Palladium-catalyzed synthesis of novel optically active tryptophan analogues

Article abstract of DOI:10.1021/ol034360d

(Matrix presented) Both unsaturated proline derivatives and optically active tryptophan analogues have been obtained via Pd-catalyzed cyclization of aniline-containing acetylenic amino acids. The side chain length of the cyclization precursor determines w

Full text of DOI:10.1021/ol034360d

ORGANIC
LETTERS
2003
Vol. 5, No. 10
1717-1720
Palladium-Catalyzed Synthesis of Novel
Optically Active Tryptophan Analogues
Bart C. J. van Esseveldt,† Floris L. van Delft,† Rene´ de Gelder,‡ and
,†
Floris P. J. T. Rutjes*
Departments of Organic and Inorganic Chemistry, NSRIM, UniVersity of Nijmegen,
ToernooiVeld 1, 6525 ED Nijmegen, The Netherlands
rutjes@sci.kun.nl
Received February 28, 2003
ABSTRACT
Both unsaturated proline derivatives and optically active tryptophan analogues have been obtained via Pd-catalyzed cyclization of aniline-
containing acetylenic amino acids. The side chain length of the cyclization precursor determines which one of the two possible products will
be formed.
Enantiomerically pure tryptophan analogues such as (S)-
isotryptophan (1, n ) 1), (S)-homoisotryptophan (1, n ) 2),
and (S)-bishomoisotryptophan (1, n ) 3) are potentially
biologically relevant R-amino acids1 of which only isotryp-
tophan itself has been previously prepared in an optically
active form.2 In that preparation, the synthesis proceeded via
cyclization of an ortho-ethynylaniline moiety that was
connected to a Scho¨llkopf chiral auxiliary. The key cycliza-
tion to the indole ring was promoted by copper, which has
also been reported as the catalyst of choice for the synthesis
of other indole systems.3
knowledge, Pd-catalyzed syntheses of 2-substituted indoles
have only been conducted using relatively simple 2-alkyn-
ylanilines as the cyclization precursors.6
We envisaged that the tryptophan analogues 1 might be
readily synthesized from the corresponding protected anilines
2 via such a Pd-catalyzed cyclization as the key step. The
anilines 2 should be easily accessible from the enantiopure
acetylene-containing R-amino acids 37 (Scheme 1). These
Scheme 1. Retrosynthesis of (S)-Tryptophan Analogues
In addition to copper, palladium-catalysts have been
frequently used in cyclization reactions of nitrogen nucleo-
philes4 onto alkenes and alkynes to provide nitrogen het-
erocycles such as pyrroles5 and indoles.6 To the best of our
† Department of Organic Chemistry.
‡ Department of Inorganic Chemistry.
(1) (a) Cady, S. G.; Sono, M. Arch. Biochem. Biophys. 1991, 292, 326.
(b) Peterson, A. C.; Migawa, M. T.; Martin, M. J.; Hamaker, L. K.;
Czerwinski, K. M.; Zhang, W.; Arend, R. A.; Fisette, P. L.; Ozaki, Y.;
Will, J. A.; Brown, R. R.; Cook, J. M. Med. Chem. Res. 1994, 3, 531. (c)
Southan, M.; Truscott, R.; Jamie, J.; Pelosi, L.; Walker, M.; Maeda, H.;
Iwamoto, Y.; Tone, S. Med. Chem. Res. 1996, 5, 343.
(2) (a) Ma, C.; Yu, S.; He, X.; Liu, X.; Cook, J. M. Tetrahedron Lett.
2000, 41, 2781. (b) Ma, C.; Liu, X.; Li, X.; Flippen-Anderson, J.; Yu, S.;
Cook, J. M. J. Org. Chem. 2001, 66, 4525.
trifunctional amino acids8 are either commercially available
(e.g., 2-amino-4-pentynoic acid)9 or readily accessible via a
chemoenzymatic procedure that has been developed in
collaboration with DSM Research (Geleen, The Nether-
lands).10
(3) Hiroya, K.; Itoh, S.; Ozawa, M.; Kanamori, Y.; Sakamoto, T.
Tetrahedron Lett. 2002, 43, 1277.
(4) Tsuji, J. Palladium Reagents and Catalysts; Wiley: New York, 1997.
To investigate the feasibility of forming the 2-substituted
indole ring via an intramolecular Pd-catalyzed reaction,
10.1021/ol034360d CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/16/2003

