Solid-phase synthesis of naltrindole derivatives using Fischer indole synthesis based on one-pot release and cyclization methodology

Article abstract of DOI:10.1021/ol020230d

(Matrix presented) We describe a new approach for the solid-phase synthesis of indoles 1 that involves a one-pot release and cyclization reaction of a solid-supported hydrazone through a Wang-type linker. Using this solid-phase methodology, we accomplishe

Full text of DOI:10.1021/ol020230d

ORGANIC
LETTERS
2
003
Vol. 5, No. 8
159-1162
Solid-Phase Synthesis of Naltrindole
Derivatives Using Fischer Indole
Synthesis Based on One-Pot Release
and Cyclization Methodology
1
†
‡
‡
‡
Hiroshi Tanaka, Hiroshi Ohno, Kuniaki Kawamura, Atsushi Ohtake,
‡
,†
Hiroshi Nagase, and Takashi Takahashi*
Department of Applied Chemistry, Tokyo Institute of Technology, Meguro,
Tokyo 152-8552, Japan, and Department of Medicinal Chemistry, Pharmaceutical
Research Laboratory, Toray Industries, Inc., 1111 Tebiro, Kamakura,
Kanagawa 248-8555, Japan
ttakashi@o.cc.titech.ac.jp
Received November 12, 2002
ABSTRACT
We describe a new approach for the solid-phase synthesis of indoles 1 that involves a one-pot release and cyclization reaction of a solid-
supported hydrazone through a Wang-type linker. Using this solid-phase methodology, we accomplished the synthesis of 40 naltrindole
derivatives.
Combinatorial chemistry involving solid-phase synthesis has
proven to be an important tool for drug discovery. Solid-
phase synthesis is especially effective for the high-speed
synthesis of the chemical libraries of highly polar compounds
because workup and purification can be achieved by only
washing and filtration. We have already reported several
of the desired compounds. Therefore, there is particular
interest in developing new linking strategies to maintain the
efficiency of the reaction using solid-linked substrates.3
Substituted indoles possess a wide range of biological
properties and, as a result, have attracted considerable
attention from organic chemists, thus resulting in the
development of effective synthetic methodology for the
synthesis of indole derivatives not only in the solution
1
solid-phase syntheses of small molecule libraries, including
2
3
Vitamin D , glycoconjugates, and morphinan derivatives.
4
5
However, loading of the substrates to a solid matrix often
reduces their chemical reactivity, thus resulting in low yields
phase but also on a solid phase. Fischer indole synthesis
is one of the most common and effective reactions for the
*
Phone: +81-3-5734-2120. Fax +81-3-5734-2884.
Tokyo Institute of Techonolgy.
Toray Industries, Inc.
(2) (a) Doi, T.; Hijikuro, I.; Takahashi, T. J. Am. Chem. Soc., 1999, 121,
6749-6750. (b) Matsuda, A.; Doi, T.; Tanaka, H.; Takahashi, T. Synlett
2001, 1101-1104. (c) Ohno, H.; Kawamura, K.; Otake, A.; Nagase, H.;
Tanaka, H.; Takahashi, T. Synlett 2002, 93-96. (d) Fuchi, N.; Doi, T.;
Cao, B.; Kahn, M.; Takahashi, T. Synlett 2002, 285-289. (e) Tanaka, H.;
Zenkoh, T.; Setoi, H.; Takahashi, T. Synlett 2002, 1427-1430.
(3) (a) van Maarseveen, J. H. Comb. Chem. High. T. Scr. 1998, 1, 185-
214. (b) James, I. W. Tetrahedron 1999, 55, 4855-4946. (c) Guillier, F.;
Orain, D.; Bradly, M. Chem. ReV. 2000, 100, 2091-2157.
†
‡
(1) (a) Sencei, P. Solid-Phase Synthesis and Combinatorial Technology;
Wiley-Interscience: New York, 2000. (b) Dorwald, F. Z. Organic Synthesis
on Solid Phase; Wiley-VCH: New York, 2000. (c) Dolle, R. E. J. Comb.
