Synthesis of (S,Z)-3-[(1H-indol-3-yl)methylidene]hexahydropyrrolo[1,2-a]pyrazin-4(1H)-one: an alternative, enaminone based, route to unsaturated cyclodipeptides

Article abstract of DOI:10.1016/j.tet.2008.01.045

A series of racemic and enantiopure (S,Z)-3-[(1H-indol-3-yl)methylidene]hexahydropyrrolo[1,2-a]pyrazin-4(1H)-one (cyclic Pro-ΔTrp) dipeptide analogues were prepared. Racemic analogues 6a-c were prepared by direct coupling of racemic cyclodipeptide enaminone (R,S)-5 with various indole derivatives. On the other hand, enantiopure analogues were prepared through a copper(I) catalyzed vinyl amidation reaction in which acyclic (S)-Pro-ΔTrp dipeptide analogues 20 and 21 were formed. Acyclic dipeptides were cyclized to enantiopure (S)-Pro-ΔTrp dipeptide analogues 24 and 25. For coupling reactions, vinyl bromides were prepared in several steps. From ethyl acetate (7), enaminone 8 was prepared and coupled with 2-methylindole and 2-phenylindole to give 9 and 10. Direct bromination of 3-(indole-3-yl)propenoates 9 and 10 at position 2 results in vinyl bromides 11 and 12. The Boc protecting group on the indole nitrogen 1′ in vinyl bromides 11 and 12 was introduced, before the copper(I) catalyzed coupling with N-Boc prolinamide 18 was performed. Enantiomeric purity of chiral intermediates and final products was determined mostly by HPLC or ¹H NMR spectroscopy and X-ray diffraction.

Full text of DOI:10.1016/j.tet.2008.01.045

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 2801e2815
www.elsevier.com/locate/tet
Synthesis of (S,Z)-3-[(1H-indol-3-yl)methylidene]hexahydropyrrolo-
[1,2-a]pyrazin-4(1H)-one: an alternative, enaminone based,
route to unsaturated cyclodipeptides
*
ˇ
Jernej Wagger, Uros Groselj, Anton Meden, Jurij Svete, Branko Stanovnik
ˇ
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Asˇkerꢀceva 5, PO Box 537, 1000 Ljubljana, Slovenia
Received 12 October 2007; received in revised form 19 December 2007; accepted 10 January 2008
Available online 16 January 2008
Abstract
A series of racemic and enantiopure (S,Z)-3-[(1H-indol-3-yl)methylidene]hexahydropyrrolo[1,2-a]pyrazin-4(1H)-one (cyclic ProeDTrp)
dipeptide analogues were prepared. Racemic analogues 6aec were prepared by direct coupling of racemic cyclodipeptide enaminone (R,S)-5
with various indole derivatives. On the other hand, enantiopure analogues were prepared through a copper(I) catalyzed vinyl amidation reaction
in which acyclic (S)-ProeDTrp dipeptide analogues 20 and 21 were formed. Acyclic dipeptides were cyclized to enantiopure (S)-ProeDTrp
dipeptide analogues 24 and 25. For coupling reactions, vinyl bromides were prepared in several steps. From ethyl acetate (7), enaminone 8
was prepared and coupled with 2-methylindole and 2-phenylindole to give 9 and 10. Direct bromination of 3-(indole-3-yl)propenoates 9 and
10 at position 2 results in vinyl bromides 11 and 12. The Boc protecting group on the indole nitrogen 10 in vinyl bromides 11 and 12 was
introduced, before the copper(I) catalyzed coupling with N-Boc prolinamide 18 was performed. Enantiomeric purity of chiral intermediates
1
and final products was determined mostly by HPLC or H NMR spectroscopy and X-ray diffraction.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Cyclodipeptides; 3-[(Indol-3-yl)methylidene]piperazine-2,5-dione; Enaminones; Indoles; Copper(I) catalyzed coupling; Natural products
1. Introduction
indole alkaloids such as VM55599,7a paraherquamide A,7b or
desmethoxy-(þ)-verruculogen TR2.8
The cyclodipeptide template, of which one amino acid
residue a,b-didehydrotryptophan or its analogue, is a com-
mon structural element in the chemistry of secondary
metabolites.1
3-[(Indol-3-yl)methylidene]piperazine-2,5-dione is a struc-
tural element present in many indole alkaloids, possessing
various biologically interesting activities. Among them are mi-
crotubule inhibiting spirotryprostatin B,2 free radical scaveng-
ing dihydroisoechinulin A,3 immunosuppresing cristatin A,4
insecticidal okaramine R5 and antifouling acting6 barettin6b
and dipodazine6c (Fig. 1). The unsaturated cyclodipeptides of
such type not only represent simple indole alkaloids, they can
be utilized also as precursors in the synthesis of more complex
Most commonly 3-alkylidenenepiperazine-2,5-diones are
in most cases synthesized via HornereEmmons reactions,7a,9
or via condensation reactions10 with suitable aldehydes, while
coupling of the N-terminus of aromatic or heteroaromatic a,b-
didehydro-a-amino acids with the C-terminus of activated es-
ters or acylhalides of N-protected a-amino acids, is ineffective
due to the impaired nucleophilicity of the N-terminal part.11 It
has to be also mentioned that chiral 3-ylidenepiperazine-2,5-
diones are sensitive to the basic reaction conditions and are
prone to racemization.10,12
Recently enaminones and related compounds, such as b-di-
methylamino-a,b-didehydroamino acid derivatives, have been
demonstrated to be versatile reagents in the synthesis of vari-
ous heterocyclic systems.13,14 This enaminone-based strategy
has been also successfully applied for the preparation of sev-
eral indole alkaloids and their analogues, such as aplysinop-
sins,15aef,16,18 meridianins,17,18 and dipodazines.12b
* Corresponding author. Tel.: þ386 1 2419 100; fax: þ386 1 2419 220.
E-mail address: branko.stanovnik@fkkt.uni-lj.si (B. Stanovnik).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.045

2802
J. Wagger et al. / Tetrahedron 64 (2008) 2801e2815
H
N
O
O
N
H
O
N
N
H
O
N
O
NH
O
N
H
O
OH
OH
HN
NH
dihidroxyisoechinulin A
spirotryprostatin B
cristatin A
NH2
NH
HN
N
H
H
O
H
O
N
O
N
OH
O
N
N
H
O
N
H
O
N
O
NH
NH
N
H
Br
Br
dipodazine
barettin
okaramine R
Figure 1.
2. Results and discussion
2.1. Preparation of racemic (RS,Z)-3-[(1H-indol-3-yl)-
methylidene]hexahydropyrrolo[1,2-a]pyrazin-4(1H)-ones
(ProeDTrp) cyclodipeptide analogues
In our recent work on dipodazine analogues,12b a problem
with partial racemization was encountered. Namely, when we
tried to introduce the chiral center with (S)-Ala into the
dipodazine derivatives 4aef via (S)-1-benzyl-6-methylpipera-
zine-2,5-dione (1) and (Z)-1-benzyl-3-[(dimethylamino)-
methylidene]-6-methylpiperazine-2,5-dione (2), we observed
partial racemization of this amino acid structural element in
the transformation of 1 into 2 with bis(dimethylamino)-tert-
butoxymethane (Bredereck’s reagent),19 due to the basic reac-
tion conditions (Scheme 1).
To avoid racemization, we substituted (S)-Ala in 1, for the
conformationally more constrained (S)-Pro, hoping to obtain a
(Z)-3-[(dimethylamino)methylidene]hexahydropyrrolo[1,2-a]-
pyrazine-1,4-dione (S)-5, as a good chiral cyclodipeptide tem-
plate, that would enable us to carry out further transformations.
Unfortunately, racemization of (S)-5 took place.20 Nevertheless,
racemic enaminone (R,S)-5 was used in coupling reactions with
different indoles, to afford three different racemic cyclic
HN
R2
R
NMe2
H
N
H
N
H
N
H
N
R1
NMe2
NMe2
O
O
O
R
t-BuO
3a-f
AcOH
N
O
N
O
N
O
anisole, reflux
2
1
4a-f
product
indole
R
H
R1
R2
H
H
3a
3b
3c
3d
3e
3f
4a
H
H
H
H
F
Me
Ph
H
4b
4c
4d
4e
4f
H
OH
H
H
H
Br
H
Scheme 1.

