Efficient synthesis of achiral seco-cyclopropylbenz[2,3-e]indoline analogues: [4-Amino-2-(5,6,7-trimethoxyindole-2-carboxamido)naphthalen-1-yl] ethyl chloride and [4-hydroxy-2-(5,6,7-trimethoxyindole-2-carboxamido) naphthalen-1-yl]ethyl chloride

Article abstract of DOI:10.1021/jo060501o

Achiral seco-aminocyclopropylbenz[2,3-e]indoline and seco- hydroxycyclopropylbenz[2,3-e]indoline (seco-CBI) analogues of the duocarmycins and CC-1065, e.g., 7 and 8, are potent anticancer agents. This paper describes significantly improved synthetic strat

Full text of DOI:10.1021/jo060501o

of naturally occurring minor groove binders include polyamides
(distamycin and netropsin),5 (+)-CC-1065 (1)6 and the duocar-
mycins7 (such as (+)-duocarmycin SA or DUMSA, 2), mito-
mycin C,8 and anthramycin.9 Examples of synthetic minor
groove binders include Hoechst 33258,10 diamidines, such as
pentamidine11 and furamidine,12 berenil,13 and numerous deriva-
tives or analogues of natural products, such as imidazole- and
pyrrolepolyamides,14 analogues of the duocarmycins and CC-
1065,15 as well as analogues of anthramycin16 and mitomycin
C.17
Efficient Synthesis of Achiral
seco-Cyclopropylbenz[2,3-e]indoline Analogues:
[4-Amino-2-(5,6,7-trimethoxyindole-2-carbox-
amido)naphthalen-1-yl]ethyl Chloride and
[4-Hydroxy-2-(5,6,7-trimethoxyindole-2-carbox-
amido)naphthalen-1-yl]ethyl Chloride
Atsushi Sato,†,# Adrienne Scott,# Tetsuji Asao,† and
Moses Lee*,‡,#
A number of research groups have reported the anticancer
activity of a wide range of analogues of the duocamycins and
CC-1065,18 such as compounds 319 and 4,20 and several of these
compounds (adozelesin, carzelesin, KW2189, and bizelesin)
have advanced to clinical trials. Due to severe toxicity to bone
marrow, only bizelesin still remains in phase II trials.21 As part
of our program in the design and discovery of novel anticancer
agents, we have concentrated on the development of achiral
analogues of the duocarmycins and CC-1065. These compounds
have been only recently reported by our group; see compounds
5-8 (Figure 1).22-24 The achiral amino- and hydroxy-seco-CBI
Department of Chemistry, Furman UniVersity,
3300 Pointsett Highway, GreenVille, South Carolina 29613,
DiVision of Natural Sciences and Department of Chemistry,
Hope College, Holland, Michigan 49423, and
Taiho Pharmaceutical Co., Ltd., 1-27, Misugidai Hanno-City,
Saitama, 357-8527, Japan
lee@hope.edu
ReceiVed March 7, 2006
(4) (a) DNA and RNA Binders; Demeunynck, M., Bailly, C., Wilson,
W. D., Eds.; Wiley-VCH: New York, 2003; Vol. 2. (b) Baraldi, P. G.;
Nunez Mdel, C.; Espinosa, A.; Romagnoli, R. Curr. Top. Med. Chem. 2004,
4, 231-239.
(5) Dervan, P. B. Science 1986, 232, 464-471.
(6) (a) Hanka, L. J.; Dietz, A.; Gerpheide, S. A.; Kuentzel, S. L.; Martin,
D. G. J. Antibiot. 1978, 31, 1211-1217. (b) Warpehoski, M. A.; Gebhard,
J.; Kelly, R. C.; Krueger, W. C.; Li, L. H.; McGovern, J. P. J. Med. Chem.
1988, 31, 590-603.
(7) (a) Ichimura, H.; Ogawa, T.; Takahashi, K.; Kobayashi, E.; Kawa-
moto, I.; Yasuzawa, T.; Takahashi, I.; Nakano, H. J. Antibiot. 1990, 43,
1037-1038. (b) Gomi, K.; Kobayashi, E.; Miyoshi, K.; Ashizawa, T.;
Okamoto, A.; Ogawa, T.; Katsumata, S.; Mihara, A.; Okabe, M.; Hirata,
T. Jpn. J. Cancer Res. 1992, 83, 113-120.
(8) Verweij, J.; Sparreboom, A.; Nooter, K. Cancer Chemother. Biol.
