A novel solid-phase synthetic method for 1,4-benzodiazepine-2,5-dione derivatives

Article abstract of DOI:10.1055/s-2008-1078484

Utilizing polymer-bound anthranilic acid derivatives 1, we were able to obtain the 1,4-benzodiazepine-2,5-dione derivatives 3 (R³ = H, R ⁴ = H, MeO, Cl) through an unprecedented reaction sequence, reductive alkylation-N-protected amino acid coupling-deprotective cyclization, in 28-71% five-step overall isolated yields and 95-99% purities from Wang resin 4. Applying the novel protocol to the resin 2, the 7-benzamido-1,4-benzodiazepine- 2,5-dione derivatives 3 (R¹ = Bn, R⁴ = 7-BzNH) could be obtained in 19-42% seven- or eight-step overall isolated yields and 92-98% purities from AMEBA resin 7. Thieme Stuttgart.

Full text of DOI:10.1055/s-2008-1078484

LETTER
1651
A Novel Solid-Phase Synthetic Method for 1,4-Benzodiazepine-2,5-dione
Derivatives
Solid-Phase
Synthesis
o
of 1,4-Benzo
o
diazepine-2,
n
5-dione
D
eri
-
vatives Kook Jeon,* Jeong-Jin Kwon, Myung-Su Kim, Young-Dae Gong
Korea Research Institute of Chemical Technology, P.O. Box 107, Yuseong-gu, Daejeon, 305-600, Korea
Fax +82(42)8607694; E-mail: moteta@krict.re.kr
Received 18 March 2008
O
O
Abstract: Utilizing polymer-bound anthranilic acid derivatives 1,
we were able to obtain the 1,4-benzodiazepine-2,5-dione deriva-
tives 3 (R3 = H, R4 = H, MeO, Cl) through an unprecedented reac-
tion sequence, reductive alkylation–N-protected amino acid
coupling–deprotective cyclization, in 28–71% five-step overall iso-
lated yields and 95–99% purities from Wang resin 4. Applying the
novel protocol to the resin 2, the 7-benzamido-1,4-benzodiazepine-
2,5-dione derivatives 3 (R1 = Bn, R4 = 7-BzNH) could be obtained
in 19–42% seven- or eight-step overall isolated yields and 92–98%
purities from AMEBA resin 7.
Ph
O
O
NH2
R4
N
OMe
O
R3
O
R4
N
5
NH2
4
7
R2
3
1
2
1
N
R1
2
3
Figure 1
Key words: combinatorial chemistry, solid-phase synthesis,
anthranilic acid, benzodiazepine, cyclative cleavage
with a-amino acids or esters,4a,7 (iv) ring closure of N-(a-
haloacetyl) derivatives of 2-aminobenzamides,4a,8 (v)
treatment of N-(a-haloacetyl) derivatives of anthranilates
with ammonia,9 (vi) palladium-catalyzed carbonylative
cyclization of N-(a-aminoacetyl) derivatives of 2-haloa-
nilines.10 Some other methods were also reported involv-
ing the reaction of a-amino ester coupled 2-
carboxyphenyl triflate and ammonia11a and the condensa-
tion of 2-aminobenzamide and 2-phenyl-4-arylideneox-
azolinones.11b
Solid-phase synthesis of combinatorial libraries has
emerged as a powerful tool for efficient drug discovery
process.1 We have recently been exploring the potential of
resin-bound anthranilic acid derivatives 1 and 2 as versa-
tile intermediates for combinatorial generation of drug-
like heterocyclic compound libraries2 (Figure 1). Herein
we would like to present a novel solid-phase synthetic
method for 1,4-benzodiazepine-2,5-dione derivatives 3
from resin-bound anthranilic acid derivatives 1 and 2.
