Syntheses of Chiral N-(Protected) Tri- and Tetrapeptide Conjugates

Article abstract of DOI:10.1111/j.1747-0285.2012.01364.x

Cbz-(protected)-tri- and tetrapeptide conjugates with steroids, sugars, terpenes, and heterocycles were prepared using Cbz-(protected)-tri- and tetrapeptidoylbenzotriazoles as active intermediates.

Full text of DOI:10.1111/j.1747-0285.2012.01364.x

ª 2012 John Wiley & Sons A/S
doi: 10.1111/j.1747-0285.2012.01364.x
Chem Biol Drug Des 2012; 80: 17–26
Research Article
Syntheses of Chiral N-(Protected) Tri- and
Tetrapeptide Conjugates
Kiran Bajaj1, Siva S. Panda1, Claudia El-
Nachef1 and Alan R. Katritzky1,2,
Peptide conjugates with sugar, steroid, and heterocyclic moieties
have previously been prepared (i) by solid-phase syntheses (20,21)
and (ii) in solution phase by stepwise synthesis using regular cou-
pling reagents like EDC, (22) TBTU, (23) DCC (24), and BOP (25).
However, such methods suffer from difficulties in product purifica-
tion and analysis by (HPLC): High Performance Liquid Chromatogra-
phy, (20) coupling steps being sensitive to the environment and
water, (20) and low yields (23), especially with glycine units (24).
*
1Center for Heterocyclic Compounds, Department of Chemistry,
University of Florida, Gainesville, FL 32611-7200, USA
2Chemistry Department, King Abdulaziz University, Jeddah, 21589
Saudi Arabia
*Corresponding author: Alan R. Katritzky, katritzky@chem.ufl.edu
Cbz-(protected)-tri- and tetrapeptide conjugates
with steroids, sugars, terpenes, and heterocycles
were prepared using Cbz-(protected)-tri- and tetra-
peptidoylbenzotriazoles as active intermediates.
We have already utilized N-acylbenzotriazoles extensively for N-
(26,27), C- (28,29), O- (30), and S-acylations (31). Previously, we
reported the facile synthesis of amino acid conjugates with ste-
roids, terpenes, and sugars. (32) Herein, we present the extension
of our methodology for the convenient and efficient formation of
Cbz-protected tri- and tetrapeptide conjugates with sugars, steroids,
terpenes, and heterocyclic nuclei of biological importance.
Key words: chemical structure, heterocycles, peptide, steroids, terp-
enes
Received 6 October 2011, revised 11 January 2012 and accepted for
publication 9 February 2012
Methods and Materials
Peptides and their derivatives such as hormones, neurotransmitters,
and neuromodulators act as signal molecules in diverse biological
and medicinal applications and thus have attracted considerable
synthetic attention (1,2). Esterifications of amino acids and peptides
for the protection of carboxylic acid functionality and for their acti-
vation to make peptide conjugates are well known (3–5).
Melting points were determined on a hot-stage apparatus and are
uncorrected. All reactions were carried out under nitrogen unless
otherwise specified. All microwave-assisted reactions were carried
out with a single-mode cavity Discover Microwave Synthesizer
(CEM Corporation, Matthews, NC, USA). Column chromatography
was conducted on flash silica gel (200–425 mesh). Visualization of
1
Peptidyl steroids, with amino acid or peptide units linked to the ste-
roidal frame, are important in living systems; examples such as cho-
lyl glycine and cholyl taurine are found in the human body (6).
Amino acid esters of hydroxylic terpenes, a class of peptide conju-
gate, are effective medicinal agents, for example, for atherosclero-
sis (7). N-protected a-aminoacyl esters derived from long-chain
alkanols containing 12–22 carbon atoms and a-amino acids or pep-
tides possess medicinal, nutritional and industrial utility (8). The
combination of sugar moieties with peptides is important in bio-
chemical processes ranging from cell growth regulation, immune
responses, and binding of pathogens to intercellular communication,
intercellular targeting, cancer cell metastasis, and inflammation (9–
11).
TLC plates was via UV and phosphomolybdic acid staining. H NMR
(300 MHz) and 13C NMR (75 MHz) spectra were determined in
CDCl3 with TMS as the internal standard, (CD3)2CO or DMSO-d6.
General procedure for the synthesis of N-Cbz-
(dipeptidoyl)benzotriazoles (1a–c)
The compounds were synthesized following our established proce-
dure (32).
Benzyl((S)-1-(((S)-1-(1H-benzo[d][1,2,3]triazol-1-
yl)-1-oxo-3-phenylpropan-2-yl)amino)-1-
oxopropan-2-yl)carbamate (Cbz-Ala-Phe-Bt) (1a)
White microcrystals (93%); mp 148–150 ꢀC; Lit mp 148–149 ꢀC.
Reported preparative methods for peptides and their conjugates
include (i) activating the C-terminus with coupling reagents such as
carbodiimides, (4) HOBt, and HOAt (3)-based uronium (12), phospho-
nium (13), and immonium salts (3) and (ii) procedures involving the
isolated C-terminus-activated intermediates such as acyl halides
(14–16), acylimidazoles (17), active alkyl and phenolic esters (18),
and acyloxy boron intermediates (19).
Benzyl((S)-1-(((S)-1-(1H-benzo[d][1,2,3]triazol-1-
yl)-1-oxo-3-phenylpropan-2-yl)amino)-3-methyl-
1-oxobutan-2-yl)carbamate (Cbz-Val-Phe-Bt) (1b)
White microcrystals (93%); mp 188–190 ꢀC; 1H NMR (CDCl3) d
8.22 (d, J = 8.7 Hz, 1H), 8.15 (d, J = 8.4 Hz, 1H), 7.68 (t,
17

Bajaj et al.
J = 7.7 Hz, 1H), 7.54 (t, J = 7.7 Hz, 1H), 7.41–7.27 (m, 5H), 7.24–
7.17 (m, 3H), 7.13–7.07 (m, 2H), 6.70 (d, J = 7.2 Hz, 1H), 6.30–6.20
(m, 1H), 5.31 (d, J = 8.4 Hz, 1H), 5.17–5.06 (m, 2H), 4.08 (t,
J = 7.2 Hz, 1H), 3.47 (dd, J = 14.1, 5.1 Hz, 1H), 3.24 (dd, J = 14.0,
7.7 Hz, 1H), 2.19–2.02 (m, 1H), 0.94 (d, J = 6.6 Hz, 3H), 0.87 (d,
J = 6.3 Hz, 3H); 13C NMR (CDCl3) d 171.3, 170.4, 156.5, 146.2,
136.4, 135.0, 131.2, 131.0, 129.4, 129.0, 128.7, 128.4, 128.3, 127.7,
126.8, 120.6, 114.5, 67.4, 60.4, 54.2, 38.8, 31.1, 19.3, 17.9. Anal.
Calcd for C28H29N5O4: C, 67.32; H, 5.85; N, 14.02; found: C, 67.44;
H, 5.86; N, 14.09.
(5S,11S)-5-Benzyl-11-isobutyl-3,6,9-trioxo-1-
phenyl-2-oxa-4,7,10-triazadodecan-12-oic acid
(Cbz-Phe-Gly-Leu-OH) (2c)
White microcrystals (80%); mp 79–81 ꢀC; 1H NMR (DMSO-d6) d
8.34–8.30 (m, 1H), 7.99 (d, J = 7.8 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H),
7.33–7.19 (m, 10H), 4.99–4.90 (m, 2H), 4.32–4.22 (m, 2H), 3.77 (d,
J = 7.8 Hz, 2H), 3.08–3.00 (m, 1H), 2.80–2.71 (m, 1H), 1.68–1.60 (m,
1H), 1.55–1.50 (m, 2H), 0.89 (d, J = 6.6 Hz, 3H), 0.85 (d, J = 6.3 Hz,
3H); 13C NMR (DMSO-d6) d 174.0, 171.9, 168.6, 156.0, 138.2, 137.0,
129.2, 128.3, 128.1, 127.7, 127.5, 126.3, 65.3, 56.3, 50.2, 41.8, 40.3,
40.1, 37.3, 24.2, 22.8, 21.4. Anal. Calcd for C25H31N3O6: C, 63.95; H,
6.65; N, 8.95; found: C, 64.06; H, 6.75; N, 8.98.
(S)-Benzyl(1-((2-(1H-benzo[d][1,2,3]triazol-1-yl)-2-
oxoethyl)amino)-1-oxo-3-phenyl-propan-2-
yl)carbamate (Cbz-Phe-Gly-Bt) (1c)
General procedure for the synthesis of N-Cbz-
tripeptidoylbenzotriazole (3a–c)
The compounds were synthesized following our established proce-
dure (33).
