Pyrrolidines and Antitumor Activity
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 13 4243
amine R′NH2 (0.1-0.3 M) in 1,2-dichloroethane at 25 °C. After
the complete disappearance of the reagents (TLC monitoring),
the solution was poured into a saturated aqueous solution of
NaHCO3 (5 mL per mmol). The organic layer was collected,
and the aqueous layer was extracted with EtOAc (10 mL per
mmol, 3 times). The combined organic extracts were dried
(MgSO4). Solvent evaporation in vacuo and flash chromatog-
raphy on silica gel gave pure diamines.
1H), 4.47 (m, 1H), 4.08 (m, 1Hâ), 3.94 (m, 1HR), 3.88 (d, 1H),
3.82 (d, 1HR), 3.73 (d, 1Hâ), 3.28 (m, 1H), 2.51 (m, 2H), 1.45,
1.36, 1.32 (3s, 15 H). 13C NMR (101 MHz, CDCl3) δ: 154.4,
154.2, 140.4, 139.2, 128.0, 127.9, 127.7, 126.7, 111.5, 83.8, 83.0,
79.7, 79.3, 78.6, 77.0, 69.1, 68.9, 63.8, 63.4, 52.1, 48.0, 47.4,
28.3, 26.9, 24.9. MS (CI-NH3): 469 (M + H+, 100), 413 (21),
361 (14), 305 (22), 261 (7), 186 (5), 142 (12). Anal. (C27H36N2O5)
C 69.29, H 7.83, N 5.95.
Procedure 2: General Method for the Acidic Cleavage
of Boc and Acetonide Moieties. A 5% solution of protected
diamines in 4:1 CF3COOH/H2O or in 4 M aqueous HCl was
stirred at 25 °C for 1 h. After solvent evaporation in vacuo,
the residue was purified by flash chromatography on silica gel
or alumina.
(2R,3R,4S)-2-({[(1R,2S)-2-Hydroxy-1,2-diphenylethyl]-
amino}methyl)pyrrolidine-3,4-diol ((+)-7c). Procedure 2:
6c (50 mg), 4:1 CF3COOH/H2O. FC (CH3CN/NH4OH 4:1): 35
mg (100%). 1H NMR (400 MHz, MeOD) δ: 7.29-7.12 (m, 10H),
5.06 (d, 1H), 4.17 (m, 1H), 4.07 (d, 1H), 3.88 (dd, 1H), 3.52 (m,
1H), 3.35 (dd, 1H), 3.23 (dd, 1H), 2.98 (dd, 1H), 2.67 (m, 1H).
13C NMR (101 MHz, MeOD) δ: 143.5, 130.8, 130.0, 129.7,
129.3, 128.8, 77.8, 75.8, 71.8, 71.2, 62.5, 51.7, 48.0. MS (CI-
NH3): 329 (M + H+, 57), 308 (2), 275 (3), 244 (3), 221 (100),
197 (9), 152 (6), 118 (35), 106 (66), 91 (40), 77 (49).
tert-Butyl(3aR,4R,6aS)-4-({[(1R)-2-Hydroxy-1-phenylethyl]-
amino}methyl)-2,2-dimethyl tetrahydro-5H-[1,3]dioxolo-
[4,5-c]pyrrole-5-carboxylate ((-)-6a). Procedure 1: 5 (261
mg, 0.96 mmol), D-(-)-R-phenylglycinol (132 mg, 0.96 mmol),
NaBH(OAc)3 (285 mg, 1.34 mmol), ClCH2CH2Cl (10 mL). FC
tert-Butyl (3aR,4R,6aS)-4-({[(1S,2R)-2-Hydroxy-1,2-
diphenylethyl]amino}methyl)-2,2-dimethyltetrahydro-
5H-[1,3]dioxolo[4,5-c]pyrrole-5-carboxylate ((-)-6d). Pro-
cedure 1: 5 (104 mg, 0.38 mmol), (1R,2S)-2-amino-1,2-
diphenylethanol (82 mg, 0.38 mmol), NaBH(OAc)3 (114 mg,
0.54 mmol), ClCH2CH2Cl (4 mL). FC (EtOAc/light petroleum
1:1): 69 mg (38%), 1.2:1 mixture of rotamers. 1H NMR (400
MHz, CDCl3) δ: 7.27-7.08 (m, 10H), 4.79 (d, 1HR), 4.75 (d,
1Hâ), 4.63 (m, 1H), 4.39 (d, 1Hâ), 4.34 (d, 1HR), 4.19 (dd,1Hâ),
4.02 (d, 1HR), 3.97 (dd, 1Hâ), 3.85-3.74 (m, 2H), 3.15 (m, 1H),
1
(EtOAc): 281 mg (74%), 1.2:1 mixture of rotamers. H NMR
(400 MHz, MeOD) δ: 7.38-7.25 (m, 5H), 4.75-4.60 (m, 2H),
4.10 (dd, 1H), 4.03 (dd, 1H), 3.75 (m, 2H), 3.66-3.51 (m, 2H),
3.37 (m, 1H), 2.64-2.43 (m, 2H), 1.48, 1.40 (2s, 9H), 1.43 (s,
3H), 1.33 (s, 3H). 13C NMR (101 MHz, MeOD) δ: 157.3, 154.6,
142.9, 130.4, 129.6, 129.4, 113.4, 85.4, 84.9, 82.2, 82.1, 81.6,
80.9, 68.9, 68.7, 67.5, 67.2, 66.2, 65.8, 53.9, 53.6, 50-49, 29.5,
28.1, 25.9. MS (CI-NH3): 394 (16), 393 (M + H+, 12), 362 (3),
338 (12), 305 (15), 262 (6), 199 (10), 142 (42), 118 (100), 91
(95), 77 (26). Anal. (C21H32N2O5) C 64.49, H 8.07.
