A novel strategy for the solid-phase synthesis of substituted indolines [12]

Full text of DOI:10.1021/ja994373f

2966
J. Am. Chem. Soc. 2000, 122, 2966-2967
A Novel Strategy for the Solid-Phase Synthesis of
Substituted Indolines
K. C. Nicolaou,* A. J. Roecker, Jeffrey A. Pfefferkorn, and
Gou-Qiang Cao
Department of Chemistry and
The Skaggs Institute for Chemical Biology
The Scripps Research Institute
10550 North Torrey Pines Road
La Jolla, California 92037
Department of Chemistry and Biochemistry
UniVersity of California, San Diego
9500 Gilman DriVe, La Jolla, California 92093
ReceiVed December 15, 1999
Figure 1. General strategy for the solid-phase cycloloading, function-
Combinatorial chemistry has become an important tool in both
drug discovery and chemical biology, and its continued success
is dependent, in part, on further advances in solid-phase organic
synthesis (SPOS).1 As the demand for drug-like and/or natural
product-like libraries continues to grow, there is an increased need
for the development of reaction sequences and linking strategies
that allow complex and diverse targets to be constructed efficiently
and reliably. Toward this end, there has been particular interest
in developing linking strategies whereby the loading and cleavage
step(s) contribute to the complexity of the target structure rather
than merely constituting extraneous manipulations.2
alization, and cleavage of substitute indolines.
Table 1. Selenium-Mediated Loadinga of O-Allyl Anilinesb
temp time purity
entry aniline R1
R2
R3 R4 product (°C) (h) (%)b
Recently, we reported a selenium-based approach for the solid-
phase combinatorial synthesis of benzopyran-containing natural
products, utilizing a novel cycloloading strategy.3 Given the
versatility of this approach, we sought to extend it toward the
solid-phase synthesis of other heterocycles. It was envisaged that
substituted o-allyl anilines (1, Figure 1) might be cycloloaded
onto a polystyrene-based selenenyl bromide resin4a via a 5-exo-
trig cyclization to afford resin-bound indoline scaffolds (2).
Elaboration of 2 would provide structures such as 3 that could
be tracelessly cleaved4a-c providing access to 1-methyl indolines
(5), a structural class from which several drug candidates have
emerged including antineoplastic sulfonamides,5a 5-hydroxy-
tryptamine receptor antagonists (5-HT3),5b and muscarine receptor
agonists and antagonists.5c Moreover, it was envisaged that the
ability of this selenium tether to generate a carbon-centered radical
upon cleavage might also be utilized to create additional complex-
ity in the target structure concomitant with release.6 Specifically,
if an intramolecular radical acceptor could be positioned in
1
2
7
8
H
H
Me
H
H
H
H
H
H
H
H
H
Me
H
t-Bu
F
Cl
Br
CN
CO2Me
NO2
OMe
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
18
19
20
21
22
23
24
25
26
27
28
-20 0.5
-20 0.5
-20 0.5
-20 0.5
-20 0.5
-20 0.5
-20 0.5
89
85
92
92
86
94
89
95
95
n/a
n/a
3
9
4
10
11
12
13
14
15
16
17
5
6
7
8
0
0
0
1.0
1.0
1.0
9
10
11
-20 0.5
a Loading ranged from 54 to 87% as determined by weight of
cleavage product. b Reaction conditions: 1.0 equiv of selenenyl bromide
resin (0.75 mmol/g), 3.0 equiv of o-allyl aniline, 3.0 equiv of SnCl4.
c Purities estimated by cleavage (n-Bu3SnH, AlBN, 90 °C), polarity-
1
based purification, and H NMR analysis.
proximity to this radical (i.e. 4), then relatively complex polycyclic
indolines (6) could be constructed. Herein we describe our
preliminary efforts aimed at the loading, elaboration, and cleavage
of such substituted indolines.7
(1) (a) Balkenhohl, F.; von dem Bussche-Hunnefeld, C.; Lansky, A.; Zechel,
C. Angew. Chem., Int. Ed. Engl. 1996, 35, 2288-2337. (b) Watson, C. Angew.
Chem., Int. Ed. 1999, 38, 1903-1908. (c) Schreiber, S. L. Bioorg. Med. Chem.
1998, 6, 1127-1152.
