Stereocontrolled solid-phase synthesis of a 90-membered library of indoline-alkaloid-like polycycles from an enantioenriched aminoindoline scaffold

Article abstract of DOI:10.1002/anie.200462298

A library of tricyclic derivatives, similar to indoline alkaloids, has been generated by using a stereocontrolled, conjugate hetero-Michael approach in both the solution and the solid phase (see scheme; P = protecting group, R = functional group). The mil

Full text of DOI:10.1002/anie.200462298

Communications
Combinatorial Chemistry
responses. An important milestone in our approach is the
development of a practical, enantioselective synthesis of a
functionalized aminoindoline scaffold, 4, that could be further
utilized in introducing skeletal diversity.[7] This scaffold is
highly unique and comprises four orthogonal protecting
groups. Our plan was to utilize the phenolic hydroxyl group
as an immobilization site in solid-phase synthesis. The
remaining three functional groups could further be used in
complexity-generating, diversity-oriented reactions. As
shown in Scheme 1, aminoindoline 4 could be easily con-
Stereocontrolled Solid-Phase Synthesis of a
90-Membered Library of Indoline-Alkaloid-like
Polycycles from an Enantioenriched
Aminoindoline Scaffold**
Zhonghong Gan, P. Thirupathi Reddy,
Sophie Quevillon, Samuel Couve-Bonnaire, and
Prabhat Arya*
With growing interest in the use of small molecules[1] for
dissecting protein–protein interactions[2] and for under-
standing signaling pathways, the need for developing
combinatorial methods to obtain small molecules that
have stereochemical and skeletal diversity has also
grown.[3,4] Owing to their structural complexity and the
diversity of their functional groups, natural products are
a source of bioactive lead compounds, and it is highly
likely that libraries of small molecules that also display
these features would serve as valuable tools.[5]
We initiated a combinatorial chemistry program that
is aimed at providing indoline-alkaloid-like complex
polycyclic compounds in a high-throughput manner.[6]
Indole and indoline alkaloids belong to an important
family of bioactive natural products, and several of these
derivatives (1–3, see Figure 1) exhibit various biological
Scheme 1. Natural-product-like and indoline-alkaloid-like complex poly-
cyclic compounds. P=protecting group, R=diverse functional groups.
verted into 5, which comprises a conjugated carboxylate ester.
Following the immobilization of 5 through the phenolic
hydroxyl group on a solid support to give 6 and upon selective
removal of the indoline protecting group, the substrate could
then be coupled to an amino acid to give 7. A key step in our
approach is the formation of a six-membered ring by a
stereoselective, conjugate hetero (e.g. aza)-Michael reaction.
This could provide the indoline-alkaloid-like tricyclic deriv-
ative 8, in which the diversity could easily be introduced at
four sites. A six-membered ring-closure strategy that involves
the trapping of the primary amine by a conjugated carboxylic
ester could also provide a general method to the synthesis of
cyclic b-amino acids.[8]
Figure 1. Examples of bioactive indole and indoline alkaloids.
[*] Dr. Z. Gan, Dr. P. T. Reddy, S. Quevillon, Dr. S. Couve-Bonnaire,
Dr. P. Arya
Chemical Biology Program
Steacie Institute for Molecular Sciences
National Research Council of Canada
100 Sussex Drive, Ottawa, Ontario, K1A0R6 (Canada)
Fax: (+1)613-952-0068
The enantioselective synthesis of aminoindoline deriva-
tive 13 is shown in Scheme 2. 5-Hydroxy-2-nitro-benzalde-
hyde (9) was converted into 10 in two steps that involve
protection of the phenol and elongation of the carbon chain.
Compound 10 was then subjected to an asymmetric amino-
hydroxylation reaction to give compound 11 in 79% yield
(> 92% ee).[9] The aminoindoline 12 was obtained from 11 in
several steps that involved 1) reduction of the carboxylate
ester (70%), 2) benzoyl-protection of the primary alcohol
(OBz, 88%), 3) tosylation of the secondary alcohol (OTs,
87%), 4) selective reduction of the nitro group, and 5) cyc-
lization under mild basic conditions (75% for two steps).
Finally, compound 13 was obtained from 12 in three steps by
which the indoline nitrogen was protected (Teoc, 98%), the
Cbz protecting group was removed under hydrogenation, and
the benzylic amine was protected with an Alloc group (85%
for two steps, see Scheme 2). The overall sequence is very
clean and the desired aminoindoline 13 could be obtained in
E-mail: prabhat.arya@nrc.ca
S. Quevillon, Dr. P. Arya
Department of Chemistry
University of Ottawa
10 Marie Curie, Ottawa, K1N 6N5 (Canada)
[**] We sincerely thank Stuart Schreiber, Jared Shaw, and the DOS team
members at the Broad Institute of Harvard and MIT for providing
alkylsilyl-linker-based macrobeads and for their help in our solid-
phase synthesis projects. This work was supported by a NRC
genomics and health initiative program, special VP-NRC funds for
chemical biology, the National Cancer Institute of Canada (NCIC),
and the Canadian Institutes of Health Research (CIHR). Malgosia
Daroszewska, Michael Barnes, and Don Leek are thanked for their
technical support.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200462298
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Angewandte
Chemie
acids. The stereochemical preference of this reaction is
postulated by the proposed transition states (18 and 19) that
may account for the attack of the nucleophile from the b face.
