4566 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 20
de Dios et al.
135.3, 133.5, 129.6, 128.1, 127.7, 126.8, 126.4, 125.2, 56.2, 40.8,
38.0. Anal. (C16H17NO4) C, H, N.
129.2, 128.2, 128.1, 128.0, 125.6, 56.4, 41.2, 40.6. Anal. (C18H19-
NO4‚2.5H2O) C, H, N.
(2R,4S)-2-Am in o-4-(2-n a p h th yl)m eth yl P en ta n ed ioic
Acid , Hyd r och lor id e (10). Alkylation of ethyl N-BOC-D-
pyroglutamate 4 with 2-naphthylmehthyl bromide (procedure
C) afforded ethyl (2R,4S)-N-BOC-4-(2-naphthyl)methyl D-
pyroglutamate 6 (Ar ) 2-naphthyl, 67%), as previously de-
scribed for the L enantiomer.24 NMR and analytical data
matched that described for the L form.24 Hydrolysis (procedure
F, 75%) afforded 10; mp 144 °C. [R]D) -21.4° (c 1.0, MeOH).
1H NMR (methanol-d4): 7.83-7.77 (m, 3H), 7.69 (s, 1H), 7.49-
7.36 (m, 3H), 3.99 (dd, J ) 8.5, 5.5 Hz, 1H), 3.26-3.19 (m,
1H), 3.09-2.97 (m, 2H), 2.43-2.28 (m, 1H), 2.00-1.86 (m, 1H).
13C NMR (methanol-d4): 177.3, 171.4, 137.8, 134.8, 133.7,
129.2, 128.7, 128.5 128.3, 127.0 126.6, 52.5, 44.4, 39.3, 32.8.
Anal. (C16H18ClNO4‚1/2H2O) C, H, N.
(2R,4S)-2-Am in o-4-(3-tr iflu or om eth yl)ben zyl P en ta n e-
d ioic Acid (19). 50%; mp 153 °C. [R]D ) -15.4° (c 1.0, DMSO).
1H NMR (methanol-d4/KOD): 7.55 (m, 2H), 7.38 (m, 2H), 3.23
(dd, J ) 9.8, 3.8 Hz, 1H), 3.10-2.89 (m, 1H), 2.82-2.59 (m,
2H), 2.05 (m, 1H), 1.48 (m, 1H). 13C NMR (methanol-d4/
KOD): 183.2, 182.7, 142.6, 134.0, 131.0, (q, J ) 32 Hz, 1C),
129.9, 126.7, 125.1 (q, J ) 269 Hz, 1C), 126.6, 56.2, 40.7. Anal.
(C13H14F3NO4) C, H, N.
(2R,4S)-2-Am in o-4-(4-ch lor o)ben zyl P en ta n ed ioic Acid
1
(20). 60%; mp 128-130 °C. [R]D ) -33.4° (c 0.5, 1 N HCl). H
NMR (methanol-d4): 7.36-7.12 (m, 4H), 3.95 (dd, J ) 8.7, 5.8
Hz, 1H), 3.12-2.70 (m, 3H), 2.40-2.12 (m, 1H), 1.98-1.75 (m,
1H). 13C NMR (methanol-d4): 176.9, 171.5, 138.5, 133.6, 131.6,
129.6, 52.0, 44.4, 38.4, 32.9. Anal. (C12H15ClNO4‚2H2O) C,
H, N.
Compounds 11-28 were prepared in an analogous manner
(yields for the last step).
