Synthesis of 8-methoxy-1-methyl-1H-benzo[de][1-6]naphthyridin-9-ol (isoaaptamine) and analogues

Article abstract of DOI:10.1021/jo001080s

8-Methoxy-1-methyl-1H-benzo[de][1,6]naphthyridin-9-ol, isoaaptamine, a PKC inhibitor isolated from sponge was synthesized. The synthesis parallels a synthesis of 8,9-dimethoxybenzo[de][1,6]-naphthyridine, aaptamine, but uses a nitromethyl substituent as a precursor of the key 5-(2-aminoethyl)-1H-quinolin-4-one intermediate. The quinolone intermediates were prepared by thermolysis (220-240 °C) of anilinomethylene derivatives of Meldrum's acid. The quinolone intermediates were N-methylated prior to cyclization to the benzo[de][1,6]naphthyridine derivatives. Aaptamine and several analogues of aaptamine and isoaaptamine were prepared including 9-demethylaaptamine, 1-methyl-8-demethylaaptamine, 1-methylaaptamine, and the 8,9-methylenedioxy analogues of aaptamine and 1-methylaaptamine.

Full text of DOI:10.1021/jo001080s

J . Org. Chem. 2000, 65, 8001-8010
8001
Syn th esis of
8-Meth oxy-1-m eth yl-1H-ben zo[d e][1,6]n a p h th yr id in -9-ol
(Isoa a p ta m in e) a n d An a logu es
Andrew J . Walz and Richard J . Sundberg*
Department of Chemistry, University of Virginia, McCormick Road, Charlottesville, Virginia 22904-4319
rjs1d@virginia.edu
Received J uly 17, 2000
8-Methoxy-1-methyl-1H-benzo[de][1,6]naphthyridin-9-ol, isoaaptamine, a PKC inhibitor isolated
from sponge was synthesized. The synthesis parallels a synthesis of 8,9-dimethoxybenzo[de][1,6]-
naphthyridine, aaptamine, but uses a nitromethyl substituent as a precursor of the key 5-(2-
aminoethyl)-1H-quinolin-4-one intermediate. The quinolone intermediates were prepared by
thermolysis (220-240 °C) of anilinomethylene derivatives of Meldrum’s acid. The quinolone
intermediates were N-methylated prior to cyclization to the benzo[de][1,6]naphthyridine derivatives.
Aaptamine and several analogues of aaptamine and isoaaptamine were prepared including
9-demethylaaptamine, 1-methyl-8-demethylaaptamine, 1-methylaaptamine, and the 8,9-methyl-
enedioxy analogues of aaptamine and 1-methylaaptamine.
The isolation of 8-methoxy-1-methyl-1H-benzo[de][1,6]-
naphthyridin-9-ol, referred to herein as isoaaptamine,
was first reported in 1988 by Fedoreev and co-workers,
who isolated the compound from a Suberitidae sponge.1
The compound was isolated again in 1990 from the Red
Sea sponge, Aaptos aaptos.2 A natural product drug
discovery program at SmithKline Beecham led to isola-
tion of isoaaptamine on the basis of anti-cancer screen-
ing.3 The purified compound showed activity as a PKC
inhibitor, but was inactive against PKA. The isolation of
the compound has again been reported recently, and it
shows cytotoxicity toward several tumor cell lines.4 The
goal of the present work was to develop a method for
synthesis of isoaaptamine and analogues in order to
explore the structural range of PKC inhibitory and
antitumor activity. Isoaaptamine is closely related struc-
turally to aaptamine5 and is also related to demethyl-
(oxy)aaptamine, which has shown cytotoxicity5 and ac-
tivity in a cell adherence assay related to PKC inhibition.6
There have been several syntheses of aaptamine,7 and
demethyl(oxy)aaptamine has also been synthesized.8
There has been no report of the synthesis of isoaaptamine.
The existing aaptamine syntheses use either the quino-
line or isoquinoline components of the benzo[de][1,6]-
naphthyridine ring as the nucleus on to which the third
ring is constructed. The former group includes the routes
developed by Cava,8 Yamanaka,9 Tollari,10 and J oule.11
The syntheses of Kelly,12 Raphael,13 and Sato14 proceed
through quinoline intermediates. After consideration and
brief exploration of some of the other routes, we decided
to adapt the Andrew-Raphael route to the synthesis of
isoaaptamine. The key step in this synthesis is the
cyclization of a 5-(2-aminoethyl)-4-quinolone to the benzo-
[de][1,6]naphthyridine ring by heating with hexameth-
yldisilazane and ammonium sulfate.
(1) Fedoreev, S. A.; Prokof’eva, N. G.; Denisenko, V. A.; Rebachuk,
N. M. Khim.-Farm. Zh. 1988, 22, 943.
(2) Kashman, Y.; Rudi, A.; Hirsch, S.; Isaacs, S.; Green, D.; Blas-
berger, D.; Carmely, S. New. J . Chem. 1990, 14, 729.
(3) Patil, A. D.; Westley, J . W.; Mattern, M.; Freyer, A. J .; Hoffman,
G. A. PCT Int. Appl. WO95/0584, March, 1995.
(4) Shen, Y.-C.; Chein, C.-C.; Hsieh, P.-W.; Duh, C.-Y. J . Fish. Soc.
Taiwan 1997, 24, 117; Shen, Y.-C.; Lin, T.-T.; Sheu, J .-H.; Duh, C.-Y.
J . Nat. Prod. 1999, 62, 1264.
(5) Aaptamine was first isolated from Aaptos aaptos: Nakamura,
H.; Kobayashi, J .; Ohizumi, Y. Tetrahedron Lett. 1982, 23, 5555;
Nakamura, H.; Kobayashi, J .; Ohizumi, Y. J . Chem. Soc., Perkin Trans
1 1987, 173. It has subsequently been isolated from several other
species of sponges. Berquist, P. R., Combie, R. C.; Kernan, M. R.
Biochem. Syst. Ecol. 1991, 19, 289. Mohamed, R.; Lee, L. J .; Omar, S.
Proc. 16th Malays. Biochem. Soc. Conf. 1991, 37. Park, S. K.; Kim, S.
S.; Park, J . D.; Hong, J . S.; Kim, I. K. J . Korean Chem. Soc. 1995, 39,
559.
Adaptation of this synthesis to isoaaptamine required
a selective protection of the 9-oxygen and, more impor-
tantly, the introduction of the N-methyl group at an
appropriate point. The construction of the quinolone
intermediate proceeds by the well-known Conrad-Lim-
(9) Sakamoto, T.; Miura, N.; Kondo, Y.; Yamanaka, H. Chem.
Pharm. Bull. 1986, 34, 2760.
(10) Bassoli, A.; Maddinelli, G.; Rindone, B.; Tollari, S.; Chicoccara,
F. J . Chem. Soc., Chem. Commun. 1987, 150.
(11) Balczewski, P.; Mallon, M. K. J .; Street, J . D.; J oule, J . A.
Tetrahedron Lett. 1990, 31, 568. Balczewski, P.; Mallon, M. K. J .;
Street, J . D.; J oule, J . A. J . Chem. Soc., Perkin Trans. 1 1990, 3193.
(12) Kelly, T. R.; Maquire, M. P. Tetrahedron 1985, 41, 3033.
(13) Andrew, R. G.; Raphael, R. A. Tetrahedron 1987, 43, 4803.
(14) Hibino, S.; Sugino, E.; Choshi, T.; Sato, K. J . Chem. Soc., Perkin
Trans. 1 1988, 2429.
(6) Longley, R. E.; McConnell, O. J .; Essich, E.; Harmody, D. J . Nat.
Prod. 1993, 56, 915.
(7) Reviewed by Sugino, E.; Choshi, T.; Hibino, S. Heterocycles 1999,
50, 543.
(8) Pelletier, J . C.; Cava, M. P. Tetrahedron Lett. 1985, 26, 1259;
Pelletier, J . C.; Cava, M. P. J . Org. Chem. 1987, 52, 616.
10.1021/jo001080s CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/13/2000

8002 J . Org. Chem., Vol. 65, No. 23, 2000
Walz and Sundberg
pach synthesis,15 using an anilinomethylene Meldrum’s
acid intermediate, as developed by Cassis, Tapai, and
Valderarrama.16 5-Nitrovanillin was benzylated and
converted to the TBS-protected cyanohydrin 5b.13 Selec-
tive reduction of the nitro group was achieved using TiCl3
near neutral pH.17 Condensation with the methoxy-
methylene derivative of Meldrum’s acid (8) provided 7b,
which was cyclized to the quinolone 9b in 56% yield. A
similar route, with the 8-hydroxy protected by a TBS
group, provided quinolone 9c. A good yield of 10b was
obtained by N-methylation of 9b, but several efforts to
reduce the cyano group to the primary amine failed,
probably because of competing debenzylation. Efforts to
N-methylate 9c were foiled by concomitant loss of the
TBS protecting group. An alternate approach using
Katritzky’s N-hydroxymethylbenzotriazole method16 suc-
ceeded for methylation of the protected cyanohydrin 6c
to give 6d . This compound was successfully condensed
with 8 to give 7d . However, 7d was recovered unchanged
from the cyclization conditions (240 °C, 1 h). This result
indicates a requirement for an unsubstituted nitrogen
in the cyclization. It appears that the N-H must play a
role in determining the rate of decomposition of the
dioxane-4,6-dione ring. Mechanistic studies of the ther-
mal decomposition of anilinomethylene Meldrum’s acid
derivatives have mainly been carried out under flash
vacuum pyrrolysis (FVP) conditions and have emphasized
the role of a 1,3-hydrogen shift.19 Under FVP conditions
the N-methylanilinomethylene derivative gives 1-phenyl-
2H-pyrrol-3-one, not N-methylquinolone.20
quinolone 9e occurred in good yield. N-Methylation with
methyl iodide gave 10e. The reduction of the cyano group
again proved troublesome, however. The best conditions
found involved use of CoCl2 and NaBH4.21 When followed
by selective protection of the primary aminomethyl group
by carboxybenzylation, 11e was obtained in 34% yield.
The reduction was hard to reproduce, however. Applica-
tion of modified Andrew-Raphael cyclization conditions13
to 11e provided 2e. Andrew and Raphael used sonication
to accelerate the reaction. We found inclusion of triethy-
lamine in the reaction made sonication unnecessary
(Scheme 1). A more efficient synthesis of 2e was eventu-
ally developed.
Because the difficulties with the previous approaches
resulted mainly from the reaction conditions required for
reduction of the cyano group, a revised route using a
nitromethyl group was developed. Condensation of ni-
tromethane with 3b catalyzed by Amberlyst A21 ion-
exchange resin,22 followed by protection with TBS triflate
gave 12b. Both nitro groups were reduced using NiCl2-
23
NaBH4 and the primary alkylamine was selectively
protected by CBZ-Cl by reaction at -78 °C f -30 °C.
The primary arylamine 14b reacted with 8 to give 15b.
The cyclization of 15b was successful, although the yield
of 16b was somewhat lower (35%) than had been achieved
with the nitrile intermediate. Good regioselectivity for
N versus O alkylation of the quinolone 16b was achieved
with methyl iodide and K2CO3 in DMF. After removal of
the CBZ protecting group by transfer hydrogenolysis,24
cyclization and aromatization gave isoaaptamine 2b in
73% yield. The overall yield of 2b was 15% (Scheme 2).
HRMS confirmed the composition of the synthetic mate-
rial, and 1H and 13C NMR comparison of synthetic
isoaaptamine with a sample of natural origin confirmed
their identity.
Cyclization of 16b gave 1b, 9-demethylaaptamine 1b.
Air oxidation gave demethyl(oxy) aaptamine 18, which
has previously been isolated as a natural product5 and
synthesized.8
Modification of the O- and N-alkylation pattern of the
isoaaptamine synthesis permitted synthesis of aaptamine
and several new analogues. Aaptamine 1f and N-methyl-
aaptamine, 2f, were prepared starting with 5-nitrovera-
traldehyde.13 Modification of the conditions of the ni-
tromethane addition were needed because of failure of
the anionic resin to produce good yields. Conditions
reported by Fernandez et al. involving TBS-chloride and
TBAF, followed by TBS-triflate,25 gave an 86% yield of
the silylated adduct 12f. Reduction of 12f was done by
transfer hydrogenation24 to give 13f. Carboxybenzylation,
condensation with 8, and cyclization to 15f proceeded in
excellent yield. After removal of the CBZ group, cycliza-
tion proceeded to give aaptamine hydrochloride in 83%
yield. The overall yield of 42% represents a modest
improvement on the 26% overall yield reported by
Andrew and Raphael using the cyano intermediate.13
An isomer of isoaaptamine, compound 2e, 1-methyl-
8-demethylaaptamine, was successfully synthesized fol-
lowing a similar route. The aldehyde 3e with reversed
placement of the methoxy and benzyloxy substituents
was prepared from 5-nitrovanillin. Conversion to the
TBS-protected cyanohydrin and the condensation with
8 proceeded smoothly to give 7e. Thermal cyclization to
1
Comparison of the H-spectrum with the published data
(15) J ones, G. In Quinolines, Part I, The Chemistry of Heterocyclic
Compounds; J ohn Wiley & Sons: New York, 1978; Vol. 32, pp 139-
150. Reitsema, R. H. Chem. Rev. 1948, 48, 43.
(16) Cassis, R.; Tapia, R.; Valderrama, J . A. Synth. Commun. 1985,
15, 125.
