A traceless solid-supported synthesis of novel pyrazinediazepinedione derivatives

Article abstract of DOI:10.1016/j.tet.2010.01.064

A simple, convenient, six-step synthesis of novel, tricyclic pyrazinebenzodiazepinedione derivatives has been described. The strategy is based on the use of the orthogonally-protected, optically pure, (S)-piperazine-2-carboxylic acid, in a Petasis reaction, followed by coupling with anthranilic acid and finally cyclizing cleavage. The investigated method was applied for the synthesis of novel bicyclic pyrazinediazepinedione derivatives. This traceless, solid-supported approach allows the preparation of a wide variety of compounds in moderate yields from commercially available or easily obtainable reagents.

Full text of DOI:10.1016/j.tet.2010.01.064

Tetrahedron 66 (2010) 2514–2519
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A traceless solid-supported synthesis of novel pyrazinediazepinedione derivatives
,b,
Adam Mieczkowski a, Janusz Jurczak a
*
a Department of Chemistry, Warsaw University, Pasteura 1, PL-02-093 Warsaw, Poland
b Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, PL-01-224 Warsaw, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 July 2009
Received in revised form 9 December 2009
Accepted 18 January 2010
Available online 22 January 2010
A simple, convenient, six-step synthesis of novel, tricyclic pyrazinebenzodiazepinedione derivatives has
beendescribed. Thestrategyisbasedontheuseof theorthogonally-protected, opticallypure, (S)-piperazine-
2-carboxylic acid, in a Petasis reaction, followed by coupling with anthranilic acid and finally cyclizing
cleavage. The investigated method was applied for the synthesis of novel bicyclic pyrazinediazepinedione
derivatives. This traceless, solid-supported approach allows the preparation of a wide variety of compounds
in moderate yields from commercially available or easily obtainable reagents.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
consequently exhibiting a pronounced aquaretic activity. These
properties motivated us to investigate the synthetic routes to novel
Due to their biological and pharmacological activities, a large
number of tricyclic and tetracyclic benzodiazepine derivatives have
been synthesized recently. Much synthetic effort has been directed
toward the synthesis of benzodiazepines condensed to various het-
erocyclic rings, such as: triazole,1 tetrazole,2 imidazole,3 isoindole,4
pyridine,5 pyrimidine,6 isoxazole,7 or pyrrole.8 Just recently,9 a novel
group of pyrazinebenzodiazepine derivatives, such as 1 (Fig. 1) was
identified as potent antagonists of the vasopressin receptor.
pyrazinebenzodiazepines of type 2.
The preparation of small molecules on solid phase appears to be
an expedient method, being utilized to generate compounds for
screening against biological systems, and to enhance the drug
discovery effort.10 Multi-component reactions (MCR) are especially
attractive for automated parallel synthesis and prove to be pow-
erful tools for producing diverse arrays of compounds, often in one
step and high yield.11 The time- and cost-saving advantage of an
efficient MCR over an equivalent multi-step linear synthesis is ob-
vious and is the driving force behind the recent resurgence of their
studies.
We report here a novel, solid-phase synthesis of 1,4-benzodiaz-
epine derivatives containing the 1,2,3,4,6,11,12,12a-octahydro-
benzo[e]pyrazin[1,2-a][1,4]diazepin-6,12-dione core 2 (Scheme 1).
Surprisingly, only one research group has reported the synthesis of
suchcompoundsandtheiranalogs todate.9,12a–c While extendingthe
developed method, we also investigated the synthetic availability of
compounds possessing the perhydropyrazine[1,2-a][1,4]diazepine-
6,12-dione core 3 (Scheme 1). To the best of our knowledge, these
compounds have not been described in the literature yet.
Cl
O
H
N
O
N
CH3
N
N
N
O
R1
O
R1
R2
R2
HN
HN
N
N
R3
O
O
N
O
O
2
3
O
O
O
R
HN
cyclative
cleavage
Figure 1.
N
R
R
O
O
N
O
N
N
The compound 1 binds to human V2 receptors with a high
affinity and is very selective with respect to V1a receptors,
N
HN
O
H2N
* Corresponding author. Tel.: þ48 22 822 02 11x296.
E-mail address: jjurczak@chem.uw.edu.pl (J. Jurczak).
Scheme 1. Construction of bi- and tricyclic pyrazinediazepinedione ring systems 2
and 3.
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.01.064

A. Mieczkowski, J. Jurczak / Tetrahedron 66 (2010) 2514–2519
2515
2. Results and discussion
derivative 8. In order to deprotect the remaining
a
-nitrogen atom,
the intermediate 8 was then treated with a piperidine solution.
Then the anthranilic acid activated with DIC/HOBt was added to
give the amino derivative 9. The final step, the cyclizing cleavage,
proceeded smoothly at 65 ꢀC in the presence of 20% CH3COOH in i-
PrOH. When either the temperature or the concentration was lower
than recommended, a significant decrease of yield was observed.
Several amines and boronic acids were also applied for the studied
synthesis. The obtained results are summarized in Table 1. Obtained
yields were calculated based on the loading of the resin with (S)-
piperazine-2-carboxylic acid.
We started our research by synthesizing the pyr-
azinebenzodiazepines of type 2. The presented synthetic route
assumes the use of optically pure (S)-piperazine-2-carboxylic acid
hydrochloride (3) as a main substrate, which is converted into an
appropriate resin-bound amino derivative 4 (Scheme 2). We de-
cided to involve the three-component Petasis condensation to ex-
tend the side chains, followed by the coupling of anthranilic acid
and cyclizing cleavage, leading to the desired compounds 2. It was
reported that the coupling with anthranilic acid proceeded
smoothly in the presence of carbodiimides, and no additional
protection of the aromatic amine group was required.13 Based on
these results, we suggested the synthetic route to the fused het-
erocyclic system 2 (Scheme 2).
Table 1
Syntheses of the pyrazinebenzodiazepinones 2
Product
No.
R1
R2
Crude
yield [%]
Purified
yield [%]
O
O
O
a
c
b
Boc
2a
2b
2c
Ph
Ph
Ph
38
50
48
24
24
28
N
N
HO
N
HO
NH
O
NH
.