Response Modif. 1999, 18, 46-58.
(9) Kopka, M. L.; Goodsell, D. S.; Baikalov, I.; Grzeskowiak, K.; Cascio,
D.; Dickerson, R. E. Biochemistry 1994, 33, 13593-13610.
(10) Kiser, J. R.; Monk, R. W.; Smalls, R. L.; Petty, J. T. Biochemistry
2005, 44, 16988-16997.
(11) Jenkins, T. C.; Lane, A. N. Biochim. Biophys. Acta. 1997, 1350,
189-204.
(12) Arafa, R. K.; Brun, R.; Wenzler, T.; Tanious, F. A.; Wilson, W.
D.; Stephens, C. E.; Boykin, D. W. J. Med. Chem. 2005, 48, 5480-5488.
(13) Waring, M. J.; Bailly, C. J. Mol. Recognit. 1997, 10, 121-127.
(14) (a) Dervan, P. B.; Edelson, B. S. Curr. Opin. Struct. Biol. 2003,
13, 284-299. (b) Dervan, P. B. Bioorg. Med. Chem. 2001, 9, 2215-2235.
(15) (a) Boger, D. L.; Johnson, D. S. Angew. Chem., Int. Ed. Engl. 1996,
35, 1438-1474. (b) Sharma, S. K.; Jia, G.; Lown, J. W. Curr. Med. Chem.
Anti-Cancer Agents 2001, 1, 27-45.
Achiral seco-aminocyclopropylbenz[2,3-e]indoline and seco-
hydroxycyclopropylbenz[2,3-e]indoline (seco-CBI) analogues
of the duocarmycins and CC-1065, e.g., 7 and 8, are potent
anticancer agents. This paper describes significantly im-
proved synthetic strategies for preparing these compounds.
Starting from Martius acid (9), the new strategy gave a 13-
fold increase in the overall yield of 7, and the use of di-
tert-butyl malonate was economically beneficial. For com-
pound 8, the new strategy employed an Emmons-Horner
reaction, followed by a Stobbe condensation, and the overall
yield was improved 15-fold.
Compounds that bind to specific sequences in the minor
groove of DNA are potentially useful as pharmaceutical agents,1
biosensors,2 and as molecular tools for probing biological
processes.3 Consequently, the field of small molecule-DNA
minor groove interactions has blossomed in recent years,4 and
a large number of compounds have been identified. Examples
(16) Chen, Z.; Gregson, S. J.; Howard, P. W.; Thurston, D. E. Bioorg
Med. Chem. Lett. 2004, 14, 1547-1549.
(17) Wang, P.; Song, Y.; Zhang, L.; He, H.; Zhou, X. Curr. Med. Chem.
2005, 12, 2893-2913.
(18) Howard, T. T.; Lingerfelt, B. M.; Purnell, B. L.; Scott, A. E.; Price,
C. A.; Townes, H. M.; McNulty, L.; Handl, H. L.; Summerville, K.; Hudson,
S. J.; Bowen, P. J.; Kiakos, K.; Hartley, J. A.; Lee, M. Bioorg. Med. Chem.
2002, 10, 2941-2952 and references given therein.
# Department of Chemistry, Furman University.
‡ Division of Natural Sciences and Department of Chemistry.
† Taiho Pharmaceutical Co., Misugidai Hanno-City, Japan.
(1) (a) AdVances in DNA Sequence Specific Agents; Jones, G. B.,
Palumbo, M., Eds.; JAI Press Inc.; Greenwich, CT, 1998; Vol. 3. (b) Wilson,
W. D.; Nguyen. B.; Tanious, F. A.; Mathis, A.; Hall, J. E.; Stephens, C.
E.; Boykin, D. W. Curr. Med. Chem. Anti-Cancer Agents 2005, 5, 389-
408. (c) Baraldi, P. G.; Bovero, A.; Fruttarolo, F.; Preti, D.; Tabrizi, M.
A.; Pavani, M. G.; Romagnoli, R. Med. Res. ReV. 2004, 24, 475-528. (d)
Neidle, S.; Thurston, D. E. Nat. ReV. Cancer 2005, 5, 285-296.