(17) Moody, C. J .; Rahimtoola, K. F. J . Chem. Soc., Perkin Trans. 1
1990, 673.
for the natural compound, and spectra of synthetic
material provided by Cava,8 J oule,11 and Kelly12 con-
firmed the identity of the product. We observed a
significantly higher melting point, 176-177 °C, than
(18) Katritzky, A. R.; Rachwal, S.; Rachwal, B. J . Chem. Soc., Perkin
Trans. 1 1987, 799.
(19) Gordon, H. J .; Martin, J . C.; McNab, H. J . Chem. Soc., Chem.
Commun. 1983, 957. Briehl, H.; Lukosh, A.; Wentrup, C. J . Org. Chem.
1984, 49, 2772.
(20) McNab, H.; Monahan, L. C. J . Chem. Soc., Chem. Commun.
1985, 213.
(21) Satoh, T.; Suzuki, S.; Suzuki, Y.; Miyaji, Y.; Imai, Z. Tetrahe-
dron Lett. 1969, 4555.
(22) Ballini, R.; Bosica, G.; Forconi, P. Tetrahedron 1996, 52, 1677.
(23) Nose, A.; Kudo, T. Chem. Pharm. Bull. 1981, 29, 1159.
(24) Ram, S.; Ehrenkaufer, R. E. Tetrahedron Lett. 1984, 25, 3415.
(25) Fernandez, R.; Gasch, C.; Gomez-Sanchez, A.; Vilchez, J . E.
Tetrahedron Lett. 1991, 32, 3225.

Synthesis of Isoaaptamine
J . Org. Chem., Vol. 65, No. 23, 2000 8003
Sch em e 1a
a
Key: (a) KOH, BnN+(Bu)3Br-, BnBr, CH2Cl2, H2O, rt, 24 h; 3b (92%); (b) AlCl3, pyridine, CHCl3, 0 °C to reflux, 24 h; 3c (98%); (c)
KF, BnBr, DMF, 140 °C, 48 h; 3d (93%); (d) KOH, BnN+(Bu)3Br-, Me2SO4, CHCl3, H2O, rt, 36 h; 3e (92%); (e) KCN, Znl2, TBS-Cl,
18-crown-6, acetonitrile, 70 °C; 3 h, 5b (92%); 48 h, 5c (82%); 5h, 5e (81%); (f) TiCl3 in 20% HCl, 4 M NH4OAc, acetone, rt, 12 h; 6b (86%);
(g) TiCl4, HgCl2, Mg, t-BuOH, THF, 15 min; 5c, 0 °C, 1.5 h; 6c (85%); (h) 1-HOCH2Bt, EtOH, rt, 24 h, NaBH4, THF, reflux, 6d (77%); (i)
8, reflux 12 h; 7b (85%); 7c (83%); 7e (88%); (j) diphenyl ether; 220 °C, 20 min, 9b (56%); 240 °C, 15 min, 9c (52%); 240 °C, min, 9e (78%);
(k) K2CO3, MeI, DMF, 70 °C, 2 h, 10e (96%); (l) CoCl2, NaBH4, MeOH, 0 °C, 2 h; CBZ-Cl, Et3N, DMAP, DMF, 0 °C, 3 h, 10e (34%); (m)
(NH4)2SO4, Et3N, HMDSA, MeOH, HCl, rt, 20 h; 2e (68%).
Sch em e 2a
The analogues in which the O(8)-O(9) methylation
pattern was reversed from that in isoaaptamine were
prepared using 3e as the starting aldehyde. The ni-
tromethane addition was successful using the Amberlyst
A-21 procedure.22 The other steps parallel the isoaapt-
amine synthesis. The final cyclization and aromatization
gave N-methyl-8-demethylaaptamine 2e in 76% yield.
The unmethylated quinolone 16e was converted to 8-dem-
ethylaaptamine 1e in 68% yield.
The final analogues targeted for synthesis were 8,9-
methylenedioxy derivatives. The nitration of 1,3-benzo-
dioxole-5-carboxaldehyde gives the 6-nitro product.26 It
was therefore necessary to find an alternate means for
introduction of nitrogen at C5. The bromoaldehyde 3d 27
was chosen as the starting material and was protected
as the dioxolane. Buchwald’s Pd-catalyzed amination
conditions28 gave 4i in 96% yield after removal of the
dioxolane protecting group. Addition of nitromethane
(Amberlyst A-21) and O-silylation proceeded efficiently
to give 12g (86%). The N-CBZ protecting group was
removed cleanly at the same time as the reduction of the
nitro group by use of transfer hydrogeneration with 10%
Pd-C and NH4+HCO2 (95%).24 The remainder of the
-
synthesis followed the previous method (Scheme 3). Both
the N-methyl, 2g, and unsubstituted, 1g, methylenedioxy
analogues were obtained.
a
Key: (a) CH3NO2, Amberlyst A-21, rt, 3 h, TBSOTf, 2,6-
lutidine, 0 °C to rt, 1 h; 12b (92%); (b) NiCl2, NaBH4, 25 °C, 25
min; 13b (86%); (c) CBZ-Cl, DMAP, K2CO3, -78 °C to -30 °C, 8
h, 14b (97%); (d) 8, reflux 4 h; 15b (87%); (e) diphenyl ether; 240
°C, 20 min, 16b (35%); (f) K2CO3, MeI, DMF; 100 °C, 2 h, 17b
(79%); (g) 10% Pd-C, NH4OAc, MeOH, 40 °C, 20 min; (h)
(NH4)2SO4, Et3N, HMDSA, reflux, 20 h; MeOH, HCl, rt, 20 h; 1b
(83%), 2b (73%); (i) MeOH, O2, 0.2 M NaHCO3, 1 h, 18 (73%).
Biologica l Activity
Compounds 1b, 1e, 2e, 1g, and 2g were submitted for
evaluation in the NCI tumor cell line panel.29 Compounds
2b , 1g, and 2g showed sufficient initial response for
previously reported. It is not clear if this represents a
different crystal form or a different state of hydration.
N-Methylation of 16f prior to the cyclization gave 17f,
which was converted to N-methylaaptamine 2f in 73%
yield. This compound was previously prepared by Hibino
et al. by a process involving N-methylation during a
thermal cyclization.14
(26) Bogert, M. T.; Elder, F. R. J . Am. Chem. Soc. 1929, 51, 532.
Parys, A. H. Rec. Trav. Chim. Pays-Bas 1930, 49, 17.
(27) Sinhababu, A. K.; Borchardt, R. T. J . Org. Chem. 1983, 48, 1941.
(28) Wolfe, J . P.; Wagaw, S.; Buchwald, S. L. J . Am. Chem. Soc.
1996, 118, 7215.
(29) Boyd, M. R. In Anticancer Drug Development Guide: Preclinical
Screening, Clinical Trials and Approval; Teicher, B., Ed.; Humana
Press: Totowa, NJ , 1997.

8004 J . Org. Chem., Vol. 65, No. 23, 2000
Walz and Sundberg
Sch em e 3a
a
Key: (a) AlCl3, pyridine, CHCl3, 0 °C to reflux, 24 h; 3c (98%); 36 h, 3h (92%); (b) KF, BnBr, DMF, 140 °C, 48 h; 3d (93%); (c) KOH,
BnN+(Bu)3Br-, Me2SO4, CHCl3, H2O, rt, 36 h; 3e (92%); 12g (86%); (d) CH3NO2, Amberlyst A-21, rt 3 h; TBSOTf, 2,6-lutidine, 0 °C to rt,
2 h, 3f (93%), CH3NO2, TBAF, Et3N, TBS-Cl, 0 °C to rt, 3 h; TBSOTf, 2,6-lutidine, 0 °C to rt, 2 h, 10e (93%); (e) NiCl2, NaBH4, 0 °C, 25
min; 13e (76%), 10% Pd-C, NH4O2CH, reflux, 2 h; 13f (100%); 13g (98%); (f) CBZ-Cl, DMAP, K2CO3, -78 to -30 °C, 8 h, 14e (97%); 14f
(84%); 14g (91%); (g) KF, CH2Br2, DMF, 140 °C, 4 h, 3i (85%); (h) HOCH2CH2OH, PTSA, benzene, reflux 24 h; 4c (98%); (i) BnNH2,
Pd2(dba)3, S-Binap, NaO-t-Bu, toulene, 90 °C, 3 h, 4j (96%); (j) PPTS, acetone, H2O, reflux, 30 min; 4i (100%); (k) 8, reflux 4 h; 15e (82%);
15f (86%); 15g (84%); (l) diphenyl ether; 240 °C, 20 min, 16e (82%); 16f (68%); 16g (67%); (m) K2CO3, MeI, DMF, 100 °C, 2 h, 17e (96%);
17f (68%); 17g (86%); (n) 10% Pd-C, NH4O2CH, MeOH, 40 min; (o) (NH4)2SO4, Et3N, HMDSA, reflux, 20 h; MeOH, HCl, rt, 20 h; 1e
(76%); 1f (85%); 1g (68%); 2e (68%); 2f (73%); 2g (91%).
with 10% aqueous NaOH and brine. The organic layer was
dried with MgSO4 and filtered, and solvents were removed in
vacuo. The residue was flash chromatographed (hexanes to
CH2Cl2) to give 6.82 g of 3b as a pale yellow oil (92% yield):
repeat testing in the primary screen but none met the
criteria for further evaluation.
Exp er im en ta l Section
1
lit.30 mp 57-58 °C; H NMR (CDCl3) δ 9.92 (s, 1H), 7.83 (d,
1H, J ) 1.83 Hz), 7.64 (d, 1H, J ) 1.83 Hz), 7.48-7.35 (m,
5H), 5.30 (s, 2H), 4.02 (s, 3H); 13C NMR (CDCl3) δ 189.5, 155.4,
146.9, 145.8, 136.2, 132.1, 129.2, 129.14, 129.08, 120.2, 113.4,
76.8, 57.2; MS m/z 288 (M + 1).
Gen er a l P r oced u r es. Starting materials were obtained
from commercial sources and used without further purification.
Tetrahydrofuran (THF) was distilled from sodium/benzophe-
none. Triethylamine (TEA), pyridine, acetonitrile, and toluene
were distilled from calcium hydride and stored under nitrogen.
Reactions under anhydrous conditions were performed using
oven-dried and/or flame-dried glassware and dry solvents
under an inert atmosphere. Melting points were determined
on a Thomas-Hoover capillary melting point apparatus in an
open capillary tube and are uncorrected. EM Science alumi-
num TLC plates coated with silica gel 60 F254 were visualized
with UV light, vanillin stain, and/or Dragendorff stain. Flash
chromatography was performed under medium pressure using
either ICN Silica 60, 32-63 Å, or EM Science silica gel 60
Geduran, 35-75 µM. Solvent removal was normally done using
a rotary evaporator under aspirator pressure. High boiling
solvents were removed using a vacuum pump. NMR spectra
were recorded at 300 MHz for proton and 75 MHz for carbon.
Multiplicities are given as s (singlet), d (doublet), t (triplet), q
(quartet), m (multiplet), and br (broad).
2-(ter t-Bu tyld im eth ylsilyloxy)-2-(4-ben zyloxy-3-m eth -
oxy-5-n itr op h en yl)eth a n on itr ile (5b). To 20 mL of freshly
distilled acetonitrile were added, in order, the aldehyde 3b
(1.00 g, 3.48 mmol), KCN (1.13 g, 17.40 mmol), 50 mg of 18-
crown-6, and 50 mg of ZnI2. A positive pressure of nitrogen
was established, and the solution was stirred at room tem-
perature for 15 min. tert-Butyldimethylsilyl chloride (TBS-
Cl) (630 mg, 4.18 mmol) was added, and the solution was
heated at 70 °C for 3 h. The solvent was removed and the
residue suspended in 50 mL of EtOAc and filtered. The filtrate
was washed several times with distilled water. The organic
layer was dried with MgSO4 and filtered and the solvent
removed in vacuo. Flash chromatography (2:1 EtOAc/hexanes)
gave 1.37 g of 5b as a pale yellow solid in 92% yield: 1H NMR
(CDCl3) δ 7.50-7.33 (m, 5H), 7.25 (s, 1H), 7.24 (s,1H), 5.50 (s,
1H), 5.19 (s, 2H), 3.97 (s, 3H), 0.96 (s, 9H), 0.27 (s, 3H), 0.19
(s, 3H); 13C NMR (CDCl3) δ 154.5, 144.8, 141.7, 135.7, 132.3,
128.3, 128.18, 128.15, 118.0, 113.1, 112.7, 75.7, 62.5, 56.3, 25.1,
17.8, -5.4, -5.6; MS m/z 428 (M+).
4-Ben zyloxy-3-m eth oxy-5-n itr oben za ld eh yd e (3b) A
mixture of 5-nitrovanillin 3a (5.00 g, 25.36 mmol), benzyl
bromide (21.70 g, 126.80 mmol), KOH (2.33 g, 56.72 mmol),
and benzyltriethylammonium chloride (2.90 g, 12.68 mmol) in
60 mL of CH2Cl2 and 60 mL of distilled water was stirred at
room temperature for 24 h under nitrogen. The aqueous layer
was extracted with CH2Cl2 and combined with the organic
layer of the reaction mixture. The CH2Cl2 solution was washed
2-(5-Am in o-4-ben zyloxy-3-m eth oxyp h en yl)-2-(ter t-bu -
tyld im eth oxysilyloxy)eth a n on itr ile (6b) The silylated cy-
anohydrin 5b (1.00 g, 2.33 mmol) was dissolved in 30 mL of
(30) Martin, P. Helv. Chim. Acta 1989, 72, 1554.

