744 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 5
No¨teberg et al.
CHCl3); 1H NMR (400 MHz, CDCl3) δ 0.71 (d, J ) 7.0 Hz, 3 H,
Val-CH3), 0.83 (dd, J ) 6.8 Hz, 3 H, Val-CH3), 2.11-2.33 (m,
1 H, Val-(CH3)2CH), 2.56-2.79 (m, 2 H, C2CH2), 2.79-2.91
(m, 2 H, C7H2), 2.97 (dd, J ) 8.1, 13.5 HZ, 1 H, C4H), 3.15
(dd, J ) 6.1, 13.4 Hz, 1 H, C4H), 3.50-3.64 (m, 1 H, C5H),
3.64-3.84 (m, 1 H, C6H), 4.09-4.23 (m, 1 H, Val-CHNH), 4.33
(dd, J ) 6.8, 9.0 Hz, 1 H, C2H), 6.02-6.20 (br s, 1 H, NH),
6.76-7.66 (m, 17 H, 14 Ar-H and 3 NH), 7.79-7.91 (m, 1 H,
C5H on pyridine), 8.08-8.20 (m, 1 H, C4H on pyridine), 8.35-
8.50 (m, 1 H, C3H on pyridine), 8.50-8.63 (m, 1 H, C6H on
pyridine). 13C NMR (100.5 MHz, CDCl3) δ 17.8, 19.6, 30.2, 38.1,
38.5, 51.4, 52.7, 59.4, 63.7, 69.6, 122.3, 126.2, 126.4, 126.7,
126.8, 126.9, 127.0, 127.4, 127.6, 128.4, 128.5, 128.8, 129.2,
129.6, 129.7, 136.1, 137.4, 137.5, 137.7, 139.8, 140.5, 148.3,
149.0, 164.8, 171.1, 175.8. Anal. (C36H41N5O4‚1.3H2O) C, H,
N.
C2H), 5.83-6.03 (br s, 1 H, NH), 6.68-6.81 (m, 1 H, NH),
6.85-7.39 (m, 12 H, 11 Ar-H and NH), 7.30-7.53 (m, 3 H, 2
Ar-H and NH), 7.73-7.86 (m, 1 H, C5H on pyridine), 8.02-
8.21 (m, 1 H, C4H on pyridine), 8.33-8.46 (m, 1 H, C3H on
pyridine), 8.46-8.60 (m, 1 H, C6H on pyridine). 13C NMR
(100.5 MHz, CDCl3) δ 17.8, 19.6, 30.3, 38.3, 38.9, 51.5, 52.7,
55.5, 59.2, 63.7, 69.2, 111.1, 120.8, 122.3, 126.3, 126.4, 126.8,
128.4, 128.6, 128.7, 128.8, 129.2, 129.9, 129.9, 133.9, 135.6,
136.0, 137.4, 137.7, 148.3, 149.1, 156.3, 164.7, 170.9, 176.3.
Anal. (C37H43N5O5‚1.6H2O) C, H, N.
m -L-Tyr osin e Am id e (13). Compound 13 (0.25 g, 84%) was
prepared from m-tyrosine (12, 0.30 g, 1.66 mmol)12 according
to the method for the preparation of 7f except 13 was purified
by column chromatography (EtOAc-MeOH 4:1) to give 13 as
1
a colorless glue. 13: [R]22 ) +5.2 (c ) 1.2, MeOH), H NMR
D
(400 MHz, CD3OD) δ 2.63-2.82 (m, 1 H), 2.90-3.09 (m, 1 H),
3.49-3.64 (m, 1 H), 6.57-6.96 (m, 3 H), 6.99-7.27 (m, 1 H).
13C NMR (67.8 MHz, CD3OD) δ 42.4, 57.2, 114.9, 117.2, 121.4,
130.5, 140.2, 158.7, 179.5. Anal. (C9H12N2O4‚0.7H2O) C, H, N.
