Versatile synthesis of chiral 2-substituted-5-oxo-1,2,3,4-tetrahydro-5H-1,4-benzodiazepines as novel scaffolds for peptidomimetic building

Article abstract of DOI:10.1016/S0040-4020(03)00681-1

The stereocontrolled synthesis of phenylalanine and tryptophan derived 5-oxo-1,2,3,4-tetrahydro-5H-1,4-benzodiazepine derivatives is described. This new methodology involves a modified Strecker reaction of N-Boc protected amino aldehydes and methyl anthra

Full text of DOI:10.1016/S0040-4020(03)00681-1

Tetrahedron 59 (2003) 4491–4499
Versatile synthesis of chiral 2-substituted-5-oxo-1,2,3,4-
tetrahydro-5H-1,4-benzodiazepines as novel scaffolds for
peptidomimetic building
a
Susana Herrero, M. Teresa Garcıa-Lopez, Edurne Cenarruzabeitia, Joaquın Del Rıo
a
b
b
´
´
´
´
and Rosario Herranza
,
*
a
´
´
Instituto de Quımica Medica (CSIC), Juan de la Cierva 3, E-28006 Madrid, Spain
´
Departamento de Farmacologıa, Universidad de Navarra, Irunlarrea 1, E-31080, Spain
b
Received 27 February 2003; accepted 30 April 2003
Abstract—The stereocontrolled synthesis of phenylalanine and tryptophan derived 5-oxo-1,2,3,4-tetrahydro-5H-1,4-benzodiazepine
derivatives is described. This new methodology involves a modified Strecker reaction of N-Boc protected amino aldehydes and methyl
anthranilate, reduction of the resulting a-amino nitriles, and lactamization. The resulting 2-substituted-5-oxo-1,2,3,4-tetrahydro-5H-1,4-
benzodiazepines were further functionalized at position 4 by alkylation or acylation reactions. One of these new tryptophan-derived 1,4-
benzodiazepines showed significant selective binding affinity at cholecystokinin CCK1 receptors (IC50¼156.5^33.2 nM). q 2003 Elsevier
Science Ltd. All rights reserved.
1. Introduction
versatile access to novel chiral 2,4-disubstituted-5-oxo-
1,2,3,4-tetrahydro-5H-1,4-benzodiazepine derivatives 1,
from amino acid-derived 2-(methoxycarbonylphenyl)amino
nitriles 2, shown in the retrosynthetic Scheme 1. This
strategy involves the application, as key step, of our
methodology for the synthesis of amino acid-derived
amino nitriles,19–22 via a modified Strecker reaction,
followed by subsequent cyano reduction, lactamization,
and introduction of diverse R2 substitutions into position 4
of the benzodiazepine ring.
The wide range of biological activities displayed by
benzodiazepine derived compounds makes benzodiazepine
scaffolds, particularly 1,4-benzodiazepine systems, among
the most important privileged structures for drug
discovery.1,2 Thus, in addition to the well-known
anxiolytic,3 sedative,4 and anticonvulsant5 activities of the
classic benzodiazepines such as diazepam, triazolam or
midazolam, several 1,4-benzodiazepine derivatives have
demonstrated activity as antitumor antibiotics,6 anti-HIV
agents,7,8 and antiarrhytmics.9 Furthermore, diverse 1,4-
benzodiazepine derivatives have also been used as con-
strained dipeptide mimics or non-peptide scaffolds in the
search of peptidomimetics either as enzyme inhibitors, such
as farnesyltransferase inhibitors,10,11 or as ligands of
G-protein coupled receptors, which include cholecysto-
kinin,12 fibrinogen,13 integrin,14 vasopressin,15 oxytocin,16
bradykinin,17 or k-opioid18 receptors.
We have studied and report herein the applicability of
retrosynthetic Scheme 1, first to the preparation of
phenylalanine derivatives. Then, taking into account the
importance of the tryptophan and the indole ring as
privileged structures in the search of cholecystokinin
receptor ligands, this methodology was extended to the
preparation of tryptophan-derived 1,4-benzodiazepine
derivatives.
In the context of our current interest in methodologies for
constructing peptidomimetics, particularly in the search of
cholecystokinin receptor ligands, we envisioned a new and
Keywords: 5-oxo-1,2,3,4-tetrahydro-5H-1,4-benzodiazepines; 1,4-
benzodiazepine derivatives; amino acid-derived amino nitriles;
peptidomimetics; Strecker synthesis; reduction; lactamization.
*
Corresponding author. Tel.: þ34-91-5622900; fax: þ34-91-5644853;
Scheme 1. Retrosynthesis of 5-oxo-1,2,3,4-tetrahydro-5H-1,4-benzodi-
azepine derivatives 1.
