, NJ . Mass spectra were processed
by the University of California Mass Spectroscopy Facility,
Riverside, CA, and the Center for Advanced Food Technology,
Rutgers University, New Brunswick, NJ .
Dichloromethane and tetrahydrofuran were distilled from
calcium hydride. Anhydrous methanol, toluene, ethyl ether, and
1.0 M hydrogen chloride in ethyl ether were obtained from
Aldrich Chemical Co.
3,6-Dim eth yl-2,4-d in itr oa n isole. In a 2-L round-bottomed
flask, 52.0 g (382 mmol) of 2,5-dimethylanisole was dissolved
into 1.0 L of trifluoroacetic acid (TFA). The solution was cooled
to -10 °C (acetone/ice bath) and stirred vigorously. A total of
158 g (2.29 mol) of NaNO2 was added into the solution in
portions (about 1 h). After this addition, another 430 mL of TFA
was added. The reaction temperature was raised slowly to room
temperature, and the solution was stirred for 24 h and then
poured into 1.0 L of ice-water. The mixture was extracted by
CH2Cl2 (4 × 500 mL), and the combined organic layer was
washed with 1 N NaHCO3 (2 × 500 mL) and brine (1 × 500
mL) and then dried over MgSO4. Filtration, followed by evapora-
tion under reduced pressure, gave a brown solid. This crude
product was recrystallized from 95% EtOH, and 63.9 g of white
crystals was obtained. The mother liquid was concentrated, and
the residue was purified by flash chromatography (1:1 CH2Cl2/
petroleum ether), yielding another 8.5 g of light yellow solid. A
total of 72.4 g was obtained (84%). Mp 63-64 °C. 1H NMR
(CDCl3): δ 2.41 (s, 3H), 2.44 (s, 3H), 3.91 (s, 3H), 7.95 (s, 1H).
MS (EI): m/z 226 (M+). Anal. Calcd for C9H10N2O5: C, 47.79;
H, 4.46; N, 12.38. Found: C, 47.75; H, 4.43; N, 12.41.
tion gave a quantitative yield of 6. This three-step
procedure allowed the synthesis of 6 on a multigram scale
in a 38% overall yield from 3,6-dimethyl-2,4-dinitroani-
sole. Oxidation of 6 with potassium nitrosodisulfonate
(Fremy’s salt) gave the corresponding quinone 9, which
was used without further purification to give the pro-
tected hydroquinone 10 by catalytic hydrogenation, fol-
lowed by treatment with 4 equiv of tert-butyldimethylsilyl
chloride and imidazole.15 The overall yield from 8 was
78%. Reduction with DIBAL gave an 89% yield of the
alcohol 11, which was converted to the corresponding
aldehyde 12 with MnO2 in 85% yield. An improved yield
(72%) of the azido alcohol 13 was obtained by reacting
(15) Kendall, P.; J ohnson, J .; Cook, C. J . Org. Chem. 1979, 44, 1421-
1424.
(16) Diisopropylvinylsulfonium triflate was prepared from diisopro-
pyl sulfide by alkylation with 2-bromoethyl triflate, followed by
treatment with silver(I) oxide in water. We gratefully acknowledge
Yufeng Wang, Rutgers University, for being the first to synthesize this
compound. See Doering, W. v. E.; Schreiber, K. J . Am. Chem. Soc. 1955,
77, 514-520.
(17) Willis, J .; Gogins, K.; Miller, L. J . Org. Chem. 1981, 46, 3215-
3218.
(18) J ones, G.; Moody, C.; Padwa, A.; Kassir, J . J . Chem. Soc., Perkin
Trans. 1 1991, 1721-1727.

