Treatment of (S )-N-phthaloyl-4,5-dehydroleucine methyl ester
(23) with bromine
β = 94.660(1)Њ, γ = 90.007(2)Њ, V = 1232.40(7) Å3, Z = 4, Dcalc
=
1.386 g cmϪ3, µ = 0.103 mmϪ1. A total of 17604 reflections were
measured, corrected for absorption and merged to yield 2685
unique reflections (Rint = 0.06). Hydrogen atom coordinates
were refined. Final agreement factors for 2685 reflections with
I>2σ(I ) and 343 parameters were R = 0.0456, wR = 0.0507 and
S = 1.07.
A solution of bromine in CCl4 (3.8 cm3, 0.11 M) was added to a
solution of the alkene 23 (130 mg, 0.48 mmol) in CCl4 (5 cm3).
The mixture was stirred for 0.25 h, then concentrated under
reduced pressure. The residue was chromatographed on silica to
give a ca. 3 : 1 mixture of diastereomers of 5-bromo-4-hydroxy-
N-phthaloylleucine γ-lactone (31) (81 mg, 50%) as colourless
crystals, mp 138–140 ЊC (Found: C, 49.62; H, 3.60; N, 4.05%.
C14H12BrNO4 requires: C, 49.73; H, 3.58; N, 4.14%); νmax/cmϪ1
3477, 2931, 1775, 1717, 1394, 1280, 1202, 1184, 1088, 956, 880,
718, 643; δH (500 MHz) 7.90–7.70 (4 H, m), 5.37 and 5.25 (0.25
and 0.75 H, dd and dd, J 9.9, 11.0 and 9.9, 11.0), 3.70 and 3.68
(0.75 and 0.25 H, d and d, J 10.5 and 11.0), 3.65 and 3.52 (0.75
and 0.25 H, d and d, J 10.5 and 11.0), 2.82 and 2.74 (0.25 and
0.75 H, dd and dd, J 11.0, 13.2 and 11.2, 12.7), 2.51 and 2.45
(0.75 and 0.25 H, dd and dd, J 9.9, 12.7 and 9.9, 13.2), 1.79 and
1.67 (0.75 and 2.25 H, s and s); δC 170.4, 169.6, 165.7 (2), 133.6,
133.5, 130.5 (2), 122.8, 122.7, 81.7, 81.2, 47.4, 46.9, 38.9, 37.9,
35.3, 35.2, 25.7. 23.5; m/z (EI) 340 (MHϩ, 4%), 338 (MHϩ, 4%),
214 (100), 196 (32), 174 (46), 160 (25), 130 (28), 104 (33), 76
(42); Found m/z (EI): MHϩ, 340.0010. C14H1381BrNO4 requires
340.0007.
Alkylation of dimethyl malonate with (S )-4Ј-bromo-N-phthaloyl-
3,4-dehydrovaline methyl ester (5)
A solution of n-butyllithium in hexanes (0.73 cm3, 1.32 M) was
added to a solution of dimethyl malonate (0.19 g, 1.4 mmol) in
THF and the mixture was stirred for 10 min, then transferred
by syringe to a solution of the bromide 5 (330 mg, 0.98 mmol)
in THF (20 cm3) under nitrogen. After stirring for 15 h, the
mixture was concentrated under reduced pressure and the resi-
due was taken up in EtOAc (20 cm3). The solution was washed
with saturated aqueous ammonium chloride (2 × 50 cm3), dried
and concentrated under reduced pressure. The residue was
chromatographed on silica to give a mixture of the three
alkenes 34–36 (250 mg, 66%), in a ratio ca. 2 : 1 : 2. Reverse
phase HPLC (column A) eluting with 10% methanol in water
was used to isolate compound 36. The remaining compounds
34 and 35 were separated using normal phase HPLC (column
B) eluting with 10% EtOAc–petroleum spirit.