Synthesis of Isoaaptamine
J . Org. Chem., Vol. 65, No. 23, 2000 8005
acetone, and 60 mL of 4 M NH4O2CCH3 solution was added.
TiCl3 (3.31 g, 21.4 mmol) was added as a 19% solution in 20%
aqueous HCl (14.6 mL). The solution was stirred at room
temperature for 12 h. The solution was extracted with CH2-
Cl2. The combined organic layers were washed with water. The
organic layer was dried with MgSO4 and filtered, and the
solvents were removed in vacuo. The residue was purified by
flash chromatography (CH2Cl2) to give 848 mg of 6b as a tan
amorphous solid in 86% yield: 1H NMR (CDCl3) δ 7.48-7.31
(m, 5H), 6.46 (d, 1H, J ) 1.47 Hz), 6.44 (d, 1H, J ) 1.95 Hz),
5.37 (s, 1H), 5.00 (s, 2H), 3.88 (s, 3H), 0.95 (s, 9H), 0.22 (s,
3H), 0.15 (s, 3H); 13C NMR (CDCl3) δ 152.9, 140.8, 137.3, 134.7,
132.1, 128.1, 128.0, 127.8, 119.1, 106.0, 99.6, 74.1, 63.6, 55.5,
25.2, 17.9, -5.4, -5.5; MS m/z 399 (M+).
5-[5-[1-(ter t-Bu tyld im eth ylsilyloxy)-1-cya n om eth yl]-2-
b en zyloxy-3-m et h oxyp h en yla m in om et h ylen e]-2,2-d im -
eth yl-1,3-d ioxa n e-4,6-d ion e (7b). Meldrum’s acid (456 mg,
3.16 mmol) was refluxed under nitrogen in 40 mL of trimethyl
orthoformate for 3 h to give 8. The aniline 6b (840 mg, 2.11
mmol) in 5 mL of trimethyl orthoformate was added and the
solution refluxed for 12 h. The solvent was removed and the
residue was flash chromatographed (1:1 EtOAc/hexanes) to
give 995 mg of 7b as a white solid (85% yield): 1H NMR
(CDCl3) δ 8.43 (d, 1H, J ) 14.65 Hz.), 7.43-7.39 (m, 2H), 7.33-
7.29 (m, 3H), 6.95 (br. s, 1H), 6.93 (br. s, 1H), 5.44 (s, 1H),
5.18 (s, 2H), 3.98 (s, 3H), 1.75 (s, 6H), 0.96 (s, 9H), 0.25 (s,
3H), 0.18 (s, 3H); 13C NMR (CDCl3) δ 164.4, 163.2, 153.4, 150.5,
137.1, 135.2, 133.3, 132.3, 129.0, 128.4, 128.1, 118.4, 106.9,
104.7, 87.6, 74.9, 63.1, 55.9, 26.7, 25.2, 17.8, -5.4, -5.5; MS
m/z 552 (M+).
2-(ter t-Bu tyld im eth ylsilyloxy)-2-[8-ben zyloxy-7-m eth -
oxy-4(1H)-qu in olin on -5-yl]eth a n on itr ile (9b). The Mel-
drum’s acid derivative 7b (200 mg, 0.361 mmol) was added to
10 mL of diphenyl ether. A stream of nitrogen was passed
through the solution for 20 min, and the flask was then
lowered into a large preheated silicone oil bath at 240 °C. The
temperature of the bath dropped to approximately 225 °C and
rose again to 240 °C in 5-7 min. The solution was stirred in
the bath for a total of 20 min and was then removed and
allowed to cool. The solvent was removed under vacuum (0.1
mmHg, 110 °C). The residue was purified by flash chroma-
tography (3:1 EtOAc/hexanes to EtOAc) to give 91 mg of 9b
(56% yield): 1H NMR (CDCl3) δ 8.51 (br s, 1H), 7.59 (s, 1H),
7.42-7.34 (m, 6H), 7.12 (s, 1H), 6.11 (dd, 1H, J ) 1.53, 7.64
Hz), 5.21 (dd, 2H, J ) 11.30, 23.50 Hz), 4.04 (s, 3H), 0.99 (s,
9H), 0.31 (s, 3H), 0.18 (s, 3H); 13C NMR (CDCl3) δ 179.3, 151.9,
137.7, 136.2, 135.8, 133.68, 133.66, 128.3, 119.6, 116.6, 110.5,
106.6, 75.1, 61.1, 55.7, 25.3, 17.8, 17.8, -5.5, -5.6; MS m/z
451 (M + 1).
2-(ter t-Bu tyld im eth ylsilyloxy)-2-[-8-ben zyloxy-7-m eth -
oxy-1-m eth yl-4(1H)-qu in olin on -5-yl]eth a n on itr ile (10b).
K2CO3 (550 mg, 3.97 mmol) was flame dried in a flask and
allowed to cool. Compound 9b (600 mg, 1.32 mmol) and 20
mL of DMF were added, followed by methyl iodide (559 mg,
3.97 mmol). The solution was stirred under nitrogen for 3 h
at 100 °C. The solution was allowed to cool and poured into
water and extracted with EtOAc. The combined organic layers
were washed with water. The organic layer was dried with
MgSO4, filtered and solvents were removed in vacuo. The crude
material was purified by flash chromatography (EtOAc) to give
600 mg of 10b in 97% yield: 1H NMR (CDCl3) δ 7.71 (br s,
1H), 7.44-7.35 (m, 5H), 7.23 (d, 1H, J ) 7.81 Hz), 7.13 (s,
1H), 6.12 (d, 1H, J ) 7.81 Hz), 4.99 (dd, 2H, J ) 11.23, 23.43
Hz), 4.02 (s, 3H), 3.90 (s, 3H), 0.99 (s, 9H),, 0.31 (s, 3H), 0.18
(s, 3H); 13C NMR (CDCl3) δ 178.7, 154.6, 145.5, 137.6, 136.6,
135.9, 135.2, 128.3, 128.1, 127.9, 119.6, 119.0, 110.4, 107.1,
76.1, 61.5, 55.8, 45.9, 25.3, 17.9, -5.5, -5.6; MS m/z 465 (M +
1).
then heated at 80 °C for 5 min. TBS-Cl (11.47 g, 76.1 mmol)
was then added and maintained at 80 °C for 48 h. The solution
was allowed to cool and the solvent removed in vacuo. The
residue was mixed with EtOAc and filtered through Celite.
The bed of Celite was rinsed with copious amounts of EtOAc.
The solvent was removed in vacuo to a volume of ap-
proximately 300 mL. This solution was washed with saturated
NaHCO3 solution, water, and brine. The organic layer was
dried with MgSO4 and filtered and the solvent removed in
vacuo. The crude material was purified by flash chromatog-
raphy (2:1 CH2Cl2/hexanes) to give 9.40 g of 5c (82% yield):
1H NMR (CDCl3) δ 7.31 (s, 1H), 7.04 (s, 1H), 5.37 (s, 1H), 3.79
(s, 3H), 0.88 (s, 9H), 0.86 (s, 9H), 0.16 (s, 3H), 0.12 (s, 3H),
0.09 (s, 3H).
2-(5-Am in o-3-ter t-bu tyld im eth lsilyloxy-4-m eth oxyp h e-
n yl)-2-(ter t-bu tyldim eth lysilyloxy)eth an on itr ile (6c). HgCl2
(1.89 g, 9.94 mmol) and 20 mL of THF were added to a flame-
dried flask, and a nitrogen atmosphere was established.
Magnesium metal (967 mg, 39.77 mmol) was added, and the
mixture was stirred at room temperature for 10 min. The
supernatant was removed with a syringe, and the residue was
washed three times with 20 mL of THF using a syringe. The
solution was cooled to 0 °C, and 9.94 mL of a 1 M solution of
TiCl4 in toluene (1.89 g, 9.94 mmol) was added dropwise and
stirred for 5 min. A solution of the nitro compound 5c (1.50 g,
3.32 mmol), 8 mL of t-BuOH, and 15 mL of THF was added
dropwise. The resulting mixture was stirred for 1.5 h at room
temperature. 50 mL of saturated NaHCO3 solution was added,
along with 100 mL of EtOAc. The mixture was then filtered
through Celite and the Celite bed was washed with EtOAc.
The organic layer was separated and the aqueous layer was
extracted with EtOAc. The combined organic solutions were
dried with MgSO4, filtered, and the solvents were removed in
vacuo. The crude material was subjected to flash chromatog-
raphy (1:1 EtOAc/hexanes) to give of the amine 6c (1.22 g) in
85% yield: 1H NMR (CDCl3) δ 6.37 (d, 1H, J ) 1.83 Hz), 6.33
(d, 1H, J ) 2.44 Hz), 5.27 (s, 1H), 3.69 (s, 3H), 0.92 (s, 9H),
0.84 (s, 9H), 0.103 (s, 9H), 0.04 (s, 3H).
5-[5-[1-(ter t-Bu tyld im eth ylsilyloxy)-1-cya n om eth yl]-3-
ter t-b u t yld im et h ylsilyloxy-2-m et h oxyp h en yla m in om e-
th ylen e]-2,2-d im eth yl-1,3-d ioxa n e-4,6-d ion e (7c). Using
the general procedure for Meldrum’s acid adduct formation
described for 7b, compound 7c (1.81 g, 3.08 mmol) was
obtained as a white solid in 83% yield: 1H NMR (CDCl3) δ
11.19 (d, 1H, J ) 14.65 Hz), 8.49 (d, 1H, J ) 14.65 Hz), 6.90
(s, 1H), 6.80 (s, 1H), 5.35 (s, 1H), 3.77 (s, 3H), 1.66 (s, 6H),
0.90 (s, 9H), 0.87 (s, 9H), 0.16 (s, 3H), 0.15 (s, 6H), 0.09 (s,
3H).
2-(ter t-Bu tyld im eth ylsilyloxy)-2-[-7-ter t-bu tyld im eth -
ylsilyloxy-8-m et h oxy-4(1H )-q u in olin on -5-yl]et h a n on i-
tr ile (9c). Using the general procedure for thermal cyclization
to a quinolone described for 9b, compound 9c (266 mg, 0.551
mmol) was obtained as a tan solid in 52% yield: 1H NMR
(CDCl3) δ 8.20 (br s, 1H), 7.29 (dd, 1H, J ) 5.49, 7.32 Hz),
7.00 (s, 1H), 6.86 (s, 1H), 5.92 (dd, 1H, J ) 1.83, 7.32 Hz),
3.67 (s, 3H), 0.79 (s, 9H), 0.71 (s, 9H), 0.03 (s, 3H), 0.02 (s,
3H), -0.01 (s, 3H).
2-(3-ter t-Bu tyld im eth oxysilyloxy-4-m eth oxyp h en yl-5-
m e t h yla m in o)-2-(t er t -b u t yld im e t h lsilyloxy)e t h a n on i-
tr ile (6d ). The amine 6c (500 mg, 0.580 mmol) and 1-hy-
droxymethylbenzotriazole (173 mg, 0.580 mmol) were dissolved
in a minimum amount of refluxing absolute ethanol. The
solution was allowed to cool and kept at room temperature
for 24 h with occasional mixing. The flask was cooled to 0 °C
for several hours. The precipitated solid was filtered and
washed with ice-cold ethanol. This solid was then dissolved
in 25 mL of THF, NaBH4 (138 mg, 3.55 mmol) was added, and
the solution was refluxed under nitrogen until the starting
material was no longer was detected by TLC. The solution was
poured into water and extracted with diethyl ether. The
organic layers were washed with both saturated NaHCO3 and
water. The combined organic solutions were dried with MgSO4
and filtered, and the solvents were removed in vacuo. The
crude material was purified by flash chromatography (2:1
CH2Cl2/hexanes) to give 382 mg of 6d (77% yield): 1H NMR
2-(ter t-Bu tyld im eth ylsilyloxy)-2-(3-ter t-bu tyld im eth yl-
silyloxy-4-m eth oxy-5-n itr oph en yl)eth an on itr ile (5c). KCN
(11.56 g, 172.5 mmol) was flame dried in a flask and allowed
to cool. 5-Nitrovanillin 3a (5.00 g, 25.4 mmol), DMAP (1.55 g,
12.7 mmol), ZnI2 (200 mg), and 18-crown-6 (200 mg) were
dissolved in 100 mL of freshly distilled acetonitrile, and a
positive pressure of nitrogen was established. The solution was

8006 J . Org. Chem., Vol. 65, No. 23, 2000
Walz and Sundberg
(CDCl3) δ 6.41 (d, 1H, J ) 2.44 Hz), 6.35 (d, 1H, J ) 1.83 Hz),
5.42 (s, 1H), 3.78 (s, 3H), 2.86 (s, 3H), 1.00 (s, 9H), 0.94 (s,
9H), 0.20 (s, 3H), 0.18 (s, 6H), 0.13 (s, 3H).
mmol) in 10 mL of dry THF was added dropwise via an
addition funnel over 15 min. The solution was stirred at -78
°C for 6 h and then allowed to warm to -30 °C and was stirred
until the starting material was no longer detected by TLC.