J. Wagger et al. / Tetrahedron 64 (2008) 2801e2815
2803
H
N
R
product
6a
R
conditions
yield
38%
O
O
N
N
3a-c
NH
NH
NMe2
(R,S)-5
Me
AcOH, reflux, 3 h
O
O
R
6b
H
AcOH, MW, 45 min 42%
i-Pr, reflux, 3.5 h 34%
NH
6c
Ph
6a-c
Scheme 2.
ProeDTrp analogues (RS,Z)-3-[(2-methyl-1H-indol-3-yl)-
methylidene]hexahydropyrrolo[1,2-a]pyrazine-1,4-dione (6a),
(RS,Z)-3-[(1H-indol-3-yl)methylidene]hexahydropyrrolo-
[1,2-a]pyrazine-1,4-dione (6b), and (RS,Z)-3-[(2-phenyl-1H-
indol-3-yl)methylidene]hexahydropyrrolo[1,2-a]pyrazine-1,4-
dione (6c) (Scheme 2).
hand, enabled us to prepare enantiomerically pure acyclic
ProeDTrp dipeptides analogues (Scheme 3).
2.2.1. Synthesis
2.2.1.1. Synthesis of (E)-ethyl 3-(dimethylamino)propenoate
(8) and subsequent coupling with indoles 3b and 3c. Ethyl
acetate (7) selected as the starting material and reacted with
bis(dimethylamino)-tert-butoxymethane (Bredereck’s reagent)
in the presence of N,N-dimethylformamide under microwave
irradiation, to afford the enaminone 8 in 76% yield. In the
reaction of 8 with 2-methyl (3a) or 2-phenylindole (3b), (E)-
ethyl 3-(2-methyl-1H-indol-3-yl)propenoate (9) and (E)-ethyl
3-(2-phenyl-1H-indol-3-yl)propenoate (10) were prepared
(Scheme 4).
2.2. Preparation of enantiopure (S,Z)-3-[(1H-indol-3-yl)-
methylidene]hexahydropyrrolo[1,2-a]pyrazin-4(1H)-ones
(ProeDTrp) cyclodipeptide analogues
Since this synthetic approach toward desired enantiomeri-
cally pure ProeDTrp cyclodipeptides was unsuccessful, a com-
pletely new synthesis was designed. For this purpose,
a retrosynthetic analysis was made, accordingly to which the
enaminone-based approach was preserved, and, on the other
2.2.1.2. Synthesis of vinyl bromides 14e16. Bromination of
compound 9 with bromine in chloroform at 0 ꢀC produced
(Z)-ethyl 2-bromo-3-(5 or 6 bromo-2-methyl-1H-indol-3-yl)-
propenoate (13). Since a brominated indole nucleus could
complicate the following coupling reactions, another method
of bromination was introduced. We selected the simple proce-
dure of Bocchi21 (used originally for the preparation for
3-haloindoles). In this manner, (E)-ethyl 3-(2-methyl-1H-in-
dol-3-yl)propenoate (9) or (E)-ethyl 3-(2-phenyl-1H-indol-3-
yl)propenoate (10) was dissolved in N,N-dimethylformamide,
cooled to 0 ꢀC, and then bromine was added dropwise. By
treatment of the reaction mixture with aqueous ammonia and
potassium disulfite, (Z)-ethyl 2-bromo-3-(2-methyl-1H-indol-
3-yl)propenoate (11) or (Z)-ethyl 2-bromo-3-(2-phenyl-1H-in-
dol-3-yl)propenoate (12) was obtained in 96 or 92% yield,
respectively.
O
N
H
OH
(2)
O
N
O
O
N
H
GP
N
NH2
+
NH
NH
R'OOC
O
R
R
R'OOC
Hal
R
(2)
NH
NH
PG
N
On prolonged heating of 11, bromine is released resulting
in a brown reaction mixture. This means that 11 is thermally
unstable, like simple 3-haloindoles.22 To avoid thermal degra-
dation of 11 and 12, a pushepull system of indole nitrogen
and bromine had to be blocked. For this purpose a tosyl pro-
tecting group was introduced on the indole nitrogen atom at
position 10 of 11. However, this tosyl protecting group turned
out to be inconvenient for several reasons. The yield of its in-
troduction was modest (40% in 14) and more important, its re-
moval resulted in racemization of the final product. Therefore,
we introduced the Boc protecting group instead, according to
the procedure reported in the literature23 for other indole de-
rivatives, to give 15 and 16 in 98 and 90% yields, respectively
(Scheme 5).
(S)-Pro- Trp dipeptide analogues
(2)
R'OOC
R'OOC
R
NMe2
enaminone
R'OOC
NH
Me
R
+
NH
Scheme 3.

2804
J. Wagger et al. / Tetrahedron 64 (2008) 2801e2815
H
N
1
COOEt
NMe2
2
R
R
t-BuO
COOEt
2'
NMe2
3b and 3c
AcOH, 95 °C
1'
3
COOEt
H
3'
N
Me
DMF, MW, 165 °C
Me2N
8 76%
4'
7
7'
5'
6'
R: Me, 9, 74%
Ph, 10, 62%
Scheme 4.
COOEt
Br
COOEt
Br
COOEt
R
R
R
Tos
HN
HN
LDA, THF, Tos-Cl
N
Br2
DMF
R: Me, 14, 40%
R: Me, 9; Ph, 10
R: Me, 11, 96%
Ph, 12, 92%
Br2 CHCl3
Br
COOEt
R
Boc
N
Br
COOEt
R
HN
R: Me, 15, 98%
Ph, 16, 90%
Br
R: Me, 13, 34%
Scheme 5.
O
O
O
HN
R
O
OEt
OEt
N
Boc
NH2
N
Boc
Br
R
CuI, K2CO3, toluene, 100 °C
+
18
N
N
N
N
R1
pyr.
(Boc)2O
R1
(NH4)2CO3
dioxan
R1: Tos, R: Me; 19; 80%
R1: Boc, R: Me; 20; 78%
R1: Boc, R: Ph; 21; 65%
R1: Tos, R: Me; 14
R1: Boc, R: Me; 15
R1: Boc, R: Ph; 16
O
N
OH
Boc
17
Scheme 6.
2.2.1.3. Copper(I) catalyzed vinyl amidation: synthesis of (S)-
ProeDTrp dipeptides analogues 19e21. The next synthetic
step was the preparation of (S)-ProeDTrp dipeptide analogues,
that would allow us a simple cyclization to the final products.
Having in mind the limitation and drawbacks of classical N-ter-
minal coupling of a,b-unsaturated aromatic or heteroaromatic
a-amino acids, we applied the Buchwald’s copper(I) catalyzed
vinyl amidation,24 to couple (S)-N-Boc-prolinamide (18) with
vinyl halides 14e16, producing the desired (S)-ProeDTrp
dipeptide analogues 19e21. Looking through the literature,
only one similar strategy was found in the synthesis of roquefor-
tine C, where heteroaromatic a,b-unsaturated a-amino acid was
incorporated in C-terminal part of the dipeptide.25
(S)-N-Boc-prolinamide (18),26bed prepared from (S)-N-Boc-
proline (17)26a was coupled with vinyl bromides 14e16 in the
presence of catalytic amounts of copper(I) iodide and N,N-dime-
thylethylenediamine as a ligand, in a Schlenk tube in toluene
in an inert atmosphere at 100 ꢀC. Using this protocol, three

J. Wagger et al. / Tetrahedron 64 (2008) 2801e2815
2805
(S)-ProeDTrp analogues were prepared in good yields;
(S)-tert-butyl 2-[3-ethoxy-1-(2-methyl-1-tosyl-1H-indol-3-yl)-
3-oxoprop-1-en-2-ylcarbamoyl]-pyrrolidine-1-carboxylate (19)
(80%), (S)-tert-butyl 3-[2-(1-(tert-butoxycarbonyl)pyrolidine-
2-carboxamido)-3-ethoxy-3-oxoprop-1-enyl]-2-methyl-1H-in-
dole-1-carboxylate (20) (78%), and (S)-tert-butyl 3-[2-(1-(tert-
butoxycarbonyl)pyrolidine-2-carboxamido)-3-ethoxy-3-oxo-
prop-1-enyl]-2-phenyl-1H-indole-1-carboxylate (21) (65%),
respectively (Scheme 6).
proceeded slowly and after 6 h of reflux, the reaction mixture
was stirred for additional 17 h at ambient temperature. To our
surprise, racemic (RS,Z)-3-[(2-methyl-1H-indol-3-yl)methyl-
idene]hexahydropyrrolo[1,2-a]pyrazine-1,4-dione (6a) was
isolated. The cause of racemization was probably due to a rel-
atively strong basic nature of the fluoride anion27 TBAF. The
next attempt of detosylation was performed by using Mg turn-
ings in methanol.28 Since piperazinedione 22 was only slightly
soluble in methanol, the yield of this reaction was very poor
(7%) and the racemization again occurred, probably because
of the magnesium methoxide formed during the reaction.
Due to these unsuccessful experiments, we decided to use
the Boc protecting group on both, the indole 10 position and
proline part. Both Boc groups in dipeptide 20 were removed
with trifluoroacetic acid according to the procedure described
in literature for deprotecting of tryptophan.29 Totally depro-
tected dipeptide 23a without further purification was cyclized
into (S,Z)-3-[(2-methyl-1H-indol-3-yl)methylidene]hexahydro-
pyrrolo[1,2-a]pyrazine-1,4-dione (24) in the same manner as
described above for the dipeptide 19 into 22. In this procedure
no racemization could be detected in the final product 24,
though the yield was only 11% over the two steps. Because
of that, another method of cyclization was examined. After de-
protection of dipeptide 20 with trifluoroacetic acid, the neu-
tralization of dipeptide trifluoroacetate 23a was performed
with aqueous sodium hydroxide, to give the dipeptide, which
was then cyclized in anhydrous toluene at 80 ꢀC to piperazine-
dione 24 in 54% over two steps. Again, no racemization was
2.2.1.4. Cyclization of (S)-ProeDTrp dipeptide analogues 19,
20 and 21 to 22 and final products, 24, 25. Initial cyclization
reactions were performed on dipeptide 19 with the 10 Tos pro-
tecting group on the indole moiety. The intention was to re-
move Boc protecting group from Pro part of the molecule
first, then to perform cyclization to cyclodipeptide followed
by detosylation of the indole 10 position in the last step. Re-
moval of the Boc group was performed in dichloromethane
with 2 M HCl in diethyl ether solution; the deprotected inter-
mediate was not isolated. The volatile components were evap-
orated and the residue was immediately used in the cyclization
reaction, which was performed in dichloromethane with
5 equiv of triethylamine added to the reaction mixture at reflux
to produce (S,Z)-3-[(2-methyl-1-tosyl-1H-indol-3-yl)methyl-
idene]hexahydropyrrolo[1,2-a]pyrazine-1,4-dione (22). Since
the chiral piperazinediones are sensitive to racemization, we
selected tetrabutylammonium fluoride (TBAF) in refluxing tet-
rahydrofuran as a mild method for detosylation. Reaction
O
O
O
N
N
N
Boc
HN
HN
HN
COOEt 1. HCl/Et2O
a) TBAF, THF
b) Mg, MeOH
O
O
Me
Me
Me
N
2. Et3N, DCM, reflux
Tos
HN
Tos
N
19
22
6a
method yield
e.e. [%]
a)
b)
54%
7%
0
0
F3COO
O
O
O
N
N
N
Boc
H2
TFA, anisole
0 °C
a) Et3N, DCM, reflux HN
HN
COOEt
HN
COOEt
O
R
R
N
R
b) toluene, 80 °C
Boc
HN
HN
20; R: Me
21; R: Ph
23a; R: Me
23b; R: Ph
method
R
yield e.e. [%]
a)
b)
b)
Me, 24
Me, 24
Ph, 25
11%
54%
39%
>99
>99
>99
Scheme 7.