Chem. 2002, 369-418. (d) Handbook of Combinatorial Chemistry; Nico-
laou, K. C., Hanko, R., Hartwig, W., Eds.; Wiley-VCH: Weinheim,
Germany, 2002; Vols. 1 and 2.
1
0.1021/ol020230d CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/19/2003

synthesis of substituted indoles from a ketone and an
arylhydrazine via cyclization of a hydrazone intermediate
under strongly acidic conditions. There are few reports of
Scheme 1. Strategy for the Solid-Phase Synthesis of
Naltrindoles 1
6
the solid-phase synthesis of simple indole derivatives using
ester-type linkers or a benzyloxy carbonyl linker, which are
stable to strongly acidic conditions.7 If the hydrazone
supported on resin through an acid-labile linker is isolable,
exposure of the solid-supported hydrazone to the acidic
cyclization conditions would result in simultaneous release
and cyclization reactions to provide the substituted indole.
The released hydrazone intermediate would easily undergo
cyclization reaction in comparison to the solid-supported
intermediate. Furthermore, this methodology requires no
additional manipulation for release of the products from the
resin. Herein we describe an effective solid-phase synthesis
of indole derivatives by Fischer indole synthesis using a
solid-supported ketone through a Wang linker.
Naltrindole (NTI) (1aA) is an efficient selective δ-opioid
8
receptor ligand. The amino substitution at the N-17 position
is essential for elicitation of intrinsic activity at the opioid
receptor. Its indole moiety causes selective binding to
δ-opioid receptors and, in addition, recently has been
proposed to be critical in its immunosuppressive activity,
9
which is not mediated via δ-opioid receptors. Therefore,
for elucidation of structure-activity relationships, new,
effective, and practical methodologies for the synthesis of
naltrindoles 1 varying at the indole moiety and the 17-N-
position are required.
hydroxymethylphenoxyethyl resin would be used as the
polymer support. The linker could survive under mildly
acidic conditions needed for the hydrazone formation and
can be cleaved under the cyclization conditions. A phenyl
Our strategy for the solid-phase synthesis of the NTI
derivatives 1 based on the one-pot release and cyclization is
illustrated in Scheme 1. The stepwise Fischer indole synthesis
of ketones 3 with phenyl hydrazine 5 via hydrazone 2 would
release the substituted indole 1. A Wang linker on a
2
-phenylethyl ether would be stable to these reaction
conditions.
We first conducted the release and cyclization reaction to
give naltrindole (NTI) (1aA) using solid-linked naltrexone
3
10
and phenylhydrazine (5a) (entry 1 in Table 1). Preparation
(
4) For recent solution-phase synthesis of the indole ring, see: Gribble,
G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045-1075.
5) For solid-phase synthesis of indoles, see: (a) Yun, W.; Mohan, R.
(
Table 1. Effect of Hydrazine on Solid-Phase Synthesis of
Indole 1aA-jA
Tetrahedron Lett. 1996, 37, 7189-7192. (b) Fagnola, M. C.; Candiani, I.;
Visentin, G.; Cabri, W.; Zarini, F.; Mongelli, N.; Bedeschi, A. Tetrahedron
Lett. 1997, 38, 2307-2310. (c) Zhang, H. C.; Brumfield, K. K.; Maryanoff,
B. Tetrahedron Lett. 1997, 38, 2439-2442. (d) Arumugan, V.; Routledge,
A.; Abell, C.; Balasubramanian, S. Tetrahedron Lett. 1997, 38, 6473-6479.
yielda
b
entry hydrazine
Ar
product (%) purity (%)
(
e) Collini, M. D.; Ellingboe, W. Tetrahedron Lett. 1997, 38, 7963-7966.
