Convenient synthesis of C-terminal di- and tri-peptide amides from N-protected dipeptidoylbenzotriazoles

Article abstract of DOI:10.1016/j.tet.2009.02.070

N-Protected dipeptidoylbenzotriazoles react with aqueous ammonia to give dipeptide primary amides (77-98%) and with N-unprotected α-amino amides to afford tripeptide primary amides (82-86%).

Full text of DOI:10.1016/j.tet.2009.02.070

Tetrahedron 65 (2009) 4923–4929
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Convenient synthesis of C-terminal di- and tri-peptide amides from N-protected
dipeptidoylbenzotriazoles
,
Ilhami Celik a, Ashraf A.A. Abdel-Fattah b
*
a Department of Chemistry, Faculty of Science, Anadolu University, 26470 Eskisehir, Turkey
b Department of Chemistry, Faculty of Science, Benha University, Benha, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
N-Protected dipeptidoylbenzotriazoles react with aqueous ammonia to give dipeptide primary amides
Received 21 October 2008
Received in revised form 12 February 2009
Accepted 26 February 2009
Available online 5 March 2009
(77–98%) and with N-unprotected
a
-amino amides to afford tripeptide primary amides (82–86%).
Ó 2009 Published by Elsevier Ltd.
1. Introduction
(where x is any amino acid residue) support growth of a leucine
auxotroph as well as the free peptide.17
Naturally occurring peptides are essential for many cellular
functions.1 Peptides modified at the C-terminus are substrates
or inhibitors for a variety of proteolytic enzymes.2 The in-
corporation of a primary amide at the C-terminus is common
modification:3 around 50% of biologically active peptides con-
N-Acylbenzotriazoles are neutral efficient coupling reagents for
N-acylation,18 C-acylation,19 and O-acylation.20 N-(Aminoacyl)-
benzotriazoles prepared from N-protected
a-amino acids were
successfully utilized for synthesis of di-, tri-, and tetrapeptides.21
As part of the synthetic strategy for the modification of peptides
at the C-terminus, we now report the synthesis of C-terminal
protected dipeptides 10a–l, (10aþ10a0),22 (10eþ10e0) and tripep-
tide amides 13a,b and (13aþ13a0) by treating N-protected
dipeptidoylbenzotriazoles 9a–l, (9aþ9a0), and (9eþ9e0) with
tain such functionality.4 Peptidyl
a-carboxamides are especially
widely distributed in animals and elicit vital physiological
effects:1a examples include oxytocin,5 lutenizing hormone re-
leasing hormone (LHRH),6 neurokinins,7 and vasopressin and
gastrine.8
aqueous ammonia or with unprotected
a-amino carboxamides
Peptidyl
a
-carboxamides are also found within protease in-
-682,679 (1) is
highly potent and selective inhibitor of HIV-1 protease
12a,b, respectively.
hibitors. For example, the pseudo pentapeptide
L
a
2. Results
(IC50¼0.42 nM, Fig. 1) (11) and
L-685,458 (2) is a potent inhibitor of
g
-secretase (IC50¼17 nM) of potential therapeutic benefit in the
2.1. Synthesis of N-protected dipeptidoylbenzotriazoles
treatment of Alzheimer’s disease and other neurological disorders
(Fig. 1).9 Cathepsin L (EC 3.4.22.16) is an example of the papain-like
cysteine proteases, which are ubiquitously distributed in the lyso-
somes of cells with prominent roles in nonspecific intracellular
protein breakdown,10 and physiologically important extra-cellular
functions.11
Treating Cbz-protected amino acids 5a–e and (5b0) with 4 equiv
of benzotriazole and 1 equiv of SOCl2 in THF or CH2Cl2 at 20 ꢀC for
2 h, following the published procedure,21a,c gave N-(Cbz-
a-amino-
acyl)benzotriazoles 6a–e and (6b0) in 78–95% (Scheme 1). Peptide
coupling was achieved by the reaction of 6a–e and (6b0) with un-
protected amino acids 7a–g and (7a0) in aqueous acetonitrile in the
presence of Et3N for 10–40 min.21b After washing with 6 M HCl, the
resulting dipeptides 8a–l, (8aþ8a0), and (8eþ8e0) were obtained in
71–95% yields (Scheme 2 and Table 1). These reactions proceed
without detectable racemization of the chiral center, as evidenced
by their NMR and HPLC analysis.21a,c,e
Recently, an Nu-nitroarginine-containing dipeptide amide [
L-
ArgNO2 -ArgNO2-NH2
-L-Lys-NH2 (LL) (3)] and [D-Lys-D (DD) (4)]
(Fig. 2)12 showed a remarkable selectivity (hundreds- to thousands-
fold) for inhibition of the neuronal isozyme of nitric oxide synthase
(nNOS) over two other isozymes.13 This nNOS selectivity has im-
plications in the potential treatment of strokes,14 migraine head-
aches,15 and Alzheimer’s disease.16 Moreover,
L-Leu-x-amides
Cbz-protected dipeptidoylbenzotriazoles 9a–l, (9aþ9a0), and
(9eþ9e0) were prepared in 64–91% yield from Cbz-protected di-
peptides 8a–l, (8aþ8a0), and (8eþ8e0) by reaction with 4 equiv of
benzotriazole and 1 equiv of SOCl2 at ꢁ15 ꢀC for 4–6 h (Scheme 2
and Table 2).21b–d
* Corresponding author.
E-mail address: ashraf25894@yahoo.com (A.A.A. Abdel-Fattah).
0040-4020/$ – see front matter Ó 2009 Published by Elsevier Ltd.
doi:10.1016/j.tet.2009.02.070

4924
I. Celik, A.A.A. Abdel-Fattah / Tetrahedron 65 (2009) 4923–4929
OH
O
OH
O
H
N
H
N
NH2
NH2
N
H
N
H
O
NHBoc
O
O
O
NHBoc
Me
Me
Me
Me
1
2
L-685,458
L-682,679
IC50 = 0.42 nM
IC50 = 17 nM
Figure 1. Chemical structures of the aspartyl protease inhibitors L-682,679 and L-685,458.
NHNO2
O
R2
O
H
N
L-ArgNO2-L-Lys-NH2 (LL)
NH2
HN
N
H
R1
H2N
7a-h, (7a')
R1
Cbz
OH
O
R2
NH2
O
O
NH2
Cbz
N
H
N
H
O
3
Bt
N
CH3CN/H2O/ Et3N
H
HO
6a-e, (6b')
8a-l, (8a-8a'), (8e+8e')
HNNO2
NH
O
H
D-Lys-D-ArgNO2 -NH2 (DD)
N
H2N
N
H
BtH, SOCl2
NH2
O
NH2
4
R1
Cbz
R1
O
O
R2
Bt
R2
Figure 2. Chemical structures of L-ArgNO2-L-Lys-NH2 (LL) and D-Lys-D-ArgNO2-NH2 (DD).
