7
A solution of pyrrolidine ketone 9b (90.0 mg, 0.199 mmol) in
dry MeOH (5 mL) was cooled to 0 °C and NaBH4 (15.1 mg,
0.399 mmol) was added portion wise. The reaction was stirred
for 1 hour, then quenched with 2M HCl (5 mL) and extracted
with CH2Cl2 (3 x 20 mL). The combined organic fractions were
washed with saturated aqueous NaHCO3 solution (2 x 20 mL),
dried with MgSO4, filtered, and concentrated in vacuo without
further purification to give 13b as a colourless oil (90.3 mg,
mg, 0.398 mmol) and imidazole (0.3 mg, 0.00398 mmol) in a
dry flask under N2 at room temperature and the reaction was
stirred for 30 mins. Carbon disulfide (0.060 mL, 0.995 mmol)
was added dropwise and the reaction stirred for 30 mins,
followed by dropwise addition of methyl iodide (0.060 mL, 0.995
mmol). The reaction was stirred for 16 hours, then quenched with
H2O (2 mL) and partitioned with CH2Cl2 (20 mL). The organic
fraction was washed with 1M HCl (20 mL), saturated aqueous
NaHCO3 solution (20 mL), and H2O (20 mL) dried with MgSO4,
filtered, and concentrated in vacuo. The crude product was
purified with flash column chromatography (25-75%
EtOAC/hexane) to give 14b as a pale yellow oil (43.0 mg, 0.124
1
0.199 mmol, 100% yield). H NMR (400 MHz, Chloroform-d) δ
7.45 – 7.25 (m, 5H, Ar-H), 7.16 (ddd, J = 7.8, 7.8, 1.8 Hz, 1H, H-
23), 7.12 (dd, J = 7.5, 1.8 Hz, 1H, H-21), 6.88 (ddd, J = 7.8, 7.5,
1.1 Hz, 1H, H-22), 6.84 (dd, J = 7.8, 1.1 Hz, 1H, H-24), 5.23 –
5.01 (m, 2H, H-5), 4.69 (s, 0.3H, O-H), 4.32 – 3.98 (m, 1H, H-
10), 3.81 (s, 3H, H-26), 3.69 – 3.47 (m, 1H, H-12), 3.47 – 3.29
(m, 2H, H-7), 2.60 (t, J = 7.5 Hz, 2H, H-19), 2.10 – 1.24 (m,
18H, CH2) ppm; 13C NMR (101 MHz, Chloroform-d) δ
157.5(157.0) (C-25), 155.6(155.0) (C-6), 137.0(136.8) (C-4),
131.4 (C-20), 129.8 (C-21), 128.6(128.6) (Ar-CH), 128.1(128.1)
(Ar-CH), 128.0(127.9) (Ar-CH), 126.9 (C-23), 120.4 (C-22),
110.3 (C-24), 70.8(70.3) (C-12 diastereomer 1), 69.8(67.7) (C-12
diastereomer 2),67.2(66.9) (C-5), 56.2(54.7) (C-10), 55.3 (C-26),
46.5(46.3) (C-7), 43.9(43.5) (CH2), 38.2(37.1) (CH2), 32.1(31.3)
(CH2), 30.2(30.0) (CH2), 30.0(29.9) (CH2), 29.8(29.8) (CH2),
29.7(29.6) (CH2), 26.2(25.8) (CH2), 23.9(23.7) (CH2),22.4(22.1)
(CH2) ppm; IR (ATR): νmax 3424, 2924, 2853 , 1678, 1600, 1587,
1493, 1454, 1411, 1356, 1336, 1290, 1240, 1212, 1187, 1162,
1101, 1049, 1029, 978, 913, 871, 808, 768, 751, 697, 675, 603,
542, 464 cm-1; HRMS (ESI) 454.2954 (M + H+. C28H40NO4
requires 454.2952); 476.2773 (M + Na+. C28H39NNaO4 requires
476.2771).
