3792 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 16
Stragies et al.
and filtered over Celite, and the solvent was removed by an
evaporator. The crude product was purified by chromatography on
silica gel using ethyl acetate/MeOH. Yield: 820 mg (74%). H
evaporator. The crude product was purified by chromatography on
silica gel using ethyl acetate/hexane. Yield: 600 mg (40%). H
1
1
NMR (DMSO-d6): δ ) 8.06 (d, 1H, J ) 8.8), 7.73 (t, 1H, J )
5.8), 7.35 (m, 5H), 6.98 (s, 2H), 5.05 (s, 2H), 4.75 (m, 1H), 4.09
(m, 1H), 3.84 (m, 1H), 3.76 (t, 2H, J ) 15.2), 3.67-3.35 (m, 3H),
3.17 (m, 2H), 2.53 (s, 6H), 2.50 (t, 1H, J ) 1.9), 2.22 (s, 3H), 2.04
(m, 2H), 1.56 (m, 2H), 1.13 (s, 9H). 13C NMR (DMSO-d6): δ )
169.1 (Cq), 168.8 (Cq), 154.1 (Cq), 141.4 (Cq), 138.4 (Cq), 136.9
(Cq), 134.4 (Cq), 131.4 (CH), 128.3 (CH), 127.7 (CH), 127.4 (CH),
80.7 (CH2), 77.6 (CH), 67.6 (CH2), 61.1 (CH2), 57.9 (CH), 57.4
(CH2), 54.7 (CH), 51.8 (CH2), 34.0 (CH2), 27.1 (CH3), 23.0 (CH2),
22.4 (CH3), 20.2 (CH3), 19.2 (Cq). LCMS: m/z 634.2 [MH+].
NMR (DMSO-d6): δ ) 8.27 (dd, 1H, J ) 0.9, 4.9), 7.72-7.62
(m, 2H), 7.47 (d, 1H, J ) 8.3), 7.07 (m, 3H), 5.02 (dd, 1H, J )
4.9, 8.3), 4.03 (mc, 1H), 3.92-3.62 (mc, 7H), 3.43 (t, 1H, J ) 6.8),
2.80 (d, 2H, J ) 2.9), 2.53 (s, 6H), 1.84 (dd, 1H, J ) 7.3, J )
14.2), 1.40 (s, 21H), 1.28 (s, 9H). 13C NMR (DMSO-d6): δ ) 169.6
(Cq), 166.7 (Cq), 154.3 (Cq), 153.5 (Cq), 150.2 (Cq), 147.3 (CH),
143.1 (Cq), 140.0 (Cq), 137.2 (CH), 133.6 (Cq), 131.7 (CH), 120.4
(CH), 119.9 (CH), 84.3 (Cq), 82.2 (Cq), 80.8 (CH), 80.3 (Cq), 67.5
(CH2), 59.7 (CH2), 57.9 (CH), 55.9 (CH), 51.3 (CH2), 50.4 (CH2),
35.9 (CH2), 27.8 (CH3), 27.5 (CH3), 27.3 (CH3), 22.4 (CH3), 20.5
(CH3). LCMS: m/z 778.6 [MH+].
Synthesis of 2S,3R,5S-3-{2-[1-(3,3-Dimethylbutyryl)-5-(pyri-
din-2-ylaminomethyl)pyrrolidin-3-yloxy]acetylamino}-2-(2,4,6-
trimethylbenzenesulfonylamino)propionic Acid (7b). 6 (15 mg,
0.02 mmol) and 300 µL of DIPEA were dissolved at 0 °C in 1 mL
of DCM. 3,3-Dimethylbutyryl chloride (4 mg, 0.02 mmol), dis-
solved in 200 µL of DCM, was added, and the solution was stirred
at 0 °C for 2 h. The solvent was evaporated and the crude reaction
mixture was redissolved in 300 µL of TFA and stirred for 2 h at
room temperature. After evaporation of the TFA, the product was
purified by HPLC and freeze-dried using ACN/H2O. Yield: 11.7
mg (83%, TFA salt). 1H NMR (DMSO-d6): (partial signal doubling
due to rotameres) δ ) 13.41 (s, broad, 1H), 8.62 (s, broad, 1H),
7.97 (d, 1H, J ) 5.9), 7.95 (d, 1H, J ) 8.8), 7.90 (m, 1H), 7.69 (t,
1H, J ) 5.9), 7.10 (m, 1H), 6.97 (s, 2H), 6.85 (t, 1H, J ) 6.6),
4.20 (m, 1H), 4.15 (m, 1H), 3.87-3.67 (m, 6H), 3.60 (dd, 1H, J )
5.1, J ) 11.7), 3.55 (m, 1H), 3.43 (m, 2H), 3.17 (m, 1H), 2.52 (s,
3H), 2.50 (m, 6H), 2.17 (m, 1H), 1.96 (m, 1H), 0.98 (s, 9H).