2 HCl
N
HN
N
O
Fmoc
Fmoc
N
O
4
5
6
O
R1
O
O
R1
R2
OH
d
e
NH
O
N
O
Fmoc
N
N
O
N
Fmoc
2d
2e
Ph
48
61
22
33
NH
F
7
8
4-Et-Ph
N
N
O
R1
O
R1
R2
R2
O
O
N
HN
N
f
2f
4-MeO-Ph
58
69
75
32
26
36
N
N
N
N
N
N
N
O
O
N
O
H2N
2g
2h
S
9
2a-i
Scheme 2. Reagents and conditions: (a) (i) Boc2O, NaOHaq, dioxane:H2O 2:1, 0 ꢀC/rt,
then FmocCl, Na2CO3; (b) (i) 4-hydroxymethyl polystyrene resin DEAD, Ph3P,
THF:CH2Cl2 3:1, 0 ꢀC/rt; (ii) 40% TFA in CH2Cl2; (c) OHC–COOH$H2O, R1-B(OH)2,
CH2Cl2–MeOH 4:1, rt; (d) DIC, HOBt, R0R00NH, DMF; (e) (i) 10% piperidine in DMF, rt; (ii)
DIC, HOBt, o–NH2–Ph–COOH, DMF, rt; (f) 20% CH3COOH in i-PrOH, 65 ꢀC.
O
2i
63
21
N
N
The solid-supported synthesis could facilitate and improve the
multi-step syntheses of complex organic molecules, although with
some limitations and disadvantages. All by-products, generated in
the previous steps of the synthesis, would be cleaved in the final
step along with the required product, giving a mixture of various
compounds. Consequently, the purification of final product would
extend the time of synthesis. We assumed that, in the projected
synthesis, only the cyclic product would be cleaved from resin, and
the non-cyclized intermediates would not be detached from the
solid support. Before the coupling with the 4-hydroxymethyl
polystyrene resin, (S)-piperazine-2-carboxylic acid was orthogo-
nally protected with two different protecting groups (Boc, Fmoc),
giving the intermediate 5, and then attached to the resin by the
ester linkage. In this step, we decided to use the Mitsunobu re-
action,14 which was a very useful procedure for synthesis of esters.
The elemental analysis of resin with attached amino acid showed
1.55% of N, which corresponds to 0.74 mmol/g of resing loading
(90% yield). In the next step, in order to remove the Boc protecting
group, the solid phase was treated with a solution of TFA. This
The synthesized tricyclic pyrazinebenzodiazepine derivatives
possess two stereogenic centers: the first one originates from the
optically-pure chiral substrate and the second one is created in the
Petasis reaction. For this reason, all the described compounds
were obtained as pairs of diastereomers in an equimolar ratio
(based on 1H NMR spectra). These pairs are inseparable by chro-
matographic methods and are characterized as mixtures of di-
astereomers. In order to assign correctly the signals in the 1H NMR
spectra to the appropriate protons in the molecule, additional
correlation spectra (COSY, HSQC, HMBC, NOE) were taken for the
selected products, these confirmed indisputably the assumed
structures. In all these syntheses, after cleavage with 20% acetic
acid in i-PrOH, we found no trace of any non-cyclized product in
the reaction mixture.
In the next part of our research, we decided to use b-amino
acids, which should result in formation of the bicyclic azepinedione
derivatives 3. Thus the amino derivative 10 was coupled with either
Boc-protected b-alanine or b-D-phenylalanine using DIC/HOBt as
deprotected the
b
-nitrogen atom of the piperazine-2-carboxylic
a coupling agent. Further treatment of the obtained intermediate
11b with 40% TFA followed by heating to 65 ꢀC with 20% CH3COOH
in i-PrOH led to the formation of the perhydropyr-
azinediazepinedione 3b in 30% total yield (63% yield of the crude
product (Scheme 3)).
acid and led to the monoprotected amino derivative 6, which was
used in the next step as an amine substrate for the Petasis reaction.
The Petasis product 7 was treated with a DIC/HOBt mixture and
then the appropriate amine was added to yield the amide

2516
A. Mieczkowski, J. Jurczak / Tetrahedron 66 (2010) 2514–2519
derivatives could be easily reduced to the pyrazinebenzodiazepines
of type 1 using lithium borohydride.12a,15 Additionally, the de-
veloped method could be utilized for the synthesis of benzodiaz-
epine derivatives incorporated into cyclic peptides, since the
benzodiazepine structure could stabilize the loop conformations.16
The biological activity of the synthesized compounds will be
reported in due course.
O
N
O
a
N
N
N
O
N
O
O
N
HN
O
N
O
BocHN
R
10
11a R=H, 11b R=Ph
4. Experimental
4.1. General
b
O
N
H
N
All reagents were obtained from Fluka and Merck and were used
without further purification. Dry dichloromethane (DCM) and
dimethylformamide (DMF) were obtained by distillation from over
calcium hydride. The optically pure (S)-piperazine-2-carboxylic
acid was obtained from ChemPacific. The Wang resin was obtained
from Novabiochem. 1H and 13C spectra were recorded on a Varian
500 MHz instrument using CD3OD as a solvent, with TMS as an
internal standard. The abbreviations used in the descriptions of
NMR spectra are as follows: Hada signal from an axial proton,
Heda signal from an equatorial proton, Hpda signal from the pi-
perazine substituent. All ESI-MS spectra were recorded on a Quat-
tro LC Micromass instrument. The IR spectra were recorded on
a Nicolet Magna 550 FTIR instrument. The IR band positions are
reported in cmꢁ1. The preparative flash chromatographic experi-
ments were performed using Merck Kieselgel 60, 230–400 mesh.
The TLC analyses were done on Merck 60 F254 aluminum plates and
visualized by using iodine vapor and UV light (254 nm) or by
spraying with an aqueous solution of (NH4)6Mo7O24 (2.5%) and
(NH4)4Ce(SO4)4 (1%) in 10% H2SO4 and heating to 110 ꢀC. The
numbering scheme of carbon atoms in the heterocyclic cores is
shown in Figure 3.
N
N
R
N
O
O
3a R=H, 3b R=Ph
Scheme 3. Reagents and conditions: (a) DIC, HOBt, BocNH–CH(R)–CH2–COOH, DMF, rt;
(b) (i) 40% TFA in CH2Cl2 (ii) 20% CH3COOH in i-PrOH, 65 ꢀC.