2522 J . Org. Chem., Vol. 64, No. 7, 1999
Notes
Meth yl 3-(3-Meth oxy-4-m eth yl-2,6-d in itr op h en yl)-2-oxo-
p r op a n oa te (7). A total of 36.2 g (307 mmol) of 95% t-BuOK
was added into a 2-L three-necked round-bottomed flask with
500 mL of anhydrous ether under a N2 atmosphere at 0 °C. A
total of 50 mL of MeOH was added dropwise which turned the
heterogeneous mixture to a clear solution. Then 36.2 g (307
mmol) of dimethyl oxalate was added in one portion. After the
mixture was stirred for 15 min, a total of 63.0 g (279 mmol) of
3,6-dimethyl-2,4-dinitroanisole in 350 mL of anhydrous ether
was added dropwise into the solution at 0 °C. The reddish
suspension was stirred at room temperature for 2 days and
filtered to collect a reddish solid. A total of 10.0 g (14%) of
unreacted 3,6-dimethyl-2,4-dinitroanisole was recovered from
the filtrate. The reddish solid was dissolved in 1 N HCl in ether
to obtain a clear yellow solution which was washed twice with
water and dried over MgSO4. Filtration, followed by evaporation
of ether, gave a brown residue. The brown residue was passed
through a short silica gel column (1:2 ethyl acetate/petroleum
ether) to remove more polar material. Recrystallization with
ethyl acetate/petroleum ether gave 54.6 g of a yellow solid (63%).
Mp 86-88 °C. 1H NMR (CDCl3): δ 2.47 (s, 3H), 3.94 (s, 6H),
4.44 (s, 2H), 8.19 (s, 1H). 13C NMR (CDCl3): δ 16.2, 38.8, 53.3,
62.5, 121.0, 129.6, 134.3, 143.5, 147.5, 154.0, 159.9, 186.6. Anal.
Calcd for C12H12N2O8: C, 46.15; H, 3.85; N, 8.97. Found: C,
46.26; H, 3.67; N, 8.88.
4,7-Bis[(1,1-d im eth yleth yl)d im eth ylsilyloxy]-5-m eth oxy-
2-(m eth oxyca r bon yl)-6-m eth ylin d ole (10). At room temper-
ature, a solution of 500 mg (2.01 mmol) of 9 in 10 mL of CH2Cl2
was stirred with 50 mg of 10% palladium on activated carbon
in a 50-mL round-bottomed flask under a H2 atmosphere for
about 0.5 h, at which point the yellow solution had turned
colorless. A total of 545 mg (8.00 mmol) of imidazole and 1.23 g
(8.00 mmol) of tert-butyldimethylsilyl chloride was added into
the flask. The mixture was stirred for 12 h at room temperature
and then filtered through a Celite pad. Concentration and
purification of the filtrate by column chromatography (6:1
petroleum ether/ether) gave 958 mg of a colorless solid (100%).
Mp 96-98 °C. 1H NMR (CDCl3): δ 0.16 (s, 6H), 0.17 (s, 6H),
1.06 (s, 9H), 1.09 (s, 9H), 2.22 (s, 3H), 3.68 (s, 3H), 3.90 (s, 3H),
7.14 (d, 1H, J ) 2.3 Hz), 8.40-8.60 (br s, 1H). 13C NMR
(CDCl3): δ -4.5, -3.8, 10.9, 18.4, 25.9, 51.9, 60.1, 107.0, 120.2,
121.4, 125.5, 128.5, 133.1, 136.3, 142.9, 162.2. MS (EI): m/z 479
(M+). Anal. Calcd for C24H41NO5Si2: C, 60.08; H, 8.61; N, 2.92.
Found: C, 59.88; H, 8.51; N, 2.85.
