N-(Cbz- and Fmoc-α-aminoacyl)benzotriazoles: Stable derivatives enabling peptide coupling of Tyr, Trp, Cys, Met, and Gln with free amino acids in aqueous media with complete retention of chirality

Article abstract of DOI:10.1055/s-2005-861782

Crystalline, chirally stable N-(Cbz- and Fmoc-α-aminoacyl) benzotriazoles 2a-f, activated derivatives of Tyr, Trp, Cys, Met and Gln undergo peptide coupling in aqueous media with unprotected L-Ala-OH and L-Phe-OH to give the chiral dipeptides in 70-98% yi

Full text of DOI:10.1055/s-2005-861782

PAPER
397
N-(Cbz- and Fmoc-a-aminoacyl)benzotriazoles: Stable Derivatives Enabling
Peptide Coupling of Tyr, Trp, Cys, Met, and Gln with Free Amino Acids in
Aqueous Media with Complete Retention of Chirality
N-(Cbz-
a
nd Fmoc
l
-
a
-ami
a
n
n
zotriazoles: Stable
R
D
erivatives . Katritzky,* Parul Angrish, Deniz Hür, Kazuyuki Suzuki
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, FL 32611-7200, USA
E-mail: katritzky@chem.ufl.edu
Received 12 October 2004
couple with a-amino acids, but mild enough to prevent
Abstract: Crystalline, chirally stable N-(Cbz- and Fmoc-a-amino-
acyl)benzotriazoles 2a–f, activated derivatives of Tyr, Trp, Cys,
Met and Gln undergo peptide coupling in aqueous media with un-
protected L-Ala-OH and L-Phe-OH to give the chiral dipeptides in
undesired side-reactions with functional groups in amino
acid side-chains, and examples have involved such esters
of N-protected a-amino acids carrying alkyl side-chains
70–98% yield. A convenient and efficient procedure under mild re- (such as Ala, Val, Phe) as well as side-chains with some
functionalities (such as Tyr, Trp, Gln, Thr2c).
action conditions for the preparation of 2a–f in 72–95% yield utiliz-
es N-Cbz- or N-Fmoc-protected a-amino acids 1a–f.
N-Acylbenzotriazoles have been employed for: (i) N-acy-
Key words: N-(protected a-aminoacyl)benzotriazole, benzotriaz-
lation in the preparation of primary, secondary, and tertia-
ole, amino acid, acylating reagent, peptide coupling
ry amides,4a and N-acylsulfonamides,4b (also see refs4c–e
)
(ii) O-acylation in additions to aldehydes to give esters,5
(iii) S-acylation for the synthesis of thiol esters,6 and (iv)
C-acylation for the preparation of 1,3-,7a 1,2-diketones,7b
a-cyano ketones,7c b-ketosulfones,7d enaminones,7e and
C-acylated pyrroles, indoles,7f 2-methylfuran and
thiophene.7g
Activation of the carboxylic acid function of N-protected
a-amino acids has attracted considerable attention due to
the importance of peptide bond formation. The many pre-
vious methods can be classified into (i) those in which no
intermediate is isolated, for example carbodiimides (DCC
or EDAC) with HOBt,1a or uronium salts,1b and (ii) isolat-
ed intermediates including N-protected a-amino acid
chlorides,1c fluorides,1d azides and phenyl esters.1a,1e–i Al-
though this type of chemistry for the formation of peptide
bonds has been well-established, to date, no single method
of choice has emerged.
Azides,1e N-hydroxysuccinimide esters,2a,b and p-nitro-
phenyl esters3 were previously utilized to achieve peptide
coupling between a C-terminal activated N-protected a-
amino acid and a non-protected a-amino acid. N-Hy-
droxysuccinimide esters2a,b and p-nitrophenyl esters3 were
reported as isolable stable solids, sufficiently reactive to
We previously reported the preparation of N-(Boc-a-ami-
no)amides from N-(Boc-a-aminoacyl)benzotriazoles and
chiral amines in 82–99% yields with no detectable
racemization8a and demonstrated the peptide coupling of
several N-(Cbz-a-aminoacyl)benzotriazoles (Cbz-Ala-Bt,
Cbz-Val-Bt, and Cbz-Phe-Bt) with unprotected amino ac-
ids in CH3CN–H2O with complete preservation of the
original chirality.8b In continuation of our extensive re-
search on N-(protected a-aminoacyl)benzotriazoles, we
now report (i) the preparation of functionalized N-(Cbz-
or Fmoc-a-aminoacyl)benzotriazoles 2a–f carrying phe-
nolic OH, NH of indole, SH, SMe, amide group, and (ii)
(L)
R2
CO2H
R1
O
R1
O
R1
O
BtH, SOCl2
H2N
R2
CH3CN/H2O/Et3N
20 °C
20 °C, CH2Cl2
Pg NH Bt
Pg NH OH
Pg NH HN
O
HO
1a–f
3a–f
2a–f
R2
CO2H
H2N
R1
O
(DL)
R2
3a–f
+
Pg NH HN
O
1a–f; N-protected Tyr, Trp, Cys, Met, Gln. R2 = -CH3, -CH2Ph
Bt = benzotriazol-1-yl
HO
4a–f
Pg = Z- (benzyloxycarbonyl), Fmoc- (9-fluorenylmethylcarbonyl)
Scheme 1
SYNTHESIS 2005, No. 3, pp 0397–0402
x
x
.
x
x
.2
0
0
5
Advanced online publication: 18.01.2005
DOI: 10.1055/s-2005-861782; Art ID: M08104SS
© Georg Thieme Verlag Stuttgart · New York

398
A. R. Katritzky et al.
PAPER
coupling reactions of 2a–f with unprotected amino acids ture. In addition, the reagents involved in the preparation
(L-Ala, D,L-Ala, L-Phe, D,L-Phe) with retention of chirali- are inexpensive, thereby offering at the same time an
ty as d monstrated by NMR and HPLC (Scheme 1).
overall cost effective methodology.
Table 1 Conversion of N-Cbz-a-Amino Acids into a-(N-Cbz-Ami-
noacyl) Benzotriazoles
Preparation of Dipeptides (3a–f, 4a–f)
Peptide coupling was carried out using equimolar amount
of 2a–f and L-Ala-OH or L-Phe-OH in a partially aqueous
medium (CH3CN–H2O, 2:1 in volume) in the presence of
Et3N (1 equiv) at 20 °C for 1 hour. After work-up, the L,L-
dipeptides 3a–f were obtained in almost pure form as in-
Compound
Yield (%)a
[a]25
Mp (°C)
165–166
100–101
88–90
D
Cbz-L-Tyr-Bt (2a)
Cbz-L-Trp-Bt (2b)
Fmoc-L-Trp-Bt (2c)
Cbz-L-Cys-Bt (2d)
Fmoc-L-Met-Bt (2e)
Cbz-L-Gln-Bt (2f)
a Isolated yield.