The solution was poured into 100 mL of water and extracted
with EtOAc. The combined organic layers were washed with
saturated NaHCO3, water, and brine. The organic layer was
dried with MgSO4 and filtered, and the solvent was removed
in vacuo. Flash chromatography (2:1 hexanes/EtOAc) gave 832
mg (97% yield) of the carbamate 14b as a pale yellow oil: 1H
NMR (CDCl3) δ 7.47-7.29 (m, 10H), 6.34 (br s, 1H), 6.31 (br
s, 1H), 5.11 (s, 2H), 4.99 (s, 2H), 4.63 (dd, 1H, J ) 3.66, 7.32
Hz), 3.82 (s, 3H), 3.71 (br s, 2H), 3.50-3.39 (m, 1H), 3.22-
3.10 (m, 1H), 0.89 (s, 9H), 0.02 (s, 3H), -0.08 (s, 3H); 13C NMR
(CDCl3) δ 156.9, 153.4, 141.0, 138.9, 138.5, 137.2, 134.5, 129.0,
128.9, 128.9, 128.6, 128.5, 106.9, 100.6, 74.8, 74.2, 67.2, 56.2,
49.9, 26.4, 18.7, -4.2, -4.5; MS m/z 536 (M+).
5-[5-[2-(Ben zyloxyca r b on yla m in o)-1-(ter t-b u t yld im e-
t h ylsilyloxy)et h yl]-2-b en zyloxy-3-m et h oxyp h en yla m i-
n om eth ylen e]-2,2-d im eth yl-1,3-d ioxa n e-4,6-d ion e (15b).
Meldrum’s acid (0.413 g, 2.87 mmol) was refluxed under
nitrogen in 35 mL of trimethyl orthoformate for 2 h. The
arylamine 14b (1.14 g, 2.39 mmol) was dissolved in 15 mL of
trimethyl orthoformate and added to the above solution and
refluxed for 4 h. The solvent was removed in vacuo and the
residue subjected to flash chromatography (2:1 hexanes/
EtOAc) to give 1.00 g of 15b as a white solid (87% yield): mp
110-111 °C after recrystallization from EtOAc/hexanes; 1H
NMR (CDCl3) δ 11.40 (d, 1H, J ) 14.65 Hz), 8.41 (d, 1H, J )
14.65 Hz), 7.40-7.27 (m, 10H), 6.82-6.80 (m, 2H), 5.14 (s, 2H),
5.10 (s, 2H), 4.99 (br t, 1H, J ) 6.41 Hz), 4.72 (br dd, 1H, J )
3.97, 7.63 Hz), 3.91 (s, 3H), 3.50-3.39 (m, 1H), 3.23-3.12 (m,
1H), 1.75 (s, 6H), 0.89 (s, 9H), 0.04 (s, 3H), -0.09 (s, 3H); 13C
NMR (CDCl3) δ 65.3, 164.1, 156.8, 153.8, 151.4, 140.2, 136.9,
136.6, 136.3, 132.7, 129.9, 129.1, 129.0, 128.8, 128.6, 107.9,
105.4, 105.2, 87.9, 75.6, 73.9, 67.3, 56.6, 49.8, 27.5, 26.3, 18.7,
-4.2, -4.5; MS m/z 691 (M+).
O-Ben zyl N-2-(ter t-Bu tyld im eth ylsilyloxy)-2-[8-ben zy-
loxy-7-m eth oxy-4(1H)-qu in olin on -5-yl]eth yl Ca r ba m a te
(16b). To a solution of 100 mL of diphenyl ether was added
15b (1.09 g, 1.57 mmol). A stream of nitrogen was passed
through the solution for 20 min and the flask was then lowered
into a large silicone oil bath preheated to 240 °C. The
temperature of the bath dropped to approximately 225 °C and
rose again to 240 °C in 5-7 min. The solution was stirred in
the bath for a total of 18 min, then removed and allowed to
cool. The solvent was removed under vacuum (0.1 mmHg, 110
°C). Flash chromatography (1:2 to 6:1 hexanes/EtOAc) gave
0.326 g of the quinolone 16b as a tan solid (35% yield). An
analytical sample, mp 63-65 °C, was obtained by recrystal-
lization from EtOAc/hexanes: 1H NMR (acetone-d6) δ 10.19
(br s, 1H), 7.55 (d, 1H, J ) 7.33 Hz), 7.42 (s, 1H), 7.39-7.06
(m, 10H), 6.54 (br t, 1H, J ) 4.58 Hz), 6.07 (br s, 1H), 5.84 (d,
1H, J ) 7.33 Hz), 5.08 (dd, 2H, J ) 10.99, 18.01 Hz), 4.86 (s,
2H), 3.90 (s, 3H), 3.50-3.40 (m, 1H), 3.37-3.29 (m, 1H), 0.83
(s, 9H), -0.02 (s, 3H), -0.16 (s, 3H); 13C NMR (acetone-d6) δ
180.3, 156.8, 152.7, 141.6, 138.1, 137.9, 137.6, 136.9, 136.4,
129.1, 128.7, 128.6, 128.5, 128.1, 128.0, 118.0, 110.9, 107.8,
74.8, 70.7, 65.9, 56.0, 49.9, 26.0, 18.4, -4.8, -5.0; MS m/z 589
(M+). Anal. Calcd for C33H40N2O6Si: C, 67.32; H, 6.85; N, 4.75.
Found: C, 67.35; H, 6.80; N, 4.69.
O-Ben zyl N-2-(ter t-Bu tyld im eth ylsilyloxy)-2-[8-ben zy-
loxy-7-m et h oxy-1-m et h yl)-4(1H )-q u in olin on -5-yl]et h yl
Ca r ba m a t e (17b). The quinolone carbamate 16b (0.480 g,
0.82 mmol), K2CO3 (0.338 g, 2.45 mmol), and CH3I (0.346 g,
2.45 mmol) were dissolved in 20 mL of DMF under nitrogen
and heated to 90-100 °C for 2 h. The solution was poured into
100 mL of water and extracted with EtOAc. The extracts were
washed with water and brine. The extract was dried with
MgSO4, filtered and the solvent removed in vacuo. The
material was purified by flash chromatography (20:1 to 4:1
CH2Cl2/acetone) to give 0.390 g of the N-methyl quinolone 17b
as a tan solid in 79% yield. An analytical sample was
recrystallized from EtOAc/hexanes: mp 146-148 °C; 1H NMR
(CDCl3) δ 7.56 (s, 1H), 7.44-7.23 (m, 10H), 7.17 (d, 1H, J )
5-[5-[5-[1-(ter t-Bu tyld im eth ylsilyloxy)-1-cya n om eth yl]-
3-ter t-bu tyld im eth ylsilyloxy-2-m eth oxyp h en yl]-N-m eth -
yla m in om et h ylen e]-2,2-d im et h yl-1,3-d ioxa n e-4,6-d ion e
(7d ) Using the general procedure for Meldrum’s acid adduct
formation, product 7d (485 mg, 0.820 mmol) was obtained in
94% yield: 1H NMR (CDCl3) δ (This compound exhibits
rotational isomerism. The peaks listed correspond to the
primary rotamer) 8.17 (s, 1H), 7.03 (d, 1H, J ) 2.44 Hz), 6.91
(d, 1H, J ) 2.44 Hz), 5.43 (s, 1H), 5.30 (s, 1H), 3.87 (s, 3H),
3.62 (s, 3H), 1.76 (s, 6H), 0.95 (s, 9H), 0.93 (s, 9H), 0.25 (s,
3H), 0.20-0.14 (m, 9H).
2-(4-Ben zyloxy-3-m et h oxy-5-n it r op h en yl)-2-(ter t-b u -
tyld im eth ylsilyloxy)n itr oeth a n e (12b). The aldehyde 3b
(4.00 g, 13.92 mmol) was dissolved in 13 mL of dry THF.
Amberlyst A-21 ion-exchange resin (9.60 g) was added, fol-
lowed by nitromethane (10.30 g, 167.04 mmol). The solution
was stirred at room temperature for 3 h. The solution was
diluted with 100 mL of EtOAc and filtered, and the resin was
washed with copious amounts of EtOAc. The filtrate was
concentrated in vacuo and the residue was recystallized from
CH2Cl2/hexanes. The nitroaldol product 5b (4.13 g) containing
less than 5% aldehyde was obtained. The adduct was dissolved
in 120 mL THF containing 2,6-lutidine (2.64 g, 24.6 mmol)
under nitrogen. The solution was cooled to 0 °C and tert-
butyldimethylsilyl triflate (TBSOTf) (5.70 g, 21.6 mmol) was
added dropwise with a syringe. The solution was stirred for 2
h while coming to room temperature. The solution was diluted
with 200 mL of EtOAc and organic layer was washed with
NaHCO3, water, and brine. The organic layer was dried with
MgSO4, filtered, and the solvent removed in vacuo. The residue
was subjected to flash chromatography (3:1 CH2Cl2/hexanes)
and 5.19 g of the silyl derivative 12b was obtained as a white
solid in 81% overall yield. An analytical sample was obtained
by recrystallization from CH2Cl2/hexanes: mp 139-141 °C; 1H
NMR (CDCl3) δ 7.48-7.33 (m, 6H), 7.18 (d, 1H, J ) 1.83 Hz),
5.42 (dd, 1H, J ) 3.05, 9.16 Hz), 5.19 (s, 2H), 4.52 (dd, 1H, J
) 9.16, 12.21 Hz), 4.41 (dd, 1H, J ) 3.66, 12.20 Hz), 3.96 (s,
3H), 0.87 (s, 9H), 0.07 (s, 3H), -0.08 (s, 3H); 13C NMR (CDCl3)
δ 155.2, 145.7, 141.9, 136.7, 136.2,129.1, 128.9, 114.0, 113.7,
82.8, 76.5, 72.1, 57.1, 26.0, 18.5, -4.3, -5.1; MS m/z 462 (M+).
Anal. Calcd for C22H30N2O7Si: C, 57.12; H, 6.54; N, 6.05.
Found: C, 57.14; H, 6.56; N, 5.99.
2-(5-Am in o-4-ben zyloxy-3-m eth oxyp h en yl)-2-(ter t-bu -
tyld im eth ylsilyloxy)eth yla m in e (13b). The dinitro deriva-
tive 12b (3.60 g, 8.43 mmol) and NiCl2-6H2O (8.02 g, 33.7
mmol) were added to 90 mL of MeOH and 45 mL of THF and
cooled to 0 °C. NaBH4 (2.96 g, 77.8 mmol) was added portion-
wise over 15 min, and the mixture was stirred at 0 °C for 10
min. The solvents were removed in vacuo, and 150 mL of
CHCl3 and 20 mL of water were added. The mixture was
filtered through Celite, and the inorganic residue was removed
from the Celite pad, triturated with 50 mL of CHCl3, and
filtered through Celite again. This procedure was repeated
until no product was detected by TLC in the CHCl3 after
trituration. The CHCl3 was concentrated in vacuo to ap-
proximately 150 mL, and the organic layer was washed with
saturated NaHCO3, water, and brine. The organic layer was
dried with MgSO4 and filtered and the solvent removed in
vacuo. The residue was purified by flash chromatography (96.5:
3:1.5 CHCl3/MeOH/TEA). The diamine 13b (2.68 g) was
obtained as a brown oil in 86% yield: 1H NMR (CDCl3) δ 7.47-
7.32 (m, 5H), 6.35 (br s, 1H), 6.29 (br s, 1H), 4.99 (d, 2H, J )
1.22 Hz), 4.55 (br t, 1H, J ) 5.50 Hz), 3.84 (s, 3H), 3.73 (br s,
2H), 2.84 (br d, 2H, J ) 5.49 Hz), 2.05 (br s, 2H), 0.92 (s, 9H),
0.07 (s, 3H), -0.06 (s, 3H); 13C NMR (CDCl3) δ 153.3, 140.9,
139.3, 138.5, 134.4, 128.88, 128.85, 128.5, 107.6, 100. 7, 76.3,
74.8, 56.2, 50.8, 26.4, 18.7, -4.1, -4.4; MS m/z 403 (M + 1).
O-Ben zyl N-2-(5-Am in o-4-ben zyloxy-3-m eth oxyph en yl)-
2-(ter t-bu tyld im eth ylsilyloxy)eth yl ca r ba m a te (14b). The
bis-amine 13b (646 mg, 1.61 mmol), DMAP (196 mg, 1.61
mmol), and K2CO3 (440 mg, 3.21 mmol) in 35 mL of dry THF
were cooled to -78 °C under nitrogen. CBZ-Cl (274 mg, 1.61

Synthesis of Isoaaptamine
J . Org. Chem., Vol. 65, No. 23, 2000 8007
7.32 Hz), 6.57 (br t, 1H, J ) 4.57 Hz), 6.05 (d, 1H, J ) 7.33
Hz), 5.43 (dd, 1H, J ) 4.88, 6.10 Hz), 5.05-4.88 (m, 4H), 3.94
(s, 3H), 3.88 (s, 3H), 3.61-3.41 (m, 2H), 0.91 (s, 9H), -0.077
(s, 3H), -0.80 (s, 3H); 13C NMR (CDCl3) δ 180.2, 156.9, 155.1,
145.8, 143.1, 138.4, 137.5, 137.3, 136.9, 135.8, 129.0, 128.8,
128.7, 128.4, 120.1, 111.4, 108.5, 76.7, 71.0, 66.7, 56.5, 50.3,
46.7, 20.4, 18.7, -4.3, -4.4; MS m/z 603 (M+). Anal. Calcd for
203 nM (ꢀ 28 005), 233 nM (ꢀ 22 251), 304 nM (ꢀ 3471), 371
nM (ꢀ 8901); EI+HRMS calcd for C13H8N2O2 212.0586, found
212.0584.