1
White microcrystals (85%); mp 169–171 ꢀC; H NMR (DMSO-d6) d
8.89 (t, J = 5.5 Hz, 1H), 8.28 (d, J = 8.4 Hz, 1H), 8.23 (d,
J = 8.1 Hz, 1H), 7.80 (t, J = 7.6 Hz, 1H), 7.70–7.60 (m, 2H), 7.35–
7.19 (m, 10H), 5.08–4.91 (m, 4H), 4.50–4.42 (m, 1H), 3.16 (dd,
J = 13.5, 3.0 Hz, 1H), 2.88–2.78 (m, 1H); 13C NMR (DMSO-d6) d
172.7, 168.5, 155.9, 145.3, 138.1, 137.0, 131.0, 130.6, 129.2, 128.3,
128.1, 127.6, 127.4, 126.6, 126.3, 120.1, 113.7, 65.2, 56.1, 42.7,
37.6. Anal. Calcd for C25H23N5O4: C, 65.64; H, 5.07; N, 15.31; found:
C, 65.67; H, 5.00; N, 15.10.
Benzyl((S)-1-(((S)-1-((2-(1H-benzo[d][1,2,3]triazol-
1-yl)-2-oxoethyl)amino)-1-oxo-3-phenylpropan-2-
yl)amino)-1-oxopropan-2-yl)carbamate(Cbz-Ala-
Phe-Gly-Bt) (3a)
1
White microcrystals (92%); mp 182–185 ꢀC; H NMR (DMSO-d6) d
8.83–8.81 (m,1H), 8.30 (d, J = 8.4 Hz, 1H), 8.23 (d, J = 8.1 Hz, 1H),
8.02 (d, J = 7.8 Hz, 1H), 7.81 (t, J = 7.8 Hz, 1H), 7.64 (t, J = 7.8 Hz,
1H), 7.45 (d, J = 7.5 Hz, 1H), 7.35–7.22 (m, 10 H), 5.02–4.96 (m,
4H), 4.70–4.68 (m, 1H), 4.03 (t, J = 6.9 Hz, 1H), 3.14–3.08 (m, 1H),
2.96–2.78 (m, 1H), 1.13 (d, J = 6.9 Hz, 3H); 13C NMR (DMSO-d6) d
172.2, 168.4, 155.6, 145.2, 137.5, 131.0, 130.5, 129.2, 128.3, 128.0,
127.7, 126.6, 126.2, 120.1, 113.7, 65.4, 53.5, 50.2, 42.6, 37.7, 18.2.
Anal. Calcd for C28H28N6O5: C, 63.63; H, 5.34; N, 15.90; found: C,
63.22; H, 5.37; N, 15.79.
General procedure for the synthesis of N-Cbz-
tripeptides (2a–c)
The compounds were synthesized following our established proce-
dure (33).
(5S,8S)-8-Benzyl-5-methyl-3,6,9-trioxo-1-phenyl-
2-oxa-4,7,10-triazadodecan-12-oic acid (Cbz-
Ala-Phe-Gly-OH) (2a)
1
White microcrystals (78%); mp 108–110 ꢀC; H NMR (DMSO-d6) d
8.35 (t, J = 5.7 Hz, 1H), 7.93–7.88 (m, 1H), 7.46–7.43 (m, 1H), 7.42–
7.25 (m, 5H), 7.24–7.16 (m, 5H), 5.00 (s, 2H), 4.60–4.52 (m, 1H),
4.01 (q, J = 6.9 Hz, 1H), 3.78 (d, J = 5.7 Hz, 2H), 3.10–2.98 (m, 1H),
2.88–2.76 (m, 1H), 1.12 (d, J = 6.9 Hz, 3H); 13C NMR (DMSO-d6) d
172.2, 171.3, 171.1, 155.2, 137.1, 136.5, 128.8, 127.9, 127.5, 127.3,
125.7, 65.0, 53.0, 49.8, 40.2, 37.2, 17.7. Anal. Calcd for C22H25N3O6.
0.5 H2O: C, 60.54; H, 6.00; N, 9.63; found: C, 60.89; H, 5.83; N,
9.73.
Benzyl((S)-1-(((S)-1-((2-(1H-benzo[d][1,2,3]triazol-
1-yl)-2-oxoethyl)amino)-1-oxo-3-phenyl-propan-
2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate
(Cbz-Val-Phe-Gly-Bt) (3b)
1
White microcrystals (93%); mp 214–215 ꢀC; H NMR (DMSO-d6) d
8.84 (brs, 1H), 8.29 (d, J = 8.1 Hz, 1H), 8.22 (d, J = 8.4 Hz, 1H),
8.07 (d, J = 8.1 Hz, 1H), 7.81 (t, J = 7.5 Hz, 1H), 7.64 (t, J = 7.5 Hz,
1H), 7.25–7.15 (m, 11H), 5.10–4.90 (m, 4H), 4.85–4.68 (m, 1H), 3.84
(t, J = 7.5 Hz, 1H), 3.19–3.05 (m, 1H), 2.95–2.80 (m, 1H), 1.98–1.79
(m, 1H), 0.80–0.60 (m, 6H); 13C NMR (DMSO-d6) d 172.1, 170.9,
168.4, 156.0, 145.3, 137,6, 137.0, 131.0, 130.6, 129.2, 128.3, 128.0,
127.6, 126.2, 120.1, 113.7, 65.4, 60.4, 53.4, 42.6, 37.9, 30.4, 19.1,
18.1. Anal. Calcd for C30H32N6O5: C, 64.73; H, 5.79; N, 15.10; found:
C, 64.60; H, 5.79; N, 15.01.
(5S,8S)-8-Benzyl-5-isopropyl-3,6,9-trioxo-1-
phenyl-2-oxa-4,7,10-triazadodecan-12-oic acid
(Cbz-Val-Phe-Gly-OH) (2b)
1
White microcrystals (91%); mp 212–215 ꢀC; H NMR (DMSO-d6) d
8.36 (t, J = 5.7 Hz, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.40–7.28 (m, 5H),
7.27–7.11 (m, 6H), 5.02 (br s, 2H), 4.68–4.55 (m, 1H), 3.86–3.71 (m,
3H), 3.02 (dd, J = 13.5, 3.9 Hz, 1H), 2.78 (dd, J = 13.8, 9.9 Hz, 1H),
1.91–1.78 (m, 1H), 0.78–0.64 (m, 6H); 13C NMR (DMSO-d6) d 171.4,
171.0, 170.8, 156.0, 137.6, 137.0, 129.2, 128.4, 128.0, 127.8, 127.7,
126.2, 65.5, 60.4, 53.5, 40.7, 37.8, 30.4, 19.2, 18.1. Anal. Calcd for
C24H29N3O6: C, 63.28; H, 6.42; N, 9.22; found: C, 63.48; H, 6.47; N,
9.20.
Benzyl((S)-1-((2-(((S)-1-(1H-Benzo[d][1,2,3]triazol-
1-yl)-4-methyl-1-oxopentan-2-yl)amino)-2-
oxoethyl)amino)-1-oxo-3-phenylpropan-2-
yl)carbamate (Cbz-Phe-Gly-Leu-Bt) (3c)
White microcrystals (84%); mp 144–146 ꢀC; H NMR (DMSO-d6) d
8.81–8.77 (m, 1H), 8.42–8.38 (m, 1H), 8.28 (d, J = 7.8 Hz, 1H), 8.20
1
18
Chem Biol Drug Des 2012; 80: 17–26

Tri- and Tetrapeptide Conjugates
(d, J = 7.2 Hz, 1H), 8.10–8.06 (m, 1H), 7.80–7.77 (m, 1H), 7.65–7.59
(m, 1H), 7.39–7.12 (m, 10H), 4.94 (s, 2H), 4.51–4.45 (m, 1H), 4.29–
4.25 (m, 1H), 3.88–3.74 (m, 2H), 3.08–3.03 (m, 1H), 2.80–2.72 (m,
1H), 1.80–1.65 (m, 1H), 1.60–1.50 (m, 2H), 0.99–0.87 (m, 6H); 13C
NMR (DMSO-d6) d 173.7, 172.6, 169.3, 169.1, 156.6, 146.0, 138.9,
137.6, 131.7, 129.9, 129.0, 128.7, 128.4, 128.1, 127.3, 126.9, 120.9
114.5, 65.9, 56.9, 51.5, 43.2, 42.8, 38.0, 24.8, 23.8, 22.2. Anal.