Treatment of (S )-N-phthaloyl-4,5-dehydroleucine methyl ester
(23) with NBS
Dimethyl
2-phthalimido-5-methoxycarbonyl-3-methylene-
hexane-1,6-dicarboxylate (34), colourless oil. (Found: C, 58.62;
H, 4.99; N, 3.52%. C19H19NO8 requires: C, 58.61; H, 4.92; N,
3.60%); νmax/cmϪ1 3480, 3004, 2955, 2847, 1721, 1467, 1436,
1385, 1205, 1030, 915, 720; δH (300 MHz) 7.95–7.70 (4 H, m),
5.40 (1 H, s), 5.26 (1 H, s), 5.21 (1 H, s), 3.77 (3 H, s), 3.72 (3 H,
s), 3.71 (1 H, t, J 8.0), 3.66 (3 H, s), 2.79 (2 H, d, J 8.0); δC (75
MHz) 169.3 (2), 167.4, 138.7, 134.6, 132.0, 123.9, 118.5, 56.4,
NBS (71 mg, 0.40 mmol) was added to a solution of the alkene
23 (110 mg, 0.40 mmol) in CCl4 (5 cm3) under nitrogen. The
mixture was heated at reflux and irradiated with a sunlamp for 1
h, then it was cooled and filtered. The filtrate was concentrated
under reduced pressure, and the residue was chromatographed
on silica, eluting with CH2Cl2–petroleum spirit (1 : 2, v/v),
to give (S)-5Ј-bromo-N-phthaloyl-4,5-dehydroleucine methyl
ester (32) (73 mg, 52%) as a colourless oil. (Found: C, 50.81; H,
4.04; N, 3.76%. C15H14BrNO4 requires: C, 51.16; H, 4.01; N,
3.98%); νmax/cmϪ1 3477, 2954, 1775, 1747, 1715, 1436, 1388,
1243, 1105, 1024, 918, 719; δH (300 MHz) 7.90–7.70 (4 H, m),
5.14 (1 H, s), 5.06 (1 H, dd, J 4.4 and 11.8), 4.95 (1 H, s), 4.05
(1 H, d, J 10.5), 3.90 (1 H, d, J 10.5), 3.76 (3 H, s), 3.27 (1 H, dd,
J 4.4, 14.8), 3.12 (1 H, dd, J 11.8, 14.8); δC (75 MHz) 168.1,
53.2, 53.0, 52.9, 50.8, 32.9; m/z (EI) 389 (Mϩ , 4%), 357 (77),
ؒ
326 (53), 298 (100), 270 (61), 258 (78), 200 (35), 132 (42), 104
(73), 76 (37); Found m/z (EI): Mϩ 389.1113. C19H19NO8
ؒ
requires 389.1111.
(E)-Dimethyl
5-methoxycarbonyl-3-methyl-2-phthalimido-
hex-2-ene-1,6-dicarboxylate (35) and (Z)-dimethyl 5-methoxy-
carbonyl-3-methyl-2-phthalimidohex-2-ene-1,6-dicarboxylate
(36) were obtained as separate species but were not dis-
tinguished on the basis of their relative stereochemistry. The
minor isomer was obtained as colourless crystals, mp 118–
119 ЊC (Found: C, 58.45; H, 5.12; N, 3.53%. C19H19NO8
requires: C, 58.61; H, 4.92; N, 3.60%); νmax/cmϪ1 3482, 3005,
2956, 2848, 1787, 1724, 1640, 1436, 1386, 1278, 1224, 1117, 885,
722, 670; δH (300 MHz) 7.95–7.75 (4 H, m), 3.67 (6 H, s), 3.66
(3 H, s), 3.64 (1 H, t, J 7.0), 2.79 (2 H, d, J 7.0), 2.39 (3 H, s);
δC (75 MHz) 167.8, 166.2, 162.2, 153.9, 133.4, 131.1, 122.8,
166.5, 139.8, 133.3, 130.6, 122.6, 117.8, 52.0, 48.9, 34.1, 31.7;