4,7-Bis[(1,1-d im eth yleth yl)d im eth ylsilyoxy]-2-(h yd r oxy-
m eth yl)-5-m eth oxy-6-m eth ylin d ole (11). In a 250 mL round-
bottomed flask, a total of 3.31 g (6.91 mmol) of 10 was dissolved
into 65 mL of dry THF under a N2 atmosphere. The solution
was cooled to -20 °C (ice/salt bath) and 35.0 mL (35.0 mmol) of
1.0 M DIBAL in THF was added dropwise with stirring (∼10
min). The reaction temperature was raised from -20 °C to -5
°C over a period of 1 h. Then the mixture was quenched with
saturated potassium sodium tartrate, allowed to warm to room
temperature and then extracted by CH2Cl2 (4 × 80 mL). The
combined organic layer was dried over Na2SO4, filtered, and
evaporated under reduced pressure. Flash chromatography (1:6
ethyl acetate/petroleum ether) gave 210 mg (6.3%) of unreacted
10 and 2.79 g of a white solid 11 (89%). Mp 123-124 °C. 1H
NMR (CDCl3): δ 0.18 (s, 6H), 0.19 (s, 6H), 1.08 (s, 9H), 1.10 (s,
9H), 1.60-1.75 (br s, 1H), 2.23 (s, 3H), 3.70 (s, 3H), 4.78 (s, 2H),
6.36 (d, 1H, J ) 2.3 Hz), 7.90-8.00 (br s, 1H). 13C NMR
(CDCl3): δ -4.5, -3.7, 10.7, 18.5, 26.0, 58.8, 60.1, 98.9, 116.4,
1-Hyd r oxy -5-m eth oxy-2-(m eth oxyca r bon yl)-6-m eth yl-4-
n itr oin d ole (8). Under a N2 atmosphere, a total of 33.5 g (107
mmol) of 7 and 62.0 g (321 mmol) of anhydrous SnCl2 was
dissolved into 500 mL of methanol. The mixture was refluxed
for 1.5 h and then poured onto ice. The aqueous emulsion was
extracted with CH2Cl2 (4 × 500 mL), and the combined organic
layer was dried over MgSO4. Filtration and concentration under
reduced pressure, followed by flash chromatography (1:1 ethyl
acetate/petroleum ether), gave 18.1 g of a yellow solid (60%).
1
Mp 142-144 °C. H NMR (CDCl3): δ 2.49 (s, 3H), 3.96 (s, 3H),
4.02 (s, 3H), 7.25 (s, 1H), 7.60 (s, 1H), 10.4-10.6 (br s, 1H). 13C
NMR (CDCl3): δ 17.2, 52.7, 62.2, 102.2, 113.7, 115.8, 122.8,
130.0, 132.4, 135.8, 149.1, 163.9. MS (EI): m/z 280 (M+). Anal.
Calcd for C12H12N2O6: C, 51.43; H, 4.29; N, 10.00. Found: C,
51.56; H, 4.29; N, 9.80.
121.2, 127.5, 132.8, 135.3, 135.7, 142.5. Anal. Calcd for C23H41
-
NO4Si2: C, 61.20; H, 9.09; N, 3.10. Found: C, 61.25; H, 9.27; N,
2.93.
4-Am in o-5-m et h oxy-2-(m et h oxyca r b on yl)-6-m et h ylin -
d ole (6). At 0 °C, a total of 4.89 g (18.5 mmol) of 8 was dissolved
into 200 mL of absolute ethanol in a 500-mL round-bottomed
flask. A total of 250 mg of 10% palladium on activated carbon
was then added. The suspension was stirred under a hydrogen
atmosphere at ambient temperature for 24 h, it was filtered
through a Celite pad, and the filtrate was evaporated in vacuo.
A total of 4.09 g of 6 was obtained (100%). The product appeared
pure by TLC and 1H NMR and was carried on to the next step
without further purification. For the purpose of characterization,
a 200 mg sample was purified by flash chromatography (1:2 ethyl
acetate/petroleum ether, with 1% diethylamine). Mp 125-126
°C. 1H NMR (CDCl3): δ 2.36 (s, 3H), 3.75 (s, 3H), 3.90 (s, 3H),
4.12 (br s, 2H), 6.58 (s, 1H), 7.12 (d, 1H, J ) 1.2 Hz), 8.80-9.00
(br s, 1H). 13C NMR (CDCl3): δ 17.0, 51.8, 59.6, 102.2, 105.8,
116.8, 125.5, 131.1, 132.5, 134.6, 138.2, 162.2. MS (EI): m/z 234
(M+). Anal. Calcd for C12H14N2O3: C, 61.15; H, 6.02; N, 11.95.