3,4-Dih yd r oxy-5-n itr oben za ld eh yd e (3c). To 5-nitrova-
nillin 3a (5.00 g, 25.4 mmol) and AlCl3 (3.72 g, 27.9 mmol)
was added 50 mL of CHCl3, and the mixture was cooled to 0
°C with an ice bath. Pyridine (8.83 g, 111.6 mmol) was added
dropwise with a syringe. The ice bath was removed and the
solution refluxed under nitrogen for 24 h. The solvent was
removed in vacuo, 300 mL of 20% HCl solution was added to
the residue, and the mixture was stirred for 30 min. The
solution was extracted with EtOAc. The extracts were com-
bined and washed with brine. The combined organic solutions
were dried with MgSO4 and filtered, and the solvents were
removed in vacuo. The crude material was filtered hot with
EtOAc. The solution was concentrated and the product pre-
cipitated using hexanes and filtered. 3c (4.53 g) was obtained
as a gray solid in 98% yield and recrystallized from EtOAc/
hexanes: mp 148-150 °C (lit.31 mp 145-148 °C); 1H NMR
(DMSO-d6) δ 9.76 (s, 1H), 7.92 (d, 1H, J ) 1.83 Hz), 7.42 (d,
1H, J ) 1.83 Hz); 13C NMR (DMSO-d6) δ 190.49, 148.33,
147.33, 137.12, 126.96, 119.66, 115.81; MS m/z 184 (M + 1).
3-Ben zyloxy-4-h yd r oxy-5-n itr oben za ld eh yd e (3d ). KF
(7.69 g, 132.4 mmol) was flame dried in a flask and allowed to
cool. The aldehyde 3c (4.85 g, 18.6 mmol) was added with 70
mL of DMF. Benzyl bromide (13.61 g, 79.6 mmol) was added,
and the mixture was heated under nitrogen at 140 °C for 48
h. To the cooled solution was added 300 mL of 10% HCl, and
the mixture was extracted with EtOAc. The extract was
washed with water and brine. The solution was dried with
MgSO4 and filtered, and the solvents were removed in vacuo.
Flash chromatography (CH2Cl2) gave 6.70 g of 3d as an orange
solid in 93% yield that was recrystallized from EtOAc/
hexanes: mp 149-150 °C; 1H NMR (DMSO-d6) δ 9.79 (s, 1H),
8.06 (d, 1H, J ) 1.83 Hz), 7.66 (d, 1H, J ) 1.22 Hz), 7.49-
7.44 (m, 2H), 7.39-7.26 (m, 3H), 5.29 (s, 2H); 13C NMR
(DMSO-d6) δ 190.34, 149.0, 148.1, 137.2, 135.9, 128.5, 128.2,
127.9, 126.8, 121.1, 114.2, 70.8; MS m/z 274 (M + 1).
C
34H42N2O6Si: C, 67.74; H, 7.02; N, 4.64. Found: C, 67.57; H,
6.94; N, 4.56.
8-Meth oxy-1-m eth yl-1H-ben zo[d e][1,6]n a p h th yr id in -9-
ol (Isoa a p ta m in e, 2b). To a flask containing N-methyl
quinolone 17b (0.260 g, 0.430 mmol) and 0.130 g of 10% Pd-C
in 8 mL of methanol was added NH4O2CH (0.217 g, 3.45
mmol). The solution was lowered into a 40 °C oil bath and
stirred for 20 min. The mixture was filtered through Celite
and washed with copious amounts of MeOH. The solvent was
removed under reduced pressure and the residue kept under
a vacuum for 24 h. The free amine (0.089 g, 0.2363 mmol) and
(NH4)2SO4 (0.013 g, 0.0984 mmol) were placed in a flask with
12 mL of HMDSA and 6 mL of TEA. The flask was flushed
with nitrogen for 20 min and then heated in an oil bath for 20
h at 130 °C. The solution was allowed to cool, and the solvents
were removed in vacuo. The residue was dissolved in 25 mL
of MeOH and filtered, 1.5 mL of concd HCl was added, and a
nitrogen atmosphere was established. The solution was stirred
at room temperature for 1.5 h. The solvents were removed
under reduced pressure, and the residual water removed by
repetitive evaporation of added MeOH under reduced pressure.
The residue was kept under vacuum for 20 min and then
dissolved in 25 mL of anhydrous MeOH. HCl gas was passed
through the solution for 1.5 h. The flask was stoppered and
kept at room temperature for 20 h. The solvent was removed
under reduced pressure and the residue was subjected to flash
chromatography. (5:3:2 CHCl3/MeOH/EtOAc) to give 0.087 g
of isoaaptamine (2b) as a yellow solid in 73% yield as the
hydrochloride salt. A pure sample was prepared by recrystal-
lization from MeOH/acetone: mp 237 °C dec; 1H NMR (DMSO-
d6) δ 9.41 (br s, 1H), 7.68 (d, 1H, J ) 7.32 Hz), 7.21 (d, 1H, J
) 6.94 Hz), 7.10 (s, 1H), 6.75 (d, 1H, J ) 6.94 Hz), 6.10 (d,
1H, 7.31 Hz), 3.99 (s, 3H), 3.92 (s, 3H); 13C NMR (DMSO-d6)
δ 153.6, 149.3, 149.2, 132.3, 129.3, 127.9, 118.1, 113.2, 101.6,
97.5, 56.6, 46.1; UV (95% EtOH) λmax 203 nM (ꢀ 33 509), 236
nM (ꢀ 19 155), 263 nM (ꢀ 26 554), 323 nM (ꢀ 7366), 393 nM (ꢀ
7464); EI+HRMS calcd for C13H12N2O2 228.0899, found 228.0896.
8-Meth oxy-1H-ben zo[de][1,6]n aph th yr idin -9-ol (9-Dem -
eth yla a p ta m in e, 1b). Using the same procedure for HMDSA-
mediated cyclization and methanolic HCL elimination, 9-dem-
ethylaaptamine hydrochloride salt 1b (66 mg, 0.263 mmol) was
obtained in 83% yield as a yellow/green solid. A pure sample
was obtained by recrystallization from MeOH/acetone: mp 205
°C dec; 1H NMR (DMSO-d6) δ 12.12 (br s, 1H), 11.90 (br d,
1H, J ) 4.89 Hz), 10.04 (s, 1H), 7.68 (t, 1H, J ) 6.45 Hz), 7.20-
7.17 (m, 1H), 7.05 (s, 1H), 6.75 (d, 1H, J ) 7.33 Hz), 6.17 (d,
1H, J ) 7.33 Hz), 3.93 (s, 3H); 13C NMR (DMSO-d6) δ 152.1,
150.1, 142.3, 129.8, 129.1, 128.3, 128.0, 116.7, 112.9, 100.6,
97.5, 56.5; UV (95% EtOH) λmax 208 nM (ꢀ 35 786), 242 nM (ꢀ
20 184), 268 nM (ꢀ 12 740), 278 nM (ꢀ 11 051), 318 nM (ꢀ 4174),
356 nM (ꢀ 3611); EI+HRMS calcd for C13H10N2O2 214.0742,
found 214.0745.
3-Ben zyloxy-4-m eth oxy-5-n itr oben za ld eh yd e (3e). The
aldehyde 3d (4.00 g, 14.6 mmol), dimethyl sulfate (18.47 g,
146.4 mmol), KOH (3.28 g, 58.52 mmol), and benzyltriethyl-
ammonium chloride (1.67 g, 7.32 mmol) were added to 60 mL
of CHCl3 and 60 mL of distilled water, and the mixture was
stirred at room temperature for 36 h under
a nitrogen
atmosphere. The aqueous layer was separated and extracted
with CHCl3. The combined organic layers were concentrated
in vacuo. The residue was taken up in diethyl ether and was
washed with 2 N NH4OH, 10% aqueous NaOH, and brine. The
organic layer was dried with MgSO4 and filtered, and the
solvents were removed in vacuo. The residue was purified by
flash chromatography (3:1 CH2Cl2/hexanes) to yield 6.82 g of
3e as a pale yellow solid (92% yield) that was recrystallized
from CH2Cl2/hexanes: mp 86-88 °C; 1H NMR (CDCl3) δ 9.90
(s, 1H), 7.84 (d, 1H, 1.84 Hz), 7.69 (d, 1H, J ) 1.83 Hz), 7.48-
7.37 (m, 5H), 5.23 (s, 2H), 4.10 (s, 3H); 13C NMR (CDCl3) δ
188.6, 153.3, 147.8, 134.8, 130.9, 128.5, 128.4, 128.3, 127.2,
119.2, 114.7, 71.3, 61.9; MS m/z 288 (M + 1).
2-(3-Ben zyloxy-4-m et h oxy-5-n it r op h en yl)-2-(ter t-b u -
tyld im eth ylsilyloxy)n itr oeth a n e (12e). Using the general
procedure for Amberlyst A-21-mediated Henry reaction de-
scribed for 12b, followed by tert-butyldimethylsilyl ether
formation, compound 12e (1.86 g, 93% yield) was obtained from
the aldehyde 3e, mp 98-99 °C, after recrystallization from
CH2Cl2/hexanes: 1H NMR (CDCl3) δ 7.45-7.33 (m, 5H), 7.19-
7.17 (m, 2H), 5.33 (dd, 1H, J ) 3.36, 9.46 Hz), 5.18 (dd, 2H, J
) 15.20, 11.60 Hz), 4.44 (dd, 1H, J ) 9.46, 11.90 Hz), 4.33
(dd, 1H, J ) 3.36, 11.90 Hz), 4.03 (s, 3H), 0.85 (s, 9H), 0.03 (s,
3H), -0.13 (s, 3H); 13C NMR (CDCl3) δ 153.1, 144.6, 142.9,
135.1, 134.9, 128.5, 128.2, 126.9, 114.7, 113.4, 81.9, 71.1, 61.7,
25.1, 17.6, -5.2, -5.9; MS 462 (M+). Anal. Calcd for C22H30N2O7-
Si: C, 57.12; H, 6.54; N, 6.05. Found: C, 57.16; H, 6.58; N,
5.99.
8-Meth oxy-1H-ben zo[de][1,6]n aph th yr idin -9-on e (Dem -
eth yloxy(oxy)a a p ta m in e, 18). 9-Demethylaaptamine 1b (75
mg, 0.296 mmol) was dissolved in 5 mL of MeOH and 3 mL of
0.2 M NaHCO3 and was stirred under an atmosphere of oxygen
at room temperature and pressure for 1 h. The MeOH was
removed in vacuo and the aqueous solution extracted with
CHCl3. The organic layer was dried with MgSO4 and filtered
and the solvent removed in vacuo. The material was purified
by flash chromatography (19:1 CHCl3/MeOH) to give 47 mg
of 18 as a green solid (73% yield). An analytical sample was
prepared by recrystallization from CHCl3/hexanes: mp 220 °C
1
dec (lit.8 mp 210-212 °C); H NMR (DMSO-d6) δ 9.09 (d, 1H,
J ) 4.27 Hz), 9.06 (d, 1H, J ) 6.11 Hz), 8.17 (d, 1H, J ) 5.49
Hz), 7.70 (d, 1H, J ) 4.27 Hz), 7.12 (s, 1H), 3.86 (s, 3H); 13C
NMR (D6-DMSO) δ 177.1, 157.4, 155.7, 148.9, 148.9, 147.5,
136.5, 126.5, 122.3, 117.8, 108.9, 5612; UV (95% EtOH) λmax
(31) Lange, R. G. J . Org. Chem. 1962, 27, 2037.

8008 J . Org. Chem., Vol. 65, No. 23, 2000
Walz and Sundberg
2-(5-Am in o-3-ben zyloxy-4-m eth oxyp h en yl)-2-(ter t-bu -
tyld im eth ylsilyloxy)eth yla m in e (13e). Using the general
procedure for nitro group reduction with NiCl2-6H2O/NaBH4
described for 13b, compound 13e (970 mg, 76% yield) was
obtained as a brown oil: 1H NMR (CDCl3) δ 7.46-7.27 (m,
5H), 6.35 (d, 1H, J ) 1.22 Hz), 6.31 (d, 1H, J ) 1.22 Hz), 5.09
(s, 2H), 4.46 (br t, 1H, J ) 5.19 Hz), 3.86 (s, 3H), 3.84 (br s,
2H), 2.76-2.72 (m, 2H), 1.18 (br s, 2H), 0.91 (s, 9H), 0.03 (s,
3H), -0.10 (s, 3H); 13C NMR (CDCl3) δ 151.2, 139.8, 138.7,
136.8, 134.9, 128.1, 127.4, 126.8, 106.2, 101.7, 76.1, 70.1, 59.6,
50.6, 25.5, 17.9, -4.9, -5.3; MS m/z 403 (M+).