Calcd for C31H34N6O5: C, 65.25; H, 6.01; N, 14.73; found: C, 65.21;
H, 5.85; N, 14.56.
(5S,11S)-5-Benzyl-11-isobutyl-3,6,9,12-tetraoxo-
1-phenyl-2-oxa-4,7,10,13-tetraazapenta decan-
15-oic acid (Cbz-Phe-Gly-leu-Gly-OH) (4c)
White microcrystals (88%); mp 109–110 ꢀC; 1H NMR (DMSO-d6) d
8.32–8.26 (m, 2H), 7.94 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 8.7 Hz, 1H),
7.35–7.17 (m, 10H), 5.10–4.90 (m, 2H), 4.38–4.32 (m, 1H), 4.30–4.23
(m,1H), 3.80–3.72 (m, 4H), 3.10–3.00 (m, 1H), 2.80–2.70 (m, 1H), 1.65–
1.60 (m, 1H), 1.51–1.45 (m, 2H), 0.88 (d, J = 6.6 Hz, 3H), 0.84 (d,
J = 6.6 Hz, 3H); 13C NMR (DMSO-d6) d 172.3, 171.8, 171.1, 168.4,
155.9, 138.2, 136.9, 129.2, 128.3, 128.0, 127.7, 127.4, 126.2, 65.3, 56.2,
50.7, 42.0, 41.0, 40.6, 37.3, 24.1, 23.1, 21.6. Anal. Calcd for C27H34N4O7:
C, 61.58; H, 6.51; N, 10.64; found: C, 61.69; H, 6.62; N, 10.48.
General procedure for the synthesis of N-Cbz-
tetrapeptides (4a–c)
The compounds were synthesized following our established proce-
dure (33).
General procedure for the synthesis of N-Cbz-
tetrapeptidoylbenzotriazole (5a–c)
The compounds were synthesized following our established proce-
dure (33) (Table 1).
(5S,8S,14S)-8-Benzyl-5,14-dimethyl-3,6,9,12-
tetraoxo-1-phenyl-2-oxa-4,7,10,13-
tetraazapentadecan-15-oic acid (Cbz-Ala-Phe-
Gly-Ala-OH) (4a)
Benzyl((S)-1-(((S)-1-((2-(((S)-1-(1H-
1
White microcrystals (74%); mp 184–186 ꢀC; H NMR (DMSO-d6) d
benzo[d][1,2,3]triazol-1-yl)-1-oxopropan-2-
yl)amino)-2-oxoethyl)amino)-1-oxo-3-
phenylpropan-2-yl)amino)-1-oxopropan-2-
yl)carbamate (Cbz-Ala-Phe-Gly-Ala-Bt) (5a)
8.26 (t, J = 6.0 Hz, 1H), 8.08 (d, J = 6.9 Hz, 1H), 7.98 (d,
J = 6.9 Hz, 1H), 7.41 (d, J = 7.8 Hz, 1H), 7.36–7.30 (m, 5H), 7.24–
7.16 (m, 5H), 5.08–4.94 (m, 2H), 4.52–4.42 (m, 1H), 4.21 (quintet,
J = 7.2 Hz, 1H), 4.08–3.96 (m, 1H), 3.73 (d, J = 5.7 Hz, 2H), 3.04
(dd, J = 13.5, 4.2 Hz, 1H), 2.88–2.78 (m, 1H), 1.28 (d, J = 7.2 Hz,
3H), 1.12 (d, J = 7.2 Hz, 3H); 13C NMR (DMSO-d6) d 173.9, 172.4,
171.1, 168.3, 155.6, 137.6, 136.9, 129.2, 128.3, 128.0, 127.7, 126.2,
65.4, 53.9, 50.1, 47.5, 41.7, 37.3, 18.0, 17.3. Anal. Calcd for
C25H30N4O7: C, 60.23; H, 6.07; N, 11.24; found: C, 59.95; H, 6.04; N,
11.07.
1
White microcrystals (72%); mp 200–202 ꢀC; H NMR (DMSO-d6) d
8.72–8.70 (m, 1H), 8.30 (d, J = 7.8 Hz, 2H), 8.22 (d, J = 8.4 Hz, 1H),
8.00 (d, J = 6.9 Hz, 1H), 7.80 (t, J = 7.5 Hz, 1H), 7.64 (t, J = 7.7 Hz,
1H), 7.46–7.10 (m, 11H), 5.66–5.60 (m, 1H), 5.02–4.96 (m, 2H),
4.48–4.45 (m, 1H), 4.02–3.95 (m, 1H), 3.82 (d, J = 5.4 Hz, 2H),
3.10–2.97 (m, 1H), 2.86–2.80 (m, 1H), 1.56 (d, J = 6.9 Hz, 3H), 1.10
(d, J = 8.1 Hz, 3H); 13C NMR (DMSO-d6) d 172.5, 171.8, 171.2,
169.1, 155.6, 145.3, 137.6, 136.9, 131.1, 130.6, 129.2, 128.3, 127.9,
127.7, 126.7, 126.2, 125.3, 120.2, 114.9, 113.9, 65.4, 53.9, 50.2,
48.5, 41.5, 37.3, 18.0, 16.7. Anal. Calcd for C31H33N7O6: C, 62.09; H,
5.55; N, 16.35; found: C, 62.12; H, 5.56; N, 15.98.
(5S,8S)-8-Benzyl-5-methyl-3,6,9,12-tetraoxo-1-
phenyl-2-oxa-4,7,10,13-tetraaza-penta decan-15-
oic acid (Cbz-Ala-Phe-Gly-Gly-OH) (4b)
1
White microcrystals (85%); mp 148–150 ꢀC; H NMR (DMSO-d6) d
8.88 (t, J = 5.4 Hz, 1H), 8.68 (t, J = 5.8 Hz, 1H), 8.57 (d, J = 7.5 Hz,
1H), 8.04 (d, J = 8.4 Hz, 1H), 8.04–7.94 (m, 5H), 7.88–7.78 (m, 5H),
5.63 (d, J = 12.6 Hz, A part of AB system, 1H), 5.57 (d, J = 12.9 Hz,
B part of AB system, 1H), 5.16–5.04 (m, 1H), 4.68–4.57 (m, 1H),
4.38–4.24 (m, 4H), 3.66–3.61 (m, 1H), 3.46–3.22 (m, 1H), 1.71 (d,
J = 6.9 Hz, 3H); 13C NMR (DMSO-d6) d 172.4, 171.1, 171.1, 169.0,
155.7, 137.6, 136.9, 129.3, 128.3, 128.0, 127.8, 126.2, 65.5, 53.8,
50.2, 41.8, 40.6, 37.4, 18.1. Anal. Calcd for C24H28N4O7: C, 59.50; H,
5.82; N, 11.56; found: C, 59.12; H, 5.84; N, 11.88.
Benzyl((S)-1-(((S)-1-((2-((2-(1H-
benzo[d][1,2,3]triazol-1-yl)-2-oxoethyl)amino)-2-
oxoethyl)amino)-1-oxo-3-phenylpropan-2-
yl)amino)-1-oxopropan-2-yl)carbamate (Cbz-Ala-
Phe-Gly-Gly-Bt) (5b)
1
White microcrystals (62%); mp 144–145 ꢀC; H NMR (DMSO-d6) d
8.62–8.55 (m, 1H), 8.42–8.36 (m, 1H), 8.29 (d, J = 8.1 Hz, 1H), 8.20
(d, J = 9.0 Hz, 1H), 8.03 (d, J = 8.2 Hz, 1H), 7.80 (t, J = 7.5 Hz, 1H),
7.63 (t, J = 7.8 Hz, 1H), 7.45 (d, J = 6.9 Hz, 1H), 7.43–7.30 (m, 5H),
Table 1: Preparation of N-Pg–tripeptidoylbenzotriazoles 3a–c and tetrapeptidoylbenzotriazoles 5a–c
Entry
Reactant
Product
Yield (%)
Mp(ꢀC)
1
2
3
4
5
6
Z–L–Ala–L–Phe–Gly–OH 2a
Z–L–Val–L–Phe–Gly–OH 2b
Z–L–Phe–Gly-L–Leu-OH 2c
Z–L–Ala–L–Phe–Gly–L-Ala-OH 4a
Z–L–Ala–L–Phe–Gly–Gly-OH 4b
Z–L–Phe–Gly–L-Leu–Gly-OH 4c
Z–L–Ala–L–Phe–Gly–Bt 3a
Z–L–Val–L–Phe–Gly–Bt 3b
Z–L–Phe–Gly-L–Leu-Bt 3c
Z–L–Ala–L–Phe–Gly–L-Ala-Bt 5a
Z–L–Ala–L–Phe–Gly–Gly-Bt 5b
Z–L–Phe–Gly–L–Leu–Gly-Bt 5c
92
93
84
72
62
79
180–182a
214–215
144–146
200–202b
144–145
280–282
b
aLit mp 186–187 ꢀC (33), Lit mp 212–214 ꢀC (33).
