A versatile linkage strategy for solid-phase synthesis of N,N-dimethyltryptamines and β-carbolines

Article abstract of DOI:10.1021/ol026729p

(matrix presented) Various tryptamines are captured by a vinylsulfonylmethyl polystyrene resin, generating a safety-catch linkage. β-Carbolines can be formed from 4 by a Pictet-Spengler reaction with the introduction of R₁. Tryptamine 4 can also be derivatized by acylation or copper-mediated coupling to introduce R₂. If X = Br, Suzuki coupling can be used to introduce R₃. After derivatization, the indole derivatives are activated with methyl iodide and released under mild basic condition.

Full text of DOI:10.1021/ol026729p

ORGANIC
LETTERS
2002
Vol. 4, No. 23
4033-4036
A Versatile Linkage Strategy for
Solid-Phase Synthesis of
N,N-Dimethyltryptamines and
â-Carbolines
Tom Y. H. Wu and Peter G. Schultz*
Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps
Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037
schultz@scripps.edu
Received August 13, 2002
ABSTRACT
Various tryptamines are captured by a vinylsulfonylmethyl polystyrene resin, generating a safety-catch linkage. â-Carbolines can be formed
from 4 by a Pictet−Spengler reaction with the introduction of R . Tryptamine 4 can also be derivatized by acylation or copper-mediated
1
coupling to introduce R . If X ) Br, Suzuki coupling can be used to introduce R . After derivatization, the indole derivatives are activated with
2
3
methyl iodide and released under mild basic condition.
The tryptamine and â-carboline scaffolds are present in many
naturally and synthetically derived molecules with interesting
biological activities.1 Consequently, many solid-phase syn-
thetic approaches have been developed to generate small
molecules containing these core structures.2-4 However, these
approaches still have limitations with regards to function-
alization of the indole scaffolds. For example, current solid-
phase methodologies for synthesizing â-carbolines deriva-
tives use linkers that leave a polar functional group (e.g.,
COOH, CONH2) after cleavage; the solid-phase synthesis
of tryptamine analogues involves attaching the molecule onto
resin either through a linkage at the indole nitrogen or an
ester/amide linkage on the benzo ring. Herein we report a
novel and versatile safety-catch linkage strategy that can be
used to generate libraries of functionalized N,N-dimethyl-
tryptamines and â-carbolines in a simple and straightforward
manner.
Our approach starts with the synthesis of different
tryptamine scaffolds (Scheme 1) in three facile steps using
previously reported protocols.5 Commercially available in-
doles 1 were reacted with oxalyl chloride in refluxing ether.
The resulting indole oxalyl chlorides were filtered and treated
(1) (a) The Alkaloids, Chemistry and Physiology; Manske, R. H. F., Ed;
Academic Press: New York, 1981; Vol. XX. (b) Oh, S. J.; Ha, H.-J.; Chi,
D. Y.; Lee, H. K. Curr. Med. Chem. 2001, 8, 999-1034. (c) Faust, R.;
Garratt, P. J.; Jones, R.; Yeh, L.-K. J. Med. Chem. 2000, 43, 1050-1061.
(2) a) Mohan, R.; Chou, Y.-L.; Morrissey, M. M. Tetrahedron Lett. 1996,
37, 3963-3966. (b) Yang, L.; Guo, L. Tetrahedron Lett. 1996, 37, 5041-
5044.
(3) a) Zhang, H.-C.; Brumfield, K. K.; Jaroskova, L.; Maryanoff, B. E.
Tetrahedron Lett. 1998, 39, 4449-4452. (b) Smith, A. L.; Stevenson, G.
I.; Lewis, S.; Patel., S.; Castro, J. L. Bioorg. Med. Chem. Lett. 2000, 10,
2693-2696.
(4) The following work was published after the submission of this
manuscript and describes a similar linkage strategy: Connors, R. V.; Zhang,
A. J.; Shuttleworth, S. J. Tetrahedron Lett. 2002, 43, 6661-6663.
(5) Slassi, A.; Edwards, L.; O’Brien, A.; Meng, C. Q.; Xin, T.; Seto, C.;
Lee, D. K. H.; MacLean, N.; Hynd, D.; Chen, C.; Wang, H.; Kamboj, R.;
Rakhit, S. Bioorg. Med. Chem. Lett. 2000, 10, 1707-1709.
10.1021/ol026729p CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/24/2002