e-mail: rosario@iqm.csic.es
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00681-1

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S. Herrero et al. / Tetrahedron 59 (2003) 4491–4499
2. Results and discussion
Table 1. Influence of temperature and time of reaction of 3a with 4, before
adding TMSCN, upon the yield of the amino nitrile 6a
The first step for the synthesis of the proposed 1,4-
benzodiazepine derivatives was the preparation of amino
nitriles 6a and 6b by a modified Strecker reaction of methyl
anthranilate (4) with the N-protected a-amino aldehydes
Boc-L-Phe-H (3a) and Boc-L-Trp-H (3b), respectively, in
the presence of trimethylsilyl cyanide (TMSCN)
(Scheme 2). Initially, this reaction was carried out applying
the reaction conditions developed for the synthesis of
C[CH(CN)NH]-pseudopeptides,19 which involves reaction
of an a-amino aldehyde with an amino acid in the presence
of ZnCl2 at -208C for 1 h, followed by in situ reaction with
TMSCN for 24 h at 08C. However, under these conditions,
amino nitriles 6a,b were obtained as minor compounds
(30%) along with cyanohydrins 7a,b (50%). This result
indicated that, due to the lower nucleophilic character of the
aniline amino group of 4 in comparison with the amino
group of amino acids, a low formation of the imine 5 had
occurred when the TMSCN was added, and, therefore, the
reaction equilibrium was shifted towards the faster for-
mation of cyanohydrins 7. The formation of imines 5 was
detected by TLC, but they could neither be isolated nor
quantified, as they reverted towards methyl anthranilate and
the corresponding amino aldehyde 3a or 3b.
Solvent
T (8C)
T (h)
% 6a
MeOHa
MeOHa
MeOHa
MeOHb
Benzeneb
220
0
20
65
80
1
1
12
12
12
30
40
60
81
20
a
Conditions for the formation of imine 5a, followed by reaction with
TMSCN at 08C for 24 h.
Conditions for the formation of imine 5a, followed by reaction with
TMSCN at room temperature for 24 h.
b
hydrogenation was carried out in the presence of two
equivalents of AcOH at 3 atm of H2 pressure, at either room
temperature or 508C, a complex mixture of degradation
compounds was obtained, from which the N-methyl amine
derivative 8a (Scheme 3) was the only compound that could
be isolated, although in low yield (20%). This compound
resulted from the hydrogenation of the cyano group,
followed by reaction of the resulting amine with formal-
dehyde, originated from the MeOH oxidation by the
metallic catalyst.25 Using EtOH as solvent also led to
degradation compounds, from which a 12% yield of the
hydrogenolysis product 9a was isolated.
To improve the yield of amino nitriles 6, it was necessary to
increase the temperature and reaction time for the imine
formation up to 658C and 24 h (Table 1), as well as the
temperature of the subsequent in situ reaction with TMSCN,
up to room temperature. Under these conditions, amino
nitriles 6a and 6b were obtained in 81 and 62% yield,
respectively, as (1:2) (R,S)-epimeric mixtures at the new
stereogenic center, which could not be resolved. Interest-
ingly, when we tried to obtain the imine 5a by azeotropic
distillation in benzene of a mixture of 3a and 4, followed by
addition of TMSCN, the amino nitrile 6a was obtained only
in 20% yield within a complex mixture of degradation
compounds.
In contrast to our previous experience in the reduction of
C[CH(CN)NH]pseudopeptides,22–24 several attempts to
reduce the cyano group in the epimeric mixture of amino
nitriles 6a by catalytic hydrogenation in the presence of
10% Pd(C) gave negative results. Thus, after four days in
MeOH at room temperature and 1 atm of H2 pressure, this
amino nitrile mixture was recovered unchanged. When this
Scheme 3. Synthesis and configuration assignment of 5-oxo-1,2,3,4-
tetrahydro-5H-1,4-benzodiazepines. Reagents: (a) H2, Pd(C), AcOH,
MeOH, 508C; (b) H2, Pd(C), AcOH, EtOH, 508C; (c) Raney Ni, NH2–
NH2·H2O, MeOH, 658C. (d) NaMeO, MeOH, 658C; (e) 2.5N HCl in
EtOAc; (f) (Cl3CO)2CO, TEA, CH2Cl2.
Scheme 2. Synthesis of amino acid-derived 2-(methoxycarbonylphenyl)-
amino nitriles. Reagents: (a) ZnCl2, MeOH; (b) TMSCN, MeOH.

S. Herrero et al. / Tetrahedron 59 (2003) 4491–4499
4493
As shown in Scheme 3, the cyano reduction of amino
nitriles 6a and 6b was satisfactorily carried out by Raney
nickel catalyzed hydrogen transfer from hydrazine hydrate
in refluxing MeOH.26 Thus, the triamine derivatives 10a and
10b were obtained in 94 and 80% yield, respectively. The
subsequent treatment of these (2:1) (R,S)-epimeric mixtures
with NaOMe in refluxing MeOH for 7–10 days led to the
corresponding 5-oxo-1,2,3,4-tetrahydro-5H-1,4-benzo-
diazepine derivatives 11a and 11b (87–65%), which were
chromatographically resolved in their respective epimers
(2R)-11a,b and (2S)-11a,b. To assign the C2 absolute
configuration in these compounds, they were transformed
into their 1,6-dioxo-1,2,3,3a,4,5-hexahydro-imidazo[3,4-
a][1,4]benzodiazepine derivatives (3aR)- and (3aS)-12a,b,
by N-Boc protection removal, followed by reaction with
bis(trichloromethyl)carbonate. The NOE effects observed in
the DPGSE-NOE spectra of compounds 12a,b, shown in
Scheme 3, allowed the assignment of configuration at C3a,
and, therefore, at C2 in 11a,b.
The possibility of introducing additional groups regio-
selectively into position 4 of the 1,4-benzodiazepine ring,
either by alkylation or acylation, was studied in both major
epimers (2R)-11a and (2R)-11b (Scheme 4). The reaction of
these compounds with MeI in the presence of NaH led to the
corresponding 4-methyl derivatives (2R)-15a,b. In the case
of the tryptophan derivative (2R)-11b, some dimethylation
at position 4 and at the indole NH was also observed,
depending on the excess of MeI and NaH used.