It was first necessary to define conditions for the cycloloading
of o-allyl anilines.8 Preliminary solution phase studies with o-allyl
aniline (7, Table 1) revealed that such unprotected anilines would
undergo a selenium-mediated cyclization with PhSeBr in the
presence of suitable Lewis acid catalysts. Hence, we attempted
the corresponding reaction on solid support by treatment of a
suspension of selenenyl bromide resin4a and aniline 7 with SnCl4
at -20 °C which resulted in rapid resin decolorization. Subsequent
treatment of this resin with n-Bu3SnH and AIBN at 90 °C
followed by polarity-based removal9 of the reaction byproducts
afforded indoline 18 in 89% purity with an approximate loading
of 87%.10 As shown in Table 1, a series of functionalized anilines
were then prepared and tested for loading.11 Substrates 8-13,
(2) For a review, see: van Maarseveen, J. H. Comb. Chem. High
Throughput Screening 1998, 1, 185-214.
(3) (a) Nicolaou, K. C.; Pfefferkorn, J. A.; Cao, G.-Q. Angew. Chem., Int.
Ed. 2000, 39, 734-739. (b) Nicolaou, K. C.; Cao, G.-Q.; Pfefferkorn, J. A.
Angew. Chem., Int. Ed. 2000, 39, 739-743.
(4) (a) Nicolaou, K. C.; Pastor, J.; Barluenga, S.; Winssinger, N. Chem.
Commun. 1998, 1947-1948. For preparations of related selenium-based resins,
see: (b) Ruhland, T.; Andersen, K.; Pedersen, H. J. Org. Chem. 1998, 63,
9204-9211. (c) Fujita, K.; Watanabe, K.; Oishi, A.; Ikeda, Y.; Taguchi, Y.
Synlett 1999, 11, 1760-1761.
(5) (a) Yoon, S. J.; Chung, Y.; Lee, M. S.; Choi, D. R.; Lee, J. A.; Yun,
D. K.; Moon, E. Y.; Hwang, H. S.; Choi, C. H.; Jung, S. H. Patent. WO
9807719 (Dong Wha Pharm. Ind. Co., Ltd., S. Korea); Chem. Abstr. 1998,
128, 204885. (b) Bermudez, J.; Dabbs, S.; Joiner, K. A.; King, F. D. J. Med.
Chem. 1990, 33, 1929-1932. (c) Adachi, S.; Koike, K.; Takayanagi, I.
Pharmacology 1996, 53, 250-258.
(6) To our best knowledge, this is the first example whereby radical
cleavage from a solid support is accompanied by subsequent intramolecular
cyclization to afford an additional ring system in the target molecule. Solid-
phase non-releasing radical cyclizations have been described previously; for
examples, see: (a) Du, X.; Armstrong, R. W. J. Org. Chem. 1997, 62, 5678-
5679. (b) Watanabe, Y.; Ishikawa, S.; Takao, G.; Toru, T. Tetrahedron Lett.
1999, 40, 3411-3414. In addition, traceless radical cleavages of selenium
resins have been described, see references 4a-c.
(7) For a previous method for the solid-phase synthesis of indolines, see:
Wang, Y.; Huang, T.-N. Tetrahedron Lett. 1998, 39, 9605-9608.
(8) For solution-phase precedent, see: (a) Clive, D. L. J.; Wong, C. K.;
Kiel, W. A.; Menchen, S. M. J. C. S. Chem. Commun. 1978, 379-380. (b)
Clive D. L. J.; Farina, V.; Singh, A.; Wong, C. K.; Kiel, W. A.; Menchen, S.
M. J. Org. Chem. 1980, 45, 2120-2126. (c) Danishefsky, S.; Berman, E. M.;
Ciufolini, M.; Etheredge, S. J.; Segmuller, B. E. J. Am. Chem. Soc. 1985,
107, 3891-3898.
10.1021/ja994373f CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/14/2000

Communications to the Editor
J. Am. Chem. Soc., Vol. 122, No. 12, 2000 2967
Table 2. Release and Cyclization of Polycyclic Indolinesa
Scheme 1. Parallel Synthesis of 1-Methyl Indolinesa
a Reaction conditions: (a) Coupling procedure A: 10.0 equiv of acid,
10.0 equiv of DCC, 1.3 equiv of 4-DMAP, CH2Cl2, 25 °C, 24 h;
coupling procedure B: 10.0 equiv of alkenyl bromide, 20.0 equiv of
NaH, DMF, 60 °C; (b) 4.0 equiv of n-Bu3SnH, 1.3 equiv of AlBN,
toluene, 90 °C, 4 h. b Products obtained as single diastereomers with
relative stereochemistry shown as determined by 1H NMR and ROESY
analysis unless otherwise noted. c Isolated yield over three steps based
on 0.75 mmol/g loading. d See Supporting Information for discussion
of stereochemical assignment.
