Synthesis of L-4,4-Difluoroglutamic Acid
J . Org. Chem., Vol. 66, No. 19, 2001 6387
1
(t), 65.60 (s), 119.15 (t, J CF ) 257.0 Hz), 125.42 (d), 126.01
(MH+, 100), 463 (M+, 40), 254 (22), 241 (21); exact mass calcd
for MH+ C27H24F2NO4 requires 464.1673, found 464.1670 (CI).
Further elution gave the unreacted pentafluorophenyl de-
rivative 14: 116 mg.
(d), 126.08 (d), 127.28 (d), 127.59 (d), 128.15 (d), 128.79 (d),
129.09 (d), 130.39 (d), 130.58 (d), 133.37 (s), 136.42 (s), 138.21
(s), 139.85 (s), 141.43 (s), 158.29 (s), 162.10 (t, 2J CF ) 26.0 Hz);
19F NMR (CDCl3, 282 MHz) -89.86 (1 F, dd, J FF ) 281.4 Hz,
1-[N-Ben zyloxyca r bon yl-(1S,2R)-1-a m in o-3,3-d iflu or o-
3-e t h o x y c a r b o n y l-4-h y d r o x y p r o p y l]-4-m e t h y l-2,6,7-
tr ioxa bicyclo[2.2.2]octa n e (21a ) a n d 1-[N-Ben zyloxyca r -
bon yl-(1S,2S)-1-a m in o-3,3-d iflu or o-3-eth oxyca r bon yl-4-
h y d r o x y p r o p y l]-4-m e t h y l-2,6,7-t r io x a b ic y c lo [2.2.2]-
octa n e (21b). Ethyl bromodifluoroacetate (8 mL, 62.4 mmol)
was slowly added to a well-stirred mixture of acid-washed zinc
dust (6.08 g, 93.6 mmol) and aldehyde 3 (5 g, 15.6 mmol)
dissolved in dry THF (150 mL) at rt, under an argon atmo-
sphere. The reaction mixture was stirred for 2 h, after which
time TLC analysis showed complete consumption of aldehyde.
After the addition of 3% aqueous NH4Cl (80 mL) and brine
(80 mL), the mixture was filtered to remove solid materials.
The solution was then extracted with EtOAc (3 × 150 mL)
and washed with brine (150 mL), and the combined organic
extracts were dried (MgSO4). After removal of the solvent
under reduced pressure and column chromatography (eluant:
2:3 EtOAc/hexane containing 1% Et3N), the desired adduct was
obtained as a 7:1 mixture of diastereoisomers 21a :21b, based
on 19F NMR, as a white foam: 4.85 g, 70%; 13C NMR (CDCl3,
75.4 MHz) δ 14.10 (q), 14.41 (q), 30.95 (s), 52.11 (t), 63.39 (d),
2
3J HF ) 12.7 Hz), -93.43 (1 F, dd, 2J FF ) 281.4 Hz, 3J HF ) 21.4
Hz); MS (CI, CH4) 463 (MH+, 100), 462 (M+, 18), 443 (72), 241
(10); exact mass calcd for MH+ C27H25F2N2O3 requires 463.1833,
found 463.1828 (CI).
Eth yl (4S,3′S)-2-Oxo-3-(9-p h en ylflu or en -9-yl)oxa zoli-
d in e -4-(2′,2′-d iflu o r o -3′-o x y t h io c a r b o n y lp e n t a flu o -
r op h en yl)p r op a n oa te (14a ) a n d Eth yl (4S,3′R)-2-Oxo-3-
(9-p h e n ylflu or e n -9-yl)oxa zolid in e -4-(2′,2′-d iflu or o-3′-
oxyt h ioca r b on ylp en t a flu or op h en yl)p r op a n oa t e (14b ).
The mixture of diastereoisomeric fluorinated alcohols 9 (1.66
g, 3.5 mmol) was dissolved in toluene (50 mL), together with
DMAP (885 mg, 7 mmol) and N-hydroxysuccinimide (403 mg,
3.5 mmol). After the addition of pentafluorophenylchlorothio-
formate (408 mg, 1.5 mmol), the reaction mixture was heated
to 90 °C and stirred overnight. The solution was then filtered
through Celite and dried (MgSO4). After removal of the solvent
under reduced pressure, the crude product was purified using
flash chromatography (eluant: 1:6 EtOAc/hexane) to yield the
desired pentafluorophenyl ester as a mixture of diastereoiso-
mers 14a and 14b: 1.47 g, 60%; 13C NMR (CDCl3, 75.4 MHz)
δ 13.60 (q), 55.09 (d), 63.07 (t), 64.07 (t), 72.21 (s), 79.76 (ddd,
2
67.17 (t), 68.84 (ddd, J CF ) 31.0, 22.9 Hz), 73.08 (t), 108.74
1
2J CF ) 21.7, 30.2 Hz), 111.09 (dd, J CF ) 258.4, 261.7 Hz),
120.39 (d), 120.69 (d), 124.78 (d), 126.42 (d), 127.51 (d), 127.73
(d, J CF ) 225.6 Hz), 128.21 (d), 128.41 (d), 128.57 (d), 129.56
(d), 129.70 (d), 129.74 (d), 137.96 (m), 139.61 (s), 139.87 (s),
140.18 (m), 141.02 (s), 144.32 (s), 146.94 (s), 149.40 (s), 157.12
1
(s), 113.97 (dd, J CF ) 261.9, 250.9 Hz), 128.25 (d), 128.67 (d),
2
136.67 (s), 156.30 (s), 163.47 (dd, J CF ) 32.7, 29.7 Hz); MS
1
(FAB) 446 (MH+, 58), 138 (64), 137 (100), 136 (85); exact mass
calcd for MH+ C20H26F2NO8 requires 446.1626, found 446.1614
(FAB).
