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R. Ramanujam et al. / Tetrahedron: Asymmetry 24 (2013) 663–668
Figure 2. Chiral HPLC enantiomeric excess evaluation of 3 aminotetrahydrofuran HCl 9 (as the benzoyl derivative 8); compound 9 obtained from 4 with (½a D27
= ꢂ28 (left) and
ꢁ
with ½a 2D7
= ꢂ39.7 (right).
ꢁ
J = 8.1, 1H), 7.7–7.83 (d, J = 6.9, 2H), 7.40–7.50 (m, 3H), 4.7–4.8 (t,
J = 5.7, 1H), 4.45–4.52 (t, J = 5.4, 4.8, 1H), 3.95–4.10 (m, 1H),
3.30–3.60 (m, 4H), 1.50–1.70 (m, 1H), 1.71–1.85 (m, 1H); 13C
NMR (300 MHz, DMSO) d (ppm) 167.05, 135.34, 131.75, 128.87,
127.93, 63.92, 58.76, 49.61, 34.62; Anal. Calcd for C11H15NO3 (FW
209.2417): C, 63.14; H, 7.23; N, 6.69. Found: C, 63.39; H, 6.92; N,
6.66. APCI MS m/z 209.93 (M+H)+; the enantiomeric purity was
established by chiral HPLC (Chirobiotic TagÒ–Eluent 80:20 – hex-
ane/ethanol)
dilute HCl. The precipitated benzoic acid was filtered off and the
aqueous layer washed with MDC and concentrated completely to
give a material which mixed with the salt. Isopropanol was added
and stirred for 1 h at room temperature. The salt was filtered off
and the reaction mass concentrated completely to give a pasty
mass. This was then stirred with IPA to crystallize out the mate-
rial, which was then filtered, washed with chilled IPA, and dried
under vacuum. Yield: 11 g (85% of theory); Melting point: 165–
170 °C; ½a 2D7
ꢁ
= ꢂ10.2 (c 1, methanol); 1H NMR (300 MHz, CDCl3)
d (ppm) 3.80–4.11 (m, 5H), 2.37–2.5 (m, 1H), 2.01–2.09 (m,
1H); 13C NMR (300 MHz, CDCl3) d (ppm) 70.49, 66.82, 51.21,
30.01; Anal. Calcd for C4H10ClNO (FW 123.5813): C, 38.88; H,
8.16; N, 11.33. Found: C, 38.97; H, 7.86; N, 11.39. The enantio-
meric excess was determined by converting 9 into its benzoyl
derivative and performing chiral HPLC analysis using Chiralpak
AD-H column (Fig. 2).
3.4. (S)-3-Benzoylamino tetrahydrofuran 8
(S)-2-Benzoylamino butane 1,4-diol (35 g, 0.167 mol) was taken
in a round-bottomed flask in toluene (350 ml) and p-toluene sul-
fonic acid (3.5 g) was added. The reaction was heated at reflux
for 10–12 h. With the help of a Dean–Stark apparatus, water was
removed azeotropically. The reaction mixture was quenched in
water, extracted with ethyl acetate, and washed with sodium
bicarbonate solution followed by brine. After drying over sodium
sulfate, it was then concentrated and stirred with hexane. The
product precipitated on chilling and was filtered and dried under
vacuum. Yield: 20 g (63%); Melting point: 106–108 °C;
3.6. (S)-2-Benzoylamino gamma butyrolactone 7
(S)-2-Amino
c-butyrolactone hydrochloride (50 g, 0.37 mol)
was taken in MDC (500 ml) and cooled to 5–10 °C. Triethylamine
(125 ml, 0.90 mol) was then added at 5–10 °C over 10 min fol-
lowed by benzoyl chloride (56.2 g, 0.40 mol) dropwise over a per-
iod of 1 h. The mixture was stirred at rt for 12 h for completion of
the reaction. The pH of the reaction mixture was adjusted to 2–3
using dilute HCl. The organic layer was separated and washed with
ammonium chloride solution twice and concentrated to give the
crude product. The crude product was stirred with hexane to pre-
cipitate the product as a white crystalline powder, which was fil-
tered and dried to obtain the product. Yield: 65 g (87% of
½
a 2D7
ꢁ
= ꢂ29.4 (c 1, methanol); 1H NMR (300 MHz, CDCl3) d (ppm)
7.77–7.80 (d, J = 9.0, 2H), 7.30–7.55 (m, 3H), 6.65–6.70 (d, J = 5.7,
1H), 4.60–4.70 (m, 1H), 3.75–3.98 (m, 4H), 2.26–2.36 (m,1H),
1.90–1.97 (m, 1H); 13C NMR (300 MHz, CDCl3) d (ppm) 167.61,
134.46, 131.79, 128.75, 127.19, 73.68, 67.19, 51.03, 33.40; Anal.
Calcd for C11H13NO2 (FW 191.2264): C, 69.09; H, 6.85; N, 7.32.
Found: C, 69.4; H, 6.53; N, 7.33. APCI MS m/z 192.03 (M+H)+.
3.5. (S)-3-Amino tetrahydrofuran hydrochloride 9
theory); Melting point:165–167 °C; ½a D27
= ꢂ27.8 (c 1, ethanol);
ꢁ
1H NMR (300 MHz, CDCl3) d (ppm) 7.77–7.80 (d, J = 7.2, 2H),
7.35–7.50 (m, 3H), 7.24–7.27 (d, J = 7.8, 1H), 4.77–4.87 (m, 1H),
4.44–4.50 (t, J = 9.0, 1H), 4.26–4.35 (m, 1H), 2.78–2.87 (m, 1H),
2.23–2.40 (m, 1H); 13C NMR (300 MHz, CDCl3) d (ppm) 176.22,
167.93, 133.16, 132.25, 128.80, 127.38, 66.47, 49.72, 30.29; Anal.
Calcd for C11H11NO3 (FW 205.2099): C, 64.38; H, 5.40; N, 6.83.
Found: C, 64.285; H, 5.36; N, 6.83. APCI MS m/z 205.95 (M+H)+.
(S)-3-Benzoylamino-tetrahydrofuran (20.0 g, 0.105 mol) was
dissolved in ethanol (ꢀ40 ml) after which sodium hydroxide solu-
tion (25 g sodium hydroxide in 120 ml water) was added. The
reaction mixture was heated at reflux for 9–10 h, after which
TLC showed the absence of starting material. The reaction mix-
ture was cooled to room temperature and was then acidified with