1436 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 10
Nagarajan et al.
was concentrated under reduced pressure. The resulting
substance (0.2 g) was dissolved in dichloromethane (5.00 mL),
di-tert-butyl dicarbonate19 (0.2 g, 0.92 mmol) and triethylamine
(0.11 g, 1.1 mmol) were added, and the mixture was stirred at
room temperature for 16 h. The mixture was concentrated
under reduced pressure, and the product was purified by flash
column chromatography on silica gel, eluting with 20% EtOAc
in hexane to give the titled N-BOC-protected ester 33b (0.16
g, 57%) as a colorless syrup: 1H NMR (CDCl3) δ 1.7-1.3 (s
over m, 17H), 2.6 (m, 2H), 3.1 (m, 2H), 3.59 (s, 2H), 3.69 (s,
3H), 7.15 (m, 4H); MW C20H31NO4 calcd 350.2331 (M + H),
found 350.2315 (M + H, HRFABMS).
2H), 1.5-1.1 (m, 16H), 1.65 (m, 12H), 1.92 (m, 1H), 2.86 (q,
4H, J ) 7.2 Hz), 2.59 (t, 2H, J ) 7.2 Hz), 3.19 (m, 2H), 3.56 (s,
2H), 3.77 (dd, 1H), 3.85 (dd, 1H), 4.35 (m, 2H), 7.15 (q, 4H, J
) 8.0 Hz); MW C33H57N5O4 calcd 588.4489 (M + H), found
588.4485 (M + H, HRFABMS). Amino acid analysis: Ser 1.03
(1.00); Lys 0.97 (1.00).
2-[4-(N-BOC-6-am in oh exyl)ph en yl]pr opion ic Acid (34d).
The title compound was prepared as described for 34b starting
from 5-hexyn-1-ol and racemic methyl 2-(p-iodophenyl)propi-
onate:17 1H NMR (CDCl3) δ 1.35 (m, 4H), 1.44 (s over m, 11H),
1.49 (d, 3H, J ) 7.2 Hz), 1.6 (m, 2H), 2.55 (t, 2H, J ) 7.1 Hz),
3.18 (br, 2H), 3.71 (q, 1H, J ) 7.2 Hz), 4.5 (br, 1H), 7.13 (d,
2H, J ) 8.1 Hz), 7.2 (d, 2H, J ) 8.1 Hz); MW C20H31NO4 calcd
356.2413 (M + Li), found 356.2376 (M + Li, HRFABMS).
[2-[4-(6-Am in oh exyl)p h en yl]p r op ion yl]-Ser -Lys-2-cy-
cloh exyleth yla m id e (48). Prepared by coupling 34d with
25 followed by deprotection as described for 26b: 1H NMR
(CD3OD) δ 0.9 (m, 2H), 1.8-1.1 (m, 26H), 1.9 (m, 2H), 2.58 (t,
2H, J ) 7.8 Hz), 2.87 (m, 4H), 3.18 (m, 2H), 3.8-3.6 (m, 3H),
4.25 (m, 2H), 7.11 (d, 2H, J ) 7.8 Hz), 7.24 (m, 2H); MW
C32H55N5O4 calcd 574.4332 (M + H), found 574.4357 (M + H,
HRFABMS). Amino acid analysis: Ser 0.97 (1.00); Lys 1.03
(1.00).
(3-(5-Am in op en tyl)p h en yla cetyl)-Ser -Lys-2-cycloh exy-
leth yla m id e (36). This compound was prepared as described
for 26b but starting from m-iodophenylacetic acid. 1H NMR
(CD3OD) δ 0.96 (m, 2H), 1.53-1.1 (m, 10H), 1.82-1.54 (m,
12H), 1.94 (m, 1H), 2.66 (t, 2H, J ) 7.5 Hz), 2.91 (m, 4H), 3.18
(m, 2H), 3.57 (s, 2H), 3.72 (m, 1H), 3.85 (m, 1H), 4.36 (m 2H),
7.42-7.05 (m, 4H); MW C30H51N5O4 calcd 546.4019 (M + H),
found 546.4036 (M + H, HRFABMS). Amino acid analysis:
Ser 0.97 (1.00); Lys 1.03 (1.00).
4-[(N-BOC-a m in o)m eth yl]iod oben zen e (40). A mixture
containing 4-(aminomethyl)iodobenzene (39, 1.5 g, 6.4 mmol)
and di-tert-butyl dicarbonate19 (1.5 g, 6.8 mmol) in dichlo-
romethane (25 mL) was stirred at room temperature for 16 h.
