Transition metal-catalyzed synthesis of novel biologically relevant tryptophan analogues

Article abstract of DOI:10.1002/adsc.200404012

A synthetic approach to the synthesis of novel tryptophan derivatives and benzofuran-containing amino acids is detailed. The sequence starts from enzymatically resolved enantiopure acetylene-containing amino acids, of which the acetylene function can be e

Full text of DOI:10.1002/adsc.200404012

FULL PAPERS
Transition Metal-Catalyzed Synthesis of Novel Biologically
Relevant Tryptophan Analogues
a
a
b
b
¬
Bart C. J. van Esseveldt, Floris L. van Delft, Jan M. M. Smits, Rene de Gelder,
Hans E. Schoemaker,c Floris P. J. T. Rutjesa,*
NSRIM, Department of Organic Chemistry, University of Nijmegen, Toernooiveld 1, 6525 ED Nijmegen, The
a
Netherlands
Fax: (þ31)-24-365-3393, e-mail: rutjes@sci.kun.nl
b
NSRIM, Department of Inorganic Chemistry, University of Nijmegen, Toernooiveld 1, 6525 ED Nijmegen, The
Netherlands
c
DSM Research, Life Science Products, PO Box 18, 6160 MD Geleen, The Netherlands
Received: January 14, 2004, Accepted: May 21, 2004
Dedicated to Joe P. Richmond on the occasion of his 60th birthday.
Supporting Information for this article is available on the WWW under http://asc.wiley-vch.de or from the author.
Abstract: A synthetic approach to the synthesis of substited indole and benzofuran moieties via Sonoga-
novel tryptophan derivatives and benzofuran-contain- shira-type coupling and metal-catalyzed cyclization.
ing amino acids is detailed. The sequence starts from
enzymatically resolved enantiopure acetylene-con-
taining amino acids, of which the acetylene function Keywords: amino acids; benzofurans; homogeneous
can be efficiently transformed into the targeted 2- catalysis; indoles; isotryptophan; palladium
Introduction
and organismal growth. Increased IDO activity there-
fore leads to starvation of cells for tryptophan, which
Indoleamine 2,3-dioxygenase (IDO) is a heme-contain- has a much more devastating effect on rapidly dividing
ing glycoprotein that is widely distributed in mammalian cells, such as microbial pathogens and tumor cells. As
tissue, including the brain, lung and small intestine.[1] a result, the IDO enzyme has apparent antimicrobial
One of the functions of IDO in cells is the cleavage of and antitumor properties. Another consequence of
the indole 2,3-double bond of (S)-tryptophan (1), using inducing IDO activity is an increase in the concentration
superoxide in the presence of free-radical generating of metabolites produced in the kynurenine pathway,
systems, such as ascorbic acid and methylene blue. The such as quinolinic acid (4) and kynurenic acid (5), both
product of this oxidative cleavage is (S)-N-formylkynur- of which are known to exhibit neurological activity.[4]
enine (2), which is subsequently hydrolyzed by a forma-
midase enzyme to give (S)-kynurenine (3, Scheme 1).
Quinolinic acid, for example, has been implicated as
an etiological factor in a range of neurodegenerative dis-
These two reactions are the first steps in the kynure- eases including AIDS-related dementia, Huntington×s
nine pathway, which in 1947 was first recognized as a ma- disease and Lyme×s disease.[5] Moreover, the upregula-
jor route for the metabolism of tryptophan to nicotina- tion of IDO activity, resulting in the elevation of quino-
mide and its nucleotide conjugates.[2] The kynurenine linic acid concentrations, is observed in several inflam-
pathway contains a number of interesting enzymes matory diseases including meningitis, septicemia and ar-
that catalyze chemical reactions which are infrequently
found in metabolism. Consequently, many of these
transformations are still mechanistically poorly under-
stood, such as the aforementioned IDO-catalyzed oxi-
dative cleavage of tryptophan (1!2).
The activity of the IDO enzyme can be induced by sev-
eral factors,[3] which results in depletion of available
tryptophan, the least abundant of the essential amino
acids required for cellular integrity. Hence, its reduced
availability affects protein synthesis, genome replication Scheme 1. The first steps in the kynurenine pathway.
Adv. Synth. Catal. 2004, 346, 823 834
DOI: 10.1002/adsc.200404012
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Scheme 3. Targeted tryptophan derivatives.
Scheme 2. Kynurenine pathway metabolites (4 and 5) and
tryptophan analogues (6 8).
thritis.[6] Consequently, in the design of novel therapies
to treat these diseases, the kynurenine pathway has
been identified as an important target for drug action.
Mechanistic workon the enzymes involved in the path-
way has therefore been stimulated, to provide informa-
tion so that specific and effective inhibitors can be de-
signed.
Especially, inhibitors of the IDO enzyme have impor-
tant clinical implications as potential therapeutic agents,
as well as to study and control the symptoms of the
aforementioned diseases which are affected by the upre-
Scheme 4. Retrosynthesis of isotryptophans.
In addition to copper, palladium catalysts[12] have
gulation of IDO activity. In addition, potent and specific been frequently used in cyclization reactions of nitrogen
inhibitors of the IDO enzyme are valuable pharmaco- nucleophiles onto alkenes and alkynes to provide nitro-
logical tools to elucidate the biological importance of gen heterocycles such aspyrroles[13] and indoles.[14] How-
the kynurenine pathway in more detail and to better un- ever, to the best of our knowledge, Pd-catalyzed synthe-
derstand the chemistry of the IDO-catalyzed reactions. ses of 2-substituted indoles have only been conducted
Tryptophan analogues constitute one class of IDO in- using relatively simple 2-alkynylanilines as the cycliza-
hibitors and therefore a wide range of tryptophan ana- tion precursors.[14] We envisaged that the tryptophan an-
logues has already been examined as inhibitors of the alogues 9 11 might be readily synthesized from the cor-
IDO enzyme. For example, replacement ofthe indole ni- responding protected anilines 12 via such a Pd-catalyzed
trogen of tryptophan by both oxygen and sulfur gave an- cyclization as the key step. The anilines 12 should be
alogues 6 and 7, respectively, which exhibited moderate easily accessible from the opticallyactive acetylene-con-
inhibitory activity toward rabbit intestine IDO.[7]
taining a-amino acids 13 15 (Scheme 4). These trifunc-
Based on studies focusing at the structural require- tional amino acids[15] are commercially available (e.g., 2-
ments for binding in the active site of the IDO enzyme, amino-4-pentynoic acid),[16] but can also be prepared via
the N-methylated analogue 8 was prepared, which is the a chemoenzymatic procedure that was developed in col-
most potent tryptophan-based IDO inhibitor reported laboration with DSM Research (Geleen, The Nether-
to date.[8] Although several tryptophan analogues have lands).[17]
exhibited inhibitory activity against the IDO enzyme,
none of these compounds inhibited IDO below micro-
molar levels. Consequently, highly potent inhibitors of Results and Discussion
human IDO (with low nanomolar affinity) are still re-
quired, and for this reason the synthesis of novel trypto- To probe the feasibility of forming the 2-substituted in-
phan analogues in an optically active form is necessary. dole ring via an intramolecular Pd-catalyzed reaction,
In the continued effort to search for novel inhibitors of cyclization precursor 17 was synthesized starting from
IDO, we envisaged that it may be of interest to synthe- the racemic propargylglycine derivative 16.[18] The Pd-
size three structurally related tryptophan analogues, catalyzed functionalization of propargylglycine deriva-
namely (S)-isotryptophan (9), (S)-homoisotryptophan tives with aromatic groups under Sonogashira-type cou-
(10) and (S)-bishomoisotryptophan (11).[9]
pling conditions has already been described by Crisp
Of these potentially biologically relevant a-amino and Robinson.[19] Modification of the reported condi-
acids, only isotryptophan (9) itself has been previously tions led to a smooth coupling of 16 with 2-iodoaniline
prepared in optically active form. In that preparation,[10] at room temperature affording precursor 17 in 88%
the synthesis proceeded via a copper-mediated cycliza- yield (Scheme 5).
tion[11] of an ortho-ethynylaniline moiety that was con-
nected to a Schˆllkopf chiral auxiliary.
Interestingly, subjecting 17 to the previously reported
cyclization conditions[14f] did not lead to the anticipated
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Novel Biologically Relevant Tryptophan Analogues
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Scheme 5. Unexpected pyrroline formation.
Scheme 6. Mechanism of pyrroline formation.
plexation of the Pd(II) catalyst to the triple bond, possi-
bly aided by coordination to the aniline nitrogen, giving
rise to the p-complex 20 (Scheme 6).
