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F. W. Foss et al. / Bioorg. Med. Chem. 17 (2009) 6123–6136
hexanes) to yield 209 mg (99%) of a yellow liquid. Rf (5% EtOAc in
hexanes) = 0.63. 1H NMR (300 MHz, CDCl3, 23 °C, d): 7.54 (d,
J = 8.6 Hz, 2H), 7.42 (d, J = 8.6 Hz, 2H), 2.40 (t, J = 7.7 Hz, 2H), 1.58
(quintet, J = 7.3 Hz, 2H), 1.44–1.37 (m, 2H), 1.35–1.23 (m 4H),
0.88 (t, J = 6.9 Hz, 3H) ppm. 13C NMR (300 MHz, CDCl3, 23 °C, d):
132.15, 131.98, 129.25, 118.71, 110.83, 95.81, 95.41, 79.52, 31.40,
28.68, 28.50, 22.62, 19.60, 14.15 ppm.
5.4.23. (S)-2,2,4-Trimethyl-oxazolidine-3,4-dicarboxylic acid 3-
tert-butyl ester (S1)
The procedures for 15 were carried out with N-Boc-a-Me-L-Ser-
OH (150 mg, 0.684 mmol) in dry acetone (1.71 mL) and 2,2-dime-
thoxypropane (1.44 mL, 8.895 mmol) with BF3ÁOEt2 (0.01 mL,
0.023 mmol). The title compound was isolated as previously de-
scribed to give 161 mg (91%) of a glassy yellow solid. Rf, 1H NMR,
and 13C NMR were consistent with racemic 15.
5.4.20. 4-Octyl-benzonitrile (13)
Alkynyl benzonitrile 12 (191 mg, 0.904 mmol) was dissolved in
45 mL of absolute ethanol and placed in a Parr reactor. To this solu-
tion was added 90 mg (0.1 G/mmol) of 10% Pd on BaSO4. The reac-
tor was filled with H2 and allowed to stir for 5 min before a vacuum
was pulled and sustained for an additional 5 min. This cycle was
repeated two more times before a pressure of 36 psi of H2 was
maintained for 50 min. At this time the vessel was disassembled
and the mixture was filtered over Celite and washed with Et2O.
The organic layer was condensed to 195 mg (100%) of a light yel-
low oil. The oil was determined to be >97% pure by NMR and used
in the following step without further purification. Rf (5% EtOAc in
hexanes) = 0.69. 1H NMR (300 MHz, CDCl3, 23 °C, d): 7.54 (d,
J = 8.1 Hz, 2H), 7.26 (d, J = 8.1 Hz, 2H), 2.64 (t, J = 7.7 Hz, 2H), 1.60
(quintet, J = 7.3 Hz, 2H), 1.39–1.12 (m 10H), 0.86 (t, J = 6.5 Hz,
3H) ppm. 13C NMR (300 MHz, CDCl3, 23 °C, d): 148.67, 132.12,
129.26, 119.24, 109.50, 36.17, 31.92, 31.07, 29.46, 29.28, 22.73,
14.18 ppm.