On the other hand, there were several reports regarding
the solid-phase synthetic methods for 1,4-benzodiaz-
epine-2,5-dione-based libraries. The first protocol in solu-
tion phase was actively adapted to the solid-phase
synthesis of 1,4-benzodiazepine-2,5-dione derivatives
varying the resin, attachment site, and substituents.4o,12
Utilization of Ugi four-component condensation products
was also reported to afford 1,4-benzodiazepine-2,5-dione
derivatives through postcleavage cyclization starting from
the resin-bound isonitriles,13a–c the resin-bound a-amino
acids,13d or the resin-bound anthranilic acids.13e In addi-
tion, the solid-phase synthesis of 1,4-benzodiazepine-2,5-
dione derivatives was performed utilizing the condensa-
tion of resin-bound isatoic anhydrides and a-amino ac-
ids.14 As an example of so-called solid/solution-phase
annulation (SPAn) reagents, the N-(a-bromoacetyl) deriv-
ative of a resin-bound anthranilic acid was utilized for the
preparation of 1,4-benzodiazepine-2,5-dione derivatives
from primary amines.15
Recently 1,4-benzodiazepine-2,5-dione derivatives, a
subclass of general 1,4-benzodiazepines,3 have attracted
much attention for their interesting biological properties
including the potential as a scaffold for RGD peptidomi-
metics,4a GPIIbIIIa-fibrinogen interaction antagonistic
activity for antithrombotic agents,4a–d p53-HDM2 interac-
tion antagonistic activity,4e–h cytotoxic4i–k and anti-
proliferative4l activities, cell adhesion inhibitory
activity,4m and HDAC inhibitory activity4n for anticancer
agents, IgE synthesis inhibitory activity in human B-cells
for treatment of allergic diseases,4o GHS receptor antago-
nistic activity for treatment of obesity and related disor-
ders,4p and endothelin receptor antagonistic activity.4q
The 1,4-benzodiazepine-2,5-dione skeleton was con-
structed in solution phase according to the following
methods: (i) cyclization of 2-nitrobenzamides,4i,5a–c 2-azi-
dobenzamides,5d–f or N-protected 2-aminobenzamides5g–i
prepared from a-amino esters or N-carboxy amino acid
anhydrides, (ii) postmodification of Ugi four-component
condensation products from anthranilic acids or 2-ni-
trobenzoic acids,6 (iii) condensation of isatoic anhydrides
Nearly all these reported solid-phase synthetic methods
except the corresponding example of SPAn reagents are
characterized by the common reaction sequence that
forms the 1,4-benzodiazepine-2,5-dione skeleton through
the prior formation of the amide bond between N-4 and C-
5 and subsequent linkage between N-1 and C-2. On the
other hand, it may be understood that it is needed to ex-
SYNLETT 2008, No. 11, pp 1651–1656
x
x
.x
x
.2
0
0
8
Advanced online publication: 11.06.2008
DOI: 10.1055/s-2008-1078484; Art ID: U02208ST
© Georg Thieme Verlag Stuttgart · New York

1652
M.-K. Jeon et al.
LETTER
NH
O
NH
O
O
H2N
Cl
Cl Cl
OH
OEt
O
O
O
N
Cl
H
H
N
N
N
O
N
N
O
O
O
N
O
G-7446 (ref. 4b)
G-7570 (ref. 4c)
H
N
NH
N
O
O
VAD-463 (ref. 4n)
Figure 2
ploit the R4 substituent as well as the R1, R2, and R3 sub- (R4 = H, R1 = Bn, R2 = Bn).17 Deprotection of the resin 6a
stituents in order to fully realize the potential of the 1,4- in 20% piperidine–DMF at room temperature directly fur-
benzodiazepine-2,5-dione scaffold for construction of nished the 1,4-benzodiazepine-2,5-dione derivative 3a
combinatorial libraries from the inspection of some exam- (Table 1) through the subsequent spontaneous cyclative
ples of 1,4-benzodiazepine-2,5-dione derivatives cleavage18 in one pot. Although the racemization-prone
(Figure 2, structure 3). As a novel approach to solid-phase phenylalanine was used,19 significant racemization was
synthesis of 1,4-benzodiazepine-2,5-dione derivatives, not observed for the reaction sequence (<1%) as deter-
we envisioned that the resin-bound anthranilic acid deriv- mined by chiral HPLC analysis of the derivative 3a com-
atives 1 and 2 could be adapted to an unprecedented reac- pared with that of the corresponding racemic reference.