This renders the acetylene sufficiently electrophilic to
undergo nucleophilic attackof the apparently more nu-
cleophilic carbamate nitrogen to give the corresponding
vinylpalladium intermediate 21. This species will under-
À
go protonolysis of the Pd C bond, thereby regenerating
the Pd(II) catalyst, to give cyclic enamide 19 as the inter-
mediate product, which under the circumstances imme-
diately reacts further toprovidepyrroline 18 as the prod-
uct. In this last step, the regenerated Pd catalyst may
possibly act as a Lewis acid by lowering the electron den-
sity of the double bond, thus facilitating intramolecular
attackof the aniline nitrogen onto the Boc group.
Intrigued by the facile cycloisomerization of 17, we set
Figure 1. PLATON drawing of the X-ray crystal structure of out to further determine the scope of this reaction.
imine 18.
Therefore, we prepared several cyclization precursors
via Sonogashira couplings of protected propargylgly-
cine 16 with (substituted) aryl iodides. The racemic sub-
formation of the corresponding indole system. Instead, stituted acetylenes 22 26 were thus obtained in good
an unexpected compound was formed as the sole prod- yields and subjected to PdCl2(MeCN)2 in MeCN at dif-
uct in 65% yield. Eventually, this product was unambig- ferent temperatures (Table 1).
uously identified as the five-membered cyclic imine 18
via an X-ray crystal structure determination (shown as the Pd catalyst did not result in any reaction at room
a PLATON drawing[20] in Fig. 1).[21]
temperature, while heating at reflux temperature led
Unfortunately, subjecting cyclization precursor 22 to
After this surprising result, amino acid 17 was again to rapid decomposition of the starting compound (en-
subjected to the same reagents, but now at room temper- try 1). Subjecting the substituted acetylene 23 to the
ature, resulting in the formation of the cyclic enamide 19 Pd catalyst at room temperature did not lead to the for-
in 54% yield after column chromatography (Scheme 5). mation of the corresponding cyclic enamide. Instead,
Subsequent treatment of this enamide with the same Pd- these conditions led to partial decomposition of the
catalyst in refluxing acetonitrile led to a rapid conver- starting compound and unexpected formation of the hy-
sion into the aforementioned pyrroline 18 in 70% yield. drated product 27 as the sole product in a yield of 32%
The latter conversion could also be accomplished by re- (entry 2). Subjecting 23 to the same conditions at reflux
fluxing 19 in acetonitrile without the Pd-catalyst pres- temperature also did not lead to a cyclization reaction.
ent, however, in that case the reaction did not go to com- Moreover, these conditions led to even more decompo-
pletion even after prolonged reaction times of over 24 h. sition of the starting material and slowed down the for-
A plausible mechanism to explain the remarkable for- mation of ketone 27. Substitution of the aromatic ring
mation of pyrroline 18 from precursor 17 involves com- with an ortho-methoxy substituent (viz. 24) did not re-
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Table 1. Scope of pyrroline formation.
Scheme 7. Mechanism of alkyne hydration.
Scheme 8. Formation of oxazolidinone 26.
zation precursor 17 into the more restricted oxazolidi-
none analogue 26 in two steps, i.e., ester reduction
with LiBH4 in THF followed by oxazolidinone forma-
tion in 52% yield (Scheme 8). Subjecting the cyclic car-
bamate 26 to the Pd catalyst at reflux temperature led to
the formation of the corresponding bicyclic product 30
[a]
Yield of isolated product after column chromatography.
sult in cyclizationeither, but gave asimilar reactionlead- in a somewhat lower isolated yield of 32% (entry 5).
ing to ketone 28 as the major product in a somewhat low-
er yield of 19% (entry 3).
The results shown in Table 1indicate that the presence
of the ortho-aniline nitrogen atom in the precursor is
Presumably, in these cases the internal acetylene un- crucial for the cycloisomerization to occur, which is in
dergoes a Pd-catalyzed hydration leading to the corre- line with the proposed mechanism. This fact significant-
sponding ketone. Similar regioselective Pd-catalyzed ly reduces the scope of this cyclization, so that this line of
hydration of substituted acetylenes has been observed research was not pursued any further.
before, and the formation of, for example, ketone 27
might be explained analogously to the reported mecha- ing the 2-substituted indole system starting from the ho-
nism[22] (Scheme 7).
mologous optically active homo- and bishomopropar-
Next, we set out to investigate the feasibility of form-
Thus, the catalytic cycle presumably involves electro- gylglycine derivatives 34 and 35, respectively, via the
philic activation of the triple bond by the Pd(II) catalyst, same pathway as used before. In order to do so, the ami-
followed by intramolecular nucleophilic attackof the es- no acids 13 15 were first converted into the correspond-
ter function. The resulting vinylpalladium intermediate ing methyl esters and protected to give the optically ac-
31 then undergoes attackby water followed by subse-
quent protonolysis of the Pd C bond to finally give ke- (Scheme 9).
tone 27 as its enol tautomer. In an attempt to improve
tive Boc-protected amino esters 33, 34 and 35
À
The Pd-catalyzed Sonogashira coupling of 34 and 35
the yield of ketone 27, the Pd-catalyzed hydration of with 2-iodoaniline afforded the cyclization precursors
acetylene 23 was conducted again in the presence of a 36 and 37 in 79 and 78% yield, respectively. To our satis-
small amount of water, according to the literature proce- faction, treatment of 36 with the Pd catalyst in refluxing
dure.[22] These conditions, however, did not facilitate the acetonitrile led to a rapid conversion into homoisotryp-
formation of ketone 27, which was even isolated in a tophanderivative 38 in 60% yield after chromatography.
somewhat lower yield of 26%.
Under the same conditions, bishomoisotryptophan de-
In addition, the acetylated aniline 25 underwent cycli- rivative 39 was also obtained in a reasonable yield of
zation at room temperature, resulting in the formation 55%. Furthermore, we proved in both cases using chiral
of the cyclic enamide 29 in 49% yield after column chro- HPLC (Chiralcel OJ) that no (partial) racemization had
matography (entry 4). Furthermore, we converted cycli- taken place during the whole synthetic sequence.
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Scheme 11. Ag-catalyzed cyclization to isotryptophan.
Scheme 9. Synthesis of isotryptophan derivatives.
Figure 2. PLATON drawing of the X-ray crystal structure of
47.
ter screening a variety of catalysts, we found that AgOTf
silver has a high affinity for double bonds and much
less for heteroatoms such as nitrogen might be the cat-
alyst of choice in effecting such a selective ring closure.
Scheme 10. Pd-catalyzed cyclization to isotryptophan.
These results actually point out that the applied cycli- In order to probe the feasibility of selective indole for-
zation conditions are suitable for the formation of the mation via an Ag-catalyzed cyclization, precursor 43
desired 2-substituted indole system. However, the was synthesized from the enantiopure propargylglycine
mode of cyclization is strongly dependent on the side- derivative 33 (Scheme 11).
chain length of the cyclization precursor. To verify this
Subjecting precursor 43 to the Ag catalyst in acetoni-
reasoning, the suitably protected biscarbamate 41 was trile at room temperature did not give any reaction.
synthesized in two steps from the enantiopure propar- However, we were pleased to see that heating the reac-
gylglycine derivative 33 (Scheme 10). The presence of tion mixture at reflux temperature indeed led to a slow
the additional Boc group in this precursor should pre- but clean conversion of the starting compound into iso-
vent the cyclization via the carbamate nitrogen, thereby tryptophan derivative 44, which was isolated in an im-
leaving the aniline nitrogen as the only reactive nucleo- proved yield of 75% after column chromatography. Ad-
phile.
ditionally, we converted the racemic Ts-protected prop-
Indeed, subjecting precursor 41 to the same Pd cata- argylglycine derivative 45[18] via Sonogashira coupling
lyst in refluxing acetonitrile led to an activation of the with 2-iodoaniline into precursor 46, which was also sub-
aniline nitrogen, which cyclized onto the triple bond af- jected to AgOTf in refluxing acetonitrile affording iso-
fording isotryptophan derivative 42 as the sole product tryptophan derivative 47 in an excellent yield of 86% af-
without loss of enantiopurity according to chiral ter chromatography. Luckily, tryptophan analogue 47
HPLC (Chiralcel OD).
appeared to be a crystalline solid suitable for an X-ray
In order to circumvent the use of the second Boc crystal structure determination, proving the formation
group on the carbamate nitrogen, we also searched for of the 2-substituted indole system (shown as a PLATON
a catalyst that would effect a selective cyclization into drawing[20] in Fig. 2).[21]
the 2-substituted indole system, without interference
Encouraged by these results, we set out to apply this
of the carbamate nitrogen in the cyclization process. Af- methodology in the synthesis of 2-substituted benzo[b]-
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Scheme 13. One-pot coupling/cyclization to benzofuran de-
rivative 51.