Analogously, the reaction of (2R)-11a and (2R)-11b with
methyl bromoacetate in the presence of NaH led to the
4-methoxycarbonyl methyl derivatives (2R)-16a and (2R)-
16b. In this case, no dialkylation was observed in the
tryptophan derivative (2R)-11b. On the other hand, the
reaction of (2R)-11a and (2R)-11b with an equivalent of
phenyl isocyanate in the presence of NaH gave the
4-phenylcarbamoyl derivatives (2R)-17a and (2R)-17b
selectively. It is worth mentioning that 1,4-benzodiazepine
derivatives 16 are N- and C-orthogonally protected and
conformationally restricted tripeptide analogues, which
could be used for the introduction of conformational
restrictions into larger peptides.
Although no racemization had previously been observed in
the synthesis of C[CH(CN)NH]pseudopeptides,19 it could
not be discharged in the synthesis of benzodiazepine
derivatives 11, due to the strong basic conditions needed
for the cyano reduction and lactamization steps, and to the
higher temperature required for the synthesis of amino
nitriles 6. To clarify this point, the phenylalanine-derived
1,4-benzodiazepine (2R)-11a was N-Boc-deprotected and
treated with excess of the Mosher acid chloride [(R)-a-
methoxy-a-(trifluoromethyl)phenylacetic acid chloride
[(R)-MTPA-Cl]]. As shown in Scheme 4, this treatment
yielded a mixture of the monoamide (2R)-13a (66%) and the
diamide (2R)-14a (22%). The fact that neither the HPLC
analysis nor the 1H NMR spectra of these compounds
showed the presence of duplicity of signals discharged the
existence of racemization in the synthesis of derivatives
11a.
Finally, as many of the biologically active 1,4-benzo-
diazepine derivatives are substituted at position 1, particu-
larly with a methyl group, such as for example in
Devazepide,27 prototype of CCK1 cholecystokinin receptor
antagonists, we also explored this possibility, which was
satisfactorily achieved by reaction of compounds (2R)-
11a,b with a 35–40% methanolic solution of formaldehyde
and NaBH3CN in the presence of AcOH, yielding
derivatives 2R)-18a,b (Scheme 4, yield .90%).
All new 5-oxo-1,2,3,4-tetrahydro-5H-1,4-benzodiazepine
derivatives 11–18a,b were evaluated as CCK1 and CCK2
receptor ligands, by measuring the inhibition of the specific
[3H]propionyl-CCK-8 binding to rat pancreas and cerebral
cortex homogenates,28 using CCK-8 and the CCK1 and
CCK2 selective antagonists Devazepide27 and PD-135,
15829 as standard compounds. Except for the tryptophan
derivative (2R)-11b, which showed selective affinity for
CCK1 receptors, with an IC50 of 156.5^33.2 nM, none of
these 1,4-benzodiazepine derivatives showed significant
binding affinity for any of both receptor subtypes at
concentrations below 10 mM. Compound (2R)-11b could
represent the starting hint for a new family of selective
CCK1 receptor ligands.
3. Conclusion
Herein we report a new efficient and versatile methodology
for the synthesis of highly functionalized chiral 5-oxo-
1,2,3,4-tetrahydro-5H-1,4-benzodiazepine derivatives from
amino acid-derived amino nitriles, which gives access to a
diversity of therapeutically privileged structures.
4. Experimental
4.1. General procedures
Scheme 4. Reactivity of 1,4-benzodiazepine derivatives. Reagents: (a) 2.5N
HCl in EtOAc; (b) (R)-MTPA-Cl, TEA, CH2Cl2; (c) MeI, NaH, THF;
(d) BrCH2CO2Me, NaH, THF; (e) Ph-NCO, NaH, THF; (f) 35–40%
HCHO in MeOH, NaBH3CN, AcOH, CH3CN.
All reagents were of commercial quality. Solvents were

4494
S. Herrero et al. / Tetrahedron 59 (2003) 4491–4499
dried and purified by standard methods. Analytical TLC was
performed on aluminum sheets coated with a 0.2 mm layer
of silica gel 60 F254, Merck. Preparative radial chromato-
graphy was performed on 20 cm diameter glass Plate coated
with a 1 mm layer of silica gel PF254 Merck. Silica gel 60
(230–400 mesh), Merck, was used for flash chromato-
graphy. Melting points were taken on a micro hot stage
apparatus and are uncorrected. Optical rotations were
with H2O (2£25 mL) and brine (25 mL), dried over
Na2SO4, and evaporated to dryness. The residue was
purified by flash chromatography using (1–20%) EtOAc–
hexane gradient for 6a and (0–3%) MeOH gradient in
CH2Cl2 for 6b as eluants. The most significant analytical
and spectroscopic data of 6a,b are summarized in Table 2.