LCMS: m/z 618.8 [MH+].
Synthesis of 2S,3R,5S-4-{[2-tert-Butoxycarbonyl-2-(2,4,6-tri-
methylbenzenesulfonylamino)ethylcarbamoyl]methoxy}-2-
formylpyrrolidine-1-carboxylic Acid Benzyl Ester (11). 10 (120
mg, 0.19 mmol) and 293 µL (2.1 mmol) of NEt3 were dissolved in
2 mL of DCM/DMSO (V/V ) 3/1) and cooled to 0 °C. SO3-
pyridine complex (302 mg, 1.9 mmol) was added and the reaction
mixture was stirred for 2 h. DCM was removed by an evaporator
and the crude reaction mixture was poured into 30 mL of ethyl
acetate. The organic layer was extracted with H2O, saturated
NaHCO3, and NaCl solution. The organic layer was dried over Na2-
SO4 and the solvent was removed by an evaporator. Yield: 109
1
mg (91%). H NMR (DMSO-d6): δ ) 9.42 (s, 1H), 8.06 (d, 1H,
J ) 8.8), 7.79 (t, 2H, J ) 5.8), 7.35 (m, 5H), 6.97 (s, 2H), 5.10
(m, 2H), 4.21 (m, 1H), 4.10 (m, 1H), 3.85-3.46 (m, 5H), 3.41 (m,
1H), 3.34 (t, 2H, J ) 11.7), 3.18 (m, 1H), 2.53 (s, 6H), 2.21 (s,
3H), 1.12(s, 9H). LCMS: m/z 632.6 [MH+].
Synthesis of 2S,3R,5S-4-{[2-Carboxy-2-(2,4,6-trimethylben-
zenesulfonylamino)ethylcarbamoyl]methoxy}-2-[(4-chloropyri-
din-2-ylamino)methyl]pyrrolidine-1-carboxylic Acid Benzyl Es-
ter (12b). 11 (40 mg, 0.063 mmol), 16.3 mg (0.127 mmol) of
4-chloropyridin-2-ylamine, and 37.8 µL (0.127 mmol) of Ti(OiPr)4
were dissolved in 500 µL of dichloroethane. After stirring for 4 h
at room temperature, 27.9 mg (0.444 mmol) of NaBH(OAc)3 was
added and the reaction was stirred overnight. Saturated NaHCO3
solution (100 µL) was added, and the mixture was stirred for 1 h
and dried with Na2SO4. The solvent was evaporated and the crude
reaction mixture was redissolved in 300 µL of TFA and stirred for
2 h at room temperature. After evaporation of the TFA, the product
was purified by HPLC and freeze-dried with ACN/H2O. Yield: 11.6
mg (23% TFA salt). 1H NMR (DMSO-d6): δ ) 7.95 (dd, 1H, J )
6.6, J ) 12.4), 7.90 (d, 1H, J ) 6.6), 7.67 (m, 1H), 7.35 (m, 5H),
6.95 (s, 2H), 6.77 (m, 1H), 5.09 (s, 2H), 4.13 (m, 2H), 4.06 (m,
1H), 3.82 (m, 2H), 3.74-3.57 (m, 4H), 3.53-3.33 (m, 4H), 3.15
(m, 1H), 2.51 (s, 6H), 2.21 (s, 3H), 2.12 (m, 1H), 1.90 (m, 1H).
LCMS: m/z 689.2 [MH+].
General Procedure B for the Synthesis of Compounds 12a-
c. Synthesis of 2S,4R-2-(tert-Butyldimethylsilanyloxymethyl)-4-
carboxymethoxypyrrolidine-1-carboxylic Acid Benzyl Ester (9).
