Methyl 2-((Succinimidooxy)carbonyl)benzoate
J . Org. Chem., Vol. 67, No. 11, 2002 3767
150 mm) using a linear gradient of 0-100% of B (0.08% TFA
in MeCN) in A (0.1% TFA in H2O) for 20 min at a flow rate of
1.2 mL/min with UV detection at 214 nm. Elemental analyses
of compound 3 were performed at the Service Centrale
d’Analyses, Solaize, France.
12.94 min; [R]D -275 (c ) 1.0, EtOH); 1H NMR (200 MHz,
DMSO-d6) δ 3.55 (d, J ) 6.5 Hz, 2H), 5.10 (m, 1H), 6.84-7.02
(m, 3H), 7.23 (d, J ) 7.9 Hz, 2H), 7.47 (d, J ) 7.7 Hz, 2H),
7.78 (s, 4H), 10.72 (s, 1H), 13.25 (s, 1H); 13C NMR (50 MHz,
DMSO-d6) δ 24.0, 52.6, 109.6, 111.3, 117.8, 118.3, 120.9, 123.2,
126.8, 130.8, 134.7, 135.9, 167.1, 170.2; MS (m/z) 335 (M +
H)+, 357 (M + Na)+.
Meth yl 2-((Su ccin im id ooxy)ca r bon yl)ben zoa te (MSB,
3). A solution of 2-(methoxycarbonyl)benzoic acid (1) (7.21 g,
40 mmol) and N-hydroxysuccinimide (2) (4.61 g, 40 mmol) in
DME (15 mL) was cooled to 0 °C. DCC (8.25 g, 40 mmol) was
added and stirring was continued at this temperature for 4 h.
The reaction mixture was allowed to stand for 2 h in a
refrigerator and then filtered. The solution was concentrated
under reduced pressure. The residue was triturated in Et2O/
hexanes, filtered out, and then dried in vacuo to afford 10.9 g
(98%) a white solid. Mp: 75-77 °C. HPLC: Rt ) 11.84 min.
1H NMR (300 MHz, CDCl3): δ 2.86 (s, 4H), 3.89 (s, 3H), 7.62
(m, 2H), 7.86 (m, 2H). 13C NMR (75 MHz, CDCl3): δ 25.7, 53.0,
127.6, 129.6, 129.9, 131.5, 131.7, 132.5, 163.2, 166.4, 169.0.
MS (m/z): 300 (M + Na)+, 316 (M + K)+. EMM: calcd for
(S)-Nr-P h th a loyl-O-ben zylser in e (6g): colorless syrup
(0.65 g, 100%);15 HPLC Rt ) 13.69 min; [R]D -44 (c ) 12,
1
CHCl3); H NMR (200 MHz, CDCl3) δ 4.23 (m, 2H), 4.51 (d,
J ) 12.0 Hz, 1H), 4.62 (d, J ) 12.0 Hz, 1H), 5.27 (dd, J ) 5.8,
9.2 Hz, 1H), 7.27 (s, 5H), 7.75 (m, 2H), 7.87 (m, 2H), 8.51 (bs,
1H); 13C NMR (50 MHz, CDCl3) δ 51.4, 66.3, 73.0, 123.6, 127.7,
127.8, 128.4, 131.8, 134.2, 137.4, 167.5, 172.8; MS (m/z) 348
(M + Na)+, 364 (M + K)+.