Chem Biol Drug Des 2012; 80: 17–26
19

Bajaj et al.
7.24–7.22 (m, 5H), 5.02–4.96 (m, 4H), 4.62–4.50 (m, 1H), 4.10–3.99
(m, 1H), 3.94–3.86 (m, 2H), 3.10–3.05 (m, 1H), 2.87–2.80 (m, 1H),
1.13 (d, J = 7.2 Hz, 3H); 13C NMR (DMSO-d6) d 172.5, 171.3, 169.7,
168.5, 155.7, 145.3, 137.6, 136.9, 131.0, 130.6, 129.3, 128.3, 128.0,
127.8, 126.6, 126.2, 120.2, 113.7, 65.5, 53.8, 50.2, 42.6, 41.8, 37.3,
18.0. Anal. Calcd for C30H31N7O6.0.5 H2O: C, 60.60; H, 5.42; N,
16.49; found: C, 60.70; H, 5.26; N, 16.22.
6H), 1.17–1.07 (m, 4H), 1.06–1.00 (m, 6H), 0.91 (d, J = 6.6 Hz, 3H),
0.89 (d, J = 7.5 Hz, 6H), 0.67 (s, 3H); 13C NMR (CDCl3) d 172.4,
171.0, 169.0, 156.4, 139.5, 136.6, 136.2, 129.4, 128.8, 128.5, 128.3,
127.2, 123.2, 75.6, 67.4, 56.9, 56.4, 54.3, 51.1, 50.2, 42.5, 41.7,
39.9, 39.7, 38.2, 37.1, 36.8, 36.4, 36.0, 32.1, 29.9, 28.4, 28.2, 27.9,
24.5, 24.1, 23.0, 22.8, 21.2, 19.5, 18.9, 18.4, 12.1. HRMS Calcd for
C49H69N3O6Na [M + Na]+ 818.5079; found 818.5089.
Benzyl((S)-1-((2-(((S)-1-((2-(1H-
benzo[d][1,2,3]triazol-1-yl)-2-oxoethyl)amino)-4-
methyl-1-oxopentan-2-yl)amino)-2-
oxoethyl)amino)-1-oxo-3-phenylpropan-2-
yl)carbamate (Cbz-Phe-Gly-Leu-Gly-Bt) (5c)
White microcrystals (79%); mp 194–195 ꢀC; H NMR (DMSO-d6) d
8.80–8.70 (m, 1H), 8.35–8.30 (m, 1H), 8.28 (d, J = 8.4 Hz, 1H), 8.21 (d,
J = 8.4 Hz, 1H), 8.04 (d, J = 8.1 Hz, 1H), 7.79 (t, J = 7.2 Hz, 1H),
7.66–7.55 (m, 2H), 7.33–7.19 (m, 10H), 4.97–4.90 (m, 4H), 4.55–4.46
(m, 1H), 4.32–4.22 (m, 1H), 3.89–3.72 (m, 2H), 3.08–3.02 (m, 1H),
2.80–2.50 (m, 1H), 1.70–1.66 (m, 1H), 1.60–1.56 (m, 2H), 0.92 (d,
J = 6.3 Hz, 3H), 0.89 (d, J = 6.3 Hz, 3H); 13C NMR (DMSO-d6) d 172.9,
171.8, 168.5, 168.4, 155.9, 145.2, 138.1, 136.9, 131.0, 130.5, 129.2,
128.2, 128.0, 127.6, 127.4, 126.6, 126.2, 120.1, 113.7, 65.2, 56.2, 50.7,
42.5, 42.0, 41.0, 37.3, 24.1, 23.1, 21.6. Anal. Calcd for C33H37N7O6: C,
63.14; H, 5.94; N, 15.62; found: C, 62.88; H, 5.92; N, 15.46.
(5S,8S)-(E)-3,7-Dimethylocta-2,6-dien-1-yl-8-
benzyl-5-methyl-3,6,9-trioxo-1-phenyl-2-oxa-
4,7,10-triazadodecan-12-oate (Cbz-Ala-Phe-Gly-
O-Nerol) (6b)
White microcrystals (50%); mp 114–116 ꢀC; 1H NMR (CDCl3) d
7.36–7.28 (m, 5H), 7.26–7.12 (m, 5H), 7.02 (d, J = 7.5 Hz, 1H), 6.92–
6.82 (m, 1H), 5.58 (d, J = 7.2 Hz, 1H), 5.30 (t, J = 7.2 Hz, 1H), 5.12–
5.00 (m, 3H), 4.80 (q, J = 7.5 Hz, 1H), 4.59 (d, J = 7.5 Hz, 2H), 4.30–
4.20 (m, 1H), 4.08–3.80 (m, 2H), 3.13 (dd, J = 13.8, 6.6 Hz, 1H), 3.01
(dd, J = 13.8, 7.2 Hz, 1H), 2.14–2.00 (m, 4H), 1.74 (s, 3H), 1.67 (s,
3H), 1.58 (s, 3H), 1.26 (d, J = 6.9 Hz, 3H); 13C NMR (CDCl3) d 172.7,
171.2, 169.6, 156.3, 143.4, 136.6, 136.3, 132.4, 129.4, 128.7, 128.6,
128.3, 128.2, 127.0, 123.6, 118.7, 67.2, 62.1, 54.2, 50.9, 41.4, 38.3,
32.3, 26.7, 25.8, 23.6, 18.6, 17.8. Anal. Calcd for C32H41N3O6: C,
68.18; H, 7.33; N, 7.45; found: C, 68.28; H, 7.57; N, 7.50.
1
(5S,8S)-((3aR,5R,5aS,8aS,8bR)-2,2,7,7-
General procedure for O-acylation: synthesis of
compounds (6a–f)
Tetramethyltetrahydro-3aH-bis([1,3]dioxolo)
[4,5-b:4¢,5¢-d]pyran-5-yl)methyl-8-benzyl-5-
isopropyl-3,6,9-trioxo-1-phenyl-2-oxa-4,7,10-
triazadodecan-12-oate (Cbz-Val-Phe-Gly-O-
Glactopyranose) (6c)
White microcrystals (47%); mp 129–131 ꢀC; 1H NMR (CDCl3) d.
7.45–7.30 (m, 5H), 7.28–7.15 (m, 5H), 6.68–6.58 (m, 2H), 5.53 (d,
J = 4.8 Hz, 1H), 5.27 (d, J = 7.5 Hz, 1H), 5.14–5.03 (m, 2H), 4.82–
4.71 (m, 1H), 4.62 (dd, J = 8.0, 2.3 Hz, 1H), 4.35–4.19 (m, 4H), 4.11–
3.88 (m, 4H), 3.20–3.10 (m, 1H), 3.08–2.98 (m, 1H), 2.14–2.00 (m,
1H), 1.51 (s, 3H), 1.43 (s, 3H), 1.33 (s, 6H), 0.88 (d, J = 6.9 Hz, 3H),
0.77 (d, J = 6.6 Hz, 3H); 13C NMR (CDCl3) d 171.3, 171.0, 169.4,
156.7, 136.6, 136.2, 129.4, 128.8, 128.5, 128.4, 127.2, 109.9, 109.0,
96.4, 71.1, 70.8, 70.6, 67.5, 66.0, 64.4, 60.9, 54.2, 41.5, 38.2, 30.8,
26.3, 26.1, 25.1, 24.7, 19.4, 17.7. Anal. Calcd for C36H47N3O11: C,
61.97; H, 6.79; N, 6.02; found: C, 61.78; H, 6.94; N, 5.91.
Compounds were prepared by using similar microwave conditions
reported for O-acylation. (34) A dried heavy-walled Pyrex tube con-
taining a small stir bar was charged with benzotriazole intermediate
3a–c or 5b–c (1 eq.), O-nucleophile (1.5 eq.), and base dimethyla-
minopyridine (DMAP) (0.1 eq.) dissolved in THF. The reaction mixture
was exposed to microwave irradiation (100 W) at 70 ꢀC for speci-
fied times. Each mixture was allowed to cool through an inbuilt sys-
tem until the temperature had fallen below 30 ꢀC (ca. 10 min). The
reaction mixture was quenched with water, extracted with EtOAc,
and the extracts were washed with (10%) Na2CO3, water, and dried
over MgSO4. The solvent was removed under reduced pressure, and
the residue was subjected to silica gel column using EtOAc ⁄ hexane
as an eluent to give the corresponding compound 6a–f.