cyclization precursor 5 was synthesized starting from the
racemic propargylglycine derivative 47 (Scheme 1).
chromatography (Scheme 3). Treatment of this enamide with
the same Pd catalyst in refluxing acetonitrile led to a rapid
conversion into the aforementioned imine 6 in 70% yield.
The latter conversion could also be accomplished by reflux-
ing 7 in acetonitrile without the Pd-catalyst present, however
the reaction did not go to completion even after prolonged
reaction times of over 24 h.
The Pd-catalyzed functionalization of propargylglycine
derivatives with aromatic groups under Sonogashira-type
coupling conditions has already been described by Crisp.11
A slight modification of the reported conditions led to a
smooth coupling of 4 with 2-iodoaniline at room temperature
affording precursor 5 in 88% yield. Interestingly, subsequent
subjection of 5 to previously reported cyclization conditions6d
Scheme 3. Synthesis of Enamide 7 Followed by Conversion
to Imine 6a
Scheme 2. Synthesis of a Racemic Cyclization Precursor and
Attempted Pd-Catalyzed Indole Formationa
a Conditions: (a) 2-iodoaniline, PdCl2(PPh3)2, CuI, Et2NH, Et2O,
rt, 2 h; (b) PdCl2(MeCN)2, MeCN, reflux, 3 h.
a Conditions: (a) PdCl2(MeCN)2, MeCN, rt, 2 h; (b) PdCl2-
(MeCN)2, MeCN, reflux, 30 min; (c) MeCN, reflux.
did not lead to the anticipated formation of the indole system.
Instead, an unexpected product was formed as the sole
product in 65%, which was unambiguously identified as the
five-membered cyclic imine 6 through an X-ray crystal
structure determination (Figure 1).12
A plausible mechanism involves complexation of the Pd-
(II) catalyst to the triple bond, possibly aided by coordination
to the aniline nitrogen, giving rise to the π-complex 8
(Scheme 4).
Scheme 4. Mechanistic Aspects of the Pd-Catalyzed
Formation of Imine 6 from Cyclization Precursor 5
Figure 1. PLATON13 drawing of the X-ray crystal structure of
imine 6.
After this surprising result, amino acid 5 was subjected to
the same reagents at room temperature, resulting in the
formation of the cyclic enamide 7 in 54% yield after
(5) (a) Gabriele, B.; Salerno, G.; Fazio, A.; Bossio, M. R. Tetrahedron
Lett. 2001, 42, 1339. (b) Grigg, R.; Savic, V. J. Chem. Soc., Chem. Commun.
2000, 873.
(6) (a) Larock, R. C.; Yum, E. K. J. Am. Chem. Soc. 1991, 113, 6689.
(b) Larock, R. C.; Yum, E. K.; Refvik, M. D. J. Org. Chem 1998, 63,
7652. (c) Cacchi, S.; Carcinelli, V.; Marinelli, F. J. Organomet. Chem. 1994,
475, 289. (d) Rudisill, D. E.; Stille, J. K. J. Org. Chem. 1989, 54, 5856.
(7) (a) Wolf, L. B.; Tjen, K. C. M. F.; Ten Brink, H. T.; Blaauw, R. H.;
Hiemstra, H.; Schoemaker, H. E.; Rutjes, F. P. J. T. AdV. Synth. Catal.
2002, 344, 70. (b) Wolf, L. B.; Tjen, K. C. M. F.; Rutjes, F. P. J. T.;
Hiemstra, H.; Schoemaker, H. E. Tetrahedron Lett. 1998, 39, 5081.
This renders the acetylene sufficiently electrophilic to
undergo nucleophilic attack of the apparently more nucleo-
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Org. Lett., Vol. 5, No. 10, 2003

