R. K. Duke et al. / Tetrahedron: Asymmetry 15 (2004) 1745–1751
1749
4
.4. Ethyl 2-methyl-4-phthalimidobutanoate 7
pantolactone (390 mg, 3 mmol) in anhydrous CH
(10 mL) and anhydrous pyridine (2 mL) under stirring.
2 2
Cl
To a solution of 6 (3.9 g, 0.014 mol) in EtOH (150 mL)
was added 10% Pd on C (45 mg) and the mixture was
hydrogenated at 4 atm for 20 h. The mixture was filtered
and the filtrate evaporated under reduced pressure to
After stirring at room temperature for 18 h, the mixture
was evaporated under reduced pressure to give a pale
brown oil. The oil was purified by short column vacuum
chromatography and eluted with CH Cl to give a pale
2
2
1
give 7 as a colourless oil (3.84 g, 98%). H NMR
(
yellow oil, which crystallised from CH
2
2
Cl /ether to give
CDCl
3
) d 1.24 (3H, d, J ¼ 7:0 Hz, 2-CH
3
), 1.26 (3H, t,
large colourless cubic crystals (1 g, 93%), mp 107–108 °C
1
J ¼ 7:1 Hz, OCH CH ), 1.78 (1H, ddd, J ¼ 13:6, 7.0,
(subl.). H NMR (CDCl ) d 1.12, 1.21 (2ꢄ 3H, 2ꢄ s,
2
3
3
6
7
7
.6 Hz, PhthNCH
.7, 7.2 Hz, PhthNCH
.0 Hz, PhthNCH CH CH), 3.75 (2H, t, J ¼ 7:1 Hz,
2
CH
2
CH), 2.10 (1H, ddd, J ¼ 13:7,
C(CH
(2H,
3
)
2
), 2.10 (3H, q, J ¼ 1:0 Hz, 2-CH
3
), 4.05, 4.07
0
2
CH
2
CH), 2.47 (1H, tq, J ¼ 7:1,
J
A;B ¼ 9:0 Hz, C4 H
2
O), 4.41–4.55 (2H, m,
0
PhthNCH CH@), 5.43 (1H, s, C2 H), 6.79 (1H, tq,
2
2
2
PhthNCH CH CH), 4.11 (2H, q, J ¼ 7:1 Hz,
J ¼ 6:7, 1.5 Hz, PhthNCH CH@), 7.72–7.78 (2H, m,
2
2
2
13
OCH
7
2
CH
.89 (2H, m, PhthN: H3, H6). C NMR (CDCl
3
), 7.69–7.75 (2H, m, PhthN: H4, H5), 7.82–
PhthN: H4, H5), 7.85–7.91 (2H, m, PhthN: H3, H6). C
), 20.0, 23.1 (C(CH
13
3
) d 14.1
OCH CH ), 17.1 (2-CH ), 31.9 (C3), 35.9 (C4), 37.2
C2), 60.4 (OCH
NMR (CDCl
3
) d 12.7 (2-CH
3
3
)
2
),
35.7 (C4), 40.3 (C3 (CH ) ), 75.4 (C4 ), 76.2 (C2 ), 123.4
0
0
0
(
(
(
(
(
(
2
3
3
3 2
2
CH
3
), 123.2 (PhthN: C4, C5), 132.1
(PhthN: C4, C5), 130.1 (C2), 132.1 (PhthN: C2A, C7A)
134.1 (PhthN: C3, C6), 136.4 (C3), 165.9 (CO), 167.6
PhthN: C2A, C7A), 133.9 (PhthN: C3, C6), 168.2
PhthN: 2ꢄ CO), 175.7 (CO). MS (CI): m=z (%) 230
100), 202 (38), 160 (36). MS (APCI): m=z (%) 276
MþH, 100), 262 (14), 230 (5). HRMS calcd for
0
(PhthN: 2ꢄ CO), 172.1 (C O). MS (CI): m=z (%) 386
(Mþ29, 6), 358 (MþH, 2), 228 (100), 202 (30). MS
(APCI): m=z (%) 375 (53), 358 (MþH, 53), 228 (100),
200 (35), 163 (23). HRMS calcd for C H NO Na
C H NO Na (MþNa): 298.1052. Found (MþNa):
15
17
4
19 19
6
2
98.1050. Anal. Calcd for C15
H
17NO
N, 5.09. Found: C, 65.16; H, 6.13; N, 4.94%.
4
: C, 65.44; H, 6.22;
(MþNa): 380.1106. Found (MþNa): 380.1105. Anal.
Calcd for C13 : C, 63.86; H, 5.36; N, 3.92.
Found: C, 63.93; H, 5.35; N, 3.90%.