The solution was diluted with dichloromethane (25 mL),
washed with 5% citric acid (2 × 20 mL) and brine (2 × 20 mL),
dried (Na2SO4), and concentrated under reduced pressure. The
resulting material was triturated with hexane, and the
precipitate was filtered, washed with hexane, and dried in a
desiccator in vacuo to afford the titled product 40 (1.7 g, 80%)
as a pale yellow powder: 1H NMR (CDCl3) δ 1.45 (s, 9H), 4.24
(d, 2H, J ) 6.0 Hz), 4.82 (br, 1H), 7.02 (d, 2H, J ) 8.1 Hz),
7.64 (d, 2H, J ) 8.1 Hz); MW C12H16NO2I calcd 334.0304 (M
+ H), found 334.0286 (M + H, HRFABMS)
7-[4-[(N-BOC-a m in o)m eth yl]p h en yl]h ep t-6-yn oic Acid
(41). To a solution of 6-heptynoic acid (0.4 g, 3.2 mmol) and
40 (1.0 g, 3 mmol) in acetonitrile (5.00 mL) were added (PPh3)2-
PdCl2 (0.2 g) and CuI (0.04 g), and the mixture was stirred at
5 °C for 30 min. After being stirred at room temperature for
4 h, the reaction mixture was concentrated under reduced
pressure, and the residue was dissolved in EtOAc (25 mL),
washed successively with 5% citric acid (2 × 10 mL) and water
(2 × 20 mL), and dried (Na2SO4). The solution was concen-
trated under reduced pressure, and the resulting orange
material was purified by flash column chromatography on
silica gel, eluting with 50% EtOAc in hexane to afford the titled
compound 41 (0.47 g, 47%) as a white powder: 1H NMR
(CDCl3) δ 1.45 (s, 9H), 1.67 (m, 2H), 1.8 (m, 2H), 2.43 (m, 4H),
4.28 (d, 2H, J ) 4.8 Hz), 4.82 (br, 1H), 7.18 (d, 2H, J ) 8.0
Hz), 7.35 (d, 2H, J ) 8.0 Hz); MW C19H25NO4 calcd 332.1862
(M + H), found 332.1844 (M + H, HRFABMS).
4-(N-BOC-6-a m in oh exyl)p h en yla cetic Acid (34b).
A
mixture of the ester 33b (0.15 g, 0.43 mmol) in THF (0.5 mL)
and LiOH (1.0 M, 1.5 mL) was stirred at room temperature
under an argon atmosphere. After 2 h, the reaction mixture
was diluted with water (5 mL), acidified with 5% citric acid,
and extracted with EtOAc (3 × 10 mL). The combined organic
extracts were washed with brine, dried (Na2SO4), and concen-
trated. The resulting material was dried in a desiccator to
give the acid 34b (0.14 g, 97%): 1H NMR (CDCl3) δ 1.7-1.2 (s
over m, 17H), 2.6 (m, 2H), 3.1 (m, 2H), 3.59 (s, 2H), 3.61 (s,
2H), 7.14 (m, 4H); MW C19H29NO4 calcd 336.2176 (M + H),
found 336.2154 (M + H, HRFABMS).
(4-(6-Am in oh exyl)p h en yla cetyl)-Ser -Lys-2-cycloh exy-
leth yla m id e, Tr iflu or oa ceta te (26b). The N-BOC-protected
acid 34b (0.12 g, 0.36 mmol) was dissolved in a mixture of
dichloromethane (3 mL) and dimethylacetamide (0.5 mL),
HOBt (0.058 g, 0.38 mmol) and DCC (0.077 g, 0.37 mmol) were
added, and the mixture was stirred at 0 °C. After 1.5 h, the
mixture was filtered, and the filtrate was added to a solution
of the dipeptide amine 25 in dimethylacetamide (1 mL)
containing N-methylmorpholine (0.046 g, 0.46 mmol), and the
mixture was stirred at room temperature for 48 h. The
solvents were distilled in vacuo, and the residue was stirred
with EtOAc (15 mL) and cold 0.25 N NaOH (10 mL) for 15
min. The organic phase was washed successively with water,
5% citric acid (2 × 10 mL), and brine, dried, and concentrated
under reduced pressure. The resulting material was triturated
with ether-hexane (1:1 v/v) and filtered. The solid (0.017 g)
thus obtained was treated with trifluoroacetic acid (1.8 mL)
and anisole (0.2 mL) and stirred at room temperature for 3.5
h. The solvents were removed under reduced pressure, and
the residue was purified by HPLC to give the desired product
26b (0.065 g) as an amorphous hygroscopic substance: 1H
NMR (CD3OD) δ 0.92 (m, 2H), 1.85-1.1 (m, 24H), 1.92 (m,
1H), 2.63 (t, 2H, J ) 7.5 Hz), 2.9 (q, 4H, J ) 7.5 Hz), 3.17 (m,
2H), 3.58 (s, 2H), 3.72 (AB q, 1H), 4.36 (2H), 7.4-7.05 (m, 4H);
MW C31H53N5O4 calcd 560.4176 (M + H), found 560.4139 (M
+ H, HRFABMS). Amino acid analysis: Ser 1.0 (1.00); Lys
1.0 (1.00).