86
95
90
76
87
72
+46.5
+35.2
+12.7
-121.7
-75.1
-27.1
1
dicated by the crude H NMR spectra. Dipeptides 3a–f
were further purified by recrystallization, typically from
CHCl3–hexanes, to give yields of 85–95% (Table 2). Mix-
tures of L,L- and L,D-dipeptide diastereomers 3a–f + 4a–f
were also prepared from each 2a–f under the same condi-
tion utilizing enantiomixtures (Table 3), D,L-Ala-OH or
D,L-Phe-OH, using the procedure described above for
preparation of L,L-dipeptides 3a–f.
144–147
98–100
161–162
Preparation of N-(Cbz- and Fmoc-a-Aminoacyl)
Benzotriazoles
Analysis of L,L-(3a–f) and L,D,L-Dipeptides (4a–f)
We previously described8b that the coupling reactions uti-
lizing N-(Cbz-aminoacyl)benzotriazoles gave the result-
ing peptides with no detectable racemization
demonstrated by 1H NMR and HPLC analysis. Likewise,
the crude dipeptides 3a–f were analyzed in NMR, and
We recently developed a new method to prepare a wide
range of N-acylbenzotriazoles utilizing 1 equivalent of a
carboxylic acid with 4 equivalents of 1H-benzotriazole
and 1 equivalent of thionyl chloride in THF or CH2Cl2 at
20 °C for two hours.9 During our study of N-acylbenzotri-
azoles, we found that carboxyl groups can frequently be
activated by this method without any side-reactions in the
presence of potential reaction sites such as phenolic OH,
thiol, indole NH and amide groups. The activation of the
carboxyl group in tyrosine, cysteine, and glutamine deriv-
atives without protection of -OH, -SH, and -CONH2
groups at their side-chains was the main objective of this
study. Therefore, the above protocol has now been applied
to achieve the preparation of N-(Cbz- and Fmoc-a-ami-
noacyl)benzotriazoles 2a–f with functionalized side-
chains (Cbz-Tyr, Cbz-Trp, Cbz-Gln, Cbz-Cys, Fmoc-Trp,
Fmoc-Met) in 72–95% yield (Table 1).
1
showed no detectable racemization (> 95%). The H
NMR spectra of diastereo-mixtures 3a–f + 4a–f were typ-
ically complicated; however, the NH proton signal at Cbz
and Fmoc groups around 8.2–8.5 ppm showed clearly two
doublets for 3 + 4 (L,L-, L,D-mixture) when 3 (L,L) gave
only one doublet. For instance, Cbz-L-Tyr-L-Phe-OH (3a)
gave only one doublet at 8.37 ppm when Cbz-L-Tyr-D,L-
Phe-OH (3a + 4a) gave two doublets at 8.30 ppm and 8.37
ppm. It appeared that the NH proton signal for 3a–f (L,L)
showed their doublet in the magnetically lower field
(higher ppm) than that of L,D-configuration. The methyl
protons of alanine (Ala) fragment were also easily moni-
1
tored in H NMR. Cbz-L-Trp-L-Ala-OH (3b) gave a no-
Cbz-Trp-Bt (2b), Fmoc-Trp-Bt (2c), and Fmoc-Met-Bt
(2e) were prepared using the procedure of our previous re-
port.8b However, in attempts to prepare Cbz-Tyr-Bt (2a)
in this manner, the wash with Na2CO3 to remove BtH
formed Tyr sodium phenolate and removed the product;
however, a wash with 6 N HCl yielded the desired com-
pound without its transfer to the aqueous layer. The crude
product of Cbz-Cys-Bt (2d) was also washed with 6 N
HCl to remove BtH to prevent the formation of thiol ester
oligomers by known reactions of N-acylbenzotriazoles,
including N-(Cbz-aminoacyl)benzotriazoles, with alphat-
ic and aromatic mercaptans.6 To obtain Cbz-Gln-Bt (2f),
the crude mixture of 2f and BtH was simply washed with
EtOAc to remove BtH (2f was not very soluble in EtOAc).
ticeable doublet for the methyl group at 1.32 ppm while
Cbz-L-Trp-D,L-Ala-OH (3b + 4b) indicated two doublets
at 1.23 ppm and 1.32 ppm. By observing the methyl pro-
tons for 3b–e and 4b–e, compounds with L,L-configura-
tion were found to have tendency to exhibit the peaks in
the lower magnetic field (higher ppm) than compounds
with L,D-conformation. In 13C NMR for mixtures of 3a–f
+ 4a–f, all of the aliphatic and the carbonyl carbons typi-
cally displayed doublets, but aromatic carbons did not
show significant differences.
The enantiopurity (> 99%) of the dipeptides 3a–f (L,L-
configuration) was further confirmed by HPLC analysis
using Chirobiotic T column (detection at 254 nm, flow
rate 0.5 mL/min, and solvent MeOH for all 3a–f). The
HPLC results obtained for the desired L,L-dipeptides 3a–
f are summarized in Table 1. HPLC results for the corre-
sponding mixtures of L,L- and L,D-dipeptides prepared
with D,L-amino acids as a second component is shown in
N-(Cbz- and Fmoc-aminoacyl)benzotriazoles 2a–f are
novel, and were characterized by 1H and 13C NMR spec-
troscopy, elemental analysis, and ORP. The compounds
2a–f are stable and can be stored at room temperature for
months without special procedure to exclude air or mois-
Synthesis 2005, No. 3, 397–402 © Thieme Stuttgart · New York

PAPER
N-(Cbz- and Fmoc-a-aminoacyl)benzotriazoles: Stable Derivatives
399
Table 2 Preparation of L,L-Dipeptides 3a–f using 2a–f
Reactant
Amino acid
L-Phe-OH
L-Ala-OH
L-Ala-OH
L-Ala-OH
L-Ala-OH
L-Phe-OH
Product
Yield (%)a
Retention timeb
Cbz-L-Tyr-Bt (2a)
Cbz-L-Trp-Bt (2b)
Fmoc-L-Trp-Bt (2c)
Cbz-L-Cys-Bt (2d)
Fmoc-L-Met-Bt (2e)
Cbz-L-Gln-Bt (2f)
a Isolated yield.
Cbz-L-Tyr-L-Phe-OH (3a)
Cbz-L-Trp-L-Ala-OH (3b)
Fmoc-L-Trp-L-Ala-OH (3c)
Cbz-L-Cys-L-Ala-OH (3d)
Fmoc-L-Met-L-Ala-OH (3e)
Cbz-L-Gln-L-Phe-OH (3f)
86
90
70
98
95
72
10.8
11.0
11.1
11.5
10.9
12.9
b For conditions, see the experimental section.