Surprisingly, the treatment of 11a with 40% TFA, followed by
heating with 20% CH3COOH in i-PrOH at 65 ꢀC didn’t result in
cleavage of any product, including required 3a. After treatment the
resin with a 95:5 mixture of TFA–H2‘O, a complex mixture of polar
compounds was obtained. MS analysis revealed, that one of the
compound possessed molecular weight 479, which suggested
the formation of non-cyclized derivative 12 (Fig. 2) as a one of the
products. Because of the failure of the cyclization-cleavage step and
formation of complex mixture, the cyclization of
termediate was not further investigated.
b-alanine in-
O
O
N
O
R1
N
HO
O
R1
N
3
2
4
R2
H2N
2
R2
HN
1
7
HN
N
N
O
5
N
R3
1
O
4
N
O
N
3
6
5
O
O
12
Figure 3.
Figure 2.
4.1.1. Protection of (S)-piperazine-2-carboxylic acid. To a solution of
3.0 g (14.8 mmol) of (S)-piperazine-2-carboxylic acid dihydro-
chloride (3) in 30 mL of dioxane and 15 mL of water, the solution of
1.5 g of NaOH (29.6 mmol) in 5 mL of water was added slowly at
0 ꢀC followed by 3.6 g (16.3 mmol) of di-tert-butyl dicarbonate.
After 5 h of stirring at the rt, 1.7 g (16.0 mmol) of solid sodium
carbonate and 4.7 g (18.2 mmol) of FmocCl were added, and the
reaction was stirred overnight. The solvent was rotary evaporated,
the obtained residue was partitioned between 100 mL of ethyl ac-
etate and 100 mL of 1 N HCl. The organic layer was washed with
brine, dried over magnesium sulfate and the solvent was evapo-
rated. The crude product was crystallized once from ethyl acetate.
The yield of Na-Fmoc-Nb-Boc-(S)-piperazine-2-carboxylic acid is
4.4 g (43%) as amorphous, cotton-like solid.
The synthesized bicyclic pyrazinediazepine derivative 3b pos-
sesses three stereogenic centers: two of them originate from the
optically-pure chiral amino acids and the third one is created in the
Petasis reaction. The compound 3b was obtained as an equimolar
pair of diastereomers (based on 1H NMR spectra) inseparable by
chromatographic methods. As in the case of the tricyclic pyr-
azinebenzodiazepines 2, the appropriate 2D NMR spectra con-
firmed the structure of the desired product. No traces of other
products were detected in the reaction mixture after cleavage of 3b
from the resin.
3. Conclusion and perspectives
In conclusion, a novel, traceless, solid-supported synthesis
leading to the new pyrazinebenzodiazepine derivatives was de-
veloped. Using this approach, an array of new products was syn-
thesized. The use of the Petasis reaction for the development of side
chains led to the compounds having a great structural diversity. The
cyclizing cleavage, applied in the last step, led to only one detect-
able product cleaved from the resin. This mild cleavage method left
the by-products resulting from incomplete or undesired reactions
on the solid support. The obtained pyrazinebenzodiazepinedione
4.2. A typical procedure for the synthesis of the
pyrazinebenzodiazepinedione derivative 2a
(a) Wang resin (1.0 g, 0.82 mmol/g, Novabiochem) was swelled
in anhydrous dichloromethane (10 mL). To this slurry, triphenyl-
phosphine (643 mg, 2.46 mmol) and Na-Fmoc-Nb-Boc-(S)-pipera-
zine-2-carboxylic acid (4) (111 mg, 2.46 mmol) were added, the
reaction mixture was cooled to 0 ꢀC under the argon atmosphere,

A. Mieczkowski, J. Jurczak / Tetrahedron 66 (2010) 2514–2519
2517
and diethyl azadicarboxylate (428 mg, 2.46 mmol) in 2 mL of THF
was added slowly. The reaction was stirred for three days, then the
resin was filtered off and washed with 50 mL of THF (3ꢂ), 50 mL of
CH2Cl2 (3ꢂ), 50 mL of MeOH (3ꢂ), then alternately with CH2Cl2 and
MeOH (3ꢂ50 mL each). The orthogonally-protected piperazinic
resin ester was swelled in 10 mL of CH2Cl2 and then 3.3 mL of TFA
was added dropwise. After one hour, the resin was filtered off and
washed with 50 mL of THF (3ꢂ), 50 mL of CH2Cl2 (3ꢂ), 50 mL of
MeOH (3ꢂ), then alternately with CH2Cl2 and MeOH (3ꢂ50 mL
each). The resin-bound amine TFA salt was then neutralized with
10% of diisopropylethylamine in CH2Cl2 and washed again with
50 mL of THF (3ꢂ), 50 mL of CH2Cl2 (3ꢂ), 50 mL of MeOH (3ꢂ), then
alternately with CH2Cl2 and MeOH (3ꢂ50 mL each). (b) The resin-
bound amino derivative 4 was swelled in CH2Cl2 (10 mL), and
glyoxylic acid (151 mg, 1.64 mmol) and phenylboronic acid
(200 mg, 1.64 mol) in 2 mL of MeOH were added. The reaction
mixture was agitated for 5 h, then filtered off and washed with
CH2Cl2 (3ꢂ50 mL). The above procedure was repeated again for the
12 h after which the resin was filtered off again and washed again
with 50 mL of THF (3ꢂ), 50 mL of CH2Cl2 (3ꢂ), 50 mL of MeOH (3ꢂ),
CH2Cl2 (3ꢂ), 50 mL of MeOH (3ꢂ), then alternately with CH2Cl2
and MeOH (3ꢂ50 mL each). (b) The resin was treated with 50 mL
of 25% solution of TFA in DCM for one hour in rt and washed with
50 mL of THF (3ꢂ), 50 mL of CH2Cl2 (3ꢂ), 50 mL of MeOH (3ꢂ),
then alternately with CH2Cl2 and MeOH (3ꢂ50 mL each). Finally,
the resin-bound intermediate was taken up in 50 mL of 10% AcOH/
i-PrOH and heated for 12 h at 50 ꢀC. The resin was filtered off and
washed with MeOH (4ꢂ25 mL). The filtrate and washings were
combined and concentrated to give a brown solid. The crude
product was purified by a column chromatography on silica gel
(1–2% MeOH in CHCl3).