1
mmol, 63% yield, 7:1 dr). H NMR (400 MHz, Chloroform-d) δ
7.14 (ddd, J = 7.8, 7.4, 1.8 Hz, 1H, H-16), 7.10 (dd, J = 7.4, 1.8
Hz, 1H, H-18), 6.86 (dd, J = 7.4, 7.4 Hz, 1H, H-17), 6.82 (d, J =
7.8 Hz, 1H, H-19), 4.50 – 4.30 (m, 0.1H, H-7 diastereomer 1),
4.27 – 4.11 (m, 0.9H, H-7 diastereomer 2), 3.80 (s, 3H, H-21),
3.66 – 3.35 (m, 3H, H-2, H-5), 2.58 (t, J = 7.8 Hz, 2H, H-14),
2.17 – 2.05 (m, 2H, CH2), 2.03 – 1.91 (m, 1H, CH2), 1.86 –1.43
(m, 7H, CH2), 1.43 – 1.17 (m, 8H, CH2) ppm; 13C NMR (101
MHz, Chloroform-d) δ 157.5 (C-20), 153.5 (C-1), 131.3 (C-15),
129.8 (C-16), 126.9 (C-18), 120.4 (C17), 110.3(C19), 77.5 (C-7),
56.6(55.3) (C-5), 55.4 (C-21), 46.5 (C-2), 35.3 (CH2), 33.8
(CH2), 33.3 (C-4), 30.2 (C-14), 29.9 (CH2), 29.6 (CH2), 29.5
(CH2), 29.5 (CH2), 24.9 (CH2), 23.1 (C-3) ppm; IR (ATR): νmax
2925, 2854, 1689, 1600, 1587, 1493, 1462, 1423, 1370, 1342,
1312, 1289, 1240, 1201, 1176, 1117, 1049, 1029, 924, 887, 753,
653, 568, 477 cm-1; HRMS (ESI) 346.2375 (M + H+. C21H32NO3
requires 346.2377); 368.2194 (M + Na+. C21H31NNaO3 requires
368.2196).
3.8. 3-Dodecyl-hexahydro-pyrrolo[1,2-c][1,3]oxazin-1-one
(mixture of diastereomers) (14a)
3.10. N-Cbz-(S)-2-(2-Dodecyl-[1,3]dithiolan-2-ylmethyl)-
pyrrolidine (15a)
A solution of hydroxy pyrrolidine 13a (47.3 mg, 0.113 mmol)
in dry THF (2 mL) was added to NaH (60% in mineral oil, 9.1
mg, 0.227 mmol) and imidazole (0.2 mg, 0.00227 mmol) in a dry
flask under N2 at room temperature and the reaction was stirred
for 30 mins. Carbon disulfide (0.040 mL, 0.566 mmol) was
added dropwise and the reaction stirred for 30 mins, followed by
dropwise addition of methyl iodide (0.040 mL, 0.566 mmol). The
reaction was stirred for 16 hours, then quenched with H2O (2
mL) and partitioned with CH2Cl2 (20 mL). The organic fraction
was washed with 1M HCl (20 mL), saturated aqueous NaHCO3
solution (20 mL), and H2O (20 mL) dried with MgSO4, filtered,
and concentrated in vacuo. The crude product was purified with
flash column chromatography (25-75% EtOAC/hexane) to give
14a as a white solid (23.4 mg, 0.0756 mmol, 67% yield, 5:1 dr).
1H NMR (400 MHz, Chloroform-d) δ 4.44 – 4.35 (m, 0.1H, H-7
diastereomer 1), 4.24 – 4.13 (m, 0.9H, H-7 diastereomer 2), 3.62
– 3.40 (m, 3H, H-2, H-5), 2.19 – 1.90 (m, 3H, CH2), 1.84 – 1.61
(m, 2H, CH2), 1.61 – 1.13 (m, 23H, CH2), 0.86 (t, J = 6.7 Hz, 3H,
H-19) ppm; 13C NMR (101 MHz, Chloroform-d) δ 153.5 (C-1),
77.5 (C-7), 56.6 (C-5), 46.5 (C-2), 35.3 (CH2), 33.8 (CH2), 33.3
(CH2), 32.0 (CH2), 29.7 (CH2), 29.7 (CH2), 29.7 (CH2), 29.7
(CH2), 29.6 (CH2), 29.6 (CH2), 29.5 (CH2), 29.4 (CH2), 24.9
(CH2), 23.1 (CH2), 22.8 (CH2), 14.2 (C-19) ppm; IR (ATR): νmax
2954, 2917, 2849, 1688, 1519, 1463, 1437, 1378, 1324, 1306,
1243, 1200, 1155, 1127, 1050, 1015, 971, 905, 887, 802, , 754,
729, 670, 655, 631, 588, 523, 483, 458 cm-1; HRMS (ESI)
310.2740 (M + H+. C19H36NO2 requires 310.2741); 332.2555 (M
+ Na+. C19H35NNaO2 requires 332.2560); mp. 63-66 °C.
