5398 J . Org. Chem., Vol. 62, No. 16, 1997
Taylor et al.
13C NMR (68 MHz, CDCl3) δ 13.9, 14.0, 24.9, 30.8, 46.7, 53.5,
60.8, 61.6, 109.9, 120.3, 123.6, 132.3, 132.6, 157.1, 170.0, 170.3,
172.4. Anal. Calcd for C17H21NO5: C, 60.89; H, 6.31; N, 4.18.
Found: C, 60.66; H, 6.41; N, 4.14.
123.8, 128.2, 128.3, 129.5, 142.1, 146.6, 148.5, 158.4, 160.5,
169.0, 170.6, 172.2, 180.4. Anal. Calcd for C31H41N5O7‚
1.25H2O: C, 60.23; H, 7.09; N, 11.33. Found: C, 60.04; H,
6.70; N, 11.27.
Dieth yl 2-[2,3-Dih yd r o-5-[(tr iflu or om eth a n esu lfon yl)-
oxy]-1-oxo-2(1H)-isoin d olyl]-L-glu ta r a te (26). To a solu-
tion of diethyl 2-(2,3-dihydro-5-hydroxy-1-oxo-2(1H)-isoindolyl)-
L-glutarate (24) (170 mg, 0.507 mmol) in 4 mL of CH2Cl2 were
added 0.08 mL (0.608 mmol, 1.2 equiv) of collidine and 0.1
mL (0.608 mmol, 1.2 equiv) of triflic anhydride at -78 °C. The
reaction mixture was stirred for 30 min, quenched with 5 mL
of water, and diluted with 30 mL of CH2Cl2. The two layers
were separated, the aqueous layer was back-extracted with
15 mL of CH2Cl2, and the combined extracts were washed with
10 mL of brine, dried over MgSO4, and evaporated under
reduced pressure. The crude product was purified by silica
gel chromatogaphy (eluting with 7:3 hexane/EtOAc) to give
201 mg (85%) of 26 as an oil: IR (neat) 2973, 1735, 1670, 1215
cm-1; 1H NMR (270 MHz, CDCl3) δ 1.19 (t, 3 H), 1.28 (t, 3 H),
2.05-2.50 (m, 4 H), 3.95-4.10 (m, 2 H), 4.21 (q, 2 H), 4.45 (d,
J ) 17.1 Hz, 1 H), 4.73 (d, J ) 17.1 Hz, 1 H), 5.06-5.12 (m, 1
H), 7.37-7.42 (m, 2 H), 7.95 (d, J ) 8.2 Hz, 1 H); 13C NMR (68
MHz, CDCl3) δ 13.9, 14.0, 25.0, 30.8, 46.6, 53.4, 60.6, 61.6,
116.5, 118.5, 121.5, 125.8, 131.6, 143.7, 151.6, 167.1, 170.2,
172.0. Anal. Calcd for C18H20F3NO8S: C, 46.25; H, 4.31; N,
3.10. Found: C, 46.52; H, 4.43; N, 3.05.
2-[2,3-Dih yd r o-5-[2-(2-a m in o-4(3H)-oxo-5,6,7,8-tetr a h y-
d r op yr id o[2,3-d ]p yr im id in -6-yl)eth yl]-1-oxo-2(1H)-isoin -
d olyl]-L-glu t a r ic Acid (6). A suspension of compound 19
(2.97 g, 5 mmol) in 60 mL of 0.5 N NaOH was stirred at rt for
3 days and filtered, and 2 N HCl was added dropwise to ∼pH
5-6. The resulting precipitate was collected by filtration,
washed three times with cold water, and dried in a desiccator
to give 6 (2.1 g, 92%) as a white solid: mp 195 °C dec; 1H NMR
(300 MHz, DMSO-d6) δ 1.50-1.70 (m, 4 H), 1.78-1.90 (m, 1
H), 1.95-2.08 (m, 1 H), 2.12-2.30 (m, 3 H), 2.70-2.85 (m, 3
H), 3.18 (d, J ) 6.5 Hz, 1 H), 4.44 (s, 2 H), 4.75-4.76 (m, 1 H),
5.94 (s, 2 H), 6.27 (s, 1 H), 7.34 (d, J ) 7.5 Hz, 1 H), 7.44 (s, 1
H), 7.60 (d, J ) 7.5 Hz, 1 H), 9.75 (br s, 1 H); FABMS calcd
for C22H25N5O6 455, found 456 (100) (M + 1). Anal. Calcd for
C22H25N5O6‚0.5HCl: C, 55.78; H, 5.43; N, 14.78. Found: C,
55.53; H, 5.10; N, 14.41.