2806
J. Wagger et al. / Tetrahedron 64 (2008) 2801e2815
Table 1
HPLC data and optical rotations for listed compounds
detected. Similarly dipeptide 21 was transformed to 23b and
then cyclized into (S,Z)-3-[(2-phenyl-1H-indol-3-yl)methyl-
idene]hexahydropyrrolo[1,2-a]pyrazine-1,4-dione (25) in tolu-
ene at 80 ꢀC. No racemization of piperazinedione 25 was
observed (Scheme 7).
Compound Mobile phase Retention time (min) [a]D
ee
(%)
tR (R)
tR (S)
(R,S)-19
(S)-19
MeCN/H2O (pH 4)¼40:60 14.7
15.4
15.3
8.5
0
MeCN/H2O (pH 4)¼40:60
d
MeCN/H2O (pH 2)¼40:60 8.8
ꢁ116.5 >99
(R,S)-22
(S)-22
0
þ42.3 >99
0
3. Structure determination
MeCN/H2O (pH 2)¼40:60
d
8.43
5.2
(R,S)-6aa MeCN/H2O (pH 2)¼40:60 6.5
(S)-6ab
(R,S)-24
(S)-24
(R,S)-25
(S)-25
a
MeCN/H2O (pH 2)¼40:60 6.4
MeCN/H2O (pH 2)¼40:60 6.4
5.1
5.1
0
0
0
Due to problems with racemization, the enantiomeric purity
of the chiral compounds had to be determined. This was done
1
mostly by HPLC, in one case also by H NMR spectroscopy
and by X-ray analysis. For the HPLC analyses, Chiralcel OD-R
chiral column was used with acetonitrile/water¼40:60 as a
mobile phase. For all analyses water was acidified with formic
acid to pH 2 or 4. In all cases racemic analogues of analyzed
compounds were prepared to be used as standards (Table 1).
For compound 19 no racemization could be seen, meaning
that copper(I) catalyzed amidation of vinyl halide 14, with
MeCN/H2O (pH 2)¼40:60
d
MeCN/H2O (pH 2)¼40:60 19.0
5.0
þ387.1 >99
0
26.9
26.8
MeCN/H2O (pH 2)¼40:60
d
þ357.5 >99
6a prepared according to Scheme 2.
6a prepared according to Scheme 7.
b
N-Boc prolinamide (18) was safe with respect to enantiomeric
purity. This indicates that such formation of unsaturated di-
peptides could perhaps be applied more generally. The
(a)
Tos
O
N
O
H
N
N
N
N
O
O
H
(S)-1
(R)- and (S)- enantiomers of 22
(S)-22
Tos
O
N
O
H
N
N
ppm (f1) 7.70
7.60
7.50
7.40
7.30
7.20
N
N
O
O
H
(S)-1
(R)-22
(b)
Tos
O
N
single enantiomer of (S)-22
O
H
N
N
N
N
O
O
H
(S)-1
(S)-22
ppm (f1) 7.70
7.60
7.50
7.40
7.30
7.20
Figure 2. (a) Partial and apodized 1H NMR spectrum, in CDCl3 at 23 ꢀC, of (R,S)-22 with (S)-1 as a CSA. Signals of amidic protons for both enantiomers of (R,S)-
22 are visible. (b) Partial and apodized 1H NMR spectrum, in CDCl3 at 23 ꢀC, of (S)-22 with (S)-1 as a CSA. Signal for only one amidic proton of (S)-22 is visible,
meaning that (S)-22 is enantiopure.

J. Wagger et al. / Tetrahedron 64 (2008) 2801e2815
2807
Figure 3. ORTEP plot of (S)-24. Cell packing is distinct for enantiomerically pure compounds. Also Z orientation around exocyclic double bond is visible.
Ellipsoids are plotted at 50% probability.
enantiomeric purity of piperazinedione 24 was also confirmed
1
The X-ray structure of piperazinedione 24 also showed that
the final product was enantiomerically pure, since the cell
packing of molecules in crystal was distinct for the enantio-
merically pure compounds (Fig. 3).
by H NMR spectroscopy using (S)-1-benzyl-6-methylpiper-
azine-2,5-dione, (our own chiral solvating agent (1)).16,30
1
From H NMR spectroscopy, splitting of the signals for the
amidic protons of (R,S)-24 could be seen, while for the (S)-
24 this was not the case (Fig. 2).
Geometrical isomerization around the double bond was de-
termined either by 1H NMR spectroscopy or X-ray diffraction.
J= 15.9 Hz; E; 9
O
O
J= 16.2 Hz; E; 10
C2
H
C2
H
O
R
O
H
C3
N C3 H
HN
J= 12.8 Hz; E
8
R: Me 9; R: Ph 10
Figure 4.

2808
J. Wagger et al. / Tetrahedron 64 (2008) 2801e2815
Figure 5. ORTEP plot of 11 showing Z orientation around exocyclic double bond. Ellipsoids are plotted at 50% probability.
Large coupling constants in propenoates 8e10 between hydro-
gen atoms on position C2 and C3 indicated that the E config-
uration was present (Fig. 4). For vinyl bromide 11, X-ray
diffraction revealed Z orientation (Fig. 5). Z orientation was
also determined in an end product 24 (Fig. 3).
241 MC Polarimeter. Microwave irradiations were performed
on CEM Corporation Discover microwave unit. Mass spectra
were recorded on an AutoSpecQ and QTof-premier spectrome-
ters, IR spectra on a PerkineElmer Spectrum BX FTIR spectro-
photometer. Microanalyses were performed on a PerkineElmer
CHN Analyser 2400. Column chromatography was performed
on silica gel (Fluka, silica gel 60, 0.04e0.06 mm).
4. Conclusion
Analogues of cyclic ProeDTrp were prepared via enami-
none-based synthesis. Cyclodipeptides 6aec were prepared
in the racemic form, with coupling of indoles 3aec with race-
mic enaminone 5. On the other hand, cyclodipeptides 22, 24,
and 25 were prepared in their enantiopure form through cop-
per(I) catalyzed vinyl amidation of N-Boc prolinamide (18)
and vinyl bromides 14e16 as DTrp analogue precursors.
This strategy represents a novel approach toward dipeptides,
where an a,b-unsaturated heteroaromatic amino acid is in
the C-terminal position. Cyclization of acyclic ProeDTrp di-
peptide analogues 19e21, formed by vinyl amidation, was
performed thermally. The enantiomeric purity of final products
24 and 25, as well as intermediates 6a, 19, and 22 was deter-
mined by HPLC and in the case of 22 also with 1H NMR spec-
troscopy, using 1 as a chiral solvating agent. X-ray crystal cell
packing data on 24 also indicated on its optical purity.
5.2. Preparation of (RS,3Z)-3-[(dimethylamino)methylidene]-
hexahydropyrrolo[1,2-a]pyrazine-1,4-dione (5)
For preparation and characterization of this compound see
Ref. 16.
5.3. Preparation of racemic cyclic ProeDTrp analogues
6aec
5.3.1. (RS,Z)-3-[(2-Methyl-1H-indol-3-yl)methylidene]hexa-
hydropyrrolo[1,2-a]pyrazine-1,4-dione (6a)
A mixture of (RS,3Z)-3-[(dimethylamino)methylidene]-
hexahydropyrrolo[1,2-a]pyrazine-1,4-dione (5) (0.157 g,
0.75 mmol) and 2-methylindole (3b) (0.098 g, 0.75 mmol)
was heated under reflux in 2 mL of glacial acetic acid for 3 h.
The solvent was evaporated in vacuo and the product was puri-
fied by column chromatography (ethyl acetate) giving 6a, which
was recrystallized from ethanol. Yield 0.084 g (38%) of white
solid, mp 270e271 ꢀC (from ethanol); [Found: C, 68.93; H,
5.96; N, 14.18. C17H17N3O2 requires C, 69.14; H, 5.80; N,
14.23%]; Rf (ethyl acetate) 0.20; nmax (KBr) 3285, 3256, 1687,
1670, 1626, 1611, 1440, 1398, 1249, 1133, 1100, 957,
744 cmꢁ1; dH (300 MHz, DMSO-d6) 1.80e2.00 (3H, m, Pro),
2.09e2.29 (1H, m, Pro), 2.37 (3H, s, CH3), 3.41e3.53 (1H,
m, Pro), 3.53e3.65 (1H, m, Pro), 4.37e4.49 (1H, m, Pro),
6.85 (1H, s, CH), 6.97e7.11 (2H, m, Ar), 7.28e7.35 (1H, m,
Ar), 7.35e7.42 (1H, m, Ar), 9.21 (1H, s, CONH), 11.34 (1H,
s, NH); MS (EI): m/z 295 (Mþ).
5. Experimental
5.1. General
Melting points were determined on a Kofler micro hot stage.
1H NMR spectra were obtained on a Bruker Avance DPX 300 at
300 MHz for 1H, and 75.5 MHz for 13C nucleus, using DMSO-
d6 and CDCl3 as solvents and TMS as the internal standard.
HPLC analysis were performed on Hewlett Packard 1050 series
Chromatographer, using Chiralcel OD-R F¼0.46ꢂ25 cm col-
umn. Optical rotations were determined on a PerkineElmer