All scaffolds in Figure 1 were tested to give >90% purity
as analogues of tryptamine 6.
Scheme 1
The safety-catch linkage described here is stable to acidic
conditions. Treatment of 4 with aldehydes in 1-10%
trifluoroacetic acid (TFA) in dichloromethane (DCM) at
room temperature for 12 h affords the â-carboline scaffold
7 through a Pictet-Spengler reaction7 without premature
cleavage of the molecule from the solid support (Scheme
2). Activation of the resin followed by Hoffman elimination
Scheme 2
with ammonia in dioxane to give the corresponding indole
oxalyl amides. These were again filtered and reduced to the
corresponding tryptamines 2 using lithium aluminum hydride
in refluxing THF. After aqueous workup, the crude tryptamines
were directly mixed with vinylsulfonylmethyl polystyrene
resin 3 (Novabiochem).6 This also served as a purification
step, as only the fully reduced tryptamines were captured
onto the resin, affording 4. Activation of the safety catch
linker can be achieved by treatment with excess methyl
iodide to form the quaternary ammonium salt 5, though other
alkylating agents have been used in the past.6 A Hoffman
elimination using N,N-diisopropylethylamine releases trypt-
amine 6 from the resin. The yield of the cleaved products
ranged from 10% to 20% overall, based on the resin-loading
level of 4. A variety of commercially available indoles with
either electron-donating or electron-withdrawing functional
groups on the benzo ring as well as alkyl and aryl groups at
the C-2 position are compatible with this scheme (Figure 1).
Purity of the resin-bound indoles is determined by cleaving
a small amount of resin and subjecting the product to LCMS.
yielded â-carboline 8. Indoles with electron-rich substituents
(e.g., alkoxy groups) tend to react with 1% TFA/DCM; other
indoles with relatively electron-neutral substituents (e.g.,
alkyl, aryl) or electron-poor substituents (e.g., halides) require
5-10% TFA/DCM. Several alkyl and aryl aldehydes were
validated to give products with purity over 80% and 10-
20% purified yield when tested with unsubstituted tryptamine
derivatized resin 4 (Figure 2).
Figure 2. R1 introduced through aldehydes.
Resin-bound tryptamine 4 can be monomethylated by
treatment with 2.0 equiv of methyl iodide in DMF for 15
min at room temperature. The resulting product (9) was
derivatized at the indole nitrogen by two different methods
(Scheme 3). A copper-mediated coupling with aryl bromides
Figure 1. Indoles used as precursors for the tryptamine scaffolds.
4034
Org. Lett., Vol. 4, No. 23, 2002

Scheme 3
or aryl iodides (depending on commercial availability)
introduced an R2 aryl substituent.8 The reaction involved
heating the resin and the aryl bromide/iodide in the presence
of copper(I) iodide, trans-1,2-diaminocyclohexane, and
potassium tert-butoxide in anhydrous dioxane at 80 °C for
1 day. Alternatively, the indole nitrogen can be acylated with
acid chlorides and isocyanates using 10 equiv of N,N-
(dimethylamino)pyridine as the base in DMF at 80 °C for
12 h. Both the N-aryl bond and the N-acyl bond are stable
in subsequent activation and cleavage steps. Both reactions
are compatible with a variety of building blocks, generating
products with over 80% purity and 10-20% purified yield
when tested with unsubstituted tryptamine resin 9 (Figure
3).
Figure 3. (a) R2Ar introduced through aryl bromides and aryl
iodides. (b) Representative R2 introduced through acid chlorides.
(c) Representative R2 introduced through isocyanates.
Scheme 4
When X is a bromine, resin-bound monomethylated
tryptamine 9 can undergo derivatization through Suzuki
coupling using tris(dibenzylideneacetone) dipalladium(0) as
the catalyst and 2-(dicyclohexylphosphino)biphenyl as the
ligand (Scheme 4).9 The resin, boronic acid, catalyst, and
ligand were reacted in anhydrous dioxane in the presence
of dry K3PO4 at 80 °C for 1 day. Eight boronic acids were
tested for this reaction, and all of them afforded the expected
products with purity over 80% and yielded between 10%
(6) Kroll, F. E. K.; Morphy, R.; Rees, D.; Gani, D. Tetrahedron Lett.
1997, 38, 8573-8576.
and 20% after purification when tested with 5-bromo-
tryptamine derivatized resin 9.
In conclusion, we have described a novel linkage strategy
for making N,N-dimethyltrypatmines and â-carbolines. The
(7) Pictet, A.; Spengler, T. Chem. Ber. 1911, 44, 2030-2036.
(8) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am. Chem.
Soc. 2001, 123, 7727-7729.
(9) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.; Buchwald, S. L. J.
Org. Chem. 2000, 65, 1158-1174.
Org. Lett., Vol. 4, No. 23, 2002
4035

solid-phase organic transformations were used to derivatize
the indole scaffold. Further work involving library synthesis
and biological testing is in progress.
Acknowledgment. We thank Dr. Bradley Backes for
helpful discussion and support and Dr. Qing Lin for
proofreading the manuscript. T.W. thanks The Fletcher Jones
Foundation and The Skaggs Foundation for predoctoral
fellowships.
Supporting Information Available: LCMS and 1H NMR
of selected compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
Figure 4. R3 introduced through boronic acids.
linkage utilizes a safety-catch vinylsulfonylmethyl resin that
is stable under acidic, basic, and heating conditions. Several
OL026729P
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Org. Lett., Vol. 4, No. 23, 2002