4.3.1. (S)-2-(R)- and (S)-2-((S)-[-oxo-1-phenyl-2-(4-phenyl-piperazin-
1-yl)ethyl)]-1,2,3,4-tetrahydrobenzo[e]pyrazino[1,2-a][1,4]diazepine-
6,12(11H,12aH)-dione (2a). Mixture of diastereomers; isolated
yield: 92 mg (24%); Rf¼0.39 (3% MeOH in CH2Cl2); 1H NMR
(500 MHz, DMSO-d6),
d
: 7.74–7.66 (m, 1H, HAr); 7.60 (d, 1H, J¼7,
HAr); 7.54–7.25 (m, 4H, HAr); 7.25–7.14 (m, 5H, HAr); 7.07 (t, 1H,
J¼8, HAr); 6.90 (d, 2H, J¼7, HAr); 6.82–6.74 (m, 1H, HAr); 4.92, 4.73
(2ꢂs, 1H, H-5); 4.30 (t, 2H, J¼11, H-4a); 4.11 (d, 2H, J¼3, H-4e);
4.08–4.00 (m, 0.5H, HpCH2NC]O); 3.92–3.70 (m, 2H,
HpCH2NC]O); 3.70–3.54 (m, 1.5H, HpCH2NC]Oþ0.5H-2a); 3.54–
3.42 (m, 0.5H, HpCH2NC]O); 3.31 (d, 0.5H, J¼11.5, 0.5H-2a); 3.24
(d, 0.5H, J¼11.5, 0.5H-2e); 3.20–2.82 (m, 5.5H, 4HpCH2NPhþH-
3aþ0.5H-2e); w2.49 (dt, 0.5H, 0.5H-3e, under signal DMSO);
2.46–2.36 (m, 1H, H-1); 2.27 (dt, J1¼3, J2¼11, 0.5H-3e); 13C NMR
then alternately with CH2Cl2 and MeOH (3ꢂ50 mL each). (c) The
b-
amino acid 6 from the previous step was swelled in dry DMF
(10 mL), and HOBt (626 mg, 4.1 mmol) followed by DIC (0.63 mL,
4.1 mmol) were added. The reaction was agitated for 3 h, after
which the resin was washed with dry DMF (3ꢂ50 mL). The resin
was swelled again in DMF (10 mL) and to this slurry was added N-
phenylpiperazine (0.63 mL, 4.1 mmol) and the reaction was
allowed to agitate for 12 h. The intermediate 7 was filtered off and
washed with DMF (3ꢂ50 mL) followed by 50 mL of THF (3ꢂ), 50 mL
of CH2Cl2 (3ꢂ), 50 mL of MeOH (3ꢂ), then alternately with CH2Cl2
and MeOH (3ꢂ50 mL each). (d) The intermediate 7 was treated
with 50 mL of 25% piperidine in DMF, then filtered off and washed
with 50 mL of THF (3ꢂ), 50 mL of CH2Cl2 (3ꢂ), 50 mL of MeOH (3ꢂ),
then alternately with CH2Cl2 and MeOH (3ꢂ50 mL each). Anthra-
nilic acid (562 mg, 4.1 mL) was dissolved in 10 ml of dry DMF and
then HOBt (626 mg, 4.1 mmol) followed by DIC (0.63 ml, 4.1 mmol)
was added. The reaction mixture was agitated for 1 h; in the
meantime, the resin was swelled in 10 mL of dry DMF, and to this
heterogeneous slurry, the solution of the activated anthranilic acid
was added. The reaction was agitated for 5 h and rinsed with dry
DMF (3ꢂ50 mL) before repeating the coupling procedure for 15 h.
Then the resin was filtered off and washed with 50 mL of THF (3ꢂ),
50 mL of CH2Cl2 (3ꢂ), 50 mL of MeOH (3x), then alternately with
CH2Cl2 and MeOH (3ꢂ50 mL each). (e) The free amine 8 was taken
up in 50 mL of 20% AcOH/i-PrOH and heated for 12 h at 60 ꢀC. The
resin was filtered off and washed several times with MeOH. The
filtrate and washings were combined and concentrated to give
a brown solid. To obtain the analytically pure samples, the crude
product 2a was purified by a column chromatography on silica gel
(1–2% MeOH in CHCl3). All final products were obtained as white
amorphous solids.
(125 MHz, DMSO-d6), d: 170.6, 170.5, 168.3, 168.0, 167.4, 167.3,
150.8, 150.6, 137.0, 136.9, 136.1, 134.3, 131.9, 130.4, 130.3, 129.7,
129.0, 128.9, 128.8, 128.1, 127.9, 127.6, 127.5, 126.5, 126.4, 123.8,
120.5, 120.4, 119.3, 119.2, 115.8, 115.7, 79.1, 68.4, 51.3, 51.2, 49.1,
48.4, 48.3, 48.1, 47.8, 47.2, 46.4, 45.0, 44.6, 41.3, 41.3; IR: 3454,
3228, 2917, 2823, 1698, 1638, 1599, 1478, 1438, 1410, 1284, 1228,
1160, 1022, 758, 698; HR ESI MS: m/z for [MþNa]þ calculated:
532.2325, found: 532.2318.
4.3.2. (S)-2-(R)- and (S)-2-((S)-2-morpholino-2-oxo-1-phenyl-ethyl)-
1,2,3,4-tetrahydrobenzo[e]pyrazino[1,2-a][1,4] diazepine-6,12(11H,12aH)-
dione (2b). Mixture of diastereomers; isolated yield: 78 mg (24%);
Rf¼0.45 (3% MeOH in CH2Cl2); 1H NMR (500 MHz, CD3OD),
d: 7.72
(t,1H, J¼7, HAr); 7.57 (d,1H, J¼7.5, HAr); 7.48 (t,1H, J¼8, HAr); 7.43 (d,
1H, J¼7, HAr); 7.40–7.28 (m, 1H, HAr); 7.26–7.20 (m, 1H, HAr); 7.07 (t,
1H, J¼7, HAr); 4.79, 4.77 (2ꢂd, 1H, H-5); 4.37, 4.33 (2ꢂd, 1H, H-4e);
4.16–4.08 (m,1H, H-4e); 3.90–3.35 (m, 8.5H, 8Hmþ0.5H-2a); 3.27 (d,
0.5H, J¼11.5, H-2a); 3.20 (dt, 0.5H, 0.5H-3a); 3.16–3.00 (m, 1H, 0.5H-
2eþ0.5H-3a); 2.89 (d, J¼11.5, 0.5H, 0.5H-2e); 2.70–2.60 (m, 1H,
0.5H-1þ0.5H-3e); 2.57 (dd, 0.5H, J1¼5.5, J2¼12.5, 0.5H-1); 2.46 (dt,
J1¼4, J2¼11.5, 0.5H, H-3e); 13C NMR (125 MHz, CD3OD),
d: 172.6,
172.3, 171.4, 170.9, 170.4, 170.2, 133.7, 133.6, 131.6, 131.6, 131.0, 130.7,
130.4, 129.8, 129.5, 129.4, 129.3, 127.8, 127.7, 125.8, 121.9, 79.5, 71.7,
71.3, 67.9, 67.8, 67.7, 67.4, 53.4, 53.3, 47.8, 47.6, 47.3, 43.7, 41.6, 41.5;
IR: 3475, 3227, 2963, 2919, 2855, 1698, 1634, 1479, 1437, 1411, 1302,
1227, 1162, 1111, 1025, 1004, 761, 702; HR ESI MS: m/z for [MþNa]þ
calculated: 457.1852, found: 457.1871.