(2) Janata, J.; Josowicz, M.; Vanysek, P.; DeVaney, D. M. Anal. Chem.
1998, 70, 179-208.
(19) (a) Kastrinky, D. B.; Boger, D. L. J. Org. Chem. 2004, 69, 2284-
2289 and references therein. (b) Aristoff, P. A.; Johnson, P. D. J. Org.
Chem. 1992, 57, 6234-6239.
(20) (a) Atwell, G. J.; Tercel, M.; Boyd, M.; Wilson, W. R.; Denny, W.
A. J. Org. Chem. 1998, 63, 9414-9420. (b) Atwell, G. J.; Milbank, J. J.
B.; Wilson, W. R.; Hogg, A.; Denny, W. A. J. Med. Chem. 1999, 42, 3400-
3411.
(21) Pitot, H. C., IV; Erlichman, C.; Reid, J. M.; Sloan, J. A.; Ames, M.
M.; Bagniewski, P. G.; Atherton-Skaff, P.; Adjei, A. A.; Rubin, J.; Rayson,
D.; Goldberg, R. M. Proc. Am. Assoc. Cancer Res. 1999, 40, 91.
(3) Yang, X.-L.; Wang, A. H.-J. Pharmacol. Ther. 1999, 83, 181-215.
10.1021/jo060501o CCC: $33.50 © 2006 American Chemical Society
Published on Web 05/16/2006
4692
J. Org. Chem. 2006, 71, 4692-4695

SCHEME 1. Original Reported Synthesis of Achiral
seco-Amino-CBI-TMI (7) and Achiral seco-CBI-TMI (8)a,24
FIGURE 1. Structures of (+)-CC-1065 (1), (+)-duocarmycin SA or
DUMSA (2), seco-CBI-TMI (3), seco-amino-CBI-TMI (4), achiral seco-
amino-CI-TMI (5), achiral seco-CI-TMI (6), achiral seco-amino-CBI-
TMI (7), and achiral seco-CBI-TMI (8).
analogues (compounds 7 and 8, respectively)24 were discovered
to be the most biologically active, as indicated by their DNA
sequence specific reactivity as well as their ability to inhibit
the growth of a human tumor (advance SC-OVCAR-3 ovarian
cancer) grown in skid mice. Moreover, unlike its chiral
counterpart 3, compound 7 had low systemic toxicity against
mice, and at an equal dose the latter compound had minimal
effect on mouse bone marrow stem cells grown in culture while
compound 3 completely killed the cells. Even though the
achiral23 seco-CBI compounds gave such desirable biological
activity, further development was limited by the availability of
compounds 7 and 8.
a Key: (a) TsCl, Et2NPh, 70 °C, 48 h (87%); (b) K2CO3, THF, reflux
(54%); (c) AcOEt, conc. HCl (70%); (d) Na2S, EtOH, reflux (11%); (e) (i)
NaNO2, H2SO4, (ii) Cu2O (42%); (f) BnBr (63%); (g) DibAl-H (100%);
(h) Ac2O, Pyr (62%); (i) (i) H2, PtO2, (ii) TMI-CO2H, PyBOP (36%); (j)
K2CO3, MeOH (87%); (k) MsCl (100%); (l) LiCl (81%); (m) H2, Pd-C
(90%); (n) CBZ-Cl, Et3N (29%); (o) NaOH (89%); (p) BH3-THF (55%);
(q) Ac2O, Pyr (55%); (r) H2, PtO2 (60%); (s) TMI-CO2H, PyBOP (81%);
(t) K2CO3, MeOH (82%); (u) (i) MsCl, (ii) LiCl (62%); (v) H2, Pd-C (68%).
SCHEME 2. Improved Preparation of Aminoester 13, a
Key Synthon for Making Achiral seco-Amino-CBI-TMI (7)
and Achiral seco-CBI-TMI (8)a
The original synthetic strategies for compounds 7 and 8 are
depicted in Scheme 1. There were, however, deficiencies in these
strategies. For preparation of compound 7, the use of an
unsymmetrical malonate diester, tert-butyl ethyl malonate, was
cost prohibitive, and the chemical transformations leading to
aminoester 13 were poor (4.2% yield from chloride 10).