NH4OH
N
Cbz
N
H
N
N
H
O
H
O
H
THF, 0 °C
2.2. Synthesis of N-protected dipeptide primary amides
H2N
10a-l, (10a+10a'), (10e+10e')
9a-l, (9a+9a'), (9e+9e')
Treatment of the N-protected dipeptidoylbenzotriazoles 9a–l,
(9aþ9a0), and (9eþ9e0) with excess aqueous ammonium hydroxide
in THF at 0 ꢀC for 2 h afforded the corresponding dipeptide primary
amides 10a–l, (10aþ10a0), and (10eþ10e0) in 77–98% yield (Scheme
2 and Table 3). The structures of 10a–l, (10aþ10a0), and (10eþ10e0)
were supported by spectral data and elemental analyses.
NMR analysis showed no detectable racemization for com-
pounds 10a–l. No signals from their corresponding diastereomers
were observed in the NMR spectra of 10a–l suggesting the enan-
tiopurity of the N-protected dipeptide amides. For example, the 1H
NMR spectrum of 10a gave a clear doublet for the methyl protons of
Scheme 2.
dipeptidoylbenzotriazoles 9a,b and (9aþ9a0) (described above)
with N-unprotected-a-amino amides 12a,b (prepared by treating
the corresponding N-Fmoc-a-aminoacylbenzotriazoles 11a (Fmoc-
L
-Met-Bt) and 11b (Fmoc-Gly-Bt) with aqueous ammonia followed
by N-deprotection with piperidine utilizing a literature method23 in
acetonitrile at ꢁ15 ꢀC for 6 h to afford the corresponding N-pro-
tected tripeptide amides 13a,b and (13aþ13a0) in 82–86% yields
(Scheme 3 and Table 4).
L-Ala fragment at 1.19 ppm, whereas a multiplet was observed for
NMR spectroscopic analysis of the tripeptide amide 13a showed
approximately 25% racemization. The 1H NMR spectrum of 13a
displayed two separate doublets with different intensities for the
the corresponding diastereomeric mixture (10aþ10a0) ranging
from 1.08 to 1.23 ppm. Furthermore, compound 10a and the cor-
responding diastereomeric mixture (10aþ10a0) were subjected to
HPLC analysis using Chirobiotic T column (detection at 254 nm,
flow rate 1.0 mL/min, and 100% MeOH as solvent). As expected,
HPLC analysis of the enantiopure LL-dipeptide amide 10a showed
a signal peak at 3.86 min. In contrast, two peaks of equal intensity
at 3.67 and 3.79 min were observed for the corresponding di-
astereomeric mixture (10aþ10a0).
methyl protons of L-Ala fragment at 1.13 ppm and 1.26 ppm,
Table 1
Preparation of dipeptides 8
N-(Cbz- -aminoacyl) Amino acid
benzotriazoles
a
Product
Yielda (%)
95
2.3. Synthesis of N-protected tripeptide primary amides
6a
6a
6a
6a
6b
6b
(6b0)
L
-Ala, 7a
DL-Ala, (7a0)
-Trp, 7b
Gly, 7c
Cbz-
Cbz-
Cbz-
Cbz-
Cbz-
L
L
L
L
L
L
-Trp-L-Ala-OH, 8a
-Trp-DL-Ala-OH, (8aþ8a0) 93
L
-Trp-
-Trp-Gly-OH, 8c
-Ala-
-Ala-
L
-Trp-OH, 8b
86
93
79
91
81
Synthesis of N-protected tripeptide primary amides 13a,b and
(13aþ13a0) was achieved by reacting the N-protected
L
L
L
-Trp, 7d
L-Trp-OH, 8d
-Glu(OBn), 7e Cbz-
L-Glu(OBn)-OH, 8e
R1
-Glu(OBn), 7e Cbz-DL-Ala-
(8eþ8e0)
L-Glu(OBn)-OH,
R1
O
O
BtH, SOCl2
THF
Cbz
6b
6c
6d
6d
6d
6d
6f
L
L
L
L
L
L
L
-Pro, 7f
-Trp, 7d
-Met, 7f
Cbz-
Cbz-
Cbz-
L
L
L
L
L
L
-Ala-
-Met-
-Phe-
-Phe-
-Phe-
-Phe-
L-Pro-OH, 8f
78
86
70
93
79
71
Cbz
N
H
Bt
N
H
OH
L
-Trp-OH, 8g
-Met-OH, 8h
-Glu(OBn)-OH, 8i
-Asp(OBn)-OH, 8j
-Lys-OH, 8k
L
6a-e, (6b')
5a-e, (5b')
-Glu(OBn), 7e Cbz-
-Asp(OBn), 7g Cbz-
L
L
L
Bt = Benzotriazol-1-yl
R1: a, LTrp; b, L-Ala; b', DL-Ala; c, L-Met; d, L-Phe; e, D-Val
-Lys, 7h
Cbz-
-Asp(OBn), 7g Cbz-
D
-Val-
L
-Asp(OBn)-OH,b 8l 83
a
Scheme 1. Compound numbers written within brackets represent a diastereomeric
mixtures or racemates; compound numbers without brackets represent enantiomers.
Isolated yield.
Novel compound.
b

I. Celik, A.A.A. Abdel-Fattah / Tetrahedron 65 (2009) 4923–4929
4925
Table 2
Conversion of dipeptides 8 into N-Cbz-dipeptidoylbenzotriazoles 9
R3
R3
O
O
(i) NH4OH
Bt
(ii) Reduction
NH2
Reactant
Product
Yielda (%)
Fmoc
N
H
H2N
12a,b
8a
Cbz-
Cbz-
Cbz-
Cbz-
Cbz-
Cbz-
L
L
L
L
L
L
-Trp-
L
-Ala-Bt, 9a
79
64
89
75
78
91
79
76
73
79
80
81
63
88
11a-b
(8aþ8a0)
-Trp-DL-Ala-Bt, (9aþ9a0)b
8b
-Trp-L-Trp-Bt, 9b
9a-b, (9a+9a')
8c
8d
8e
-Trp-Gly-Bt, 9cb
-Ala-
-Ala-
L-Trp-Bt, 9d
R2
O
L-Glu(OBn)-Bt, 9e
(8eþ8e0)
Cbz-DL-Ala-
L
-Glu(OBn)-Bt, (9eþ9e0)
O
R3
8f
Cbz-
Cbz-
Cbz-
Cbz-
Cbz-
Cbz-
Cbz-
L
L
L
L
L
L
-Ala-
-Met-L
-Trp-Bt, 9gb
-Phe-
-Phe-
-Phe-
-Phe-
L
-Pro-Bt, 9fb
R1
N
H
N
H
8g
8h
8i
8j
8k
8l
O
L
-Met-Bt, 9h
NH
Cbz
NH2
L
L
L
-Glu(OBn)-Bt, 9i
-Asp(OBn)-Bt, 9j
-Lys-Bt, 9k
13a-b, (13a+13a')
D
-Val-
L
-Asp(OBn)-Bt, 9lb
Scheme 3.
a
Isolated yield.