Table 2. The L,L and L,D-mixtures (3 + 4) were clearly esters of N-hydrosuccinimide or p-nitrophenol for the
separated to show two peaks of L,L- and L,D-diastereo- peptide couplings.
mers using the chiral column; the L,L-compounds all have
shorter retention time than L,D-compounds in these condi-
tions.
Melting points were determined on a capillary point apparatus
equipped with a digital thermometer. NMR spectra were recorded
1
in CDCl3 or DMSO-d6 with TMS for H (300 MHz) and 13C (75
In conclusion, the convenient preparation of N-(Cbz- or
Fmoc-a-aminoacyl) benzotriazoles converted from N-
Cbz- or Fmoc- protected amino acids (Tyr, Trp, Cys, Met,
and Gln) has been demonstrated under mild conditions,
and examples of peptide couplings utilizing non-protected
MHz) as the internal reference. HPLC analyses were performed on
Beckman system gold programmable solvent module 126 using
Chirobiotic T column (4.6 × 250 mm), detection at 254 nm, flow
rate of 0.5 mL/min and MeOH as an eluting solvent. N-Cbz- and
Fmoc-amino acids purchased from Fluka and amino acids pur-
amino acids in partially aqueous solution has been per- chased from Acros, were used without further purification.
formed to produce the corresponding dipeptides with neg-
ligible racemization in NMR and HPLC studies. Our
results in the preparation of dipeptides using Cbz-Tyr-Bt
(2a), Cbz-Trp-Bt (2b), Fmoc-Trp-Bt (2c) are comparable
Preparation of N-(Cbz- and Fmoc-Aminoacyl)benzotriazoles
2a–f; General Procedure
Thionyl chloride (5 mmol) was added to a solution of 1H-benzotri-
azole (20 mmol) in anhyd THF (15 mL) at 25 °C, and the reaction
to those in the conventional methods. However, Cbz-Cys-
Bt (2d) is the first example of C-activated Cys derivative
isolated without protection of the thiol group. Reactions
of conventional Cbz-Gln active esters often require puri-
fication by column chromatography. Use of Cbz-Gln-Bt
(2f) can simplify the process, and avoid the loss of prod-
ucts. Overall, the present method offers an advantageous
and economical procedure utilizing inexpensive reagents
(1H-benzotriazole, thionyl chloride) for the C-activation
and shorter reaction times (< 2 h) than those (> 20 h) with
mixture was stirred for 20 min at 35–40 °C. The reaction mixture
was cooled in an ice-bath, and the N-protected amino acid (5 mmol)
dissolved in anhyd THF (5 mL) was added dropwise. After stirring
for 2 h at 25 °C, the white precipitate formed during the reaction was
filtered off, and the filtrate was concentrated under reduced pres-
sure. The residue was diluted with EtOAc (100 mL) and the solution
was washed with 6 N HCl solution (3 × 50 mL) for 2a and 2d, or
sat. Na2CO3 solution (3 × 50 mL) for 2b, 2c, and 2e, sat. NaCl solu-
tion (50 mL), and dried over anhyd MgSO4. Removing solvents un-
der reduced pressure gave the products 2a–e. In case of 2f, the
product was obtained by simply washing the crude mixture with
EtAOc after the concentration. Products 2a–f were further recrystal-
lized from CHCl3–hexanes for elemental analysis.
Table 3 Preparation of Mixtures of L,D,L-Dipeptides 3a–f + 4a–f
Reactant
Amino acid
Product
Yield (%)a
Retention Timeb
LL
LD
2a
D,L-Phe-OH
D,L-Ala-OH
D,L-Ala-OH
D,L-Ala-OH
D,L-Ala-OH
D,L-Phe-OH
Cbz-L-Tyr-D, L-Phe-OH (3a + 4a)
Cbz-L-Trp-D,L-Ala-OH (3b + 4b)
Fmoc-L-Trp-D,L-Ala-OH (3c + 4c)
Cbz-L-Cys-D,L-Ala-OH (3d + 4d)
Fmoc-L-Met-D,L-Ala-OH (3e + 4e)
Cbz-L-Gln-D,L-Phe-OH (3f + 4f)
86
90
68
71
72
74
10.8
11.0
11.3
11.6
10.9
13.0
11.7
12.9
13.6
24.3
15.9
15.9
2b
2c
2d
2e
2f
a Isolated yield.
b For conditions, see the experimental section.
Synthesis 2005, No. 3, 397–402 © Thieme Stuttgart · New York

400
A. R. Katritzky et al.
PAPER
Benzyl N-[(1S)-2-(1H-1,2,3-Benzotriazol-1-yl)-1-(4-hydroxy-
benzyl)-2-oxoethyl]carbamate [Cbz-L-Tyr-Bt (2a)]
White microcrystals (86%); mp 165–166 °C; [a]D23 +46.5 (c = 1.5,
DMF).
Anal. Calcd for C17H16N4O3S: C, 57.29; H, 4.52; N, 15.72. Found:
C, 56.89; H, 4.20; N, 15.36.
9H-Fluoren-9-ylmethyl N-[(1S)-1-(1H-1,2,3-benzotriazol-1-yl-
carbonyl)-3-(methylsulfanyl)propyl]carbamate [Fmoc-L-Met-
1H NMR (DMSO-d6): d = 2.97 (dd, J = 13.7, 9.9 Hz, 1 H,
CHCH2Ar), 3.21 (dd, J = 13.7, 4.0 Hz, 1 H, CHCH2Ar), 5.00 (s, 2
H, OCH2Ph), 5.63–5.70 (unresolved m, 1 H, NCHCH2), 6.65 (d,
J = 8.0 Hz, 2 H), 7.13 (d, J = 8.0 Hz, 2 H), 7.32–7.34 (m, 5 H), 7.64
(dd, J = 8.3, 6.9 Hz, 1 H, Bt), 7.82 (dd, J = 8.4, 6.9 Hz, 1 H, Bt),
8.23–8.34 [m, 2 H (Bt), 1 H (NH)], 9.27 (s, 1 H, OH).
13C NMR (CDCl3): d = 35.7, 56.5, 65.8, 113.9, 115.1, 120.2, 126.8,
126.9, 127.7, 127.9, 128.3, 130.0, 130.5, 131.1, 136.6, 145.3, 156.1,
156.2, 171.9.
Bt (2e)]
White microcrystals (87%); mp 98–100 °C; [a]D23 = –75.1 (c = 1.5,
DMF).