4.1.2. Synthesis of (2RS,3S)-3-(tert-butoxycarbonyl)-
amino-2-(2-methoxycarbonyl)phenylamino-1-methyl-
amino-4-phenylbutane (8a). 10% Pd(C) (200 mg) and
acetic acid (32 mL, 0.5 mmol) were added to a solution of
the amino nitrile 6a (200 mg, 0.5 mmol) in MeOH (30 mL),
and the mixture was hydrogenated at 3 atm of H2 pressure
and 508C for two days. Afterward, the catalyst was filtered
off and washed with MeOH. The filtrate was evaporated,
and the residue was purified by flash chromatography using
(5–30%) EtOAc–hexane gradient as eluant. Compound 8a
was isolated in 20% yield (43 mg) as a foam. RP-HPLC tR
8.75 min [mBondapak C18, CH3CN/0.05% TFA (45:55)];
1H RMN (300 MHz, CDCl3) d 1.30 (s, 9H, Boc), 2.18 (s,
3H, N–CH3), 2.50 (m, 1H, 4-H), 2.66 (dd, 1H, J¼8,
13.5 Hz, 4-H), 2.75 (m, 2H, 2- and 1-H), 2.97 (dd, 1H, J¼3,
13.5 Hz, 1-H), 3.74 (s, 3H, O–CH3), 4.10 and 4.26 (2m, 1H,
3-H), 5.40 and 5.60 (2bs, 1H, NH-Boc), 6.50 [t, 1H,
J¼7.5 Hz, 4-H (N–Ph)], 6.58 and 6.78 [2d, 1H, J¼8 Hz,
6-H (N–Ph)], 7.02–7.30 [m, 6H, 4-Ph and 5-H (N–Ph)],
7.69 and 7.80 (2d, 1H, J¼7 Hz, 1-NH), 7.82 [dd, 1H, J¼2,
8 Hz, 3-H (N–Ph)]. Anal. calcd for C24H33N3O4: C 67.42,
H 7.78, N 9.83. Found: C 67.49, H 8.06, N 9.94.
1
measured on a Perkin Elmer 141 polarimeter. H NMR
spectra were recorded at 300, 400 or 500 MHz, using TMS
as reference, and 13C NMR spectra were recorded at 50, 75
or 125 MHz. Elemental analyses were obtained on a CH-O-
RAPID apparatus. Analytical RP-HPLC was performed on a
Waters mBondapak C18 (3.9£300 mm, 10 mm) column,
with a flow rate of 1 mL/min, and using a tunable UV
detector set at 214 nm. Mixtures of CH3CN (solvent A) and
0.05% TFA in H2O (solvent B) were used as mobile phases.
4.1.1. General procedure for the synthesis of amino acid-
derived 2-(methoxycarbonyl-phenyl)amino nitriles 6a
and 6b. Methyl anthranilate (1.21 g, 8 mmol) and ZnCl2
(0.60 g, 4.4 mmol) were added to a solution of the
corresponding amino aldehyde 3a19 or 3b19 (4 mmol) in
MeOH (75 mL), and the mixture was refluxed for 12 h. This
reaction mixture was left to cool at room temperature for
adding TMSCN (0.60 mL, 4.8 mmol), and the stirring was
continued at this temperature for additional 24 h. Then, the
solvent was evaporated and the residue was dissolved in
EtOAc (75 mL). This solution was successively washed
Table 2. Analytical and spectroscopic data of amino nitriles 6a,b and triamine derivatives 10a,b
[(2R)-6aþ(2S)-6a]
(S)
[(2R)-6bþ(2S)-6b]
(S)
[(2R)-10aþ(2S)-10a]
[(2R)-10bþ(2S)-10b]
In
R1
Ph
In
Ph
CH2-NH2
(R)
R2
CN
(R)
(1:2)
81
CN
(R)
(1:2)
62
CH2-NH2
(R)
( p ) Configuration
(2R:2S)
Yield (%)
Mp (8C)
tR (min)
(A:B)b
(S)
(S)
(2:1)a
94
(2:1)a
79
Foam
31.48
(40:60)
C23H27N3O4
151–155 (EtOAc)
29.85
(40:60)
Foam
15.05
(35:65)
C23H31N3O4
Foam
11.68
(35:65)
C25H32N4O4
17.21
(35:65)
Formulac
C25H28N4O4
1H RMNd
1-H
2-H
2.88, 2.95
3.68
4.10
2.90, 2.97
5.20
8.09
2.95, 3.05
2.84, 2.95
3.66
4.24
3.08
5.20
2.90
4.30
4.40
2.90, 3.20
4.70
8.30
4.40
4.70
3.10, 3.20
4.85
8.30
4.35
4.60
3.25, 3.40
3-H
4.33
4.45
2.90
4.84
7.84
3.88
3-CH2
NH-Boc
NH-Ph
OCH3
2.98, 3.05
4.80
2.78, 2.88
4.78
8.08
8.12
3.87
3.80
3.77
3.81
3.78
3.86
3.88
13C NMRe
C1
C2
C3
3-CH2
CO2Me
117.19
53.40
48.45
38.33
168.40
117.77
52.52
48.15
24.45
168.43
42.04
55.61
53.59
37.36
169.06
43.04
56.41
54.67
38.38
169.90
41.90
52.71
55.82
27.04
169.09
43.38
53.76
56.76
29.24
169.70
48.10
a
After the cyano reduction the ligand preference in the CIP notation rules changes.
mBondapak C18 (10 mm, 3.9£300 mm), A¼CH3CN, B¼0.05% TFA in H2O.
Satisfactory analyses for C, H, N.
Spectra registered at 300 or 500 MHz in CDCl3, assigned with the help of DQCOSY spectra.