H
11NO
4
4
.5. 2-Methyl-4-phthalimidobutanoic acid 8
4.7. [(2R)-(3,3-Dimethylbutyro-1,4-lactonyl)]-2-methyl-4-
phthalimidobutanoate 9
HCl (6 M, 60 mL) was added to a well-stirred solution of
(5.24 g, 19 mmol) in glacial acetic acid (100 mL). The
7
mixture was heated (90 °C) under stirring for 3 days and
evaporated under reduced pressure to give a colourless
oil. The oil was crystallised from light petroleum/
CH Cl and recrystallised from light petroleum/ethyl
2 2
acetate to give the saturated acid 8 as fine white needles
To a solution of the saturated acid 8 (1.6 g, 6.5 mmol) in
anhydrous benzene (40 mL) was added SOCl (2 mL,
2
26 mmol). After standing at room temperature for 18 h,
the solvent was removed from the mixture by distillation
leaving a brown liquid residue. The residue was added to
a solution of (ꢁ)-(R)-pantolactone (1.2 g, 9.4 mmol) in
5
;13
(
1
4.6 g, 98%), mp 111–112 °C (subl.), lit.
mp 114–
) d 1.27 (3H, d,
), 1.78 (1H, ddd, J ¼ 13:9, 7.0, 6.8 Hz,
ꢄ PhthNCH CH CH), 2.13 (1H, ddd, J ¼ 13:9, 7.0,
1
15 °C, 112–113 °C. H NMR (CDCl
3
2 2
CH Cl (50 mL) and anhydrous pyridine (10 mL). The
J ¼ 7:0 Hz, 2-CH
3
mixture was left standing at room temperature for 18 h
then evaporated under reduced pressure to give a light
brown semi-solid. Purification by short column vacuum
1
6
7
1
2
2
.8 Hz, 1 ꢄ PhthNCH
.0 Hz, PhthNCH CH
.4 Hz, PhthNCH CH CH), 7.69–7.75 (2H, m, PhthN:
2
CH
CH), 3.78 (2H, dt, J ¼ 7:0,
2
2
CH), 2.50 (1H, tq, J ¼ 7:1,
2
2
2 2
chromatography (CH Cl ) afforded a mixture of the
required pantolactonyl diastereoisomeric esters, the
(R,R)-diastereoisomer and the (R,S)-diastereoisomer
2
13
H4, H5), 7.82–7.88 (2H, m, PhthN: H3, H6). C NMR
CDCl ) d 16.9 (2-CH ), 31.9 (C3), 35.9 (C4), 37.0 (C2),
23.3 (PhthN: C4 and C5), 132.2 (PhthN: C2A, C7A),
33.9 (PhthN: C3, C6), 168.3 (PhthN: 2 ꢄ CO), 181.1
1
(
1
1
3
3
(2.26 g, 85%). H NMR (CDCl
3
) d 1.15, 1.17, 1.23, 1.27
(4ꢄ 3H, 4ꢄ s, 2ꢄ C(CH ) ), 1.33 (3H, d, J ¼ 7:2 Hz, 2-
3
2
CH
m, PhthNCH
CH CH), 2.58–2.71 (2H, m, PhthNCH
3
), 1.69 (3H, d, J ¼ 7:0 Hz, 2-CH
CH CH), 2.10–2.22 (2H, m, PhthNCH
CH CH), 3.76–
3
), 1.78–1.90 (2H,
(
CO). MS (CI): m=z (%) 230 (100), 202 (60), 160 (68).
2
2
2
MS (APCI): m=z (%) 262 (100), 248 (MþH, 36), 230
2
2
2
(
12). Anal. Calcd for C H NO : C, 63.15; H, 5.30; N,
4
3.81 (4H, m, 2ꢄ PhthNCH CH CH), 4.02–4.10 (4H, m,
13
13
2
2
0
0
0
5
.66. Found: C, 63.29; H, 5.30; N, 5.62%.
2ꢄ C4 H
2
O), 5.388 (1H, s, C2 H), 5.404 (1H, s, C2 H),
7
.69–7.75 (4H, m, 2ꢄ PhthN: H4, H5), 7.82–7.89 (4H,
m, 2ꢄ PhthN: H3, H6). The diastereoisomers were
separated by short column vacuum chromatography
using silica gel H60 (column i.d. 4:5 ꢄ 8:5 cm) and eluted
with light petroleum/ethyl acetate (7:3) in 50 mL frac-
tions. Fractions were analysed by TLC using two sol-
vent systems, light petroleum/ethyl acetate (2:1) and
4.6. [(2R)-(3,3-Dimethylbutyro-1,4-lactonyl)]-2-methyl-4-
phthalimidobut-2-enoate 11
To a suspension of the unsaturated acid 10 (735 mg,
3 mmol) in anhydrous benzene (20 mL) was added
SOCl (1 mL, 14 mmol). The mixture was refluxed under
CHCl . Generally, TLC plates were developed twice in
3
2
stirring until the evolution of HCl ceased (ꢃ3 h). The
volatile materials were removed by distillation leaving a
pale brown residue, which crystallised as light brown
needles. The residue was dissolved in anhydrous CH Cl
the same solvent system before visualisation with 0.5%
KMnO in 2.5% aqueous K CO . Fractions enriched
4 2 3
with the less polar diastereoisomer were combined and
evaporated under reduced pressure to give a white solid
residue. Crystallisation from cyclohexane/ethyl acetate
2
2
(
10 mL) then added dropwise to a solution of (ꢁ)-(R)-