tion sequence, even in solution phase, that constructs the The reaction sequence was successfully applied to the res-
ring skeleton through the prior formation of the amide in-bound anthranilic acid derivatives 1 under the above
bond between N-1 and C-2 and subsequent linkage be- established conditions to afford some 1,4-benzodiaz-
tween N-4 and C-5 using N-protected amino acids as con- epine-2,5-dione derivatives 3 (R3 = H) in 28–71% five-
necting building blocks,16 and that in particular the step overall isolated yields and 95–99% purities from
intermediate resin 2 could provide 1,4-benzodiazepine- Wang resin 4 as summarized in Table 1. The solid-phase
2,5-dione derivatives encompassing diverse amino-relat- reactions to the final products 3 were checked by on-bead
ed functional groups for R4 substituent (Schemes 1 and 2). ATR-FTIR spectroscopy and the compounds 3 in Table 1
are unknown except 3a4n and 3e,20 and all final products
In order to confirm the possibilities, we first started the in-
1
3a–o were characterized on the basis of H NMR, 13C
vestigation from the resin-bound anthranilic acid deriva-
NMR, and LC–UV–MS spectral data.
tives 1 prepared by our previously reported procedure2a,b
from Wang resin 4 (Scheme 1). The N-benzylation of the Utilizing the novel protocol established for the resin-
resin 1a (R4 = H) under the reported conditions2a gave the bound anthranilic acid derivatives 1 (Scheme 1), we pro-
N-benzylated anthranilate resin 5a (R4 = H, R1 = Bn). Re- ceeded to the preparation of the 1,4-benzodiazepine-2,5-
action of the intermediate 5a with N-Fmoc-protected phe- dione derivatives 3 with amino-related benzamido func-
nylalanine (R2 = Bn, 3 equiv) in the presence of POCl3 (3 tionality at the 7-position from the resin intermediate 2
equiv) and pyridine (6 equiv) in CH2Cl2 at room tempera- (Scheme 2). The resin intermediate 2, prepared on the ba-
ture afforded the amino acid coupled anthranilate resin 6a sis of our previously reported procedure,2b was subjected
O
O
O
O
H
OH
ref. 2a,b
ref. 2a
NH2
N
R1
4
R4
R4
1
5
O
O
FmocHN
O
R2
R2
R4
O
OH
NH
R2
piperidine
DMF, r.t.
NHFmoc
O
N
R1
N
R1
POCl3, py
CH2Cl2, r.t.
O
R4
3 (R3 = H)
6
Scheme 1
Synlett 2008, No. 11, 1651–1656 © Thieme Stuttgart · New York

LETTER
Solid-Phase Synthesis of 1,4-Benzodiazepine-2,5-dione Derivatives
1653
Table 1 Yields and Purities of Compounds 3a–o (R3 = H)
to the reaction sequence (reductive alkylation using benz-
aldehyde, Fmoc-protected amino acid coupling, and
deprotective cyclization) to afford the resin-bound 1,4-
benzodiazepine-2,5-dione derivatives 9. The cleavage of
the resins 9 was accomplished in 50% TFA–CH2Cl2 at
room temperature successfully to give the final products,
7-benzamido-1,4-benzodiazepine-2,5-dione derivatives 3
(R1 = Bn, R3 = H, R4 = 7-BzNH) in 35–42% seven-step
overall isolated yields and 92–98% purities from AMEBA
resin 7. The results are summarized in Table 2. To exploit
the possibility for the preparation of 1,4-benzodiazepine-
2,5-diones with substituents at the 4-position, the resin 9
(R2 = H) was treated with benzyl bromide (3 equiv) in the
presence of Cs2CO3 (3 equiv) in DMF at 60 °C, and the
subsequent cleavage in 50% TFA–CH2Cl2 at room tem-
perature gave the expected N-benzylated product 3u (R1 =
R3 = Bn, R2 = H, R4 = 7-BzNH) in 19% eight-step overall
isolated yield and 96% purity from AMEBA resin 7. Sim-
ilarly in the case of the resin 1, the solid-phase reactions
in Scheme 2 were also checked by on-bead ATR-FTIR
spectroscopy. Significant racemization was not observed
for the reaction sequence (<1%) as determined by chiral
HPLC analysis of the derivative 3p. The compounds 3
(R4 = 7-BzNH) in Table 2 are all unknown and were char-
Compd. R4
R1
R2
Yield
(%)a
Purity
(%)b
3a
3b
3c
3d
3e
3f
H
Bn
Bn
s-Bu
i-Bu
Me
H
52
49
65
46
38
66
68
70
37
41
39
29
71
65
28
99
98
99
99
99
99
95
99
99
99
98
99
99
99
99
H
Bn
H
Bn
H
Bn
H
Bn
H
4-MeOBn
4-FBn
4-O2NBn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
3g
3h
3i
H
H
MeO
MeO
MeO
MeO
Cl
3j
2-MeBn
3-FBn
i-Bu
3k
3l
3m
3n
3o
Bn
1
acterized on the basis of H NMR, 13C NMR, and LC–
Cl
4-NCBn
UV–MS spectral data.