Spectra registered at 50 or 125 MHz in CDCl3, assigned with the help of HMQC spectra.
b
c
d
e

S. Herrero et al. / Tetrahedron 59 (2003) 4491–4499
4495
Table 3. Analytical and spectroscopic data of the 5-oxo-1,2,3,4-tetrahydro-5H-1,4-benzodiazepine derivatives (2R)- and (2S)-11a,b
(2R)-11a
CH2-Ph
(2R)
(2S)-11a
CH2-Ph
(2S)
(2R)-11b
CH2-In
(2R)
(2S)-11b
CH2-In
(2S)
21
C24H28N4O3
17.63 (30:70)
R1
( p ) Configuration
Yield (%)
Formulaa
tR (min) (A:B)b
[a]2D0
61
26
43
C22H27N3O3
17.88 (30:70)
2105 (c, 1 in MeOH)
C22H27N3O3
16.08 (30:70)
þ129 (c, 1 in MeOH)
C24H28N4O3
18.26 (30:70)
293 (c, 1 in MeOH)
þ63 (c, 1 in MeOH)
1H RMNc
1-H
2-H
4.65
3.63
4.25
3.65
3.50
3.50
4.00
3.56
3-H
4-H
3.40, 3.45
7.38
4.00
2.81, 3.02
4.90
0 and 6
13
2
3.38, 3.49
7.18
3.90
2.78, 2.85
5.03
0 and 6
15
3
3.30, 3.40
7.24
4.12
3.00
4.80
0 and 7
14.5
2
3.29, 3.38
6.64
3.99
2.96
4.94
0 and 7
14.5
2
10-H
10-CH2
NH-Boc
J2,3
J3,3
J3,4
13C NMRd
C2
C3
C5
C1
10-CH2
63.48
41.02
172.11
54.54
36.92
61.80
43.26
172.00
55.54
38.45
63.31
41.07
172.19
53.34
26.99
61.68
43.58
171.91
54.19
28.22
0
Isolated as foams.
a
Satisfactory analyses for C, H, N.
mBondapak C18 (10 mm, 3.9£300 mm), A¼CH3CN, B¼0.05% TFA in H2O.
b
c
d
Spectra registered at 400 or 500 MHz in CDCl3, assigned with the help of DQCOSY spectra.
Spectra registered at 50 or 125 MHz in CDCl3, assigned with the help of HMQC spectra.
4.1.3. Synthesis of (2S)-2-(tert-butoxycarbonyl)amino-1-
(2-methoxycarbonyl)phenylamino-3-phenylpropane
(9a). 10% Pd(C) (200 mg) and acetic acid (32 mL,
0.5 mmol) were added to a solution of the amino nitrile 6a
(200 mg, 0.5 mmol) in EtOH (30 mL), and the mixture was
hydrogenated at 3 atm of H2 pressure and 508C for two days.
Afterward, the catalyst was filtered off and washed with
EtOH. The filtrate was evaporated, and the residue was
purified by flash chromatography using (5–30%) EtOAc–
hexane gradient as eluant. Compound 9a was isolated in
12% yield (23 mg) as a foam. RP-HPLC tR 9.96 min
through silica gel 60 (230–400 mesh), and the silica was
washed with boiling MeOH (5£10 mL).The filtrates were
evaporated, and the residue was purified by flash chroma-
tography using (0–5%) MeOH–CH2Cl2 gradient as eluant.
The most significant analytical and spectroscopic data of
10a,b are summarized in Table 2.
4.1.5. General procedure for the synthesis of 5-oxo-
1,2,3,4-tetrahydro-5H-1,4-benzodiazepine derivatives
(2R)- and (2S)-11a,b. Sodium methoxide (220 mg,
4 mmol) was added to a solution of the corresponding
epimeric mixture of triamines 10a or 10b (1 mmol) in dry
MeOH (75 mL), and the solution was refluxed for 7–10
days. Afterward, the solvent was evaporated and the residue
was dissolved in EtOAc (75 mL). The solution was washed
with H2O (20 mL) and brine (25 mL), dried over Na2SO4,
and evaporated to dryness. The residue was purified by flash
chromatography, using (0–5%) MeOH–CH2Cl2 gradient as
eluant, which also resolved the epimeric mixtures into their
respective (2R)- and (2S)-epimers. The most significant
analytical and spectroscopic data of 1,4-benzodiazepine
derivatives (2R)- and (2S)-11a,b are summarized in Table 3.
1
[mBondapak C18, CH3CN/0.05% TFA (45:55)]; H RMN
(200 MHz, CDCl3) d 1.45 (s, 9H, Boc), 2.90 (d, 2H,
J¼6 Hz, 3-H), 3.22 (dd, 1H, J¼5, 13 Hz, 1-H), 3.35 (dd, 1H,
J¼5, 13 Hz, 1-H), 3.90 (s, 3H, O–CH3), 4.15 (m, 1H, 2-H),
4.63 (d, 1H, J¼7 Hz, NH-Boc), 6.60 [t, 1H, J¼7 Hz, 4-H
(N–Ph)], 6.71 [d, 1H, J¼7 Hz, 6-H (N–Ph)], 7.13–7.40 [m,
6H, 4-Ph and 5-H (N–Ph)], 7.80 [dd, 1H, J¼2, 8 Hz, 3-H
(N–Ph)], 8.00 (bs, 1H, 1-NH). Anal. calcd for C22H28N2O4:
C 68.73, H 7.34, N 7.29. Found: C 68.84, H 7.53, N 7.42.