Found: C, 61.17; H, 6.12; N, 11.98.
4,7-Bis[(1,1-d im eth yleth yl)d im eth ylsilyloxy]-2-for m yl-5-
m eth oxy-6-m eth ylin d ole (12). Under a N2 atmosphere, 1.96
g (4.34 mmol) of 11 was dissolved into 145 mL of dry CH2Cl2 in
a 250-mL round-bottomed flask. A total of 3.78 g (43.4 mmol) of
freshly activated MnO2 (MnO2 was heated at 110 °C in an oven
for 24 h) was added to the solution during the first 4 h (2 equiv/
h). After the solution was stirred for another 8 h at room
temperature (monitored by TLC), it was filtered through a Celite
pad and concentrated. Flash chromatography (1:14 ether/
petroleum ether) gave 1.65 g of a yellow solid (85%). Mp 108-
110 °C. 1H NMR (CDCl3): δ 0.18, (s, 12H), 1.07, (s, 9H), 1.08,
(s, 9H), 2.23, (s, 3H), 3.69 (s, 3H), 7.20 (d, 1H, J ) 2.3 Hz), 8.50-
8.65 (br s, 1H), 9.73 (s, 1H). 13C NMR (CDCl3): δ -4.5, -3.7,
11.1, 18.5, 25.9, 60.2, 113.0, 121.6, 122.6, 129.6, 133.3, 134.7,
136.9, 143.1, 181.2. MS (EI): m/z 449 (M+). Anal. Calcd for
C
23H39NO4Si2: C, 61.43; H, 8.74; N, 3.11. Found: C, 61.73; H,
8.63; N, 2.95.
1-Azid o-5,8-bis[(1,1-d im eth yleth yl)d im eth ylsilyloxy]-2,3-
d ih yd r o-2-h yd r oxy-7-m eth oxy-6-m eth yl-1H-p yr r olo[1,2-a ]-
in d ole (13). In a 100-mL round-bottomed flask, a total of 350
mg (0.78 mmol) of 12 and 47.4 mg (1.56 mmol) of NaH (80%
dispersion in mineral oil) was stirred in 10 mL of dry THF under
N2 at 0 °C. After 20 min, a total of 439 mg (1.17 mmol) of
diisopropylvinylsulfonium triflate in 10 mL of dry THF was
added slowly into the flask. Then the reaction mixture was
stirred about 14 h at ambient temperature. A total of 507 mg
(7.8 mmol) of NaN3 in 5.0 mL of 1:1 acetone-water was added
to the mixture, and the reaction mixture was stirred at room
temperature for 12 h. A total of 25 mL of water was added, and
the aqueous solution was extracted by CH2Cl2 (4 × 20 mL). The
combined organic layers were dried over Na2SO4, filtered, and
evaporated under reduced pressure. The residue was purified
by flash chromatography (7:2:1 petroleum ether:CH2Cl2:ether).
A total of 20 mg of unreacted 12 and 290 mg of 13 as a colorless
5-Meth oxy-2-(m eth oxyca r bon yl)-6-m eth ylin d ole-4,7-d i-
on e (9). In a 2-L three-necked round-bottomed flask, a total of
12.1 g (44.0 mmol) of potassium nitrosodisulfonate (Fremy’s salt)
was dissolved into 900 mL of 0.2 M NaH2PO4 at 0 °C. Then 4.40
g (18.8 mmol) of 6 in 200 mL of acetone was added into the flask.