Cl
pyridyl-3-methyl Bn
In conclusion, we were able to establish a novel efficient
protocol for the construction of 1,4-benzodiazepine-2,5-
dione skeleton utilizing the resin-bound anthranilic acid
derivatives 1 and 2.21 The reaction sequence, reductive
alkylation–N-protected amino acid coupling–deprotective
a Five-step overall isolated yields from Wang resin 4 (loading capac-
ity = 0.92 mmol/g) after silica gel column chromatography.
b Determined on the basis of LC–UV(200–400 nm)–MS spectrum of
the isolated products after silica gel column chromatography.
Ph
O
Ph
O
O
O
H
N
N
benzaldehyde
OMe
OMe
NH2
ref. 2b
O
NaBH(OAc)3
DCE, r.t.
NH
Bn
7
8
2
O
R2
OH
NHFmoc
Ph
O
O
O
i)
H
N
POCl3, py
CH2Cl2, r.t.
N
Ph
NH
NH
TFA
R2
R2
O
CH2Cl2, r.t.
ii) piperidine
DMF, r.t.
N
N
O
O
Bn
Bn
9
3 (R1 = Bn, R3 = H, R4 = 7-BzNH)
BnBr
Cs2CO3
DMF, 60 °C
R2 = H
Ph
O
O
O
Bn
Bn
N
H
N
Ph
N
N
TFA
O
CH2Cl2, r.t.
N
N
O
O
Bn
3u (R1 = R3 = Bn, R2 = H, R4 = 7-BzNH)
Bn
10
Scheme 2
Synlett 2008, No. 11, 1651–1656 © Thieme Stuttgart · New York

1654
M.-K. Jeon et al.
LETTER
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cyclization, was unprecedented even in solution phase and
in particular the intermediate resin 2 enabled us to exploit
the diverse amino-related functionalities at the 7-position
of the scaffold. The examination of the scope and limita-
tion of the protocol for diversification of the substituents
of 1,4-benzodiazepine-2,5-dione skeleton is currently in
progress focusing on the amino-related functionalities
other than amido group.
Table 2 Yields and Purities of the Compounds 3p–u (R4 = 7-BzNH)
Compound R1
R2
R3
H
Yield (%)a Purity (%)b
3p
3q
3r
3s
3t
Bn
Bn
Bn
Bn
Bn
Bn
Bn
i-Bu
i-Pr
Me
H
40
35
39
42
38
19
98
95
93
95
92
96
H
H
H
H
3u
H
Bn
a Seven- or eight-step overall isolated yields from AMEBA resin 7
(loading capacity = 1.6 mmol/g) after silica gel column chromatogra-
phy.
b Determined on the basis of LC–UV (200–400 nm)–MS spectrum of
the isolated products after silica gel column chromatography.
Acknowledgment
We are grateful to the Center for Biological Modulators and the Ko-
rea Research Institute of Chemical Technology for financial support
of this research.
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Synlett 2008, No. 11, 1651–1656 © Thieme Stuttgart · New York

LETTER
Solid-Phase Synthesis of 1,4-Benzodiazepine-2,5-dione Derivatives
1655
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1985, 24, 905.
(10) (a) Mori, M.; Uozumi, Y.; Ban, Y. J. Chem. Soc., Chem.
Commun. 1986, 841. (b) Mori, M.; Kimura, M.; Uozumi,
Y.; Ban, Y. Tetrahedron Lett. 1985, 26, 5947.