Dieth yl 2-(2,3-Dih yd r o-6-iod o-1(2H)-oxoisoin d olyl)-L-
glu ta r a te (28). This compound was prepared from methyl
5-iodo-2-methylbenzoate10 (27) in 43% yield as a yellow oil
following the procedure described above for the preparation
of 16: IR (film) cm-1 3400 (br), 3280 (br), 2990 (m), 1974 (vst),
1694 (vst), 1453 (s), 1417 (s), 1311 (m), 1289 (s), 1203 (s); MS
(EI) m/z (rel intensity) 445 (84), 400 (83), 372 (90), 326 (86),
Dieth yl 2-[2,3-Dih yd r o-5-[2-[2-(p iva loyla m in o)-4(3H)-
oxopyr ido[2,3-d]pyr im idin -6-yl]eth yn yl]-1-oxo-2(1H)-isoin -
d olyl]-L-glu ta r a te (18). Meth od A. To a flask containing
0.21 g (0.93 mmol) of Pd(OAc)2, 0.57 g (1.86 mmol) of tri-o-
tolylphosphine, 6.67 g (15 mmol) of 16, 230 mL of MeCN, 8.5
g (84 mmol) of Et3N were added 88 mg (0.46 mmol) of CuI
and 3.78 g (14 mmol) of 2-pivaloyl-6-ethynyl-5-deazapterin
(17). The solution was refluxed for 5.5 h, cooled to rt, filtered,
and concentrated. The crude product was chromatographed
using 2.5% MeOH/CH2Cl2 to give 4.50 g (55%) of 18 as a pale
1
298 (100); H NMR (CDCl3, 250 MHz) δ 1.19 (t, 3 H), 1.26 (t,
3 H), 2.10-2.55 (m, 4 H), 3.97-4.15 (m, 2 H), 4.18 (q, 2 H),
4.37 (d, J ) 18 Hz, 1 H), 4.56 (d, J ) 18 Hz, 1 H), 5.10 (m, 1
H), 7.27 (d, J ) 2.5 Hz, 1 H), 7.86 (d, J ) 2.5 Hz, 1 H), 8.21 (s,
1 H); 13C NMR (CDCl3, 75 MHz) δ 13.99, 14.03, 24.95, 30.83,
46.70, 53.32, 60.59, 61.53, 95.91, 124.65, 132.96, 133.80,
140.32, 140.90, 167.38, 170.29, 172.12; HRMS (EI) m/z calcd
for C17H20INO5 445.0388, found 445.0378. Anal. Calcd for
C17H20INO5: C, 45.86; H, 4.53; N, 3.15. Found: C, 45.57; H,
4.44; N, 2.85.
1
yellow solid: mp 207-208 °C; H NMR (300 MHz, CDCl3) δ
1.19 (t, 3 H), 1.26 (t, 3 H), 2.12-2.60 (m, 4 H), 3.95-4.12 (m,
2 H), 4.22 (q, 2 H), 4.38 (d, J ) 17.5 Hz, 1 H), 4.64 (d, J ) 17.5
Hz, 1 H), 5.02-5.18 (m, 1 H), 7.63-7.66 (m, 2 H), 7.86 (d, J )
7.5 Hz, 1 H), 8.40 (br s, 1 H), 8.63 (d, 1 H), 9.01 (s, 1 H), 12.10
(br s, 1 H); 13C NMR (75 MHz, CDCl3) δ 14.0, 14.1, 25.0, 26.8,
30.9, 40.4, 46.7, 53.4, 60.6, 61.6, 87.3, 92.6, 114.8, 116.9, 124.0,
125.7, 126.0, 131.5, 131.9, 138.5, 141.8, 149.5, 158.2, 161.0,
168.2, 170.5, 172.3, 180.7. Anal. Calcd for C31H33N5O7: C,
63.36; H, 5.66; N, 11.92. Found: C, 63.12; H, 5.66; N, 11.88.
