8044
D. J. Burkhart et al. / Tetrahedron 57 .2001) 8039±8046
mixture was cooled to room temperature, ®ltered and
washed with CH2Cl2, the ®ltrate was washed with brine,
dried 6Na2SO4), ®ltered and evaporated. Kugelrohr distil-
lation produced 16.81 g 7 as a yellow oil, bp 1088C/
was washed with brine, and dried 6Na2SO4), evaporated
under reduced pressure, the residue was puri®ed by
Chromatotron 6hexane±EtOAc) to afford the desired
product as following 11±22.
1
0.11 mm Hg, yield 97%. H NMR d 7.09 6br, 1H, NH),
4.18 6t, 2H, J8 Hz, CH2) 4.04 6m, 2H, CH2), 3.86 6m,
2H, CH2), 3.70 6t, 1H, J8 Hz, OH), 2.50 6s, 3H, CH3),
1.76 6s, 3H, CH3), 1.39 6s, 6H, CH3). 13C NMR d 167.5,
160.3, 157.4, 116.4, 105.5, 69.3, 64.6, 56.8, 26.8, 24.4, 12.1.
EIMS m/z: 284 6M1), 252. HRCIMS m/z Calcd for
C13H20N2O5 6M11): 285.1450. Found 285.1439.
5.3.1. 3-Isoxazolecarboxylic acid 5-ethyl-4-.2,5,5-
trimethyl-1,3-dioxan-2-yl)-ethyl ester .11). Kugelrohr
distillation at 1108C/0.06 mm Hg, colorless solid, mp 59±
618C, yield 81%. 1H NMR d 0.66 6s, 3H), 1.21 6s, 3H), 1.32
6t, J7.70 Hz, 3H), 1.38 6t, J7.18 Hz, 3H), 1.66 6s, 3H),
2.87 6q, J7.70 Hz, 2H), 3.37 6s, 4H), 4.40 6q, J7.18 Hz,
2H). 13C NMR d 11.7, 14.0, 19.4, 21.8, 22.5, 29.8, 30.1,
62.4, 71.9, 96.2, 113.0, 156.4, 161.9, 171.9. MS m/z: 298
[6M11)1], 282. HRCIMS m/z Calcd for C15H23NO5 6M11):
298.1654. Found 298.1659.
5.2.3.
3-.4,5-Dihydro-4,4-dimethyl-1,3-dioxolan-2-yl)-
isoxazole .9). Compound 7 616.81g, 59.0 mmol), Ph3P
620.0 g, 76.3 mmol) and abs. MeCN were placed in a
round bottom ¯ask, stirred under nitrogen to form clear
solution. The ¯ask was cooled with an ice-water bath,
12.0 mL CCl4 was added over 3 h, and stirred for another
hour, NEt3 617.0 mL) was added over 2 h, the reaction was
allowed to warm to room temperature over 12 h. The reac-
tion mixture was ®ltered and concentrated. Two Kugelrohr
distillations produced 12.86 g 9 as yellowish oil, 908C/
5.3.2. 3-Isoxazolecarboxylic acid 5-.2-phenylethyl)-4-
.2,5,5-trimethyl-1,3-dioxan-2-yl)-ethyl ester .12). Yield
72%, colorless solid, mp 59.5±60.58C. H NMR d 0.57 6s,
1
3H), 1.15 6s, 3H), 1.36 6t, J7.18 Hz, 3H), 1.42 6s, 3H),
3.03±3.316m, 8H), 4.57 6q, J7.18 Hz, 2H), 7.12±7.30
6m, 5H). 13C NMR d 14.0, 21.8, 22.5, 28.1, 29.7, 29.9,
33.4, 62.5, 71.8, 96.2, 114.5, 126.6, 128.5, 128.7, 140.1,
156.4, 161.8, 169.8. Calcd for C21H27NO5: C, 67.43; H,
7.29; N, 3.74. Found: C, 67.43, H, 7.29; N, 3.68.
1
0.08 mm Hg, yield 82%. H NMR d 3.99 6s, 2H), 3.83±
3.89 6m, 2H), 3.55±3.62 6m, 2H), 2.35 6s, 3H), 1.58 6s,
3H), 1.24 6s, 6H). 13C NMR d 166.8, 154.4, 152.2, 117.0,
104.6, 79.2, 67.8, 64.0, 27.5, 26.1, 11.3. IR: 1713 cm21
.
EIMS m/z: 267 [6M11)1], 251. HRCIMS m/z Calcd for
C13H15N2O4 6M11): 267.1344. Found: 267.1351.