The reaction mixture was stirred for 10 h at ambient temper-
ature and then extracted by CH2Cl2 (3 × 500 mL). The combined
organic layer was dried over MgSO4, filtered, and evaporated
under reduced pressure. A total of 3.65 g of 9 was obtained (78%).
1
The product appeared pure by TLC and H NMR and was carried
on to the next step without further purification. For the purpose
of characterization, a 200 mg sample was purified by flash
chromatography (2:5 ethyl acetate/petroleum ether). Mp 225-
226 °C. 1H NMR (CDCl3): δ 1.98 (s, 3H), 3.92 (s, 3H), 4.07 (s,
3H), 7.16 (s, 1H), 9.70-10.20 (br s, 1H). 13C NMR (CDCl3): δ
8.7, 52.5, 61.4, 112.4, 123.6, 127.4, 128.8, 132.9, 158.3, 160.5,
178.1, 178.7. MS (EI): m/z 249 (M+). Anal. Calcd for C12H11
-
oil was obtained (72%). IR: 2099 (N3), 3439 (broad, OH) cm-1
.
NO5: C, 57.83; H, 4.45; N, 5.62. Found: C, 57.80; H, 4.42; N,
5.50.
1H NMR (CDCl3): δ 0.16 (s, 6H), 0.17 (s, 6H), 1.02 (s, 9H), 1.05
(s, 9H), 2.19 (s, 3H), 3.68 (s, 3H), 4.17 (dd, 1H, J 1 ) 2.0 Hz, J 2

Notes
J . Org. Chem., Vol. 64, No. 7, 1999 2523
) 11.6 Hz), 4.46 (dd, 1H, J 1 ) 4.8 Hz, J 2 ) 11.6 Hz), 4.65-4.70
(br m, 1H), 4.72 (d, 1H, J ) 3.0 Hz), 6.50 (s, 1H). 13C NMR
(CDCl3): δ -4.4, -3.1, 11.0, 18.6, 26.0, 53.1, 60.0, 64.0, 80.3,
95.8, 117.1, 125.2, 126.0, 133.6, 135.7, 136.2, 142.7. Anal. Calcd
for C25H42N4O4Si2: C, 57.88; H, 8.16. Found: C, 58.14; H, 7.99.
1-Azid o-9-for m yl-2,3-d ih yd r o-2-(m eth a n esu lfon yloxy)-7-
m eth oxy-6-m eth yl-5,8-bis[(1,1-d im eth yleth yl)d im eth ylsi-
lyloxy]-1H-p yr r olo[1,2-a ]in d ole. In a 50-mL round-bottomed
flask, a total of 378 µL (4.20 mmol) of POCl3 was added dropwise
to 2.5 mL of anhydrous DMF under N2 at 0 °C. After the mixture
was stirred for 45 min, a total of 313 mg (0.525 mmol) of 5 in
20.0 mL of dry THF was added slowly (∼20 min). The solution
was stirred at ambient temperature for 20 h. Then, 10 mL of
water was added, and the mixture was stirred at room temper-
ature for 4 h. This aqueous solution was extracted by CH2Cl2 (3
× 20 mL). The combined organic layer was dried over Na2SO4.
Filtration, evaporation, and flash chromatography (1:4 ethyl
acetate/petroleum ether) gave 315 mg of a white solid (96%).
61.3, 61.8, 62.0, 84.2, 114.5, 121.0, 124.2, 126.2, 127.5, 128.2,
129.5, 136.0, 151.0, 153.5, 157.5, 178.6, 178.8. Anal. Calcd for
C
22H20N4O9S: C, 51.16; H, 3.88; N, 10.85. Found: C, 51.18; H,
3.85; N, 10.46.