J. Wagger et al. / Tetrahedron 64 (2008) 2801e2815
2809
5.3.2. (RS,Z)-3-[(1H-Indol-3-yl)methylidene]hexahydro-
pyrrolo[1,2-a]pyrazine-1,4-dione (6b)
volatile components were evaporated in vacuo. The dark brown
residue was purified by column chromatography (25% ethyl
acetate/petroleum ether), giving a yellow oil 8. Yield 0.542 g
(76%); Rf (25% ethyl acetate/petroleum ether) 0.26; nmax
(NaCl) 3530, 2930, 1676, 1617, 1499, 1388, 1255, 1158, 1096,
978, 764, 787 cmꢁ1; dH (300 MHz, CDCl3) 1.26 (3H, t, J¼
7.2 Hz, CH3), 2.88 (6H, s, N(CH3)2), 4.13 (2H, q, J¼7.2 Hz,
CH2), 4.52 (1H; d, J¼12.8 Hz, CH), 7.44 (1H, d, J¼12.8 Hz,
CH); dC (75.5 MHz, CDCl3) 14.8, 58.6, 84.2, 152.7, 169.4;
MS (EI): m/z 143 (Mþ); HRMS (EI): Mþ, found 143.0951.
C7H13NO2 requires 143.0946.
To
a
solution of (RS,3Z)-3-[(dimethylamino)methyl-
idene]hexahydropyrrolo[1,2-a]pyzrazine-1,4-dione (5) (0.098 g,
0.75 mmol) in 2 mL of glacial acetic acid, indole (3a) (0.088 g,
0.75 mmol)wasaddedandthemixturewasstirredinaclosedves-
sel mode under microwave irradiation (CEM Discover,
P¼300 W, T¼125 ꢀC) for 45 min. The reaction mixture was
cooled, volatile components were evaporated, and the product
was purified by column chromatography (ethyl acetate) to give ti-
tle compound 6b, which was recrystallized from ethanol. Yield
0.089 g (42%) of yellow solid, mp 276e279 ꢀC (from ethanol);
[Found: C, 68.31; H, 5.48; N, 14.73. C16H15N3O2 requires C,
68.31; H, 5.37; N, 14.94%]; Rf (ethyl acetate) 0.20; nmax (KBr)
3345, 3055, 1673, 1601, 1533, 1444, 1397, 1243, 1133, 935,
764, 752, 710 cmꢁ1; dH (300 MHz, DMSO-d6) 1.75e2.05 (3H,
m, Pro), 2.10e2.30 (1H, m, Pro), 3.40e3.60 (2H, m, Pro),
4.30e4.42 (1H, m, Pro), 6.99 (1H, s, CH), 7.06e7.13 (1H, m,
Ar), 7.13e7.20 (1H, m, Ar), 7.40e7.45 (1H, m, Ar), 7.62e7.68
(1H, m, Ar), 7.92 (1H, d, J¼1.9 Hz, Ar), 9.56 (1H, s, CONH),
11.62 (1H, s, NH); dC (75.5 MHz, DMSO-d6) 21.5, 27.9, 44.9,
58.1, 107.9, 108.0, 111.7, 118.0, 119.7, 121.9, 124.1, 126.3,
126.8, 135.5, 159.1, 166.8; MS (EI): m/z 281 (Mþ); HRMS
(EI): Mþ, found 281.1170. C16H15N3O2 requires 281.1164.
5.4.2. General procedure for coupling of indole 3b and 3c
with propenoate 8
(E)-Ethyl 3-(dimethylamino)propenoate (8) was dissolved
in glacial acetic acid, one of the indole derivative 3b or 3c
was added and the reaction mixture was heated at 95 ꢀC.
5.4.2.1.
(E)-Ethyl
3-(2-methyl-1H-indol-3-yl)propenoate
(9). (E)-Ethyl 3-(dimethylamino)propenoate (8) (2.864 g,
20 mmol), 2-methylindole (3b) (2.624 g, 20 mmol), and glacial
acetic acid (13 mL) were reacted according to the general proce-
dure for 1.5 h. After cooling the reaction mixture to room tem-
perature, the product 9 precipitated from the reaction mixture.
This was collected by filtration, washed with water/ethanol¼1:1
solution, and dried in a desiccator (over NaOH). Yield 3.410 g
(74%) of pale white solid, mp 131 ꢀC (solid becomes black),
190 ꢀC (black solid melts); [Found: C, 73.36; H, 6.75; N, 6.07.
C14H15NO2 requires C, 73.34; H, 6.59; N, 6.11%]; nmax (KBr)
3292, 2980, 2897, 1688, 1607, 1575, 1454, 1363, 1323, 1279,
1175, 1149, 1027, 967, 741, 726 cmꢁ1; dH (300 MHz, DMSO-
d6) 1.26 (3H, t, J¼7.2 Hz, CH3), 3.31 (3H, s, CH3), 4.17 (2H,
q, J¼7.2 Hz, CH2), 6.26 (1H, d, J¼15.8 Hz, CH), 7.07e7.14
(2H, m, Ar), 7.33e7.39 (1H, m, Ar), 7.74e7.79 (1H, m, Ar),
7.85 (1H, d, 15.8 Hz, CH), 11.70 (1H, s, NH); dH (300 MHz,
CDCl3) 1.36 (3H, t, J¼7.2 Hz, CH3), 2.50 (3H, s, CH3), 4.29
(2H, q, J¼7.2 Hz, CH2), 6.43 (1H, d, J¼15.9 Hz, CH), 7.19
(2H, m, Ar), 7.30 (1H, m, Ar), 7.85 (1H, m, Ar), 7.95 (1H, d,
J¼15.9 Hz, CH), 8.49 (1H, s, NH); dC (75.5 MHz, CDCl3)
12.3, 14.5, 60.1, 109.6, 110.9, 112.1, 119.9, 121.4, 122.4, 126.4,
135.7, 137.5, 140.0, 168.8; MS (EI): m/z 229 (Mþ); HRMS (EI):
Mþ, found 229.1110. C14H15NO2 requires 229.1103.
5.3.3. (RS,Z)-3-[(2-Phenyl-1H-indol-3-yl)methylidene]hexa-
hydropyrrolo[1,2-a]pyrazine-1,4-dione (6c)
A
mixture
of
(RS,3Z)-3-[(dimethylamino)methyl-
idene]hexahydropyrrolo[1,2-a]pyrazine-1,4-dione (5) (0.157 g,
0.75 mmol), 2-phenylindole (3c) (0.098 g, 0.75 mmol), and
three drops of concentrated hydrochloric acid was heated under
reflux in 4 mL of 2-propanol for 3.5 h. The reaction mixture was
cooled, the solvent evaporated in vacuo, and the residue purified
by column chromatography (ethyl acetate), giving title com-
pound 6c, which was then recrystallized from ethanol/water.
Yield 0.092 g (34%) of pale yellow solid, mp 229e231 ꢀC
(from ethanol/water); [Found: C, 73.68; H, 5.44; N, 11.62.
C22H19N3O2 requires C, 73.93; H, 5.36; N, 11.76%]; Rf (ethyl
acetate) 0.39; nmax (KBr) 3341; 3299, 1695, 1663, 1622, 1449,
1432, 1379, 1310, 1229, 1114, 745, 699 cmꢁ1; dH (300 MHz,
DMSO-d6) 1.80e2.00 (3H, m, Pro), 2.15e2.30 (1H, m, Pro),
3.40e3.52 (1H, m, Pro), 3.55e3.65 (1H, m, Pro), 4.40e4.47
(1H, m, Pro), 6.86 (1H, s, CH), 7.05e7.12 (1H, m, Ar), 7.16e
7.30 (1H, m, Ar), 7.37e7.58 (5H, m, Ph), 7.64e7.68 (2H, m,
Ar), 9.27 (1H, s, CONH), 11.77 (1H, s, NH).
5.4.2.2.
(E)-Ethyl
3-(2-phenyl-1H-indol-3-yl)propenoate
(10). (E)-Ethyl 3-(dimethylamino)propenoate (8) (1.718 g,
12 mmol), 2-phenylindole (3c) (2.319 g, 12 mmol), and glacial
acetic acid (10 mL) were reacted according to the general proce-
dure for 1.75 h. The volatile components were evaporated and
yellow oily residue slowly crystallized. The solid was collected
and recrystallized from methanol giving pure title product 10.
Yield 2.132 g (62%), mp 152e154 ꢀC (from methanol); [Found:
C, 78.09; H, 5.89; N, 4.65. C19H17NO2 requires C, 78.33; H,
5.88; N, 4.81%]; nmax (KBr) 3295, 3054, 2977, 1667, 1619,
1455, 1391, 1365, 1233, 1052, 981, 841, 775, 741 cmꢁ1; dH
(300 MHz, CDCl3) 1.33 (3H, t, J¼7.2 Hz, CH3), 4.25 (2H, q,
J¼7.2 Hz, CH2), 6.59 (1H, d, J¼16.2 Hz, CH), 7.25e7.35
(2H, m, Ar), 7.40e7.60 (6H, m, Ar), 7.95e8.04 (1H, m, Ar),
5.4. Preparation of enantiomerically pure cyclic ProeDTrp
analogues
5.4.1. (E)-Ethyl 3-(dimethylamino)propenoate (8)
To ethyl acetate (7) (2 mL, 20 mmol) in a Pyrex vial, dime-
thylformamide (3 mL) and bis(dimethylamino)-tert-butoxyme-
thane (Bredereck’s reagent, 1.044 mL, 5 mmol) were added.
The vial was flushed with argon, closed with a rubber septum,
and irradiated with microwave in a closed vessel mode (CEM
Discover, P¼300 W, T¼165 ꢀC) for 15 min. The cooled reac-
tion mixture was transferred into round bottom flask and the

