N-(Ethoxycarbonylmethyl)-N-(4-nitrobenzenesulfonyl)-L-phenyl-
alanine tert-butyl ester 4a
mixture was stirred at room temperature for 1 hour, then
concentrated under reduced pressure to give the compounds
5a–c and 6a–c.
85% yield; Rf (EtOAc–cyclohexane [1 : 4]) 0.50; δH (250 MHz,
CDCl ) 8.18 (d, 2H, J 8.9, CH᎐CH–C–NO ), 8.00 (d, 2H,
᎐
3
2
J 8.9, CH᎐CH–C–NO ), 7.15 (m, 3H, Ph), 7.04 (m, 2H, Ph),
N-(Ethoxycarbonylmethyl)-N-(4-nitrobenzenesulfonyl)-L-leucine
᎐
2
4.40 (m, 1H, CH–CO2tBu), 4.27 (s, 2H, CH2–CO2Et), 4.12
(q, 2H, J 7.2, O–CH2–CH3), 2.96 (m, 2H, CH2–Ph), 1.23 (t, 3H,
J 7.2, O–CH2–CH3), 1.11 (s, 9H, tBu); δC (62 MHz, CDCl3)
167.84, 167.28, 149.14, 144.21, 134.34, 127.94, 127.88, 127.17,
125.75, 122.44, 81.49, 60.33, 58.41, 44.19, 35.74, 26.29, 12.76;
m/z (ESI) (M ϩ Na)ϩ 515.
5a
Quantitative yield; Rf (EtOAc–cyclohexane [1 : 2]) 0.40;
δH (250 MHz, CDCl ) 8.15 (dd, 2H, J 9.1, CH᎐CH–C–NO ),
7.90 (dd, 2H, J 9.1, CH᎐CH–C–NO ), 4.56 (t, 1H, J 7.3, CH–
CO2H), 3.93 (m, 4H, CH2–CO2–CH2–CH3), 1.51 (m, 1H,
CH3–CH–CH3), 1.31 (m, 2H, CH–CH2–CH), 1.01 (m, 3H, O–
CH2–CH3), 0.64 (d, 3H, J 6.6, Me), 0.62 (d, 3H, J 6.6, Me);
δC (62 MHz, CDCl3) 176.92, 170.54, 150.66, 144.57, 129.49,
124.46, 62.70, 58.21, 46.24, 39.27, 24.47, 22.68, 21.48, 14.16;
m/z (ESI) (M ϩ H)ϩ 403, (M ϩ Na)ϩ 425.
᎐
3
2
᎐
2
N-(2-Phenyl-2-oxoethyl)-N-(4-nitrobenzenesulfonyl)-L-phenyl-
alanine tert-butyl ester 4b
24% yield; Rf (EtOAc–CH2Cl2–cyclohexane [1 : 4 : 12]) 0.43;
δH (300 MHz, CDCl ) 8.27 (d, 2H, J 8.7, CH᎐CH–C–NO ),
᎐
3
2
8.10 (d, 2H, J 8.7, CH᎐CH–C–NO ), 7.88 (m, 2H, Ph), 7.60
᎐
2
N-(2-Phenyl-2-oxoethyl)-N-(4-nitrobenzenesulfonyl)-L-leucine
5b
(m, 3H, Ph), 7.19 (m, 5H, Ph), 5.11 (s, 2H, CH2–C(O)–Ph), 4.49
(q, 1H, J 8.7, CH–CO2tBu), 3.00 (d, 2H, J 8.7, CH2–Ph), 1.12
(s, 9H, tBu); δC (62 MHz, CDCl3) 194.36, 169.64, 150.71,
146.76, 136.41, 135.48, 134.65, 130.17, 129.70, 129.31, 128.66,
127.88, 124.56, 83.55, 62.40, 51.15, 38.19, 28.38; m/z (ESI)
(M ϩ H)ϩ 525.