(S)-Nr-P h t h a loyl-O-b en zylt yr osin e (6h ): white solid
(0.76 g, 94%); mp 213-215 °C (lit.10a mp 213 °C); HPLC Rt )
15.76 min; [R]D -212 (c ) 1.0, AcOH); 1H NMR (200 MHz,
DMSO-d6) δ 3.25 (dd, J ) 11.3, 14.1 Hz, 1H), 3.38 (dd, J )
5.1, 14.1 Hz, 1H), 4.92 (s, 2H), 5.06 (dd, J ) 5.1, 11.3 Hz, 1H),
6.77 (d, J ) 8.6 Hz, 2H), 7.03 (d, J ) 8.6 Hz, 2H), 7.29 (m,
5H), 7.80 (s, 4H), 13.21 (bs, 1H); 13C NMR (50 MHz, DMSO-
d6) δ 33.0, 53.1, 69.0, 114.5, 123.3, 127.6, 128.3, 129.3, 129.7,
130.7, 134.8, 137.0, 156.9, 167.1, 170.0; MS (m/z) 402 (M +
H)+, 424 (M + Na)+, 440 (M + K)+.
C
13H11NO6 m/z 300.0484 (M + Na)+, found 300.0495. Anal.
Calcd for C13H11NO6: C, 56.32; H, 4.00; N, 5.05. Found: C,
56.30; H, 4.03; N, 5.15.
Typ ica l P r oced u r e for N-P h t h a loyla t ion of Com -
p ou n d s 4. The amine (2.0 mmol) and sodium carbonate (1.06
g, 10 mmol) were dissolved in water (15 mL), and then
acetonitrile (25 mL) was added followed by methyl 2-((succin-
imidooxy)carbonyl)benzoate (3, 0.55 g, 2.0 mmol). The mixture
was vigorously stirred until HPLC or TLC analysis indicated
the absence of 3 (Table 1). The solution was acidified to pH
1-2 with 2 N HCl, diluted with EtOAc (100 mL), and washed
with 1 N HCl (2 × 100 mL) and water (2 × 100 mL). The
organic phase was dried with Na2SO4, filtered, and concen-
trated in vacuo to afford the desired, pure N-phthaloyl
compound 6 in good to excellent yield.
N r-P h t h a loyl-(S )-O-(b e n zylse r in yl)-(S )-isole u cin a -
m id e (6i): white solid (0.56 g, 65%); mp 164-165 °C (lit.9b
mp 164-165 °C); HPLC Rt ) 14.56 min; [R]D -43.9 (c ) 0.9,
1
MeOH); H NMR (200 MHz, DMSO-d6) δ 0.69 (t, J ) 7.3 Hz,
3H), 0.74 (d, J ) 7.0 Hz, 3H), 0.97 (m, 2H), 1.65 (m, 1H), 3.92-
4.15 (m, 3H), 4.36 (d, J ) 12.1 Hz, 1H), 4.48 (d, J ) 12.1 Hz,
1H), 5.00 (dd, J ) 5.9, 9.4 Hz, 1H), 6.98 (s, 1H), 7.14 (m, 5H),
7.38 (s, 1H), 7.83 (m, 4H), 8.16 (d, J ) 8.8 Hz, 1H); 13C NMR
(50 MHz, DMSO-d6) δ 10.7, 15.4, 24.1, 35.8, 51.8, 56.8, 66.4,
71.7, 123.0, 127.3, 127.4, 128.1, 131.7, 134.4, 137.9, 166.2,
167.5, 172.7; MS (m/z) 460 (M + Na)+; EMM m/z calcd for
(S)-Nr-P h th a loylp h en yla la n in e (6a ): white solid (0.59
g, 100%); mp 183-185 °C (lit.2a mp 183-185 °C); HPLC Rt )
13.70 min; [R]D -212 (c ) 1.0, EtOH); 1H NMR (200 MHz,
CDCl3) δ 3.61 (d, J ) 8.7 Hz, 2H), 5.25 (t, J ) 8.7 Hz, 1H),
7.20 (m, 5H), 7.65-7.84 (m, 4H), 9.38 (bs, 1H); 13C NMR (50
MHz, CDCl3) δ 34.5, 53.2, 123.6, 126.9, 128.6, 128.9, 131.5,
134.2, 136.5, 167.5, 174.5; MS (m/z) 296 (M + H)+, 318 (M +
Na)+.