Novel compound.
b
side-chain deprotection takes place in concert with cleavage); (v)
ammonolysis of support-bound esters of side-chain deprotected
peptide with liquid ammonia or ammonia/MeOH solution,33 or
ammonia/THF,34 (limited to side-chain deprotected peptides and
requiring well-sealed containers, as trace amounts of moisture can
result in the production of acid as a contaminant);35 and (vi)
deprotection and cleavage of solid-supported N-tetrachloro-
phthaloyl peptides.36
Biosynthetic techniques include: (vii) oxidative cleavage of
polypeptides by peptidylglycine alpha-amidating monooxygenase
(PAM);37 (viii) enzymatic couplings of an acyl donor component
(esters or thioesters) with an acyl acceptor component (amino acid
amides).38 Enzymatic approaches have attracted interest for years
because they take place in an aqueous medium and occur with high
stereo- and regio-selectivity in mild conditions of pH and temper-
ature with no need for side-chain protection. However, they may be
restricted to specific substrates, require long reaction times, and/or
give the products in low yield.38
respectively. However for compound 13b no signals for any corre-
sponding diastereomer were observed. The enantiopurity of tri-
peptide amide 13b was further confirmed by HPLC analyses using
Chirobiotic T column (detection at 254 nm, flow rate 1 mL/min, and
MeOH as solvent): tripeptide amide 13b gave a single retention
time, whereas the diastereomeric mixture (13aþ13a0) showed two
retention times as expected (Table 4).
Traditional syntheses of primary carboxamides (i) treat acids or
derived acid halides, anhydrides or esters with ammonia.24 How-
ever, the exothermic reactions of ammonia with acyl halides must
be controlled; acid anhydrides and ammonia can also form im-
ides.25 Additionally, these methods are often not suitable for
selective amidation.26 Other reported methods include: (ii)
ammonolysis of N-protected amino acids with diaminomethane
dihydrochloride,27 (iii) treatment of acids with ammonia-releasing
agents (NH4OH, NH4Cl or (NH4)2CO3) in the presence of benzo-
triazol-1-yl-oxytripyrrolidinophosphonium hexafluoro-phosphate
(PyBOP) and N-hydroxybenzotriazole (HOBt),28 1-ethyl-3-(3-
dimethylaminopropyl)carbodiimide (EDC) and N-hydroxy-7-aza-
benzotriazole (HOAt) or HOBt (48), N,N0-dicylcohexyl-carbodiimide
(DCC) and HOAt or HOBt,29 p-tolylsulfonyl chloride (TsCl),30 or N-
ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ).31 Difficul-
ties can arise from the insolubility of starting materials, competitive
hydrolysis or partial racemization in approaches (ii) and (iii).
We have shown that our methodology offers convenient pre-
parative and work-up procedures, and uses inexpensive reagents to
prepare N-protected di- and tripeptide primary amides from
readily available N-protected dipeptidoylbenzotriazoles in good
yields (77–98%) as compared with literature methods.
3. Summary
Peptidyl a-carboxamides have also been prepared previously by
several solid phase and biosynthetic methods. Solid phase syn-
theses include (iv) acidolytic cleavage of peptide from support-
bound benzylamine- or benzhydrylamine-based handles,32 (but
In summary, we have developed a convenient and efficient
approach for a broad range of chirally pure dipeptide primary
amides (average yield 88%), by treating the corresponding N-
protected dipeptidoylbenzotriazoles with aqueous ammonia. The
approach was extended to the preparation of tripeptide primary
amides (average yield 83%) by using some of the same substrates
Table 3
Conversion of 9 into dipeptide amides 10
Yielda (%) Mp (ꢀC)
[a]
D
23
with N-unprotected a-amino amides. These results, coupled with
Reactant Product
the simplicity of isolation and purification procedures, make this
approach competitive with literature methods.
9a
Cbz-
L
L
L
L
L
L
-Trp-
L
-Ala-NH2, 10ab
79
95
96
86
77
98
168–170
ꢁ9.5
(9aþ9a0) Cbz-
-Trp-DL-Ala-NH2,c (10aþ10a0)
157–160 ꢁ20.7
192–194 ꢁ36.6
151–155 ꢁ26.4
9b
9c
9d
9e
Cbz-
Cbz-
Cbz-
Cbz-
-Trp-L-Trp-NH2, 10b
-Trp-Gly-NH2, 10c
-Ala-
-Ala-
L
-Trp-NH2, 10d
-Glu(OBn)-NH2, 10e
201–202
162–163
138–139
ꢁ7.7
ꢁ3.0
ꢁ4.7
Table 4
Conversion of 9a,b and (9aþ9a0) into tripeptide amides 13
L
(9eþ9e0) Cbz-DL-Ala-
L
-Glu(OBn)-NH2, (10eþ10e0) 90
Reactant Amino amide Product
9a Met-NH2, 12a Cbz- -Trp-
Met-NH2, 13a
Yielda (%) Mp (ꢀC)
[a]
D
23
9f
9g
9h
9i
9j
9k
9l
Cbz-
Cbz-
Cbz-
Cbz-
Cbz-
Cbz-
Cbz-
L
L
L
L
L
L
-Ala-
-Met-
-Phe-
-Phe-
-Phe-
-Phe-
L
-Pro-NH2, 10f
L
95
91
94
96
98
92
88
161–162 ꢁ37.6
218–220 ꢁ12.7
208–210 ꢁ14.8
205–207 ꢁ10.6
-Trp-NH2, 10g
-Met-NH2, 10h
-Glu(OBn)-NH2, 10i
-Asp(OBn)-NH2, 10j
-Lys-NH2, 10k
L
L
-Ala-
82
82
86
222–224 ꢁ33.30
164–166 ꢁ17.92
220–221 ꢁ15.36
L
(9aþ9a0) Gly-NH2, 12b Cbz-
L-Trp-DL-Ala-
L
L
L
Gly-NH2,b (13aþ13a0)
162–163
193–195
ꢁ3.0
ꢁ8.5
9b
Gly-NH2, 12b Cbz-L-Trp-L-Trp-
Gly-NH2,c 13b
D
-Val-
L
-Asp(OBn)-NH2, 10l
195–196 ꢁ32.9
a
b
c
a
b
c
Isolated yield.
Isolated yield.
HPLC for (13aþ13a0): 9.90 and 11.82 min.
HPLC for 13b: 8.17 min.
HPLC for 10a: 3.86 min.
HPLC for (10aþ10a0): 3.67 and 3.79 min.

4926
I. Celik, A.A.A. Abdel-Fattah / Tetrahedron 65 (2009) 4923–4929
4. Experimental
J¼8.2 Hz, 1H), 8.25 (d, J¼8.2 Hz, 1H), 7.82 (t, J¼7.6 Hz, 1H), 7.72 (d,
J¼7.7 Hz, 1H), 7.64 (t, J¼7.7 Hz, 1H), 7.56 (d, J¼8.5 Hz, 1H), 7.37–7.23
(m, 7H), 7.08 (t, J¼7.3 Hz,1H), 7.00 (t, J¼7.3 Hz,1H), 5.02 (t, J¼5.9 Hz,
2H), 4.97 (s, 2H), 4.49–4.44 (m, 1H), 3.25 (dd, J¼14.4, 3.4 Hz, 1H),
4.1. General
All mps are uncorrected. NMR spectra were recorded on a Varian
Gemini (300 MHz) spectrometer in DMSO-d6 with TMS for 1H
(300 MHz) and 13C (75 MHz) as an internal reference. IR spectra were
recorded on a Unicam SP-1200 infrared spectrophotometer using KBr
Wafer technique. N-Cbz-amino acids and amino acids were purchased
from Fluka (Buchs, Switzerland) and Acros (Suwanee, GA, USA), were
used without further purification. Elemental analyses were performed
on a Carlo Erba-1106 instrument. Optical rotation values were mea-
sured with the use of the sodium D line. HPLC analyses were per-
formed on Beckman system gold programmable solvent module 126
using Chirobiotic T column (4.6ꢂ250 mm), detection at 254 nm, flow
rate 1.0 mL/min, and with methanol as solvent.