(21) Representative Procedures for Preparation of
Compounds 3
Preparation of (S)-2-{Benzyl[2-(Fmoc-amino)-3-
phenylpropionyl]amino}benzoate Resin (6a; R4 = H, R1 =
Bn, R2 = Bn): To a mixture of the resin 5a2a,b (R4 = H, R1 =
Bn, 100 mg, theoretically 0.077 mmol) and Fmoc-
phenylalanine (93 mg, 0.23 mmol) in CH2Cl2 (2 mL) at r.t.
were added pyridine (37 mg, 0.46 mmol) and phosphorous
oxychloride (37 mg, 0.23 mmol). The mixture was stirred at
r.t. for 10 h and the resin was filtered, washed several times
with CH2Cl2, DMF, MeOH, H2O, and MeOH, and dried in a
vacuum oven to give 6a (124 mg). On-bead ATR-FTIR:
3418 (NH), 3028, 2921, 1722 (OC=O, NH-Fmoc,
(11) (a) Kraus, G. A.; Liu, P. Tetrahedron Lett. 1995, 36, 7595.
(b) Subhashini, N. J. P.; Hanumanthu, P. Indian J. Chem.,
Sect. B: Org. Chem. Incl. Med. Chem. 2000, 39, 198.
(12) (a) Boojamra, C. G.; Burow, K. M.; Ellman, J. A. J. Org.
Chem. 1995, 60, 5742. (b) Boojamra, C. G.; Burow, K. M.;
Thompson, L. A.; Ellman, J. A. J. Org. Chem. 1997, 62,
1240. (c) Cheng, M.-F.; Fang, J.-M. J. Comb. Chem. 2004,
6, 99. (d) Goff, D. A.; Zuckermann, R. N. J. Org. Chem.
1995, 60, 5744. (e) Mayer, J. P.; Zhang, J.; Bjergarde, K.;
Lenz, D. M.; Gaudino, J. J. Tetrahedron Lett. 1996, 37,
8081. (f) Smith, R. A.; Bobko, M. A.; Lee, W. Bioorg. Med.
Chem. Lett. 1998, 8, 2369. (g) Migihashi, C.; Sato, F.
J. Heterocycl. Chem. 2003, 40, 143. (h) Kamal, A.; Reddy,
G. S. K.; Raghavan, S. Bioorg. Med. Chem. Lett. 2001, 11,
387. (i) Kamal, A.; Reddy, G. S. K.; Reddy, K. L.;
Raghavan, S. Tetrahedron Lett. 2002, 43, 2103.
overlapped), 1664 (NC=O), 1601, 1512, 1492, 1451, 1241,
1076, 1028, 824, 757, 738, 697 cm–1.
Preparation of (S)-1,3-Dibenzyl-1,4-benzodiazepine-2,5-
dione (3a; R4 = H, R1 = Bn, R2 = Bn): To the resin 6a (R4 =
H, R1 = Bn, R2 = Bn, 124 mg, theoretically 0.074 mmol) was
added 20% piperidine–DMF (2 mL) and the mixture was
stirred at r.t. for 7.5 h. The mixture was filtered and washed
with CH2Cl2. The filtrate was evaporated in vacuo and the
residue was purified by a silica gel column chromatography
(n-hexane–EtOAc, 1:1) to afford 3a (14 mg, 52%; 99%
purity on the basis of LC–UV–MS spectrum). Chiral HPLC
analysis of the derivative 3a was performed using
CHIRALCEL OD-H (0.46 × 25 cm, DAICEL) column, 10%
EtOH in hexane eluent at 0.6 mL/min flow rate, and UV
detector at l = 254 nm and showed a major peak at the tR =
22.40 min and a trace (<1%) at tR = 20.20 min. In the case of
the corresponding racemic reference prepared from racemic
phenylalanine by the same method, the HPLC spectrum
showed two peaks at tR = 21.87 and 23.17 min under the
same conditions. 1H NMR (500 MHz, CDCl3): d = 3.08 (dd,
J = 7.9, 14.5 Hz, 1 H), 3.48 (dd, J = 6.7, 14.5 Hz, 1 H), 4.14
(m, 1 H), 5.10 (d, J = 15.7 Hz, 1 H), 5.14 (d, J = 15.7 Hz, 1
H), 6.74 (br d, J = 5.4 Hz, 1 H), 7.10 (d, J = 7.2 Hz, 2 H),
7.20–7.30 (m, 10 H), 7.44 (dt, J = 1.5, 8.4 Hz, 1 H), 7.80 (dd,
J = 1.5, 7.8 Hz, 1 H). 13C NMR (125 MHz, CDCl3): d = 34.8,
52.2, 53.8, 122.3, 126.2, 126.8, 127.1, 127.5, 128.8, 129.4,
130.4, 132.6, 136.3, 136.6, 140.1, 168.4, 169.7 (shortage of
two aromatic carbon peaks maybe due to peak overlapping).