C
24H27N3O5 438.2029 (M + H)+, found 438.2106.
Meth yl Nr-p h th a loyl-(S)-O-(ben zyltyr osin yl)-(S)-va li-
n a te (6j): white solid (0.76 g, 74%); mp 113-115 °C (lit.9b mp
113-115 °C); HPLC Rt ) 17.29 min; [R]D -114.9 (c ) 1.1,
MeOH); 1H NMR (200 MHz, CDCl3) δ 0.88 (d, J ) 6.9 Hz, 3H),
0.97 (d, J ) 6.9 Hz, 3H), 2.20 (m, 1H), 3.53-3.58 (m, 2H), 3.70
(s, 3H), 4.63 (dd, J ) 4.75, 8.62 Hz, 1H), 4.98 (s, 2H), 5.18 (dd,
J ) 6.96, 9.71 Hz, 1H), 6.77 (m, 1H), 6.83 (d, J ) 8.6 Hz, 2H),
(S)-Nr-P h th a loylva lin e (6b): white solid (0.44 g, 89%);
mp 117-118 °C (lit.8 mp 113-116 °C); HPLC Rt ) 12.76 min;
1
7.15 (d, J ) 8.6 Hz, 2H), 7.38 (m, 5H), 7.70-7.85 (m, 4H); 13
C
[R]D -69 (c ) 1.0, EtOH); H NMR (200 MHz, CDCl3) δ 0.88
(d, J ) 6.8 Hz, 3H), 1.13 (d, J ) 6.7 Hz, 3H), 2.45 (m, 1H),
4.58 (d, J ) 8.4 Hz, 1H), 7.70 (m, 2H), 7.83 (m, 2H), 8.08 (bs,
1H); 13C NMR (50 MHz, CDCl3) δ 6.19.6, 21.0, 28.5, 57.7, 123.7,
131.7, 134.3, 167.8, 173.9; MS (m/z) 248 (M + H)+, 270 (M +
Na)+.
NMR (50 MHz, CDCl3) δ 17.7, 18.9, 31.3, 34.3, 52.2, 56.1, 57.4,
70.0, 115.1, 123.6, 127.4, 127.9, 128.5, 128.9, 13.0, 131.5, 134.3,
136.9, 157.8, 168.0, 168.5, 172.1; MS (m/z) 515 (M + H)+, 537
(M + Na)+, 553 (M + K)+; EMM m/z calcd for C30H30N2O6
515.2182 (M + H)+, found 515.2189.
(S)-Nr-P h th a loylisoleu cin e (6c): white solid (0.42 g,
(S)-Nr-P h th a loylp h en yla la n in ol (6k ): white solid (0.56
g, 100%); mp 104-106 °C ((lit.9b mp 104-106 °C); HPLC Rt )
13.63 min; [R]D 134.1 (c ) 1.1, MeOH); 1H NMR (200 MHz,
CDCl3) δ 3.15 (m, 2H), 3.87 (m, 1H), 4.06 (dd, J ) 7.8, 11.6
Hz, 1H), 4.58 (m, 1H), 5.21 (bs, 1H), 7.15 (m, 5H), 7.57-7.71
(m, 4H); 13C NMR (50 MHz, CDCl3) δ 34.8, 55.3, 62.6, 123.3,
126.7, 128.6, 129.0, 131.6, 134.1, 137.5, 169.0; MS (m/z) 282
(M + H)+, 304 (M + Na)+; EMM m/z calcd for C17H15NO3
282.1130 (M + H)+, found 282.1157.