(5S,8S)-(8S,9S,10R,13R,14S,17R)-10,13-
Dimethyl-17-((R)-6-methylheptan-2-yl)-
2,3,4,7,8,9,10,11,12,13,14,15,16,17-
(5S)-(8R,9S,13S,14S)-13-Methyl-17-oxo-
7,8,9,11,12,13,14,15,16,17-decahydro-6H-
cyclopenta[a]phenanthren-3-yl-8-benzyl-5-
isopropyl-3,6,9-trioxo-1-phenyl-2-oxa-4,7,10-
triazadodecan-12-oate (Cbz-Val-Phe-Gly-O-
estrone) (6d)
tetradecahydro-1H-cyclopenta[a]phenanthren-3-
yl 8-benzyl-5-methyl-3,6,9-trioxo-1-phenyl-2-
oxa-4,7,10-triazadodecan-12-oate (Cbz-Ala-Phe-
Gly-O-Cholesterol) (6a)
White microcrystals (45%); mp 162–163 ꢀC; 1H NMR (CDCl3) d
7.40–7.30 (m, 5H), 7.29–7.15 (m, 5H), 6.76 (d, J = 7.2 Hz, 1H),
6.70–6.60 (m, 1H), 5.38–5.34 (m,1H), 5.27 (d, J = 6.6 Hz, 1H), 5.14–
5.00 (m, 2H), 4.80–4.70 (m,1H), 4.66–4.58 (m, 1H), 4.22–4.16 (m,
1H), 4.08–3.98 (m, 1H), 3.90–3.80 (m, 1H), 3.22–3.10 (m, 1H), 3.09–
3.00 (m, 1H), 2.30 (d, J = 7.8 Hz, 2H), 2.01–1.93 (m, 2H), 1.90–1.78
(m, 4H), 1.62–1.40 (m, 8H), 1.36–1.28 (m, 2H), 1.27 (d, J = 7.2 Hz,
1
White flakes (35%); mp 151–153 ꢀC; H NMR (CDCl3) d 7.38–7.30
(m, 6H), 7.28–7.22 (m, 2H), 7.22–7.16 (m, 4H), 6.87–6.78 (m, 2H),
6.60 (d, J = 7.8 Hz, 1H), 5.30–5.20 (m, 1H), 5.14–4.98 (m, 3H),
4.85–4.71 (m, 1H), 4.34–3.80 (m, 4H), 3.23–2.98 (m, 3H), 2.87 (dd,
J = 8.9, 4.1 Hz, 1H), 2.58–1.91 (m, 4H), 1.70–1.35 (m, 5H), 0.90 (s,
3H), 0.87 (dd, J = 6.9, 3.3 Hz, 3H), 0.76 (dd, J = 6.6, 3.0 Hz, 3H);
13C NMR (CDCl3) d 171.3, 170.9, 169.5, 168.5, 156.9, 148.3, 138.3,
20
Chem Biol Drug Des 2012; 80: 17–26

Tri- and Tetrapeptide Conjugates
137.9, 136.6, 136.2, 129.4, 128.9, 128.8, 128.5, 128.4, 127.3, 126.7,
121.5, 118.6, 61.7, 61.1, 54.3, 50.6, 48.1, 44.3, 41.5, 38.2, 36.1,
31.8, 30.6, 29.6, 26.5, 26.0, 21.8, 19.4, 14.4, 14.1. HRMS Calcd for
C42H49N3O7Na [M + Na]+: 730.3463; found: 730.3472.
(m, 1H), 3.19–3.08 (m, 1H), 2.91–2.82 (m, 1H), 1.12 (d, J = 6.6 Hz,
3H); 13C NMR (DMSO-d6) d 196.2, 172.3, 171.9, 155.6, 137.6, 137.0,
134.5, 129.5, 129.4, 129.2, 128.3, 128.1, 127.7, 126.9, 126.3, 65.4,
53.7, 50.2, 48.8, 37.3, 18.2. Anal. Calcd for C28H29N3O5S.H2O: C,
62.55; H, 5.81; N, 7.82; found: C, 62.85; H, 5.49; N, 7.46.
(5S,8S)-(3aR,5R,6R,6aR)-5-((R)-2,2-Dimethyl-1,3-
dioxolan-4-yl)-2,2-dimethyltetrahydrofuro[2,3-
d][1,3]dioxol-6-yl-8-benzyl-5-methyl-3,6,9,12-
tetraoxo-1-phenyl-2-oxa -4,7,10,13-
(5S,8S)-Methyl-8-benzyl-5-methyl-3,6,9,12-
tetraoxo-1-phenyl-2-oxa-13-thia-4,7,10-
triazapentadecan-15-oate (7b)
1
tetraazapentadecan-15-oate (Cbz-Ala-Phe-Gly-
Ala-O-diacetoneglucose) (6e)
White powder (83%); mp 158–160 ꢀC; H NMR (DMSO-d6) d 8.85–
8.82 (m, 1H), 8.07 (d, J = 8.1 Hz, 1H), 7.42–7.18 (m, 11H), 5.03–4.99
(m, 2H), 4.62–4.59 (m, 1H), 4.09–3.98 (m, 3H), 3.76 (s, 2H), 3.64 (s,
3H), 3.14–3.06 (m, 1H), 2.91–2.85 (m, 1H), 1.14 (d, J = 6.9 Hz, 3H);
13C NMR (DMSO-d6) d 197.6, 172.3, 171.9, 168.9, 155.6, 137.6,
137.0, 129.2, 128.3, 128.1, 127.7, 126.3, 65.4, 53.7, 52.4, 50.1, 48.5,
37.3, 30.2, 18.2. Anal. Calcd for C25H29N3O7S: C, 58.24; H, 5.67; N
8.15; found: C, 58.08; H, 5.63; N, 8.04.
1
White microcrystals (58%); mp 102–104 ꢀC; H NMR (CDCl3) d 7.40–
7.29 (m, 7H), 7.26–7.09 (m, 6H), 5.86 (d, J = 3.6 Hz, 1H), 5.76 (d,
J = 6.1 Hz, 1H), 5.27–5.25 (m, 1H), 5.10–5.00 (m, 2H), 4.78 (q,
J = 7.2 Hz, 1H), 4.49 (d, J = 3.6 Hz, 1H), 4.40–4.34 (m, 1H), 4.24–4.1.8
(m, 2H), 4.16–3.99 (m, 4H), 3.98–3.80 (m, 2H), 3.12–2.95 (m, 2H), 1.50 (s,
3H), 1.38 (s, 3H), 1.30–1.25 (m, 9H), 0.92–0.82 (m, 1H); 13C NMR (CDCl3)
d 173.1, 171.4, 169.4, 168.8, 156.5, 136.5, 136.3, 129.4, 128.8, 128.5,
128.2, 127.3, 112.5, 109.6, 105.2, 83.3, 79.8, 72.5, 67.4, 54.8, 51.1, 43.0,
41.4, 38.3, 27.1, 26.9, 26.4, 25.4, 18.6. Anal. Calcd for C36H46N4O12: C,
59.49; H, 6.38; N, 7.71; found: C, 59.26; H, 6.56; N, 7.35.