philic carbamate nitrogen to give the corresponding vinylpal-
ladium intermediate 9. This species will undergo protonolysis
of the Pd-C bond (and regeneration of the Pd(II) catalyst)
to give the cyclic enamide 7, which under the circumstances
immediately reacts further to provide the pyrroline 6 as the
product. In the last step, the regenerated Pd-catalyst may
possibly act as a Lewis acid by lowering the electron density
of the double bond, thus facilitating intramolecular attack
of the aniline nitrogen onto the Boc-group.
Table 1. Pd-Catalyzed Cyclizations of Several Functionalized
Cyclization Precursors
Having observed the mild and facile cycloisomerization
of 5, we set out to investigate this type of reaction somewhat
further to gain insight into the scope and limitations of the
observed cyclization. Therefore, we prepared several cy-
clization precursors via Sonogashira couplings between
protected propargylglycine 4 and (substituted) aryl iodides.
The racemic substituted acetylenes 10-13 were thus obtained
in good yields and subjected to the cyclization conditions at
different temperatures (Table 1).
Unfortunately, subjection of the substituted acetylenes 10-
12 to the cyclization conditions did not lead to the formation
of the corresponding cyclic enamides. In the case of 10, a
relatively clean reaction was observed affording hydrolysis
product 16 as the sole product in a yield of 31%. With
substrate 12, a similar reaction was observed leading to the
formation of ketone 17 as the major product in a somewhat
lower yield of 19%. Presumably, in these cases the internal
acetylene undergoes a Pd-catalyzed regioselective hydration
leading to the corresponding ketone.14 Cyclization precursor
11 did not give any reaction at room temperature, while
heating at reflux temperature led to rapid decomposition of
the starting compound.
The acetylated aniline 13 underwent cyclization at room
temperature, resulting in the formation of the cyclic enamide
18 in 49% yield after column chromatography.
In addition, we converted cyclization precursor 5 into the
more restricted oxazolidinone analogue 14 in two steps, i.e.,
ester reduction (LiBH4, THF) followed by oxazolidinone
formation (NaH, THF, reflux) in 52% yield. Subjection of
the cyclic carbamate 14 to the Pd catalyst at reflux led to
the formation of the corresponding bicyclic product 19 in a
somewhat lower isolated yield of 32%. These preliminary
results indicate that the presence of the ortho-aniline nitrogen
atom in the precursor is crucial for the cycloisomerization
a Isolated yield after column chromatography.
to occur. As shown before, cyclization precursor 5 could not
be cyclized to the desired isotryptophan derivative. Therefore,
we were pleased that subjection of the suitably protected
biscarbamate 15 to the same Pd-catalyst in refluxing aceto-
nitrile led to the formation of isotryptophan analogue 20 as
the sole product without loss of enantiopurity according to
chiral HPLC (Chiralcel OD).
Next, we investigated the feasibility of synthesizing
optically active homologous isotryptophan derivatives start-
ing from the homo- and bishomopropargylglycine derivatives
21 and 24,10a respectively, using the same pathway. Thus,
the Pd-catalyzed Sonogashira coupling of the optically active
homo- and bishomopropargylglycine derivatives 21 and 24
with 2-iodoaniline afforded the cyclization precursors 22 and
25 in 79 and 78% yields, respectively (Scheme 5).
(8) For a review on applications of unsaturated amino acids, see: Rutjes,
F. P. J. T.; Wolf, L. B.; Schoemaker, H. E. J. Chem. Soc, Perkin Trans. 1
2000, 4197.
(9) In this article, referred to as propargylglycine; 2-amino-5-hexynoic
acid is homopropargylglycine, etc.
(10) (a) Wolf, L. B.; Sonke, T.; Tjen, K. C. M. F.; Kaptein, B.;
Broxterman, Q. B.; Schoemaker, H. E.; Rutjes, F. P. J. T. AdV. Synth. Catal.
2001, 343, 662. (b) Sonke, T.; Kaptein, B.; Boesten, W. H. J.; Broxterman,
Q. B.; Kamphuis, J.; Formaggio, F.; Toniolo, C.; Rutjes, F. P. J. T.;
Schoemaker, H. E. In StereoselectiVe Biocatalysis; Patel, R. N., Ed.; Marcel
Dekker: New York, 2000; p 23.
(11) Crisp, G. T.; Robinson, T. A. Tetrahedron 1992, 48, 3239.
(12) Crystallographic data have been deposited at the Cambridge
Crystallographic Data Centre as supplementary publication no. CCDC
203097.
(13) Spek, A. L. PLATON, A Multipurpose Crystallographic Tool;
Utrecht University: Utrecht, The Netherlands, 2002.
(14) For similar regioselective Pd-catalyzed hydration of substituted
acetylenes, see: Imi, K.; Imai, K.; Utimoto, K. Tetrahedron Lett. 1987,
28, 3127.
Subjection of 22 to the cyclization conditions led to a rapid
conversion into homoisotryptophan analogue 23 in 60% yield
Org. Lett., Vol. 5, No. 10, 2003
1719

the starting materials. Furthermore, we demonstrated the
possibility of constructing novel pyrroline derivatives in
reasonable yields via an intramolecular Pd-catalyzed cyclo-
isomerization. In addition, some insight was gained regarding
the scope and limitations of the observed cycloisomerizations.
Currently, we are further exploring the scope of these types
of cyclization reactions.
Scheme 5. Pd-Catalyzed Synthesis of Novel Optically Active
Tryptophan Analoguesa
Acknowledgment. T. Sonke (DSM Research, Geleen,
The Netherlands) and R. P. M. Storcken (Department of
Organic Chemistry, University of Nijmegen) are kindly
acknowledged for conducting the enzymatic resolution of
the amino acid amides.
a Conditions: (a) 2-iodoaniline, PdCl2(PPh3)2, CuI, Et2NH, Et2O,
rt, 3 h; (b) PdCl2(MeCN)2, MeCN, reflux, 30 min.
after chromatography. Under the same conditions, bisho-
moisotryptophan analogue 26 was also obtained in a reason-
able yield of 55%. In both cases, we proved using chiral
HPLC (Chiralcel OJ) that no (partial) racemization had taken
place during the whole synthetic sequence.
In conclusion, we have developed a short and efficient
synthesis of three novel tryptophan analogues in optically
active forms using acetylene-containing R-amino acids as
Supporting Information Available: Experimental pro-
cedures, characterization data, and 1H and 13C NMR spectra
for compounds 5-7, 13-16, 18-20, 22, 23, 25, and 26.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL034360D
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Org. Lett., Vol. 5, No. 10, 2003