2.60-2.38 (m, 2H), 1.45, 1.42 (2s, 9H), 1.39, 1.28 (2s, 6H). 13
C
(2R,3R,4S)-2-({[(1R)-2-Hydroxy-1-phenylethyl]amino}-
methyl)pyrrolidine-3,4-diol ((+)-7a). Procedure 2: 6a (25
mg), 4 M HCl. FC (CH3CN/NH4OH 4:1): 16 mg (100%). 1H
NMR (400 MHz, MeOD) δ: 7.42-7.29 (m, 5H), 4.26 (ddd, 1H),
3.97 (dd, 1H), 3.83 (dd, 1H), 3.70 (dd, 1H), 3.64 (dd, 1H), 3.49-
3.43 (d and m, 2H), 3.25 (dd, 1H), 2.93 (dd, 1H), 2.78 (dd, 1H).
13C NMR (101 MHz, MeOD) δ: 142.6, 130.6, 129.6, 129.4, 75.5,
71.9, 68.3, 67.5, 63.7, 51.5, 48.1). MS (CI-NH3): 253 (M + H+,
9), 221 (8), 150 (7), 120 (100), 91 (17). Electrospray: 253.31.
Anal. (C13H20N2O3) C 61.76, H 7.95, N 11.08.
tert-Butyl(3aR,4R,6aS)-4-({[(1S)-2-Hydroxy-1-phenylethyl]-
amino}methyl)-2,2-dimethyl tetrahydro-5H-[1,3]dioxolo-
[4,5-c]pyrrole-5-carboxylate ((+)-6b). Procedure 1: 5 (97
mg, 0.36 mmol), L-(+)-R-phenylglycinol (49 mg, 0.36 mmol),
NaBH(OAc)3 (106 mg, 0.50 mmol), ClCH2CH2Cl (3 mL). FC
(EtOAc): 84 mg (60%), 1.7:1 mixture of rotamers.1H NMR (400
MHz, MeOD) δ: 7.37-7.26 (m, 5H), 4.76 (m, 1H), 4.56 (d, 1HR),
4.49 (d, 1Hâ), 4.14 (dd, 1Hâ), 4.00 (dd, 1HR), 3.76 (m, 2H), 3.68-
3.52 (m, 2H), 3.36 (m, 1H), 2.66 (m, 1H), 2.46 (dd, 1H), 1.50
(s, 3H), 1.43, 1.41 (2s, 9H), 1.30 (s, 3H). 13C NMR (101 MHz,
MeOD) δ: 157.2, 142.8, 130.4, 129.7, 129.5, 113.4, 85.7, 85.3,
82.2, 82.1, 81.7, 80.9, 68.8, 67.4, 66.3, 65.7, 54.4, 53.6, 50-49,
29.5, 28.1, 25.8. MS (CI-NH3): 394 (100), 393 (M + H+, 49),
362 (55), 338 (16), 306 (35), 262 (13), 199 (16), 150 (72), 91
(48). Anal. (C21H32N2O5) C 64.33, H 8.33, N 7.01.
NMR (101 MHz, CDCl3) δ: 155.0, 154.5, 140.1, 139.2, 128.3,
128.2, 128.1, 127.8, 127.6, 126.9, 126.7, 111.5, 83.9, 83.1, 80.0,
79.9, 79.3, 78.7, 77.2, 69.1, 68.1, 63.9, 62.8, 52.1, 51.8, 47.8,
47.2, 28.3, 26.9, 25.0. MS (CI-NH3): 469 (M + H+, 100), 413
(26), 361 (10), 305 (20), 261 (5), 186 (2), 142 (10), 84 (12). Anal.
(C27H36N2O5) C 69.30, H 7.69, N 5.94.