9-[(Am in oca r b on yloxy)m et h yl]-1-a zid o-2,3-d ih yd r o-2-
(m eth a n esu lfon yloxy)-7-m eth oxy-6-m eth yl-1H-pyr r olo[1,2-
a ]in d ole-5,8-d ion e (18). In a 100 mL round-bottomed flask, a
total of 35 mg (0.068 mmol) of 17 was dissolved into 10 mL of
dry CH2Cl2 under N2 at -78 °C (dry ice/acetone bath). Then
ammonia gas was bubbled through the solution for 30 min. After
the ammonia was stopped, the temperature of the green-yellow
solution was raised from -78 °C to room temperature slowly
(∼3 h). The solution was concentrated and purified by flash
chromatography (3:2 ethyl acetate/petroleum ether). A total of
23 mg of a yellow oil was obtained (77%). IR: 2107 (N3) cm-1
.
1H NMR (CDCl3): δ 1.96 (s, 3H), 3.12 (s, 3H), 4.05 (s, 3H), 4.45-
4.66 (m, 2H), 4.83 (br s, 2H), 5.27 (d, 1H, J ) 1.5 Hz), 5.36 (s,
2H), 5.41-5.51 (m, 1H). 13C NMR (acetone-d6): δ 8.5, 38.4, 52.6,
58.6, 61.4, 63.1, 86.4, 117.4, 124.7, 128.0, 128.6, 136.7, 157.2,
158.3, 179.0, 179.5. HRMS, m/z (M+, C16H17N5O8S) calcd 439.0798,
obsd 439.0798.
Mp 138-140 °C. IR: 2111 (N3), 1654 (CHO) cm-1 1H NMR
.
(CDCl3): δ 0.21 (s, 6H), 0.22 (s, 6H), 1.01 (s, 9H), 1.04 (s, 9H),
2.22 (s, 3H), 3.10 (s, 3H), 3.72 (s, 3H), 4.61 (m, 2H), 5.41 (d, 1H,
J ) 3.2 Hz), 5.50 (s, 1H), 10.47 (s, 1H). 13C NMR (CDCl3): δ
-3.8, -3.7, -3.0, -2.8, 11.6, 18.6, 18.7, 25.9, 26.1, 38.6, 52.7,
60.3, 61.9, 84.2, 113.4, 119.1, 123.3, 124.4, 134.7, 136.9, 141.6,
145.8, 186.7. Anal. Calcd for C27H44N4O7SSi2: C, 51.92; H, 7.05;
N, 8.97. Found: C, 52.10; H, 6.84; N, 8.84.
1-Azid o-9-for m yl-2,3-d ih yd r o-2-(m eth a n esu lfon yloxy)-7-
m eth oxy-6-m eth yl-1H-p yr r olo[1,2-a ]in d ole-5,8-d ion e (15).
In a 50-mL round-bottomed flask, a total of 100 mg (0.16 mmol)
of the preceding aldehyde was dissolved into 10 mL of dry CH2-
Cl2 under N2 at room temperature. A total of 70.5 mg (0.32
mmol) of pyridinium chlorochromate (PCC) was added. After the
reaction mixture was stirred for 5 h, it was concentrated under
reduced pressure, and the product was purified by flash chro-
matography (2:3 ethyl acetate/petroleum ether). A total of 51
mg of an orange solid 15 was obtained (81%). Mp decomposed
> 150 °C. IR: 2116 (N3), 1650 (CHO) cm-1. 1H NMR (CDCl3): δ
2.01 (s, 3H), 3.12 (s, 3H), 4.10 (s, 3H), 4.61 (s, 1H), 4.62 (s, 1H),
5.45 (s, 2H), 10.42 (s, 1H). 13C NMR (CDCl3): δ 8.5, 38.7, 52.6,
61.4, 61.8, 83.9, 118.2, 125.4, 127.7, 128.4, 140.4, 157.6, 178.7
(merged), 186.1. Anal. Calcd for C15H14N4O7S: C, 45.68; H, 3.55;
N, 14.21. Found: C, 45.78; H, 3.51; N, 14.04.