Scheme 12. Synthesis of benzofuran analogue 49.
furans, which might give us the opportunity to also ac- lene 50 was subsequently reacted with 2-iodophenol un-
cess the oxygen-containing counterparts of tryptophan der the aforementioned modified Sonogashira condi-
analogues 9 11 (see Scheme 3). In order to investigate tions to give initially the corresponding intermediate
the possible formation of a 2-substituted benzo[b]furan phenol, which was after 4 h completely consumed to
via a similar intramolecular Pd- or Ag-catalyzed reac- give the enantiopure tryptophan analogue 51 as the
tion, the racemic propargylglycine derivative 45 was first sole product in 74% yield (Scheme 13).
reacted with 2-iodophenol under Sonogashira coupling
conditions to afford the appropriate precursor 48
(Scheme 12).
Conclusion
To our surprise, these conditions indeed led to the for-
mation of the expected precursor 48 in 64%, but in addi-
tion the eventually desired tryptophan analogue 49 was
found in 16% yield. Without separation, we subjected
the obtained mixture to AgOTf in refluxing acetonitrile
to see whether this catalyst would effect the cyclization
of phenol 48 into benzofuran 49. Unfortunately, howev-
er, refluxing the mixture for more than 20 h in the pres-
ence of AgOTf did not lead to an increase in the conver-
sion of 48 into 49 as judged by TLC. Obviously, this be-
havior can be explained by the lower nucleophilicity of
the phenol compared to the previously used anilines.
In line with this reasoning, we added Et2NH (1 equiv.)
to the reaction mixture to see if this would facilitate
the formation of benzofuran 49. Indeed, the addition
ofEt2NH led to arapid conversionof phenol 48 into ben-
zofuran 49, however, the reaction did not go to comple-
tion and also led to partial decomposition of the remain-
ing phenol. Considering these results, we again turned
our attention to the Sonogashira reaction of propargyl-
glycine derivative 45 with 2-iodophenol. We envisaged
that a modification of the applied conditions, i.e., using
Et2NH as base and solvent at reflux temperature, might
be beneficial to the formation of tryptophan analogue
49. Thus, subjecting acetylene 45 to these modified con-
ditions led to the formation of a mixture of phenol 48
and benzofuran 49 in an improved ratio in favor of 49
in a combined yield of 71% (Scheme 12).
A short and efficient preparation of novel optically ac-
tive tryptophan analogues is described. The aniline-con-
taining homo- and bishomopropargylglycine derivatives
36 and 37 underwent a rapid Pd-catalyzed cyclization to
afford the corresponding tryptophan analogues 38 and
39 in reasonable yields. In contrast to these results, treat-
ment of the aniline-containing propargylglycine deriva-
tive 17 with the same Pd catalyst led toan unexpected cy-
cloisomerization affording pyrroline 18. In addition,
some insight was gained regarding the scope and limita-
tions of the observed cycloisomerization.
Furthermore, in the case of 43 we demonstrated the
possibility of circumventing the Pd-catalyzed cycloiso-
merization by the selective construction of tryptophan
analogue 44 via Ag-catalyzed indole formation. Finally,
we explored the possibility to apply the developed meth-
odology in the synthesis of 2-subsituted benzofurans.
This led to modified conditions in the Sonogashira reac-
tion of propargylglycine derivative 50 with 2-iodophe-
nol, allowing the direct synthesis of tryptophan ana-
logue 51 via a tandem cross-coupling cyclization process.
Currently, further studies concerning the scale-up of
these compounds, the synthesis of additional new tryp-
tophan derivatives and biological evaluation of these
compounds as inhibitors of IDO are being carried out
in collaboration with Chiralix BV (Nijmegen, The Neth-
erlands).[24]
After this result, it became apparent to us that it would
be feasible to convert propargylglycine derivative 45
completely into tryptophan analogue 49 if the reaction
mixture would be refluxed for more than 2 h. To achieve
this tandem cross-coupling cyclization process,[23] we
first converted enantiomerically pure propargylglycine
13 into propargylglycine derivative 50 by esterification
using thionyl chloride in MeOH and subjected it to pyr-
Experimental Section
General Information
All reactions were carried out under an atmosphere of dry ni-
trogen, unless stated otherwise. Infrared (IR) spectra were ob-
idine and p-toluenesulfonyl chloride in CH2Cl2. Acety- tained using an ATI Mattson Genesis Series FTIR spectrome-
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Novel Biologically Relevant Tryptophan Analogues
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ter and wavelengths (n) are reported in cmÀ1. Optical rotations
31.5, 28.3, 14.9; HRMS (CI): calcd. for C12H20NO4 (MHþ):
242.1392; found: 242.1395.
˜
were measured on a Perkin-Elmer 241 polarimeter, using con-
centrations (c) in g/100 mL in the indicated solvents. 1H and 13C
nuclear magnetic resonance (NMR) spectra were determined
in CDCl3, unless indicated otherwise, using
a Bruker
Methyl (2S)-2-[tert-Butoxycarbonyl)amino]-6-
DMX300 (300 MHz) spectrometer. Chemical shifts (d) are giv-
en in ppm downfield from tetramethylsilane. HRMS measure-
ments were carried out using a Fisons (VG) Micromass 7070E
or a Finnigan MAT900S instrument. Flash chromatography
was performed with Acros Organics silica gel (0.035
0.070 nm) using the indicated solvent (mixture). Rf values
were obtained by using thin layer chromatography (TLC) on
silica gel-coated glass plates (Mercksilica gel 60 F 254) with
the indicated solvent (mixture). Melting points were deter-
mined with a B¸chi melting point B-545 apparatus. THF and
Et2O were distilled from sodium and benzophenone. Heptane,
EtOAc and CH2Cl2 were distilled from CaH2. Et2NH was dis-
tilled from and stored over KOH. If necessary, other solvents
were distilled from the appropriate drying agents prior to
use. Unless stated otherwise, all commercially available re-
agents were used as received.
heptynoate (35)
Following the same procedure as for 33, (S)-bishomopropar-
gylglycine 15 (1.00 g, 7.08 mmol) was protected and purified
by chromatography (EtOAc/heptane,1:6) to afford 35 as a col-
orless oil; yield: 1.33 g (5.21 mmol, 74%); Rf ¼0.20 (EtOAc/
20
˜
heptane, 1:4); [a]D : þ71.7 (c 1.0, CH2Cl2); IR (neat): n¼
3296, 2953, 1741, 1712, 1504 cmÀ1
;
1H NMR (300 MHz,
CDCl3): d¼5.03 (br d, J¼6.9 Hz, 1H), 4.31 (m, 1H), 3.75 (s,
3H), 2.23 (dt, J¼2.4, 6.9 Hz, 2H), 1.96 (t, J¼2.7 Hz, 1H),
1.91 (m, 1H), 1.80 1.53 (m, 3H), 1.45 (s, 9H); 13C NMR
(75 MHz, CDCl3): d¼172.9, 155.2, 83.4, 80.0, 69.1, 53.2, 52.5,
32.0, 28.6, 24.6, 18.4; HRMS (CI): calcd. for C13H22NO4
(MHþ): 256.1549; found: 256.1549.
Methyl (2S)-2-{[(4-Methylphenyl)sulfonyl]amino}-4-
pentynoate (50)
Methyl (2S)-2-[(tert-Butoxycarbonyl)amino]-4-
pentynoate (33)
A suspension of 13 (500 mg, 4.42 mmol) in MeOH (20 mL) was
treated dropwise at 08C with SOCl2 (0.7 ml, 9.5 mmol) and
heated at reflux for 4 h. The reaction mixture was concentrated
under vacuum to give the crude amino ester as the HCl salt.
The crude residue was suspended in CH2Cl2 (75 mL), pyridine
(2.2 mL, 28.4 mmol) and p-TsCl (1.68 g, 8.81 mmol) were add-
ed and the reaction mixture was stirred for 65 h at room tem-
perature. Saturated aqueous CuSO4 (100 mL) was added to
the reaction mixture and the layers were separated. The aque-
ous layer was extracted with CH2Cl2 (3Â50 mL) and the com-
bined organic layers were washed with saturated aqueous
NaHCO3 (50 mL), brine (50 mL), dried (MgSO4) and concen-
trated under vacuum. The crude product was purified by chro-
matography (EtOAc/heptane,1:3) to afford 50 as a white solid;
A suspension of 13 (1.00 g, 8.84 mmol) in MeOH (30 mL) was
treated dropwise at 08C with SOCl2 (1.4 mL, 19.0 mmol) and
heated at reflux for 4 h. The reaction mixture was concentrated
under vacuum to give the crude amino ester as the HCl salt.