1H NMR (DMSO-d6): d = 2.08 (s, 3 H, CH3S), 2.12–2.20 (m, 1 H,
CH2CH2CH), 2.23–2.33 (m, 1 H, CH2CH2CH), 2.61–2.79 (m, 2 H,
CH2CH2S), 4.23–4.31 (m, 1 H, CH, Fmoc), 4.38 (d, J = 6.8 Hz, 2 H,
CH2, Fmoc), 5.64–5.71 (m, 1 H), 7.30–7.48 (m, 4 H), 7.65 (dd, J =
7.7, 6.9 Hz, 1 H, Bt), 7.74 (d, J = 7.4 Hz, 2 H), 7.82 (dd. J = 7.5, 6.9
Hz, 1 H, Bt), 7.90 (d, J = 7.4 Hz, 2 H), 8.25 (d, J = 8.3 Hz, 1 H, Bt),
8.28–8.34 (m, 2 H, Bt, NH).
13C NMR (DMSO-d6): d = 14.2, 29.6, 29.7, 46.6, 53.4, 65.9, 114.0,
120.1, 120.2, 125.2, 126.7, 127.1, 127.6, 130.7, 131.1, 140.7, 143.7,
145.3, 156.4, 171.9.
Anal. Calcd for C23H20N4O4: C, 66.34; H, 4.82; N, 13.45. Found: C,
66.35; H, 4.73; N, 13.20.
Benzyl N-[(1S)-2-(1H-1,2,3-Benzotriazol-1-yl)-1-(1H-indol-3-
ylmethyl)-2-oxoethyl]carbamate [Cbz-L-Trp-Bt (2b)]
Pale yellow crystals (95%); mp 100–101 °C; [a]D23 +35.2 (c = 1.5,
DMF).
Anal. Calcd for C26H24N4O3S: C, 66.08; H, 5.12; N, 11.86. Found:
C, 65.97; H, 5.08; N, 11.52.
1H NMR (CDCl3): d = 3.43 (dd, J = 14.7, 7.1 Hz, 1 H, ArCH2CH),
3.61 (dd, J = 14.7, 7.1 Hz, 1 H, ArCH2CH), 5.06 (s, 2 H, PhCH2O),
5.70 (d, J = 7.5 Hz, 1 H, CH2CHN), 6.13 (dd, J = 12.5, 7.0 Hz, 1 H,
NH), 6.90–6.98 (m, 3 H), 7.08–7.13 (m, 1 H), 7.29 (m, 5 H), 7.40
(d, J = 7.8 Hz, 1 H), 7.47–7.52 (m, 1 H, Bt), 7.58–7.63 (m, 1 H, Bt),
8.12 (d, J = 8.2 Hz, 1 H, Bt), 8.16 (d, J = 8.2 Hz, 1 H, Bt), 8.22 (br
s, 1 H, NH).
13C NMR (CDCl3): d = 28.7, 55.1, 67.2, 109.0, 111.2, 114.3, 118.3,
119.7, 120.2, 122.2, 123.1, 126.4, 127.1, 128.1, 128.4, 128.5, 130.7,
131.0, 135.9, 136.1, 145.9, 155.9, 171.1.
Benzyl N-[(1S)-4-Amino-1-(1H-1,2,3-benzotriazol-1-ylcarbon-
yl)-4-oxobutyl]carbamate [Cbz-L-Gln-Bt (2f)]
Pale violet microcrystals (72%); mp 161–162 °C; [a]D23 –27.1 (c =
1.5, DMF).
1H NMR (DMSO-d6): d = 2.05–2.09 (m, 1 H, CH2CH2CH), 2.22–
2.35 (m, 3 H, COCH2CH2CH), 5.06 (s, 2 H, PhCH2O), 5.51–5.54
(unresolved m, 1 H, CH2CHN), 6.83–6.92 (m, 2 H, NH2), 7.36 (un-
resolved m, 5 H), 7.65 (dd, J = 8.2, 6.9 Hz, 1 H, Bt), 7.82 (dd, J =
8.2, 6.9 Hz, 1 H, Bt), 8.24 (d, J = 8.2 Hz, 1 H, NH), 8.31 (d, J = 7.8
Hz, 2 H, Bt).
Anal. Calcd for C25H21N5O3: C, 68.33; H, 4.82; N, 15.94. Found: C,
68.18; H, 4.77; N, 16.12.
13C NMR (DMSO-d6): d = 26.5, 31.1, 54.1, 65.9, 114.1, 120.2,
126.8, 127.8, 127.9, 128.4, 130.6, 131.1, 136.7, 145.4, 156.3, 171.8,
173.1.
9H-Fluoren-9-ylmethyl N-[1-(1H-1,2,3-Benzotriazol-1-ylcarbo-
nyl)-2-(indol-3-ylmethyl)]carbamate [Fmoc-L-Trp-Bt (2c)]
White microcrystals (90%); mp 88–90 °C; [a]D +12.7 (c = 1.5,
DMF).
Anal. Calcd for C23H20N4O4: C, 59.84; H, 5.02; N, 18.36. Found: C,
59.59; H, 5.00; N, 18.11.
23
Preparation of Cbz- and Fmoc-L,L-dipeptides 3a–e; General
Procedure
1H NMR (DMSO-d6): d = 3.27 (dd, J = 14.6, 9.9 Hz, 1 H,
ArCH2CH), 3.52 (dd, J = 14.6, 4.1 Hz, 1 H, ArCH2CH), 4.15–4.30
(m, 3 H, CH2, CH, Fmoc), 5.74–5.81 (unresolved m, 1 H,
CH2CHN), 6.97–7.09 (m, 2 H), 7.17–7.46 (m, 6 H), 7.61–7.84 (m,
5 H), 7.88 (d, J = 7.4 Hz, 2 H), 8.25 (d, J = 8.2 Hz, 1 H, Bt), 8.28 (d,
J = 8.3 Hz, 1 H, Bt), 8.36 (d, J = 7.1 Hz, 1 H, NH), 10.89 (s, 1 H,
NH).
13C NMR (DMSO-d6): d = 27.1, 46.5, 55.6, 65.9, 109.2, 111.5,
114.0, 118.2, 118.5, 120.1, 120.2, 121.0, 124.4, 125.2, 126.7, 126.8,
127.1, 127.6, 130.6, 131.1, 136.1, 140.7, 143.6, 143.7, 145.3, 156.2,
172.2.
The starting material 2 (1 mmol) was added to a solution of an ami-
no acid (1 mmol) with Et3N (1 equiv) in CH3CN–H2O (10 mL/4
mL). The reaction mixture was stirred at r.t. for about 1 h (until TLC
showed the absence of 2). CH3CN in the solution was removed un-
der reduced pressure, and EtOAc was added. The organic solution
was washed with 6 N HCl, and dried over MgSO4. After evapora-
tion of solvent, the residue was crystallized or precipitated out from
CHCl3–hexanes.