3.00 (dd, J¼14.4, 10.5 Hz, 1H). 13C NMR:
¼173.0, 169.6, 155.9, 145.3,
d
137.0, 131.0, 130.6, 128.3, 127.7, 127.5, 127.2, 126.6, 124.0, 120.9,
120.2, 118.5, 118.2, 113.8, 111.3, 110.2, 65.3, 55.4, 42.6, 27.9. Anal.
Calcd for C27H24N6O4: C, 65.31; H, 4.87; N, 16.93. Found: C, 65.63; H,
4.99; N, 16.55.
4.4.3. Benzyl N-(1S)-2-[(2S)-2-(1H-1,2,3-benzotriazol-1-
ylcarbonyl)tetrahydro-1H-pyrrol-1-yl]-1-methyl-2-
oxoethylcarbamate (Cbz-
Yield: 76%; white microcrystals; mp 52–54 ꢀC; [
1.66, DMF). 1H NMR:
L-Ala-L-Pro-Bt, 9f)
23
a
]
–29.8 (c
D
d
¼8.34 (d, J¼8.2 Hz, 1H), 8.26 (d, J¼8.1 Hz,
1H), 7.84 (t, J¼7.7 Hz, 1H), 7.71–7.61 (m, 2H), 7.42–7.33 (m, 5H),
5.76 (dd, J¼8.8, 5.1 Hz, 1H), 5.04 (AB, JAB¼16.2, 12.6 Hz, 2H),
4.46 (t, J¼7.2 Hz, 1H), 3.88–3.76 (m, 2H), 2.50–2.46 (m, 1H),
4.2. N-(Cbz-
N-(Cbz-
a-aminoacyl)benzotriazoles 6: general procedure
2.25–2.10 (m, 3H), 1.27 (d, J¼7.0 Hz, 3H). 13C NMR:
d
¼171.4,
a
-aminoacyl)benzotriazoles 6a–e and (6b0) were pre-
170.7, 155.8, 145.5, 137.2, 131.3, 130.8, 128.5, 128.0, 127.9, 127.0,
120.4, 114.1, 65.6, 59.3, 48.1, 47.0, 29.0, 25.3, 16.7. Anal. Calcd for
C22H23N5O4: C, 62.70; H, 5.50; N, 16.62. Found: C, 62.49; H,
5.57; N, 16.91.
pared according to the literature procedure.18,20,21a
4.3. Dipeptides 8: general procedure
N-Cbz-protected dipeptides 8a–l, (8aþ8a0), and (8eþ8e0) were
4.4.4. Benzyl N-[(1S)-1-([(1S)-2-(1H-1,2,3-benzotriazol-1-yl)-1-
(1H-indol-2-ylmethyl)-2-oxoethyl]-aminocarbonyl)-3-
prepared according to the literature procedure.38,20,21a
(methylsulfanyl)propyl]carbamate (Cbz-
Yield: 73%; white microcrystals; mp 171–173 ꢀC; [
1.58, DMF). 1H NMR:
L-Met-L-Trp-Bt, 9g)
23
4.3.1. (3S)-4-(Benzyloxy)-3-[((2R)-2-[(benzyloxy)carbonyl]amino-
a]
þ18.0 (c
D
3-methylbutanoyl)amino]-4-oxobutanoic acid (Cbz-
D
-Val-
L
-Asp(3-
d
¼10.94 (s, 1H), 8.91 (d, J¼5.8 Hz, 1H), 8.29 (d,
OBn)-OH, 8l)
J¼8.1 Hz, 1H), 8.22 (d, J¼8.2 Hz, 1H), 7.82 (t, J¼7.6 Hz, 1H), 7.66 (t,
J¼7.6 Hz, 1H), 7.59–7.55 (m, 2H), 7.38–7.28 (m, 7H), 7.06 (t, J¼7.5 Hz,
1H), 6.96 (t, J¼7.3 Hz, 1H), 5.96–5.90 (m 1H), 5.04 (AB, JAB¼17.3,
12.4 Hz, 2H), 4.28–4.26 (m, 1H), 3.53 (dd, J¼14.7, 4.8 Hz, 1H), 3.37–
3.31 (m, 1H), 2.51 (t, J¼7.8 Hz, 2H), 2.07 (s, 3H), 1.94–1.85 (m, 2H).
23
Yield: 83%; white microcrystals; mp 114–115 ꢀC; [
a
]
ꢁ19.3 (c
D
1.65, DMF). 1H NMR:
d
¼8.42 (d, J¼7.8 Hz, 1H), 7.39–7.30 (m, 11H),
5.12 (s, 2H), 5.07 (s, 2H), 4.65 (dd, J¼13.5, 7.0 Hz, 1H), 3.96 (t,
J¼7.8 Hz, 1H), 2.91 (dd, J¼16.3, 5.6 Hz, 1H), 2.75 (dd, J¼16.4, 7.2 Hz,
1H), 1.98–1.92 (m, 1H), 0.84 (t, J¼6.5 Hz, 6H). 13C NMR:
d
¼172.1,
13C NMR:
d
¼172.2, 171.4, 155.9, 145.3, 136.9, 136.0, 131.0, 130.5,
171.2,170.2,156.3,137.3,136.1,128.6,128.5,128.2,128.0,127.9,127.8,
65.9, 65.5, 60.0, 48.7, 36.1, 30.7, 19.2, 18.0. IR: nmax 3430–2500 (br),
1705, 1645, 1620, 1590, 1425 cmꢁ1. Anal. Calcd for C24H28N2O7: C,
63.15; H, 6.18; N, 6.14. Found: C, 62.82; H, 6.34; N, 6.29.
128.3, 127.8, 128.6, 126.7, 124.2, 121.0, 120.2, 118.4, 118.0, 114.0, 111.4,
108.7, 65.7, 53.8, 53.4, 31.7, 29.5, 26.9, 14.6. Anal. Calcd for
C30H30N6O4S: C, 63.14; H, 5.30; N, 14.73. Found: C, 62.98; H, 5.21; N,
15.04.