2
21a : 1H NMR (CDCl3, 300 MHz) δ 0.80 (3 H, s), 1.32 (3 H,
t, J ) 7.1 Hz), 3.24 (1 H, br. s), 3.92 (6 H, s), 4.26-4.35 (3 H,
m), 4.66 (1 H, dd, 3J HF ) 18.3, J ) 5.4 Hz), 5.13 (2 H, m), 5.43
(1 H, d, J ) 10.3 Hz), 7.32 (5 H, m); 19F NMR (CDCl3, 282
(s), 160.84 (t, J CF ) 29.7 Hz), 189.58 (s).
14a : 1H NMR (CDCl3, 300 MHz) δ 1.25 (3 H, t, J ) 7.2 Hz),
3
4.10 (2 H, m), 4.58 (3 H, m), 5.03 (1 H, dd, J HF ) 15.9 Hz, J
) 8.4 Hz), 7.20-7.48 (10 H, m), 7.71 (2 H, m), 8.07 (1 H, m);
2
3
MHz) -112.69 (1 F, dd, J FF ) 264.6 Hz, J HF ) 6.4 Hz),
19F NMR (CDCl3, 282 MHz) δ -111.76 (1 F, dd, J FF ) 264.7
2
2
3
-125.35 (1 F, dd, J FF ) 264.6 Hz, J HF ) 19.2 Hz).
21b: 19F NMR (CDCl3, 282 MHz) -112.33 (1 F, d, J FF
3
2
3
Hz, J HF ) 8.5 Hz), -116.83 (1 F, dd, J FF ) 264.7 Hz, J HF
)
2
)
16.9 Hz), -151.93 (2 F, d, J ) 19.2 Hz), -156.38 (1 F, t, J )
262.5 Hz), -124.68 (1 F, dd, 2J FF ) 264.6 Hz, 3J HF ) 17.1 Hz).
1-[N-Ben zyloxyca r bon yl-(1S,2R)-1-a m in o-3,3-d iflu or o-
3-eth oxyca r bon yl-4-oxyth ioca r bon ylim id a zolep r op yl]-4-
m eth yl-2,6,7-tr ioxa bicyclo[2.2.2]octa n e (22a ) a n d 1-[N-
B e n zy lo x y c a r b o n y l-(1S ,2S )-1-a m in o -3,3-d iflu o r o -3-
et h oxyca r b on yl-4-oxyt h ioca r b on ylim id a zolep r op yl]-4-
m eth yl-2,6,7-tr ioxabicyclo[2.2.2]octan e (22b). Thiocarbonyl-
diimidazole (349 mg, 1.76 mmol) and the diastereoisomeric
mixture of adducts 21a and 21b (491 mg, 1.1 mmol) were
dissolved in dry THF (15 mL) and stirred at rt, under an argon
atmosphere, for 10 h. The resulting reaction mixture was then
washed with 5% aqueous NH4Cl (15 mL), aqueous NaHCO3
(15 mL), and brine (15 mL). After drying (MgSO4), the solvent
was removed to yield an oily residue that was purified by
column chromatography (eluant: 1:3 EtOAc/hexane containing
1% Et3N). The mixture of thioester derivatives 22a and 22b
was obtained as a white foam: 465 mg, 76%; 13C NMR (CDCl3,
75.4 MHz) δ 13.63 (q), 14.00 (q), 30.72 (s), 52.11 (t), 63.60 (d),
67.34 (t), 72.82 (t), 75.51 (dt, 2J CF ) 27.2 Hz), 107.12 (s), 111.75
3
21.5 Hz), -161.9 (2 F, dt, J FF ) 21.5, 19.2 Hz); MS (CI, CH4)
705 (M+, 7), 704 (16), 241 (100).