Quantitative yield; Rf (EtOAc–cyclohexane [1 : 2]) 0.38; δH (300
MHz, CDCl ) 8.40 (d, 2H, J 8.7, CH᎐CH–C–NO ), 8.20
᎐
3
2
(d, 2H, J 8.7, CH᎐CH–C–NO ), 7.96 (d, 2H, J 8.1, Ph), 7.65
᎐
2
(t, 1H, J 8.1, Ph), 7.53 (t, 2H, J 8.1, Ph), 5.00 (AB, 2H, J 18.9,
CH2–C(O)–Ph), 4.44 (m, 1H, CH–CO2H), 1.65 (m, 1H, CH3–
CH–CH3), 1.27 (m, 2H, CH–CH2–CH), 0.84 (d, 3H, J 6.3, Me),
0.82 (d, 3H, J 6.3, Me); δC (62 MHz, CDCl3) 194.74, 174.21,
150.48, 145.86, 134.70, 130.81, 129.77, 129.45, 128.43, 127.36,
124.49, 58.39, 52.34, 39.76, 24.82, 22.79, 22.06; m/z (ESI)
(M ϩ H)ϩ 435.
Alkylation using nucleophile substitution. Procedure B leading to
compounds 3c and 4c
To a solution of N-(4-nitrobenzenesulfonyl)-amino acid tert-
butyl ester (1 eq.) in MeCN were added R2X (1.7 eq), then
K2CO3 (2.0 eq.). The reaction mixture was stirred at room tem-
perature for 5 hours, then concentrated under reduced pressure.
The residue was solubilized in EtOAc and the organic layer was
successively washed with a 5% NaHCO3 aqueous solution,
brine and 5% citric acid aqueous solution, then dried over
MgSO4. The organic solvent was removed in vacuo to give a
residue which was purified by flash chromatography on silica
gel to give the compounds 3c and 4c.
N-(2-(4-Methoxyphenyl)-2-oxoethyl)-N-(4-nitrobenzene-
sulfonyl)-L-leucine 5c
Quantitative yield; Rf (EtOAc–toluene [1 : 6]) 0.33; mp 173 ЊC;
δH (250 MHz, DMSO) 10.50 (s, 1H, COOH ), 8.41 (d, 2H, J 8.7,
CH᎐CH–C–NO ), 8.19 (d, 2H, J 8.7, CH᎐CH–C–NO ), 8.00
᎐
᎐
2
2
(d, 2H, J 9.0, CH᎐CH–C–OMe), 7.09 (d, 2H, J 9.0, CH᎐CH–
᎐
᎐
C–OMe), 4.95 (AB, 2H, J 19.2, CH2–C(O)–Ph), 4.32 (m, 1H,
CH–CO2H), 3.87 (s, 3H, O–CH3), 1.87 (m, 1H, CH3–CH–CH3),
1.47 (m, 2H, CH–CH2–CH), 0.84 (d, 3H, J 6.6, Me), 0.80
(d, 3H, J 6.6, Me); δC (62 MHz, DMSO) 195.54, 171.58, 163.38,
149.70, 145.00, 131.50, 130.14, 129.63, 128.99, 128.14, 125.34,
122.92, 114.83, 58.75, 56.34, 53.68, 36.58, 23.68, 22.54, 21.66;
m/z (ESI) (M Ϫ H)Ϫ 463.
N-(2-(4-Methoxyphenyl)-2-oxoethyl)-N-(4-nitrobenzene-
sulfonyl)-L-leucine tert-butyl ester 3c
95% yield; Rf (EtOAc–toluene [1 : 6]) 0.63; δH (300 MHz,
CDCl ) 8.38 (d, 2H, J 9.3, CH᎐CH–C–NO ), 8.20 (d, 2H, J 9.3,
᎐
3
2
CH᎐CH–C–NO ), 7.92 (d, 2H, J 9.0, CH᎐CH–C–OMe),
᎐
᎐
2
6.97 (d, 2H, J 9.0, CH᎐CH–C–OMe), 5.02 (AB, 2H, J 18.9,
᎐
CH2–C(O)–Ph), 4.31 (t, 1H, J 7.5, CH–CO2tBu), 3.90 (s, 3H,
O–CH3), 1.70 (m, 1H, CH3–CH–CH3), 1.57 (m, 2H, CH–CH2–
CH), 1.35 (s, 9H, tBu), 0.87 (d, 3H, J 6.6, Me), 0.84 (d, 3H,
J 6.6, Me); δC (62 MHz, CDCl3) 192.52, 170.53, 164.47, 150.31,
146.49, 130.57, 129.85, 129.48, 128.60, 128.13, 125.75, 124.21,
114.44, 82.99, 58.87, 55.94, 50.37, 40.20, 28.25, 24.98, 22.61,
21.85; m/z (ESI) (M ϩ H)ϩ 521, (M ϩ Na)ϩ 543.