4.3. A procedure for the synthesis of the
perhydropyrazinediazepinedione derivative 3b
4.3.3. (S)-2-(R)- and (S)-2-((S)-2-(4-methoxybenzylamino)-2-oxo-1-
phenylethyl)-1,2,3,4-tetrahydrobenzo[e]pyrazino [1,2-a][1,4] diaze-
(a) The amino derivative 10, was obtained by the procedure
used for the synthesis of the pyrazinebenzodiazepinedione de-
pine-6,12(11H,12aH)-dione (2c). Mixture
of
diastereomers;
rivatives 2. 1.09 g of Boc-protected
b-D-phenylalanine (4.1 mmol)
isolated yield: 99 mg (28%); Rf¼0.47 (3% MeOH in CH2Cl2); 1H
was dissolved in 10 mL of dry DMF and then HOBt (626 mg,
4.1 mmol) followed by DIC (0.63 mL, 4.1 mmol) were added. The
reaction mixture was agitated for 1 h; in the meantime, the resin
was swelled in 10 mL of dry DMF, and the solution of the activated
amino acid was added to slurry of the amino derivative 10. The
reaction was agitated for 5 h and rinsed with dry DMF (3ꢂ50 mL)
before repeating the coupling procedure for 15 h. Then the resin
was filtered off and washed with 50 mL of THF (3ꢂ), 50 mL of
NMR (500 MHz, CD3OD), d: 7.73–7.67 (m, 1H, HAr); 7.47–7.42 (m,
1H, HAr); 7.36–7.23 (m, 1H, HAr); 7.23–7.18 (m, 3H, HAr); 7.06–7.01
(m, 1H, HAr); 6.85–6.80 (m, 1H, HAr); 4.49, 4.39 (2ꢂdAB, 1H,
J¼14.5, NH2CH2Ph); 4.36 (s, 1H, H-5); 4.32 (s, 1H, H-5); 3.97 (d,
1H, J¼3.5, H-4e); 3.72 (s, 3H, OCH3); 3.17–3.06 (m, 2H, H-3eþH-
2e); 3.03 (d, 1H, J¼11.5, H-3e); 2.28 (dt, 1H, J1¼11.5, J2¼11.5 H-3e);
1.75 (dd, 1H, J1¼5, J2¼12.5, H-1); 13C NMR (125 MHz, CD3OD),
d:
173.2, 172.9, 172.7, 170.5, 170.4, 160.3, 138.0, 135.0, 133.7, 132.4,

2518
A. Mieczkowski, J. Jurczak / Tetrahedron 66 (2010) 2514–2519
131.5, 131.1, 131.0, 130.3, 130.2, 129.9, 129.3, 129.1, 128.1, 126.0,
122.0, 114.8, 114.7, 55.7, 55.6, 52.4, 52.3, 47.5, 43.5, 42.3; IR: 3443,
3287, 3061, 2921, 2835, 1692, 1643, 1513, 1478, 1438, 1409, 1303,
1249, 1175, 1162, 1032, 761, 701; HR ESI MS: m/z for [MþNa]þ
calculated: 507.2008, found: 507.2011.
120.4, 120.0, 119.2, 115.7, 115.6, 113.5, 113.2, 51.3, 51.2, 49.1, 48.4,
48.2, 48.0, 47.7, 46.9, 46.8, 46.3, 44.9, 44.6, 41.2; IR: 3455, 3239,
2911, 2832, 1703, 1643, 1615, 1598, 1511, 1475, 1452, 1435, 1409,
1291, 1228, 1176, 1162, 1020, 756, 697; HR ESI MS: m/z for
[MþNa]þ calculated: 562.2430, found: 562.2409.
4.3.4. (S)-2-(R)- and (S)-2-(S)-2-(4-fluorophenylamino)-2-oxo-1-phe-
nylethyl-1,2,3,4-tetrahydrobenzo[e]pyrazino [1,2-a][1,4] diazepine-
6,12(11H,12aH)-dione (2d). Mixture of diastereomers; Isolated
yield: 75 mg (22%); Rf¼0.51 (3% MeOH in CH2Cl2); 1H NMR
4.3.7. (S)-2-(R)- and (S)-2-((R)-2-oxo-2-(4-phenylpiperazin-1-yl)-1-
(thiophen-2-yl)ethyl)-1,2,3,4-tetrahydrobenzo [e]pyrazino[1,2-a][1,4]di-
azepine-6,12(11H,12aH)-dione (2g). Mixture of diastereomers; iso-
lated yield: 101 mg (26%); Rf¼0.47 (3% MeOH in CH2Cl2); 1H NMR
(500 MHz, CD3OD),
d
: 7.96–7.88 (m, 1H, HAr); 7.86–7.72 (m, 2H,
(500 MHz, CD3OD), d: 7.50–7.46 (m, 1H, HAr); 7.45–7.42 (m, 1H,
HAr); 7.56–7.44 (m, 2H, HAr); 7.42–7.21 (m, 1H, HAr); 7.15–6.98 (m,
1H, HAr); 4.64, 3.89, (2ꢂs, 1H, H-5); 4.40 (d, 0.5H, J¼13, H-4a);
4.37–4.30 (m, 1H, H-4eþH-4a); 4.11 (d, 0.5H, J¼3.5, 0.5H-4e); 3.56
(d, 0.5H, J¼12, H-2a); 3.30 (m, 1H, 0.5H-3aþ0.5H-2a); 3.17, 2.68
(2ꢂd, J¼12, H-2e); 3.10 (dt, 0.5H, J1¼3.5, J2¼12, H-3a); 2.49, 1.88
(2ꢂdd, 1H, J1¼4.5, J2¼12.5, H-1); 2.43, 2.04 (2ꢂdt, J1¼3.5, J2¼12,
HAr); 7.26–7.20 (m, 1H, HAr); 7.10–7.05 (m, 1H, HAr); 7.03–6.98 (m,
1H, HAr); 6.94 (d, 1H, J¼8, HAr); 6.83 (t, 1H, J¼7, HAr); 5.30 (s, 1H, H-
5); 4.36 (d, 1H, J¼13, H-4a); 4.14 (dd, 1H, J1¼2.5, J2¼5.5, H-4e); 4.00–
3.89 (m, 1H, HpCH2NC]O); 3.89–3.79 (m, 2H, 2HpCH2NC]O);
3.79–3.70 (m,1H, HpCH2NC]O); 3.43 (d,1H, J¼13, H–2a); 3.29–3.21
(m, 2H, 2HpCH2NPh); 3.20–3.12 (m, 1H, H-5a); 3.12–3.04 (m, 1H,
HpCH2NPh); 3.04–2.90 (m, 2H, HpCH2NPhþH-2e); 2.67–2.56 (m,
H-3e); 13C NMR (125 MHz, CD3OD),
d: 172.8, 172.6, 172.0, 171.9,
170.7, 161.8, 159.9, 138.2, 135.9, 135.6, 134.4, 133.8, 133.7, 131.5,
131.4, 130.1, 129.9, 129.8, 129.6, 129.3, 129.2, 128.4, 128.2, 127.1,
126.1, 126.0, 123.9, 123.8, 123.7, 122.0, 121.9, 116.2, 116.1, 116.0,
115.9, 77.4, 75.7, 52.8, 52.5, 52.3, 52.2, 47.5, 42.5; IR: 3456, 3258,
2966, 2923, 2852, 1692, 1643, 1608, 1529, 1509, 1477, 1408, 1306,
1211, 1159, 1033, 838, 760, 701; HR ESI MS: m/z for [M]þ calcu-
lated: 459.1848, found: 459.1827.