4.1.4. General procedure for the reduction of amino
nitriles 6a,b. Synthesis of 10a and 10b. Raney Ni (900 mg)
and hydrazine hydrate (1.94 mL, 40 mmol) were added to a
solution of the corresponding amino nitrile 6a or 6b
(2 mmol) in MeOH (100 mL), and the resulting reaction
mixture was refluxed for 1 h. Then, the mixture was filtered
4.1.6. General procedure for the synthesis of 1,6-dioxo-
1,2,3,3a,4,5-hexahydroimidazo[3,4-a][1,4]-benzo-diaze-
pines (3aR)- and (3aS)-12a,b. A solution of the corre-
sponding 1,4-benzodiazepine derivative (2R)- and

4496
S. Herrero et al. / Tetrahedron 59 (2003) 4491–4499
Table 4. Analytical and spectroscopic data of the 1,6-dioxo-1,2,3,3a,4,5-hexahydroimidazo[3,4-a][1,4]benzodiazepines (3aR)- and (3aS)-12a,b
(3aR)-12a
CH2-Ph
(3aR)
(3aS)-12a
(3aR)-12b
CH2-In
(3aR)
(3aS)-12b
CH2-In
(3aS)
64
C20H18N4O2
Foam
R1
CH2-Ph
(3aS)
46
( p ) Configuration
Yield (%)
Formulaa
Mp (8C)
58
44
C18H17N3O2
260–262 (MeOH)
5.71 (30:70)
2143 (c, 1 in DMSO)
C18H17N3O2
180–183 (EtOAc–hexane)
6.61 (30:70)
þ34 (c, 1 in MeOH)
C20H18N4O2
.320 (CH2Cl2-MeOH)
6.38 (30:70)
26 (c, 1 in MeOH)
tR (min) (A:B)b
[a]2D0
6.68 (30:70)
þ29 (c, 1 in MeOH)
1H RMNc
2-H
3-H
6.81
4.06
6.96
3.84
6.81
4.16
6.95
3.88
3a-H
4-H
5-H
3-CH2
J3,3a
J3a,4
4.20
3.20, 3.42
8.32
2.86, 3.04
8
0 and 5
15.5
5 and 7
3.81
2.70, 3.08
8.20
2.85, 2.90
–
0 and 4
15
4 and 7
4.22
3.18, 3.48
8.38
2.98, 3.20
8
0 and 5
15.5
5 and 7
3.83
2.82, 3.10
8.22
2.98
8
0 and 4
15
4 and 7
J4,4
J5,4
13C NMRd
C1
C3
C3a
C4
159.84
54.12
64.97
40.10
170.53
36.98
159.03
54.51
65.47
41.45
169.96
39.63
160.06
53.06
64.83
40.00
170.45
27.04
159.23
54.09
66.04
41.73
170.13
29.84
C6
3-CH2
a
Satisfactory analyses for C, H, N.
mBondapak C18 (10 mm, 3.9£300 mm), A¼CH3CN, B¼0.05% TFA in H2O.
b
c
d
Spectra registered at 300 MHz in DMSO-d6, assigned with the help of DQCOSY spectra.
Spectra registered at 50 or 75 MHz in DMSO-d6, assigned with the help of HMQC spectra.
(2S)-11a,b (0.2 mmol) in 2.5N solution of HCl in EtOAc
(10 mL) was stirred at room temperature for 2–5 h. This
solution was evaporated to dryness, and the residue was
dissolved in H2O (3 mL) and lyophilized. The resulting
residue was dissolved in dry CH2Cl2 (15 mL), and the
solution was cooled to 08C. Then, TEA (28 mL, 0.2 mmol),
bis(trichloromethyl)carbonate (60 mg, 0.2 mmol), and TEA
(168 mL, 1.2 mmol) were added successively, and the
reaction mixture was stirred at 08C for 30 min. Afterward,
this mixture was diluted with CH2Cl2 (15 mL), washed with
H2O (2£10 mL) and brine (2£10 mL), dried over Na2SO4,
and evaporated. The residue was purified by flash
chromatography using (0–6%) MeOH–CH2Cl2 gradient
as eluant. The most significant analytical and spectroscopic
data of (3aR)- and (3aS)-12a,b are summarized in Table 4.
successively, and the reaction mixture was stirred at 08C
for 30 min. Afterward, this mixture was diluted with
CH2Cl2 (10 mL), successively washed with saturated
NaHCO3 (2£3 mL), H2O (2£3 mL) and brine (2£3 mL),
dried over Na2SO4, and evaporated. The residue was
purified by flash chromatography using (0–5%) MeOH–
CH2Cl2 gradient as eluant, to give the monoamide (2R)-13a
and the diamide (2R)-14a.