Moreover, the overall yield for the 13-step synthesis of
compound 7 from Martius acid 9 was 0.047%. The synthesis
of compound 8 was hampered by the moderate-yielding
diazotization of aminoester 13 (42%). This limitation was
exacerbated by the difficulty in scaling up the reaction. When
the reaction was increased to 3 g, the yield precipitously dropped
to 4%. Moreover, the 13-step conversion of Martius acid 9 to
compound 8 was accomplished with an overall yield of 0.14%.
To produce sufficient quantities of compounds 7 and 8 for
biological studies, our group endeavored to overcome the
deficiencies encountered in the original synthetic strategies by
incorporating more efficient reactions, as well as developing
new synthetic strategies. The results are reported herein.
An improved synthesis of amino ester 13 is illustrated in
Scheme 2 (synthetic details are given in the Supporting
Information), and it follows a similar nucleophilic aromatic
a Key: (a) NaH, THF, reflux, 1 h (quant); (b) Na2S, EtOH, reflux, 0.5
h (quant); (c) CF3CO2H, CH2Cl2, rt, 16 h (78%); (d) conc. H2SO4, EtOH,
reflux, 5 h (69%).
substitution strategy used in our original synthesis.24 However,
the use of di-tert-butyl malonate in the reaction with chloride
1025 was found to be superior to tert-butyl ethyl malonate.
Diester 16 was produced in quantitative yield, compared to a
yield of 54% when tert-butyl ethyl malonate was used. Selective
reduction of the 4-nitro group of diester 16 was also improved;
presumably, the di-tert-butyl group created a larger steric
hindrance, and hence, reduction of the 2-nitro group was
suppressed. Removal of the tert-butyl groups and decarboxyl-
ation of the malonate were readily achieved by treatment of
compound 17 with trifluoroacetic acid. Fisher esterification of
the resulting amino acid 18 yielded the desired aminoester 13
in good yield. The overall yield from chloride 10 to aminoester
13 was increased from 4.2% in the original synthesis to 54%
(22) (a) Kupchinsky, S.; Centioni, S.; Howard, T.; Trzupek, J.; Roller,
S.; Carnahan, V.; Townes, H.; Purnell, B.; Price, C.; Handl, H.; Summerville,
K.; Johnson, K.; Toth, J.; Hudson, S.; Kiakos, K.; Hartley, J. A.; Lee, M.
Bioorg. Med. Chem. 2004, 12, 6221-6236. (b) Toth, J. L.; Trzupek, J. D.;
Flores, L. V.; Kiakos, K.; Hartley, J. A.; Pennington, W. T.; Lee, M. Med.
Chem. 2005, 1, 13-19.
(23) Daniell, K.; Stewart, M.; Madsen, E.; Le, M.; Handl, H.; Brooks,
N.; Kiakos, K.; Hartley, J. A.; Lee, M. Bioorg. Med. Chem. Lett. 2005, 15,
177-180.
(24) Sato, A.; McNulty, L.; Cox, K.; Kim, S.; Scott, A.; Daniell, K.;
Summerville, K.; Price, C.; Hudson, S.; Kiakos, K.; Hartley, J. A.; Asao,
T.; Lee, M. J. Med. Chem. 2005, 48, 3903-3918.
(25) (a) Talen, H. W. TraV. Chim. 1928, 47, 329-3349. (b) Ullmann,
F.; Bruck, W. Ber. 1908, 41, 3932-3939.
J. Org. Chem, Vol. 71, No. 12, 2006 4693

SCHEME 3. Emmons-Horner Reaction, Followed by
Stobbe Condensation Approach to the Synthesis of Achiral
seco-CBI-TMI (8)a
Stobbe condensation to produce acetate 23 in 57% yield.
Removal of the benzyl group in 23 was readily achieved in
88% yield by catalytic hydrogenation over 10% palladium-
carbon, and the resulting carboxylic acid group in compound
24 was selectively reduced by borane-THF. Alcohol 25 was
isolated in quantitative yield from acid 24. The alcohol moiety
of compound 25 was protected with a trityl group, which was
accomplished in 75% yield by reaction with triphenylmethyl
chloride. The acetoxy group of compound 26 was transformed
in “one-pot” by ethanolysis with potassium carbonate and
ethanol, followed by trapping the alkoxide intermediate with
benzyl bromide. The benzyl-protected intermediate 27 was
produced in 92% yield. Hydrolysis of the ethyl ester in
compound 27 yielded carboxylate 28 in quantitative yield, which
was transformed into amine 29 in 40% yield by reaction with
diphenyl phosphoryl azide in a Curtius rearrangement reaction,
followed by decomposition of the isocyanate intermediate with
refluxing water.