The crude residue was dissolved in dioxane/water (80 mL,
1:1, v/v), NaHCO3 (2.23 g, 26.5 mmol) and Boc2O (3.88 g,
17.8 mmol) were added and the reaction mixture stirred for
4 h at room temperature. Dioxane was evaporated under vac-
uum and the remaining aqueous solution was extracted with
EtOAc (3Â25 mL). The combined organic layers were dried
(MgSO4) and concentrated under vacuum. Purification by
chromatography (EtOAc/heptane,1:6) afforded 33 as a color-
yield: 970 mg (3.45 mmol, 78%); Rf ¼0.28 (EtOAc/heptane,
less oil; yield: 1.62 g (7.13 mmol, 81%); Rf ¼0.65 (EtOAc/hep-
20
˜
1:2); [a]D : þ16.5 (c 1.0, CH2Cl2); mp 83.28C; IR (neat): n¼
20
˜
tane,1:1); [a]D : þ47.7 (c 1.1, CH2Cl2); IR (neat): n¼3298,
3261, 2950, 1705, 1593, 1433 cmÀ1
;
1H NMR (300 MHz,
2978, 1745, 1712, 1504, 1437 cmÀ1
;
1H NMR (300 MHz,
CDCl3): d¼7.71 (d, J¼8.1 Hz, 2H), 7.27 (d, J¼8.1 Hz, 2H),
5.45 (d, J¼9.0 Hz, 1H), 4.10 (m, 1H), 3.60 (s, 3H), 2.66 (m,
2H), 2.41 (s, 3H), 2.02 (t, J¼2.7 Hz, 1H); 13C NMR (75 MHz,
CDCl3): d¼169.8, 143.7, 136.7, 129.6, 127.1, 77.6, 72.4, 54.2,
53.1, 24.4, 21.9; HRMS (EI): calcd. for C13H15NO4S: 281.0722;
found: 281.0722.
CDCl3): d¼5.32 (br d, J¼6.6 Hz, 1H), 4.46 (m, 1H), 3.76 (s,
3H), 2.73 (br m, 2H), 2.03 (t, J¼2.1 Hz, 1H), 1.45 (s, 9H);
13C NMR (75 MHz, CDCl3): d¼170.9, 154.9, 80.3, 78.6, 71.7,
52.8, 52.1, 28.6, 23.1; HRMS (CI): calcd. for C11H18NO4
(MHþ): 228.1236; found: 228.1236.
Methyl (2S)-2-[(tert-Butoxycarbonyl)amino]-5-
hexynoate (34)
General Procedure for the Sonogashira Cross-
Coupling Reactions
Following the same procedure as for 33, (S)-homopropargyl-
glycine 14 (0.98 g, 7.71 mmol) was protected and purified by
chromatography (EtOAc/heptane, 1:6) to afford 34 as a white
solid; yield: 1.14 g (4.72 mmol, 61%); Rf ¼0.24 (EtOAc/hep-
tane, 1:4); [a]2D0: þ9.9 (c 1.0, CH2Cl2); mp 59.08C; IR (neat):
˜
(300 MHz, CDCl3): d¼5.24 (br d, J¼6.9 Hz, 1H), 4.39 (m,
1H), 3.75 (s, 3H), 2.28 (dt, J¼2.7, 7.5 Hz, 2H), 2.05 (m, 1H),
2.01 (t, J¼2.4 Hz, 1H), 1.89 (m, 1H), 1.45 (s, 9H); 13C NMR
(75 MHz, CDCl3): d¼172.7, 155.3, 82.8, 80.0, 69.3, 52.8, 52.4,
To a solution of the acetylene-containing amino acid, aryl hal-
ide (1.2 equivs.) and Et2NH (5 equivs.) in Et2O, CuI (10 mol %)
and the Pd catalyst (5 mol %) were added. The mixture was
stirred at room temperature under an N2 atmosphere for the in-
dicated time. The reaction mixture was poured into a saturated
aqueous solution of NH4Cl and after separation of the organic
layer the aqueous layer was extracted with Et2O (2 Â). The
combined organic layers were washed with brine, dried
(MgSO4) and concentrated under vacuum. The crude product
waspurifiedbyflashchromatographytoaffordthepureproduct.
n¼3367, 3253, 2983, 1732, 1676, 1512 cmÀ1
;
1H NMR
Adv. Synth. Catal. 2004, 346, 823 834
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Bart C. J. van Esseveldt et al.
FULL PAPERS
Methyl (2S)-5-(2-Aminophenyl)-2-[(tert-
butoxycarbonyl)amino]-4-pentynoate (43)
4-[3-(2-Aminophenyl)-2-propynyl]-1,3-oxazolan-2-one
(26)
According to the general procedure, to a solution of 33
(303 mg, 1.33 mmol), 2-iodoaniline (351 mg, 1.60 mmol) and
Et2NH (0.70 mL, 6.73 mmol) in Et2O (18 mL), CuI (28 mg,
0.15 mmol) and PdCl2(PPh3)2 (47 mg, 0.07 mmol) were added
and the resulting mixture was stirred for 2 h. Work-up and pu-
rification by chromatography (EtOAc/heptane, 1:3) afforded
43 as a light-brown oil; 356 mg (1.12 mmol, 84%); Rf ¼0.28
To a solution of 17 (535 mg, 1.68 mmol) in THF (20 mL),
LiBH4 (73 mg, 3.36 mmol) was added at 08C. The reaction mix-
ture was allowed to reach room temperature and stirred for
24 h. Upon completion, the reaction mixture was quenched
by adding water (1 mL) and stirred further for 15 min at
room temperature, after which time the mixture was poured
into water (30 mL). The aqueous solution was extracted with
EtOAc (100 mL) and the organic layer was washed with water
(2Â30 mL), brine (2Â30 mL), dried (MgSO4) and concentrat-
ed under vacuum. The crude product was purified by chroma-
tography (EtOAc/heptane, 1:1) to afford the corresponding
(EtOAc/heptane, 1:2); [a]2D0: þ82.2 (c 0.5, CH2Cl2); IR
1
(neat): n¼3369, 2978, 1743, 1711, 1618, 1493 cmÀ1; H NMR
˜
(300 MHz, CDCl3): d¼7.17 (dd, J¼1.5, 7.6 Hz, 1H), 7.04 (m,
1H), 6.59 (m, 2H), 5.57 (br d, J¼8.3 Hz, 1H), 4.56 (m, 1H),
4.31 (s, 2H), 3.73 (s, 3H), 2.95 (d, J¼5.2 Hz, 2H), 1.42 (s, 9H);
13C NMR (75 MHz, CDCl3): d¼171.6, 155.1, 148.2, 131.9,
129.3, 117.3, 114.1, 107.3, 88.8, 80.4, 80.0, 52.5, 52.3, 28.1,
24.1; HRMS (EI): calcd. for C17H22N2O4: 318.1580; found:
318.1580.
amino alcohol 32 as
a light-yellow oil; yield: 386 mg
1
(1.33 mmol, 79%); H NMR (300 MHz, CDCl3): d¼7.21 (d,
J¼7.6 Hz, 1H), 7.05 (m, 1H), 6.63 (m, 2H), 5.34 (d, J¼
8.6 Hz, 1H), 4.31 (br s, 2H), 3.86 (br s, 1H), 3.71 (m, 3H), 2.71
(d, J¼6.1 Hz, 2H), 1.43 (s, 9H).
To a solution of amino alcohol 32 (366 mg, 1.26 mmol) in
THF (30 mL), NaH (52 mg of a 60% dispersion in mineral
oil, 1.31 mmol) was added. The reaction mixture was heated
at reflux for 22 h, diluted with MeOH (3 mL) and concentrated
under vacuum. The crude product was purified by chromatog-
raphy (EtOAc/heptane, 3:1) to afford 26 as a light-yellow sol-
id; yield: 179 mg (0.83 mmol, 66%); Rf ¼0.13 (EtOAc/heptane,
Methyl 2-[(tert-Butoxycarbonyl)amino]-5-phenyl-4-
pentynoate (23)
À1
According to the general procedure, to a solution of 16
(384 mg, 1.69 mmol), iodobenzene (417 mg, 0.49 mmol) and
Et2NH (0.88 mL, 8.50 mmol) in Et2O (18 mL), CuI (33 mg,
0.17 mmol) and PdCl2(PPh3)2 (60 mg, 0.09 mmol) were added
and the resulting mixture was stirred for 2 h. Work-up and pu-
rification by chromatography (EtOAc/heptane, 1:6) afforded
23 as a yellow oil; yield: 448 mg (1.48 mmol, 87%); Rf ¼0.28
˜
2:1); mp 147.28C; IR (neat): n¼3352, 1732, 1614 cm
;
1H NMR (300 MHz, CDCl3): d¼7.24 (dd, J¼1.7, 8.3 Hz,
1H), 7.11 (dt, J¼1.6, 7.7 Hz, 1H), 6.67 (m, 2H), 5.68 (br s,
1H), 4.57 (dd, J¼8.3, 8.9 Hz, 1H), 4.28 (dd, J¼4.6, 8.9 Hz,
1H), 4.13 (m, 3H), 2.76 (dd, J¼1.4, 5.6 Hz, 2H); 13C NMR
(75 MHz, CDCl3): d¼157.3, 150.8, 132.5, 129.9, 123.5, 118.1,
114.6, 88.3, 81.2, 69.4, 66.0, 26.7; HRMS (EI): calcd. for
C12H12N2O2: 216.0899; found: 216.0898.
