D. T. Racys et al. / Bioorg. Med. Chem. 18 (2010) 4775–4782
4781
4.7. (S)-Benzyl-2-((S)-2-(hydroxymethyl)piperidine-1-
carbonyl)pyrrolidine-1-carboxylate 9
2
(29.7 mg, 0.086 mmol, 68%);
½
a 2D3
ꢄ
ꢁ45.2 (c 1.0 in CHCl3)
(SS), (found: (ESI+) 367.1630 (M + Na+). C19H24N2NaO4 requires
367.1628); mmax 2943 (C–H str), 2873, 1699, 1648 (C@O str),
1412, 1351, 1237, 1165, 1117, 764, 742, and 697 cmꢁ1; dH
(700 MHz; CDCl3; Me4Si, rotamers) 9.52 and 9.47 (1H, 2 ꢂ s,
–COH), 7.20–7.45 (5H, m, Ph-CH), 4.91–5.23 (3H, m, ꢁC(@O)OCH2,
–N–CH–), 4.82 (½H, dd, J 2.8, 8.7, –N–CH– (1 conformer)), 4.73
(½H, dd, J 2.8, 8.7, –N–CH– (1 conformer)), 3.85 (½H, d, J 13.3,
–N–HCH– (1 conformer)), 3.62–3.73 (1½H, m, –N–HCH– (1½H)),
3.48–3.62 (1H, m, –N–HCH–), 3.13 (½H, dd, J 2.9, 12.7, –N–HCH–
(1 conformer)), 3.04 (½H, dd, J 2.9, 12.7, –N–HCH– (1 conformer))
and 1.11–2.29 (10H, m, alkyl-H); dC (176 MHz; CDCl3; Me4Si, rota-
mers) 202.18, 201.33, 201.08 and 200.14 (–COH), 172.45, 172.35
and 171.94 (–NC(@O)CH–), 155.04, 154.99, 154.90 and 154.33
(–NC(@O)O–), 136.95 and 136.82 (Ph-C1), 128.52, 128.43, 128.06,
128.01, 127.95 and 127.82 (Ph-C2,3,4,5,6), 67.12 and 66.97
(–C(@O)OCH2–), 59.43 and 59.20 (–NCH–), 57.41 and 56.77
(–NCH–), 47.25 and 46.72 (–NCH2–), 44.00 and 43.80 (–NCH2–),
30.59 and 29.50 (–CH2–), 25.08, 25.03, 24.45, 24.11, 23.41 and
23.14 (3 ꢂ –CH2–) and 21.19 and 21.13 (–CH2–); m/z (ESI+) 367.1
(M+Na+, 34%), 345.2 (M+H+, 100) and 301.2 (M+ꢁCH2COH, 16).
(S)-Benzyl-2-((S)-2-((tert-butyldimethylsilyloxy)methyl)piperi-
dine-1-carbonyl)-pyrrolidine-1-carboxylate 8 (92 mg, 0.2 mmol,
1.0 equiv) was dissolved in THF (1.2 mL), and cooled in an ice bath.