(2S,5S,6R)-3-Aza -2-[p -(p -m et h ylp h en yl)b en zyl]-5-h y-
d r oxy-7-p h en yl-6-[(p icolyl-L-va lin yl)a m in o]h ep t a n oyl
Am id e (16b). Compound 16b (21 mg, 46%) was prepared from
11f (44 mg, 72 µmol) and 4-methylphenylboronic acid (26 mg,
0.19 mmol) using the same procedure as in the synthesis of
16a . 16b: [R]22D ) -39.9 (c ) 0.7, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 0.85 (d, J ) 6.9 Hz, 3 H, Val-CH3), 0.91 (d, J ) 6.8
Hz, 3 H, Val-CH3), 2.14-2.20 (m, 1 H, Val-(CH3)2CH), 2.20 (s,
3 H, Ar-CH3), 2.60-2.77 (m, 2 H, C2-CH2), 2.77-3.01 (m, 3
H, C4H and C7H2), 3.08-3.22 (m, 1 H, C4H), 3.41-3.55 (m, 1
H, C5H), 3.59-3.72 (m, 1 H, C6H), 4.05-4.22 (m, 1 H, Val-
CHNH), 4.32 (dd, J ) 6.5, 8.7 Hz, 1 H, C2H), 5.78-5.98 (br s,
1 H, NH), 6.64-6.78 (m, 1 H, NH), 6.85-6.99 (m, 1 H, NH),
6.99-7.09 (m, 1 H, Ar-H), 7.09-7.19 (m, 4 H, 4 Ar-H), 7.19-
7.39 (m, 4 H, 4 Ar-H), 7.48-7.60 (m, 5 H, 4 Ar-H, NH), 7.78-
7.91 (m, 1 H, C5H on pyridine), 8.07-8.22 (m, 1 H, C4H on
pyridine), 8.33-8.49 (m, 1 H, C3H on pyridine), 8.53-8.67 (m,
1 H, C6H on pyridine). 13C NMR (100.5 MHz, CDCl3) δ 17.7,
19.6, 21.1, 30.1, 38.2, 38.9, 51.5, 52.6, 59.3, 63.9, 69.7, 122.3,
126.3, 126.5, 126.8, 127.2, 127.4, 128.4, 128.6, 129.2, 129.5,
136.1, 136.8, 137.4, 137.7, 139.7, 148.3, 149.1, 164.7, 170.9,
176.2. Anal. (C37H43N5O4‚H2O‚HCOOH) C, H, N.
N-(ter t-Bu tyloxyca r bon yl)-m -L-Tyr osin e Am id e (14).
The primary amine 13 (0.36 g, 2.0 mmol), Boc2O (0.88 mg, 4.0
mmol) and NaHCO3 (0.34, 4.0 mmol) were suspended in a
mixture of water and THF (1:1, 30 mL) and stirred overnight.
The mixture was extracted with EtOAc (30 mL), and the
organic phase was dried, filtered, and evaporated. The product
was purified by column chromatography (CH2Cl2-MeOH 9:1)
to give 14 (0.43 g, 77%) as a white powder. 14: [R]22D ) +21.8
1
(c ) 1.0, CHCl3); H NMR (270 MHz, CDCl3) δ 1.38 (s, 9 H),
2.77-3.10 (m, 2 H), 4.30-4.49 (m, 1 H), 5.48-5.70 (m, 1 H),
6.44 (br s, 1 H), 6.55-6.83 (m, 4 H), 6.98-7.16 (m, 1 H). 13C
NMR (67.8 MHz, CDCl3) δ 28.2, 38.3, 55.4, 80.5, 114.3, 116.2,
121.0, 129.7, 137.8, 155.8, 156.5, 175.1. Anal. (C14H20N2O4) C,
H, N.
N-(ter t-Bu tyloxyca r bon yl)-m -(tr iflu or om eth a n esu lfo-
n yloxy)-L-p h en yla la n in ea m id e (15). Compound 14 (0.760
g, 2.71 mmol), N-phenyltrifluoromethanesulfonimide (1.94 g,
5.43 mmol), K2CO3 (0.75 g, 5.43 mmol), and triethylamine (1.88
mL, 13.56 mmol) were refluxed in CH2Cl2 (100 mL) for 30 min.