4-(N-BOC-5-a m in op en tyl)p h en yla cetic Acid (34a ). Pre-
pared in a similar manner as described for compound 34b:
yield 86%; colorless liquid; 1H NMR (CDCl3) δ 1.44 (s, 9H),
1.45 (m, 2H), 1.5 (m, 2H), 1.6 (m, 2H), 2.6 (t, 2H, J ) 7.8 Hz),
3.1 (m, 2H, J ) 7.2 Hz), 3.59 (s, 2H), 3.62 (s, 3H), 7.15 (q, 4H,
J ) 8.4 Hz); MW C18H27NO4 calcd 328.2100 (M + Li), found
328.2105 (M + Li, HRFABMS).
(4-(5-Am in op en tyl)p h en yla cetyl)-Ser -Lys-2-cycloh exy-
leth yla m id e (26a ). Prepared in a similar manner as de-
scribed for compound 26b: yield 43%; white amorphous
1
powder; H NMR (CD3OD) δ 0.92 (m, 2H), 1.8-1.1 (m, 22H),
1.92 (m, 1H), 2.61 (t, 2H), 2.89 (m, 4H), 3.18 (m, 2H), 3.56 (s,
2H), 3.72 (m, 1H), 3.85 (m, 1H), 4.35 (m, 2H), 7.15 (m, 4H);
MW C30H51N5O4 calcd 546.4019 (M + H), found 546.4014 (M
+ H, HRFABMS). Amino acid analysis: Ser 1.02 (1.00); Lys
0.98 (1.00).
[7-[4-(Am in om et h yl)p h en yl]-6-h ep t yn oyl]-Ser -Lys-2-
cycloh exyleth yla m id e (37). This compound was prepared
by coupling 41 with 25 followed by deprotection as described
for 26b: 1H NMR (CD3OD) δ 0.95 (m, 2H) 1.9-1.4 (m, 20H),
1.95 (m, 1H), 2.33 (t, 2H, J ) 8.9 Hz), 2.46 (t, 2H, J ) 8.9 Hz),
2.92 (t, 2H, J ) 8.9 Hz), 3.2 (m, 2H), 3.75 (m, 1H), 3.85 (m,
1H), 4.1 (s, 2H), 4.35 (m, 2H), 7.29 (m, 4H); MW C31H49N5O4
calcd 556.3863 (M + H), found 556.3881 (M + H, HRFABMS).
Amino acid analysis: Ser 0.97 (1.00); Lys 1.03 (1.00).
7-[4-[(N-BOC-am in o)m eth yl]ph en yl]h eptan oic Acid (42).
The acetylenic acid24 41 (0.2 g, 0.6 mmol) was dissolved in
EtOAc (10 mL) and hydrogenated at 40 psi in the presence of
5% Pd/C (0.15 g) for 3.5 h. The suspension was filtered, the
filtrate was concentrated under reduced pressure, and the
4-(N-BOC-8-a m in ooctyl)p h en yla cetic Acid (34c). This
compound was prepared in a similar manner as described for
1
34b: yield 82%; white powder; H NMR (CDCl3) δ 1.27 (m,
8H), 1.44 (s over m, 11H), 1.58 (m, 2H), 2.58 (t, 2H, J ) 7.8
Hz), 3.08 (m, 2H), 3.61 (s, 2H), 7.15 (q, 4H, J ) 8.1 Hz); MW
C21H34NO4 calcd 370.2570 (M + Li), found 370.2567 (M + Li,
HRFABMS).
(4-(8-Am in ooct yl)p h en yla cet yl)-Ser -Lys-2-cycloh exy-
leth yla m id e (26c). This compound was prepared in a similar
manner as described for 26b: 1H NMR (CD3OD) δ 0.94 (m,