1
2
3
4
5
6
7
8
9
0
5a
5b
5c
5d
5e
5f
5g
5h
5i
phenyl
4-chlorophenyl
4-i-propylphenyl 1cA
1a A
1bA
quant
90
92
88
95
92
82
90
90
93
76
54
93
85
68
71
57
48
(f) Smith, A. L.; Stevenson, G. I.; Swain, C. J.; Castro, J. L. Tetrahedron
Lett. 1998, 39, 8317-8320. (g) Zhang, H.-C.; Brumfield, K. K.; Jaroskova,
L.; Maryaoff, B. E. Tetrahedron Lett. 1998, 39, 4449-4452.(h) Stephensen,
H.; Zaragoza, F. Tetrahedron Lett. 1999, 40, 5799-5802. (i) Zhang, H.-
C.; Ye, H.; Moretto, A. F.; Brumfield, K. K.; Maryanoff, B. E. Org. Lett.
1-naphthyl
1d A
1eA
1fA
2-methylphenyl
4-methylphenyl
2-chlorophenyl
4-methoxyphenyl 1h A
2-methoxyphenyl 1iA
2
000, 2, 89-92. (j) Zhang, H.-C.; Ye, H.; White, K. B.; Maryanoff, B. E.
Tetrahedron Lett. 2001, 42, 4751-4754. (k) Wu, T. Y. H.; Ding, S.; Gray,
N. S.; Schultz, P. G. Org. Lett. 2001, 3, 3827-3830. (l) Macleod, C.;
Hartley, C. R.; Hamprecht, D. W. Org. Lett. 2002, 4, 75-78. (m) Brase,
S.; Gil, C.; Knepper, K. Bioorg. Med. Chem. 2002, 10, 2415-2437. (n)
Yamazaki, K.; Kondo, Y. J. Comb. Chem. 2002, 4, 191-192. (o) Wacker,
D. A.; Kasireddy, P. Tetrahedron Lett. 2002, 43, 5189-5191.
1gA
1
5j
3-methylphenyl
1jA
91
93c
(6) Robinson, R. The Fisher Indole Synthesis; Wiley-Interscience: New
a
Yield was estimated by measurement of mass weight. b Purity was
York, 1982.
c
estimated by HPLC-MS analysis using UV absorption in 254 nm. Mixture
(
7) (a) Hutchins, S. M.; Chapman, K. T. Tetrahedron Lett. 1996, 37,
of 6′- and 4′-regioisomers in a ratio of 2.5:1.
4
869-4872. (b) Yang, L. Tetrahedron lett. 2000, 41, 6981-6984. (c)
Copper, L. C.; Chicchi, G. G.; Dinnell, K.; Elliott, J. M.; Hollingworth, G.
J.; Kunts, M. M.; Locker K. L.; Morrison D.; Shaw, D. E.; Tsao, K.-L.;
Watt, A. P.; Williams, A. R.; Swain, C. J. Bioorg. Med. Chem. Lett. 2001,
of the solid-supported naltrexone 3 was achieved by treat-
ment of commercially available naltrexone (4) with a
hydroxymethylphenoxyethyl resin (0.42 mmol/g)11 in the
1
1, 1233-1236
(
8) (a) Portoghese, P. S.; Sultana, M.; Nagase, H.; Takemori, A. E. J.
Med. Chem. 1988, 31, 281-284. (b) Portoghese, P. S.; Sultana, M.;
Takemori, A. E. J. Med. Chem. 1990, 33, 1714-1720.
3
presence of diethylazodicarboxylate (DEAD) and PPh in
(9) Gaveriaux-Ruff, C.; Filliol, D.; Simonin, F.; Matthes, H. W. D.;
Kieffer, B. L. J. Pharmacol. Exp. Ther. 2001, 298, 1193-1198.
THF. The loading yield was determined by cleavage of 3
1160
Org. Lett., Vol. 5, No. 8, 2003

under acidic conditions, followed by measurement of mass
recovery of naltrexone (4), which was 92% on the basis of
the resin. Fischer indole synthesis using solid-linked naltr-
exone 3 was examined next. Hydrazone formation of
Scheme 2a
Figure 1. Aldehydes for a building block.
shown in Table 1. Most of the examples proceeded well to
give the corresponding indoles 1bA, 1dA-gA, and 1jA in
1
1
excellent yields with a good purity (95-68%) (entries 2,
-7, and 10, Table 1). Substitution of the phenylhydrazine
4
with an electron-donating group led to reduced purity of the
desired indoles (entries 3, 8, and 9). Use of m-methyl-
phenylhydrazine resulted in a mixture of two regioisomers
8
b
1
hA (6′-: 4′- ) 2.5:1).