14b: 1H NMR (CDCl3, 300 MHz) δ 1.25 (3 H, t, J ) 7.2
Hz), 4.10 (2 H, m), 4.58 (4 H, m), 7.20-7.48 (10 H, m), 7.71 (2
H, m), 8.07 (1 H, m); 19F NMR (CDCl3, 282 MHz) δ -113.29 (1
2
3
2
F, dd, J FF ) 266.7 Hz, J HF ) 8.5 Hz), -118.72 (1 F, dd, J FF
3
) 266.7 Hz, J HF ) 15.0 Hz), -152.57 (2 F, d, J ) 16.9 Hz),
3
-156.75 (1 F, t, J ) 21.5 Hz), -161.87 (2 F, dt, J FF ) 21.5,
16.9 Hz).
Eth yl (4S)-2-Oxo-3-(9-p h en ylflu or en -9-yl)oxa zolid in e-
4-(2′,2′-d iflu or o)p r op a n oa te (15). A solution of the difluori-
nated derivative 14 (490 mg, 0.695 mmol) dissolved in toluene
(15 mL) was degassed for 15 min before being heated to reflux
under an Ar atmosphere. A mixture of Bu 3SnH (0.56 mL, 2.09
mmol) and AIBN (30 mg, 0.15 mmol) dissolved in toluene (1
mL) was then added dropwise to the hot solution. After being
heated for an additional 10 min, the reaction mixture was
cooled to rt and quenched by the addition of H2O (0.1 mL).
The solvent was removed under reduced pressure, and the
residue was purified using flash chromatography (eluant: 5:2
hexane/EtOAc) to yield the deoyxygenated ester 15 as a white
foam. A portion was recrystallized (EtOAc/hexane) to give 15
as white crystals: 119 mg, 37% (49% based on recovered 14);
mp 182.0-183.5 °C; [R]20D ) -41.8° (c ) 1.02, CHCl3); 1H NMR
(CDCl3, 300 MHz) δ 0.84 (3 H, t, J ) 7 Hz), 3.57 (2 H, ddd,
3J HF ) 24.3, 12.9 Hz, J ) 8.4 Hz), 3.87 (2 H, m), 4.69 (3 H, m),
6.54 (2 H, m), 6.71 (1 H, s), 6.87-7.01 (5 H, m), 7.13 (1 H, m),
7.33 (1 H, m), 7.54 (2 H, m), 7.73 (1 H, m); 13C NMR (CDCl3,
1
(t, J CF ) 258.9 Hz), 118.17 (d), 128.19 (d), 128.45 (d), 130.96
2
(d), 135.92 (s), 137.19 (d), 155.80 (s), 161.54 (dd, J CF ) 31.2,
30.7 Hz), 182.63 (s); MS (FAB) 556 (MH+, 33), 154 (70), 91
(100); exact mass calcd for MH+ C24H28F2N3O8S requires
556.1565, found 556.1560 (FAB).
22a : 1H NMR (CDCl3, 300 MHz) δ 0.76 (3 H, s), 1.27 (3 H,
t, J ) 7.1 Hz), 3.77-3.86 (6 H, m), 4.24 (2 H, m), 4.62 (1 H,
dd, J ) 10.8, 1.0 Hz), 5.13-5.19 (3 H, m), 6.74 (1 H, m), 7.04
(1 H, m), 7.36 (5 H, m), 7.62 (1 H, m), 8.34 (1 H, m); 19F NMR
2
3
(CDCl3, 282 MHz) -113.87 (1 F, dd, J FF ) 269.0 Hz, J HF
)
2
2
3
75.4 MHz) δ 13.29 (q), 47.18 (tt, J CF ) 18.0 Hz), 57.57 (d),
61.65 (t), 62.69 (t), 65.51 (s), 116.90 (dd, J CF ) 254.0, 259.0
9.7 Hz), -115.19 (1 F, dd, J FF ) 269.0 Hz, J HF ) 11.7 Hz).
2
1
22b: 19F NMR (CDCl3, 282 MHz) -113.45 (1 F, dd, J FF
)
3 2
Hz), 125.27 (d), 126.11 (d), 127.61 (d), 127.85 (d), 128.40 (d),
128.93 (d), 129.18 (d), 130.01 (d), 130.59 (d), 131.61 (d), 131.75
(d), 133.42 (s), 136.36 (s), 138.11 (s), 139.60 (s), 141.68 (s),
158.13 (s), 161.50 (t, 2J CF ) 32 Hz); 19F NMR (CDCl3, 282 MHz)
270.0 Hz, J HF ) 9.6 Hz), -115.78 (1 F, dd, J FF ) 270.0 Hz,
3J HF ) 11.8 Hz).
1-[N-Ben zyloxyca r b on yl-(1S)-1-a m in o-3,3-d iflu or o-3-
eth oxycar bon ylpr opyl]-4-m eth yl-2,6,7-tr ioxabicyclo[2.2.2]-
octa n e (23). The diastereoisomeric mixtures of thioester
derivatives 22 (430 mg, 0.78 mmol) and Et3SiH (6.2 mL, 39
2
3
δ -89.47 (1 F, dd, J FF ) 262.5 Hz, J HF ) 13.0 Hz), -111.37
(1 F, dd, J FF ) 262.5 Hz, J HF ) 25.7 Hz); MS (CI, CH4) 464
2
3