(2R)-2-[(1S)-1-[(R)-1-Methoxy-1-trifluoromethyl-phenyl-
acetyl]amino-2-phenylethyl]-5-oxo-1,2,3,4-tetrahydro-5H-
1,4-benzodiazepine (2R)-13a. White solid (11.0 mg, 52%);
[a]2D0¼2238 (c, 0.1 in CHCl3); mp 190–1938C (EtOAc–
hexane). tR 4.80 min (mBondapak C18; CH3CN/0.05% TFA
1
50:50); H RMN (300 MHz, CDCl3, 608C), d (ppm): 2.69
[dd, 1H, J¼11, 14 Hz, 20-H (ethyl)]; 3.06 (s, 3H, O–CH3);
3.22 [dd, 1H, J¼4.5, 14 Hz, 20-H (ethyl)]; 3.27 (dd, 1H,
J¼4, 12 Hz, 3-H); 3.44 (ddd, 1H, J¼2, 7, 12 Hz, 3-H); 3.58
(m, 1H, 2-H); 4.20 (bs, 1H, 1-H); 4.39 [m, 1H, 10-H (ethyl)];
6.48 (t, 1H, J¼4 Hz, 4-H); 6.59 (d, 1H, J¼8 Hz, 9-H); 6.81
(t, 1H, J¼8 Hz, 7-H); 6.88 (d, 1H, J¼5 Hz, 10-NH); 7.10–
7.28 (m, 11H, Ph and 8-H); 7.77 (dd, 1H, J¼2, 8 Hz, 6-H).
4.1.7. Synthesis of the Mosher amide derivatives (2R)-
13a and (2R)-14a. A solution of the 5-oxo-1,2,3,4-
tetrahydro-5H-1,4-benzodiazepine
(2R)-11a
(15 mg,
40 mmol) in 2.5 N solution of HCl in EtOAc (10 mL) was
stirred at room temperature for 2–5 h. This solution was
evaporated to dryness, and the residue was dissolved in H2O
(3 mL) and lyophilized. The resulting residue was dissolved
in dry CH2Cl2 (5 mL), and the solution was cooled to 08C.
Then, TEA (5.8 mL, 40 mmol), (R)-MTPA-Cl (11.8 mL,
60 mmol), and TEA (8.7 mL, 60 mmol) were added
(2R)-4-[(R)-1-Methoxy-1-trifluoromethyl-phenylacetyl]-2-
[(1S)-1-[(R)-1-methoxy-1-trifluoromethyl-phenylacetyl]-
amino-2-phenylethyl]-5-oxo-1,2,3,4-tetrahydro-5H-1,4-

S. Herrero et al. / Tetrahedron 59 (2003) 4491–4499
4497
Table 5. Analytical and spectroscopic data of the phenylalanine-derived 5-oxo-1,2,3,4-tetrahydro-5H-1,4-benzodiazepine derivatives (2R)-15–18a
(2R)-15a
(2R)-16a
(2R)-17b
(2R)-18b
R1
Me
H
82
C23H29N3O3
84–85 (EtOAc–hexane)
28.16 (30:70)
CH2–CO2Me
H
96
C25H31N3O5
Foam
17.21 (30:70)
CONH–Ph
H
76
C29H32N4O4
Foam
5.71 (25:75)
H
Me
94
R2
Yield (%)
Formulaa
Mp (8C)
tR (min) (A:B)b
C23H29N3O3
Foam
32.41 (25:75)
1H RMNc
1-R 2
2-H
4.44
3.64
4.32
4.03
5.30
3.89
3.04
3.54
3-H
3.24, 3.52
3.04 (Me)
4.00
2.80
4.75
3.40, 3.60
3.70 (OMe) 4.16, 4.35 (CH2CO2Me)
3.72
2.74, 2.86
4.33
3.64, 4.86
11.80 (CONH)
4.16
2.98, 3.12
6.28
3.46, 3.65
7.31
4.44
2.73, 2.82
5.80
4-R 1
10-H
CH2-Ph
NH-Boc
J2,3
0 and 8
14
0 and 7
14
0 and 9
14
4 and 5
12
J3,3
13C NMRd
C2
C3
C5
C1
CH2-Ph
R1
R2
62.54
37.55
169.89
54.84
36.18
49.39 (Me)
–
62.62
47.83
170.37
54.51
64.46
42.21
174.00
57.01
37.85
157.40 (CONH)
71.32
41.04
172.51
52.17
39.05
–
0
37.86
50.83 (OMe) 50.15 (CH2CO2Me) 170.15 (CO2Me)
–
39.34
a
Satisfactory analyses for C, H, N.
mBondapak C18 (10 mm, 3.9£300 mm), A¼CH3CN, B¼0.05% TFA in H2O.
b
c
Spectra registered at 200 or 300 MHz in CDCl3 for (2R)-15a and (2R)-16a, and in (CD3)2CO for (2R)-17a and (2R)-18a, assigned with the help of DQCOSY
spectra.
d
Spectra registered at 50 or 75 MHz in CDCl3 for (2R)-15a and (2R)-16a, and in (CD3)2CO for (2R)-17a and (2R)-18a, assigned with the help of HMQC
spectra.
benzodiazepine (2R)-14a. Foam (5.0 mg, 17%);
[a]2D0¼2218 (c, 0.1 in CHCl3). tR 6.90 min (mBondapak
C18; CH3CN/0.05% TFA 50:50); 1H RMN (300 MHz,
CDCl3, 608C), d (ppm): 2.82 [dd, 1H, J¼11, 14 Hz, 20-H
(ethyl)]; 3.04 [dd, 1H, J¼5, 14 Hz, 20-H (ethyl)]; 3.10 (s,
3H, O–CH3); 3.38 (s, 3H, O–CH3); 3.80 (m, 2H, 3-H); 4.20
(m, 1H. 2-H); 4.41 [m, 1H, 10-H (ethyl)]; 5.17 (bs, 1H, 1-H);
6.57 (d, 1H, J¼8 Hz, 9-H); 6.70 (t, 1H, J¼8 Hz, 7-H); 6.89
[d, 1H, J¼8 Hz, NH(amide)]; 7.00–7.44 (m, 16H, Ph and
8-H); 7.55 (d, 1H, J¼8 Hz, 6-H).