(2S)-2-{[(2S)-2-{[(Benzyloxy)carbonyl]amino}-3-(4-hydroxy-
phenyl)propanoyl]amino}-3-phenyl-propanoic Acid [Cbz-L-
Tyr-L-Phe-OH (3a)]
Anal. Calcd for C32H25N5O3: C, 72.85; H, 4.78; N, 13.27. Found: C,
72.55; H, 4.80; N, 12.97.
White microcrystals (86%); mp 149–151 °C; [a]D23 –30.8 (c = 1.5,
DMF).
Benzyl N-[(1S)-2-(1H-1,2,3-Benzotriazol-1-yl)-2-oxo-1-(sulfa-
nylmethyl)ethyl]carbamate [Cbz-L-Cys-Bt (2d)]
White microcrystals (76%); mp 144–147 °C; [a]D23 –121.7 (c = 1.5,
DMF).
1H NMR (DMSO-d6): d = 3.17 (dd, J = 13.8, 9.9 Hz, 1 H, SCH2CH),
3.54 (dd, J = 13.7, 4.1 Hz, 1 H, SCH2CH), 5.04 (s, 2 H, PhCH2O),
5.88 (unresolved m, 1 H, CH2CHN), 7.34 (unresolved m, 5 H), 7.62
(dd, J = 7.7, 6.9 Hz, 1 H, Bt), 7.80 (dd, J = 7.7, 6.9 Hz, 1 H, Bt), 8.12
(d, J = 8.3 Hz, 1 H, Bt), 8.20 (d, J = 8.3 Hz, 1 H, Bt), 8.33 (d, J =
7.1 Hz, 1 H, NH); exchangeable 1 H (-SH) was missing.
1H NMR (DMSO-d6): d = 2.60–2.64 (m, 1 H, ArCH2CH), 2.88 (dd,
J = 14.4, 3.3 Hz, 1 H, ArCH2CH), 2.94–3.01 (m, 1 H, ArCH2CH),
3.12 (dd, J = 14.0, 5.1 Hz, 1 H, ArCH2CH), 4.20–4.25 (m, 1 H,
COCHN), 4.45–4.48 (m, 1 H, COCHN), 4.96–5.01 (m, 2 H,
PhCH2O), 6.67 (d, J = 8.2 Hz, 2 H), 7.06 (s, 1 H, NH), 7.09 (s, 1 H,
OH), 7.24–7.44 (m, 11 H), 8.28 (d, J = 7.7 Hz, 1 H), 9.22 (s, 1 H,
NH), 12.77 (s, 1 H, CO2H).
13C NMR (DMSO-d6): d = 36.7, 47.2, 53.4, 56.3, 65.1, 114.8, 126.4,
127.3, 127.5, 127.6, 128.1, 128.2, 128.3, 129.2, 130.1, 137.0, 137.4,
155.7, 171.7, 172.4.
13C NMR (DMSO-d6): d = 37.2, 53.2, 66.0, 113.9, 120.2, 126.9,
127.8, 128.0, 128.4, 130.5, 131.3, 136.6, 145.3, 156.2, 170.3.
Synthesis 2005, No. 3, 397–402 © Thieme Stuttgart · New York

PAPER
N-(Cbz- and Fmoc-a-aminoacyl)benzotriazoles: Stable Derivatives
401
Anal. Calcd for C26H26N2O6: C, 67.52; H, 5.67; N, 6.06. Found: C,
67.65; H, 5.64; N, 5.73.
J = 7.7 Hz, 2 H), 8.25 (d, J = 6.9 Hz, 1 H, NH), 12.53 (br s, 1 H,
CO2H).
13C NMR (DMSO-d6): d = 14.6, 17.0, 29.5, 31.9, 46.6, 47.5, 53.5,
65.6, 120.1, 125.3, 127.0, 127.6, 140.7, 143.7, 143.9, 155.9, 171.3,
174.0.
(2S)-2-{[(2S)-2-{[(Benzyloxy)carbonyl]amino}-3-(1H-indol-3-
yl)propanoyl]amino}propanoic Acid [Cbz-L-Trp-L-Ala-OH,
(3b)]
White microcrystals (90%); mp 140–144 °C; [a]D23 –22.5 (c = 1.5,
Anal. Calcd for C23H26N2O5S: C, 62.42; H, 5.92; N, 6.33. Found: C,
62.18; H, 6.06; N, 6.08.
DMF).
1H NMR (DMSO-d6): d = 1.32 (d, J = 7.2 Hz, 3 H, CH3CH), 2.90
(dd, J = 14.6, 10.4 Hz, 1 H, ArCH2CH), 3.15 (dd, J = 14.6, 3.2 Hz,
1 H, ArCH2CH), 4.22–4.38 (m, 2 H, 2 × COCHN), 4.88–4.98 (m, 2
H, PhCH2O), 6.96–7.04 (m, 1 H), 7.06–7.09 (m, 1 H), 7.18 (s, 1 H),
7.22–7.38 (m, 7 H), 7.70 (d, J = 7.7 Hz, 1 H, NH), 8.38 (d, J = 7.1
Hz, 1 H, NH), 10.82 (s, 1 H, NH), 12.60 (s, 1 H, CO2H).
13C NMR (DMSO-d6): d = 17.2, 27.8, 47.6, 55.2, 65.2, 110.2, 111.3,
118.2, 116.6, 120.8, 124.0, 127.3, 127.5, 127.7, 128.3, 136.1, 137.0,
155.8, 171.8, 174.1.
(2S)-2-{[(2S)-5-Amino-2-{[(benzyloxy)carbonyl]amino}-5-oxo-
pentanoyl]amino}-3-phenylpropanoic Acid [Cbz-L-Gln-L-Phe-
OH (3f)]
White microcrystals (from water) (62%); mp 188–190 °C (lit.3 198–
199 °C); [a]D23 +3.6 (c = 1.5, DMF) [lit.3 +4.7 (c = 1.0, DMF)].
1H NMR (DMSO-d6): d = 1.64–1.69 (m, 1 H, CHCH2CH2), 1.83–
1.90 (m, 1 H, CHCH2CH2), 2.01–2.17 (m, 2 H, ArCH2CH), 2.86–
2.95 (m, 1 H, CH2CH2CO), 3.02–3.10 (m, 1 H, CH2CH2CO), 3.96–
4.00 (m, 3 H, CONH2, COCHN), 4.43 (dd, J = 13.0, 8.0 Hz, 1 H,
COCHN), 5.01 (s, 2 H, PHCH2O), 6.78 (s, 1 H, NH), 7.18–7.28 (m,
5 H), 7.30–7.40 (m, 5 H), 8.13 (d, J = 7.7 Hz, 1 H, NH), 12.73 (s, 1
H, CO2H).