Meth od B. To a solution of 200 mg (0.428 mmol) of 26 in
4 mL of DMF were added 25 mg (0.0214 mmol, 0.05 equiv) of
Pd(PPh3)4, 0.3 mL (2.14 mmol, 5.0 equiv) of triethylamine, and
150 mg (0.556 mmol, 1.3 equiv) of 2-pivaloyl-6-ethynyl-5-
deazapterin (17). The mixture was heated to 80 °C and stirred
for 3 h, and the solvent was then removed under reduced
pressure. Workup as described above gave 174 mg (69%) of
18, mp 206-208 °C, identical with the sample of 18 prepared
as described above by method A.
2-[2,3-Dih yd r o-6-[2-(2-a m in o-4(3H)-oxo-5,6,7,8-tetr a h y-
d r op yr id o[2,3-d ]p yr im id in -6-yl)et h yl]-1(2H )-oxoisoin -
d olyl]-L-glu ta r ic Acid (7). Compound 28 was coupled with
17, following the procedure given above for the preparation of
18, to give d ieth yl 2-[2,3-d ih yd r o-6-[2-(p iva loyla m in o)-
4(3H )-oxop yr id o[2,3-d ]p yr im id in -6-yl)e t h yn yl]-1-oxo-
2(1H)-isoin d olyl]-L-glu ta r a te. This compound was obtained
in 45% yield as a pale brown foam: mp 208-210 °C; IR (KBr)
cm-1 3200 (br), 2900 (m), 1735 (vst), 1680 (vst), 1624 (vst),
1597 (vst), 1466 (s), 1447 (s), 1375 (s), 1244 (s), 1200 (s), 1148
(s), 732 (s); MS (EI) m/z (rel intensity) 587 (20), 530 (13), 440
1
(21), 382 (12), 170 (33), 77 (100); H NMR (CDCl3, 300 MHz)
δ 1.20 (t, 3 H), 1.28 (t, 3 H), 1.35 (s, 9 H), 2.10-2.60 (m, 4 H),
3.90-4.15 (m, 2 H), 4.21 (q, 2 H), 4.47 (d, J ) 18 Hz, 1 H),
4.67 (d, J ) 18 Hz, 1 H), 5.05-5.15 (m, 1 H), 7.50 (d, J ) 9
Hz, 1 H), 7.73 (d, J ) 9 Hz, 1 H), 8.04 (s, 1 H), 8.42 (s, 1 H),
8.62 (s, 1 H), 8.99 (s, 1 H), 12.13 (s, 1 H); 13C NMR (75 MHz,
CDCl3) δ 13.8, 13.8, 24.7, 24.5, 30.6, 40.2, 46.8, 53.2, 60.3, 61.3,
85.7, 92.0, 114.5, 116.5, 122.1, 122.9, 126.7, 132.0, 134.6, 138.0,
141.8, 149.5, 157.8, 160.3, 167.8, 170.2, 172.1, 180.9; HRMS
(EI) calcd for C31H33N5O7 587.2380, found 587.2408. Anal.