Table 2. Combinatorial Synthesis of Naltrindole Derivatives
aB-eG
1
a
Reagents and conditions: (a) FmocCl, Na
, CH Cl , 0 °C, 56%; (c) hydroxymethylphenoxy-
ethyl polystyrene resin, DEAD, PPh , 1 h, rt; (d) 20% piperidine
in CH Cl , rt; (e) 6, NaBH CN, DMF-AcOH (100:1); (f) 5 ,4 Å
MS, AcOH-CH Cl (1:1), rt.; (g) 10%TFA /CH Cl , rt.
2 3
CO aqueous THF,
yield
(%)a
purity
(%)b
rt, 88%; (b) BBr
3
2
2
entry
aldehyde
hydrazine
product
3
2
2
3
1
2
3
4
5
6
7
8
9
11a
11a
11a
11a
11a
11b
11b
11b
11b
11b
11c
11c
11c
11c
11c
11d
11d
11d
11d
11d
11e
11e
11e
11e
11e
11f
11f
11f
11f
11f
5a
5b
5c
5d
5e
5a
5b
5c
5d
5e
5a
5b
5c
5d
5e
5a
5b
5c
5d
5e
5a
5b
5c
5d
5e
5a
5b
5c
5d
5e
1a B
1bB
1cB
1d B
1eB
1a C
1bC
1cC
1d C
1eC
1a D
1bD
1cD
1d D
1eD
1a E
1bE
1cE
1d E
1eE
1a F
1bF
1cF
1d F
1eF
1a G
1bG
1cG
1d G
1eG
77
81
76
62
88
76
81
79
59
88
85
90
81
61
94
71
81
79
60
92
71
77
74
56
83
76
91
85
64
91
81
68
65
81
74
80
79
49
86
86
77
82
64
88
83
72
76
55
89
78
63
72
60
52
66
79
77
48
83
80
2
2
2
2
naltrexone 3 was achieved by treatment with an excess of
phenylhydrazine (5a) under mildly acidic conditions (CH
Cl /AcOH ) 1:1) in the presence of 4 Å MS at room
temperature. After removal of the excess phenylhydrazine
5a) by washing and filtration, exposure of the hydrazone 2
to 10% TFA in CH Cl for 0.5 h released NTI 1aA in
2
-
2
(
10
1
1
1
1
1
1
2
3
4
5
2
2
quantitative yield with 93% purity, which was determined
by HPLC-MS analysis of the residue on the basis of UV
absorption at 254 nm.1
2,13
The applicability of the indole
synthesis to other phenyl hydrazines 5b-j is examined as
16
7
1
(
10) Typical procedure for the solid-phase synthesis of naltrindole
derivatives 1: To a mixture of hydroxymethylphenoxyethyl resin (Watanabe;
.42 mmol/g, 1.00 g, 420 µmol), naltrexone (4) (1.02 g, 3 mmol), and PPh3
0.45 g, 1.7 mmol) in THF (8 mL) was added DEAD (40% toluene solution,
.68 mL, 1.5 mmol) in THF (2 mL) slowly at room temperature. After the
18
19
0
1
2
3
24
25
6
7
8
0
(
0
2
2
2
2
mixture was shaken for 1 h at the same temperature, the solvents were
then removed by filtration. The resulting beads were washed with THF,
DMF, MeOH, THF, and CH2Cl2 and dried in vacuo to give resin-supported
naltrexone 3 (1.05 g). The loading yield was determined by cleavage of 3
under acidic conditions, followed by measurement of mass recovery of
naltrexone (4), which was 92% on the basis of the resin. To the beads (50
mg) were added 4 Å MS (powder, 60 mg) and the mixture of phenylhy-
drazine HCl in CH2Cl2-AcOH (1:1) (1 mL) at room temperature. After
being shaken for 1 h at the same temperature, the mixture was filtered and
then washed with DMF, MeOH, THF, and CH2Cl2. The resulting resins
were treated with 10% TFA/CH2Cl2 (1 mL) for 30 min at room temperature,
filtered, and then washed with CH2Cl2. The combined filtrates were
evaporated and dried in vacuo to give 10.4 mg of morphinan compound
2
2
2
29
30
a
Yield was estimated by measurement of mass weight. b Purity was
estimated by HPLC analysis using UV absorption at 254 nm.