81%); mp 123-125 °C (lit.8 mp 122-124 °C); HPLC Rt ) 13.76
1
min; [R]D -56 (c ) 1, MeOH); H NMR (200 MHz, CDCl3) δ
0.87 (t, J ) 7.2 Hz, 3H), 1.14 (d, J ) 6.7 Hz, 3H), 1.51 (m,
2H), 2.53 (m, 1H), 4.70 (d, J ) 8.4 Hz, 1H), 7.75 (m, 2H), 7.86
(m, 2H), 8.49 (bs, 1H); 13C NMR (50 MHz, CDCl3) δ 10.9, 16.8,
25.9, 34.4, 57.1, 123.6, 131.7, 134.3, 167.9, 174.0; MS (m/z) 262
(M + H)+, 284 (M + Na)+.
Nr-P h th a loyl-r-m eth yla la n in e (6d ): white solid (0.39 g,
83%); mp 150-152 °C (lit.3b mp 152-153 °C); HPLC Rt ) 11.48
min; 1H NMR (200 MHz, DMSO-d6) δ 1.72 (s, 6H), 7.84 (s,
4H), 12.83 (bs, 1H); 13C NMR (50 MHz, CDCl3) δ 24.2, 52.3,
122.9, 128.8, 134.6, 167.9, 173.8; MS (m/z) 234 (M + H)+, 256
(M + Na)+, 272 (M + K)+.
Nr-P h th aloyl-(S)-O-ben zyltyr osin am ide (6l): white solid
(0.58 g, 73%); mp 158 °C (lit.9b mp 158 °C); HPLC Rt ) 15.18
min; [R]D -162.1 (c ) 1.0, MeOH); 1H NMR (200 MHz, CDCl3)
δ 3.45 (d, J ) 8.4 Hz, 2H), 4.92 (s, 2H), 5.04 (t, J ) 8.4 Hz,
1H), 6.08 (s, 1H), 6.30 (s, 1H), 6.76 (d, J ) 8.7 Hz, 2H), 7.05
(d, J ) 8.7 Hz, 2H), 7.32 (m, 5H), 7.62-7.76 (m, 4H); 13C NMR
(50 MHz, CDCl3) δ 34.0, 55.6, 69.9, 115.1, 123.5, 127.5, 127.9,
128.5, 128.9, 129.9, 131.4, 134.3, 136.9, 157.7, 168.0, 171.1;
MS (m/z) 423 (M + Na)+, 439 (M + K)+; EMM m/z calcd for
(S)-Nr-P h th a loyl-O-(2,6-d ich lor oben zyl)tyr osin e (6e):
white solid (0.89 g, 95%); mp 158-160 °C (lit.1a mp 159 °C);
1
HPLC Rt ) 16.84 min; [R]D +6.3 (c ) 1.2, MeOH); H NMR
(200 MHz, CDCl3) δ 3.55 (d, J ) 8.3 Hz, 2H), 5.15 (s, 2H),
5.19 (t, J ) 8.3, 1H), 6.83 (d, J ) 8.6 Hz, 2H), 7.11 (d, J ) 8.6
Hz, 2H), 7.14-7.33 (m, 3H), 7.67 (m, 2H), 7.76 (m, 2H), 8.21
(bs, 1H); 13C NMR (50 MHz, CDCl3) δ 33.7, 53.3, 55.4, 115.4,
123.6, 128.5, 129.9, 130.4, 131.6, 132.2, 134.2, 137.0, 157.8,
167.6, 174.1; MS (m/z) 471 (M + H)+, 493 (M + Na)+.
C
24H20N2O4 401.1501 (M + H)+, found 401.1510.
Nr-P h th a loyl-(S)-O-ben zylser in a m id e (6m ): white hy-
groscopic solid (0.5 g, 77%);9b HPLC Rt ) 13.12 min; [R]D -32.1
(14) Ohki, S.; Nagasaka, T. Chem. Pharm. Bull. 1971, 19, 545.
(15) De Haas, G. H.; Van Deenen, L. L. M. Recl. Trav. Chim. Pays-
Bas 1962, 81, 215.
(S)-Nr-P h th a loyltr yp top h a n (6f): yellow solid (0.67 g,
100%); mp 192-194 °C (lit.14 mp 194-196 °C); HPLC Rt )