The mixture was washed with water, dried, filtered, and
evaporated. The product was purified by column chromatog-
(2S,5S,6R)-3-Aza -2-[p -(m -a m in op h en yl)b en zyl]-5-h y-
d r oxy-7-p h en yl-6-[(p icolyl-L-va lin yl)a m in o]h ep t a n oyl
Am id e (16c). Compound 16c (13 mg, 28%) was prepared from
11f (46 mg, 75 µmol) and 3-aminophenylboronic acid (42 mg,
0.31 mmol) using the same procedure as in the synthesis of
16a except the HPLC gradient was changed (H2O (0.1%
raphy to give 15 (1.00 g, 89%) as a white powder. 15: [R]22
)
D
1
+1.63 (c ) 1.0, CHCl3); H NMR (270 MHz, CDCl3) δ 1.41 (s,
9 H), 2.93-3.31 (m, 2 H), 4.30-4.59 (m, 1 H), 5.10-5.37 (m, 1
H), 5.81 (br s, 1 H), 6.22 (br s, 1 H), 7.00-7.56 (m, 4 H). 13C
NMR (67.8 MHz, CDCl3) δ 28.2, 37.9, 54.8, 80,5, 118.7 (q, J )
320 Hz), 119.8, 122.3, 129.5, 130.3, 139.8, 149.5, 155.4, 173.2.
Anal. (C15H19F3N2O6S) C, H, N.
HCOOH) f H2O-AcCN 7:3 (0.1% HCOOH)). 16c: [R]22
)
D
-22.2 (c ) 0.5, CHCl3-MeOH 1:1); 1H NMR (400 MHz, CDCl3,
CD3OD 1:1); δ 0.87 (d, J ) 6.6 Hz, 3 H, Val-CH3), 0.93 (d, J )
6.7 Hz, 3 H, Val-CH3)), 1.27 (br s, 2 H, ArNH2), 2.18-2.33 (m,
1 H, Val-(CH3)2CH), 2.55-2.77 (m, 2 H, C2-CH2), 2.77-3.01
(m, 3 H, C4H and C7H2), 3.01-3.27 (m, 1 H, C4H), 3.27-3.48
(m, 1 H, C5H), 3.48-3.71 (m, 1 H, C6H), 4.00-4.20 (m, 1 H,
Val-CHNH), 4.20-4.38 (m, 1 H, C2H), 5.40-5.61 (br s, 1 H,
NH), 6.29-6.52 (m, 1 H, Ar-H), 6.55-6.80 (m, 1 H, Ar-H),
6.80-7.00 (m, 2 H, 2 Ar-H), 7.00-7.33 (m, 8 H, 6 Ar-H, 2
NH),7.33-7.65 (m, 4 H, 3 Ar-H, NH), 7.72-7.96 (m, 1 H, C5H
on pyridine), 7.96-8.22 (m, 1 H, C4H on pyridine), 8.22-8.45
(m, 1 H, C3H on pyridine), 8.45-8.66 (m, 1 H, C6H on
pyridine). 13C NMR (100.5 MHz, CD3OD) δ 17.0, 30.1, 36.5,
36.6, 49.4, 52.4, 58.7, 61.6, 67.6, 113.3, 114.1, 116.6, 121.5,
125.6, 126.2, 126.6, 127.5, 128.4, 128.9, 133.1, 137.0, 140.0,
140.8,146.5,147.8,148.3,164.40,171.4,171.8.Anal.(C36H42N6O4‚
H2O‚0.8HCOOH) C, H, N.