4.4. N-Cbz-protected dipeptidoylbenzotriazoles 9: general
procedure
4.4.5. Benzyl (3S)-4-(1H-1,2,3-benzotriazol-1-yl)-3-[((2R)-2-
[(benzyloxy)carbonyl]amino-3-methylbutanoyl)amino]-4-
oxobutanoate (Cbz-
Yield: 86%; white microcrystals; mp 109–110 ꢀC; [
1.80, DMF). 1H NMR:
D-Val-Asp(OBn)-Bt, 9l)
23
N-Cbz-protected dipeptidoylbenzotriazoles 9a–l, (9aþ9a0), and
(9eþ9e0) were prepared according to the literature procedure.18,21
a]
–10.8 (c
D
d¼9.05 (d, J¼6.7 Hz, 1H), 8.27 (d, J¼8.4 Hz, 1H),
8.21 (d, J¼8.2 Hz, 1H), 7.81 (t, J¼7.6 Hz, 1H), 7.64 (t, J¼7.7 Hz, 1H),
7.36–7.29 (m, 11H), 5.98 (dd, J¼13.7, 6.7 Hz, 1H), 5.17–4.98 (m, 4H),
3.97 (dd, J¼15.3, 6.7 Hz, 1H), 3.30 (dd, J¼16.8, 5.4 Hz, 1H), 3.01 (dd,
J¼16.8, 8.4 Hz,1H), 1.96–1.89 (m, 1H), 0.81 (d, J¼6.9 Hz, 3H), 0.75 (d,
4.4.1. Benzyl N-((1S)-2-[2-(1H-1,2,3-benzotriazol-1-yl)-1-methyl-
2-oxoethyl]amino-1-(1H-indol-2-ylmethyl)-2-oxoethyl)carbamate
(Cbz-
L
-Trp-DL-Ala-Bt, (9aþ9a0))
23
Yield: 64%; white microcrystals; mp 142–144 ꢀC; [
a
]
D
–8.4 (c
J¼6.6 Hz, 3H). 13C NMR:
¼171.8, 169.9, 169.6, 156.3, 145.5, 137.2,
d
1.81, DMF). 1H NMR:
d¼10.84 (s, 1H), 9.04–8.97 (m, 1H), 8.32–8.24
135.8, 131.2, 130.8, 128.5, 128.4, 128.2, 128.1, 128.0, 127.9, 127.8,
126.9, 120.4, 114.1, 66.3, 65.6, 59.9, 49.7, 35.5, 30.6, 19.2, 18.0. Anal.
Calcd for C30H31N5O6: C, 64.62; H, 5.60; N,12.56. Found: C, 64.55; H,
5.59; N, 12.28.
(m, 2H), 7.82 (t, J¼7.7 Hz, 1H), 7.73–7.63 (m, 2H), 7.44 (d, J¼8.7 Hz,
1H), 7.35–7.19 (m, 7H), 7.06–6.97 (m, 2H), 5.67–5.63 (m,1H), 4.93 (d,
J¼3.7 Hz, 2H), 4.45–4.41 (m, 1H), 3.16–3.12 (m, 1H), 2.94–2.91 (m,
1H), 1.61–1.49 (m, 3H). 13C NMR:
d
¼172.6, 172.3, 171.9, 155.9, 155.7,
145.4, 137.0, 136.1, 131.1, 130.7, 128.3, 127.7, 127.5, 127.4, 127.2, 126.9,
126.7, 124.1, 124.0, 120.8, 120.2, 118.6, 118.2, 114.0, 111.3, 110.0, 109.9,
65.3, 65.0, 55.1, 54.9, 48.7, 48.6, 31.0, 27.8, 16.7, 16.6. IR: nmax 3100,
3060, 2915,1715,1650,1620,1410 cmꢁ1. Anal. Calcd for C28H26N6O4:
C, 65.87; H, 5.13; N, 16.46. Found: C, 65.61; H, 5.27; N, 16.43.
4.5. Dipeptide primary amides 10: general procedure
To a solution of N-protected dipeptidoylbenzotriazoles 9a–l,
(9aþ9a0), and (9eþ9e0) (0.2 mmol) in THF (10 mL) was added
NH4OH (2 mmol) in THF (10 mL) at 0 ꢀC and the reaction mixture
was stirred for 2 h at 0 ꢀC. THF was removed in vacuo, and the solid
formed was dissolved in EtOAc (50 mL), washed with 5% Na2CO3
(3ꢂ15 mL), dried over MgSO4. Removing solvents under reduced
pressure gave an oil, which was recrystallized from EtOAc/hexanes
to give 10a–l, (10aþ10a0), and (10eþ10e0).
4.4.2. Benzyl N-((1S)-2-[2-(1H-1,2,3-benzotriazol-1-yl)-2-
oxoethyl]amino-1-(1H-indol-2-ylmethyl)-2-oxoethyl)carbamate (Z-
L
-Trp-
Yield: 75%; white microcrystals; mp 186–187 ꢀC; [
1.73, DMF). 1H NMR:
¼10.87 (s, 1H), 8.89 (t, J¼5.1 Hz, 1H), 8.30 (d,
L-Gly-Bt, 9c)
23
a]
–27.3 (c
D
d

I. Celik, A.A.A. Abdel-Fattah / Tetrahedron 65 (2009) 4923–4929
4927
4.5.1. Benzyl N-[(1S)-2-[(1S)-2-amino-1-methyl-2-oxoethyl]-
amino-1-(1H-indol-2-ylmethyl)-2-oxoethyl]carbamate
(Cbz- -Trp- -Ala-NH2, 10a)
Yield: 79%; white microcrystals; mp 168–170 ꢀC; [
1.42, DMF). 1H NMR:
4.5.6. Benzyl (4S)-5-amino-4-[(2-[(benzyloxy)carbonyl]-
aminopropanoyl)amino]-5-oxopentanoate
L
L
(Cbz-DL-Ala-
L
-Glu(4-OBn)-NH2, (10eþ10e0))
23
23
a
]
D
ꢁ9.5 (c
Yield: 90%; white microcrystals; mp 138–139 ꢀC; [
a]
–4.7 (c
D
d
¼10.86 (s, 1H), 8.09 (d, J¼7.4 Hz, 1H), 7.68 (d,
1.33, DMF). 1H NMR:
d
¼8.12–7.93 (m, 1H), 7.58 (t, J¼6.2 Hz, 1H),
J¼7.7 Hz, 1H), 7.47 (d, J¼8.1 Hz, 1H), 7.39–7.27 (m, 7H), 7.20 (s, 1H),
7.13–7.08 (m, 2H), 7.03–6.99 (m,1H), 4.99 (s, 2H), 4.36–4.25 (m, 2H),
3.18 (dd, J¼14.6, 4.0 Hz, 1H), 2.77 (dd, J¼14.3, 9.9 Hz, 1H), 1.26 (d,
7.44–7.34 (m, 11H), 7.19 (d, J¼15.5 Hz, 1H), 5.12 (s, 2H), 5.05 (s, 2H),
4.29–4.23 (m, 1H), 4.13–4.04 (m, 1H), 2.44–2.36 (m, 2H), 2.10–1.98
(m, 1H), 1.88–1.81 (m, 1H), 1.23 (dd, J¼7.0, 1.2 Hz, 3H). 13C NMR:
J¼7.0 Hz, 3H). 13C NMR:
d
¼174.2, 171.4, 155.9, 137.0, 136.1, 128.3,
d
¼172.9, 172.8, 172.6, 172.4, 172.3, 155.9, 155.8, 137.0, 136.9, 136.2,
127.7, 127.4, 127.3, 123.9, 120.9, 118.6, 118.2, 111.3, 110.2, 65.3, 55.6,
48.0, 27.7, 18.5. IR: nmax 3250, 3090, 3045, 2925, 1705, 1640, 1530,
1515, 1490, 1440 cmꢁ1. Anal. Calcd for C22H24N4O4: C, 64.69; H,
5.92; N, 13.72. Found: C, 64.95; H, 6.00; N, 13.32.
128.4, 128.3, 128.0, 127.9, 127.8, 65.5, 51.4, 50.2, 30.0, 27.3, 27.0, 18.0.