TBAF (1 M) solution in THF (0.40 mL, 0.40 mmol, 2.0 equiv) was
carefully added, while the reaction was stirred at +4 °C. After 2 h
distiled the reaction was complete and water was added to quench
the reaction. The suspension was extracted with DCM, and diethyl
ether. The organic layer was washed with brine, dried over MgSO4
and was concentrated in vacuo (64 mg). The material 9 was puri-
fied on silica using hexane:ethyl acetate eluent system to give
the desired product 9 (44 mg, 0.127 mmol, 64%); ½a D28
ꢁ34.0 (c
ꢄ
0.97 in CHCl3) (SS); (found: (ESI+) 347.1964 (M+Na+) and
369.1795 (M+H+). C19H27N2O4 requires 347.1965; C19H27N2NaO4
requires 369.1785); mmax 3413 (O–H str), 2939, 2873 (C–H str),
1697, 1631 (C@O str), 1415, 1352, 1254, 1209, 1167, 1120, 1021,
919, 728 and 697 cmꢁ1; dH (700 MHz; CDCl3; Me4Si, rotamers)
7.19–7.32 (5H, m, Ph-CH), 4.91–5.20 (2H, m, –C(@O)OCH2–),
4.45–4.91 (2H, m, –N–CH– (½H), –N–HCH– (½H)), 4.13 (½H, br s,
–N–CH– (1 conformer)), 4.06 (½H, dd, J 4.1, 9.9, –HCH–OH (1 con-
former)), 3.41–3.86 (3½H, m, –HCH–OH (1½H), –N–HCH– (2H)),
3.24 (1 4H, m, –N–HCH– (1 conformer)), 3.07 (1 4H, ddd, J 2.5, 12.9,
–N–HCH– (1 conformer)), 3.00 (1 4H, ddd, J 2.5, 12.9, –N–HCH–
4.9. (S)-Benzyl 2-(2-formyl-1H-pyrrole-1-carbonyl)pyrrolidine-
1-carboxylate 3
(1 conformer)), 2.69 (½H, dt, J 2.6, 13.4, –N–HCH– (1 conformer)),
To a dry, clean round bottomed flask were added cbz-proline
(1.05 g, 4.2 mmol, 1.0 equiv), dry toluene (10 mL), and thionyl chlo-
ride (0.55 mL, 7.56 mmol, 1.8 equiv). The reaction mixture was de-
gassed and purged with argon two times. The reaction was stirred
under reflux conditions under nitrogen atmosphere for 1.5 h. [a col-
our change was noted shortly after heating began when the mixture
became yellow]. The reaction was allowed to cool down to room
temperature, and the reaction mixture was concentrated to a dark
yellow oil in vacuo. In a separate flask a solution of pyrrole-2-car-
boxaldehyde 10 (600 mg, 6.3 mmol, 1.5 equiv), and triethylamine
(0.62 mL, 8.4 mmol, 2.0 equiv) were mixed in DCM (10 mL). The
mixture was carefully added to the acyl chloride prepared in the pre-
vious step. The resulting mixture was degassed and purged with ar-
gon. The reaction was stirred for 1 d under nitrogen atmosphere. The
mixture was poured into 0.1 M HCl aq (21 mL). DCM (40 mL) was
added and phases were separated. The organic fraction was washed
successively with distiled water (20 mL), brine (50 mL), sat Na2CO3
aq sol (150 mL), distiled water (2 ꢂ 100 mL), brine (100 mL), and
dried over MgSO4. The organic layer was concentrated in vacuo to
crude dark green oil 3 (1.02 g). The oil was separated on silica using
hexane:ethyl acetate (100:0–50:50) gradient eluent system. The de-
sired product 3 (670 mg, 2.05 mmol, 49%) was isolated as colourless
1
2.50 (1H, br s, –OH), 2.40
(
4H, dt,
J
2.6, 13.4, –N–HCH–
(1 conformer)) and 1.10–2.25 (10H, m, alkyl-H); dC (176 MHz;
CDCl3; Me4Si, rotamers) 173.15, 173.04, 172.15 and 171.81
(–NC(@O)CH–), 155.41, 154.97, 154.41 and 154.36 (–NC(@O)O–),
136.94, 136.80, 136.68 and 136.60 (Ph-C1), 128.67, 128.57,
128.50, 128.39, 128.35, 127.99, 127.93, 127.88 and 127.83 (Ph-
C2,3,4,5,6), 67.34, 67.25, 67.06 and 66.94 (–C(@O)OCH2–), 62.33,
62.21, 62.02 and 60.84 (HO–CH2–), 57.84, 57.30, 57.20 and 56.79
(–NCH–), 55.53, 54.34, 51.18 and 51.08 (–NCH–), 47.30, 47.26,
46.99 and 46.75 (–NCH2–), 41.56, 41.25 and 37.14 (–NCH2–),
30.72, 30.50, 29.98 and 29.50 (–CH2–), 27.68, 26.46, 25.45, 25.32,
25.25, 24.95, 24.83, 24.71, 24.12, 23.52, 23.40, 24.11, 24.00, 23.52
and 23.40 (3 ꢂ –CH2–) and 19.94, 19.72, 19.68 and 19.56 (–CH2–
); m/z (ESI+) 385 (M+K+, 3%), 369 (M+Na+, 100), 347 (M+H+, 72)
329 (M+ꢁOH, 21), 303 (M+ꢁ43, 48) and 239 (M+ꢁPhCH2O, 3).