1
aA TFA salt with 93% purity determined by reversed-phase HPLC.
Org. Lett., Vol. 5, No. 8, 2003
1161

We next achieved a combinatorial synthesis of naltrindole
derivatives 1 varying the 17-N-position and the indole ring.
Scheme 2) Six aldehydes 6a-f for N-substitution and five
stepwise indole-formation conditions with the five phenyl-
hydrazines 5a-e provided 30 NTI derivatives 1. Analysis
of the obtained crude mixtures using HPLC-MS based on
UV absorption at 254 nm revealed 20 compounds with more
than 70% purity, which was acceptable for initial biological
assay (Table 2). The rest were obtained in moderate purity
(70-48%) but can be readily purified.
In conclusion, we have demonstrated a one-pot release and
cyclization reaction for the solid-phase synthesis of indole
derivatives 1 by Fischer indole synthesis. In this new release
strategy, release and cyclization reactions proceeded simul-
taneously to provide good yields of the corresponding indole
derivatives. We applied this methodology to the solid-phase
synthesis of naltrindole derivatives 1 to provide 40 indoles
in moderate purity. Biological assay of the indole derivatives
is currently underway.
(
hydrazines 5a-e for indole formation were used (Figure 1).
Protection of the secondary amine of noroxycodone (7) with
Fmoc-Cl gave Fmoc derivative 8 (88%). Cleavage of the
methyl ether of the phenol with boron tribromide provided
phenol 9 in 55% yield. Immobilization of phenol 9 was
achieved under Mitsunobu reaction conditions to provide the
solid-supported ether 10. The loading yield was determined
by cleavage of 10 under acidic conditions, followed by
measurement of mass recovery and HPLC analysis using UV
absorption at 254 nm, to be 97% yield with 96.6% purity.
Introduction of N-substitution to the Fmoc-protected amine
1
0 was achieved by removal of the Fmoc group with
piperidine in DMF solution, followed by treatment with the
six aldehydes 6a-f and NaBH CN in DMF-AcOH (100:
), afforded the corresponding tert-amines 11 in good purity
76-89%), as determined by analysis of their cleaved
3
1
(
Acknowledgment. This work was performed under the
management of the Research Association for Biotechnology
as a part of the Industrial Science and Technology Frontier
Program supported by NEDO (New Energy and Industrial
Technology Development Organization). We are also grateful
to Professor Dr. Hiroshi Handa for his helpful discussion.
residues using UV absorption at 254 nm. Reduction of the
solid-linked ketone to the secondary alcohol was not
observed under these conditions. Exposure of ketone 11 to
(11) Hydroxymethylphenoxyethyl resin was supplied by Watanabe
Chemical.
(
12) Reaction of solid-linked ketone on Wang resin instead of the
Supporting Information Available: Experimental pro-
cedures for syntheses and full characterization of compounds
1aA-jA, 1aB-eB, 1aC-eC, 1aD-eD, 1aE-eE, 1aF-eF,
hydroxymethylphenoxyethyl resin resulted in the reduced purity (79%
purity) of 5aA. HPLC-MS analysis of the mixture showed that it contained
NTI derivatives bearing the 4-hydroxylbenzyl moiety. These results indicate
that the acid-stable base polymer is essential for the solid-phase indole
formation.
1
aG-eG, 8, and 9. This material is available free of charge
(
13) Column: HYPERSIL ODS 3 µm, 4.6 × 75 mm; flow rate 1 mL/
min. Mobile phase: 0.1% HCOOH in H2O:0.1% HCOOH in MeCN )
5:5 (0 min) and then 0:100 (8 min). UV: 254 nm.
via the Internet at http://pubs.acs.org.
9
OL020230D
1162
Org. Lett., Vol. 5, No. 8, 2003