˜
(EtOAc/heptane, 1:4); IR (neat): n¼3375, 2977, 1747, 1716,
1598 cmÀ1
;
1H NMR (300 MHz, CDCl3): d¼7.38 (m, 2H),
7.28 (m, 3H), 5.42 (d, J¼8.3 Hz, 1H), 4.56 (m, 1H), 3.79 (s,
3H), 2.95 (m, 2H), 1.46 (s, 9H); 13C NMR (75 MHz, CDCl3):
d¼171.1, 154.9, 131.5, 128.0, 127.6, 122.8, 83.7, 83.4, 79.8,
52.3, 52.1, 28.1, 23.6; HRMS (EI): calcd. for C17H21NO4:
303.1471; found: 303.1471.
Methyl (2S)-6-(2-Aminophenyl)-2-[(tert-
butoxycarbonyl)amino]-5-hexynoate (36)
According to the general procedure, to a solution of 34
(518 mg, 2.15 mmol), 2-iodoaniline (565 mg, 2.58 mmol) and
Et2NH (1.12 mL, 10.7 mmol) in Et2O (20 mL), CuI (40 mg,
0.21 mmol) and PdCl2(PPh3)2 (75 mg, 0.107 mmol) were added
and the resulting mixture was stirred for 2 h. Work-up and pu-
rification by chromatography (EtOAc/heptane, 1:3) afforded
36 as a light-brown oil; yield: 562 mg (1.69 mmol, 79%); Rf ¼
Methyl 5-[2-(Acetylamino)phenyl]-2-[(tert-
butoxycarbonyl)amino]-4-pentynoate (25)
0.27 (EtOAc/heptane, 1:2); [a]2D0: þ4.9 (c 1.0, CH2Cl2); IR
1
(neat): n¼3461, 3369, 2975, 1734, 1701, 1617 cmÀ1; H NMR
According to the general procedure, to a solution of 16
(367 mg, 1.62 mmol), N1-(2-iodophenyl)acetamide (465 mg,
1.78 mmol) and Et2NH (0.84 mL, 8.16 mmol) in Et2O
(18 mL), CuI (32 mg, 0.17 mmol) and PdCl2(PPh3)2 (57 mg,
0.08 mmol) were added and the resulting mixture was stirred
for 2 h. Work-up and purification by chromatography
(EtOAc/heptane, 1:2) afforded 25 as a colorless oil; yield:
471 mg (1.31 mmol, 81%); Rf ¼0.21 (EtOAc/heptane, 1:2);
˜
(300 MHz, CDCl3): d¼7.20 (dd, J¼1.4, 7.7 Hz, 1H), 7.03 (m,
1H), 6.60 (m, 2H), 5.33 (br d, J¼8.5 Hz, 1H), 4.50 (br m,
1H), 4.32 (br s, 2H), 3.69 (s, 3H), 2.53 (t, J¼6.9 Hz, 2H), 2.11
(m, 1H), 1.92 (m, 1H), 1.42 (s, 9H); 13C NMR (75 MHz,
CDCl3): d¼172.9, 155.4, 148.2, 132.0, 129.0, 117.3, 114.1,
107.9, 93.1, 79.8, 78.3, 52.6, 52.3, 31.5, 28.2, 16.0; HRMS (EI):
calcd. for C18H24N2O4: 332.1736; found: 332.1734.
À1
˜
IR (neat): n¼3329, 2980, 1738, 1693, 1579, 1518, 1444 cm
;
1H NMR (300 MHz, CDCl3): d¼8.25 (s, 1H), 8.22 (s, 1H),
7.20 (m, 2H), 6.88 (m, 1H), 5.64 (d, J¼8.2 Hz, 1H), 4.52 (m,
1H), 3.68 (s, 3H), 2.93 (dd, J¼5.0, 17.2 Hz, 1H), 2.83 (dd, J¼
5.9, 17.0 Hz, 1H), 2.22 (s, 3H), 1.33 (s, 9H); 13C NMR
(75 MHz, CDCl3): d¼171.5, 169.1, 155.2, 139.3, 131.5, 129.0,
123.0, 119.8, 111.8, 90.7, 80.1, 79.0, 52.5, 52.1, 28.0, 24.2, 24.0;
HRMS (EI): calcd. for C19H24N2O5: 360.1685; found: 360.1674.
Methyl (2S)-7-(2-aminophenyl)-2-[(tert-
butoxycarbonyl)amino]-6-heptynoate (37)
According to the general procedure, to a solution of 35
(322 mg, 1.26 mmol), 2-iodoaniline (337 mg, 1.54 mmol) and
Et2NH (0.67 mL, 6.43 mmol) in Et2O (18 mL), CuI (27 mg,
830
¹ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Novel Biologically Relevant Tryptophan Analogues
FULL PAPERS
0.14 mmol) and PdCl2(PPh3)2 (49 mg, 0.07 mmol) were added
and the resulting mixture was stirred for 2 h. Work-up and pu-
rification by chromatography (EtOAc/heptane, 1:3) afforded
37 as a yellow oil; yield: 341 mg (0.98 mmol, 78%); Rf ¼0.26
(EtOAc/heptane, 1:2); [a]2D0: þ10.8 (c 1.0, CH2Cl2); IR
1H NMR (300 MHz, CDCl3): d¼7.22 (dd, J¼1.2, 7.5 Hz,
1H), 7.07 (m, 1H), 6.65 (m, 2H), 5.02 (br m, 1H), 4.32 (br m,
1H), 4.15 (s, 2H), 3.75 (s, 3H), 2.52 (t, J¼6.9 Hz, 1H), 2.30 (t,
J¼6.6 Hz, 1H), 2.08 1.56 (m, 4H), 1.46 (s, 9H); 13C NMR
(75 MHz, CDCl3): d¼172.9, 155.2, 147.3, 132.0, 128.9, 117.8,
114.2, 108.6, 94.4, 80.1, 77.9, 53.3, 52.5, 32.2, 28.6, 25.1, 19.6;
HRMS (EI): calcd. for C19H26N2O4: 346.1893; found: 346.1900.
127.0, 117.3, 114.3, 107.2, 88.1, 80.9, 54.5, 52.7, 25.0, 21.3;
HRMS (EI): calcd. for C19H20N2O4S: 372.1144; found:
372.1145.
À1
˜
(neat): n¼3356, 2978, 1738, 1712, 1614, 1493, 1454 cm
;
General Procedure for the Pd- and Ag-Catalyzed
Cyclization Reactions
To a solution of the cyclization precursor in MeCN, the catalyst
(10 mol %) was added. The mixture was stirred at reflux tem-
perature under an N2 atmosphere for the indicated time. The
reaction mixture was concentrated under vacuum and purified
by flash chromatography to afford the pure product.