(2R,4S)-2-Am in o-4-(4-n itr o)ben zyl P en ta n ed ioic Acid ,
Hyd r och lor id e (21). 45%; mp 159-161 °C. [R]D ) -32.4° (c
0.6, DMSO). 1H NMR (methanol-d4): 8.17 and 7.48 (AA′BB′
system, 4H), 4.03 (dd, J ) 8.1, 5.9 Hz, 1H), 3.22-3.01 (m, 3H),
2.39-2.27 (m, 1H), 2.00-1.92 (m, 1H). 13C NMR (methanol-
d4): 176.5, 171.3, 148.3, 147.8, 131.3, 124.5, 52.8, 44.1, 38.6,
33.1. Anal. (C12H15ClN2O6) C, H, N.
(2R,4S)-2-Am in o-4-(2-ch lor o)ben zyl P en ta n ed ioic Acid
(11). 67%; mp 153 °C. 1H NMR (methanol-d4/KOD): 7.48-
7.09 (m, 4H), 3.21 (dd, J ) 10.1, 3.1 Hz, 1H), 3.11-2.62 (m,
3H), 2.18-2.01 (m, 1H), 1.55-1.48 (m, 1H). 13C NMR (methanol-
d4/KOD): 177.1, 171.4, 137.0, 135.0, 132.5, 130.5, 129.3, 128.1,
52.5, 42.7, 36.8, 32.8. Anal. (C12H14ClNO4‚1/2H2O) C, H, N.
(2R,4S)-2-Am in o-4-(2-br om o)ben zyl P en ta n ed ioic Acid
(12). 48%. mp 163-164 °C. [R]D ) -9.2 (c 0.2, DMSO). 1H
NMR (methanol-d4/KOD): 7.49 (d, J ) 7.8 Hz, 1H), 7.35 (dd,
J ) 7.8, 1.5 Hz, 1H), 7.20 (t, J ) 7.3 Hz, 1H), 7.05 (m, 1H),
3.21 (dd, J ) 10.1, 2.9 Hz, 1H), 3.05 (m, 1H), 2.82-2.68 (m,
2H), 2.10 (m, 1H), 1.45 (m, 1H). 13C NMR (methanol-d4/
KOD): 183.3, 182.8, 141.3, 133.6, 132.4 128.9, 128.5, 125.7,
56.3, 47.8, 41.0, 40.7. Anal. (C12H14BrNO4) C, H, N.
(2R,4S)-2-Am in o-4-(2-ph en yl)ben zyl P en ta n ed ioic Acid
(13). 78%; mp 144-145 °C. [R]D ) -33.0° (c 0.5, 2 N NaOH).
1H NMR (methanol-d4/KOD): 7.49-6.98 (m, 9H), 3.12-2.85
(m, 2H), 2.70-2.48 (m, 2H), 1.90-1.75 (m, 1H), 1.28-1.05 (m,
1H). 13C NMR (methanol-d4/KOD): 177.5, 175.4, 143.7, 142.5,
136.7 131.2, 130.6 130.3, 129.3, 128.6 128.0 127.6, 43.8, 36.1,
32.7, 20.9. Anal. (C18H19NO4‚1/2H2O) C, H, N.
(2R,4S)-2-Am in o-4-(4-tr iflu or om eth yl)ben zyl P en ta n e-
d ioic Acid (22). 90%; mp 109 °C. [R]D ) -13.2° (c 1.0, MeOH).
1H NMR (methanol-d4): 7.58 and 7.43 (AA′BB′ system, 4H),
3.97 (s, 1H), 3.21-3.01 (m, 3H), 2.40-2.31 (m, 1H), 1.94-1.80
(m, 1H). 13C NMR (methanol-d4): 176.9, 171.8, 144.4, 130.9,
129.9 (q, J ) 32.0 Hz, 1C), 126.3 (q, J ) 3.8 Hz, 2C), 125.7 (q,
J ) 270.2 Hz, 1C), 52.8, 44.3, 38.8, 32.2. Anal. (C13H14F3NO4‚
1/2H2O) C, H, N.
(2R,4S)-2-Am in o-4-(4-m et h oxy)b en zyl P en t a n ed ioic
Acid (23). 75%; mp 166-167 °C. [R]D ) -4.9° (c 0.39, DMSO).