N-(Ethoxycarbonylmethyl)-N-(4-nitrobenzenesulfonyl)-L-phenyl-
alanine 6a
Quantitative yield; Rf (EtOAc–cyclohexane [1 : 2]) 0.37; δH (300
MHz, CDCl ) 8.20 (d, 2H, J 8.9, CH᎐CH–C–NO ), 7.95 (d,
᎐
3
2
2H, J 8.9, CH᎐CH–C–NO ), 7.22 (m, 3H, Ph), 7.12 (m, 2H,
᎐
2
Ph), 4.64 (m, 1H, CH–CO2H), 4.17 (m, 4H, CH2–CO2–CH2–
CH3), 3.04 (m, 2H, CH2–Ph), 1.28 (t, 3H, J 7.2, O–CH2–CH3);
δC (62 MHz, CDCl3) 174.31, 170.02, 150.54, 146.17, 136.78,
135.92, 129.45, 129.21, 128.84, 127.66, 124.44, 62.49, 58.61,
46.72, 36.67, 14.42; m/z (ESI) (M ϩ Na)ϩ 459.
N-(2-(Naphthalen-2-yl)-2-oxoethyl)-N-(4-nitrobenzenesulfonyl)-
L-phenylalanine tert-butyl ester 4c
87% yield; Rf (EtOAc–cyclohexane [1 : 6]) 0.28; mp 59 ЊC;
δH (250 MHz, CDCl ) 8.12 (d, 2H, J 9.3, CH᎐CH–C–NO ),
᎐
3
2
7.80 (d, 2H, J 9.3, CH᎐CH–C–NO ), 7.73 (m, 4H, Naphthyl),
᎐
2
7.42 (m, 3H, Naphthyl), 7.02 (m, 5H, Ph), 5.09 (s, 2H, CH2–
C(O)–Naphthyl), 4.37 (m, 1H, CH–CO2tBu), 2.90 (m, 2H,
CH2–Ph), 0.99 (s, 9H, tBu); δC (62 MHz, CDCl3) 193.57,
168.95, 149.93, 146.02, 135.85, 132.38, 132.13, 129.82, 129.41,
129.01, 128.72, 128.55, 128.31, 127.86, 126.97, 123.75, 123.18,
82.76, 61.73, 50.54, 37.48, 27.65; m/z (ESI) (M ϩ H)ϩ 575.
N-(2-Phenyl-2-oxoethyl)-N-(4-nitrobenzenesulfonyl)-L-phenyl-
alanine 6b
Quantitative yield; Rf (EtOAc–cyclohexane [1 : 4]) 0.17; mp 144
ЊC; δ (300 MHz, CDCl ) 8.25 (d, 2H, J 9.3, CH᎐CH–C–NO ),
᎐
H
3
2
8.00 (d, 2H, J 9.3, CH᎐CH–C–NO ), 7.89 (d, 2H, J 7.2, Ph),
᎐
2
7.68 (t, 1H, J 7.2, Ph), 7.52 (t, 2H, J 7.2, Ph), 7.24 (m, 3H, Ph),
7.13 (m, 2H, Ph), 4.91 (AB, 2H, J 18.9, CH2–C(O)–Ph), 4.53
(m, 1H, CH–CO2H), 3.18 (m, 2H, CH2–Ph); δC (62 MHz,
CDCl3) 195.74, 172.97, 150.91, 145.62, 136.55, 135.47, 134.72,
129.90, 129.84, 129.59, 128.92, 128.09, 124.81, 62.26, 51.12,
37.53; m/z (ESI) : (M ϩ H)ϩ 469, (M ϩ Na)ϩ 491.
Cleavage of the tert-butyl ester function. General procedure
leading to compounds 5a–c and 6a–c
To a solution of N,N-disubstituted-amino acid tert-butyl ester
(1 eq.) in CH2Cl2 at 0 ЊC was added TFA (20 eq.). The reaction
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 7 9 3 – 7 9 9
797