ESI–MS: m/z = 357 [M + H]+.
Preparation of Methyl 5-Benzamido-2-benzylamino-
benzoate Resin (8): To a mixture of the resin 22b (460 mg,
theoretically 0.53 mmol), prepared from AMEBA resin (1.6
mmol/g), and benzaldehyde (169 mg, 1.59 mmol) in DCE (5
mL) at r.t. was added NaBH(OAc)3 (338 mg, 1.59 mmol).
The mixture was stirred at r.t. for 5 h and the resin was
filtered, washed several times with CH2Cl2, DMF, MeOH,
H2O and MeOH, and dried in a vacuum oven to give 8 (482
mg). On-bead ATR–FTIR: 3365 (NH), 3026, 2922, 1681
(OC=O), 1643 (NC=O), 1610, 1587, 1505, 1494, 1451,
1382, 1214, 1196, 1156, 1113, 1029, 819, 756, 697 cm–1.
Preparation of (S)-Methyl 5-Benzamido-2-{benzyl[2-
(13) (a) Hulme, C.; Peng, J.; Morton, G.; Salvino, J. M.; Herpin,
T.; Labaudiniere, R. Tetrahedron Lett. 1998, 39, 7227.
(b) Kennedy, A. L.; Fryer, A. M.; Josey, J. A. Org. Lett.
2002, 4, 1167. (c) Chen, J. J.; Golebiowski, A.;
Klopfenstein, S. R.; West, L. Tetrahedron Lett. 2002, 43,
4083. (d) Hulme, C.; Ma, L.; Kumar, N. V.; Krolikowski, P.
H.; Allen, A. C.; Labaudiniere, R. Tetrahedron Lett. 2000,
41, 1509. (e) Dener, J. M. Int. Patent, WO 2000056721,
2000; Chem. Abstr. 2000, 133, 266873.
(14) Kamal, A.; Reddy, K. L.; Shankaraiah, V. D. N. Synlett
2004, 1841.
(15) Dolle, R. E.; MacLeod, C.; Martinez-Teipel, B.; Barker, W.;
Seida, P. R.; Herbertz, T. Angew. Chem. Int. Ed. 2005, 44,
5830.
(16) A referee pointed out a report in which the solution-phase
synthesis of 1,4-benzodiazapine-2,5-dione using a similar
strategy was described. See: Gordon-Wylie, S. W.; Teplin,
E.; Morris, J. C.; Trombley, M. I.; McCarthy, S. M.; Cleaver,
W. M.; Clark, G. R. Crystal Growth Design 2004, 4, 789.
(17) Although several other conditions for the resin 5a and
N-Fmoc-protected phenylalanine (R2 = Bn, 3 equiv) were
examined varying coupling agent [DCC, DIC, EDC, O-
benzotriazole-N,N,N¢,N¢-tetramethyluronium hexafluoro-
phosphate (HBTU), 2-(7-aza-1H-benzotriazole-1-yl)-
1,1,3,3-tetramethyluronium hexafluorophosphate (HATU),
O-(benzotriazol-1-yl)-N,N,N¢,N¢-tetramethyluronium
tetrafluoroborate (TBTU), BOP, PyBOP, 2-chloro-1,3-
dimethylimidazolidium hexafluorophosphate (CIP), 1,1¢-
carbonyldiimidazole (CDI), N,N¢-disuccinimidyl carbonate
(DSC), or diphenylphosphoryl azide (DPPA)], additive
[none, N-hydroxybenzotriazole (HOBt), 1-hydroxy-7-aza-
benzotriazole (HOAt), or N-hydroxysuccinimide (HOSu)],
base [none, pyridine, Et3N, diisopropylethylamine (DIEA),
or NMM], solvent [CH2Cl2, THF, DMF, or N,N-dimethyl-
acetamide (DMA)] at r.t. or elevated temperatures, they did
Synlett 2008, No. 11, 1651–1656 © Thieme Stuttgart · New York

1656
M.-K. Jeon et al.