5.4.24. Compound 16
To a solution of amino acid 15 (174 mg, 0.672 mmol) stirring in
dry CH2Cl2 (17 mL) was added PyBOP (350 mg, 0.672 mmol) and i-
Pr2NEt (0.12 mL, 0.672 mm), followed by amidoxime 14 (167 mg,
0.672 mmol). The reaction was stirred at room temperature for
12–16 h. The mixture was diluted with Et2O (15 mL) and washed
with saturated aqueous NH4Cl (2 Â 5 mL) and brine (2 Â 5 mL),
then concentrated and purified by column chromatography
(100 mL SiO2, 1:3 EtOAc/hexanes) to give 289 mg (88%) of an off-
white solid. Rf (1:3 EtOAc/hexanes) = 0.44. 1H NMR (300 MHz,
CDCl3, 23 °C, d): major rotamer = 7.56 (d, J = 7.7 Hz, 2H), 7.14 (d,
J = 7.7 Hz, 2H), 5.68 (br s, 1H), 5.23 (s, 1H), 4.26 (d, J = 8.8 Hz,
1H), 3.79 (d, J = 8.0 Hz, 1H), 2.56 (t, J = 7.7 Hz, 2H), 1.66 (s, 3H),
1.60 (d, J = 11.5 Hz, 6H), 1.45 (s, 9H), 1.28–1.18 (m, 10H), 0.83 (t,
J = 6.4 Hz, 3H); and minor rotamer = 7.56 (d, J = 7.7 Hz, 2H), 7.14
(d, J = 7.7 Hz, 2H), 5.68 (br s, 1H), 5.23 (s, 1H), 4.16 (d, J = 8.8 Hz,
1H), 3.82 (d, J = 8.0 Hz, 1H), 2.56 (t, J = 7.7 Hz, 2H), 1.64 (s, 3H),
1.57 (d, J = 11.5 Hz, 6H), 1.37 (s, 9H), 1.28–1.18 (m, 10H), 0.83 (t,
J = 6.4 Hz, 3H) ppm. 13C NMR (300 MHz, CDCl3, 23 °C, d): (two rota-
mers) 170.15, 168.97, 160.28, 157.18, 152.49, 151.08, 146.26,
128.66, 126.78, 96.03, 95.73, 81.15, 73.82, 73.36, 65.80, 65.31,
35.82, 31.89, 31.28, 29.47, 29.23, 28.50, 28.17, 27.04, 26.20,
24.88, 24.79, 23.66, 22.70, 22.13, 21.12, 14.46 ppm.
5.4.21. N-Hydroxy-4-octyl-benzamidine (14)
The general procedure for amidoxime formation was used to
convert benzonitrile 13 (195 mg, 0.904 mmol) in 95% EtOH
(1.4 mL) to the desired product with triethylamine (0.29 mL,
2.079 mmol) and hydroxylamine hydrochloride (138 mg,
1.989 mmol) The remaining precipitate was dried to 187 mg
(74%) of an off-white solid. Rf (5% MeOH in CHCl3) = 0.59. 1H
NMR (300 MHz, CDCl3, 23 °C, d): 8.29 (br s, 1H), 7.52 (d,
J = 7.7 Hz, 2H), 7.18 (d, J = 7.7 Hz, 2H), 5.22 (br s, 1H), 2.59 (t,
J = 7.5 Hz, 2H), 1.68–1.53 (m, 2H), 1.32–1.21 (m, 10H), 0.87 (t,
J = 6.4 Hz, 3H) ppm. 13C NMR (300 MHz, CDCl3, 23 °C, d): 175.87,
145.77, 128.91, 126.15, 95.49, 46.00, 35.96, 32.06, 31.47, 29.63,
29.44, 22.5, 14.31 ppm. MS (ESI+) m/z 349 [M+H]+.
5.4.25. Compound S2
The above procedure was performed to condense amidoxime 14
(154 mg, 0.621 mmol) and protected amino acid S1 (161 mg,
0.621 mmol) with PyBOP (323 mg, 0.621 mmol) and i-Pr2NEt
(0.11 mL, 0.621 mmol) in dry CH2Cl2 (16 mL). The reaction was
purified by flash chromatography (100 mL SiO2, 1:3 EtOAc/hex-
anes) to give 248 mg (82%) of an off-white solid. Rf, 1H NMR, and
13C NMR were consistent with racemic 16.