(2£5 mL), 1N HCl ((2£5 mL), H2O (5 mL), and brine
(5 mL), dried over Na2SO4, and evaporated to dryness. The
residue was purified by flash chromatography using (0–5%)
MeOH–CH2Cl2 gradient as eluant. The most significant
analytical and spectroscopic data of 1,4-benzodiazepine
derivatives (2R)-15a,b and (2R)-16a,b are summarized in
Tables 5 and 6.
4.1.9. General procedure for the N-acylation of 5-oxo-
1,2,3,4-tetrahydro-5H-1,4-benzodiazepine derivatives
(2R)-11a,b at position 4. Synthesis of compounds (2R)-
17a,b. NaH (60% suspension in mineral oil; 4 mg,
0.1 mmol) and phenyl isocyanate (12 mL, 0.11 mmol)
were successively added to a solution of the corresponding
5-oxo-1,2,3,4-tetrahydro-5H-1,4-benzodi-azepine deriva-
tive (2R)-11a or (2R)-11b (0.1 mmol) in dry THF
(15 mL), and the resulting reaction mixture was stirred,
under argon, at room temperature for 30 min. Then, after
evaporation of the solvent, the reaction mixture was
dissolved in EtOAc (20 mL). This solution was successively
washed with H2O (2£5 mL), 1N HCl (2£5 mL), H2O
(5 mL), and brine (5 mL), dried over Na2SO4, and
evaporated to dryness. The residue was purified by flash
chromatography using 20% EtOAc in hexane as eluant. The
4.1.8. General procedure for the N-alkylation of 5-oxo-
1,2,3,4-tetrahydro-5H-1,4-benzodiazepine derivatives
(2R)-11a and (2R)-11b at position 4. Synthesis of
compounds 15a,b and 16a,b. NaH (60% suspension in
mineral oil; 20 mg, 0.5 mmol) and the appropriate halide
(MeI or BrCH2CO2Me; 0.5 mmol) were successively added
to a solution of the corresponding 5-oxo-1,2,3,4-tetrahydro-
5H-1,4-benzodiazepine derivative (2R)-11a or (2R)-11b
(0.1 mmol) in dry THF (15 mL), and the resulting reaction
mixture was stirred, under argon, at room temperature for a
period of 30 min to 48 h. Then, after evaporation of the
solvent, the reaction mixture was dissolved in EtOAc
(20 mL). This solution was successively washed with H2O

4498
S. Herrero et al. / Tetrahedron 59 (2003) 4491–4499
Table 6. Analytical and spectroscopic data of the tryptophan-derived 5-oxo-1,2,3,4-tetrahydro-5H-1,4-benzodiazepine derivatives (2R)-15–18b
(2R)-15b
Me
H
52
(2R)-16b
(2R)-17b
(2R)-18b
R1
CH2–CO2Me
H
76
C27H33N4O5
10.36 (30:70)
CONH–Ph
H
56
C31H33N5O4
19.30 (40:60)
H
Me
79
C25H30N4O3
9.75 (30:70)
R2
Yield (%)
Formulaa
tR (min) (A:B)b
C25H30N4O3
6.30 (35:65)
1H RMNc
1-R 2
2-H
4.40
3.75
4.48
3.76
4.72
3.84
3.02
3.62
3-H
3.35, 3.62
3.11 (Me)
4.22
3.05
4.50
3.44, 3.66
3.70 (OMe) 4.11, 4.38 (CH2CO2Me)
3.63, 4.83
11.77 (CONH)
4.26
3.12, 3.20
4.64
3.36, 3.44
6.56
4.52
2.84, 2.96
4.40
4-R 1
10-H
4.23
3.05
4.53
2 and 8
14
CH2-In
NH-Boc
J2,3
4 and 8
15
5 and 7
14
6 and 10
15
J3,3
13C NMRd
C2
C3
C5
62.47
48.39
173.56
53.76
27.34
36.00 (Me)
–
62.51
47.76
170.35
54.55
63.03
41.23
173.28
54.36
29.67
69.36
39.91
171.07
54.50
28.32
–
0
C1
CH2-In
R1
27.41
52.17 (OMe) 49.99 (CH2CO2Me) 170.20 (CO2Me)
–
156.00 (CONH)
–
R2
40.86
Isolated as foams.
a
Satisfactory analyses for C, H, N.
mBondapak C18 (10 mm, 3.9£300 mm), A¼CH3CN, B¼0.05% TFA in H2O.
b
c
d
Spectra registered at 400 or 500 MHz in CDCl3, assigned with the help of DQCOSY spectra.
Spectra registered at 50 or 125 MHz in CDCl3, assigned with the help of HMQC spectra.
most significant analytical and spectroscopic data of 1,4-
benzodiazepine derivatives (2R)-17a and (2R)-17b are
summarized in Tables 5 and 6.
Acknowledgements
This work has been supported by CICYT (SAF2000-0147).
4.1.10. General procedure for the N-methylation of
5-oxo-1,2,3,4-tetrahydro-5H-1,4-benzodiazepine deriva-
tives (2R)-11a,b at position 1. Synthesis of compounds
(2R)-18a,b. A 35–40% solution of formaldehyde in MeOH
(31 mL, 1.1 mmol) was added to a solution of the
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