(2R,3R,4S)-2-({[(1S,2R)-2-Hydroxy-1,2-diphenylethyl]-
amino}methyl)pyrrolidine-3,4-diol ((+)-7d). Procedure 2:
6d (52 mg), 4:1 CF3COOH/H2O. FC (CH3CN/NH4OH 4:1): 36
mg (100%). 1H NMR (400 MHz, MeOD) δ: 7.30-7.14 (m, 10H),
4.95 (d, 1H), 4.20 (ddd, 1H), 3.96 (d, 1H), 3.88 (dd, 1H), 3.49
(ddd, 1H), 3.32 (dd, 1H), 3.22 (dd, 1H), 2.82 (dd, 1H), 2.76 (dd,
1H). 13C NMR (101 MHz, MeOD) δ: 143.8, 141.2, 130.6, 129.9,
129.7, 129.3, 129.0, 78.9, 75.4, 72.0, 70.5, 62.9, 51.7, 47.7. MS
(CI-NH3): 329 (M + H+, 23), 221 (19), 197 (44), 180 (10), 133
(33), 105 (100), 91 (61), 77 (52).
tert-Butyl (3aR,4R,6R,6aS)-4-({[(1R)-2-Hydroxy-1-
phenylethyl]amino}methyl)-6-[(methoxymethoxy)meth-
yl]-2,2-dimethyltetrahydro-5H-[1,3]dioxolo[4,5-c]pyrrole-
5-carboxylate ((-)-9). Dimethylsulfoxide (DMSO) (35 µL,
0.50 mmol, 2.4 equiv) was added to a solution of oxalyl chloride
(21 µL, 0.24 mmol, 1.15 equiv) in anhydrous dichloromethane
(1.5 mL) and cooled to -78 °C. After 20 min, alcohol 8 (72 mg,
0.21 mmol, 1 equiv) in solution in anhydrous dichloromethane
(2.5 mL) was added dropwise. After 20 min, triethylamine (144
µL, 1.04 mmol, 5 equiv) was added, and the mixture was
warmed to -30 °C for 20 min. The mixture was poured into
water (5 mL) and extracted with dichloromethane (5 mL, 3
times). The combined organic phases were washed with brine
(5 mL), dried over MgSO4, filtered, and concentrated in vacuo
to afford a crude aldehyde. Sodium triacetoxyborohydride (62
mg, 0.29 mmol, 1.4 equiv) was added portionwise to a stirred
solution of the crude aldehyde (0.21 mmol, 1 equiv) and d-(-)-
R-phenylglycinol (29 mg, 0.21 mmol, 1 equiv) in anhydrous
dichloroethane (2 mL). After being stirred at room temperature
overnight, the solution was poured into a saturated aqueous
solution of NaHCO3 (5 mL). The organic layer was collected,
and the aqueous layer was extracted with CH2Cl2 (5 mL, 3
times). The combined organic extracts were dried (MgSO4).
Solvent evaporation in vacuo and flash chromatography on
silica gel (EtOAc) afforded (-)-9 (63 mg, 65%, 2 steps). 1H NMR
(400 MHz, CDCl3) δ: 7.38-7.26 (m, 5H), 4.79 (dd, 1H), 4.67
(s, 2H), 4.64 (m, 1H), 4.39-3.99 (m, 2H), 3.89 (m, 1H), 3.81-
3.69 (m, 4H), 3.55 (dd, 1H), 3.39 (s, 3H), 2.66 (m, 2H), 1.53,
1.39 (2s, 15 H). 13C NMR (101 MHz, CDCl3) δ: 154.2, 140.2,
(2R,3R,4S)-2-({[(1S)-2-Hydroxy-1-phenylethyl]amino}-
methyl)pyrrolidine-3,4-diol ((+)-7b). Procedure 2: 6b (30
25
mg), 4 M HCl. FC (CH3CN/NH4OH 4:1): 19 mg (100%). [R]589
25
) +42, [R]57725 ) +46, [R]54625 ) +50, [R]43525 ) +85, [R]405
)
+99 (c ) 0.55, H2O). 1H NMR (400 MHz, MeOD) δ: 7.42-
7.31 (m, 5H), 4.24 (ddd, 1H), 3.97 (dd, 1H), 3.83 (dd, 1H), 3.70
(dd, 1H), 3.64 (dd, 1H), 3.57 (ddd, 1H), 3.43 (dd, 1H), 3.27 (dd,
1H), 2.91 (dd, 1H), 2.80 (dd, 1H). 13C NMR (101 MHz, MeOD)
δ: 142.5, 130.6, 129.6, 129.5, 75.4, 72.0, 68.5, 66.9, 62.9, 51.8,
47.7. MS (CI-NH3): 253 (M + H+, 14), 221 (8), 235 (2), 195
(4), 138 (36), 116 (48), 98 (100), 84 (47). Anal. (C13H20N2O3) C
61.91, H 7.92, N 11.22.
tert-Butyl (3aR,4R,6aS)-4-({[(1R,2S)-2-Hydroxy-1,2-
diphenylethyl]amino}methyl)-2,2-dimethyltetrahydro-
5H-[1,3]dioxolo[4,5-c]pyrrole-5-carboxylate ((-)-6c). Pro-
cedure 1: 5 (114 mg, 0.42 mmol), (1S,2R)-2-amino-1,2-
diphenylethanol (90 mg, 0.42 mmol), NaBH(OAc)3 (125 mg,
0.59 mmol), ClCH2CH2Cl (4 mL). FC (EtOAc/light petroleum
1
1:1): 120 mg (61%), 1.2:1 mixture of rotamers. H NMR (400
MHz, CDCl3) δ: 7.41-7.14 (m, 10H), 4.77 (d, 1H), 4.56 (m,