To complete the synthesis of target compound 8, the amino
group of compound 29 was coupled to the carboxylic acid
moiety of 5,6,7-trimethoxyindole-2-carboxylic acid (TMI-CO2H)
in the presence of 1-[3-(dimethylamino)propyl]-3-ethylcarbo-
diimide hydrochloride (EDCI) and 1-hydroxybenzotriazole
(HOBt). The desired product 30 was isolated in 58% yield.
Removal of the trityl group in compound 30 by treatment with
hydrochloric acid, followed by reaction of the corresponding
alcohol with methanesulfonyl chloride, gave mesylate 32 in
quantitative yield. Nucleophilic substitution of the mesylate
group with a chloride afforded compound 33 in 81% yield. Final
removal of the benzyl group by catalytic hydrogenation yielded
the target compound 8 in 91% yield. The overall yield in the
synthesis of compound 8 from ethyl benzoyl acetate is 2.1%,
and it represents a 15-fold improvement over the original
synthesis. Moreover, amine 29 could be prepared on a multigram
scale. With the new methods for synthesizing compounds 7 and
8, sufficient quantities have been prepared for further biological
investigations.
a Key: (a) K2CO3, 70 °C (88%); (b) BnO2C-CHdPPh3, toluene, reflux
(41%); (c) CF3CO2H, CH2Cl2, rt, 16 h (quant); (d) Ac2O, NaOAc, reflux
(57%); (e) H2, 10% Pd-C (88%); (f) BH3-THF (quant); (g) trityl chloride,
Pyr (75%); (h) K2CO3, EtOH, BnBr (92%); (i) NaOH, EtOH, (quant); (j)
DPPA, Et3N, THF, (40%); (k) TMI-CO2H, EDCI, HOBt, Pyr, (58%); (l)
conc. HCl, CH2Cl2, MeOH (quant); (m) MsCl, Et3N, CH2Cl2 (quant); (n)
LiCl, DMF (81%); (o) H2, 10% Pd-C (91%).
in the present approach. With this improvement, the overall yield
for synthesizing the achiral amino-seco-CBI compound 7 from
Martius acid (9) was improved from 0.047% to 0.61%, even
though it required an additional step. An improved synthesis
of compound 13 could also benefit the preparation of achiral
hydroxy-seco-CBI compound 8; the overall yield was increased
to 1.8% (13-fold). Unfortunately, this benefit could not be
realized since the diazotization step could not be scaled-up to
multigram quantities because the reaction mixture could not be
adequately stirred, even when a mechanical stirrer was em-
ployed. Consequently, a different synthetic strategy was de-
signed.
Scheme 3 depicts a synthetic strategy for the preparation of
achiral hydroxy-seco-CBI compound 8. This approach uses an
Emmons-Horner reaction, followed by Stobbe condensation
to produce the key achiral seco-CBI synthon. An advantage to
this route is that it employs a totally different approach to install
the hydroxyl group. Reaction of ethyl benzoyl acetate with tert-
butyl bromoacetate gave diester 20 in excellent yield. Emmons-
Horner condensation of the ketone moiety in compound 20 with
a benzyl (triphenylphosphoranylidene)acetate in refluxing tolu-
ene smoothly gave alkene 21 in 41% yield. In this strategy, the
three different ester groups in compound 21 could be conve-
niently and selectively deprotected. Treatment of alkene 21 with
trifluoroacetic acid selectively removed the tert-butyl group,
affording acid 22 in quantitative yield. Reaction of acid 22 with
refluxing acetic anhydride and sodium acetate promoted a
Experimental Section
(4-Acetoxy-2-ethoxycarbonylnaphthalen-1-yl)ethyl Triphenyl-
methyl Ether 26. To a solution of 25 (3.80 g, 12.57 mmol) in
pyridine (40 mL) was added triphenylmethyl chloride (8.40 g, 30.2
mmol) and the mixture stirred overnight. The mixture was
concentrated and diluted with AcOEt (200 mL), and the organic
layer was washed with water (50 mL) and brine (20 mL), dried
(Na2SO4), and evaporated. The residue was purified by silica gel
column chromatography (AcOEt/petroleum ether ) 1:8) to yield
26 (5.10 g, 75%) as a yellow foam. The foam was solidified with
1
EtOH: mp 146-156 °C; H NMR (CDCl3, 500 MHz) δ 8.11 (d,
J ) 9.0 Hz, 1H), 7.86 (d, J ) 9.0 Hz, 1H), 7.65 (s, 1H), 7.57 (t,
J ) 7.5 Hz, 1H), 7.52 (t, J ) 8.0 Hz, 1H), 7.36 (m, 6H), 7.17-
7.27 (m, 9H), 4.35 (q, J ) 7.5 Hz, 2H), 4.80 (t, J ) 7.0 Hz, 2H),
3.49 (t, J ) 7.0 Hz, 2H), 2.47 (s, 3H), 1.35 (t, J ) 7.0 Hz, 3H); IR
(neat) νmax 3058, 2980, 1768, 1719, 1604, 1512, 1490, 1466, 1449,
1420, 1368, 1344, 1274, 1244, 1219 cm-1; EIMS m/z 544 (M+,
2); EIHRMS m/z 544.2238 (M+, C36H32O5 requires 544.2250).