Methyl (2S)-5-(2-Aminophenyl)-2-[di(tert-
butoxycarbonyl)amino]-4-pentynoate (41)
Methyl 5-{2-[(tert-Butoxycarbonyl)amino]phenyl}-3,4-
dihydro-2H-2-pyrrolecarboxylate (18)
To a solution of 33 (274 mg, 1.21 mmol) in MeCN (5 mL),
DMAP (46 mg, 0.38 mmol) and Boc2O (528 mg, 2.42 mmol)
were added and the resulting mixture was stirred at room tem-
perature for 20 h. Upon completion, the reaction mixture was
concentrated under vacuum and purified by chromatography
(EtOAc/heptane, 1:9) to afford 40 as a colorless oil; yield:
According to the general procedure, to a solution of 17
(340 mg, 1.07 mmol) in MeCN (10 mL), PdCl2(MeCN)2
(28 mg, 0.11 mmol) was added and the resulting mixture was
heated to reflux for 3 h. Purification by chromatography
(EtOAc/heptane, 1:6) afforded 18 as a white solid; yield:
222 mg (0.70 mmol, 65%). An X-ray crystal structure determi-
nation was carried out after recrystallization from hexane. Rf ¼
1734, 1720, 1604, 1576, 1522, 1446 cmÀ1; 1H NMR (300 MHz,
CDCl3): d¼11.9 (s, 1H), 8.42 (d, J¼8.4 Hz, 1H), 7.40 (m,
2H), 6.96 (t, J¼8.3 Hz, 1H), 4.99 (m, 1H), 3.78 (s, 3H), 3.25
3.00 (m, 2H), 2.35 2.09 (m, 2H), 1.52 (s, 9H); 13C NMR
(100 MHz, CDCl3): d¼177.4, 172.9, 153.5, 140.9, 131.9, 130.5,
120.8, 118.5, 118.4, 79.7, 74.4, 52.2, 36.9, 28.3, 25.1; HRMS
(EI): calcd. for C17H22N2O4: 318.1580; found: 318.1576.
Crystal data: transparent colorless, regular thickplatelets,
triclinic, space group PÀ1, C17H22N2O4, 318.37, unit-cell dimen-
sions: a¼5.9502(6) ä; a¼76.621(12)8, b¼9.4955(8) ä; b¼
79.367(8)8, c¼16.0415(19) ä;g¼77.358(10)8, Z¼2, calculated
density: 1.241 Mg/m3. Data collection: Enraf-Nonius CAD4/w-
2# diffractometer, Mo-Ka (graphite mon.)/0.71073 ä, crystal
size 0.31Â0.23Â0.11 mm, T¼293(2) K, q range 2.82 to
27.478, 1352 ([Io>2s(Io)]) reflections measured, semi-empiri-
cal absorption correction from y-scans. Structural analysis and
refinement: full-matrix least-squares on F2, goodness-of-fit on
F2 1.005, SHELXL-97 weight parameters 0.063700, 0.000000,
1
360 mg (1.10 mmol, 91%); H NMR (300 MHz, CDCl3): d¼
5.16 (dd, J¼6.6, 8.4 Hz, 1H), 3.72 (s, 3H), 2.93 (m, 2H), 1.96
(t, J¼2.7 Hz, 1H), 1.50 (s, 18H).
˜
0.45 (EtOAc/heptane,1:2); mp 78.08C; IR (neat): n¼2980,
According to the general procedure, to a solution of biscar-
bamate 40 (337 mg, 1.03 mmol), 2-iodoaniline (272 mg,
1.24 mmol) and Et2NH (0.55 mL, 5.26 mmol) in Et2O
(18 mL), CuI (22 mg, 0.12 mmol) and PdCl2(PPh3)2 (37 mg,
0.05 mmol) were added and the resulting mixture was stirred
for 2 h. Work-up and purification by chromatography
(EtOAc/heptane, 1:4) afforded 41 as a brown oil; yield:
394 mg (0.94 mmol, 91%); Rf ¼0.15 (EtOAc/heptane, 1:4);
20
˜
[a]D : À89.2 (c 0.5, CH2Cl2); IR (neat): n¼3465, 3373, 2980,
1790, 1743, 1695, 1616 cmÀ1
;
1H NMR (300 MHz, CDCl3):
d¼7.17 (dd, J¼1.2, 7.5 Hz, 1H), 7.03 (dt, J¼1.5, 8.1 Hz, 1H),
6.59 (m, 2H), 5.22 (dd, J¼6.3, 9.3 Hz, 1H), 4.21 (s, 2H), 3.75
(s, 3H), 3.25 (dd, J¼6.3, 17.4 Hz, 1H), 3.18 (dd, J¼9.3,
17.4 Hz, 1H), 1.48 (s, 18H); 13C NMR (75 MHz, CDCl3): d¼
169.8, 169.4, 151.8, 151.5, 148.0, 132.1, 129.1, 117.4, 114.0,
108.0, 90.6, 83.6, 79.4, 73.5, 67.4, 57.0, 52.6, 28.3, 21.9 HRMS
(EI): calcd. for C22H30N2O6: 418.2104; found: 418.2099.
final
R
indices [I>2s(I)]: R1¼0.0710, wR2¼0.1262,
SHELXL-97 (Sheldrick, 1997).
Methyl 5-(2-Aminophenyl)-2-{[(4-
methylphenyl)sulfonyl]amino}-4-pentynoate (46)
1-(tert-Butyl) 2-Methyl 5-(2-aminophenyl)-2,3-
dihydro-1H-1,2-pyrroledicarboxylate (19)
According to the general procedure, to a solution of 45
(402 mg, 1.43 mmol), 2-iodoaniline (377 mg, 1.72 mmol) and
Et2NH (0.75 mL, 7.20 mmol) in Et2O (18 mL), CuI (29 mg,
0.15 mmol) and PdCl2(PPh3)2 (50 mg, 0.07 mmol) were added
and the resulting mixture was stirred for 2 h. Work-up and pu-
rification by chromatography (EtOAc/heptane, 1:2) afforded
46 as a light-brown oil; yield: 473 mg (1.27 mmol, 89%); Rf ¼
According to the general procedure, to a solution of 17
(424 mg, 1.33 mmol) in MeCN (10 mL), PdCl2(MeCN)2
(35 mg, 0.13 mmol) was added and the resulting mixture was
stirred for 2 h. Purification by chromatography (EtOAc/hep-
tane, 1:3) afforded 19 as a white solid; yield: 227 mg
(0.71 mmol, 54%); Rf ¼0.27 (EtOAc/heptane, 1:3); mp
˜
0.16 (EtOAc/heptane, 1:2); IR (neat): n¼3377, 3275, 1739,
1616, 1493 cmÀ1
;
1H NMR (300 MHz, CDCl3): d¼7.75 (d,
139.18C; IR (neat): n¼3442, 3357, 2972, 1730, 1668, 1649,
˜
1
J¼8.3 Hz, 2H), 7.27 (d, J¼8.2 Hz, 2H), 7.13 (m, 2H), 6.65
(m, 2H), 5.51 (d, J¼8.9 Hz, 1H), 4.22 (m, 3H), 3.61 (s, 3H),
2.94 (d, J¼5.2 Hz, 2H), 2.41 (s, 3H); 13C NMR (75 MHz,
CDCl3): d¼170.5, 148.3, 143.6, 136.7, 131.9, 129.5, 129.4,
1603, 1402 cmÀ1; H NMR (300 MHz, CDCl3): d¼7.06 (m,
2H), 6.59 (m, 2H), 5.00 (dd, J¼2.1, 3.5 Hz, 1H), 4.92 (dd, J¼
2.5, 11.2 Hz, 1H), 4.50 (br s, 2H), 3.77 (s, 3H), 3.07 (ddd, J¼
2.1, 11.2, 18.9 Hz, 1H), 2.53 (dt, J¼3.5, 17.0 Hz, 1H), 1.14 (s,
Adv. Synth. Catal. 2004, 346, 823 834
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Bart C. J. van Esseveldt et al.
FULL PAPERS
9H); 13C NMR (75 MHz, CDCl3): d¼173.7, 152.1, 145.3, 142.4,
129.2, 129.0, 119.1, 116.6, 114.2, 108.4, 80.5, 60.5, 52.6, 32.0, 27.7;
HRMS (EI): calcd. for C17H22N2O4: 318.1580; found: 318.1583.
Methyl (2S)-2-[(tert-Butoxycarbonyl)amino]-4-(1H-2-
indolyl)butanoate (38)
According to the general procedure, to a solution of 36
(556 mg, 1.67 mmol) in MeCN (16 mL), PdCl2(MeCN)2
(43 mg, 0.17 mmol) was added and the resulting mixture was
stirred for 30 min. Purification by chromatography (EtOAc/
heptane, 1:4) afforded 38 as a light-brown oil; yield: 334 mg
(1.00 mmol, 60%); Rf ¼0.14 (EtOAc/heptane, 1:3); [a]2D0:
Methyl 2-[(tert-Butoxycarbonyl)amino]-5-oxo-5-
phenylpentanoate (27)
According to the general procedure, to a solution of 23
(438 mg, 1.44 mmol) in MeCN (16 mL), PdCl2(MeCN)2
(37 mg, 0.14 mmol) was added and the resulting mixture was
stirred at room temperature for 70 h. Purification by chroma-
tography (EtOAc/heptane, 1:4) afforded 27 as a light-yellow
solid; yield: 149 mg (0.46 mmol, 32%); Rf ¼0.39 (EtOAc/hep-
˜
À26.8 (c 0.5, CH2Cl2); IR (neat): n¼3381, 2954, 1693, 1504,
1
1454 cmÀ1; H NMR (300 MHz, CDCl3): d¼9.15 (br s, 1H),
7.50 (d, J¼7.5 Hz, 1H), 7.32 (d, J¼7.8 Hz, 1H), 7.06 (m, 2H),
6.22 (s, 1H), 5.22 (br d, J¼8.1 Hz, 1H), 4.43 (br m, 1H), 3.67
(s, 3H), 2.82 (m, 2H), 2.14 (m, 1H), 1.93 (m, 1H), 1.47 (s, 9H);
13C NMR (75 MHz, CDCl3): d¼172.7, 155.9, 138.2, 136.0,
128.6, 121.0, 119.7, 119.4, 110.8, 99.9, 80.7, 52.8, 52.7, 34.5,
28.6, 24.3; HRMS (EI): calcd. for C18H24N2O4: 332.1736; found:
332.1727.