4.8. (S)-Benzyl-2-((S)-2-formylpiperidine-1-carbonyl)pyrroli-
dine-1-carboxylate 2
To
0.369 mmol) in anhydrous DCM at ꢁ78 °C was added dropwise
solution anhydrous DMSO (50 L, 0.637 mmol) in anhydrous
a stirred 2 M solution of oxalyl chloride (184.5 ll,
l
oil, which darkened and degraded over time; ½a D20
ꢁ101.28 (c 1.26 in
ꢄ
DCM (0.10 mL). After 10 min solution of (S)-benzyl 2-((S)-2-
(hydroxymethyl)piperidine-1-carbonyl)pyrrolidine-1-carboxylate
9 (44 mg, 0.127 mmol) in anhydrous DCM (0.15 mL) was added
dropwise. After 3 h a low resolution MS sample was taken; m/
z + 1 = 347. Triethylamine (0.154 mL, 1.11 mmol) was added. The
colourless reaction mixture instantly became yellow. The reaction
was allowed to warm up to room temperature. The mixture was
then poured into distiled water (5 mL), and was separated. The
aqueous layer was extracted with dichloromethane (3 ꢂ 10 mL).
The organic fractions were combined and washed with brine, sat-
urated NaHCO3 aqueous solution, distiled water, and brine. The or-
ganic layer was dried over magnesium sulphate and concentrated
in vacuo to give yellow oily residue 2 (60 mg, crude). Low resolu-
tion MS analysis confirmed it as the desired product 2; m/
z + 1 = 301, 345, 367. 1H NMR also confirmed the formation of
the product 2. The crude oil 2 was purified on silica using gradient
hexane:ethyl acetate eluent system (Rf = 0.145 with 50:50 hex-
ane:ethyl acetate). The compound was isolated as a colourless oil
CHCl3) (S); (found: (ESI+) 349.1165 (M+Na+). C18H18N2NaO4 re-
quires 349.1159); mmax 3124, 2957, 2885 (C–H str), 1695, 1663
(C@O str), 1547, 1443, 1410, 1353, 1259, 1170, 1110, 1023, 978,
871, 773 and 695 cmꢁ1; dH (400 MHz; CDCl3; Me4Si, rotamers)
10.30 and 10.11 (1H, s, –COH), 7.51 and 7.33 (1H, br d, J 1.57,
–NCH@CH–), 7.10–7.45 (5H, m, Ph-CH), 7.20–7.30 (1H, m,
–NC@CH–), 6.42 and 6.34 (1H, dd, J 3.3, NCH@CH), 4.98–5.25 (3H,
m, –OCH2– and –NCH–CH@O), 3.57–3.85 (2H, m, –NCH2–), 2.45
(1H, m, –NCHCH2–), 1.95–2.23 (3H, m, –NCHCH2– and –NCH2CH2–);
dC (100 MHz; CDCl3; Me4Si, rotamers) 182.30 and 181.94
(–COH), 171.81 and 171.57 (–NC(@O)CH–), 155.86 and 155.07
(–NC(@O)O–), 136.38, 135.93 and 135.72 (C–COH and Ph-C1),
128.53 and 128.45, 128.13, 127.90 and 127.85 (Ph-C2,3,4,5,6),
125.86 and 125.56 (–NCH@CH–), 123.28 and 122.98 (–NC@CH–),
113.27 and 113.22 (–NCH@CH–), 67.41 (–OCH2–), 59.98 and 59.46
(–NCH–CH@O), 47.19 and 46.68 (–NCH2–), 31.64 and 30.61
(–NCHCH2–), 24.44 and 23.60 (–NCH2CH2–); m/z (ESI+) 349
(M+Na+, 70%), 327 (M+H+, 100), 309 (M+ꢁ17, 3), 283 (17) and 255