Pyrrolidine ketone 9a (42.4 mg, 0.102 mmol) and 1,2-
ethanedithiol (0.17 mL, 2.04 mmol) was dissolved in dry CH2Cl2
(0.7 mL, 0.16M) under N2. BF3.Et2O (0.15 mL, 1.22 mmol) was
added dropwise and the reaction stirred for 4 hours. The reaction
was quenched with acetone (0.6 mL), diluted with saturated
aqueous NaHCO3 solution (10 mL), and extracted with CH2Cl2 (2
x 10 mL). The combined organic fractions were dried with
MgSO4, filtered and concentrated in vacuo. The crude material
was purified by column chromatography (10% EtOAc/hexane) to
give 15a as a colourless oil (14.9 mg, 0.0303 mmol, 30% yield).
1H NMR (400 MHz, Chloroform-d) δ 7.39 – 7.23 (m, 5H, Ar-H),
5.18 – 5.05 (m, 2H, H-5), 4.20 – 4.01 (m, 1H, H-10), 3.43 – 3.30
(m, 2H, H-7), 3.32 – 3.00 (m, 4H, H-25, H-26), 2.52 (d, J = 14.2
Hz, 0.5H, H-11), 2.31 (d, J = 14.2 Hz, 0.5H, H-11), 2.11 – 2.07
(m, 1H, H-9), 2.01 – 1.76 (m, 6H, CH2), 1.55 – 1.00 (m, 20H,
CH2), 0.86 (t, J = 6.7 Hz, 3H, H-24) ppm; 13C NMR (101 MHz,
Chloroform-d) δ 154.8 (C-6), 134.9 (C-4), 128.5 (Ar-CH), 127.9
(Ar-CH), 127.8 (Ar-CH), 69.8 (C-12), 66.9 (66.6) (C-5), 56.4
(55.8) (C-10), 46.0 (C-7), 45.4 (C-11), 44.6 (CH2), 39.6 (C-25),
39.1 (C-26), 32.1(31.6) (C-9), 32.0 (CH2), 29.8 (CH2), 29.6
(CH2), 29.5 (CH2), 26.8 (CH2), 24.0(23.2) (C-8), 22.8 (C-23),
14.2 (24) ppm; IR (ATR): νmax 2923, 2852, 1700, 1497, 1455,
1408, 1356, 1337, 1186, 1029, 768, 750, 697, 602 cm-1; HRMS
(ESI) 492.2950 (M + H+. C28H46NO2S2 requires 492.2964);
514.2778 (M
+
Na+. C28H45NNaO2S2 requires 514.2784);
25
530.2717 (M + K+. C28H45KNO2S2 requires 530.2733); [α]D
-
23.6° (c 0.71, CHCl3).
3.11. N-Cbz-(S)-2-{2-[7-(2-Methoxy-phenyl)-heptyl]-
[1,3]dithiolan-2-ylmethyl}-pyrrolidine (15b)
3.9. 3-[7-(2-Methoxy-phenyl)-heptyl]-hexahydro-pyrrolo[1,2-
c][1,3]oxazin-1-one (mixture of diastereomers) (14b)
Pyrrolidine ketone 9b (55.9 mg, 0.124 mmol) and 1,2-
ethanedithiol (0.210 mL, 2.48 mmol) was dissolved in dry
CH2Cl2 (0.8 mL, 0.16M) under N2. BF3.Et2O (0.180 mL, 1.49
A solution of hydroxy pyrrolidine 13b (90.3 mg, 0.199 mmol)
in dry THF (2 mL) was added to NaH (60% in mineral oil, 15.9