˜
tane, 1:2); mp 109.48C; IR (neat): n¼3359, 1736, 1699, 1680,
1
1599, 1514, 1448 cmÀ1; H NMR (300 MHz, CDCl3): d¼7.92
(d, J¼7.2 Hz, 2H), 7.48 (m, 3H), 5.14 (br d, J¼7.2 Hz, 1H),
4.37 (m, 1H), 3.73 (s, 3H), 3.08 (m, 2H), 2.30 (m, 1H), 2.08
(m, 1H), 1.41 (s, 9H); 13C NMR (75 MHz, CDCl3): d¼198.5,
172.7, 155.3, 136.6, 133.1, 128.5, 128.0, 80.1, 53.3, 52.6, 34.8,
28.6, 27.3; HRMS (CI): calcd. for C17H24NO5 (MHþ):
322.1654; found: 322.1659.
Methyl (2S)-2-[(tert-Butoxycarbonyl)amino]-5-(1H-2-
indolyl)pentanoate (39)
1-(tert-Butyl) 2-Methyl 5-[2-(acetylamino)phenyl]-2,3-
dihydro-1H-1,2-pyrroledicarboxylate (29)
According to the general procedure, to a solution of 37
(226 mg, 0.65 mmol) in MeCN (12 mL), PdCl2(MeCN)2
(17 mg, 0.07 mmol) was added and the resulting mixture was
stirred for 30 min. Purification by chromatography (EtOAc/
heptane, 1:4) afforded 39 as a light-brown oil; yield: 125 mg
(0.36 mmol, 55%); Rf ¼0.17 (EtOAc/heptane, 1:3); [a]2D0:
According to the general procedure, to a solution of 25
(376 mg, 1.04 mmol) in MeCN (14 mL), PdCl2(MeCN)2
(29 mg, 0.11 mmol) was added and the resulting mixture was
stirred for 2 h. Purification by chromatography (EtOAc/hep-
tane, 1:3) afforded 29 as a white solid; yield: 184 mg
(0.51 mmol, 49%); Rf ¼0.25 (EtOAc/heptane, 1:2); mp
˜
þ5.2 (c 0.5, CH2Cl2); IR (neat): n¼3377, 2949, 1734, 1691,
1
1504, 1456 cmÀ1; H NMR (300 MHz, CDCl3): d¼8.30 (br s,
˜
108.78C; IR (neat): n¼3357, 2974, 1738, 1684, 1643, 1581,
1H), 7.49 (d, J¼7.2 Hz, 1H), 7.25 (m, 1H), 7.05 (m, 2H), 6.20
(s, 1H), 5.11 (br d, J¼7.2 Hz, 1H), 4.40 (br m, 1H), 3.72 (s,
3H), 2.79 (m, 2H), 1.91 1.65 (m, 4H), 1.47 (s, 9H); 13C NMR
(75 MHz, CDCl3): d¼172.9, 155.5, 138.9, 135.9, 128.6, 120.9,
119.7, 119.4, 110.4, 99.6, 80.3, 53.0, 52.5, 32.8, 28.6, 27.5, 25.5;
HRMS (EI): calcd. for C19H26N2O4: 346.1893; found: 346.1894.
1
1524, 1443 cmÀ1; H NMR (300 MHz, CDCl3): d¼8.69 (br s,
1H), 8.44 (d, J¼8.3 Hz, 1H), 7.27 (m, 1H), 7.16 (dd, J¼1.6,
7.6 Hz, 1H) 6.97 (m, 1H), 5.07 (dd, J¼2.0, 3.4 Hz, 1H), 4.98
(dd, J¼2.3, 11.0 Hz, 1H), 3.82 (s, 3H), 3.12 (ddd, J¼2.0, 11.0,
17.0 Hz, 1H), 2.55 (dt, J¼2.9, 17.0 Hz, 1H), 2.24 (s, 3H), 1.08
(s, 9H); 13C NMR (75 MHz, CDCl3): d¼173.7, 169.3, 151.4,
140.9, 136.8, 128.9, 128.4, 122.6, 122.5, 119.7, 110.2, 81.3, 60.6,
52.9, 32.3, 27.6, 24.7; HRMS (EI): calcd. for C19H24N2O5:
360.1685; found: 360.1682.
Methyl (2S)-2-[Di(tert-butoxycarbonyl)amino]-3-(1H-
2-indolyl)propanoate (42)
5-(2-Aminophenyl)-7,7a dihydro-1H-pyrrolo[1,2-c]-
[1,3]oxazol-3-one (30)
According to the general procedure, to a solution of 41
(327 mg, 0.78 mmol) in MeCN (12 mL), PdCl2(MeCN)2
(20 mg, 0.08 mmol) was added and the resulting mixture was
stirred for 3 h. Purification by chromatography (EtOAc/hep-
tane, 1:6) afforded 42 as a white solid; yield: 170 mg
According to the general procedure, to a solution of 26
(120 mg, 0.56 mmol) in MeCN (10 mL), PdCl2(MeCN)2
(14 mg, 0.05 mmol) was added and the resulting mixture was
stirred for 2 h. Purification by chromatography (EtOAc/hep-
tane, 2:1) afforded 30 as a light-yellow oil; yield: 38 mg
(0.41 mmol, 52%); Rf ¼0.28 (EtOAc/heptane, 1:3); mp
20
˜
143.08C; [a]D : À99.9 (c 1.0, CH2Cl2); IR (neat): n¼3392,
(0.18 mmol, 32%); Rf ¼0.19 (EtOAc/heptane, 2:1); IR
2983, 1743, 1726, 1685, 1456 cmÀ1
;
1H NMR (300 MHz,
(neat): n¼3462, 3356, 1745, 1616, 1491, 1454 cmÀ1; H NMR
1
˜
CDCl3): d¼8.45 (s, 1H), 7.47 (d, J¼8.1 Hz, 1H), 7.24 (d, J¼
7.7 Hz, 1H), 7.04 (m, 2H), 6.25 (d, J¼1.2 Hz, 1H), 5.15 (t, J¼
6.9 Hz, 1H), 3.75 (s, 3H), 3.61 (dd, J¼6.6, 15.0 Hz, 1H), 3.28
(dd, J¼7.2, 15.0 Hz, 1H), 1.40 (s, 18H); 13C NMR (75 MHz,
CDCl3): d¼171.1, 151.7, 136.1, 134.9, 128.5, 121.2, 119.9,
119.5, 110.6, 101.8, 83.6, 58.4, 52.7, 30.1, 28.2; HRMS (EI):
calcd. for C22H30N2O6: 418.2104; found: 418.2105.
(300 MHz, CDCl3): d¼7.28 (dd, J¼1.5, 7.5 Hz, 1H), 7.13 (dt,
J¼1.8, 7.7 Hz, 1H), 6.71 (m, 2H), 5.45 (t, J¼2.7 Hz, 1H),
4.79 (m, 1H), 4.67 (t, J¼8.7 Hz, 1H), 4.21 (dd, J¼6.6, 8.7 Hz,
1H), 4.16 (br s, 2H), 2.73 (m, 2H); 13C NMR (75 MHz,
CDCl3): d¼157.4, 145.0, 141.3, 130.0, 129.9, 118.3, 116.4,
116.3, 112.1, 69.9, 59.9, 36.0; HRMS (EI): calcd. for C12H12N2
O2: 216.0899; found: 216.0891.