Anal. Calcd for C23H27N3O6: C, 62.57; H, 6.16; N, 9.52. Found: C,
62.42; H, 6.16; N, 9.65.
4.5.7. Benzyl N-(1S)-2-[(2S)-2-(aminocarbonyl)tetrahydro-1H-
4.5.2. Benzyl N-((1S)-2-[(1S)-2-amino-1-(1H-indol-2-ylmethyl)-2-
oxoethyl]amino-1-(1H-indol-2-ylmethyl)-2-oxoethyl)carbamate
pyrrol-1-yl]-1-methyl-2-oxoethylcarbamate (Cbz-
L
-Ala-
L
-Pro-
NH2, 10f)
23
(Cbz-
Yield: 96%; white microcrystals; mp 192–194 ꢀC; [
1.68, DMF). 1H NMR:
L
-Trp-
L
-Trp-NH2, 10b)
Yield: 95%; white microcrystals; mp 161–162 ꢀC; [
a
]
–37.6 (c
D
23
a
]
–36.6 (c
1.88, DMF). 1H NMR:
d
¼7.52 (d, J¼7.4 Hz, 1H), 7.39–7.25 (m, 5H),
D
d¼10.84 (s, 1H), 10.81 (s, 1H), 8.03 (d, J¼7.7 Hz,
7.21 (br s, 1H), 6.89 (br s, 1H), 5.00 (s, 2H), 4.31 (t, J¼7.0 Hz, 1H), 4.21
(dd, J¼8.20, 3.5 Hz, 1H), 3.59–3.55 (m, 2H), 2.05–1.76 (m, 4H), 1.20
1H), 7.61 (d, J¼7.7 Hz, 2H), 7.44–7.44 (m, 2H), 7.34–7.27 (m, 5H),
7.24–7.22 (m, 2H), 7.16 (s, 1H), 7.11–7.08 (m, 2H), 7.06–7.03 (m, 2H),
6.99–6.94 (m, 2H), 4.94 (s, 2H), 4.56–4.52 (m, 1H), 4.33–4.28 (m,
1H), 3.18–2.99 (m, 3H), 2.88 (d, J¼14.2, 10.2 Hz, 1H). 13C NMR:
(d, J¼6.7 Hz, 3H). 13C NMR:
¼173.6, 170.8, 155.7, 137.1, 128.4, 127.8,
d
127.7, 65.3, 59.5, 48.0, 46.5, 29.2, 24.5, 16.8. Anal. Calcd for
C16H21N3O4: C, 60.18; H, 6.63; N, 13.16. Found: C, 60.00; H, 6.73; N,
12.96.
d¼173.4, 171.7, 156.0, 137.1, 136.2, 136.2, 128.5, 127.8, 127.6, 127.6,
127.4, 123.9, 123.7, 121.0, 118.7, 118.4, 111.5, 111.4, 110.4, 110.1, 65.5,
55.9, 53.3, 28.0, 27.8. Anal. Calcd for C30H29N5O4: C, 68.82; H, 5.58;
N, 13.38. Found: C, 68.65; H, 5.62; N, 13.40.
4.5.8. Benzyl N-[(1S)-1-([(1S)-2-amino-1-(1H-indol-2-ylmethyl)-
2-oxoethyl]aminocarbonyl)-3-(methylsulfanyl)propyl]carbamate
(Cbz-
Yield: 91%; white microcrystals; mp 218–220 ꢀC; [
(c 1.50, DMF). 1H NMR:
L-Met-L-Trp-NH2, 10g)
23
4.5.3. Benzyl N-[(1S)-2-[(2-amino-2-oxoethyl)amino]-1-(1H-indol-
a
]
–12.7
D
2-ylmethyl)-2-oxoethyl]carbamate (Cbz-
Yield: 86%; white microcrystals; mp 151–155 ꢀC; [
1.82, DMF). 1H NMR:
L
-Trp-Gly-NH2, 10c)
d
¼10.8 (s, 1H), 7.90 (d, J¼7.8 Hz, 1H), 7.59
23
a
]
D
–26.4 (c
(d, J¼7.8 Hz, 1H), 7.54 (d, J¼7.8 Hz, 1H), 7.43 (s, 1H), 7.35–7.27 (m,
6H), 7.13–7.03 (m, 3H), 6.96 (t, J¼7.3 Hz, 1H), 5.02 (d, J¼4.4 Hz,
2H), 4.52–4.45 (m, 1H), 4.08–4.04 (m, 1H), 3.13 (dd, J¼15.0,
5.1 Hz, 1H), 3.00 (dd, J¼14.9, 8.0 Hz, 1H), 2.39 (t, J¼7.6 Hz, 2H),
d
¼10.86 (s, 1H), 8.32 (t, J¼5.6 Hz, 1H), 7.66 (d,
J¼7.7 Hz, 1H), 7.54 (d, J¼7.8 Hz, 1H), 7.39–7.35 (m, 3H), 7.32–7.28
(m, 3H), 7.23–7.21 (m, 2H), 7.16–7.08 (m, 2H), 7.01 (t, J¼7.4 Hz, 1H),
4.99 (s, 2H), 4.36–4.29 (m, 1H), 3.70 (dd, J¼12.4, 5.7 Hz, 2H), 3.19
(dd, J¼14.6, 4.4 Hz, 1H), 2.97 (dd, J¼14.6, 9.7 Hz, 1H). 13C NMR:
1.99 (s, 3H), 1.84–1.73 (m, 2H). 13C NMR:
d
¼173.4, 171.3, 156.2,
137.1, 136.1, 128.5, 128.0, 127.9, 127.6, 123.6, 121.0, 118.7, 118.4,
111.4, 110.1, 65.7, 54.2, 53.2, 31.8, 29.7, 27.8, 14.7. Anal. Calcd for
C24H28N4O4S: C, 61.52; H, 6.02; N, 11.96. Found: C, 61.69; H, 6.16;
N, 11.68.
d¼172.2, 171.0, 156.2, 137.1, 136.2, 128.5, 127.9, 127.7, 127.4, 124.0,
121.0, 118.6, 118.4, 111.5, 110.3, 65.5, 55.8, 42.2, 27.7. Anal. Calcd for
C21H22N4O4: C, 63.95; H, 5.62; N, 14.20. Found: C, 64.10; H, 5.68; N,
13.82.