O-Ben zyl N-2-(5-Am in o-4-ben zyloxy-3-m eth oxyph en yl)-
2-(t-bu tyld im eth ylsilyloxy)eth yl ca r ba m a te (14e). Using
the general procedure for selective protection of the primary
amine described for 14b, compound 14e (1.00 g, 97% yield)
was obtained as a pale yellow oil: 1H NMR (CDCl3) δ 7.45-
7.27 (m, 10H), 6.38 (br s, 1H), 6.34 (br s, 1H), 5.11 (s, 2H),
5.07 (s, 2H), 4.96 (m, 1H), 4.61 (dd, 1H, J ) 3.97, 7.03 Hz),
3.85 (s, 3H), 3.84 (s, 2H), 3.46-3.36 (m, 1H), 3.18-3.08 (m,
1H), 0.88 (s, 9H), 0.50 (s, 3H), -0.11 (s, 3H); 13C NMR (CDCl3)
δ 152.1, 140.70, 139.6, 137.8, 135.9, 128.9, 128.3, 127.7, 107.1,
102.7, 92.0, 86.7, 81.2, 76.9, 71.0, 60.5, 51.4, 26.4, 18.7, -4.1,
-4.4; MS m/z 536 (M+).
5-[5-[2-(Ben zyloxyca r b on yla m in o)-1-(ter t-b u t yld im e-
t h ylsilyloxy)et h yl]-3-b en zyloxy-2-m et h oxyp h en yla m i-
n om eth ylen e]-2,2-d im eth yl-1,3-d ioxa n e-4,6-d ion e (15e).
Using the general procedure for Meldrum’s acid adduct forma-
tion described for 7c, compound 15e (1.12 g, 1.79 mmol) was
obtained in 90% yield, mp 108-109 °C,after recrystallization
from EtOAc/hexanes: 1H NMR (CDCl3) δ 11.66 (d, 1H, J )
14.65 Hz), 8.64 (d, 1H, J ) 14.65 Hz), 7.46-7.26 (m, 10H),
6.95 (s, 1H), 6.84 (s, 2H), 5.11 (br s, 4H), 4.98 (m, 1H), 4.73
(m, 1H), 4.00 (s, 3H), 3.48-3.36 (m, 1H), 3.24-3.11 (m, 1H),
1.76 (s, 6H), 0.88 (s, 9H), 0.02 (s, 3H), -0.10 (s, 3H); 13C NMR
(CDCl3) δ 165.7, 164.1, 156.8, 152.6, 151.4, 139.8, 139.2, 136.9,
136.6, 131.9, 129.2, 129.0, 129.0, 128.7, 128.7, 127.9, 109.8,
105.5, 105.3, 81.2, 73.9, 71.5, 67.3, 61.8, 49.9, 27.6, 26.3, 18.7,
-4.2, -4.5; MS m/z 691 (M+).
O-Ben zyl N-2-(ter t-Bu tyld im eth ylsilyloxy)-2-[7-ben zy-
loxy-8-m eth oxy-4(1H)-qu in olin on -5-yl]eth yl Ca r ba m a te
(16e). Using the general procedure for thermal cyclization in
diphenyl ether, 16e was obtained as an off white solid (850
mg, 82% yield). An analytical sample was prepared by recrys-
tallization from EtOAc/hexanes: mp 139-141 °C; 1H NMR
(acetone-d6) δ 10.38 (br s, 1H), 7.62 (br t, 1H, J ) 6.41 Hz),
7.49 (s, 1H), 7.45-7.11 (m, 10H), 6.57 (br t, 1H, J ) 4.88 Hz),
6.09-6.03 (m, 1H), 5.90 (d, 1H, J ) 7.32 Hz), 5.20 (dd, 2H, J
) 12.11, 20.76 Hz), 4.85 (s, 2H), 3.85 (s, 3H), 3.48-3.28 (m,
2H), 0.80 (s, 9H), -0.03 (s, 3H), -0.17 (s, 3H); 13C NMR
(CDCl3) δ 181.1, 157.2, 151.9, 141.4, 137.9, 137.4, 136.8, 136.7,
135.4, 129.2, 128.9, 128.7, 128.4, 128.1, 127.9, 118.3, 111.5,
109.4, 71.4, 70.6, 66.9, 61.5, 50.2, 26.4, 18.7, -4.2, -4.5; MS
m/z 589 (M+). Anal. Calcd for C33H40N2O6Si: C, 67.32; H, 6.85;
N, 4.75. Found: C, 67.14; H, 6.79; N, 4.77.
Celite and washed with copious amounts of MeOH. The solvent
was removed in vacuo and the residue kept under vacuum for
24 h. The free amine and (NH4)2SO4 (28 mg, 0.212 mmol) were
placed in a flask containing 30 mL of HMDSA and 15 mL of
TEA. The reaction was carried out as described for 2b. The
crude product was purified by flash chromatography (85:15
CHCl3/MeOH). The residue was recrystallized from MeOH/
acetone. 1-Methyl-8-demethylaaptamine hydrochloride salt
(2e) (97 mg, 68% yield) was obtained as yellow crystals: mp
194-196 °C; 1H NMR (DMSO-d6) δ 7.80 (d, 1H, J ) 7.32 Hz),
7.29 (d, 1H, J ) 7.32 Hz), 6.89 (s, 1H), 6.75 (d, 1H, J ) 7.33
Hz), 6.34 (d, 1H, 7.33 Hz), 3.93 (s, 3H), 3.56 (s, 3H); 13C NMR
(DMSO-d6) δ 157.9, 148.6, 148.4, 135.2, 133.2, 133.1, 129.3,
116.8, 112.3, 105.7, 93.4, 61.9, 45.4; UV (95% EtOH) λmax 202
nM (ꢀ 24 372), 231 nM (ꢀ 14 786), 261 nM (ꢀ 20 326), 273 nM
(ꢀ 19 183), 316 nM (ꢀ 3413), 387 nM (ꢀ 5973); EI+HRMS calcd
for C13H12N2O2 228.0899, found 228.0898.
8-Dem eth yla a p ta m in e (1e). Using the general procedure
for HMDSA-mediated cyclization and methanolic HCl elimina-
tion as described for 2b, 8-demethylaaptamine, 1e, was
obtained was obtained from 16e in 76% overall yield as a
hydrochloride salt (110 mg) and was recrystallized from
MeOH/acetone: mp 227-229 °C dec; 1H NMR (CD3OD) δ 7.69
(d, 1H, J ) 7.32 Hz), 7.09 (d, 1H, J ) 7.33 Hz), 6.72 (s, 1H),
6.66 (d, 1H, J ) 7.32 Hz), 6.26 (d, 1H, J ) 6.71 Hz), 3.87 (s,
3H); 13C NMR (CD3OD) δ 155.9, 149.5, 140.27, 133.9, 131.9,
130.8, 127.9, 115.5, 111.8, 104.6, 97.3, 59.1; UV (95% EtOH)
λmax 201 nM (ꢀ 21, 482), 234 nM (ꢀ 20, 482), 268 nM (ꢀ 24,
120), 312 nM (ꢀ 4, 329), 361 nM (ꢀ 5, 428); EI+HRMS calcd for
C
13H10N2O2 214.0742, found 214.0749.
2-(3,4-Dim eth oxy-5-n itr op h en yl)-2-(ter t-bu tyld im eth -
ylsilyloxy)n itr oeth a n e (12f). TBAF(3H2O) (3.44 g, 10.92
mmol) was dissolved in 75 mL of THF and cooled to 0 °C.
Nitromethane (2.67 g, 43.7 mmol), 3,4-dimethoxy-5-nitrobenz-
aldehyde13 (5.00 g, 21.8 mmol), TEA (3.31 g, 32.8 mmol), and
TBS chloride (6.58 g, 43.7 mmol) were added sequentially. The
reaction was stirred for 2 h while coming to room temperature.
The solution was filtered, and the residue was washed with
EtOAc. The filtrate was washed with water and brine. The
organic layer was dried with MgSO4 and filtered, and the
solvent was removed in vacuo. The residue was subjected to
flash chromatography (1.5:1 hexane/EtOAc) to yield 6.07 g of
the impure nitroaldol adduct. The adduct was dissolved in 125
mL dry THF containing 2,6-lutidine (5.60 g, 52.3 mmol) under
nitrogen. The solution was cooled to 0 °C, and TBSOTf (8.29
g, 31.38 mmol) was added dropwise using a dry syringe. The
solution was stirred for 2 h and was poured into 100 mL of
EtOAc. The organic layers were washed with saturated
NaHCO3, water, and brine. The organic layer was dried with
MgSO4 and filtered, and the solvent was removed in vacuo.
Flash chromatography (6.5:3.5 CH2Cl2/hexanes) gave 7.20 g
of the silyl derivative 12f as a white solid in 86% yield that
was recrystallized from hexanes: mp 92-94 °C; 1H NMR
(CDCl3) δ 7.34 (d, 1H, J ) 1.83 Hz), 7.16 (d, 1H, J ) 1.22 Hz),
5.42 (dd, 1H, J ) 3.36, 9.47 Hz), 4.50 (dd, 1H,J ) 9.46, 11.90
Hz), 4.40 (dd, 1H,J ) 3.05, 12.10 Hz), 3.99 (s, 3H), 3.94 (s,
3H), 0.87 (s, 9H), 0.06 (s, 3H), -0.07 (s, 3H); 13C NMR (CDCl3)
δ 155.1, 145.3, 143.4, 136.1, 113.8, 113.7, 82.8, 72.1, 65.5, 57.0,
26.0, 18.5, -4.3, -5.1; MS m/z 387 (M + 1). Anal. Calcd for
O-Ben zyl N-2-(ter t-Bu tyld im eth ylsilyloxy)-2-[7-ben zy-
loxy-8-m eth oxy-1-m eth yl-4(1H)-qu in olin on -5-yl]eth yl Car -
ba m a te (17e). Using the general procedure for N-methylation
of quinolones, 17e (128 mg, 96% yield) was obtained as an off-
white solid. An analytical sample was recrystallized from
1
EtOAc/hexanes: mp 156-158 °C; H NMR (CDCl3) δ 7.61 (s,
C16H26N2O7Si: C, 49.73; H, 6.78; N, 7.24. Found: C, 49.80; H,
6.80; N, 7.20.
1H), 7.49-7.22 (m, 11H), 6.58 (br t, 1H, J ) 4.89 Hz), 6.07 (d,
1H, J ) 7.32 Hz), 5.42 (br t, 1H, J ) 5.20 Hz), 5.20 (dd, 2H, J
) 11.60, 17.09 Hz), 5.01 (s, 2H), 4.00 (s, 3H), 3.85 (s, 3H), 3.58-
3.41 (m, 2H), 0.88 (s, 9H), -0.05 (s, 3H), -0.10 (s, 3H); 13C
NMR (CDCl3) δ 180.2, 156.9, 154.5, 145.9, 142.9, 137.9, 137.7,
137.5, 136.8, 129.2, 128.9, 128.7, 128.4, 127.9, 120.4, 111.4,
109.8, 71.4, 70.9, 66.7, 62.2, 50.3, 46.5, 26.4, 18.7, -4.3, -4.4;
MS m/z 603 (M+). Anal. Calcd for C34H42N2O6Si: C, 67.74; H,
7.02; N, 4.64. Found: C, 67.75; H, 6.99; N, 4.67.
2-(5-Am in o-3,4-d im eth oxyp h en yl)-2-(ter t-bu tyld im eth -
ylsilyloxy)eth yla m in e (13f). The dinitro compound 12f (1.50
g, 3.71 mmol) and 400 mg of 10% Pd-C were stirred in 20 mL
of MeOH and 10 mL of THF. NH4O2CH (2.39 g, 37.8 mmol)
was added, and the flask was refluxed in a preheated oil bath
for 1 h, after which an additional 2 equiv of NH4O2CH was
added. The solution was refluxed for another 1 h and allowed
to cool. The solution was filtered though Celite, and the Celite
pad was washed with 100 mL of MeOH. The solvent was
evaporated and the residue taken up in CHCl3 and washed
with saturated NaHCO3 solution, water, and brine. The
organic layer was dried with MgSO4 and filtered and the
solvent removed in vacuo. The diamine 13f (1.30 g) was
obtained as a clear oil in 100% yield: 1H NMR (CDCl3) δ 6.31
9-Meth oxy-1-m eth yl-1H-ben zo[d e][1,6]n a p h th yr id in -8-
ol (1-Meth yl-8-d em eth yla a p ta m in e, 2e). To a flask contain-
ing the N-methylquinolone 17e (318 mg, 0.527 mmol) and 156
mg of 10% Pd-C in 10 mL of methanol was added NH4O2CH
(267 mg, 3.45 mmol). The solution was placed in a 40 °C oil
bath and stirred for 20 min. The mixture was filtered through

Synthesis of Isoaaptamine
J . Org. Chem., Vol. 65, No. 23, 2000 8009
(d, 1H, J ) 1.84 Hz), 6.29 (d, 1H, J ) 1.22 Hz), 5.49 (br t, 1H,
J ) 5.19 Hz), 3.81 (s, 3H), 3.80 (s, 3H), 2.77 (br d, 2H, J )
5.49 Hz), 0.91 (s, 9H), 0.05 (s, 3H), -0.07 (s, 3H); 13C NMR
(CDCl3) δ 153.1, 140.5, 139.6, 135.3, 106.8, 100.5, 76.9, 60.2,
56.0, 51.4, 26.3, 18.7, -4.1, -4.5; MS m/z 327 (M + 1).