2810
J. Wagger et al. / Tetrahedron 64 (2008) 2801e2815
8.00 (1H, d, 16.2 Hz, CH); 8.47 (1H, br s, NH); dC (75.5 MHz,
CDCl3) 14.4, 60.1, 109.8, 111.5, 114.1, 120.8, 121.7, 123.4,
126.5, 128.9, 129.0, 129.1, 131.3, 136.4, 139.7, 142.4, 168.6;
MS (EI): m/z 291 (Mþ); HRMS (EI): Mþ, found 291.1268.
C19H17NO2 requires 291.1259.
(Mþ); HRMS (EI): Mþ, found 307.0219. C14H14BrNO2 requires
307.0208.
5.4.4.2. (Z)-Ethyl 2-bromo-3-(2-phenyl-1H-indol-3-yl)prope-
noate (12). (E)-Ethyl 3-(2-phenyl-1H-indol-3-yl)propenoate
(10) (1.681 g, 5.8 mmol), N,N-dimethylformamide (26 mL),
bromine (0.300 mL, 5.8 mmol), ice cold water (250 mL), and
potassium disulfite (0.264 g, 1.1 mmol) were reacted according
to the general procedure. (Z)-Ethyl 2-bromo-3-(2-methyl-1H-
indol-3-yl)propenoate (11) precipitated as a white solid and
was collected by filtration. Yield 1.966 g (92%). For further pu-
rification, propenoate 12 was recrystallized from methanol.
Yield 1.432 g (67%) as a yellow solid, mp 137e140 ꢀC (decom-
position); [Found: C, 61.67; H, 4.50; N, 3.64. C19H16BrNO2 re-
quires C, 61.64; H, 4.36; N, 3.78%]; nmax (KBr) 3305, 1682,
1607, 1452, 1390, 1260, 1235, 1075, 1048, 914, 872,
743 cmꢁ1; dH (300 MHz, CDCl3) 1.37 (3H, t, J¼7.2 Hz,
CH3), 4.35 (2H, q, J¼7.2 Hz, CH2), 7.18e7.26 (1H, m, Ar),
7.26e7.32 (1H, m, Ar), 7.32e7.37 (1H, m, Ar), 7.39e7.47
(2H, m, Ar), 7.48e7.53 (1H, m, Ar), 7.53e7.58 (1H, m, Ar),
7.78e7.84 (1H, m, Ar), 8.49 (1H, s, CH), 8.83 (1H, s, NH);
dC (75.5 MHz, CDCl3) 14.2, 62.5, 108.9, 111.3, 113.1, 120.6,
122.4, 123.1, 126.1, 128.2, 128.7, 129.0, 131.9, 136.1, 137.6,
139.1, 163.6; MS (EI): m/z 369 (Mþ); HRMS (EI): Mþ, found
369.0376. C19H16BrNO2 requires 369.0364.
5.4.3. (Z)-Ethyl 2-bromo-3-(5 or 6 bromo-2-methyl-1H-
indol-3-yl)propenoate (13)
To (E)-ethyl 3-(2-methy-1H-indol-3-yl)propenoate (9)
(1.582 g, 6.90 mmol) dissolved in 75 mL of chloroform and
cooled to 0 ꢀC, bromine (0.461 mL, 8.97 mmol) was added
dropwise. The reaction mixture was stirred for 25 min at 0 ꢀC
and then the volatile components were evaporated in vacuo,
and the residue was purified by column chromatography (25%
ethyl acetate/petroleum ether). On mobile phase evaporation
the product 13, while still wet, was yellow, butwhen dry it turned
to violet. Yield 0.901 g (34%) of violet solid, mp 97 ꢀC (decom-
position, 13 is thermolabile); Rf (25% ethyl acetate/petroleum
ether) 0.18; nmax (KBr) 3298, 2976, 1690, 1606, 1567, 1450,
1365, 1235, 1062, 897, 799, 752 cmꢁ1; d (300 MHz, DMSO-
d6) 1.31 (3H, t, J¼7.2 Hz, CH3), 2.43 (3H, s, CH3), 4.28 (2H,
q, J¼7.2 Hz, CH2), 7.20 (1H, dd, J1¼8.3 Hz, J2¼1.9 Hz, Ar),
7.52 (1H, d, J¼1.9 Hz, Ar), 7.58 (1H, d, J¼8.3 Hz, Ar), 8.43
(1H, s, CH), 11.86 (1H, s, NH); MS (EI): m/z 387 (Mþ);
HRMS (EI): Mþ, found 384.9330. C14H13Br2NO2 requires
384.9313.
5.4.5. (Z)-Ethyl 2-bromo-3-(2-methyl-1-tosyl-1H-indol-3-
yl)propenoate (14)
5.4.4. General procedure for preparation of vinyl bromides
11 and 12
To a dry 100 mL round bottom flask with magnetic stirrer,
(Z)-ethyl 2-bromo-3-(2-methyl-1H-indol-3-yl)propenoate (11)
(1.54 g, 5 mmol) was added and the flask was stoppered with
a rubber septum. Through the septum, 18 mL of anhydrous tet-
rahydrofuran was added and the solution was cooled to ꢁ78 ꢀC.
Lithium diisopropylamide (3.25 mL of 2 M in tetrahydrofuran
solution, 6.5 mmol) was added dropwise. The reaction mixture
was stirred at ꢁ78 ꢀC for 45 min, and then tosylchloride
(1.144 g, 6 mmol) dissolved in 6 mL of anhydrous tetrahydrofu-
ran was added rapidly. Stirring at ꢁ78 ꢀC continued for 1 h, af-
terward the reaction mixture was left to stir at ambient
temperature for 20 h, resulting in a yellow suspension. The reac-
tion was quenched with 30 mL of 0.3 M aqueous solution of so-
dium hydrogencarbonate. The tetrahydrofuran was evaporated
in vacuo and the water phase was extracted with 3ꢂ60 mL of di-
ethyl ether. The organic phase was then washed with 20 mL of
0.1 M aqueous solution of sodium thiosulfate, 2ꢂ20 mL of wa-
ter, 2ꢂ20 mL of brine, and dried with sodium sulfate. The vol-
atile components were evaporated in vacuo and the yellow
oily residue was purified by column chromatography (25% ethyl
acetate/petroleum ether), and the oily product was recrystallized
from methanol giving title product 14 as a colorless solid. Yield
0.915 g (40%), mp 113e115 ꢀC (from methanol); [Found: C,
54.75; H, 4.50; N, 2.99. C20H21BrNO4S requires: C, 54.55; H,
4.36; N, 3.03%]; Rf (25% ethyl acetate/petroleum ether) 0.40;
nmax (KBr) 2928, 1725, 1622, 1453, 1377, 1243, 1177, 1090,
1043, 917, 812, 747 cmꢁ1; dH (300 MHz, DMSO-d6): 1.31
(3H, t, J¼7.2 Hz, CH3), 2.33 (3H, s, CH3), 2.55 (3H, s, CH3),
4.30 (2H, q, J¼7.2 Hz, CH2), 7.27 (1H, ddd, J1¼7.5 Hz,
One of the propenoate 9 or 10 was dissolved in dimethyl-
formamide, cooled to 0 ꢀC, and bromine was added dropwise.
The reaction mixture was left stirring at 0 ꢀC for 0.5 h. After
that it was poured into ice cold water in which ammonia
(flushed for 1.5 min with gaseous ammonia), and potassium
disulfite were dissolved. The product 11 or 12 precipitated
as a solid and was collected by filtration.
5.4.4.1. (Z)-Ethyl 2-bromo-3-(2-methyl-1H-indol-3-yl)prope-
noate (11). (E)-Ethyl 3-(2-methy-1H-indol-3-yl)propenoate
(9) (2.293 g, 10 mmol), N,N-dimethylformamide (45 mL), bro-
mine (0.581 mL, 10.1 mmol), ice cold water (350 mL), and po-
tassium disulfite (0.5 g, 2.2 mmol) were reacted according to the
general procedure. (Z)-Ethyl 2-bromo-3-(2-methyl-1H-indol-
3-yl)propenoate (11) precipitated as a white solid and was
collected by filtration. Yield 2.949 g (96%). For further purifica-
tion, propenoate 11 was recrystallized from methanol. Total
yield 1.911 g (62%) of colorless solid, mp 122 ꢀC (decomposi-
tion); [Found: C, 54.34; H, 4.66; N, 4.33. C14H14BrNO2 re-
quires: C, 54.56; H, 4.58; N, 4.55%]; nmax (KBr) 3289, 2978,
1682, 1606, 1460, 1391, 1323, 1245, 1054, 901, 872,
741 cmꢁ1; dH (300 MHz, DMSO-d6) 1.31 (3H, t, J¼7.2 Hz,
CH3), 2.45 (3H, s, CH3), 4.28 (2H, q, J¼7.2 Hz, CH2), 7.02e
7.15 (2H, m, Ar), 7.32e7.37 (1H, m, Ar), 7.61e7.68 (1H, m,
Ar), 8.47 (1H, s, CH), 11.73 (1H, s, NH); dC (75.5 MHz,
DMSO-d6) 13.1, 14.0, 61.9, 107.0, 107.8, 111.0, 119.5, 120.7,
121.2, 125.3, 135.6, 136.8, 139.6, 162.8; MS (EI): m/z 307