LETTER
mixture was stirred at r.t. for 12 h and the mixture was
(Fmoc-amino)-3-phenylpropionyl]amino}benzoate
Resin (R2 = Bn): To a mixture of the resin 8 (100 mg,
theoretically 0.10 mmol) and Fmoc-phenylalanine (116 mg,
0.300 mmol) in CH2Cl2 (2 mL) at r.t. were added pyridine
(47 mg, 0.60 mmol) and phosphorus oxychloride (46 mg,
0.30 mmol). The mixture was stirred at r.t. for 10 h and the
resin was filtered, washed several times with CH2Cl2, DMF,
MeOH, H2O and MeOH, and dried in a vacuum oven to give
the amino acid coupled intermediate resin (R2 = Bn, 125
mg). On-bead ATR-FTIR: 3418 (NH), 3027, 2924, 1724
(OC=O, N-Fmoc, overlapped), 1650 (2 × NC=O,
filtered and washed with CH2Cl2. The filtrate was
evaporated in vacuo and the residue, dissolved in CH2Cl2,
was passed through a SAX cartridge and washed with
CH2Cl2. The filtrate was evaporated in vacuo and the residue
was purified by a silica gel column chromatography (n-
hexane–EtOAc, 1:1) to afford 3p (19 mg, 40%; 98% purity
on the basis of LC–UV–MS spectrum). Chiral HPLC
analysis of the derivative 3p was performed using the same
protocol as that for the derivative 3a and showed a major
peak at tR = 70.42 min and a trace (<1%) at tR = 53.44 min.
In the case of the corresponding racemic reference prepared
from racemic N-Fmoc-phenylalanine by the same method,
the HPLC spectrum showed two peaks at tR = 52.28 and
71.32 min under the same conditions: 1H NMR (500 MHz,
CDCl3): d = 3.00 (dd, J = 8.1, 14.4 Hz, 1 H), 3.43 (dd, J =
6.5, 14.4 Hz, 1 H), 4.14 (m, 1 H), 5.02 (d, J = 15.5 Hz, 1 H),
5.17 (d, J = 15.5 Hz, 1 H), 6.31 (br, 1 H), 7.08 (d, J = 6.5 Hz,
2 H), 7.16–7.28 (m, 9 H), 7.43 (t, J = 7.9 Hz, 2 H), 7.53 (t,
J = 7.4 Hz, 1 H), 7.78 (d, J = 2.6 Hz, 1 H), 7.86 (d, J = 8.5
overlapped), 1611, 1504, 1493, 1450, 1264, 1197, 1159,
1030, 822, 757, 735, 698 cm–1.
Preparation of (S)-7-Benzamido-1,3-dibenzyl-1,4-
benzodiazepine-2,5-dione Resin (9; R2 = Bn): To the
amino acid coupled intermediate resin (R2 = Bn, 139 mg,
theoretically 0.11 mmol) at r.t. was added 20% piperidine–
DMF (2 mL). The mixture was stirred at r.t. for 7.5 h and the
resin was filtered, washed several times with CH2Cl2, DMF,
and MeOH, and dried in a vacuum oven to give 9 (R2 = Bn,
112 mg). On-bead ATR-FTIR: 3418 (NH), 3027, 2923, 1662
(3 × NC=O, overlapped), 1610, 1493, 1450, 1263, 1195,
1158, 1115, 1031, 824, 734, 698 cm–1.
Hz, 2 H), 8.32 (dd, J = 2.6, 8.9 Hz, 1 H), 8.84 (br s, 1 H). 13
C
NMR (125 MHz, CDCl3): d = 34.9, 52.1, 53.8, 121.3, 123.5,
124.8, 127.0, 127.2, 127.3, 127.6, 128.7, 128.8, 128.9,
129.3, 132.2, 134.5, 135.7, 135.9, 136.5, 136.7, 166.1,
168.1, 169.4 (shortage of one aromatic carbon peak maybe
due to peak overlapping). ESI–MS: m/z = 476 [M + H]+.
Preparation of (S)-7-Benzamido-1,3-dibenzyl-1,4-
benzodiazepine-2,5-dione (3p; R1 = R2 = Bn, R3 = H, R4 =
7-BzNH): To the resin 9 (R2 = Bn, 112 mg, theoretically
0.10 mmol) at r.t. was added 50% TFA–CH2Cl2 (2 mL). The
Synlett 2008, No. 11, 1651–1656 © Thieme Stuttgart · New York