(5S,8S,14R)-8-Benzyl-5,14-dimethyl-3,6,9,12,15-
pentaoxo-1-phenyl-2-oxa-16-thia-4,7,10,13-
tetraazaoctadecan-18-oic acid (7c)
1
Off-white microcrystals (70%); mp 103–105 ꢀC; H NMR (DMSO-d6)
(5S,11S)-(1S,2S)-2-Isopropyl-5-methylcyclohexyl
5-benzyl-11-isobutyl-3,6,9,12-tetra oxo-1-
d. 8.52 (d, J = 7.2 Hz, 1H), 8.36–8.28 (m, 1H), 7.99 (d, J = 7.8 Hz,
1H), 7.42 (d, J = 7.2 Hz, 1H), 7.38–7.30 (m, 5H), 7.25–7.18 (m, 5H),
5.07–4.94 (m, 2H), 4.55–4.38 (m, 2H), 4.07–3.97 (m, 1H), 3.78 (t,
J = 5.6 Hz, 1H), 3.62 (s, 2H), 3.08–3.00 (m, 1H), 2.88–2.78 (m, 1H),
1.28 (d, J = 6.9 Hz, 3H), 1.11 (d, J = 6.9 Hz, 3H); 13C NMR (DMSO-
d6) d 200.9, 172.4, 171.2, 169.6, 169.0, 155.6, 137.6, 136.9, 129.2,
128.3, 128.0, 127.7, 126.2, 65.4, 54.5, 53.9, 50.1, 41.8, 37.3, 30.9,
18.0, 17.3. HRMS Calcd for C27H32N4O8NaS [M + Na]+: 595.1833;
found: 595.1835.
phenyl-2-oxa-4,7,10,13-tetraazapentadecan-15-
oate (Cbz-Phe-Gly-Leu-Gly-O-menthol) (6f)
White microcrystals (42%); mp 104–106 ꢀC; 1H NMR (CDCl3) d. 7.40–
7.06 (m, 13H), 5.79 (d, J = 6.6 Hz, 1H), 5.06 (d, A part of AB system,
J = 12 .0 Hz, 1H), 4.98 (d, B part of AB system, J = 12.3 Hz, 1H),
4.76–4.51 (m, 3H), 4.04–3.83 (m, 4H), 3.14 (dd, J = 15.0, 5.4 Hz, 1H),
3.00–2.92 (m, 1H), 2.18–2.10 (m, 1H), 1.98–1.91 (m, 1H), 1.89–1.78
(m, 1H), 1.68–1.50 (m, 5H), 1.49–1.31 (m, 2H), 1.03–0.88 (m, 14), 0.71
(d, J = 6.9 Hz, 3H); 13C NMR (CDCl3) d 172.5, 172.3, 169.7, 169.1,
156.5, 136.6, 136.2, 129.4, 128.8, 128.7, 128.4, 128.2, 127.2, 75.9,
67.3, 56.5, 51.9, 47.1, 43.4, 41.6, 41.2, 40.9, 38.4, 34.3, 31.5, 26.4,
24.9, 23.6, 23.1, 22.2, 22.1, 20.9, 16.5. HRMS Calcd for C37H52N4O7Na
[M + Na]+: 687.3728; found: 687.3743.
(5S,11S)-S-Benzyl-5-benzyl-11-isobutyl-3,6,9,12-
tetraoxo-1-phenyl-2-oxa-4,7,10,13-
tetraazapentadecane-15-thioate (7d)
1
White microcrystals (94%); mp 186–187 ꢀC; H NMR (DMSO-d6) d
8.67 (t, J = 5.56 Hz, 1H), 8.32 (t, J = 5.1 Hz, 1H), 8.03 (d, J = 8.7 Hz,
1H), 7.60 (d, J = 8.4 Hz, 1H), 7.39–7.19 (m, 15H), 4.95 (s, 2H), 4.42–
4.22 (m, 2H), 4.10 (s, 2H), 4.05–4.00 (m, 2H), 3.81–3.74 (m, 2H), 3.09–
3.00 (m, 1H), 2.81–2.70 (m, 1H), 170–1.60 (m, 1H), 1.59–1.49 (m, 2H),
0.89 (d, J = 6.3 Hz, 3H), 0.85 (d, J = 6.0 Hz, 3H); 13C NMR (DMSO-d6)
d 197.8, 172.7, 171.8, 168.6, 155.9, 138.2, 137.7, 136.9, 129.2, 128.7,
128.5, 128.3, 128.0, 127.7, 127.4, 127.1, 126.2, 65.3, 56.2, 50.9, 48.7,
42.0, 40.6, 37.3, 31.7, 24.1, 23.0, 21.5. Anal. Calcd for C34H40N4O6S:
C, 64.54; H, 6.37; N 8.85; found: C, 64.50; H, 6.50; N, 8.48.
General procedure for S-acylation: synthesis of
compounds (7a–d)
Mercapto nucleophile (1 eq.) was dissolved in THF and triethyl
amine (1.5 eq.). Benzotriazole intermediate (1 eq.) was added to the
solution, and the mixture was stirred at room temperature for 1–
2 h. The mixture was then acidified with 6 N HCl, concentrated,
and then diluted with ethyl acetate. The organic layer was washed
with 6 N HCl and dried over anhydrous MgSO4, filtered, and then
evaporated to give the desired compound.
General procedure for N-acylation: synthesis of
compounds (8a, 8d)
(5R,8R)-S-Phenyl 8-benzyl-5-methyl-3,6,9-trioxo-
1-phenyl-2-oxa-4,7,10-triaza-dodecane-12-
thioate (7a)
White microcrystals (78%); mp 146–147 ꢀC; H NMR (DMSO-d6) d
8.89–8.86 (m, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.47–7.25 (m, 16H),
N-nucleophile (1 eq.) was dissolved in THF and triethylamine (1.5 eq.).
The benzotriazole intermediate (1 eq.) was added to the solution, and
the mixture was stirred at room temperature for 1 h. The mixture
was acidified with 6 N HCl and then diluted with ethyl acetate. The
organic layer was washed with 6 N HCl and dried over anhydrous
MgSO4, and filtered and evaporated to give the desired compound.
1
5.02–4.90 (m, 2H), 4.63–4.59 (m, 1H), 4.13–4.05 (m, 2H), 4.06–4.01
Chem Biol Drug Des 2012; 80: 17–26
21

Bajaj et al.
Benzyl((S)-1-(((S)-1-((2-((3-(1H-imidazol-1-
yl)propyl)amino)-2-oxoethyl)amino)-1-oxo-3-
phenylpropan-2-yl)amino)-1-oxopropan-2-
yl)carbamate (8a)
129.2, 128.3, 128.0, 127.6, 126.2, 119.4, 113.4, 65.5, 60.4, 53.6,
42.7, 37.7, 30.4, 19.1, 18.0. HRMS Calcd for C29H34N5O5 [M + H]+:
532.2554; found: 532.2572.
1
White microcrystals (75%); mp 134–137 ꢀC; H NMR (DMSO-d6) d
8.30–8.20 (m, 1H), 8.08 (d, J = 7.2 Hz, 1H), 7.78–7.72 (m, 1H), 7.61
(s, 1H), 7.48 (d, J = 7.5 Hz, 1H), 7.38–7.30 (m, 5H), 7.23–7.20 (m,
5H), 7.16 (s, 1H), 6.88 (s, 1H), 5.02–4.88 (m, 2H), 4.52–4.40 (m, 1H),
4.08–3.90 (m, 3H), 3.79–3.68 (m, 1H), 3.66–3.54 (m, 1H), 3.08–2.99
(m, 3H), 2.92–2.78 (m, 1H), 1.92–1.78 (m, 2H), 1.12 (d, J = 6.9 Hz,
3H); 13C NMR (DMSO-d6) d 172.7, 171.2, 168.6, 155.7, 137.6, 137.3,
136.9, 129.2, 128.3, 128.0, 127.7, 126.2, 119.3, 65.5, 54.2, 50.2,
43.4, 42.2, 37.1, 35.7, 30.7, 17.9. Anal. Calcd for C28H34N6O5: C,
62.91; H, 6.41; N 15.72; found: C, 62.56; H, 6.46; N, 15.52.
Benzyl ((S)-1-(((S)-1-((2-(((S)-1-((6-
methoxybenzo[d]thiazol-2-yl)amino)-1-oxo
propan -2-yl)amino)-2-oxoethyl)amino)-1-oxo-3-
phenylpropan-2-yl)amino)-1-oxopropan-2-
yl)carbamate (8c)
1
White microcrystals (60%); mp 148–150 ꢀC; H NMR (DMSO-d6) d
8.28–8.22 (m, 1H), 8.00 (d, J = 7.2 Hz, 1H), 7.63 (d, J = 8.7 Hz, 1H),
7.58–7.52 (m, 1H), 7.41 (d, J = 8.4 Hz, 2H), 7.36–7.30 (m, 5H),
7.26–7.18 (m, 6H), 7.06–6.90 (m, 1H), 5.02–4.92 (m, 2H), 4.58–4.42
(m, 2H), 4.01 (t, J = 7.2 Hz, 1H), 3.84–3.62 (m, 5H), 3.08–2.98 (m,
1H), 2.88–2.68 (m, 1H), 1.35 (d, J = 7.2 Hz, 3H), 1.11 (d, J = 7.2 Hz,
3H); 13C NMR (DMSO-d6) d 172.1, 172.0, 171.2, 168.7, 156.1, 142.6,
137.6, 137.0, 132.8, 129.2, 128.3, 128.0, 127.7, 126.2, 121.1, 114.9,
104.7, 65.5, 55.6, 53.9, 50.7, 48.6, 41.7, 37.3, 22.7, 18.1, 17.6 Anal.