1-Azido-2,3-dih ydr o-9-(h ydr oxym eth yl)-2-(m eth an esu lfo-
n yloxy)-7-m et h oxy-6-m et h yl-1H-p yr r olo[1,2-a ]in d ole-5,8-
d ion e (16). A total of 127 mg (0.32 mmol) of 15 was partially
dissolved into 10 mL of methanol at room temperature. Then
61 mg (1.6 mmol) of NaBH4 was added. Bubbles could be seen
immediately, and the yellow color of the solution turned colorless
in 5 min. Air was then bubbled through the solution. The air
was stopped when a yellow solid appeared in the methanol
solution. A total of 10 mL of water was added, and the aqueous
solution was extracted by CH2Cl2 (3 × 10 mL). The combined
yellow organic layer was dried over Na2SO4. Filtration, evapora-
tion of the solvent under reduced pressure, and flash chroma-
tography (3:2 ethyl acetate/petroleum ether) gave 94 mg of a
8-[(Am in oca r b on yloxy)m et h yl]-1,1a ,2,8b -t et r a h yd r o-6-
m eth oxy-5-m eth yla zir in o[2′,3′:3,4]p yr r olo[1,2-a ]in d ole-4,7-
d ion e (14). In a 25-mL round-bottomed flask, a total of 18 mg
(0.041 mmol) of 18 was dissolved into 2.2 mL of 10:1 THF/H2O.
Then, 40 µL of NEt3 was added, followed by 16.2 mg (0.060
mmol) of PPh3. The mixture was stirred at room-temperature
overnight. A total of 10 mL of water was added, and the aqueous
solution was extracted with CH2Cl2 (3 × 10 mL). The combined
CH2Cl2 portions were dried over Na2SO4. Filtration, evaporation
of the solvent under reduced pressure, and flash chromatography
(5:95 methanol/ethyl acetate) gave 9 mg of an orange solid (70%).
Mp decomposed > 200 °C. 1H NMR: because 14 exists as a
mixture of invertomers (isomers by inversion at the aziridine
center) and the isomerization is very slow at room temperature,
some shoulder peaks could be seen. This is more obvious in
CDCl3 than in pyridine-d5. (CDCl3): δ 1.93 (s, 3H), 1.96 (s, minor
isomer’s peak), 3.49 (t, 1H, J ) 3.8 Hz, with a small side peak
at 3.44), 3.62 (br s, 1H), 4.02 (s, 3H, with a small shoulder peak),
4.22-4.44 (m, 2H, with small side peaks at 4.05-4.20), 4.67 (br
s, 2H), 5.27 (d, J ) 12.9 Hz, 1H), 5.36 (d, J ) 12.9 Hz, 1H).
(C5D5N): δ 1.97 (s, 3H), 3.35 (t, 1H, J ) 3.7 Hz), 3.76-3.84 (m,
1H), 3.97-4.16 (m, 1H), 4.00 (s, 3H), 4.38 (d, 1H, J ) 14.1 Hz),
5.72 (d, 2H, J ) 0.92 Hz), 7.74 (br s, 2H). MS (EI): m/z 317
(M+). HRMS, m/z (M+, C15H15N3O5) calcd 317.1012, obsd 317.1010.
7-Am in o-9-[(a m in oca r bon yloxy)m eth yl]-1-a zid o-2,3-d i-
h yd r o-2-(m eth a n esu lfon yl- oxy)-6-m eth yl-1H-p yr r olo[1,2-
a ]in d ole-5,8-d ion e (19) a n d 7-a m in o-1-a zid o-2,3-d ih yd r o-
9-(h yd r oxylm eth yl)-2-(m eth a n esu lfon yloxy)-6-m eth yl-1H-
p yr r olo[1,2-a ] in d ole-5,8-d ion e (20). In
a 25-mL round-
bottomed flask, a total of 33 mg (0.064 mmol) of 17 was dissolved
into 3.0 mL of 2.0 M ammonia in methanol under N2. The
mixture was stirred at room temperature for 24 h. The original
yellow-colored solution had turned red and a black precipitate
was formed. The solvent was removed under reduced pressure
and acetone was used to rinse out the products except the black
precipitate. The red acetone solution was concentrated and
purified by flash chromatography (3:2 ethyl acetate/petroleum
ether). A total of 15 mg of a red oil of 19 (55%) and 5 mg of 20
yellow solid (74%). Mp decomposed > 150 °C. IR: 2109 (N3) cm-1
.