5.3.3. 3-Isoxazolecarboxylic acid 5-[.2,2-hydroxy-
methyl)propyl]-4-.2,5,5-trimethyl-1,3-dioxan-2-yl)-ethyl
1
ester .13). Yield 68%, colorless solid, mp 103±1048C. H
5.2.4. 3-Isoxazolecarboxylic acid 5-methyl-4-.2,5,5-
trimethyl-1,3-dioxan-2-yl)-ethyl ester .8). The procedure
for the preparation of compound 6 was used. Kugelrohr
distillation produced 8, as a colorless solid and was recrys-
tallized with hexane, bp 938C/0.05 mm Hg, mp 80±828C,
yield: 96%. 1H NMR d8-THF d 0.66 6s, 3H, dioxCH3a, 1.21
6s, 3H, dioxCH3b, 1.38 6t, J7.20 Hz, 3H, esterCH3), 1.65
6s, 3H, dioxCH3c, 2.47 6s, 3H, isoxCH3), 3.36 6q,
J10.93 Hz, 4H, dioxCH2), 4.39 6q, J7.20 Hz, 2H,
esterCH2). 13C NMR d8-THF d 11.1 6isoxCH3), 14.0
6esterCH3), 21.7 6dioxCH3a, 22.6 6dioxCH3b, 29.8
6dioxCH3c, 30.16dioxC5), 62.4 6esterCH 2), 72.3 6dioxCH2),
96.8 6dioxC2), 114.0 6isoxC-4), 156.4 6isoxC-3), 161.6
6esterCO), 167.6 6isoxC-5). 13C NMR 6solid state) 11.9,
14.9, 21.5, 22.7, 30.2, 31.9, 63.6, 71.7, 96.9, 114.8, 157.3,
163.0, 169.3; IR: 1735 cm21. EIMS m/z: 284 [6M11)1],
268. Anal. Calcd For C14H21NO5: C, 59.35; H, 7.39; N,
4.94. Found: C, 59.35; H, 7.40; N, 4.90.
NMR d 0.69 6s, 3H), 1.18 6s, 3H), 1.33 6s, 6H), 1.38 6t, J
7.18 Hz, 3H), 1.73 6s, 3H), 2.26 6s, 1H), 3.07 6s, 2H), 3.36
6q, J10.77, 7.18 Hz, 4H), 4.40 6q, J7.18 Hz, 2H). 13C
NMR d 13.9, 21.8, 22.3, 29.3, 29.9, 39.4, 62.4, 70.8, 71.6,
96.3, 115.9, 156.3, 161.7, 167.9. MS m/z: 326, 197. Calcd
for C17H27NO6: C, 59.81; H, 7.97; N, 4.10. Found: C, 60.01;
H, 7.91; N, 4.26.
5.3.4. 3-Isoxazolecarboxylic acid 4-.2,5,5-trimethyl-1,3-
dioxan-2-yl)-5-[.trimethylsilyl) methyl]-ethyl ester .14).
Yield 66%, colorless crystals, mp 87±88C. 1H NMR d 0.10
6s, 9H), 0.51 6s, 3H), 1.10 6s, 3H), 1.24 6t, J7.18 Hz, 3H),
1.52 6s, 3H), 2.216s, 2H), 3.2162, 4H), 4.25 6q, J7.18 Hz,
2H). 13C NMR d 0.0, 14.9, 17.1, 22.7, 23.4, 30.7, 30.9, 63.2,
72.6, 97.2, 112.5, 157.3, 162.9, 171.8. EIMS m/z: 340
[6M215)1]. Calcd for C17H29NO5Si: C, 57.44; H, 8.22; N,
3.94. Found: C, 57.73; H, 8.28; N, 3.91.
5.3.5. 3-Isoxazolecarboxylic acid 4-.2,5,5-trimethyl-1,3-
dioxan-2-yl)-5-[.trimethylstannyl) methyl]-ethyl ester
.15). Yield 42%, colorless solid, mp 90±928C. H NMR d
5.3. General procedure for lateral lithiation
1
0.16 6s, 9H), 0.60 6s, 3H), 1.14 6s, 3H), 1.32 6t, J7.18 Hz,
3H), 1.57 6s, 3H), 2.41 6d, 2.82 Hz, 2H), 3.30 6s, 3H), 4.34
6q, J7.18 Hz, 2H). 13C NMR d 2.4, 9.2, 13.9, 21.8, 22.5,
29.7, 62.3, 71.7, 96.3, 109.4, 156.4, 162.0, 173.3. EIMS m/z:
447 [6M11)1], 165. HRCIMS m/z Calcd for C17H29NO5Sn:
447.1068. Found 447.0991.
To a solution of diisopropylamine 60.29 mL) in THF under
nitrogen at 0,58C was added nBuLi in hexane 62.1mmol).
The solution was stirred for 10 min and then cannulated into
a solution of 8 6566.6 mg, 2.0 mmol) in 15 mL of THF
under nitrogen that was already cooled to 2788C.
The mixture was stirred for 10 min. An electrophile
62.1mmol) solution in 5 mL of THF under nitrogen was
cannulated again into this mixture in 5 min 6if the electro-
phile was a liquid, it was added with a syringe). The reaction
mixture was allowed to warm to room temperature in 6 h.
Saturated NH4Cl solution was added and the solution was
concentrated under reduced pressure to remove THF. The
aqueous-oil mixture was extracted with EtOAc. The extract
5.3.6. 3-Isoxazolecarboxylic acid 5-[.methylthio)methyl]-
4-.2,5,5-trimethyl-1,3-dioxan-2-yl)-ethyl ester .16). Yield
61%, colorless solid, mp 67±688C. 1H NMR d 0.66 6s, 3H),
1.19 6s, 3H), 1.38 6t, J7.18 Hz, 3H), 1.69 6s, 3H), 2.26 6s,
3H), 3.38 6s, 4H), 3.82 6s, 2H), 4.40 6q, J7.18 Hz, 2H). 13C
NMR d 14.0, 16.8, 21.8, 22.4, 27.3, 29.7, 29.8, 62.6, 72.0,