Calcd for C33H36N6O7S: C, 59.99; H, 5.49; N 12.72; found: C, 59.61;
H, 5.50; N, 12.50.
Benzyl ((S)-1-((2-(((S)-4-methyl-1-((2-(4-
methylpiperazin-1-yl)-2-oxoethyl)amino)-1-
oxopentan-2-yl)amino)-2-oxoethyl)amino)-1-oxo-
3-phenylpropan-2-yl)carbamate (8d)
1
White microcrystals (68%); mp 181–183 ꢀC; H NMR (DMSO-d6) d
8.29 (t, J = 5.7 Hz, 1H), 8.01 (t, J = 5.3 Hz, 1H), 7.93 (d, J = 8.4 Hz,
1H), 7.56 (d, J = 8.4 Hz, 1H), 7.34–7.18 (m, 10H), 4.95–4.89 (m, 2H),
4.42–4.34 (m, 1H), 4.30–4.22 (m, 1H), 3.91 (d, J = 5.4 Hz, 2H), 3.76
(t, J = 5.7 Hz, 2H), 3.41–3.36 (m, 4H), 3.04 (dd, J = 13.6, 3.9 Hz,
1H), 2.75 (dd, J = 13.5, 11.1 Hz, 1H), 2.27–2.22 (m, 4H), 2.15 (s,
3H), 1.65–1.58 (m, 1H), 1.51–1.45 (m, 2H), 0.87 (dd, J = 6.3 Hz, 3H),
0.83 (d, J = 6.3 Hz, 3H); 13C NMR (DMSO-d6) d 172.0, 171.8, 168.5,
166.6, 156.0, 138.2, 137.0, 129.2, 128.3, 128.1, 127.7, 127.5, 126.3,
65.3, 56.3, 54.6, 54.2, 51.0, 45.7, 43.9, 42.1, 41.3, 41.0, 37.3, 24.1,
23.1, 21.6. Anal. Calcd for C32H44N6O6: C, 63.14; H, 7.29; N 13.81;
found: C, 62.84; H, 7.38; N, 13.68.
General procedure for C-acylation: synthesis of
compounds (9a–b)
A solution of benzotriazole intermediate 3a, 5c (1eq.), C-nucleophile
(1eq.), and DMAP (1eq.) in THF (5 mL), was added to a dried heavy-
walled Pyrex tube with a small stir bar. This reaction mixture was
exposed to microwave irradiation (70 ꢀC, 50 W) for specified time
with a simultaneous cooling. After the reaction was completed (moni-
tored by TLC), the THF was evaporated, and the solution was acidified
and then extracted with ethyl acetate. The solvent was removed
under reduced pressure, and the residue was purified by recrystalliza-
tion from ethyl acetate to give the corresponding product 9a and 9b.
General procedure for N-acylation: synthesis of
compounds (8b–c)
Compounds were prepared by using similar reaction condition
reported for (a-aminoacyl)benzotriazoles. (35) A dried heavy-walled
Pyrex tube containing a small stir bar was charged with benzotriaz-
ole intermediate (1 eq.), and N-nucleophile (1 eq.) was dissolved in
DMF. The reaction mixture was exposed to microwave irradiation
(60 W) at 65 ꢀC temperature for specified times. Each mixture was
allowed to cool through an inbuilt system until the temperature had
fallen below 30 ꢀC (ca. 10 min). Each reaction mixture was
quenched with water, and the solid obtained was filtered and
washed with 10% Na2CO3 and water to give the desired compound.
Benzyl-((S)-1-(((S)-1-((2-(4,4-dimethyl-2,6-
dioxocyclohexylidene)-2-hydroxyethyl) amino)-
1-oxo-3-phenylpropan-2-yl)amino)-1-oxopropan-
2-yl)carbamate (9a)
1
White microcrystals (69%); mp 103–105 ꢀC; H NMR (DMSO-d6) d
8.78–8.60 (m, 1H), 8.40–8.26 (m, 1H), 7.84–7.55 (m, 11H), 5.38 (br
s, 2H), 5.05–4.82 (m, 2H), 4.94–4.81 (m, 2H), 4.43–4.40 (m, 1H),
4.20–4.16 (m, 1H), 3.45–3.38 (m, 1H), 3.26–3.18 (m, 1H), 2.89 (s,
4H), 1.50 (d, J = 7.5 Hz, 3H), 1.40–1.30 (m, 6H); 13C NMR (DMSO-
d6) d 200.6, 195.2, 172.1, 171.3, 171.1, 155.5, 137.6, 136.9, 129.2,
128.3, 127.9, 127.7, 126.2, 111.1, 65.4, 53.5, 50.2, 47.5, 37.7, 30.7,
27.5, 18.1. HRMS Calcd for C30H35N3O7Na [M + Na]+ 572.2367;
found 572.2377.
Benzyl((S)-3-methyl-1-oxo-1-(((S)-1-oxo-1-((2-oxo-
2-(pyridin-2-ylamino)ethyl)amino)-3-
phenylpropan-2-yl)amino)butan-2-yl)carbamate
(8b)
Benzyl-((S)-1-((2-(((S)-1-((2-(2,6-dioxocyclohexyl)-
2-oxoethyl)amino)-4-methyl-1-oxo-pentan-2-
yl)amino)-2-oxoethyl)amino)-1-oxo-3-
1
White microcrystals (68%); mp 214–215 ꢀC; H NMR (DMSO-d6) d
10.47 (s, 1H), 8.50–8.30 (m, 2H), 8.05 (d, J = 8.1 Hz, 2H), 7.85–7.72
(m, 1H), 7.50–7.05 (m, 12H), 5.02 (s, 2H), 4.72–4.58 (m, 1H), 4.10–
3.90 (m, 2H), 3.82 (t, J = 7.2 Hz, 1H), 3.15–3.00 (m, 1H), 2.90–2.75
(m, 1H), 1.99–1.72 (m, 1H), 0.80–0.61 (m, 6H); 13C NMR (DMSO-d6)
d 171.5, 170.9, 168.3, 156.0, 151.7, 148.0, 138.2, 137.7, 137.0,
phenylpropan-2-yl)carbamate (9b)
1
White microcrystals (69%); mp 103–105 ꢀC; H NMR (DMSO-d6) d
8.37–8.26 (m, 1H), 8.22–8.15 (m, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.58 (d,
J = 8.4 Hz, 1H), 7.36–7.18 (m, 10H), 5.02–4.88 (m, 2H), 4.50–4.20 (m,
22
Chem Biol Drug Des 2012; 80: 17–26

Tri- and Tetrapeptide Conjugates
4H), 3.88–3.67 (m, 2H), 3.07–2.98 (m, 1H), 2.80–2.65 (m, 2H), 2.55–
2.27 (m, 3H), 1.95–1.44 (m, 5H), 0.89 (d, J = 6.0 Hz, 3H), 0.86 (d,
J = 6.3 Hz, 3H); 13C NMR (DMSO-d6) d 201.1, 172.3, 171.8, 168.5,
155.9, 138.2, 136.9, 129.2, 128.3, 128.0, 127.7, 127.4, 126.2, 112.1,
65.2, 56.2, 50.8, 47.6, 42.0, 41.0, 37.3, 24.1, 23.1, 21.6, 18.7. HRMS
Calcd for C33H41N4O8 [M + H]+ 621.2919; found 621.2931. HRMS
Calcd for C33H41N4O8Na [M + Na]+ 643.2738; found 643.2757.
91%). Compounds 2a–c and 4a–c were further activated by ben-
zotriazole to obtain known intermediates 3a, 5a and novel interme-
diates 3b–c and 5b–c in good yields (62–93%). These tri-
peptidoylbenzotriazoles 3a–c and tetrapeptidoylbenzotriazoles 5a–
c were used as active intermediates to prepare peptide conjugates
(Scheme 1, Table 1).
O-Acylations carried out by tri- and
Results and Discussion
tetrapeptidoylbenzotriazoles
Compounds 3a–b, 5b, and 5c were reacted with a variety of ste-
roids, terpenes, and sugar derivatives in the presence of catalytic
amount of DMAP under microwave irradiations at 70 ꢀC and 65 W
power for 1.5–3 h to afford novel peptide conjugates 6a–f in yields
of 35–58% (Scheme 2, Table 2).
