6520
C.Pesenti et al./ Tetrahedron 57 72001) 6511±6522
65.3, 66.0, 67.6, 126.0 -q, JC,F282.6 Hz), 126.1 -q, JC,F
A suspension of 22 -76 mg) in 3.6 mL of dry AcOEt was
treated with 1.2 equiv. of NMM, cooled to 2108C, then
1.2 equiv. of iso-BuO2CCl were added under stirring.
After 5 min. a suspension of 21 -1 equiv.) in 2.5 mL of
AcOEt was added. The mixture was stirred for 4 days at
rt, then centrifuged and the solid was washed several
times with AcOEt, MeOH and ®nally n-Hex to provide
100 mg -65%) of Iva-Val-Val--Tfm)GABOB-Ala-
-Tfm)GABOB-OMe -23) as an amorphous solid: mp
282.3 Hz), 128.6, 128.8, 129.3, 137.7, 157.5, 171.7, 171.8,
173.9; FT-IR -KBr): 3424, 3310, 1702, 1670, 1608, 1542,
1265; MS -DIS EI, 70 eV) m/z -%): 576 [-M1H)1, 7], 575
-M1z, 9), 557 [-M±H2O)1z, 11], 347 -C15H18F3N2O41, 27),
325 -C12H16F3N2O51, 10), 303 -C13H12F3NO41, 9), 202
-C8H14N2O41z, 5), 170 -C5H7F3NO21, 4). Anal. Calcd for
C22H27F6N3O8: C, 45.92; H, 4.73; N, 7.30. Found: C,
45.96; H, 4.75; N, 7.26.
265±2708C -dec.); [a]D 232.2 -c 0.36, DMSO); 1H
20
5.4.14. Synthesis of H-ꢀTfm)GABOB-Ala-ꢀTfm)GA-
BOB-OMe ꢀ21). Palladium hydroxide [Pd-OH)2/CÐ
50 mg] was added neat to a stirred solution of Z--Tfm)GA-
BOB-Ala--Tfm)GABOB-OMe -20) -1.043 mmol, 600 mg)
in MeOH -45 mL) and the reaction mixture was kept vigor-
ously stirred under hydrogen atmosphere at rt for 30 min.
After TLC monitoring -n-Hex/AcOEt 1:9), the palladium
powder was ®ltered over a Celite pad, washing the black
solid with MeOH -3£30 mL). The solvent was removed in
vacuo and the residue was puri®ed by FC with AcOEt
to give H--Tfm)GABOB-Ala--Tfm)GABOB-OMe -21)
NMR -DMSO-d6) d 8.08 -d, J7.0 Hz, 1H), 8.06 -d,
J9.5 Hz, 1H), 8.00 -d, J9.5 Hz, 1H), 7.90 -d,
J9.0 Hz, 1H), 7.79 -d, J9.0 Hz, 1H), 5.35 -br signal,
2H), 4.65±4.50 -m, 2H), 4.44 -dq, J7.0 and 7.1 Hz,
1H), 4.31 -dd, J9.0 and 7.2 Hz, 1H), 4.35±4.25 -m,
2H), 4.20 -dd, J9.0 and 7.1 Hz, 1H), 2.31 and 2.28
-m, 2H), 2.25 -dd, J14.9 and 8.5 Hz, 1H), 2.19 -dd,
J14.9 and 4.4 Hz, 1H), 2.10±1.85 -m, 5H), 1.24 -d,
J7.1 Hz, 3H), 0.90±0.80 -m, 18H); 19F NMR -DMSO-
d6) d 271.20 -br d, J8.3 Hz), 271.08 -br d, J
8.2 Hz); 13C NMR -DMSO-d6) d 173.3, 171.8, 171.62,
171.59, 171.3, 169.5, 124.9 -q, J284.3 Hz, 2C), 64.2,
63.8, 57.8, 57.7, 52.9 -q, J26.9 Hz), 52.4 -q,
J27.7 Hz), 48.2, 44.4, 39.5, 38.5, 30.1, 29.9, 25.6,
22.2, 19.19, 19.17, 18.23, 18.18, 17.7. MS -DIS EI, 70
e V) m/z -%): 710 [-M1H)1, 4], 692 [-M1H2H2O)1, 6].
Anal. Calcd for C29H47F6N5O9: C, 48.13; H, 6.55; N, 9.68.
Found: C, 48.16; H, 6.55; N, 9.66.
20
-450 mg, 98% yield): Rf 0.35 -AcOEt); [a]D 243.6 -c
1.0 in MeOH); mp 198±1998C -AcOEt); 1H NMR
-CD3OD1D2O) d: 1.39 -d, J7.2 Hz, 3H), 2.26 -d,
J7.0 Hz, 2H), 2.55 -dd, J14.7 and 7.0 Hz, 1H), 2.58
-dd, J14.7 and 7.0 Hz, 1H), 3.25 -dq, J2.1 and 8.2 Hz,
1H), 3.68 -s, 3H), 4.38 -dt, J2.1 and 7.0 Hz, 1H), 4.42 -q,
J7.2 Hz, 1H), 4.52 -dt, J1.4 and 7.0 Hz, 1H), 4.61 -dq,
J1.4 and 8.2 Hz, 1H); 19F NMR -CD3OD) d: 273.82 -br d,
J8.2 Hz, 3F), 271.71 -br d, J8.2 Hz, 3F); 13C NMR
5.4.17. Synthesis of Iva-Val-Val-ꢀTfm)GABOB-Ala-
ꢀTfm)GABOB-OHꢀ1). A solution of LiOH.H2O -1.19
mmol, 50 mg) in water -1 mL) was added to a stirred
solution of Iva-Val-Val--Tfm)GABOB-Ala--Tfm)GA-
BOB-OMe -23) -0.097 mmol, 70 mg) in DMSO -12 mL).