(4-Benzyloxy-2-ethoxycarbonylnaphthalen-1-yl)ethyl Triph-
enylmethyl Ether 27. To a solution of 26 (5.10 g, 9.36 mmol) in
EtOH (50 mL) was added K2CO3 (1.55 g, 11.24 mmol), and the
mixture was heated to reflux overnight. At that time, benzyl bromide
(1.34 mL, 11.2 mmol) was added, and the reaction was heated to
reflux for 4 h. The mixture was cooled to rt and filtered and the
filtrate concentrated. The residue was diluted with AcOEt (200 mL),
and the organic layer was washed with water (50 mL) and brine
4694 J. Org. Chem., Vol. 71, No. 12, 2006

(20 mL), dried (Na2SO4), and evaporated. The residue was purified
by silica gel column chromatography (AcOEt/petroleum ether )
1:8) to yield 27 (5.10 g, 92%) as a yellow foam. The foam was
(20 mL), dried (Na2SO4), and concentrated. The residue was purified
by silica gel column chromatography (AcOEt/petroleum ether )
1:1) to yield 31 (0.80 g, quant) as a yellow oil: 1H NMR (CDCl3,
500 MHz) δ 9.96 (s, 1H), 9.25 (s, 1H), 8.39 (d, J ) 8.0 Hz, 1H),
7.85 (d, J ) 8.5 Hz, 1H), 7.75 (s, 1H), 7.71 (dd, J ) 3.5, 5.8 Hz,
1H), 7.57 (d, J ) 7.5 Hz, 2H), 7.53 (m, 1H), 7.43 (t, J ) 7.5 Hz,
2H), 7.36 (t, J ) 7.0 Hz, 1H), 7.06 (s, 1H), 6.84 (s, 1H), 5.30 (s,
2H), 4.21 (t, J ) 6.0 Hz, 2H), 4.08 (s, 3H), 3.95 (s, 3H), 3.91 (s,
3H), 3.37 (t, J ) 5.0 Hz, 2H); IR (neat) νmax 3272, 2932, 1726,
1644, 1594, 1540, 1505, 1464, 1409, 1370, 1263, 1236 cm-1; EIMS
m/z 527 (M + H+, 18).
1
precipitated with diisopropyl ether: mp 112-114 °C; H NMR
(CDCl3, 500 MHz) δ 8.36 (d, J ) 8.0 Hz, 1H), 8.01 (d, J ) 8.0
Hz, 1H), 7.49-7.55 (m, 3H), 7.34-7.46 (m, 8H), 7.13-7.32 (m,
12H), 5.26 (s, 2H), 4.37 (q, J ) 7.0 Hz, 2H), 3.69 (t, J ) 7.5 Hz,
2H), 3.46 (t, J ) 7.0 Hz, 2H), 1.35 (t, J ) 7.5 Hz, 3H); IR (neat)
ν
max 3059, 2979, 1748, 1569, 1512, 1491, 1449, 1366, 1272, 1228
cm-1; EIMS m/z 592 (M+, 15); EIHRMS m/z 592.2617 (M+,
C41H36O4 requires 592.2614).