Anal. Calcd for C22H23N3O5: C, 64.54; H, 5.66; N, 10.03. Found: C,
64.44; H, 5.66; N, 10.03.
(2S)-2-{[(2S)-2-{[(9H-Fluoren-9-ylmethoxy)carbonyl]amino}-
3-(1H-indol-3-yl)propanoyl]amino}propanoic Acid [Fmoc-L-
Trp-L-Ala-OH (3c)]
13C NMR (DMSO-d6): d = 27.8, 31.5, 36.7, 45.4, 54.2, 65.4, 126.4,
127.7, 127.8, 128.2, 128.4, 129.2, 137.0, 137.4, 155.8, 171.6, 172.8,
173.8.
White microcrystals (70%); mp 155–156 °C; [a]D23 –15.7 (c = 1.5,
DMF).
Anal. Calcd for C22H25N3O6: C, 61.82; H, 5.89; N, 9.83. Found: C,
61.67; H, 5.98; N, 9.87.
1H NMR (DMSO-d6): d = 1.31 (d, J = 7.1 Hz, 3 H, CH3CH), 2.89–
2.97 (m, 1 H, ArCH2CH), 3.10–3.21 (m, 1 H, ArCH2CH), 4.13 (ap-
parent s, 2 H, CH2, Fmoc), 4.19–4.33 (m, 3 H, CH (Fmoc), 2 ×
COCHN), 6.95–7.00 (m, 1 H), 7.03–7.08 (m, 1 H), 7.19–7.43 (m, 6
H), 7.51 (d, J = 8.5 Hz, 1 H), 7.59–7.66 (m, 2 H), 7.71 (d, J = 7.7
Hz, 1 H), 7.87 (d, J = 7.1 Hz, 2 H), 8.37 (d, J = 7.1 Hz, 1 H, NH),
10.82 (s, 1 H, NH), 12.57 (s, 1 H, CO2H).
13C NMR (DMSO-d6): d = 17.1, 27.8, 46.5, 47.5, 55.2, 65.6, 110.2,
111.3, 118.1, 118.6, 120.1, 120.8, 123.9, 125.4, 127.0, 127.3, 127.6,
136.1, 140.6, 143.7, 143.8, 155.8, 171.8, 174.1.
2-{[(2S)-2-{[(Benzyloxy)carbonyl]amino}-3-(4-hydroxyphe-
nyl)propanoyl]amino}-3-phenylpropanoic Acid (Cbz-L-Tyr-
D,L-Phe-OH, 3a + 4a)
White microcrystals (72%); mp 115–117 °C; [a]D23 –13.3 (c = 1.5,
DMF).
1H NMR (DMSO-d6): d = 2.57–2.60 (m, 2 H, ArCH2CH), 2.81–
2.97 (unresolved m, 4 H, ArCH2CH), 3.06–3.10 (unresolved m, 2 H,
ArCH2CH), 4.18–4.21 (unresolved m, 2 H, COCHN), 4.42–4.44
(unresolved m, 2 H, COCHN), 4.92–4.97 (unresolved m, 4 H,
PhCH2O), 6.59–6.71 (unresolved m, 4 H), 6.94–7.05 (m, 4 H),
7.09–7.39 (m, 22 H), 8.23 (d, J = 7.7 Hz, 1 H), 8.36 (d, J = 8.3 Hz,
1 H), 9.15–9.28 (m, 2 H, NH), 12.75 (s, 2 H, CO2H).
Anal. Calcd for C29H27N3O5: C, 70.01; H, 5.47; N, 8.45. Found: C,
69.68; H, 5.48; N, 8.25.
(2S)-2-({(2S)-2-[(3-Phenylpropanoyl)amino]-3-sulfanylpro-
panoyl}amino)propanoic Acid [Cbz-L-Cys-L-Ala-OH (3d)]
White microcrystals (98%); mp 161–164 °C; [a]D23 –111.9 (c = 1.5,
DMF).
13C NMR (DMSO-d6): d = 14.0, 22.1, 31.0, 36.7, 36.8, 37.1, 53.2,
53.4, 56.3, 65.1, 65.2, 114.7, 114.8, 115.0, 115.1, 126.4, 127.3,
127.5, 127.6, 128.1, 128.2, 128.3, 129.2, 129.3, 130.0, 130.1, 137.1,
137.4, 155.7, 171.5, 171.7, 172.8, 172.9.
1H NMR (DMSO-d6): d = 1.29 (d, J = 7.1 Hz, 3 H, CH3CH), 2.85–
2.89 (m, 1 H, SCH2CH), 3.14–3.20 (m, 1 H, SCH2CH), 4.23 (t, J =
7.2 Hz, 1 H, COCHN), 4.34–4.39 (unresolved m, 1 H, COCHN),
5.04 (s, 2 H, PhCH2O), 7.35–7.41 (unresolved m, 5 H), 7.69 (d, J =
8.2 Hz, 1 H, NH), 8.27–8.29 (m, 1 H, NH), 12.68 (br s, 1 H, CO2H);
exchangeable 1 H (-SH) was missing.
Anal. Calcd for C26H26N2O6: C, 67.52; H, 5.67; N, 6.06. Found: C,
67.18; H, 5.82; N, 5.68.
2-{[(2S)-2-{[(Benzyloxy)carbonyl]amino}-3-(1H-indol-3-yl)pro-
panoyl]amino}propanoic Acid (Cbz-L-Trp-D,L-Ala-OH, 3b +
4b)
13C NMR (DMSO-d6): d = 17.0, 47.7, 53.7, 65.0, 65.6, 127.7, 127.8,
128.4, 136.9, 156.0, 169.9, 173.8.
White microcrystals (94%); mp 93–95 °C; [a]D –19.5 (c = 1.5,
DMF).
23
Anal. Calcd for C15H20N2O5S: C, 51.52; H, 5.56; N, 8.58. Found: C,
51.94; H, 5.36; N, 8.08.
1H NMR (DMSO-d6): d = 1.23 (d, J = 8.0 Hz, 3 H, CH3CH), 1.31
(d, J = 7.5Hz, 3 H, CH3CH), 2.85–2.95 (m, 2 H, ArCH2CH), 3.05–
3.15 (m, 2 H, ArCH2CH), 4.16–4.37 (m, 4 H, COCHN), 4.92–4.94
(m, 4 H, PhCH2O), 6.94–7.00 (m, 2 H), 7.03–7.08 (m, 2 H), 7.16
(unresolved m, 2 H), 7.23–7.37 (m, 14 H), 7.63–7.70 (m, 2 H), 8.30
(d, J = 7.4 Hz, 1 H), 8.36 (d, J = 7.4 Hz, 1 H, N H), 10.81 (s, 2 H,
NH), 12.59 (s, 2 H, CO2H).