2H, H-5eþH-1); 13C NMR (125 MHz, CD3OD),
d: 172.5, 170.5, 170.4,
142.5,138.4,139.0,133.7,131.6,130.1,129.4, 128.2,127.8,127.2,125.7,
121.8, 121.4, 117.8, 113.9, 53.3, 52.0, 50.8, 50.4, 47.2, 46.9, 44.1, 43.4,
41.8; IR: 3239, 3092, 2923, 1694, 1641, 1599, 1496, 1478, 1438, 1408,
1286, 1229, 1161, 1031, 760, 697; HR ESI MS: m/z for [MþNa]þ cal-
culated: 538.1889, found: 538.1892.
4.3.8. (S)-2-(R)- and (S)-2-((S)-1-(naphthalen-2-yl)-2-oxo-2-(4-
phenylpiperazin-1-yl)ethyl)-1,2,3,4-tetrahydrobenzo [e]pyrazino[1,2-
4.3.5. (S)-2-(R)- and (S)-2-((S)-1-(4-ethylphenyl)-2-oxo-2-(4-phenyl-
piperazin-1-yl)ethyl)-1,2,3,4-tetrahydrobenzo [e]pyrazino[1,2-a][1,4]di-
azepine-6,12(11H,12aH)-dione (2e). Mixture of diastereomers;
isolated yield: 132 mg (33%); Rf¼0.41 (3% MeOH in CH2Cl2); 1H
a][1,4]diazepine-6,12(11H,12aH)-dione
astereomers; isolated yield: 147 mg (36%); Rf¼0.58 (3% MeOH in
CH2Cl2); 1H NMR (500 MHz, CD3OD),
: 7.95–7.70 (m, 7H, HAr);
(2h). Mixture
of
di-
d
NMR (500 MHz, DMSO-d6),
d
: 7.74–7.64 (m, 1H, HAr); 7.52–7.44 (m,
7.75–7.45 (m, 5H, HAr); 7.29–7.24 (m, H, HAr); 7.21–7.15 (m, 2H,
HAr); 7.12–7.00 (m, 1H, HAr); 4.60, 4.49 (2ꢂs, 1H, H-5); 4.37 (d, 1H,
J¼12.5, H-4a); 4.21 (dd, 1H, J1¼2.5, J2¼5.5, H-4e); 4.03–3.94 (m,
1H, HpCH2NC]O); 3.88–3.70 (m, 3H, 3HpCH2NC]O); 3.53 (d, 1H,
J¼13, H-2a); 3.24–3.05 (m, 4H, 2HpCH2NPhþH-2eþH-3a); 3.05–
2.92 (m, 2H, 2HpCH2NC]O); 2.87–2.79 (m, 1H, HpCH2NC]O);
2H, HAr); 7.34 (d, 1H, J¼13, HAr); 7.25–7.14 (m, 5H, HAr); 7.07 (t, 1H,
J¼8, HAr); 6.93–6.87 (m, 2H, HAr); 6.81–6.78 (m, 1H, HAr); 4.86, 4.68
(2ꢂs, 1H, H-5); 4.36–4.24 (m, 1H, H-4a); 4.09 (s, 1H, H-4e); 4.06–
3.98 (m, 0.5H, 0.5HpCH2NC]O); 3.90–3.70 (m, 1.5H,
1.5HpCH2NC]O); 3.70–3.63 (m, 1.5H, HpCH2NC]Oþ0.5H-2a);
3.51–3.42 (m, 0.5H, HpCH2NC]O); 3.30 (m, 0.5H, H-2a); 3.26–3.14
(m, 1H, 0.5H-2eþ0.5HpCH2NC]O); 3.12–2.80 (m, 5.5H,
4HpCH2NPhþH-3aþ0.5H-2e); 2.59 (q, 2H, J¼7, CH2CH3); 2.45–2.35
(m, 1H, H-1); 2.30–2.22 (m, 0.5H, 0.5H-3e); 1.16 (t, 3H, J¼7,CH2CH3).
Half peak of H-3e covered by DMSO peak; 13C NMR (125 MHz,
2.79–2.70 (m, 2H, H-1þH-3e); 13C NMR (125 MHz, CD3OD),
d:
173.0, 172.7, 171.4, 170.5, 152.4, 138.4, 138.1, 134.8, 134.4, 133.7,
132.5, 131.6, 131.5, 131.1, 130.8, 130.2, 130.1, 130.0, 129.6, 129.5,
129.3, 128.2, 127.9, 127.6, 127.5, 126.1, 126.0, 125.8, 122.0, 121.9,
121.5, 117.8, 114.8, 113.9, 75.6, 75.3, 66.7, 55.7, 53.4, 52.9, 52.6,
52.5, 52.4, 50.8, 50.6, 47.7, 47.5, 44.2, 43.5, 43.4, 42.4, 41.7; IR:
3454, 3217, 3056, 2910, 2814, 1695, 1637, 1599, 1478, 1439, 1413,
1280, 1227, 1060, 1021, 757, 694; HR ESI MS: m/z for [MþNa]þ
calculated: 582.248, found: 582.2474.