O-Ben zyl N-2-(5-Am in o-3,4-d im eth oxyp h en yl)-2-(ter t-
bu tyld im eth ylsilyloxy)eth yl Ca r ba m a te (14f). Using the
general procedure for selective benzyloxycarbonyl protection,
14f was obtained as a pale yellow oil (1.14 g, 2.12 mmol) in
84% yield: 1H NMR (CDCl3) δ 7.37-7.31 (m, 5H), 6.32 (br s,
2H), 5.11 (br s, 2H), 5.02-4.94 (m, 1H), 4.63 (dd, 1H, J ) 3.66,
7.32 Hz), 3.81 (br s, 6H), 3.49-3.39 (m, 1H), 3.19-3.09 (m,
1H), 0.89 (s, 9H), 0.02 (s, 3H), -0.08 (s, 3H); 13C NMR (CDCl3)
δ 156.9, 153.2, 140.8, 138.9, 137.2, 135.5, 128.9, 128.6, 106.8,
100.4, 74.2, 67.1, 60.3, 56.1, 49.9, 26.3, 18.7, -4.2, -4.6; MS
460 (M + 1).
83% yield) as a yellow solid and recrystallized from MeOH/
acetone: mp 198-199 °C dec; H NMR (DMSO-d6) δ 7.83 (d,
1
1H, J ) 7.32 Hz), 7.40 (d, 1H, J ) 7.32 Hz), 7.16 (s, 1H), 6.87
(d, 1H, J ) 7.33 Hz), 6.30 (d, 1H, 7.32 Hz), 3.94 (s, 6H), 3.72
(s, 3H); 13C NMR (DMSO-d6) δ 168.7, 158.8, 148.9, 148.8, 134.5,
133.7, 129.8, 117.5, 113.0, 102.2, 98.4, 62.2, 56.7, 45.5; UV (95%
EtOH) λmax 205 nM (ꢀ 25, 924), 240 nM (ꢀ 20, 229), 260 nM (ꢀ
20, 739), 273 nM (ꢀ 19, 183), 317 nM (ꢀ 3, 831), 386 nM (ꢀ 5,
625); EI+HRMS calcd for C14H14N2O2 242.1055, found 242.1052.
8,9-Dim et h oxy-1H -b en zo[d e][1,6]n a p h t h ir id in e
(Aa p ta m in e, 1f). Using the general procedure for HMDSA-
mediated cyclization and methanolic HCL elimination, aapt-
amine hydrochloride 1f (104 mg, 0.392 mmol) was obtained
in 73% yield. The yellow solid was recrystallized from MeOH/
acetone to give yellow crystals: mp 176-177 °C; 1H NMR
(DMSO-d6) δ 12.26 (br s, 1H), 7.79 (d, 1H, J ) 7.33 Hz), 7.37
(d, 1H, J ) 7.32 Hz), 7.08 (s, 1H), 6.84 (d, 1H, J ) 7.32 Hz),
6.31 (d, 1H, 6.71 Hz), 3.93 (s, 3H), 3.77 (s, 3H); 13C NMR (D6-
DMSO) δ 156.9, 149.8, 142.1, 133.8, 132.7, 131.4, 129.9, 116.4,
112.8, 101.0, 98.2, 60.4, 56.6; UV (95% EtOH) λmax 202 nM (ꢀ
24, 372), 238 nM (ꢀ 20, 703), 257 nM (ꢀ 21, 775), 313 nM (ꢀ 4,
740), 374 nM (ꢀ 5, 479); EI+HRMS calcd for C13H12N2O2
228.0899, found 228.0903.
5-[5-[2-(Ben zyloxyca r b on yla m in o)-1-(ter t-b u t yld im e-
t h ylsilyloxy)et h yl]-2,3-d im et h oxyp h en yla m in om et h yl-
en e]-2,2-d im eth yl-1,3-d ioxa n e-4,6-d ion e (15f). Using the
general procedure for Meldrum’s acid adduct formation, 15f
was obtained as a white solid (2.82 g, 4.44 mmol) in 86% yield
1
and recrystallized from EtOAc/hexanes: mp 134-137 °C; H
NMR (CDCl3) δ 11.63 (d, 1H, J ) 14.03 Hz), 8.63 (d, 1H, J )
14.65 Hz), 7.38-7.29 (m, 5H), 6.93 (br s, 1H), 6.78 (br s, 1H),
5.10 (s, 2H), 4.99 (br t, 1H, J ) 6.13 Hz), 4.76 (dd, 1H, J )
3.36, 7.02 Hz), 3.96 (s, 3H), 3.86 (s, 3H), 3.50-3.40 (m, 1H),
3.23-3.12 (m, 1H), 1.75 (s, 6H), 0.90 (s, 9H), 0.05 (s, 3H), -0.07
(s, 3H); 13C NMR (CDCl3) δ 165.7, 164.1, 156.8, 153.5, 151.4,
139.9, 138.7, 136.9, 131.8, 128.9, 128.6, 107.9, 105.5, 104.9,
88.1, 73.8, 67.2, 61.6, 56.5, 48.9, 27.6, 26.3, 18.6, -4.3, -4.5;
MS m/z 614 (M+).
7-Br om o-1,3-ben zod ioxd e-5-ca r boxa ld eh yd e (3i). KF
(9.72 g, 167.30 mmol) was flame dried in a flask and allowed
to cool. 5-Bromo-3,4-dihydroxybenzaldehyde31 (4.00 g, 18.4
mmol) was added with 50 mL of DMF. Dibromomethane (3.12
g, 18.40 mmol) was added, and the mixture was heated at 140
°C for 4 h. The cooled solution was mixed with water and
extracted three times with diethyl ether. The combined organic
extracts were washed once with a 10% NaOH. The organic
solution was dried with MgSO4, filtered, and solvents were
removed in vacuo. The crude material was purified by flash
chromatography (CH2Cl2) to yield 3.26 g of 3i as a white solid
(85% yield) that was recrystallized from CH2Cl2/hexanes: mp
O-Ben zyl
N-2-(ter t-Bu t yld im et h ylsilyloxy)-2-[7,8-
d im eth oxy-4(1H)-qu in olin on -5-yl]eth yl Ca r ba m a te (16f)
Using the general procedure for thermal cyclization, 16f was
obtained as an off-white solid (771 mg, 1.48 mmol) in 89% yield
and was recrystallized from acetone/hexanes: mp 165-167 °C;
1H NMR (CDCl3) δ 8.98 (br s, 1H), 7.47 (t, 1H, J ) 6.41 Hz),
7.42 (s, 1H), 7.36-7.25 (m, 5H), 6.51 (br t, 1H, J ) 4.57 Hz),
6.11 (d, 1H, J ) 7.33 Hz), 5.47-5.41 (m, 1H), 5.01 (s, 2H),
3.95 (s, 3H), 3.93 (s, 3H), 3.63-3.42 (m, 2H), 0.91 (s, 9H), 0.07
(s, 3H), -0.07 (s, 3H); 13C NMR (CDCl3) δ 181.1, 157.1, 152.6,
141.5, 137.8, 137.4, 136.6, 134.9, 128.9, 128.3, 118.0, 111.3,
107.9, 70.7, 66.8, 61.4, 56.4, 50.2, 26.4, 18.6, -4.3, -4.5; MS
m/z 513 (M + 1). Anal. Calcd for C27H36N2O6Si: C, 63.25; H,
7.08; N, 5.46. Found: C, 63.06; H, 7.06; N, 5.44.
1
130-131 °C (lit.27 mp 125-127 °C); H NMR (CDCl3) δ 9.76
(s, 1H), 7.54 (s, 1H), 7.26 (s, 1H), 6.16 (s, 2H); 13C NMR (CDCl3)
δ 189.5, 151.7, 149.4, 133.3, 131.4, 106.7, 103.1, 101.3; MS m/z
231 (M + 2), 229 (M+).
7-Br om o-5-(1,3-dioxolan -2-yl)-1,3-ben zodioxole (3j). The
aldehyde 3i (2.89 g, 12.62 mmol), ethylene glycol (3.45 g, 55.72
mmol). and 50 mg of PTSA in 60 mL of benzene were refluxed
for 24 h under nitrogen using a Dean-Stark apparatus for
azeotropic removal of water. The cooled reaction solution was
washed with 10% aqueous KOH, water, and brine. The organic
layer was dried with MgSO4 and filtered, and the solvent was
removed in vacuo. The crude material was purified by flash
chromatography (2:1 hexane/EtOAc) to give 3.38 g of the acetal
3j as a yellow oil in 98% yield: 1H NMR (CDCl3) δ 7.11 (s,
1H), 6.89 (s, 1H), 6.04 (s, 2H), 5.69 (s, 1H), 4.13-3.97 (m, 4H);
13C NMR (CDCl3) δ 148.6, 146.9, 134.1, 124.1, 106.5, 103.2,
102.2, 100.8, 65.8; MS m/z 275 (M + 2), 273 (M+). Anal. Calcd
for C17H17NO4: C, 68.25; H, 5.72; N, 4.68. Found: C, 68.05;
H, 5.74; N, 4.60.
7-Be n zyla m in o-5-(1,3-d ioxola n -2-yl)-1,3-b e n zod iox-
ole (4j). To the dioxalane 3j (2.38 g, 8.72 mmol) under nitrogen
were added benzylamine (1.12 g, 10.5 mmol), Pd2(dba)3 (80 mg,
0.87 mmol), (S)-BINAP (150 mg, 0.24 mmol), and t-BuONa
(1.17 g, 12.20 mmol). A 100 mL portion of degassed toluene
was added, and nitrogen was flushed above the solution for
15 min. The flask was sealed and placed in an oil bath
preheated to 90 °C and stirred at that temperature for 3 h.
The cooled solution was diluted with 200 mL of diethyl ether
and filtered through Celite. The solvents were removed in
vacuo, and the residue was purified by flash chromatography
(2:1 hexane/EtOAc) to give 2.50 g of 4j as a pale yellow oil in
96% yield: 1H NMR (CDCl3) δ 7.40-7.27 (m, 5H), 6.49 (s, 1H),
6.46 (s, 1H), 5.93 (s, 2H), 5.68 (s, 1H), 4.40 (d, 2H, J ) 5.49
Hz), 4.11-3.95 (m, 4H), 3.92 (br s, 1H); 13C NMR (CDCl3) δ
147.9, 139.8, 134.9, 133.3, 132.9, 129.2, 128.1, 127.9, 105.8,
104.4, 101.6, 98.0, 65.7, 48.8; MS m/z 300 (M + 1).
O-Ben zyl
N-2-(ter t-Bu t yld im et h ylsilyloxy)-2-[7,8-
d im et h oxy-1-m et h yl-4(1H )-q u in olin on -5-yl]et h yl Ca r -
ba m a te (17f). Using the general procedure for N-methylation
of quinolones, 17f was obtained as an off white solid (280 mg,
0.531 mmol) in 68% yield and recrystallized from EtOAc/
1
hexanes: mp 73-75 °C; H NMR (acetone-d6) δ 7.49 (s, 1H),
7.45 (d, 1H, J ) 7.33 Hz), 7.25-7.16 (m, 5H), 6.57 (br t, 1H, J
) 4.58 Hz), 6.07 (br s, 1H), 5.81 (d, 1H, J ) 7.94 Hz), 4.85 (s,
2H), 3.92 (s, 3H), 3.86 (s, 3H), 3.72 (s, 3H), 3.48-3.27 (m, 2H),
0.82 (s, 9H), -0.03 (s, 3H), -0.18 (s, 3H); 13C NMR (d6-
Acetone) δ 178.6, 155.8, 154.4, 145.7, 141.5, 137.3, 136.9,
136.64, 127.9, 127.3, 127.2, 119.3, 109.6, 107.7, 70.1, 64.9, 60.6,
55.1, 49.0, 45.1, 25.1, 17.5, -5.8, -5.9; MS m/z 527 (M + 1).
Anal. Calcd for C28H38N2O6Si: C, 63.85; H, 7.27; N, 5.32.
Found: C, 63.57; H, 7.33; N, 5.23.
8 , 9 -D i m e t h o x y -1 -m e t h y l -1 H -b e n z o [ d e ] [ 1 , 6 ] -
n a p h th yr id in e (N-Meth yla a p ta m in e, 2f). The N-meth-
ylquinolone 17f (430 mg, 0.815 mmol) and 95 mg of 20%
Pd(OH)2-C in 20 mL of methanol were stirred under an
atmosphere of hydrogen at room temperature and pressure
for 45 min. The mixture was filtered through Celite and was
washed with copious amounts of methanol. The solvent was
removed under reduced pressure and the residue put under a
vacuum pump for 24 h. The free amine and (NH4)2SO4 (0.013
g, 0.0984 mmol) were placed in a flask with 15 mL of HMDSA
and 8 mL of TEA and fitted with a condenser. The reaction
and workup was carried out as for 2b. The product was
purified by flash chromatography (85:15 chloroform/MeOH)
and recrystallized from methanol and EtOAc. N-Methy-
laaptamine (2f) was obtained as a hydrochloride salt (189 mg,
7-Ben zylam in o-1,3-ben zodioxole-5-car boxaldeh yde (4i).