13C NMR (DMSO-d6): d = 14.0, 17.2, 17.3, 22.1, 27.8, 28.2, 31.0,
47.5, 55.2, 55.3, 65.2, 110.0, 110.1, 111.3, 118.1, 118.6, 120.8,
123.9, 124.0, 127.3, 127.4, 127.5, 127.7, 128.3, 136.0, 136.1, 137.0,
137.1, 155.7, 155.8, 171.5, 171.8, 174.0, 174.1.
(2S)-2-{[2-{[(9H-Fluoren-9-ylmethoxy)carbonyl]amino}-4-(me-
thylsulfanyl)butanoyl]amino}propanoic Acid [Fmoc-L-Met-L-
Ala-OH (3e)]
23
White microcrystals (95%); mp 155–156 °C; [a]D –9.7 (c = 1.5,
DMF).
1H NMR (DMSO-d6): d = 1.29 (d, J = 7.1 Hz, 3 H, CH3CH), 1.76–
1.97 (m, 2 H, CHCH2CH2), 2.05 (s, 3 H, CH3S), 2.45–2.50 (m, 2 H,
CH2CH2S), 4.09–4.29 (m, 5 H), 7.30–7.35 (m, 2 H), 7.42–7.44 (m,
2 H), 7.58 (d, J = 8.3 Hz, 1 H, NH), 7.71–7.75 (m, 2 H), 7.89 (d,
Anal. Calcd for C22H23N3O5: C, 64.54; H, 5.66; N, 10.26. Found: C,
64.70; H, 6.06; N, 9.69.
Synthesis 2005, No. 3, 397–402 © Thieme Stuttgart · New York

402
A. R. Katritzky et al.
PAPER
2-{[(2S)-2-{[(9H-Fluoren-9-ylmethoxy)carbonyl]amino}-3-(1H-
indol-3-yl)propanoyl]amino}propanoic Acid (Fmoc-L-Trp-D,L-
Ala-OH, 3c + 4c)
White microcrystals (68%); mp 136–138 °C: [a]D –0.6 (c = 1.5,
DMF).
7.18–7.23 [m, 10 H (ArH), 2 H (NH)], 7.28–7.42 (m, 10 H, ArH),
8.10–8.12 (m, 2 H, NH), 12.76 (s, 2 H, CO2H).
13C NMR (DMSO-d6): d = 8.6, 27.8, 31.3, 31.5, 36.7, 36.9, 45.6,
53.3, 53.4, 54.2, 54.3, 65.4, 126.4, 127.7, 127.8, 128.1, 128.3,
129.2, 137.0, 137.3, 155.8, 171.4, 171.6, 172.8, 173.6, 173.7.
23
1H NMR (DMSO-d6): d = 1.21 (d, J = 7.1 Hz, 3 H, CH3CH), 1.32
(d, J = 7.1 Hz, 3 H, CH3CH), 2.90–2.98 (m, 2 H, ArCH2CH), 3.08–
3.15 (m, 2 H, ArCH2CH), 4.14 (m, 6 H, CH2, CH in Fmoc), 4.19–
4.26 (m, 2 H, COCHN), 4.28–4.34 (m, 2 H, COCHN), 6.97–7.00
(m, 2 H), 7.04–7.08 (m, 2 H), 7.19–7.43 (m, 12 H), 7.48–7.54 (m, 2
H), 7.60–7.72 (m, 6 H), 7.87 (d, J = 7.1 Hz, 4 H), 8.31 (d, J = 7.1
Hz, 1 H, NH), 8.38 (d, J = 7.1 Hz, 1 H, NH), 10.82 (s, 2 H, NH),
12.60 (s, 2 H, CO2H).
13C NMR (DMSO-d6): d = 17.2, 17.4, 27.8, 28.2, 46.6, 47.6, 55.2,
55.3, 65.7, 110.1, 110.3, 111.3, 118.2, 118.6, 120.1, 120.8, 123.9,
125.4, 127.1, 127.3, 127.4, 127.6, 136.0, 136.1, 140.6, 143.7, 143.8,
155.7, 155.8, 171.6, 171.9, 174.0, 174.1.
Anal. Calcd for C22H25N3O6: C, 61.82; H, 5.89; N, 9.83. Found: C,
61.90; H, 5.91; N, 10.07.
References
(1) (a) Gross, M.; Meienhofer, J. The Peptides; Academic Press:
New York, 1979. (b) Carpino, L. A.; Ionescu, D.; El-Faham,
A. J. Org. Chem. 1996, 61, 2460. (c) Carpino, L. A.; Sadat-
Aalaee, D.; Beyermann, M. J. Org. Chem. 1990, 55, 1673.
(d) Carpino, L. A.; Sadat-Aalaee, D.; Chao, H. G.; DeSelms,
R. H. J. Am. Chem. Soc. 1990, 112, 9651. (e) Bodanszky,
M.; Klausner, Y. S.; Ondetti, M. A. Peptide Synthesis; John
Wiley & Sons: New York, 1976. (f) Moroder, L.; Toniolo,
C. Synthesis of Peptides and Peptidomimetics, In Houben–
Weyl; Georg Thieme Verlag: Stuttgart, New York, 2001,
E22a. (g) Moroder, L.; Toniolo, C. Synthesis of Peptides and
Peptidomimetics, In Houben–Weyl; Georg Thieme Verlag:
Stuttgart, New York, 2001, E22b. (h) Katritzky, A. R.;
Suzuki, K.; Singh, S. K. Arkivoc 2004, 12. (i) Han, S.-Y.;
Kim, Y.-A. Tetrahedron 2004, 60, 2447.
Anal. Calcd for C29H27N3O5: C, 70.01; H, 5.47; N, 8.45. Found: C,
70.03; H, 5.53; N, 7.70.
2-{[(2S)-2-[(3-phenylpropanoyl)amino]-3-sulfanyl pro-
panoyl]amino}propanoic Acid (Cbz-L-Cys-D,L-Ala-OH, 3d +
4d)
23
White microcrystals (71%); mp 153–155 °C (lit.10 40–44 °C); [a]D
–99.9 (c = 1.5, DMF).
(2) (a) Anderson, G. W.; Zimmerman, J. E.; Callahan, F. M. J.
Am. Chem. Soc. 1964, 86, 1839. (b) Linton, S. D.;
Karanewsky, D. S.; Ternansky, R. J.; Chen, N.; Guo, X.;
Jahangiri, K. G.; Kalish, V. J.; Meduna, S. P.; Robinson, E.