DMSO-d6), d: 170.4, 168.4, 168.1, 167.3, 167.2, 150.7, 150.6, 143.0,
142.9, 136.9, 136.8, 133.3, 131.8, 131.5, 130.3, 130.2, 129.7, 129.3,
128.9, 128.8, 127.6, 127.5, 127.2, 126.4, 126.3, 123.8, 120.4, 119.2,
119.1, 115.7, 115.6, 68.1, 51.2, 49.1, 48.4, 48.2, 48.1, 47.0, 46.3, 44.9,
44.6, 41.3, 27.7, 15.4, 15.3; IR: 3446, 3226, 2963, 2925, 2870, 1696,
1640, 1600, 1495, 1478, 1439, 1411, 1284, 1228, 1160, 1021, 759, 694;
HR ESI MS: m/z for [M]þ calculated: 538.2818, found: 538.2817.
4.3.9. (S)-2-(R)- and (S)-2-((S)-1-(6-methoxynaphthalen-2-yl)-2-
oxo-2-(4-phenylpiperazin-1-yl)ethyl)-1,2,3,4-tetrahydrobenzo[e]pyr-
azino[1,2-a][1,4]diazepine-6,12(11H,12aH)-dione (2i). Mixture of
diastereomers; isolated yield: 91 mg (21%); Rf¼0.55 (3% MeOH in
4.3.6. (S)-2-(R)- and (S)-2-((S)-1-(4-methoxyphenyl)-2-oxo-2-(4-
phenylpiperazin-1-yl)ethyl)-1,2,3,4-tetrahydro- benzo[e]pyrazino[1,2-
a][1,4]diazepine-6,12(11H,12aH)-dione (2f). Mixture of diastereo-
mers; isolated yield: 128 mg (32%); Rf¼0.37 (3% MeOH in
CH2Cl2); 1H NMR (500 MHz, DMSO-d6),
d: 7.90–7.60 (m, 4H, HAr);
7.60–7.54 (m, 1H, HAr); 7.52–7.44 (m, 1H, HAr); 7.32–7.27 (m, 1H,
HAr); 7.24–7.12 (m, 1H, HAr); 7.07 (t, 1H, J¼9, HAr); 6.93–6.83 (m, 2H,
HAr); 6.78 (q, 1H, J¼6, HAr); 5.05, 4.86 (2ꢂs, 1H, H-6); 4.31 (t, 1H,
J¼13, H-4a); 4.41–4.01 (m, 1.5H, H-4eþ0.5HpCH2NC]O); 3.96–
3.74 (m, 5H, 2HpCH2NC]OþOCH3); 2.72–3.58 (m, 1.5H,
HpCH2NC]Oþ0.5H-2a); 3.32–3.10 (m, 1H, 0.5HpCH2NC]Oþ0.5H-
2e); 3.10–2.79 (m, 5.5H, 4HpCH2NPhþH-3aþ0.5H-2e); 2.62, 2.44 (m,
1.5H, H-1þ0.5H-3e, partially under DMSO peak); 2.37 (dt, J1¼3,
CH2Cl2); 1H NMR (500 MHz, DMSO-d6),
d: 7.74–7.66 (m, 1H, HAr);
7.52–7.44 (m, 2H, HAr); 7.35 (d, 1H, J¼8.5HAr); 7.24–7.18 (m, 3H,
HAr); 7.07 (t, 1H, HAr); 6.95–6.86 (m, 4H, HAr); 6.84–6.74 (m, 1H,
HAr); 4.85, 4.67 (2ꢂs, 1H, H-5); 4.29 (t, 1H, J¼12, H-4a); 4.09 (s,
1H, H-4e); 4.07–4.00 (m, 0.5H, 0.5CH2NC]O); 3.91–3.52 (m, 6H,
2.5CH2NC]OþOCH3þ0.5H-2a); 3.51–3.41 (m, 0.5H, CH2NC]O);
3.29 (d, 0.5H, J¼12.5, 0.5H-2a); 3.24–3.13 (m, 1H, 0.5H,
0.5CH2NC]OþH-2e); 3.13–2.78 (m, 5.5H, 4CH2NPhþH-5aþ0.5H-
2e), w2.48 (dt, 0.5H, 0.5H-3e, under the signal of DMSO); 2.44–
2.35 (m, 1H, H-1); 2.25 (dt, 0.5H, J1¼3.5, J2¼11.5, 0.5H-3e); 13C
J2¼11, 0.5H-3e); 13C NMR (125 MHz, DMSO-d6),
d: 170.6, 170.4,
168.4,168.2,167.3,167.2, 157.4,150.7,150.6,137.0, 136.8, 133.7,133.6,
131.9, 131.3, 130.3, 129.9, 129.3, 128.9, 128.8, 128.3, 128.2, 128.0,
127.9, 127.5, 126.6, 126.4, 126.3, 126.1, 123.8, 120.4, 119.2, 119.1, 118.6,
118.5, 115.7, 115.6, 105.7, 105.6, 55.9, 55.1, 51.3, 49.1, 48.4, 48.3, 48.1,
47.7, 47.3, 47.2, 46.2, 45.0, 44.7, 41.3; IR: 3455, 3229, 2918, 2826,
1696, 1636, 1604, 1504, 1495, 1480, 1438, 1410, 1392, 1268, 1227,
NMR (125 MHz, DMSO-d6),
d: 170.5, 170.4, 168.6, 168.3, 167.3,
167.2, 158.6, 158.5, 150.8, 150.6, 136.9, 136.8, 131.8, 130.9, 130.3,
130.2, 130.1, 128.9, 128.8, 127.9, 126.4, 126.3, 126.1, 123.8, 120.4,

A. Mieczkowski, J. Jurczak / Tetrahedron 66 (2010) 2514–2519
2519
1161, 1025, 759, 695; HR ESI MS: m/z for [MþNa]þ calculated:
P.; Thomas, A. W. Bioorg. Med. Chem. Lett. 2002, 12, 1881; (c) Broggini, G.;
Garanti, L.; Molteni, G.; Zecchi, G. Tetrahedron 1998, 54, 14859.