(2S,5S,6R)-3-Aza -6-[(ter t-b u t yloxyca r b on yl)a m in o]-5-
h yd r oxy-7-p h en yl-2-[m -(tr iflu or om eth a n esu lfon yloxy)-
ben zyl]h ep ta n oyl Am id e (8g). Compound 15 (0.32 g, 0.78
mmol) was dissolved in a mixture of TFA and CH2Cl2 (1:1, 10
mL), and the mixture was stirred for 15 min and evaporated.
The residue was dissolved in CH2Cl2 and washed twice with
Na2CO3 (aq, 1 M). The organic phase was dried, filtered, and
evaporated. The residue and epoxide 5 (0.15 g, 0.57 mmol)
were reacted according to the procedure as in the synthesis of
8a to give 8g (0.26 g, 79%). 8g: [R]22D ) -3.0 (c ) 1.6, CHCl3);
1H NMR (270 MHz, CDCl3) δ 1.39 (s, 9 H), 1.46-1.92 (m, 1
H), 2.47-2.73 (m, 2 H), 2.73-3.02 (m, 3 H), 3.02-3.21 (m, 1
H), 3.21-3.38 (m, 1 H), 3.40-3.60 (m, 1 H), 3.67-3.98 (m, 1
H), 4.77-5.00 (m, 1 H), 5.60 (br s, 1 H), 6.78 (br s, 1 H), 7.03-
7.48 (m, 10 H). 13C NMR (67.8 MHz, CDCl3) δ 28.1, 38.5, 51.6,
53.7, 63.3, 69.7, 79.3, 118.5 (q, J ) 321 Hz), 119.5, 122.0, 126.2,
128.3, 129.1, 130.3, 138.1, 140.3, 149.4, 150.1, 176.3. Anal.
(C33H38F3N3O9S‚0.5H2O) C, H, N.
(2S,5S,6R)-3-Aza -3-(ben zyloxyca r bon yl)-6-[(ter t-bu tyl-
oxyca r b on yl)a m in o]-5-h yd r oxy-7-p h en yl-2-[m -(t r iflu o-
r om et h a n esu lfon yloxy)b en zyl]h ep t a n oyl Am id e (9g).
Compound 9g (0.25 g, 78%) was prepared from 8g (0.26 g, 0.45
mmol), Na2CO3 (96 mg, 0.90 mmol), and Z-Cl (0.13 mL, 0.90
mmol) using the same procedure as in the synthesis of 9a .
9g: [R]22D ) -140.6 (c ) 1.1, CHCl3); 1H NMR (270 MHz, CD3-
OD) δ 1.05-1.45 (m, 9 H), 2.22-2.44 (m, 1 H), 2.52-2.88 (m,
2 H), 3.08-3.37 (m, 3 H), 3.43-3.66 (m, 1 H), 3.80-4.05 (m, 1
(2S,5S,6R)-3-Aza -5-h yd r oxy-2-[p -(o-m et h oxyp h en yl)-
ben zyl]-7-p h en yl-6-[(p icolyl-L-va lin yl)a m in o]h ep ta n oyl
Am id e (16d ). Compound 16d (18 mg, 38%) was prepared from
11f (45 mg, 74 µmol) and 2-methoxyphenylboronic acid (34 mg,
0.22 mmol) using the same procedure as in the synthesis of
16a . 16d : [R]22D ) -41.9 (c ) 0.7, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 0.87 (d, J ) 6.8 Hz, 3 H, Val-CH3), 0.93 (dd, J ) 6.8
Hz, 3 H, Val-CH3), 2.11-2.32 (m, 1 H, Val-(CH3)2CH), 2.51-
2.70 (m, 2 H, C2-CH2), 2.70-2.90 (m, 3 H, C4H and C7H2),
3.16-3.30 (dd, J ) 5.4, 13.4 Hz, 1 H, C4H), 3.47-3.51 (m, 1
H, C5H), 3.51-3.69 (m, 1 H, C6H), 3.73 (s, 3 H, OCH3), 4.00-
4.14 (m, 1 H, Val-CHNH), 4.22-4.42 (dd, J ) 6.8, 8.9 Hz, 1 H,