D.; Ullman, B. R.; Wu, J. C.; Pham, B.; Kodandapani, L.;
Smidt, R.; Diaz, J.-L.; Fritz, L. C.; von Krosigk, U.; Roggo,
S.; Schmitz, A.; Tomaselli, K. J. Bioorg. Med. Chem. Lett.
2002, 12, 2973. (c) Iselin, B. M.; Schwyzer, R. Helv. Chim.
Acta 1961, 43, 1760.
1H NMR (DMSO-d6): d = 1.29–1.33 (m, 6 H, CH3CH), 2.85–2.92
(m, 2 H, CHCH2S), 3.13–3.17 (m, 2 H, CHCH2S), 4.22–4.27 (m, 2
H, COCHN), 4.38 (unresolved m, 2 H, COCHN), 5.08 (s, 4 H,
PhCH2O), 7.36–7.60 (unresolved m, 10 H), 7.57–7.64 (m, 2 H,
NH), 8.30–8.35 (m, 2 H, NH), 12.64 (s, 2 H, CO2H).
13C NMR (DMSO-d6): d = 17.0, 17.3, 47.7, 53.6, 65.0, 65.6, 127.7,
127.8, 128.3, 136.9, 156.0, 169.7, 169.9, 173.8, 173.9.
Anal. Calcd for C14H18N2O5S: C, 51.52; H, 5.56; N, 8.58. Found: C,
51.38; H, 5.17; N, 8.28.
(3) Gagnon, P.; Huang, X.; Therrien, E.; Keillor, J. W.
Tetrahedron Lett. 2002, 43, 7717.
(4) (a) Katritzky, A. R.; He, H.-Y.; Suzuki, K. J. Org. Chem.
2000, 65, 8210. (b) Katritzky, A. R.; Hoffmann, S.; Suzuki,
K. Arkivoc 2004, xii, 14. (c) Katritzky, A. R.; Yang, H.;
Zhang, S.; Wang, M. Arkivoc 2002, xi, 39. (d) Katritzky, A.
R.; Chang, H.-X.; Yang, B. Synthesis 1995, 503.
(e) Katritzky, A. R.; Yang, B.; Semenzin, D. J. Org. Chem.
1997, 62, 726.
(5) (a) Katritzky, A. R.; Pastor, A.; Voronkov, M. V. J.
Heterocyclic Chem. 1999, 36, 777. (b) Katritzky, A. R.;
Denisko, O. V.; Fang, Y.; Zhang, L.; Wang, Z. Arkivoc
2001, xi, 41.
2-{[2-{[(9H-Fluoren-9-ylmethoxy)carbonyl]amino}-4-(methyl-
sulfanyl)butanoyl]amino}propanoic Acid (Fmoc-L-Met-D,L-
Ala-OH, 3e + 4e)
White microcrystals (72%); mp 109–110 °C; [a]D –7.8 (c = 1.5,
DMF).
1H NMR (DMSO-d6): d = 1.26 (d, J = 4.1 Hz, 3 H, CH3CH), 1.28
(d, J = 4.4 Hz, 3 H, CH3CH), 1.80–2.00 (m, 4 H, CHCH2CH2), 2.04
(s, 6 H, CH3S), 2.41–2.51 (m, 4 H, CH2CH2S), 4.10–4.28 [m, 6 H
(CH2), CH (Fmoc), 4 H (COCHN)], 7.23–7.36 (m, 4 H), 7.39–7.44
(m, 4 H), 7.53–7.58 (m, 2 H), 7.71–7.75 (m, 4 H), 7.89 (d, J = 7.5
Hz, 4 H), 8.17 (d, J = 7.1 Hz, 1 H, NH), 8.24 (d, J = 7.1 Hz, 1 H,
NH), 12.57 (s, 2 H, CO2H).
13C NMR (DMSO-d6): d = 14.6, 17.0, 17.4, 29.5, 29.6, 31.8, 46.6,
47.5, 53.5, 65.6, 120.1, 125.3, 127.0, 127.6, 140.7, 143.7, 143.9,
155.9, 171.1, 171.3, 173.9, 174.0.
23
(6) Katritzky, A. R.; Shestopalov, A. A.; Suzuki, K. Synthesis
2004, 1806.
(7) (a) Katritzky, A. R.; Pastor, A. J. Org. Chem. 2000, 65,
3679. (b) Wang, X.; Zhang, Y. Tetrahedron Lett. 2002, 43,
5431. (c) Katritzky, A. R.; Abdel-Fattah, A. A. A.; Wang,
M. J. Org. Chem. 2003, 68, 4932. (d) Katritzky, A. R.;
Abdel-Fattah, A. A. A.; Wang, M. J. Org. Chem. 2003, 68,
1443. (e) Katritzky, A. R.; Fang, Y.; Donkor, A.; Xu, J.
Synthesis 2000, 2029. (f) Katritzky, A. R.; Suzuki, K.;
Singh, S. K.; He, H.-Y. J. Org. Chem. 2003, 68, 5720.
(g) Katritzky, A. R.; Suzuki, K.; Singh, S. K. Croat. Chem.
Acta 2004, 77, 175.
(8) (a) Katritzky, A. R.; Wang, M.; Yang, H.; Zhang, S.;
Akhmedov, N. G. Arkivoc 2002, viii, 134. (b) Katritzky, A.
R.; Suzuki, K.; Singh, S. K. Synthesis 2004, 2645.
(9) Katritzky, A. R.; Zhang, Y.; Singh, S. K. Synthesis 2003,
2795.
Anal. Calcd for C23H26N2O5S: C, 62.42; H, 5.92; N, 6.33. Found: C,
62.26; H, 6.00; N, 6.01.
2-{[(2S)-5-amino-2-{[(Benzyloxy)carbonyl]amino}-5-oxopen-
tanoyl]amino}-3-phenylpropanoic Acid (Cbz-L-Gln-D,L-Phe-
OH, 3f + 4f)
23
White microcrystals (74%); mp 148–150 °C; [a]D –0.5 (c = 1.5,
DMF).
1H NMR (DMSO-d6): d = 1.54–1.89 (m, 4 H, CHCH2CH2), 1.95–
2.00 (m, 2 H, CH2CH2CO), 2.06–2.13 (m, 2 H, CH2CH2CO), 2.85–
2.95 (m, 2 H, ArCH2CH), 3.04–3.11 (m, 4 H, ArCH2CH, CONH2),
3.95–4.05 (unresolved m, 2 H, COCHN), 4.39–4.43 (m, 2 H,
COCHN), 4.95–5.06 (m, 4 H, PhCH2O), 6.74–6.76 (m, 2 H, NH),
(10) Bounaga, S.; Galleni, M.; Laws, A. P.; Page, M. I. Bioorg.
Med. Chem. 2001, 9, 503.
Synthesis 2005, No. 3, 397–402 © Thieme Stuttgart · New York