(4-Benzyloxy-2-aminonaphthalen-1-yl)ethyl Triphenylmethyl
Ether 29. To a solution of 27 (0.501 g, 2.89 mmol) in THF (10
mL) were added EtOH (15 mL), water (10 mL), and NaOH (0.10
g). The mixture was heated to reflux overnight. The organic solvents
were evaporated, and the precipitate was filtered and dried (Na2SO4)
to yield 28 (0.500 g, 100%) as a white solid. Compound 28 (0.47
g, 0.80 mmol) was dissolved in THF (10 mL), and Et3N (0.13 mL,
0.96 mmol) followed by diphenyl phosphorylazide (DPPA) (0.21
mL, 0.96 mmol) were added. The mixture was heated to reflux for
2 h, and water (18 mL) was added. The resulting mixture was
further heated to reflux 3 days. The mixture was extracted with
AcOEt (200 mL), and the organic layer was washed with brine
(20 mL), dried (Na2SO4), and evaporated. The residue was purified
by silica gel column chromatography (AcOEt/petroleum ether )
1:4) to yield 29 (0.17 g, 40%) as a pale yellow solid: mp 174-
[4-Benzyloxy-2-(5,6,7-trimethoxyindole-2-carboxamido)naph-
thalen-1-yl]ethyl Mesylate 32. To a chilled solution (ice bath) of
31 (80 mg, 0.15 mmol) and triethylamine (0.090 mL, 0.61 mmol)
in CH2Cl2 (2 mL) was added methanesulfonyl chloride (0.050 mL,
0.61 mmol). The reaction mixture was stirred for 1 h. It was diluted
with CH2Cl2 (50 mL) and washed with H2O (10 mL) and brine
(20 mL). The organic layer was dried (Na2SO4) and concentrated
under reduced pressure to yield 32 (0.11 g, quant) as a brown oil:
1H NMR (CDCl3, 500 MHz) δ 9.24 (s, 1H), 8.47 (s, 1H), 8.41 (d,
J ) 8.0 Hz, 1H), 7.85 (d, J ) 8.5 Hz, 1H), 7.71 (dd, J ) 3.5, 5.5
Hz, 1H), 7.60 (t, J ) 7.0 Hz, 1H), 7.48-7.56 (m, 3H), 7.44 (t, J
) 8.0 Hz, 2H), 7.37 (t, J ) 7.5 Hz, 1H), 7.18 (s, 1H), 6.88 (s, 1H),
5.28 (s, 2H), 4.63 (t, J ) 6.5 Hz, 2H), 4.09 (s, 3H), 3.95 (s, 3H),
3.93 (s, 3H), 3.56 (t, J ) 6.5 Hz, 2H), 2.86 (s, 3H); IR (neat) νmax
3330, 3099, 2933, 2874, 1725, 1649, 1592, 1537, 1502, 1466, 1411,
1369, 1306, 1238 cm-1; EIMS m/z 509 (M+ - CH3SO3H, 72).
[4-Benzyloxy-2-(5,6,7-trimethoxyindole-2-carboxamido)naph-
thalen-1-yl]ethyl Chloride 33.24 To a solution of 32 (0.11 g, 0.17
mmol) in dry DMF (2 mL) that was kept under a N2 atmosphere
was added LiCl (0.290 g, 6.94 mmol) at rt, and the mixture was
stirred for 3 days. The reaction mixture was diluted with AcOEt
(100 mL), washed with H2O (20 mL) and brine (10 mL), dried
(Na2SO4), and concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (AcOEt/
petroleum ether ) 1:4) to yield 33 (75 mg, 81%) as a white solid:
mp 180-184 °C; 1H NMR (CDCl3, 500 MHz) δ 9.23 (s, 1H), 8.63
(s, 1H), 8.42 (d, J ) 7.5 Hz, 1H), 7.84 (d, J ) 8.5 Hz, 1H), 7.53-
7.60 (m, 4H), 7.49 (t, J ) 8.0 Hz, 1H), 7.44 (t, J ) 7.0 Hz, 2H),
7.38 (t, J ) 7.5 Hz, 1H), 6.99 (s, 1H), 6.88 (s, 1H), 5.29 (s, 2H),
4.10 (s, 3H), 4.05 (t, J ) 6.0 Hz, 2H), 3.96 (s, 3H), 3.93 (s, 3H),
3.60 (t, J ) 6.0 Hz, 2H); IR (neat) νmax 3271, 2932, 1722, 1634,
1592, 1537, 1503, 1464, 1409, 1370, 1306, 1258, 1237 cm-1; EIMS
m/z 545 (M+, 5). A sample of compound 33 was hydrogenated
over 10% Pd-C using the reported method to produce target
molecule 8 in 91% yield.24
1
176 °C; H NMR (CDCl3, 500 MHz) δ 8.23 (d, J ) 8.5 Hz, 1H),
7.62 (d, J ) 8.5 Hz, 1H), 7.52 (d, J ) 7.0 Hz, 2H), 7.39 (m, 6H),
7.17-7.24 (m, 12H), 6.40 (s, 1H), 5.20 (s, 2H), 3.99 (s br, 2H),
3.44 (t, J ) 7.0 Hz, 2H), 3.14 (t, J ) 7.0 Hz, 2H); IR (neat) νmax
3391, 3060, 2874, 1729, 1625, 1600, 1516, 1490, 1449, 1407, 1372,
1281, 1236 cm-1; EIMS m/z 535 (M+, 6); EIHRMS m/z 535.2513
(M+, C38H33NO2 requires 535.2511).