5.4.22. (R,S)-2,2,4-Trimethyl-oxazolidine-3,4-dicarboxylic acid
3-tert-butyl ester (15)
5.4.26. (R,S)-2,2,4-Trimethyl-4-[3-(4-octyl-phenyl)-[1,2,4]oxadiazol-
5-yl]-oxazolidine-3-carboxylic acid tert-butyl ester (17)
D,L-a-Me-Ser-OH (0.5 G, 4.2 mmol) was dissolved in a 10% solu-
tion of Na2CO3 (11.5 mL). To this solution was added Boc2O
(2.748 G, 12.6 mmol) in dioxanes (8.4 mL) and the mixture was al-
lowed to stir for 36 h. When completed the reaction mixture was
washed with Et2O (3 Â 25 mL) and was acidified with 10% HCl be-
fore being extracted with EtOAc (5 Â 25 mL). The EtOAc layers
were combined, dried (Na2SO4) and concentrated to an amorphous
white solid.
The white solid, following 3 h of drying, but without further
purification, was dissolved in dry acetone (10.5 mL)and 2,2-dime-
thoxypropane (6.7 mL). To this solution was added BF3ÁOEt2
(0.03 mL, 0.21 mmol). The reaction was stirred for 3 h at room
temperature and concentrated to a brown solid. The solid was
dissolved in EtOAc (25 mL), washed with H2O (3 Â 15 mL), dried
(Na2SO4), and concentrated to 1.140 G (>95%, two steps) of off-
white solid. Rf (10% MeOH/CHCl3) = 0.65. 1H NMR (300 MHz,
CDCl3, 23 °C, d): 11.46 (br s, 1H), 4.14–4.04 (m, 1H), 3.78–3.70
(m, 1H), 1.57–1.43 (9H), 1.40–1.31 (m, 9H) ppm. 13C NMR
(300 MHz, CDCl3, 23 °C, d): major rotamer = 177.87, 150.92,
96.46, 80.89, 73.78, 65.26, 28.30, 26.24, 23.31, 21.68; and minor
rotamer = 177.31, 151.80, 95.66, 81.08, 73.30, 65.72, 28.38,
26.86, 24.77, 20.55 ppm.
Condensation product 16 (289 mg, 0.590 mmol) was dis-
solved in dry DMF (12 mL) and heated to 110 °C for 6 h. After
this time, the reaction was concentrated and purified by flash
chromatography (100 mL SiO2, 1:3 EtOAc/hexanes) to yield
198 mg (71%) of the title product as clear oil. Crude material
(ꢀ10%) was isolated and saved for further purification if
needed. Rf (1:3 EtOAc/hexanes) = 0.83. 1H NMR (300 MHz, CDCl3,
23 °C, d): major rotamer = 7.97 (d, J = 8.5 Hz, 2H), 7.28 (d,
J = 8.5 Hz, 2H), 4.24 (d, J = 8.8 Hz, 1H), 3.99 (d, J = 8.8 Hz, 1H),
2.64 (t, J = 7.7 Hz, 2H), 1.91 (s, 3H), 1.75 (s, 3H), 1.70 (s, 3H),
1.49–1.43 (m, 2H), 1.36–1.23 (m, 10H), 1.21 (s, 9H), 0.86 (t,
J = 6.7 Hz, 3H); and minor rotamer = 7.95 (d, J = 8.5 Hz, 2H),
7.25 (d, J = 8.5 Hz, 2H), 4.19 (d, J = 8.8 Hz, 1H), 3.97 (d,
J = 8.8 Hz, 1H), 2.62 (t, J = 7.7 Hz, 2H), 1.96 (s, 3H), 1.74 (s,
3H), 1.63 (s, 3H), 1.49–1.43 (m, 2H), 1.36–1.23 (m, 10H), 1.25
(s, 9H), 0.86 (t, J = 6.7 Hz, 3H) ppm. 13C NMR (300 MHz, CDCl3,
23 °C, d): (two rotamers) 180.79, 168.73, 150.85, 14683,
146.48, 129.17, 128.99, 127.66, 127.59, 124.22, 96.87, 96.07,
95.54, 81.28, 81.02, 74.88, 74.88, 74.52, 61.03, 36.21, 32.09,
31.48, 29.67, 29.47, 28.56, 28.26, 27.17, 26.59, 25.38, 23.90,
23.02, 22.89, 21.99, 14.34 ppm.