Syntheses of Cbz-protected-
tripeptidoylbenzotriazole and
tetrapeptidoylbenzotriazole
The Cbz-protected tripeptides 2a–c and tetrapeptides 4a–c were
synthesized by our previously reported method by stepwise coupling
(33) of amino acids with subsequent benzotriazole-activated N-pro-
tected amino acid analogs in solution phase in good yields (67–
Compounds 6a–f were fully characterized by 1H NMR and 13C
NMR and elemental analysis. The tri- and tetrapeptide conjugates
Scheme 1: Syntheses of
benzotriazole derivatives of tri-
and tetrapeptides.
Scheme 2: O-Acylation of N–
Pg-tri- and tetrapeptidoylbenzo-
triazoles.
Chem Biol Drug Des 2012; 80: 17–26
23

Bajaj et al.
Table 2: O-Acylation with N–Pg-tri- and tetrapeptidoylbenzotriazoles
Product
Reactant
Reactant
Time
Yield (%)
Mp(ꢀC)
6a
6b
6c
6d
6e
6f
Z–L–Ala–L–Phe–Gly–Bt 3a
Z–L–Ala–L–Phe–Gly–Bt 3a
Z–L–Val–L–Phe–Gly–Bt 3b
Z–L–Val–L–Phe–Gly–Bt 3b
Z–L–Ala–L–Phe–Gly–Gly-Bt 5b
Z–L–Phe–Gly–L–Leu–Gly-Bt 5c
Cholesterol
Nerol
Galactopyranose
Estrone
Diacetone glucose
Menthol
1 h 45 min
1 h 30 min
1 h 30 min
2 h 15 min
1 h 45 min
1 h 45 min
45
50
47
35
58
42
162–163
114–116
129–132
151–153
102–104
104–106
are at least 95% chirally pure as supported by the NMR spectra of
N-Acylation with tri- and
6a–f, which showed no duplication of signals (Appendix S1).
tetrapeptidoylbenzotriazoles
Compounds 3a–b and 5a, 5c were reacted with different N-nu-
cleophiles in the presence of base to give the corresponding chi-
rally pure N-acylated tripeptides 8a–b and tetrapeptides 8c–d
(Scheme 4, Table 4). Compounds 3a and 5c were reacted with
N-nucleophiles in the presence of triethylamine at 20 ꢀC for 1 h
to give the corresponding tripeptide conjugate 8a (75%) and tet-
rapeptide conjugate 8d (68%). Compounds 3b and 5b reacted
with heterocyclic N-nucleophiles under microwave irradiation at
65 ꢀC for 30 min in DMF to give the corresponding chirally pure
peptide conjugates 8b (68%) and 8c (60%). Compounds 8a–d
were fully characterized by NMR spectroscopy and elemental anal-
ysis (Appendix S1).
S-Acylation with tri- and
tetrapeptidoylbenzotriazoles
Compounds 3a, 5a and 5c were reacted with S-nucleophiles in
the presence of triethylamine at room temperature for 2 h to give
their corresponding S-acylated tripeptide conjugates 7a–b (78–
83%) and tetrapeptide conjugates 7c–d (68–94%) (Scheme 3,
1
Table 3). The chiral purity of 7a–d was supported by their H NMR
and 13C NMR spectra, which showed no evidence of epimerization
in their S-acylated tri- and tetrapeptide conjugates (Appendix S1).
1
The H NMR spectra of compounds 7a and 7b showed prominent
doublets for the methyl protons of alanine unit at 1.14 ppm, and
13C NMR showed prominent signals for all carbonyls of the tripep-
tide unit in the range of 196.2–155.6 ppm. Duplicate signals are
absent in the 13C NMR spectra of compounds 7a–b. Compound 7c
showed sharp singlets of CH2 protons of mercaptoacetic acid unit
and Cbz group at 3.62 and 4.99 ppm, respectively, with no other
repetition of signals in the NMR spectrum. Compound 7d also
showed singlet of CH2 protons of benzyl group and Cbz group at
4.10 and 4.95 ppm, respectively, with no other repeated signals
confirming the formation of chirally pure 7c and 7d.
The chiral purity of compounds 8a–d was confirmed by 1H NMR
and 13C NMR. Tripeptide conjugate 8a and tetrapeptide conjugate
8c showed doublets for the methyl protons of the alanine unit at d
1.12 ppm (8a) and 1.35, 1.12 ppm (8c) with no duplication of sig-
nals in 1H NMR and 13C NMR spectra. Compound 8b showed
prominent singlet of NH proton of aminopyridine unit at 10.47 ppm,
and compound 8d showed sharp singlet for the methyl protons of
the N-methylpiperazine unit at 2.15 ppm with no other duplication
1
of signals in H NMR and 13C NMR spectra, which confirms the for-
mation of chirally pure 8b and 8d.
Scheme 3: S-Acylation of N–
Pg-tri- and tetrapeptidoylbenzo-
triazoles.
Table 3: S-Acylation with N–Pg-tri- and tetrapeptidoylbenzotriazoles
Product
Reactant
Reactant
Yield (%)
Mpt(ꢀC)
7a
7b
7c
7d
Z–L–Ala–L–Phe–Gly–Bt 3a
Z–L–Ala–L–Phe–Gly–Bt 3a
Z–L–Ala–L–Phe–Gly–L-Ala-Bt 5a
Z–L–Phe–Gly–L–Leu–Gly-Bt 5c
Thiophenol
78
83
68
94
146–148
158–160
103–105
186–187
Methylmercaptoacetate
Mercaptoacetic acid
Benzyl mercaptan
24
Chem Biol Drug Des 2012; 80: 17–26

Tri- and Tetrapeptide Conjugates
Scheme 4: N-Acylation of N–
Pg-tri- and tetrapeptidoylbenzo-
triazoles.
Table 4: N-Acylation with N–Pg-tri- and tetrapeptidoylbenzotriazoles
Product
Reactant
Reactant
Conditions
Yield (%)
Mpt(ꢀC)
8a
8b
8c
8d
Z–L–Ala–L–Phe–Gly–Bt 3a
Z–L–Val–L–Phe–Gly–Bt 3b
Z–L–Ala–L–Phe–Gly–L-Ala-Bt 5a
Z–L–Phe–Gly–L–Leu–Gly-Bt 5c
N-(3-Amino-propyl)-imidazole
2-Aminopyridine
2-Amino-6-methoxy-benzothiazole
N-Methylpiperazine
THF, TEA, 1 h, RT
75
68
60
68
65–69
214–215
148–150
181–183
DMF, 65ꢀ, MW, 0.5 h
DMF, 65ꢀ, MW, 0.5 h
THF, TEA, 1 h, RT
Scheme 5: C-Acylation of N–
Pg-tri- and tetrapeptidoylbenzo-
triazoles.
Table 5: C-Acylation with N–Pg-tri- and tetrapeptidoylbenzotriazoles
Product
Reactant
Reactant
Yield (%)
Mpt(ꢀC)
9a
9b
Z–L–Ala–L–Phe–Gly–Bt 3b
Z–L–Phe–Gly–L–Leu–Gly-Bt 5c
Dimedone
1,3 Cyclohexanedione
69
61
135–137
188–190
C-Acylation using tri- and
tetrapeptidoylbenzotriazoles
temperature. They offer an efficient preparation of chirally pure N-
protected tri- and tetrapeptide conjugates with sugars, steroids,
terpenes, and different heterocycles by O-, S-, N-, and C-acylations
in synthetically useful yields without detectable racemization.
Compounds 3a and 5a were reacted with different C-nucleophiles
in the presence of 1 equivalent of DMAP in MW at 70 ꢀC under
50 W irradiation power to give the corresponding tripeptide conju-
gate 9a (69%) and tetrapeptide conjugate 9b (61%) (Scheme 5,
Table 5). Compounds 9a and 9b were fully characterized by NMR
and HRMS analysis. No evidence for epimerization was found in
Acknowledgments
1
the H NMR and 13C NMR spectra of 9a and 9b.
We thank the University of Florida, The Kenan Foundation, and King
Abdulaziz University, Jeddah, Saudi Arabia, for financial support.
Conclusion
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Supporting Information
Additional Supporting Information may be found in the online ver-
sion of this article:
1
Appendix S1. H NMR and 13C NMR spectra for 1b–c, 2a–c,
3a–c, 4a–c, 5a–c, 6a–f, 7a–d, 8a–d, 9a–b.
Please note: Wiley-Blackwell is not responsible for the content or
functionality of any supporting materials supplied by the authors.
Any queries (other than missing material) should be directed to the
corresponding author for the article.
26
Chem Biol Drug Des 2012; 80: 17–26