1H NMR (D2O/KOD): 7.11 (d, J ) 8.5 Hz, 2H), 6.83 (d, J )
8.5 Hz, 2H), 3.71 (s, 3H), 3.10 (dd, J ) 9.5, 4.3 Hz, 1H), 2.71-
2.54 (m, 2H), 2.53-2.45 (m, 1H), 1.89-1.79 (m, 1H), 1.48-
1.39 (m, 1H). 13C NMR (D2O/KOD): 182.7, 181.8, 156.1, 132.2,
129.1, 129.1, 112.9, 112.9, 54.4, 53.7, 47.4, 37.4, 37.1. Anal.
(C13H17NO5) C, H, N.
(2R,4S)-2-Am in o-4-(3-ch lor o)ben zyl P en ta n ed ioic Acid
1
(14). 55%; [R]D ) -3.2° (c 0.31, DMSO). H NMR (methanol-
d4/KOD): 7.30-7.01 (m, 4H), 3.19 (dd, J ) 9.7, 3.3 Hz, 1H),
3.00-2.85 (m, 1H), 2.71-2.50 (m, 2H), 2.05 (m, 1H), 1.45 (m,
1H). 13C NMR (methanol-d4/KOD): 177.0, 171.0, 141.8, 135.1,
130.9, 130.0, 128.4, 127.6, 51.6, 51.8, 44.3, 38.5, 32.9. Anal.
(C12H14ClNO4‚1/2H2O) C, H, N.
(2R,4S)-2-Am in o-4-(4-ph en yl)ben zyl P en ta n ed ioic Acid
(24). 55%; mp 162-163 °C. 1H NMR (methanol-d4/KOD):
7.58-7.12 (m, 9H), 3.29-3.12 (m, 1H), 3.11-2.88 (m, 1H),
2.79-2.55 (m, 2H), 2.05 (m, 1H), 1.47 (m, 1H). 13C NMR
(methanol-d4/KOD): 184.0, 183.3, 142.2, 143.3, 139.9, 132.1,
130.7, 129.8, 128.1, 127.7, 56.4, 40.7, 40.5. Anal. (C18H19NO4)
C, H, N.
(2R,4S)-2-Am in o-4-(3-br om o)ben zyl P en ta n ed ioic Acid
1
(15). 95%; mp 174-175 °C. [R]D ) -41.4° (c 0.5, 1 N HCl). H
NMR (D2O/KOD): δ 7.41 (s, 1H), 7.30-7.13 (m, 3H), 3.23-
3.18 (m, 1H), 2.95-2.87 (m, 1H), 2.66-2.61 (m, 2H), 2.01-
1.96 (m, 1H), 1.51-1.46 (m, 1H). 13C NMR (D2O/KOD/methanol-
d4): 183.4, 182.9, 144.9, 133.0, 131.0 129.9, 129.1, 123.1, 56.2,
49.5, 40.6. Anal. (C12H14BrNO4) C, H, N.
(2R,4S)-2-Am in o-4-(3-m et h oxy)b en zyl P en t a n ed ioic
Acid (16). 78%; mp 148 °C. [R]D ) -37.2° (c 0.5, 1 N HCl). 1H
NMR (methanol-d4/D2O): 7.29 (t, J ) 8.9 Hz, 1H), 7.11-6.91
(m, 3H), 3.81 (s, 3H), 3.73 (dd, J ) 8.4, 5.4 Hz, 1H), 3.29-2.31
(m, 3H), 2.31-2.24 (m, 1H), 2.21-1.94 (m, 1H). 13C NMR
(methanol-d4/D2O): 187.6, 187.0, 162.8, 146.7, 133.8, 126.0,
118.6, 116.0, 59.7, 58.9, 52.2, 43.1, 42.8. Anal. (C13H17NO5‚1/
2H2O) C, H, N.
(2R,4S)-2-Am in o-4-(3-n itr o)ben zyl P en ta n ed ioic Acid
(17). 50%; mp 169 °C. [R]D ) -10.3° (c 0.35, DMSO). 1H NMR
(methanol-d4/KOD): 8.12 (s, 1H), 8.02 (d, J ) 8.1 Hz, 1H), 7.68
(d, J ) 7.6 Hz, 1H), 7.49 (t, J ) 7.9 Hz, 1H), 3.22 (m, 1H),
3.01 (m, 1H), 2.90-2.59 (m, 2H), 2.09 (m, 1H), 1.51 (m, 1H).