The reaction mixture was stirred at rt for 6 h, monitored by
TLC -AcOEt/MeOH9:1), diluted with water, added with a
1N aqueous HCl solution up to pH 1 and the organics were
extracted with AcOEt -3£10 mL). The combined organic
layers were dried in vacuo and a grey residue was obtained
and washed several times with water, AcOEt, MeOH and
®nally acetone to give pure Iva-Val-Val--Tfm)GABOB-
Ala--Tfm)GABOB-OH -1) -43 mg, 85% yield):
-CD3OD) d: 18.0, 39.6, 41.3, 50.7, 52.3, 54.4 -q, JC,F
282.0 Hz), 57.0 -q, JC,F282.0 Hz), 65.3, 66.4, 126.2 -q,
JC,F27.1 Hz), 127.7 -q, JC,F29.0 Hz), 172.7, 173.3,
176.0; FT-IR -KBr) -cm21): 3500, 3332, 1729, 1648,
1528, 1446, 1393, 1299; MS -DIS EI, 70 eV) m/z -%):
441 -M1z, 4), 440 [-M2H)1, 12], 213 -C7H12F3N2O21, 4),
212 -C7H11F3N2O21z, 5). Anal. Calcd for C14H21F6N3O6: C,
38.10; H, 4.80; N, 9.52. Found: C, 38.06; H, 4.85; N, 9.56.
5.4.15. Synthesis of Iva-Val-Val-OHꢀ22). iso-Valeroyl
chloride -0.925 mmol, 112 mg) and a 4N NaOH solution
-0.462 mL) were added dropwise and simultaneously to a
stirred solution of commercial H-Val-Val-OH -0.925 mmol,
200 mg) in a 4N NaOH solution -0.462 mL). After few
minutes, a white precipitate was formed and after 30 min
a 1N aqueous HCl solution was added up to pH 1 together
with MeOH -5 mL) to dissolve the solid. The solvents were
evaporated in vacuo and the residue was puri®ed by FC in
CHCl3/MeOH/CH3CO2H97:3:1 to give Iva-Val-Val-OH
-22) -170 mg, 82% yield): Rf 0.35 -CHCl3/MeOH/AcOH
20
[a]D 227.6 -c 0.4 in DMSO); mp 254±2608C -acetone);
1H NMR -DMSO-d6) d: 0.80±0.90 -m, 18H), 1.24 -d,
J7.1 Hz, 3H), 1.85±2.10 -m, 5H), 2.19 -dd, J14.9 and
4.4 Hz, 1H), 2.25 -dd, J14.9 and 8.5 Hz, 1H), 2.28 and
2.31 -m, 2H), 4.20 -dd, J9.0 and 7.1 Hz, 1H), 4.25±4.35
-m, 2H), 4.31 -dd, J9.0 and 7.2 Hz, 1H), 4.44 -dq, J7.0
and 7.1 Hz, 1H), 4.50±4.65 -m, 2H), 5.35 -br signal, 2H),
7.79 -d, J9.0 Hz, 1H), 7.90 -d, J9.0 Hz, 1H), 8.00 -d,
J9.5 Hz, 1H), 8.06 -d, J6.5 Hz, 1H), 8.08 -d, J9.8 Hz,
1H); 19F NMR -DMSO-d6), d: 271.20 -br d, J8.3 Hz, 3F),
271.80 -br d, J8.2 Hz, 3F); 13C NMR -DMSO-d6) d: 17.7,
18.2, 18.2, 19.2, 19.2, 22.2, 25.6, 29.9, 30.1, 38.5, 39.5,
44.4, 48.2, 52.4 -q, JC,F27.7 Hz), 52.9 -q, JC,F26.9 Hz),
57.7, 57.8, 63.8, 64.2, 124.9 -q, JC,F284.3 Hz), 169.5,
171.3, 171.6, 171.6, 171.8, 173.3; FT-IR -KBr) -cm21):
3432, 3297, 1638, 1542, 1388, 1270; MS -DIS EI, 70 eV)
m/z -%): 710 [-M1H)1, 4], 692 [-M1H2H2O)1, 6], 495
20
97:3:1); [a]D 248.1 -c 1.1 in MeOH); mp 166±1678C
-diisopropylether); 1H NMR -CD3OD1D2O) d: 0.8±1.0 -m,
18H), 1.9±2.3 -m, 5H), 4.23 -d, J8.1 Hz, 1H), 4.32 -d,
J5.7 Hz, 1H); 13C NMR -CD3OD) d: 18.3, 19.1, 19.6,
19.8, 22.8, 27.5, 31.7, 31.8; 46.0, 58.9, 60.2, 174.1, 174.6,
175.6; FT-IR -KBr) -cm21): 3299, 2965, 1719, 1638,
1546, 1467, 1215; MS -DIS EI, 70 eV) m/z -%): 301
[-M1H)1, 12], 184 -C10H19NO21z, 4). Anal. Calcd for
C15H28N2O4: C, 59.98; H, 9.39; N, 9.33. Found: C, 59.96;
H, 9.35; N, 9.30.
1
1
-C22H38F3N4O5
,
4), 493 -C22H36F3N4O5
,
7), 312
-C12H21F3N3O31, 20). Anal. Calcd for C28H45F6N5O9:
C, 47.39; H, 6.39; N, 9.87. Found: C, 47.36; H, 6.35; N,
9.89.
5.4.16. Synthesis of Iva-Val-Val-ꢀTfm)GABOB-Ala-
ꢀTfm)GABOB-OMe ꢀ23). Coupling between 21 and 22.