J. Wagger et al. / Tetrahedron 64 (2008) 2801e2815
2811
J2¼7.5 Hz, J3¼1.2 Hz, Ar), 7.30e7.40 (4H, m, 2H-Arþ2H-
Tos), 7.74e7.81 (2H, m, Tos), 8.07 (1H, d, J¼8.1 Hz, Ar), 8.28
(1H, s, CH); dC (75.5 MHz, CDCl3) 13.9, 14.8, 20.9, 62.5, 114.0,
116.3, 118.5, 119.9, 123.6, 124.5, 126.2, 127.0, 130.2, 134.49,
134.52, 135.1, 135.3, 145.5, 161.7; MS (EI): m/z 463 (Mþ);
HRMS (EI): Mþ, found 461.0305. C20H21BrNO4S requires
461.0296.
5.4.7. (S)-N-Boc proline (17)
(S)-Proline (2.303 g, 20 mmol) was suspended in 40 mL of
dichloromethane. Triethylamine (3.733 mL, 26 mmol) was
added, followed by di-tert-butyl dicarbonate (6.303 g,
28.9 mmol) solvated in 2 mL of dichloromethane. The mixture
was stirred at room temperature for 2.5 h. Afterward, the reac-
tion was quenched with 10 mL of saturated aqueous citric acid
solution, washed with brine (2ꢂ15 mL) and water (15 mL).
The organic layer was dried with sodium sulfate and evapo-
rated in vacuo. The yellow syrup-like residue was dissolved
in hot ethyl acetate (5 mL) and 50 mL of n-hexane was added.
Upon cooling at ꢁ25 ꢀC, (S)-N-Boc proline crystallized, and
the solid was collected by filtration.26a Yield 3.727 g (87%)
of white solid, mp 133e134 ꢀC (from ethyl acetate/n-hexane),
lit.26a mp 135e137 ꢀC; nmax (KBr) 2976, 2718, 1736, 1637,
1430, 1367, 1217, 1131, 1069, 978, 899, 852, 775 cmꢁ1; dH
(300 MHz, CDCl3) 1.44 (3H, br s, C(CH3)3), 1.49 (6H, br s,
C(CH3)3), 1.80e2.15 (3H, m, Pro), 2.18e2.51 (1H, m, Pro),
3.25e3.62 (2H, m, Pro), 4.20e4.41 (1H, m, Pro).
5.4.6. General procedure for preparation of N-Boc
protected vinyl bromides 15 and 16
Di-tert-butyl dicarbonate was dissolved in 30 mL of anhy-
drous tetrahydrofuran, one of the vinyl bromide 11 or 12
and N,N-dimethylaminopyridine (DMAP) were added and
the reaction mixture was stirred at room temperature for addi-
tional 0.5 h. The solvent was removed in vacuo, residue dis-
solved in 50 mL of dichloromethane, and washed with
3ꢂ100 mL of 1.5 M aqueous hydrochloric acid. The organic
phase was dried with sodium sulfate, evaporated in vacuo,
and an oily residue purified by column chromatography.
5.4.6.1. (Z)-tert-Butyl 3-(2-bromo-3-ethoxy-3-oxoprop-1-enyl)-
2-methyl-1H-indole-1-carboxylate (15). Di-tert-butyl dicar-
bonate (1.753 g, 8 mmol), (Z)-ethyl 2-bromo-3-(2-methyl-1H-
indol-3-yl)propenoate (11) (1.650 g, 5.4 mmol), and DMAP
(65.4 mg, 0.54 mmol) were reacted according to the general pro-
cedure. Purified by column chromatography (90% chloroform/
methanol). Yield 2.135 g (98%) of colorless oil that crystallized
intowhite solid, mp102e105 ꢀC; Rf (90%chloroform/methanol)
0.33; nmax (KBr) 2979, 2932, 1805, 1731, 1622, 1475, 1458,
1369, 1323, 1245, 1143, 1043, 841, 746 cmꢁ1; dH (300 MHz,
CDCl3) 1.41 (3H, t, J¼7.2 Hz, CH3), 1.70 (9H, s, C(CH)3),
2.57 (3H, s, CH3), 4.38 (2H, q, J¼7.2 Hz, CH2), 7.18e7.33
(2H, m, Ar), 7.40e7.48 (1H, m, Ar), 8.08e8.15 (1H, m, Ar),
8.34 (1H, s, CH); dC (75.5 MHz, CDCl3) 14.2, 16.5, 28.2, 62.7,
84.3, 115.0, 115.5, 117.4, 119.5, 122.7, 124.0, 127.2, 135.6,
135.8, 136.6, 150.3, 162.8; MS (EI): m/z 407 (Mþ); HRMS
(EI): Mþ, found 407.0746. C19H22BrNO4 requires 407.0732.
5.4.8. (S)-N-Boc prolinamide (18)
(S)-N-Boc proline (17) (3.702 g, 17.2 mmol) was dissolved
in 85 mL of dioxane. Pyridine (0.860 mL), di-tert-butyl dicar-
bonate (4.875 g, 22.3 mmol), and ammonium carbonate
(2.144 g; 22.3 mmol) were added. The reaction mixture was
stirred at room temperature over night (19 h). The volatile com-
ponents were evaporated in vacuo and 85 mL of ethyl acetate
was added. The solution was washed with 81 mL of 20% aque-
ous citric acid solution and 85 mL of brine. The water phases
were extracted with 3ꢂ100 mL of ethyl acetate, combined,
dried with sodium sulfate, and evaporated invacuo. The oily res-
idue was purified by column chromatography (95% chloroform/
methanol), giving clear oily product, which was recrystallized
from hot diethyl ether. White solid was collected by filtra-
tion.26b,c Yield 3.016 g (82%) of white solid, mp 108 ꢀC (from
diethyl ether), lit.26d mp 104e106 ꢀC; Rf [95% chloroform/
methanol] 0.29; [a]D25 ꢁ42.7 (c 1, EtOH), lit.26d [a]2D6 ꢁ43.4 (c
1, EtOH); nmax (KBr): 3385,3204, 2976, 1676, 1412, 1362,
1174, 1121, 927, 780 cmꢁ1; dH (300 MHz, CDCl3) 1.44 (9H,
s, C(CH3)3), 1.75e2.45 (4H, m, Pro), 3.44 (2H, br s, Pro),
4.27 (1H, br s, Pro), 5.46 (2H, br s, CONH2, trans), 6.00 (1H,
br s, 1H of CONH2, cis), 6.84 (1H, br s, 1H of CONH2, cis);
trans/cis¼1:1.
5.4.6.2. (Z)-tert-Butyl 3-(2-bromo-3-ethoxy-3-oxoprop-1-enyl)-
2-phenyl-1H-indole-1-carboxylate (16). Di-tert-butyl dicar-
bonate (1.689 g, 7.74 mmol), (Z)-ethyl 2-bromo-3-(2-phenyl-
1H-indol-3-yl)propenoate (12) (1.432 g, 3.9 mmol), and
DMAP (94.6 mg, 0.77 mmol) were reacted according to the
general procedure. Purified by column chromatography (4.8%
ethyl acetate/petroleum ether) gave 16. Yield 1.635 g (90%) of
yellow oil that crystallized over night, at þ4 ꢀC, into yellow
solid, mp 115e118 ꢀC; Rf (4.8% ethyl acetate/petroleum ether)
0.30; nmax (KBr) 2978, 2937, 1736, 1721, 1615, 1475, 1455,
1354, 1331, 1224, 1154, 1083, 1044, 878, 849, 748 cmꢁ1; dH
(300 MHz, CDCl3) 1.27 (9H, s, C(CH)3), 1.32 (3H, t,
J¼7.2 Hz, CH3), 4.29 (2H, q, J¼7.2 Hz, CH2), 7.28e7.50
(7H, m, 5H-Phþ2H-Ar), 7.62e7.70 (1H, m, Ar), 7.98 (1H, s,
CH), 8.26 (1H, br d, J¼8.1 Hz, Ar); dC (75.5 MHz, CDCl3)
14.1, 27.4, 62.6, 84.0, 115.3, 116.2, 116.7, 121.9, 122.8, 124.9,
126.0, 127.9, 128.3, 129.7, 133.1, 136.6, 136.9, 139.6, 149.7,
162.8; MS (EI): m/z 471 (Mþ); HRMS (EI): Mþ, found
469.0900. C24H24BrNO4 requires 469.0889.
5.4.9. General procedure for copper catalyzed coupling
of N-protected vinyl bromides 14e16 with N-Boc
prolinamide (18)
Cuprous iodide and finely powdered potassium carbonate
were oven dried (100 ꢀC) in vacuum for 2 h and were loaded
into a Schlenk tube. One of the N-protected vinyl bromide 14,
15 or 16 and (S)-N-Boc prolinamide (18) were dried in desicca-
tor (over NaOH) over night and also loaded into a Schlenk tube,
which was stoppered with a rubber septum. Air was evacuated
under vacuum and the tubewas backfilled with argon. This cycle
was repeated twice. Then through the tube septum N,N0-dime-
thylethylenediamine and anhydrous toluene were added. The
Schlenk tube was then heated in an oil bath at 100 ꢀC. After