4.5.9. Benzyl N-((1S)-2-[(1S)-1-(aminocarbonyl)-3-(methyl-
sulfanyl)propyl]amino-1-benzyl-2-oxoethyl)carbamate
4.5.4. Benzyl N-((1S)-2-[(1S)-2-amino-1-(1H-indol-2-ylmethyl)-2-
oxoethyl]amino-1-methyl-2-oxoethyl)carbamate (Cbz-
L
-Ala-
L
-Trp-
(Cbz-
Yield: 94%; white microcrystals; mp 208–210 ꢀC; [
(c 0.92, DMF). 1H NMR:
L-Phe-L-Met-NH2, 10h)
23
NH2, 10d)
a
]
–14.8
D
23
Yield: 77%; white microcrystals; mp 201–202 ꢀC; [
a
]
–7.6 (c
d¼8.13 (d, J¼8.1 Hz, 1H), 7.61 (d, J¼8.4 Hz,
D
1.62, DMF). 1H NMR:
d
¼10.86 (s, 1H), 7.88 (d, J¼8.0 Hz, 1H), 7.62 (d,
1H), 7.40–7.19 (m, 11H), 7.15 (s, 1H), 4.98 (s, 2H), 4.36–4.27 (m,
2H), 3.06 (dd, J¼13.8, 4.1 Hz, 1H), 2.78 (dd, J¼13.6, 10.6 Hz, 1H),
2.50–2.46 (m, 2H), 2.07 (s, 3H), 2.00–1.95 (m, 1H), 1.85–1.81 (m,
J¼7.7 Hz, 1H), 7.53 (d, J¼7.3 Hz, 1H), 7.43–7.34 (m, 7H), 7.16–7.11 (m,
2H), 7.09–7.02 (m, 1H), 7.00 (t, J¼7.3 Hz, 1H), 5.05 (AB, JAB¼19.4,
12.6 Hz, 2H), 4.50 (dd, J¼13.1, 7.4 Hz, 1H), 4.09–4.06 (m, 1H), 3.16
(dd, J¼14.7, 5.1 Hz, 1H), 3.03 (dd, J¼14.6, 8.0 Hz, 1H), 1.19 (d,
1H). 13C NMR:
d
¼173.1, 171.6, 156.1, 138.2, 137.1, 129.4, 128.5, 128.2,
127.9, 127.6, 126.4, 65.4, 56.4, 51.9, 38.0, 32.1, 29.7, 14.8. Anal. Calcd
for C22H27N3O4S: C, 61.52; H, 6.34; N, 9.78. Found: C, 61.14; H,
6.39; N, 9.50.
J¼7.1 Hz, 3H). 13C NMR:
¼173.2, 172.2, 155.8, 137.0, 136.0, 128.4,
d
127.8, 127.4, 123.5, 120.8, 118.5, 118.2, 111.2, 110.0, 65.5, 53.0, 50.3,
27.6, 18.0. Anal. Calcd for C22H24N4O4: C, 64.69; H, 5.92; N, 13.72.
Found: C, 64.78; H, 5.99; N, 13.51.
4.5.10. Benzyl (4S)-5-amino-4-[((2S)-2-[(benzyloxy)carbonyl]-
amino-3-phenylpropanoyl)amino]-5-oxopentanoate
4.5.5. Benzyl (4S)-5-amino-4-[((2S)-2-[(benzyloxy)carbonyl]-
aminopropanoyl)amino]-5-oxopentanoate
(Cbz-
Yield: 96%; white microcrystals; mp 205–207 ꢀC; [
(c 1.1, DMF). 1H NMR:
L-Phe-L-Glu(4-OBn)-NH2, 10i)
23
a
]
–10.6
D
(Cbz-
Yield:98%;white microcrystals;mp162–163 ꢀC;[
DMF). 1H NMR:
L
-Ala-
L
-Glu(4-OBn)-NH2, 10e)
d
¼8.10 (d, J¼8.0 Hz, 1H), 7.60 (d, J¼8.4 Hz,
a]
23 –3.0 (c1.32,
1H), 7.41–7.38 (m, 5H), 7.37–7.22 (m, 11H), 7.16 (s, 1H), 5.13 (s,
2H), 4.96 (s, 2H), 4.34–4.24 (m, 2H), 3.05 (dd, J¼13.9, 4.0 Hz,
1H), 2.78 (dd, J¼13.6, 10.7 Hz, 1H), 2.41 (t, J¼8.0 Hz, 2H), 2.06–
D
d¼7.90 (d, J¼8.0 Hz, 1H), 7.53 (d, J¼7.1 Hz, 1H), 7.36–
7.34 (m,11H), 7.13 (s,1H), 5.09 (s, 2H), 5.01 (d, J¼7.7 Hz, 2H), 4.23 (dd,
J¼13.2, 8.1 Hz, 1H), 4.05 (t, J¼7.1 Hz, 1H), 2.37 (t, J¼7.8 Hz, 2H), 2.09–
2.00 (m, 1H), 1.84–1.77 (m, 1H), 2.40 (d, J¼7.0 Hz, 3H). 13C NMR:
1.79 (m, 2H). 13C NMR:
d
¼172.9, 172.4, 171.6, 156.0, 138.2, 137.1,
136.4, 129.3, 128.6, 128.5, 128.2, 128.2, 128.1, 127.9, 127.6, 126.4,
65.7, 65.4, 56.4, 51.8, 37.3, 30.2, 27.5. Anal. Calcd for
C29H31N3O6: C, 66.99; H, 6.04; N, 8.12. Found: C, 67.00; H, 6.10;
N, 7.92.
d¼172.9, 172.4, 155.8, 137.0, 136.2, 128.4, 128.3, 128.0, 127.9, 127.7,
65.5, 65.4, 51.5, 50.2, 30.0, 27.3, 17.9. Anal. Calcd for C23H27N3O6: C,
62.57; H, 6.16; N, 9.52. Found: C, 62.57; H, 6.19; N, 9.45.

4928
I. Celik, A.A.A. Abdel-Fattah / Tetrahedron 65 (2009) 4923–4929
4.5.11. Benzyl (3S)-4-amino-3-[((2S)-2-[(benzyloxy)carbonyl]-
amino-3-phenylpropanoyl)amino]-4-oxobutanoate
4.6.2. Benzyl N-[(1S)-2-(2-[(2-amino-2-oxoethyl)amino]-1-
methyl-2-oxoethylamino)-1-(1H-indol-2-ylmethyl)-2-oxoethyl]-
(Cbz-
Yield: 94%; white microcrystals; mp 163–165 ꢀC; [
(c 1.61, DMF). 1H NMR:
L
-Phe-
L
-Asp(3-OBn)-NH2, 10j)
carbamate (Cbz-
L
-Trp-DL-Ala-Gly-NH2, (13aþ13a0))
23
a
]
–28.6
Yield: 86%; white microcrystals; mp 164–166 ꢀC. 1H NMR:
D
d
¼8.39 (d, J¼8.0 Hz, 1H), 7.61 (d,
d
¼10.84 (s, 1H), 8.36–8.28 (m, 1H), 8.06–8.00 (m, 1H), 7.68–7.60 (m,
J¼8.1 Hz, 1H), 7.40–7.25 (m, 17H), 5.13 (s, 2H), 4.97 (s, 2H), 4.61
1H), 7.53–7.46 (m, 1H), 7.35–7.24 (m, 7H), 7.17–7.13 (m, 2H), 7.06 (t,
J¼7.4 Hz, 1H), 6.97 (t, J¼7.2 Hz, 1H), 4.99 (s, 2H), 4.29–4.23 (m, 2H),
3.70–3.60 (m, 2H), 3.16–3.06 (m, 1H), 2.98–2.87 (m, 1H), 1.24–1.12
(q, J¼7.7 Hz, 1H), 4.34–4.30 (m, 1H), 3.04 (d, J¼9.9 Hz, 1H),
2.91–2.64 (m, 3H). 13C NMR:
d
¼172.1, 171.6, 170.3, 156.1, 138.2,
137.1, 136.2, 129.4, 128.6, 128.5, 128.2, 128.1, 128.1, 127.9, 127.6,
126.4, 65.9, 65.4, 56.4, 49.5, 37.4, 36.4. Anal. Calcd for
C28H29N3O6: C, 66.79; H, 5.80; N, 8.34. Found: C, 66.55; H, 5.82;
N, 8.20.