The amino acetal 4j (1.00 g, 3.34 mmol) and PPTS (250 mg,
1.00 mmol) in 19 mL of acetone and 1 mL of water were
refluxed for 30 min. The acetone was removed in vacuo, and

8010 J . Org. Chem., Vol. 65, No. 23, 2000
Walz and Sundberg
50 mL of EtOAc was added. The organic layer was washed
with saturated NaHCO3, water, and brine. The organic layer
was dried with MgSO4 and filtered, and the solvent was
removed in vacuo. The residue was purified by flash chroma-
tography (2:1 hexane/EtOAc) to give 860 mg of the aldehyde
4i as a pale yellow oil in 100% yield: 1H NMR (CDCl3) δ 9.72
(s, 1H), 7.39-7.28 (m, 5H), 6.88 (s, 1H), 6.86 (s, 1H), 6.05 (s,
2H), 4.44 (d, 2H, J ) 5.49 Hz), 4.09 (t, 1H, J ) 5.49 Hz); 13C
NMR (CDCl3) δ 191.4, 148.4, 139.7, 139.0, 133.3, 132.8, 129.3,
128.1, 127.9, 110.3, 102.5, 100.8, 48.5; MS m/z 256 (M + 1).
7-(Ben zyla m in o)-5-(1-ter t-bu tyld im eth ylsilyloxy-2-n i-
tr oeth yl)-1,3-ben zod ioxole (12g). Using the general proce-
dure for Amberlyst A-21-mediated Henry reaction followed by
tert-butyldimethylsilyl ether formation, compound 12g (1.15
g, 2.66 mmol) was obtained in 86% overall yield (based on
Using the general procedure for thermal cyclization to a
quinolone derivative, compound 16g (616 mg, 1.23 mmol) was
obtained as an off-white solid in 67% yield and was recrystal-
lized from EtOAc/hexanes: mp 170-172 °C; 1H NMR (CDCl3)
δ 9.03 (br s, 1H), 7.37-7.21 (m, 6H), 7.17 (br t, 1H, J ) 6.41
Hz), 6.58-6.53 (m, 1H), 5.96 (d, 1H, J ) 7.93 Hz), 5.90 (d, 2H,
J ) 24.42 Hz), 5.49-5.41 (m, 1H), 5.02 (s, 2H), 3.86 (br t, 1H,
J ) 10.38 Hz), 3.49 (br d, 1H, J ) 11.59 Hz), 0.90 (s, 9H),
-0.05 (s, 3H), -0.06 (s, 3H); 13C NMR (CDCl3) δ 180.5, 157.7,
148.6, 140.9, 137.4, 137.1, 133.8, 129.0, 128.6, 128.2, 127.0,
118.7, 111.3, 105.0, 103.0, 70.0, 67.0, 49.3, 26.4, 18.7, -4.4,
-4.5; MS m/z 497 (M + 1). Anal. Calcd for C26H32N2O6Si: C,
62.88; H, 6.49; N, 5.64. Found: C, 62.88; H, 6.50; N, 5.58.
O-Ben zyl N-2-(ter t-Bu tyld im eth ylsilyloxy)-2-[9-m eth -
yl-1,3-d ioxolo[4,5-h ]-6(9H)qu in olin on -6-yl]eth yl Ca r ba m -
a te (17g). Using the general procedure for N-methylation of
quinolones, 17g was obtained as an off-white solid (390 mg,
76% yield) and recrystallized from from EtOAc/hexanes: mp
1
recovered aldehyde 4i): mp 133-135 °C; H NMR (CDCl3) δ
7.37-7.28 (m, 5H), 6.34 (s, 1H), 6.29 (s, 1H), 5.94 (s, 2H), 5.22
(dd, 1H, J ) 3.06, 9.77 Hz), 4.45 (dd, 1H, J ) 9.77, 11.60 Hz),
4.39 (d, 2H, J ) 5.49 Hz), 4.29 (dd, 1H, J ) 3.05, 12.20 Hz),
4.01 (t, 1H, J ) 5.80), 0.82 (s, 9H), -0.02 (s, 3H), -0.16 (s,
3H); 13C NMR (CDCl3) δ 147.1, 138.4, 133.8, 133.40, 132.1,
128.3, 127.1, 127.0, 104.0, 100.8, 96.7, 82.6, 72.5, 47.7, 25.2,
17.7, -5.1, -6.0; MS m/z 431 (M + 1). Anal. Calcd for
1
197-199 °C; H NMR (CDCl3) δ 7.42 (s, 1H), 7.36-7.25 (m,
5H), 7.17 (d, 1H, J ) 7.32 Hz), 6.60 (t, 1H, J ) 4.56 Hz), 6.04
(d, 2H, J ) 17.70 Hz), 6.03 (d, 1H, J ) 7.93 Hz), 5.41-5.35
(m, 1H), 5.00 (s, 2H), 3.94 (s, 3H), 3.59-3.40 (m, 2H), 0.89 (s,
9H), 0.06 (s, 3H), -0.07 (s, 3H); 13C NMR (CDCl3) δ 179.7,
156.9, 149.9, 143.8, 142.8, 137.5, 134.5, 129.4, 128.8, 128.4,
128.1, 120.2, 111.3, 106.0, 101.7, 70.5, 66.7, 50.1, 44.4, 24.4,
18.7, -4.4, -4.5; MS m/z 511 (M + 1). Anal. Calcd for
C
22H30N2O5Si: C, 61.37; H, 7.02; N, 6.50. Found: C, 61.38; H,
6.98; N, 6.45.
7-Am in o-5-(1-ter t-b u t yld im et h ylsilyloxy)2-a m in oet h -
yl)1,3-ben zod ioxole (13g). To a stirred solution of the
silylated nitroaldol adduct 12g (1.02 g, 2.37 mmol) and 650
mg of 10% Pd-C in 45 mL of methanol and 15 mL of THF
was added NH4O2CH (1.50 g, 23.70 mmol), and the flask was
placed in a preheated oil bath at °C. The solution refluxed for
1 h and was allowed to cool. The solution was filtered though
Celite, and the Celite pad was washed with 100 mL of EtOAc.
The organic layer was washed with saturated NaHCO3 solu-
tion, water, and brine. The organic layer was dried with MgSO4
and filtered, and the solvent was removed in vacuo. The
residue was flash chromatographed (98:2 CHCl3/TEA to 88:
10:2 CHCl3/MeOH/TEA) to give 700 mg of 13g as an amor-
phous solid in 95% yield: 1H NMR (CDCl3) δ 6.32 (s, 1H), 6.26
(s, 1H), 5.91 (s, 2H), 4.47 (t, 1H, J ) 5.49 Hz), 3.55 (br s, 2H),
2.75 (d, 2H, J ) 5.50 Hz), 1.28, (br s, 2H), 0.90 (s, 9H), 0.05 (s,
3H), -0.07 (s, 3H); 13C NMR (CDCl3) δ 148.2, 138.5, 133.9,
129.9, 108.7, 101.3, 98.3, 77.1, 51.6, 26.4, 18.7, -4.1, -4.5; MS
m/z 311 (M + 1).
O-Ben zyl N-[2-(7-Am in o-1,3-ben zod ioxol-5-yl)-2-(ter t-
bu tyld im eth ylsilyloxy)eth yl] Ca r ba m a te (14 g) Using the
general procedure for selective CBZ protection of the primary
alkylamine, compound 14g (285 mg, 0.639 mmol) was obtained
as a pale yellow oil in 91% yield: 1H NMR (CDCl3) δ 7.38-
7.30 (m, 5H), 6.34 (s, 1H), 6.26 (s, 1H), 5.92 (s, 2H), 5.10 (s,
2H), 4.98-4.92 (m, 1H), 4.60 (dd, 1H, J ) 4.27, 6.72 Hz), 3.54
(br s, 2H), 3.54 (m, 2H), 3.43-3.34 (m, 1H), 3.19-3.09 (m, 1H),
0.88 (s, 9H), 0.01 (s, 3H), -0.09 (s, 3H); 13C NMR (CDCl3) δ
156.9, 148.4, 137.6, 137.2, 134.2, 130.1, 129.1, 128.6, 127.4,
108.8, 101.4, 98.3, 74.2, 67.1, 50.1, 26.3, 18.7, -4.2, -4.6; MS
m/z 444 (M+).
C
27H34N2O6Si: C, 63.50; H, 6.71; N, 5.48. Found: C, 63.49; H,
6.70; N, 5.51.
6-M e t h y l-1,3-d i o x o lo [4,5-d ]b e n z o [d e][1,6]n a p h -
th yr id in e (N-Meth ylm eth ylen ed ioxya a p ta m in e, 2g). Us-
ing the general procedure for HMDSA-mediated cyclization
and methanolic HCl elimination, 17g was converted to N-
methylmethylenedioxyaaptamine hydrochloride salt (2g) (134
mg, 0.504 mmol), obtained as a green/yellow solid (91% yield)
that was recrystallized from MeOH/acetone to give light green
crystals: mp 260 °C dec; 1H NMR (DMSO-d6) δ 7.69 (d, 1H, J
) 7.32 Hz), 7.37 (d, 1H, J ) 6.71 Hz), 7.03 (s, 1H), 6.84 (d,
1H, J ) 6.71 Hz), 6.16 (d, 1H, J ) 7.33 Hz), 6.15 (s, 2H), 3.83
(s, 3H); 13C NMR (D2O) 152.6, 147.9, 145.8, 132.69, 130.5,
127.8, 124.5, 117.6, 113.3, 102.3, 98.6, 97.3, 42.7; UV (95%
EtOH) λmax 205 nM (ꢀ 33 509), 236 nM (ꢀ 19 155), 263 nM (ꢀ
26 554), 323 nM (ꢀ 7366), 393 nM (ꢀ 7464); EI+HRMS calcd
for C13H10N2O2 226.0742, found 226.0740.
1,3-Dioxlo[4,5-d ]ben zo[d e][1,6]n a p h th yr id in e (Meth -
ylen ed ioxya a p ta m in e, 1g). Using the general procedure for
HMDSA-mediated cyclization and methanolic HCl elimination,
16g gave methylenedioxyaaptamine hydrochloride salt 1g (67
mg, 0.269 mmol) as a green/yellow solid (68% yield) that was
1
recrystallized from MeOH/acetone: mp 254 °C dec; H NMR
(DMSO-d6) δ 12.23 (br s, 1H), 7.70 (d, 1H, J ) 6.71 Hz), 7.31
(d, 1H, J ) 6.71 Hz), 6.97 (s, 1H), 6.81 (d, 1H, J ) 7.33 Hz),
6.25 (s, 2H); 13C NMR (D3O) δ 151.8, 148.6, 139.9, 131.7, 129.6,
127.4, 122.0, 116.7, 113.4, 103.3, 97.7, 96.8; UV (95% EtOH)
λmax 204 nM (ꢀ 32 358), 232 nM (ꢀ 20 870), 260 nM (ꢀ 26 172),
319 nM (ꢀ 6053), 400 nM (ꢀ 5692); EI+HRMS Calcd for
C
13H8N2O2 212.0586, Found 212.0587.
5-[2-(Ben zyloxyca r b on yla m in o)-1-(ter t-b u t yld im et h -
yl-silyloxy)eth yl]-1,3-d ioxola n -7-yla m in om eth ylen e-2,2-
d im eth yl-1,3-d ioxa n e-4,6-d ion e (15g). The general proce-
dure for Meldrum’s acid adduct formation provided compound
15g (927 mg, 1.54 mmol) as white solid in 84% yield which
Ack n ow led gm en t. We thank Dr. Randall J ohnson
and Dr. Alan J . Freyer of Smith Kline Beecham for
providing 1H- and 13C-spectrostopic data for natural
isoaaptamine. We thank Professors Ross Kelly, J ohn
J oule, and Michael Cava for spectroscopic data for
synthetic aaptamine.
1
was recrystallized from EtOAc/hexanes: mp 159-162 °C; H
NMR (CDCl3) δ 11.19 (d, 1H, J ) 14.65 Hz), 8.81 (d, 1H, J )
14.04 Hz), 7.37-7.30 (m, 5H), 6.73 (s,1H), 6.70 (s, 1H), 6.08
(d, 1H, J ) 1.22 Hz), 5.09 (s, 2H), 4.98 (br t, 1H, 5.80 Hz),
4.73-4.68 (m, 1H), 3.45-3.33 (m, 1H), 3.22-3.11 (m, 1H), 1.75
(s, 6H), 0.88 (s, 9H), 0.04 (s, 3H), -0.07 (s, 3H); 13C NMR
(CDCl3) δ 165.9, 163.7, 156.8, 154.4, 149.9, 138.9, 137.2, 136.9,
128.9, 128.6, 121.4, 109.8, 105.7, 104.9, 102.9, 88.2, 73.6, 67.2,
48.9, 27.5, 26.3, 18.6, -4.2, -4.5; MS m/z 598 (M+).
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
data for intermediates and target compounds 1b,e-g, 2b,e-
g, and 18. National Cancer Institute screening data in the
COMPARE format for compounds 1g and 2b ,e-g. This
material is available free of charge via the Internet at
http://pubs.acs.org.
O-Ben zyl N-2-(ter t-Bu tyld im eth ylsilyloxy)-2-[1,3-d iox-
olo[4,5-h ]-6(9H)-qu in olin on -6-yl]eth yl Ca r ba m a te (16g).
J O001080S