13C NMR (methanol-d4/KOD): 183.0, 182.9, 149.4, 144.7, 137.0,
130.4, 124.8, 122.0, 56.3, 49.4, 40.7, 40.6. Anal. (C12H14N2O6)
C, H, N.
(2R,4S)-2-Am in o-4-(3-p h en yl)ben zyl P en ta n ed ioic Acid
(18). 85%; mp 149-151 °C. [R]D ) -7.7° (c 0.4, DMSO). 1H
NMR (methanol-d4/KOD): 7.61-7.12 (m, 9H), 3.29-2.90 (m,
2H), 2.79-2.55 (m, 2H), 2.05 (m, 1H), 1.50 (m, 1H). 13C NMR
(methanol-d4/KOD): 184.0, 183.2, 142.7, 142.5, 142.2, 129.8,
(2R,4S)-2-Am in o-4-(4-ter t-bu tyl)ben zyl P en ta n ed ioic
Acid (25). 57%; mp 150-152 °C. 1H NMR (methanol-d4/
KOD): 7.21 and 7.16 (AA′BB′, 4H), 3.21 (dd, J ) 9.8, 2.8 Hz,
1H), 2.90-2.87 (m, 1H), 2.62-2.54 (m, 2H), 2.08-2.02 (m, 1H),
1.53-1.40 (m, 1H), 1.24 (s, 9H). 13C NMR (methanol-d4/
KOD): 184.1, 182.9, 149.5, 139.1, 129.8, 126.0, 56.3, 49.2, 40.5,
35.1, 31.9, 31.8. Anal. (C16H23NO4‚2H2O) C, H, N.
(2R,4S)-2-Am in o-4-(3,5-d ich lor o)ben zyl P en ta n ed ioic
1
Acid (26). 80%; mp 144 °C. [R]D ) -27.4° (c 0.84, DMSO). H
NMR (methanol-d4/KOD): 7.30-7.10 (m, 3H), 3.24 (m, 1H),
2.98-2.50 (m, 3H), 2.04 (m, 1H), 1.52 (m, 1H). 13C NMR
(methanol-d4/KOD): 182.8, 146.6, 135.6, 128.9, 126.8, 56.2,
40.8, 40.2. Anal. (C12H13Cl2NO4‚H2O) C, H, N.
(2R,4S)-2-Am in o-4-(3,5-d itr iflu or om eth yl)ben zyl P en -
ta n ed ioic Acid (27). 65%; mp 152-153 °C. [R]D ) -11.9° (c
0.63, DMSO). 1H NMR (methanol-d4/KOD): 7.82 (s, 2H), 7.58
(s, 1H), 3.21 (dd, J ) 8.5, 5.3 Hz, 1H), 3.20-2.95 (m, 1H), 2.94-
2.52 (m, 2H), 2.05 (m, 1H), 1.50 (m, 1H). 13C NMR (methanol-
d4/KOD): 183.0, 182.7, 145.7, 132.4 (q, J ) 32.7 Hz), 130.7,
124.9 (q, J ) 270 Hz), 120.5, 56.2, 49.2, 40.8, 40.4. Anal.
(C14H13F6NO4‚1/2H2O) C, H, N.
(2R,4S)-2-Am in o-4-(3,4,5-tr im eth oxy)ben zyl P en tan edio-
ic Acid (28). 25%; mp 188-189 °C. [R]D ) -4.3° (c 0.4, DMSO).
1H NMR (D2O/KOD): 6.50 (brs, 2H), 3.71 (brs, 6H), 3.61 (s,
3H), 3.05 (m, 1H), 2.59 (m, 2H), 2.49 (m, 1H), 1.80 (m, 1H),