[4-Benzyloxy-2-(5,6,7-trimethoxyindole-2-carboxamido)naph-
thalen-1-yl]ethyl Triphenylmethyl Ether 30. To a solution of 29
(1.40 g, 2.61 mmol) in dry pyridine (28 mL) were added 5,6,7-
trimethoxy-2-carboxylic acid (0.980 g, 3.92 mmol), 1-hydroxyben-
zotriazole (0.530 g, 3.92 mmol), and 1-[3-(dimethylamino)propyl]-
3-ethylcarbodiimide hydrochloride (1.50 g, 7.84 mmol). The
reaction mixture was kept under a N2 atmosphere at rt and stirred
for 3 h. The mixture was heated to 60 °C for 3 days and then
concentrated, diluted with AcOEt (200 mL), washed with water
(50 mL) and brine (50 mL), dried (Na2SO4), and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (AcOEt/petroleum ether ) 1:2) to yield 30 (1.17
g, 58%) as a white solid: mp 198-200 °C; 1H NMR (CDCl3, 500
MHz) δ 9.15 (s, 1H), 9.12 (s, 1H), 8.43 (d, J ) 9.5 Hz, 1H), 7.76
(d, J ) 9.5 Hz, 1H), 7.62 (m, 3H), 7.43-7.48 (m, 4H), 7.38 (t, J
) 6.5 Hz, 1H), 7.27 (m, 6H), 7.15 (m, 9H), 6.53 (s, 1H), 6.29 (s,
1H), 5.35 (s, 2H), 4.07 (s, 3H), 3.94 (s, 3H), 3.90 (s, 3H), 3.65 (t,
J ) 5.0 Hz, 2H), 3.35 (t, J ) 5.5 Hz, 2H); IR (neat) νmax 3282,
Acknowledgment. Support from the Camille and Henry
Dreyfus Foundation, Research Corporation, Taiho Pharmaceuti-
cal Company of Japan, the National Science Foundation (REU),
and the National Cancer Institute is gratefully acknowledged.
We acknowledge the assistance of Ms. Susan Kim.
2936, 1652, 1593, 1537, 1501, 1461, 1410, 1368, 1306, 1235 cm-1
;
TOFMS (ES+) m/z 791 (M + Na+, 100); TOFHRMS m/z 791.3102
(M + Na+, C50H44N2O6Na requires 791.3092).
Supporting Information Available: The general experimental
details, the synthesis of compounds 13, 16-18, and 20-25, as well
[4-Benzyloxy-2-(5,6,7-trimethoxyindole-2-carboxamido)naph-
thalen-1-yl]ethanol 31. To a solution of 30 (1.10 g, 1.43 mmol)
in CH2Cl2 (22 mL) were added MeOH (5 mL) and concentrated
HCl (1 mL) at rt. The solution was stirred for 1.5 h. The reaction
mixture was extracted with AcOEt (100 mL), and the organic layer
was washed with saturated aqueous NaHCO3 (20 mL) and brine
1
as the 500 MHz H NMR spectra of 7, 8, 13, 16-18, 20, 23-26,
and 28-33 are provided. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO060501O
J. Org. Chem, Vol. 71, No. 12, 2006 4695