ϩ
m/z (EI) 353 (Mϩ , 6%), 351 (M , 6%), 272 (100), 240 (12), 212
ؒ
ؒ
(53), 160 (10), 130 (35), 104 (37), 76 (37); Found m/z (EI): Mϩ
,
ؒ
353.0083. C15H1481BrNO4 requires 353.0086.
2-Methylene-1-phthalimidocyclopropanecarboxylic acid methyl
ester (33)
Sodium hydride (60% in mineral oil, 66 mg, 1.7 mmol) was
added to a solution of the bromide 5 (0.55 g, 1.6 mmol) in THF
(20 cm3). The mixture was stirred at room temperature for 48 h,
then diluted with CH2Cl2 (50 cm3), washed with saturated
aqueous ammonium chloride (2 × 50 cm3), dried and concen-
trated under reduced pressure. The residue was chromato-
graphed on silica to give the title compound (33) (84 mg, 20%)
as colourless crystals, mp 139–140 ЊC (Found: C, 65.13; H, 4.40;
N, 5.44%. C14H11NO4 requires: C, 65.37; H, 4.31; N, 5.44%);
νmax/cmϪ1 3486, 2925, 2854, 1780, 1725, 1437, 1391, 1284, 1112,
907, 720; δH (300 MHz) 7.90–7.70 (4 H, m), 6.17 (1 H, apparent
t, J 2.5), 5.77 (1 H, apparent t, J 2.5), 3.70 (3 H, s), 2.69 (1 H,
apparent dt, J 11.1, 2.5), 2.20 (1 H, apparent dt, J 11.1, 2.5);
δC (75 MHz) 177.4, 168.2, 134.6, 132.2, 130.2, 123.9, 109.8,
118.0, 102.6, 52.0, 51.3, 48.1, 34.4, 18.5; m/z (EI) 389 (Mϩ , 7%),
ؒ
357 (87), 325 (24), 270 (85), 210 (8), 132 (66), 104 (100), 76 (43),
59 (15). The major isomer was obtained as colourless crystals,
mp 93–95 ЊC. (Found: C, 58.58; H, 4.92; N, 3.54%. C19H19NO8
requires: C, 58.61; H, 4.92; N, 3.60%); νmax/cmϪ1 3483, 3003,
2955, 2848, 1786, 1725, 1640, 1436, 1387, 1225, 1116, 1061,
885, 722; δH (300 MHz) 7.90–7.75 (4 H, m), 3.86 (1 H, t, J 8.0),
3.77 (6 H, s), 3.68 (3 H, s), 3.38 (2 H, d, J 8.0), 1.85 (3 H, s);
δC (75 MHz) 169.3, 166.9, 163.2, 155.4, 134.7, 132.2, 124.1,
119.8, 53.0, 52.7, 50.6, 33.7, 22.0; m/z (EI) 390.1 (MHϩ, 8%),
357 (93), 325 (31), 270 (82), 210 (10), 132 (80), 104 (100), 76
(50), 59 (15).
53.3, 33.4, 20.3; m/z (EI) 257 (Mϩ , 100%), 242 (31), 198 (70),
ؒ
132 (50), 104 (90), 76 (72); Found m/z (EI): Mϩ , 257.0685.
ؒ
References
C14H11NO4 requires 257.0688.
1 For a review see: R. M. Williams, Synthesis of Optically Active
α-Amino Acids, in Organic Chemistry Series, Volume 7, eds. J. E.
Baldwin and P. D. Magnus, Pergamon Press, Oxford, 1989.
2 For examples see: R. O. Duthaler, Tetrahedron, 1994, 50, 1539–
1650.
Crystal structure determination of compound 33‡
¯
C14H11NO4, Mr = 257.24, triclinic, space group P1, (no. 2), a =
7.0050(2) Å, b = 12.8848(4) Å, c = 13.7023(5) Å, α = 91.151(1)Њ,
3 C. J. Easton, Chem. Rev., 1997, 97, 53–82.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 4 9 2 – 2 4 9 8
2497