Calcd for C31H33N5O7: C, 63.36; H, 5.66; N, 11.92. Found: C,
63.59; H, 5.91; N, 11.70. Catalytic reduction of this ethynyl
intermediate under the conditions described previously for the
preparation of 19 from 18 gave d ieth yl 2-[2,3-d ih yd r o-6-[2-
[2-(p iva loyla m in o)-4(3H )-oxo-5,6,7,8-t et r a h yd r op yr id o-
[2,3-d ]p yr im id in -6-yl]et h yl]-1-oxo-2(1H )-isoin d olyl]-L-
glu ta r a te in 75% yield as a colorless foam: mp 176-177 °C;
IR (film) cm-1 3400 (br), 3280 (br), 2930 (s), 2900 (s), 1797
(vst), 1685 (vst), 1647 (vst), 1572 (vst), 1478 (s); 1H NMR (250
MHz, CDCl3) δ 1.15-1.30 (overlapping triplets, 6 H), 1.29 (s,
9 H), 1.60-1.90 (m, 3 H), 2.10-2.55 (m, 5 H), 2.70-3.10 (m, 4
H), 3.40-3.55 (d, 1 H), 4.01-4.10 (m, 2 H), 4.16 (q, 2 H), 4.36
(d, J ) 17.5 Hz, 1 H), 4.54 (d, J ) 17.5 Hz, 1 H), 4.76 (br s, 1
H), 5.10 (m, 1 H), 7.38 (s, 2 H), 7.68 (s, 1 H), 8.00 (br s, 1 H),
11.25 (br s); 13C NMR (75 MHz, CDCl3) δ 14.0, 14.1, 25.0, 25.2,
26.9, 30.3, 30.9, 32.9, 34.9, 40.1, 46.0, 46.6, 53.2, 60.6, 61.5,
122.8, 123.2, 131.9, 132.2, 139.3, 142.3, 148.1, 158.0, 160.5,
169.2, 170.6, 172.3, 179.7; MS (EI) m/z (rel intensity) 595 (100),
550 (20), 495 (40), 250 (53). Anal. Calcd for C31H41N5O7: C,
Dieth yl 2-[2,3-Dih yd r o-5-[2-[2-(p iva loyla m in o)-4(3H)-
oxo-5,6,7,8-tetr a h yd r op yr id o[2,3-d ]p yr im id in -6-yl]eth yl]-
1-oxo-2(1H)-isoin d olyl]-L-glu ta r a te (19). A solution of 18
(4.4 g, 7.5 mmol) in 250 mL of MeOH was hydrogenated in
the presence of 400 mg of 10% Pd-C under H2 (50 psi) for 20
h. The solution was filtered, the filtrate was evaporated under
reduced pressure, and the residual solid was purified by
chromatography using 3% MeOH/CH2Cl2 to give an intermedi-
ate (3.5 g, 79%) in which (by NMR) the acetylenic bond had
been reduced, but the pyridine ring was still aromatic.
Further reduction of 3.4 g (5.75 mmol) of this intermediate in
the presence of 350 mg of Pd-C (10%) in 80 mL of MeOH
under H2 (50 psi) for 2 days, followed by filtration and
evaporation of the filtrate, gave 19 (3.2 g, 92%) as a colorless
1
foam: mp 166-167 °C; H NMR (300 MHz, CDCl3) δ 1.18 (t,
3 H), 1.23-1.29 (m, 3 H), 1.29 (s, 9 H), 1.60-1.90 (m, 3 H)
2.08-2.50 (m, 5 H), 2.70-3.08 (m, 4 H), 3.30-4.45 (m, 1 H),
3.95-4.07 (m, 2 H), 4.16-4.24 (q, 2 H), 4.33 (d, J ) 21 Hz, 1
H), 4.57 (d, J ) 21 Hz, 1H), 4.73 (br s, 1 H), 5.10 (m, 1 H),
7.27 (m, 2 H), 7.75 (d, J ) 9 Hz, 1 H), 7.90 (br s, 1 H), 11.25
(br s, 1 H); 13C NMR (75 MHz, CDCl3) δ 14.0, 14.0, 24.9, 25.0,
26.7, 30.4, 30.8, 33.4, 40.1, 46.6, 46.7, 53.2, 60.5, 61.4, 122.6,