a Reaction conditions: (a) 27.0 equiv of COCl2, CH2Cl2, 0 °C, 1 h;
(b) 10.0 equiv R2NHx, 27.0 equiv of Et3N, CH2Cl2, 25 °C, 12 h; (c) 4.0
equiv of n-Bu3SnH, 1.3 equiv of AlBN, toluene, 90 °C, 2 h; (d) 10.0
equiv of R3CO2H, 10.0 equiv of DCC, 1.3 equiv of 4-DMAP, CH2Cl2,
25 °C, 16 h. b Isolated yields over four steps (40-45) or five steps (46-
48) based on 0.75 mmol/g loading.
by taking better advantage of the ability of this selenium tether
to generate a carbon-centered radical. Hence, the secondary
nitrogen of indoline (18, Table 2) was coupled to a series of
olefinic acceptors via either amide or alkyl linkages to form
derivatives of type 49 which could be cleaved with concomitant
cyclization to provide polycyclic indolines of type 6. For example,
DCC coupling of indoline 18 with 1-cyclopentene-1-carboxylic
acid 50 afforded the corresponding amide which was then
suspended in toluene at 90 °C and a solution of n-Bu3SnH and
AIBN was slowly added over a 4 h interval. Gratifyingly,
tetracycle 55 was released as the sole product and a single
diastereomer in 26% yield over three steps. Coupling of 18 with
1-cyclohexene-1-carboxylic acid 51 and trans-cinnamic acid 52
followed by release afforded tetracycle 56 and tricycle 57 in 36
and 13% yields, respectively. over three steps. In addition,
alkylation (NaH, DMF, 60 °C) of indoline 18 with either allyl or
crotyl bromide (53 and 54) led to the formation of tricycles 58
and 59 in 18 and 19% yields, respectively.
In conclusion, we have described a highly efficient method
for the solid-phase synthesis of substituted indoline scaffolds
which can be elaborated and tracelessly cleaved providing access
to members of the medicinally important 1-methyl indoline class.
Moreover, this linking strategy also allows for a novel cleavage
approach whereby additional ring systems can be formed through
a radical cyclization during the release step. The use of this latter
cleavage option in conjunction with the development of highly
functionalized indoline scaffolds should allow for the construction
of complex natural product-like compound libraries.
bearing alkyl substituents or halogens, underwent facile loading
under these conditions (-20 °C, 0.5 h), whereas those with
electron-withdrawing groups (14 and 15) required slightly modi-
fied conditions (0 °C, 1 h). The only failures noted were 4-nitro
aniline 16 and 4-methoxy aniline 17.
With this collection of resin-bound indolines (18-26) now in
hand, we set out to test their proposed applications. First, we
undertook the solid-phase synthesis of a collection of 1-methyl
indolines resembling previously reported 5-HT3 receptor anta-
gonists5b to demonstrate how the current linking strategy might
be employed in combinatorial synthesis. The generalized synthetic
strategy is outlined at the top of Scheme 1. Hence, resin-bound
indolines were converted to acyl chlorides (29) by treatment with
phosgene, and these acyl chlorides were then reacted with various
amines (R2NHx) to afford ureas (30).5b If the amine used was
piperazine (35), the remaining secondary amine was then coupled
with a carboxylic acid (R3CO2H). All of the resulting indolines
(30 or 32) were tracelessly cleaved to produce compounds of type
31 or 33. The parallel application of this sequence to indoline
scaffolds 18, 19, and 25, amines 34-36, and carboxylic acids
37-39 resulted in the formation of 1-methyl indolines 40-48.
Notwithstanding the utility of these 1-methyl indolines, our
second goal was to develop a more functional cleavage protocol
Acknowledgment. Financial support for this work was provided by
The Skaggs Institute for Chemical Biology, The National Institutes of
Health (U.S.A.), and the Department of Defense (fellowship to J.P.).
(9) Separation of the desired indoline cleavage products from organotin
byproducts represents an obstacle to the combinatorial use of this methodology.
The polarity-based purification used here relies on the desired product being
prontonated and taken into the aqueous phase such that the organotin species
can be removed with the organic phase. For a review of other applicable
methods, see: Curran, D. P. Angew. Chem., Int. Ed. 1998, 37, 1174-1196.
(10) Purities of products are estimated based upon integration of 1H NMR
signals of isolated cleavage products after polarity-based9 purification.
(11) See Supporting Information for preparation of o-allyl anilines.
Supporting Information Available: Representative procedures and
physical data for all compounds (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
JA994373F