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(b) Robarge, K. D.; Dina, M. S.; Somers, T. C.; Lee, A.; Rawson, T. E.; Olivero,
A. G.; Tischler, M. H.; Webb, R. R., II; Weese, K. J.; Aliagnas, I.; Blackburnt, B.
K. Bioorg. Med. Chem. 1998, 6, 2345.
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Braccio, M.; Roma, G.; Ballabeni, V.; Tognolini, M.; Calcina, F.; Barocelli, E. Eur. J.
Med. Chem. 2002, 37, 933.
612.2587; found: 612.2610.
4.3.10. (8S,10aS)-2-(R)- and (8S,10aS)-2-((S)-2-oxo-1-phenyl-2-(4-
phenylpiperazin-1-yl)ethyl)-8-phenylhexahydropyra-zino[1,2-
a][1,4]diazepine-6,10(7H,10aH)-dione (3b). Mixture of diaster-
eomers; isolated yield: 119 mg (30%); Rf¼0.48 (3% MeOH in
CH2Cl2); 1H NMR (500 MHz, CD3OD),
d: 7.40–7.25 (m, 8H, HAr);
4. Pigeon, P.; Decroix, B. Tetrahedron Lett. 1997, 38, 2985.
5. Failli, A.; Shumsky, J. S.; Steffan, R. J.; Caggiano, T. J.; Williams, D. K.; Trybulski,
E. J.; Ning, X.; Lock, Y.; Tanikella, T.; Hartmann, D.; Chan, P. S.; Park, C. H. Bioorg.
Med. Chem. Lett. 2006, 16, 954.
6. Di Braccio, M.; Grossi, G.; Ceruti, M.; Rocco, F.; Loddo, R.; Sanna, G.; Busonera,
B.; Murreddu, M.; Marongiu, M. E. Il Farmaco 2005, 60, 113.
7. Ruano, J. L. G.; Gil, J. I. A.; Fraile, A.; Castro, A. M. M.; Martin, M. R. Tetrahedron
Lett. 2004, 45, 4653.
8. Thurston, D. E.; Subhas Bose, D. Chem. Rev. 1994, 94, 433.
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Gunnet, J. W.; Hageman, W.; Look, R.; Moore, J. B. Lett. Drug Des. Discovery 2005,
2, 219.
7.22–7.17 (m, 2H, HAr); 7.14–7.05 (m, 1H, HAr); 6.89–6.79 (m, 2H,
HAr); 4.56, 4.51 (2ꢂs, 1H, H-7); 4.32–4.20 (m, 2H, H-5a,e); 3.80–
3.46 (m, 4H, HpCH2NC]O); 3.27–3.20 (m, 2H, H–6a,e); 3.15–3.05,
3.05–2.85, 2.66–4.49 (3ꢂm, 6H, 4HpCH2NPhþH-3a,eþH-1); 2.44,
2.40 (2ꢂdt, 1H, J1¼3, J2¼12, H-4a); 2.24, 1.94; (2ꢂdt, 1H, J1¼3,
J2¼12, H-4e); 2.09, 1.89 (2ꢂt, 1H, J¼11.5, H-2); 13C NMR (125 MHz,
CD3OD), d:170.9, 170.8, 167.8, 167.8, 167.1, 167.0, 136.1, 136.0, 131.7,
131.6, 130.5, 130.4, 130.1, 130.0, 129.8, 129.7, 129.6, 128.8, 128.7,
121.6, 117.8, 57.1, 56.8, 56.6, 55.2, 54.4, 50.7, 50.6, 50.4, 50.2, 46.7,
46.6, 44.9, 43.3, 43.2, 42.2, 42.0, 41.7; IR: 3446, 3254, 2922, 2857,
2822, 1684, 1656, 1599, 1495, 1439, 1336, 1273, 1154, 1018, 759,
702; HR ESI MS: m/z for [MþNa]þ calculated: 560.2637, found:
560.2646.
10. Bunin, B. The Combinatorial Index; Academic: San Diego, 1998; pp. 77–212.
11. Multicomponent Reactions; Zhu, J., Bienayme, H., Eds.; Wiley-VCH GmbH & Co.
KGaA: Weinheim, 2005.
12. (a) Matthews, J. M.; Dyatkin, A. B.; Evangelisto, M.; Gauthier, D. A.; Hecker, L. R.;
Hoekstra, W. J.; Liu, F.; Poulter, B. L.; Sorgi, K. L.; Maryanoff, B. E. Tetrahedron:
Asymmetry 2004, 15, 1259; (b) Matthews, J. M.; Hoekstra, W. J.; Dyatkin, A. B.;
Hecker, L. R.; Hlasta, D. J.; Poulter, B. L.; Andrade-Gordon, P.; de Garavilla, L.;
Demarest, K. T.; Ericson, E.; Gunnet, J. W.; Hageman, W.; Look, R.; Moore, J. B.;
Reynolds, C. H.; Maryanoff, B. E. Bioorg. Med. Chem. Lett. 2004, 14, 2747;
(c) Dyatkin, A. B.; Hoekstra, W. J.; Hlasta, D. J.; Andrade-Gordon, P.; de Garavilla,
L.; Demarest, K. T.; Gunnet, J. W.; Hageman, W.; Look, R.; Maryanoff, B. E. Bioorg.
Med. Chem. Lett. 2002, 12, 3081.
Acknowledgements
The authors are grateful to Prof. Wiktor Kozminski for the help
in analysis of the correlation NMR spectra.
13. Boojamra, C. G.; Burow, K. M.; Thompson, L. A.; Ellman, J. A. J. Org. Chem. 1997,
62, 1240.
14. Mitsunobu, O.; Yamada, Y. Bull. Chem. Soc. Jpn. 1967, 40, 2380.
15. Massa, S.;Corelli, F.; Stefancich, G.; DeMartino, G. J. Heterocycl. Chem.1980,17,1781.
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Tetrahedron 1993, 49, 3593; (b) Ripka, W. C.; De Lucca, G. V.; Bach, A. C., II;
Pottorf, R. S.; Blaney, J. M. Tetrahedron 1993, 49, 3609.
References and notes
1. (a) Bertelli, L.; Biagi, G.; Giorgi, I.; Livi, O.; Manera, C.; Scartoni, V.; Martini, C.;
Giannaccini, G.; Trincavelli, L.; Barili, P. L. Il Farmaco 1998, 53, 305; (b) Fruscella,