784
S. D. Bull et al.
LETTER
temperature for 4 days. The mixture was then poured into
provided (3R,6S,2’S)-N,N’-di(p-methoxybenzyl)-3-
isopropyl-6-ethylpropanoate-piperazine-2,5-dione 5a (15
mg, 3%). mp 136 C (ethyl acetate / hexane); (Found: C, 67.7;
H, 7.3; N, 5.6. C28H36N2O6 requires C, 67.7; H, 7.3; N, 5.6%);
[ ]23D = +62.4 (c 1.0 in CHCl3); max(KBr)/cm-1 2984, 2933,
1739 (ester), 1640 (amide); H(400 MHz, CDCl3) 0.83 (d, 3H,
J 6.9 Hz), 0.98 (d, 3H, J 6.9 Hz), 1.10 (d, 3H, J 7.0 Hz), 1.26
(t, 3H, J 7.1), 2.30 (m, 1H), 3.10 (dq, 1H, J 3.0, 6.9, 6.9, 6.9
Hz), 3.778 (d, 1H, J 3.1 Hz) 3.782 (d, 1H, J 14.6 Hz), 3.81 (s,
6H), 3.99 (d, 1H, J 14.9 Hz), 4.14-4.38 (m, 2H), 4.70 (d, 1H,
J 3.2 Hz), 5.27 (d, 1H, J 14.9 Hz), 5.43 (d, 1H, J 14.7 Hz),
6.86-6.88 (m, 4H), 7.14-7.27 (m, 4H); C (100 MHz, CDCl3)
8.64, 11.8, 14.1, 31.7, 40.0, 46.1 46.2, 55.23, 55.26, 60.0,
60.8, 62.2, 114.0, 114.2, 126.9, 127.3, 130.0, 130.2, 159.3,
159.4, 164.4, 165.8, 172.0; m/z (APCI) 497 (MH+, 10%), 121
(100).
Deprotection of ethyl ester 4a; Ethyl ester 4a (400 mg, 0.81
mmol) was stirred in TFA at reflux for 48 h. The mixture was
cooled and excess TFA removed in vacuo. Column
chromatography (Al2O3; ether:hexane, 1:1, followed by ethyl
acetate:ethanol, 3:1) afforded diketopiperazinedione 6 as a
white solid (124 mg, 60%), mp 204 C; [ ]23D = (+88.5 c 0.99
in CHCl3); max(KBr)/cm-1 1741 (ester), 1673(amide); H(400
MHz, d4-MeOH) 0.98 (d, 3H, J 6.9 Hz), 1.07 (d, 3H, J 7.1 Hz),
1.23 (d, 3H, J 7.2 Hz), 1.30 (t, 3H, J 7.1), 2.32 (m, 1H), 3.23
(dq, 1H, J 7.3, 7.3, 7.3, 2.8 Hz), 3.87 (dd, 1H, J 3.3, 0.8 Hz),
4.21(m, 2H), 4.50 (dd, 1H, J 2.6, 0.8 Hz), 7.18-7.56 (2H, br);
C (100 MHz, d4-MeOH) 11.9, 14.8, 17.4, 19.2, 34.7, 43.7,
57.2, 61.8, 169.5, 170.1, 175.4; m/z (APCI) 257 (MH+, 40%),
211 (100); (Found: MH+ 257.1501, C12H21N2O4 requires
257.1506).
saturated NaHCO3 (100 ml) and extracted with ether, the
organic phase dried (MgSO4) and the solvent removed under
vacuum to provide bis-lactim ether 7 as a clear oil (105 mg,
95%); [ ]23D = +27.3 (c 0.7 in CHCl3); max(KBr)/cm-1 1738
(ester), 1696 (lactim ether); H(400 MHz, CDCl3) 0.70 (d, 3H,
J 6.8 Hz), 0.90 (d, 3H, J 6.9 Hz), 1.04 (d, 3H, J 6.9 Hz), 1.28
(t, 3H, J 7.3), 2.25 (m, 1H), 3.05 (dq, 1H, J 6.9, 6.9, 6.9, 4.0
Hz), 3.63 (3H, s), 3.71 (3H, s), 3.97 (t, 1H, J 3.4, 3.7 Hz), 4.20
(2H, q, J 7.4 Hz), 4.57 (t, 1H, J 4.0, 3.7 Hz); C (100 MHz,
CDCl3) 9.9, 14.2, 16.6, 19.0, 19.6, 30.3, 31.8, 42.2, 52.41,
52.46, 57.3, 60.4, 60.8, 161.9, 164.1, 173.9; m/z (APCI) 285
(MH+, 100%); (Found: MH+ 285.1822. C14H25N2O4 requires
285.1814).
Bis-lactim ether 7 (200 mg, 0.70 mmol) was stirred in 0.5 M
aqueous TFA (5 mL) and THF (10 mL) at room temperature
for 24 hours then the solvent removed and the resultant oil was
loaded onto a short column of silica. Elution (ether :
dimethlyethylamine, 20:1) gave a mixture of (2R,3R)-8 and
L-valine methyl ester which were separated by fractional
distillation (0.5 mm, room temperature) to provide (2R,3R)-
3-methyl-aspartic acid, 4-ethyl, 1-methyl diester 8 as an oil
(104 mg, 76%). [ ]23D = -8.6 (c 0.7 in CHCl3); max(thin film)/
cm-1 3391, 2980, 1732 (ester); H(400 MHz, CDCl3) 1.17 (d,
3H, J 7.1 Hz), 1.26 (t, 3H, J 7.1), 2.96 (1H, m), 3.75 (3H, s),
3.97 (1H, br), 4.17 (2H, q, J 7.1 Hz); C (100 MHz, CDCl3)
11.3, 14.1, 42.7, 52.2, 55.8, 60.9, 174.2; m/z (APCI) 190
(MH+, 100%) 116 (89); (Found: MH+ 190.1082. C8H16NO4
requires190.1079). The diastereoisomeric excess (>95%) and
enantiomeric excess (>98%) were determined from the 19
F
NMR spectrum of the Mosher’s amide derivative of 8.
Diketopiperazinedione 6 (100 mg, 0.39 mmol) and
trimethyloxonium tetrafluoroborate (230 mg, 1.56 mmol)
were stirred in 1-butyl-3-1H-methylimidazolium
Article Identifier:
1437-2096,E;2001,0,06,0781,0784,ftx,en;D07801ST.pdf
tetrafluoroborate9 (4 mL) under vacuum (2 mm of Hg) at room
Synlett 2001, No. 6, 781–784 ISSN 0936-5214 © Thieme Stuttgart · New York