1H NMR (CDCl3): δ 1.45-1.75 (br s, 1H), 1.98 (s, 3H), 3.12 (s,
3H), 4.04 (s, 3H), 4.55 (s, 1H), 4.56 (d, 1H, J ) 5.9 Hz), 4.82 (d,
2H, J ) 4.2 Hz), 5.20 (d, 1H, J ) 1.6 Hz), 5.46 (m, 1H). Anal.
Calcd for C15H16N4OS: C, 45.45; H, 4.04; N, 14.14. Found: C,
45.69; H, 3.95; N, 13.89.
(21%) was obtained. For 19: IR: 2111 (N3) cm-1 1H NMR
.
(CDCl3): δ 1.86 (s, 3H), 3.12 (s, 3H), 4.54-4.59 (m, 2H), 4.76-
4.82 (br s, 2H), 5.00 (br s, 2H), 5.23 (d, 1H, J ) 1.6 Hz), 5.35 (s,
2H), 5.43-5.49 (m, 1H). 13C NMR (acetone-d6): δ 8.3, 38.5, 52.5,
58.8, 63.0, 86.6, 107.0, 116.9, 122.6, 130.3, 134.5, 147.8, 157.3,
177.3, 179.2. For 20: 1H NMR (CDCl3): δ 1.87 (s, 3H), 3.11 (s,
3H), 4.56 (d, 2H, J ) 3.1 Hz), 4.78-4.84 (m, 2H), 4.99 (br s,
2H), 5.17 (d, 1H, J ) 1.1 Hz), 5.41-5.48 (m, 1H). MS (EI): m/z
381 (M+). HRMS, m/z (M+, C14H15N5O6S) calcd 381.0743, obsd
381.0743.
1-Azid o-2,3-d ih yd r o-2-(m eth a n esu lfon yloxy)-7-m eth oxy-
6-m eth yl-9-[(p h en oxy- ca r bon yloxy)m eth yl]-1H-p yr r olo-
[1,2-a ]in d ole-5,8-d ion e (17). In a 100-mL round-bottomed
flask, a total of 94 mg (0.24 mmol) of 16 was partially dissolved
into 20 mL of dry CH2Cl2 under N2 at 0 °C. Then, 313 µL (1.20
mmol) of pyridine and 313 µL (1.20 mmol) of phenyl chlorofor-
mate were added via syringe. The solution was stirred at
ambient temperature for 5 h. Then it was washed with 1 N
NaHCO3 (3 × 10 mL), 1 N HCl (3 × 10 mL), and brine (3 × 10
mL) and dried over Na2SO4. Filtration and evaporation of the
solvent under reduced pressure, followed by flash chromatog-
raphy (2:3 ethyl acetate/petroleum ether), gave 110 mg of a
Ack n ow led gm en t. We gratefully acknowledge the
financial support of the donors of the Petroleum Re-
search Fund, administered by the American Chemical
Society, and of the National Science Foundation
(CHE-9502149).
yellow oil (90%). IR: 2110 (N3) cm-1 1H NMR (CDCl3): δ 1.97
.
(s, 3H), 3.07 (s, 3H), 4.06 (s, 3H), 4.48-4.68 (m, 2H), 5.27-5.31
(m, 1H), 5.42-5.50 (m, 1H), 5.53 (d, 2H, J ) 2.6 Hz), 7.14-7.31
(m, 3H), 7.33-7.45 (m, 2H). 13C NMR (CDCl3): δ 8.5, 38.7, 51.7,
J O981143V