832
¹ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
Adv. Synth. Catal. 2004, 346, 823 834

Novel Biologically Relevant Tryptophan Analogues
FULL PAPERS
(EtOAc/heptane, 1:2); mp 118.28C; [a]2D0: þ5.7 (c 1.0, CH2
Methyl (2S)-2-[(tert-Butoxycarbonyl)amino]-3-(1H-2-
indolyl)propanoate (44)
˜
Cl2); IR (neat): n¼3252, 2954, 1744, 1593, 1454, 1429,
1416 cmÀ1
;
1H NMR (300 MHz, CDCl3): d¼7.60 (d, J¼
According to the general procedure, to a solution of 43
(351 mg, 1.10 mmol) in MeCN (12 mL), AgOTf (29 mg,
0.11 mmol) was added and the resulting mixture was stirred
for 20 h. Purification by chromatography (EtOAc/heptane,
8.4 Hz, 2H), 7.42 (d, J¼6.6 Hz, 1H), 7.30 7.08 (m, 5H), 6.41
(d, J¼0.9 Hz, 1H), 5.36 (d, J¼9.0 Hz, 1H), 4.32 (m, 1H), 3.57
(s, 3H) 3.19 (d, J¼5.7 Hz, 2H), 2.33 (s, 3H); 13C NMR
(75 MHz, CDCl3): d¼170.7, 154.7, 152.1, 143.5, 136.5, 129.4,
128.2, 127.0, 123.9, 122.7, 120.6, 110.9, 105.5, 54.7, 53.0, 32.9,
21.8; HRMS (EI): calcd. for C19H19NO5S: 373.0984; found:
373.0986.
1:3) afforded 44 as
a light-yellow oil; yield: 261 mg
(0.82 mmol, 75%); Rf ¼0.29 (EtOAc/heptane, 1:2); [a]2D0:
˜
þ46.8 (c 1.0, CH2Cl2); IR (neat): n¼3378, 2976, 1692,
1498 cmÀ1; 1H NMR (300 MHz, CDCl3): d¼8.27 (s, 1H), 7.51
(d, J¼7.5 Hz, 1H), 7.28 (m, 1H), 7.08 (m, 2H), 6.25 (d, J¼
1.5 Hz, 1H), 5.13 (br d, J¼10.8 Hz, 1H), 4.63 (br m, 1H), 3.74
(s, 3H), 3.27 (d, J¼5.4 Hz, 2H), 1.45 (s, 9H); 13C NMR
(75 MHz, CDCl3): d¼172.3, 155.2, 136.2, 133.3, 128.4, 121.5,
120.0, 119.7, 110.7, 102.0, 80.5, 53.4, 52.8, 31.6, 28.6; HRMS
(EI): calcd. for C17H22N2O4: 318.1580; found: 318.1578.
Acknowledgements
DSM Research is kindly acknowledged for their hospitality dur-
ing the enzymatic resolutions. Theo Sonke (DSM Research, Life
Science Products, Geleen, The Netherlands) and Roy P. M.
Storcken are kindly acknowledged for conducting the enzymat-
ic resolution of the amino acid amides. Christien A. Schorting-
huis is kindly thanked for performing chiral HPLC analyses.
Methyl 3-(1H-2-Indolyl)-2-{[(4-
methylphenyl)sulfonyl]amino}propanoate (47)
According to the general procedure, to a solution of 46
(360 mg, 0.97 mmol) in MeCN (12 mL), AgOTf (25 mg,
0.10 mmol) was added and the resulting mixture was stirred
for 20 h. Purification by chromatography (EtOAc/heptane,
1:3) afforded 47 as a white solid; yield: 310 mg (0.83 mmol,
86%). An X-ray crystal structure determination was carried
out after recrystallization from Et2O. Rf ¼0.37 (EtOAc/hep-
References and Notes
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˜
tane, 1:1); mp 146.38C; IR (neat): n¼3356, 3239, 1714, 1593,
1450, 1429 cmÀ1
;
1H NMR (300 MHz, CDCl3): d¼8.26 (s,
1H), 7.64 (d, J¼8.4 Hz, 2H), 7.26 (d, J¼7.8 Hz, 1H), 7.15 (m,
3H), 7.05 (m, 2H), 6.14 (t, J¼1.2 Hz, 1H), 5.33 (d, J¼5.7 Hz,
1H), 4.21 (br d, J¼5.1 Hz, 1H) 3.56 (s, 3H), 3.24 (d, J¼
5.1 Hz, 2H), 2.38 (s, 3H); 13C NMR (75 MHz, CDCl3): d¼
171.8, 143.8, 136.2, 136.0, 132.4, 129.6, 128.2, 127.1, 121.6,
120.0, 119.7, 110.9, 102.0, 56.0, 53.0, 32.2, 21.8; HRMS (EI):
calcd. for C19H20N2O4S 372.1144, found 372.1144.
Crystal data: transparent colorless, regular fragments, tri-
clinic, space group PÀ1, C19H20N2O4S, 372.43, unit-cell dimen-
sions: a¼10.6303(5) ä; a¼73.937(5)8, b¼11.7369(8) ä; b¼
88.550(6)8, c¼15.9793(11) ä; g¼75.558(5)8, Z¼4, calculated
density: 1.335 Mg/m3. Data collection: Nonius KappaCCD/
area detector f and w scan, Mo-Ka (graphite mon.)/
0.71073 ä, crystal size 0.18Â0.16Â0.08 mm, T¼208(2) K, q
range 3.56 to 27.508, 4836 ([Io>2s(Io)]) reflections measured,
no absorption correction. Structural analysis and refinement:
full-matrix least-squares on F2, goodness-of-fit on F2 1.016,
SHELXL-97 weight parameters 0.066500, 0.298900, final R in-
dices [I>2s(I)]: R1¼0.0624, wR2¼0.1269, SHELXL-97
(Sheldrick, 1997).
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Methyl (2S)-3-Benzo[b]furan-2-yl-2-{[(4-
methylphenyl)sulfonyl]amino}-propanoate (51)
According to the general procedure, to a solution of 50
(344 mg, 1.22 mmol), 2-iodophenol (333 mg, 1.51 mmol) in
Et2NH (18 mL), CuI (24 mg, 0.13 mmol) and PdCl2(PPh3)2
(45 mg, 0.06 mmol) were added and the resulting mixture
was stirred at reflux temperature for 4 h. Work-up and purifica-
tion by chromatography (EtOAc/heptane, 1:2) afforded 51 as
a light-yellow solid; yield: 337 mg (0.90 mmol, 74%); Rf ¼0.23
¬
dregal, C. Lamas, J. Barluenga, M. Perez, M. A. Gar-
¬
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Adv. Synth. Catal. 2004, 346, 823 834
asc.wiley-vch.de
¹ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
833

Bart C. J. van Esseveldt et al.
FULL PAPERS
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tion of diethyl acetamidomalonate with propargyl bro-
mide (1.2 equivs.) and NaH (1.1 equivs.), followed by es-
ter and amide hydrolysis with concomitant decarboxyla-
tion in 2 M HCl under reflux conditions.
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Tool, Utrecht University, Utrecht, The Netherlands,
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[21] Crystallographic data (excluding structure factors) of
compounds 18 and 47 have been deposited with the
Cambridge Crystallographic Data Centre as supplemen-
tary publications no. CCDC-203097 (compound 18) and
no. CCDC-237704 (compound 47). Copies of the data
can be obtained free of charge on application to
CCDC, 12 Union Road, Cambridge CB21EZ, UK
[Fax: int. codeþ44(1223)336 033; E-mail: depos-
it@ccdc.cam.ac.uk].
[16] Referred to as propargylglycine; 2-amino-5-hexynoic
acid is homopropargylglycine, etc.
[22] K. Imi, K. Imai, K. Utimoto, Tetrahedron Lett. 1987, 28,
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[17] a) L. B. Wolf, Ph. D. Thesis, University of Amsterdam
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Rutjes, Adv. Synth. Catal. 2001, 343, 662; c) T. Sonke,
B. Kaptein, W. H. J. Boesten, Q. B. Broxterman, J. Kam-
phuis, F. Formaggio, C. Toniolo, F. P. J. T. Rutjes, H. E.
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Patel), Marcel Dekker: New York, 2000; p. 23.
[18] Amino acids 16 and 45 have been synthesized from rac-
emic propargylglycine via esterification followed by N-
protection. Racemic propargylglycine is commercially
available, but alternatively can be synthesized via alkyla-
[23] For similar Pd-catalyzed coupling cyclization approaches
to 2-substituted benzo[b]furans, see: a) W.-M. Dai, K. W.
Lai, Tetrahedron Lett. 2002, 43, 9377; b) P. G. Wyatt, M. J.
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Pagni, Tetrahedron 2001, 57, 8017; d) M. Inoue, M. W.
Carson, A. J. Frontier, S. J. Danishefsky, J. Am. Chem.
Soc. 2001, 123, 1878.
[24] For more information, see: www.chiralix.com.
834
¹ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
Adv. Synth. Catal. 2004, 346, 823 834