(m, 3H). 13C NMR:
d¼172.3, 172.2, 172.0, 170.9, 156.1, 156.0, 136.9,
137.0, 136.9, 136.1, 128.3, 127.8, 127.7, 127.5, 127.3, 124.0, 120.8, 118.6,
118.5, 118.2, 111.3, 110.1, 109.8, 65.5, 65.3, 55.7, 55.5, 48.6, 41.9, 27.6,
17.8, 17.7. HRMS calcd for C24H27N5O5 [MþH]þ 466.2085, found
466.2063.
4.5.12. Benzyl N-(5S)-6-amino-5-[((2S)-2-[(benzyloxy)carbonyl]-
amino-3-phenylpropanoyl)amino]-6-oxohexylcarbamate
4.6.3. Benzyl N-((1S)-2-[(1S)-2-[(2-amino-2-oxoethyl)amino]-1-
(1H-indol-2-ylmethyl)-2-oxoethyl]amino-1-(1H-indol-2-ylmethyl)-
(Cbz-
Yield: 92%; white microcrystals; mp 193–195 ꢀC; [
(c 1.68, DMF). 1H NMR:
J¼8.5 Hz, 1H), 7.38–7.26 (m, 17H), 7.09 (s, 1H), 5.04 (s, 2H), 4.98
(s, 2H), 4.34–4.20 (m, 2H), 3.09–2.98 (m, 3H), 2.78 (t, J¼12.6 Hz,
1H), 1.74–1.52 (m, 2H), 1.46–1.40 (m 2H), 1.34–1.27 (m, 2H). 13C
L-Phe-L
-N6-Lys-NH2, 10k)
23
a
]
–8.5
2-oxoethyl)carbamate (Cbz-L-Trp-L-Trp-Gly-NH2, 13b)
D
d
¼8.05 (d, J¼8.0 Hz, 1H), 7.59 (d,
Yield: 86%; white microcrystals; mp 220–221 ꢀC. 1H NMR:
d
¼10.90 (s, 1H), 10.85 (s, 1H), 8.30–8.23 (m, 2H), 7.68–7.61 (m, 2H),
7.50 (d, J¼8.2 Hz, 1H), 7.38–7.32 (m, 5H), 7.29–7.23 (m, 4H), 7.18–
7.15 (m, 2H), 7.10 (t, J¼7.4 Hz, 2H), 7.04–6.98 (m, 2H), 4.98 (s, 2H),
4.59 (q, J¼12.9 Hz, 1H), 4.38–4.30 (m, 1H), 3.74 (dd, J¼16.8, 6.0 Hz,
1H), 3.60 (dd, J¼16.8, 5.3 Hz, 1H), 3.24 (dd, J¼16.7, 5.0 Hz, 1H), 3.14–
NMR:
d
¼173.6, 171.5, 156.2, 156.0, 138.3, 137.4, 137.2, 129.4,
128.5, 128.4, 128.2, 127.9, 127.8, 127.6, 127.5, 126.4, 65.4, 65.3,
56.4, 52.5, 40.5, 37.5, 32.7, 29.3, 22.7. Anal. Calcd for
C31H36N4O6: C, 66.41; H, 6.47; N, 9.99. Found: C, 66.20; H, 6.37;
N, 9.70.
3.04 (m, 2H), 2.91 (dd, J¼14.6, 10.2 Hz, 1H). 13C NMR:
¼172.1, 171.5,
d
170.9, 155.9, 136.9, 136.1, 128.3, 127.7, 127.5, 127.4, 127.3, 123.8, 123.7,
120.9, 118.6, 118.4, 118.2, 111.3, 110.2, 109.9, 65.4, 55.6, 53.8, 42.1,
27.6, 27.5. Anal. Calcd for C32H32N6O5: C, 66.19; H, 5.55; N, 14.47.
Found: C, 65.84; H, 5.61; N, 14.28.
4.5.13. Benzyl (3S)-4-amino-3-[((2R)-2-[(benzyloxy)carbonyl]-
amino-3-methylbutanoyl)amino]-4-oxobutanoate
(Cbz-
Yield: 88%; white microcrystals; mp 195–195 ꢀC; [
(c 1.70, DMF). 1H NMR:
D-Val-L-Asp(3-OBn)-NH2, 10l)
Acknowledgements
23
a]
–33.0
D
d¼8.46 (d, J¼8.4 Hz, 1H), 7.49 (d, J¼7.4 Hz,
The authors gratefully acknowledge Professor Alan R. Katritzky
for his generous help by allowing us to implement this work in his
labs and also for his valuable suggestions.
1H), 7.40–7.23 (m, 12H), 5.06 (d, J¼2.1 Hz, 2H), 5.02 (s, 2H), 4.68–
4.61 (m, 1H), 3.75 (t, J¼7.4 Hz, 1H), 2.89 (dd, J¼16.1, 4.8 Hz, 1H), 2.60
(dd, J¼16.2, 9.1 Hz, 1H), 1.91–1.85 (m, 1H), 0.84–0.78 (m, 6H). 13C
NMR:
d
¼172.2, 171.4, 170.3, 156.5, 136.9, 136.0, 128.4, 128.0, 127.9,
References and notes
127.9, 65.7, 65.5, 60.8, 49.2, 36.1, 29.6, 19.0, 18.6. Anal. Calcd for
C24H29N3O6: C, 63.28; H, 6.42; N, 9.22. Found: C, 63.18; H, 6.48; N,
9.03.
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methylsulfanyl)propyl]amino-1-methyl-2-oxoethylamino)-1-(1H-
indol-2-ylmethyl)-2-oxoethyl]carbamate (Cbz-L-Trp-L-Ala-L-Met-
NH2, 13a)
Yield: 82%; white microcrystals; mp 222–224 ꢀC. 1H NMR:
d
¼10.86 (s, 1H), 8.33–8.28 (m, 1H), 7.92–7.90 (m, 1H), 7.71
(d, J¼8.0 Hz, 1H), 7.51 (d, J¼8.1 Hz, 1H), 7.38–7.27 (m, 7H), 7.21–
7.17 (m, 2H), 7.10 (t, J¼7.4 Hz, 1H), 7.01 (t, J¼7.3 Hz, 1H), 5.00–4.97
(m, 2H), 4.37–4.24 (m, 3H), 3.18–3.14 (m, 1H), 2.98–2.90 (m, 1H),
2.51–2.39 (m, 2H), 2.06 (s, 3H), 2.00–1.94 (m, 1H), 1.88–1.76 (m,
1H), 1.28–1.12 (m, 3H). 13C NMR:
d¼173.1, 172.2, 172.1, 156.1, 137.1,
136.2, 128.5, 127.8, 127.7, 127.6, 127.4, 124.1, 121.0, 118.8, 118.3,
111.4, 110.3, 65.4, 55.6, 51.8, 48.7, 32.1, 29.7, 17.9, 14.8. Anal. Calcd
for C27H33N5O5S: C, 60.09; H, 6.16; N, 12.98. Found: C, 59.78; H,
6.25; N, 12.68.

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