2812
J. Wagger et al. / Tetrahedron 64 (2008) 2801e2815
that heating was turned off and the reaction mixture was stirred
continuously. The reaction mixture was then eluted through
a 4 cm plug of silica gel with 40 mL of ethyl acetate. Volatile
components were evaporated in vacuo and brown residue puri-
fied by column chromatography.
acetate/petroleum ether) 0.27; [a]2D2 ꢁ85.6 (c 0.15, CHCl3); nmax
(KBr) 3288, 2978, 1732, 1695, 1477, 1458, 1396, 1322, 1258,
1158, 1118, 1028, 842, 770, 748 cmꢁ1; dH (300 MHz, CDCl3)
1.36 (9H, s, C(CH)3), 1.37 (3H, t, J¼7.2 Hz, CH3), 1.40e1.65
(3H, m, Pro), 1.69 (9H, s, C(CH)3), 2.10e2.30 (1H, m, Pro),
2.58 (3H, s, CH3), 3.10e3.25 (2H, m, Pro), 4.20e4.45 (3H,
m, CH2þ1H-Pro), 7.10e7.20 (1H, m, Ar), 7.20e7.25 (1H, m,
Ar), 7.30 (1H, d, J¼7.5 Hz, Ar), 7.37 (1H, s, CH), 8.09 (1H, d,
J¼7.8 Hz, Ar), 8.73 (1H, br s, CONH); dC (75.5 MHz, CDCl3)
14.1, 15.3, 28.1, 28.2, 29.0, 29.2, 46.9, 59.9, 61.5, 80.5, 84.1,
114.2, 115.5, 119.1, 122.1, 122.6, 123.6, 126.4, 127.2, 135.9,
137.4, 150.3, 164.6, 169.9; MS (EI): m/z¼541 (Mþ); HRMS
(EI): Mþ, found 541.2788. C29H39N3O7 requires 541.2777.
5.4.9.1. (S)-tert-Butyl 2-[3-ethoxy-1-(2-methyl-1-tosyl-1H-in-
dol-3-yl)-3-oxoprop-1-en-2-ylcarbamoyl]-pyrrolidine-1-carb-
oxylate (19). Cuprous iodide (19.8 mg, 0.1 mmol), potassium
carbonate (0.257 g, 2 mmol), (Z)-ethyl 2-bromo-3-(2-methyl-
1-tosyl-1H-indol-3-yl)propenoate (14) (0.462 g, 1.0 mmol),
(S)-N-Boc prolinamide (18) (0.257 g, 1.2 mmol), N,N0-dime-
thylethylenediamine (21.5 mL, 0.2 mmol), and anhydrous tolu-
ene (2 mL) were reacted according to the general procedure for
12 h at 100 ꢀC and afterward for additional 11 h. Purified by col-
umn chromatography (25% ethyl acetate/petroleum ether). The
colorless oily product was then dissolved in dichloromethane, n-
heptane was added, and solvents were rapidly evaporated in va-
cuo. The product 19 was formed as a white foam. Yield 0.475 g
(80%), mp 66e71 ꢀC (from dichloromethane/n-heptane); Rf
(25% ethyl acetate/petroleum ether) 0.14; [a]2D7 ꢁ116.5 (c 0.5,
CHCl3), ee>99%; nmax (KBr) 3369, 2978, 1698, 1494, 1476,
1454, 1396, 1366, 1260, 1176, 1121, 1080, 1020, 990,
748 cmꢁ1; dH (300 MHz, CDCl3) 1.35 (3H, t, J¼7.2 Hz,
CH3), 1.41 (9H, s, C(CH3)3), 1.46e1.77 (3H, m, Pro), 1.85e
2.15 (1H, m, Pro), 2.33 (3H, s, CH3), 2.58 (3H, s, CH3), 3.00e
3.35 (2H, m, Pro), 4.24 (1H, br s, Pro), 4.32 (2H, q, J¼7.2 Hz,
CH2), 7.10e7.35 (6H, m, CHþ2H-Tosþ3H-Ar), 7.60e7.70
(2H, m, 2H-Tos), 8.10e8.18 (1H, m, Ar), 8.87 (1H, br s,
CONH); dC (75.5 MHz, CDCl3) 14.5, 14.7, 21.9, 23.1, 28.7,
32.3, 47.3, 60.2, 62.1, 81.1, 115.0, 116.6, 120.1, 121.4, 123.7,
124.5, 126.8, 127.3, 127.9, 130.3, 136.6, 136.8, 137.0, 145.1,
156.4, 164.8, 169.7; MS (EI): m/z¼595 (Mþ); HRMS (EI):
Mþ, found 595.2366. C31H37N3O7S requires 595.2352.
In the same manner (R,S)-19 was prepared and used for
HPLC analysis.
5.4.9.3. (S)-tert-Butyl 3-[2-(1-(tert-butoxycarbonyl)pyrroli-
dine-2-carboxamido)-3-ethoxy-3-oxoprop-1-enyl]-2-phenyl-
1H-indole-1-carboxylate (21). Cuprous iodide (19.8 mg,
0.1 mmol), potassium carbonate (0.287 g, 2 mmol), (Z)-tert-bu-
tyl 3-(2-bromo-3-ethoxy-3-oxoprop-1-enyl)-2-phenyl-1H-
indole-1-carboxylate (16) (0.468 g, 1.0 mmol), (S)-N-Boc
prolinamide (18) (0.257 g, 1.2 mmol), N,N0-dimethylethylene-
diamine (22 mL, 0.2 mmol), and anhydrous toluene (2 mL)
were reacted according to the general procedure for 13 h at
100 ꢀC and afterward for additional 11 h. Purified by column
chromatography (25% ethyl acetate/petroleum ether). The
colorless oily product was then dissolved in dichloromethane,
n-heptane was added, and solvents were rapidly evaporated in
vacuo. The product 21 was formed as a yellow foam. Yield
0.389 g (65%), mp 65e68 ꢀC (from dichloromethane/n-hep-
tane); Rf (25% ethyl acetate/petroleum ether) 0.25; [a]2D2 ꢁ108.5
(c 0.18, CHCl3); nmax (KBr): 3382, 2979, 1732, 1699, 1477,
1455, 1396, 1368, 1227, 1153, 1076, 1016, 755 cmꢁ1; dH
(300 MHz, CDCl3) 1.26 (9H, s, C(CH)3), 1.27 (3H, t, J¼7.2 Hz,
CH3), 1.41 (9H, s, C(CH)3), 1.42e1.58 (2H, m, Pro), 1.58e1.72
(1H, m, Pro), 2.08e2.21 (1H, m, Pro), 3.08e3,28 (2H, m, Pro),
4.15e4.38 (3H, m, CH2þ1H-Pro), 7.03 (1H, s, CH), 7.21 (1H,
br t, J¼7.5 Hz, Ar), 7.28e7.35 (1H, m, Ar), 7.37e7.45 (6H, m,
5H-Phþ1H-Ar), 8.25 (1H, d, J¼8.4 Hz, Ar), 9.01 (1H, br s,
CONH); dC (75.5 MHz, CDCl3) 14.2, 23.8, 27.4, 28.2, 47.0,
60.3, 61.4, 72.2, 80.6, 83.7, 115.4, 116.4, 120.4, 122.7, 123.4,
124.5, 125.5, 126.6, 127.7, 128.1, 130.2, 133.4, 136.9, 139.5,
149.8, 164.6, 169.6; MS (EI): m/z¼603 (Mþ); HRMS (EI): Mþ,
found 603.2959. C34H41N3O7 requires: 603.2945.
HPLC analysis using Chiralcel OD-R F¼0.46ꢂ25 cm col-
umn and water (pH¼4, HCOOH)/acetonitrile¼60:40 as mobile
phase. For (R,S)-19 (flow¼1.5 mL/min, l¼254 nm); tR
(R)¼14.7 min, tR (S)¼15.4 min and for (S)-19 (flow¼1.5 mL/
min, l¼254 nm); tR (S)¼15.3 min.
5.4.9.2. (S)-tert-Butyl 3-[2-(1-(tert-butoxycarbonyl)pyrroli-
dine-2-carboxamido)-3-ethoxy-3-oxoprop-1-enyl]-2-methyl-
1H-indole-1-carboxylate (20). Cuprous iodide (19.8 mg,
0.1 mmol), potassium carbonate (0.287 g, 2 mmol), (Z)-tert-bu-
tyl 3-(2-bromo-3-ethoxy-3-oxoprop-1-enyl)-2-methyl-1H-indole-
1-carboxylate (15) (0.408 g, 1.0 mmol), (S)-N-Boc prolinamide
18 (0.297 g, 1.4 mmol), N,N0-dimethylethylenediamine
(21.5 mL, 0.2 mmol), and anhydrous toluene (1.8 mL) were re-
acted according to the general procedure for 12.5 h at 100 ꢀC
and afterward for additional 12 h. Purified by column chroma-
tography (25% ethyl acetate/petroleum ether). The colorless
oily product was then dissolved in dichloromethane, n-heptane
was added, and solvents were rapidly evaporated in vacuo. The
product 20 was formed as a white foam. Yield 0.421 g (78%),
mp 60e63 ꢀC (from dichloromethane/n-heptane); Rf (25% ethyl
5.4.10. (S,Z)-3-[(2-Methyl-1-tosyl-1H-indol-3-yl)methyl-
idene]hexahydropyrrolo[1,2-a]pyrazine-1,4-dione (22)
(S)-tert-Butyl 2-[3-ethoxy-1-(2-methyl-1-tosyl-1H-indol-3-
yl]-3-oxoprop-1-en-2-ylcarbamoyl)pyrrolidine-1-carboxylate
(19) (0.882 g, 1.48 mmol) was dissolved in 120 mL dichloro-
methane, cooled to 0 ꢀC, and 15 mL of 2 M hydrochloric acid
in diethyl ether was added. The reaction mixture was then left
to stir at room temperature for 20 h. The volatile components
were evaporated in vacuo and to the remaining yellow oily resi
due, 120 mL of dichloromethane and triethylamine (1.1 mL,
7.4 mmol) were added. The reaction mixture was stirred under
reflux for 3 h. The volatile components were then evaporated
in vacuo thoroughly and the flask was backfilled with another

J. Wagger et al. / Tetrahedron 64 (2008) 2801e2815
2813
portion of dichloromethane (120 mL) and triethylamine
(1.1 mL, 7.4 mmol). The reaction mixture was again stirred un-
der reflux for 40 min, volatile components were evaporated in
vacuo, and the residue purified by column chromatography
(ethyl acetate), giving 22 as a white solid. Yield 0.472 g
(71%), mp 125e127 ꢀC (from 2-propanol); [Found: C, 64.28;
H, 5.46; N, 9.16. C24H23N3O4S requires C, 64.13; H, 5.16; N,
9.35%]; Rf (ethyl acetate) 0.26; [a]2D0 þ42.3 (c 0.3, CHCl3),
ee>99%; nmax (KBr) 3463, 3188, 2957, 1693, 1636, 1454,
1374, 1242, 1176, 1089, 996, 812, 763, 746 cmꢁ1; dH
(300 MHz, CDCl3) 1.85e2.20 (3H, m, Pro), 2.37 (3H, s,
CH3), 2.40e2.50 (1H, m, Pro), 2.56 (3H, s, CH3), 3.58e3.67
(1H, m, Pro), 3.78e3.87 (1H, m, Pro), 4.22e4.32 (1H, m,
Pro), 6.89 (1H, s, CH), 7.21 (1H, s, CONH), 7.22e7.38 (5H,
m, 3H-Arþ2H-Tos), 7.68e7.76 (2H, m, 2H-Tos), 8.21e8.27
(1H, m, Ar); MS (EI): m/z¼449 (Mþ); HRMS (EI): Mþ, found
449.1421. C24H23N3O4S requires 449.1409.
of saturated aqueous sodium hydrogencarbonate and with
20 mL of brine. The volatiles were evaporated in vacuo and res-
idue was purified by column chromatography (ethyl acetate).
Yield 11 mg (7%) of white solid; Rf (ethyl acetate) 0.16.
Method A as well as method B proved to be unsatisfactory
in retaining absolute configuration in (S)-proline residue. Both
HPLC analyses and optical rotation showed complete racemi-
zation, thus giving racemic (S,Z)-3-[(2-methyl-1H-indol-3-yl)-
methylidene]hexahydropyrrolo[1,2-a]pyrazine-1,4-dione (6a).
5.4.12. (S,Z)-3-[(2-Methyl-1H-indol-3-yl)methylidene]-
hexahydropyrrolo[1,2-a]pyrazine-1,4-dione (24)
First the (S)-tert-butyl 3-[2-(1-(tert-butoxycarbonyl)pyrroli-
dine-2-carboxamido)-3-ethoxy-3-oxoprop-1-enyl]-2-methyl-
1H-indole-1-carboxylate (20) was deprotected with trifluoro-
acetic acid in dichloromethane and then cyclized into
(S,Z)-3-[(2-methyl-1H-indol-3-yl)methylidene]hexahydropyr-
rolo[1,2-a]pyrazine-1,4-dione (24) in two different manners.
In the same manner (R,S)-22 was prepared and used for
HPLC analysis.
HPLC analysis of enantiomeric purity using Chiralcel OD-R
F¼0.46ꢂ25 cm column and water (pH¼2, HCOOH)/
acetonitrile¼60:40 as mobile phase. For (R,S)-22 (flow¼1.5 mL/
min, l¼254 nm); tR (R)¼8.78 min, tR (S)¼8.45 min and for (S)-
22 (flow¼1.5 mL/min, l¼254 nm); tR (S)¼8.43 min.
5.4.12.1. Method A. Dipeptide 20 (0.492 g, 0.91 mmol) was
dissolved in 3 mL of dichloromethane, 1 mL of anisole was
added and the solution was cooled to 0 ꢀC. Then 6 mL of tri-
fluoroacetic acid was added and the reaction mixture was stirred
at 0 ꢀC for 5 h. The volatile components were evaporated thor-
oughly in vacuo at 35 ꢀC. To the brown residue of 23a, 70 mL
of dichloromethane and triethylamine (0.637 mL, 4.6 mmol)
were added and the reaction mixture was heated to reflux for
4 h. After that time, the volatile components were evaporated
thoroughly, the reaction flask was backfilled with 70 mL of di-
chloromethane and a new portion of triethylamine (1.274 mL,
9.2 mmol). The reaction mixture was again refluxed for 1.5 h,
the volatile components were removed, and residue was purified
by column chromatography (ethyl acetate) to give 24 as a white
solid. Yield 30.5 mg (11%) over two steps.
1H NMR (300 MHz, CDCl3) analysis of enantiomeric pu-
rity using (S)-1-benzyl-6-methylpiperazine-2,5-dione (1) as
a CSA at 296 K. For (R,S)-22; dR (1H, br s, 7.40, NH), dS
(1H, br s, 7.43, NH) and for (S)-22; dS (1H, br s, 7.46, NH).
5.4.11. (RS,Z)-3-[(2-Methyl-1H-indol-3-yl)methylidene]-
hexahydropyrrolo[1,2-a]pyrazine-1,4-dione (6a)
For detosylation of (S,Z)-3-[(2-methyl-1-tosyl-1H-indol-
3-yl)methylidene]hexahydropyrrolo-[1,2-a]pyrazine-1,4-dione
(22), two different methods were used, though both were un-
successful with respect to the enantiomeric purity on (S)-pro-
line residue.
5.4.12.2. Method B. Dipeptide 20 (0.277 g, 0.51 mmol) was
dissolved in 2 mL of dichloromethane, 0.6 mL of anisole was
added and solution was cooled to 0 ꢀC. Then 3.4 mL of trifluoro-
acetic acid was added and the reaction mixture was stirred at
0 ꢀC for 5.5 h. To the deprotected dipeptide 23a, dichlorome-
thane (15 mL) was added and the reaction mixture was poured
into 20 mL ofice cold water. The organicphasewas then washed
with 2ꢂ20 mL of 3 M aqueous hydrochloric acid. The com-
bined water phases were cooled to 0 ꢀC, and basified carefully
to pH¼8. The water phase was then extracted with 3ꢂ30 mL
of dichloromethane, dried with sodium sulfate, and evaporated
in vacuo. To the residue, 50 mL of anhydrous toluene was added
and the solution was heated at 80 ꢀC for 4.5 h. Volatile compo-
nents were evaporated in vacuo and the residue was purified by
column chromatography (ethyl acetate) giving 24 as a white
solid. Yield 81.3 mg (54%) over two steps, mp 256e258 ꢀC
(n-heptane/dichloromethane); [Found: C, 68.92; H, 5.76; N,
14.00. C17H17N3O2 requires C, 69.14; H, 5.80; N, 14.23%]; Rf
(ethyl acetate) 0.15; [a]2D3 þ387.1 (c 0.06, DMSO); nmax (KBr)
3286, 3256, 1687, 1670, 1650, 1612, 1441, 1249, 957,
744 cmꢁ1; dH (300 MHz, DMSO-d6) 1.77e1.97 (3H, m, Pro),
2.12e2.27 (1H, m, Pro), 2.37 (3H, s, CH3), 3.40e3.50 (1H,
5.4.11.1. Method A. (S,Z)-3-[(2-Methyl-1-tosyl-1H-indol-3-
yl)methylidene]hexahydropyrrolo[1,2-a]pyrazine-1,4-dione
(22) (0.135 g, 0.3 mmol) was dissolved in 5 mL of anhydrous
tetrahydrofuran, tetrabutylammonium fluoride (0.75 mL of
1 M in THF, 0.75 mmol) was added and reaction mixture
was heated to reflux for 6 h and stirred for another 17 h at am-
bient temperature. After that the volatile components were
evaporated in vacuo and the residue purified by column chro-
matography (ethyl acetate). Yield 47.9 g (54%) of white solid;
Rf (ethyl acetate) 0.16.
5.4.11.2. Method B. (S,Z)-3-[(2-Methyl-1-tosyl-1H-indol-3-
yl)methylidene]hexahydropyrrolo[1,2-a]pyrazine-1,4-dione
(22) (0.225 g, 0.5 mmol) was suspended in 12 mL anhydrous
methanol and Mg turnings (0.304 g, 12.5 mmol) were added.
When H2 started to evolve, the reaction mixture was cooled to
0 ꢀC and stirred at this temperature for 7 h. The reaction was
quenched with 20 mL of saturated water solution of ammonium
chloride and mixture extracted with 4ꢂ20 mL of dichlorome-
thane. The combined organic phases were washed with 20 mL