The conjugate hetero-Michael reaction is highly reproducible
and gives the desired cyclic product(s) upon use of different
amino acid derivatives.
The model solid-phase synthesis is shown in Scheme 4.
Compound 20 was obtained from 13 in a few steps to perform
solid-phase synthesis. In our hands, this scaffold gave poor
loading with the use of (4-methoxyphenyl)diisopropylsilyl-
propyl
polystyrene
beads
(50–100 mm,
loading
1.4 mmolgÀ1).[10] At this stage, we decided to work with
compound 21a, in which a three-carbon spacer was intro-
duced between the aromatic moiety and the primary alcohol
group.[11] As expected, the loading of 21a with commercially
available silyl-linker-based beads and with the macrobeads
(500–560 mm loading 1.29 mmolgÀ1)[12,13] worked very well to
give product 21b (1.12 mmolgÀ1, 87% upon cleavage of the
product from the macrobead support).
Scheme 2. a) 1) MEMCl, DIPEA, 97%; 2) (EtO)2P(O)CH2COOEt, NaH,
94%; b) Sharpless aminohydroxylation, 79%; c) 1) LiBH4, 70%;
2) BzCl, pyridine, 88%; 3) TsCl, DMAP, 87%; 4) H2, Lindlar cat.;
5) K2CO3, THF, 75% for two steps; d) 1) TeocCl, pyridine, 98%; 2) H2,
10% Pd/C, MeOH; 3) AllocCl, pyridine, 85% for two steps. MEM=
Methoxyethoxymethyl, DIPEA=diisopropylethylamine, Cbz=carboben-
zyloxy, Bz=benzyl, Ts=p-toluenesulfonyl, DMAP=4-dimethylamino-
pyridine, Teoc=(trimethylsilyl)ethoxycarbonyl, Alloc=Allyloxycarbonyl.
The next series of steps were then attempted on the solid
support. The indoline amine was first deprotected of its Fmoc
group and then coupled with the Fmoc-protected amino acid
chloride (first diversity) to give the amino acid coupled
product, 22. Several attempts were then made to optimize the
conditions for the solid-phase coupling reaction, and the use
of collidine as a base gave the best results. The coupled
product, 22, was then treated with piperidine, and, as
observed in the synthesis carried out in solution, we were
pleased that the primary amine was trapped with the
conjugated carboxyl ester to give the tricyclic derivative 23
during the removal of the Fmoc group. Once again, as with
the solution-state synthesis, the in situ conjugate hetero-
Michael reaction was highly reproducible in the solid phase.
The mild conditions for this cyclization reaction are highly
appealing and attractive to explore its potential in the
generation of a molecule library. The stereochemical outcome
of this reaction was found to be dependent upon the choice of
the amino acid, and the ratio of the two diastereomers, 25 and
26, varied from 5:1 to 1:1.[14] To complete the test sequence in
the solid phase, 23 was then subjected to 1) an amide coupling
reaction to introduce the second diversity, 2) removal of the
Alloc protecting group to give the free amine, and 3) reaction
with carboxylic acid chloride to introduce the third diversity
and to give 24. Finally, compounds 25 and 26 were obtained
upon cleavage of the substrates from the support under
large quantities (5–10 g) in a short period. With a practical
method in hand for this scaffold, the next step was to prepare
15, a key starting material to explore the stereoselective,
conjugate hetero-Michael approach.
Scheme 3 shows our model study to obtain a tricyclic
derivative by use of a stereoselective, conjugate hetero-
Michael approach as the key step. Conversion of 13 into the
conjugated ester 14 required the removal of the protecting
group at the primary alcohol (99%), oxidation of the alcohol
to the aldehyde, followed by a Wittig chain extension (93%
for two steps). In a test study, upon removal of the Teoc group,
the indoline amine was coupled with the amino acid chloride
to give N-Fmoc-protected derivative 15 (88% for two steps).
Upon removal of the Fmoc group (20% piperidine), we were
delighted that the six-membered ring formed under these
mild conditions. The primary amine generated in situ was
easily trapped by the conjugated carboxylate ester in a
stereoselective manner to give the cyclic compounds 16
(major) and 17 (minor) in 96% overall yield (R1 = Me, > 10:1
ratio of two diastereomers, 82% d.r. for the major product).