2814
J. Wagger et al. / Tetrahedron 64 (2008) 2801e2815
m, Pro), 3.50e3.62 (1H, m, Pro), 4.35e4.45 (1H, m, Pro), 6.86
(1H, s, CH); 7.02 (1H, ddd, J1¼6 Hz, J2¼6 Hz, J3¼3 Hz, Ar),
7.08 (1H, ddd, J1¼6 Hz, J2¼6 Hz, J3¼3 Hz, Ar), 7.32 (1H, br
d, J¼6 Hz, Ar), 7.39 (1H, d, J1¼6 Hz, Ar), 9.20 (1H, s,
CONH), 11.33 (1H, s, NH); dC (75.5 MHz, DMSO-d6) 12.5,
21.5, 28.0, 44.8, 58.4, 105.2, 109.1, 110.8, 118.8, 119.2,
120.6, 125.4, 126.5, 135.6, 136.4, 158.7, 166.0; MS (EI):
m/z¼295 (Mþ); HRMS (EI): Mþ, found 295.1330. C17H17N3O2
requires: 295.1321.
HPLC analysis using Chiralcel OD-R F¼0.46ꢂ25 cm col-
umn and water (pH¼2, HCOOH)/acetonitrile¼60:40 as mobile
phase. For (R,S)-24 (flow¼1.5 mL/min; l¼254 nm); tR
(R)¼6.4 min, tR (S)¼5.1 min and for (S)-24 (flow¼1.5 mL/
min, l¼254 nm); tR (S)¼5.0 min. Both cyclizations of 20e24,
in method A and in method B, did retained absolute configura-
tion on proline residue, though yield in method B was much bet-
ter. Enantiomeric purity was also confirmed by X-ray
determination.
5.5. X-ray structure analysis for compounds 11 and 24
Single crystal X-ray diffraction data of compounds 11 and
24 were collected at room temperature on a Nonius Kappa
CCD diffractometer using the Nonius Collect Software.31
DENZO and SCALEPACK32 were used for indexing and scal-
ing of the data and the structures were solved by means of
SIR97.33 Refinement was done using Xtal3.434 program pack-
age and the crystallographic plots were prepared by ORTEP-
III.35 Crystal structures were refined on F values using the
full-matrix least-squares procedure. The non-hydrogen atoms
were refined anisotropically in all cases, while the positions
of hydrogen atoms were geometrically calculated and their
positional and isotropic atomic displacement parameters
were not refined. Absorption correction was not necessary.
The Regina36 weighting scheme was used in all cases.
Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
numbers CCDC 656803 and 656804. Copies of the data can
be obtained, free of charge, on application to CCDC, 12 Union
Road, Cambridge, CB2 1EZ, UK [fax: þ44(0)-1223-336033 or
e-mail: deposit@ccdc.cam.ac.uk].
5.4.13. (S,Z)-3-[(2-Phenyl-1H-indol-3-yl)methylidene]-
hexahydropyrrolo[1,2-a]pyrazine-1,4-dione (25)
Dipeptide 21 (0.533 g, 0.88 mmol) was dissolved in 4 mL of
dichloromethane, 1.1 mL of anisole was added and solution was
cooled to 0 ꢀC. Then 5.9 mL of trifluoroacetic acid was added
and the reaction mixturewas stirred at 0 ꢀC for 7 h. To the depro-
tected dipeptide 23b, dichloromethane (20 mL) was added and
the reaction mixture was poured into 25 mL of ice cold water.
The organic phase was then washed with 5ꢂ20 mL of water.
The combined aqueous phases were cooled to 0 ꢀC, and basified
carefully to pH¼8. The water phase was then extracted with
4ꢂ30 mL of dichloromethane, dried with sodium sulfate, and
evaporated invacuo. To the residue, 65 mL of anhydrous toluene
was added and the solution was heated at 80 ꢀC for 6 h. The vol-
atile components were evaporated in vacuo and the residue was
purified by column chromatography (66% ethyl acetate/petro-
leum ether) giving 25 as a yellow solid. Yield 0.124 g (39%)
over two steps, mp 239e241 ꢀC (ethanol/water); [Found: C,
73.71; H, 5.33; N, 11.67. C22H19N3O2 requires: C, 73.93; H,
5.36; N, 11.76%]; Rf (66% ethyl acetate/petroleum ether)
0.34; [a]1D9 þ357.5 (c 0.16, DMSO); nmax (KBr) 3357, 3249,
2954, 1686, 1668, 1620, 1450, 1434, 1386, 1310, 1237, 1156,
743 cmꢁ1; dH (300 MHz, DMSO-d6) 1.80e2.00 (3H, m, Pro),
2.15e2.30 (1H, m, Pro), 3.40e3.50 (1H, m, Pro), 3.55e3.65
(1H, m, Pro), 4.42e4.47 (1H, m, Pro), 6.86 (1H, s, CH),
7.06e7.12 (1H, m, Ar), 7.17e7.27 (1H, m, Ar), 7.38e7.60
(5H, m, Ph), 7.65e7.69 (2H, m, Ar), 9.27 (1H, s, CONH),
11.77 (1H, s, NH); dC (75.5 MHz, DMSO-d6) 21.8, 28.9, 45.8,
59.2, 105.7, 110.4, 111.6, 119.6, 121.2, 123.2, 126.3, 126.8,
127.8, 128.7, 129.0, 131.7, 136.2, 137.3, 158.2, 165.1; MS
(EI): m/z¼357 (Mþ); HRMS (EI): Mþ, found 357.1485.
C22H19N3O2 requires 357.1477.
Acknowledgements
The financial support from Slovenian Research Agency
through grants P0-0502-0103, P1-0179 and J1-6689-0103-04
is gratefully acknowledged. We thank pharmaceutical compa-
nies Krka d.d. (Novo mesto, Slovenia) and Lek d.d., a Sandoz
Company (Ljubljana, Slovenia) for financial support. Crystallo-
graphic data were collected on the Kappa CCD Nonius diffrac-
tometer in the Laboratory of Inorganic Chemistry, Faculty of
Chemistry and Chemical Technology, University of Ljubljana,
Slovenia. We acknowledge with thanks the financial contribu-
tion of the Ministry of Science and Technology, Republic of
Slovenia through grant Packet X-2000 and PS-511-102, which
thus made the purchase of the apparatus possible.
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