The stereochemistry of the new stereogenic center was
assigned by NMR spectroscopy studies. The ease of the
asymmetric, conjugate hetero-Michael approach to yield the
tricylic product was a pleasant surprise and it opens a simple
and very attractive approach to the synthesis of cyclic b-amino
=
Scheme 3. a) 1) K2CO3, MeOH, 99%; 2) Dess–Martin periodinane; 3) Ph3P CHCOOEt, 93% for two steps; b) 1) TBAF; 2) Fmoc alanine chloride,
pyridine, 88%; c) 20% piperidine, 96%. TBAF=tetra-n-butylammonium fluoride, Fmoc=9-fluorenylmethoxycarbonyl.
Angew. Chem. Int. Ed. 2005, 44, 1366 –1368
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Communications
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Scheme 4. a) and b) see Supporting Information; c) (4-methoxyphenyl)diisopropylsilyl-propyl poly-
styrene macrobeads (500–560 mm, loading 1.29 mmolgÀ1), 87% after cleavage from support;
d) 1. 20% piperidine; 2. Fmoc amino acid chloride, collidine; e) 20% piperidine; f) 1. R2COCl, pyri-
dine; 2. Pd(PPh3)4; 3. R3COCl, pyridine; g) pyridine–HF; 80–85% yield of 25 and 26 over 7 steps
from 21b.
[5] For selected examples of solid-phase library
synthesis on benzopyrans as a privileged sub-
structure, see: a) K. C. Nicolaou, J. A. Pfefferkorn, G.-Q. Cao,
Angew. Chem. 2000, 112, 750 – 755; Angew. Chem. Int. Ed. 2000,
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Angew. Chem. 2000, 112, 755 – 759; Angew. Chem. Int. Ed. 2000,
39, 739 – 743; c) K. C. Nicolaou, J. A. Pfefferkorn, A. J. Roecker,
G.-Q. Cao, S. Barluenga, H. J. Mitchell, J. Am. Chem. Soc. 2000,
122, 9939 – 9953; d) K. C. Nicolaou, J. A. Pfefferkorn, H. J.
Mitchell, A. J. Roecker, S. Barluenga, G.-Q. Cao, R. L. Affleck,
J. E. Lillig, J. Am. Chem. Soc. 2000, 122, 9954 – 9967; e) K. C.
Nicolaou, J. A. Pfefferkorn, S. Barluenga, H. J. Mitchell, A. J.
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skeletally diverse architectures, see: a) M. D. Burke, E. M.
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126, 14095 – 14104.
[8] For a review on b-amino acids, see: M. Liu, M. P. Sibi,
Tetrahedron 2002, 58, 7991 – 8035.
[9] The %ee values were determined by chiral HPLC.
[10] The resin was purchased from Novabiochem.
[11] For the synthesis of 21a, see the Supporting Information.
[12] J. A. Tallarico, K. M. Depew, H. E. Pelish, N. J. Westwood, C. W.
Lindsley, M. D. Shair, S. L. Schreiber, M. A. Foley, J. Comb.
Chem. 2001, 3, 312 – 318.
[13] The alkylsilyl-linker-based macrobeads were provided by ICCB,
Harvard Medical School, Harvard University.
[14] The explanation for the decrease in diastereoselectivity during
the solid-phase conjugate hetero-Michael reaction is not clear at
this stage.
[15] For detailed information on library synthesis, see the Supporting
Information.
desilylation conditions. Interestingly, compounds 25 and 26
were obtained from 21b in seven steps in 80–85% overall
yield. The overall sequence on the solid support utilizes very
mild reaction conditions that include a crucial in situ con-
jugate hetero-Michael reaction to give functionalized amino-
indoline-based, alkaloid-like, tricyclic derivatives. With alkyl-
silyl-linker-based macrobeads, this method was further uti-
lized in the generation of a test library of 90 compounds (two
diastereomers per well) by an IRORI split-and-mix-type
encoded method. After completion of the library synthesis,
the beads were taken out of the IRORI Kans and then
subjected to desilylation cleavage conditions.[15]
To summarize, a library of indoline-alkaloid-like polycyc-
lic compounds was synthesized on the basis of an enantiopure
aminoindoline scaffold. The key reaction was the stereo-
selective, conjugate hetero-Michael reactions with nitrogen
nucleophiles to obtain cyclic b-amino acid derived com-
pounds. Furthermore, biological studies of this library in
various cellular assays are in progress and the findings will be
reported in due course.
Received: October 14, 2004
Published online: January 26, 2005
Keywords: combinatorial chemistry · cyclization ·
.
indoline alkaloids · protecting groups · solid-phase synthesis
[1] a) S. L. Schreiber, Chem. Eng. News 2003, 81, 51 – 61; b) T. Gura,
Nature 2000, 407, 282 – 284; c) R. L. Strausberg, S. L. Schreiber,
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Angew. Chem. Int. Ed. 2005, 44, 1366 –1368