8 (1.5 g, 4.1 mmol), 558 mg (8.2 mmol) of imidazole, and 800 mg
(8.2 mmol) of tert-butyldimethylsilyl chloride were dissolved in
50 mL of DMF and stirred overnight. The reaction mixture was
dissolved in 300 mL of MTBE; extracted with water, saturated
NaHCO3, and NaCl solution; and dried with Na2SO4. The solvent
was removed by an evaporator. The crude reaction mixture was
dissolved in 40 mL of MeOH, and 688 mg (16.4 mmol) of LiOH
was added. After stirring overnight, NH4Cl was added, and the
solids were filtered off. The solvent was removed by an evaporator
and the product was purified by chromatography on silica gel using
1
ethyl acetate/hexane. Yield: 2.08 g (>116%, siloxane). H NMR
(DMSO-d6): δ ) 7.94 (m, 1H), 7.37 (m, 3H), 7.30 (m, 1H), 5.06
(m, 3H), 4.16 (m, 1H), 3.84 (m, 1H), 3.64-3.15 (m, 4H), 2.06 (m,
1H), 2.00 (m, 2H) 1.02 (s, 9H), 0.99 (s, 6H). 13C NMR (DMSO-
d6): δ ) 185.4 (Cq), 172.0 (Cq), 128.3 (CH), 127.7 (CH), 127.3
(CH), 76.7 (CH), 67.2 (CH2), 65.8 (CH2), 61.2 (CH2), 57.8 (CH),
51.7 (CH2), 22.1 (CH3), 15.1 (Cq), -0.3 (CH3). LCMS: m/z 367.4
[M-(tert-butyl)+].
General Procedure for the Synthesis of Compounds 1, 19a-
d. The compounds were purified by HPLC with >98% purity (10-
20 mg). The corresponding overall yields were between 15 and
55%.
Synthesis of 12S,14R,30S-4-{[2-Carboxy-2-(2,4,6-trimethyl-
benzenesulfonylamino)ethylcarbamoyl]methoxy}-2-(pyridin-2-
ylaminomethyl)pyrrolidine-1-carboxylic Acid Benzyl Ester (1).4
(17 mg, 40 µmol), 14 mg (0.0409 mmol) of 5, 20 mg (41 µmol) of
HBTU, and 16 mL (120 µmol) of DIPEA were dissolved in 2 mL
of DMF and stirred for 2 h. The solvent was removed by an
evaporator and the crude product was purified by HPLC. The
product was dissolved in 2 mL of TFA and the mixture stirred for
2 h at room temperature. After evaporation of the TFA, the crude
product was freeze-dried using ACN/H2O. Yield: 14.4 mg (47%,
TFA salt). 1H NMR (DMSO-d6): δ ) 8.59 (s, broad, 1H) 7.94 (d,
1H, J ) 8.8), 7.94 (s, broad, 1H), 7.70 (t, 1H, J ) 5.8), 7.35 (s,
broad, 3H), 7.31 (s, broad, 2H), 7.11 (d, 1H, J ) 9.2), 6.96 (s,
2H), 6.92-6.76 (m, 2H), 5.09 (s, 2H), 5.02 (t, 1H, J ) 12.2), 4.11
(s, broad, 2H), 3.88-3.35 (m, 8H) 2.52 (s, 6H), 2.22 (s, 3H), 1.89
(m, 1H). 13C NMR (DMSO-d6): δ ) 171.2 (Cq), 169.2 (Cq), 153.3
(Cq), 141.3 (Cq), 138.4 (Cq), 136.7 (Cq), 134.5 (Cq), 131.4 (CH),
128.4 (CH), 127.8 (CH), 127.5 (CH), 112.1 (CH), 77.2 (CH), 73.2
Synthesis of 2S,3R,5S-4-{[2-tert-Butoxycarbonyl-2-(2,4,6-tri-
methylbenzenesulfonylamino)ethylcarbamoyl]methoxy}-2-hy-
droxymethylpyrrolidine-1-carboxylic Acid Benzyl Ester (10). 9
(1.0 g, 2.3 mmol), 884 mg (2.33 mmol) of HBTU, and 795 µL
(4.7 mmol) of DIPEA were dissolved in 20 mL of DMF and stirred
for 10 min. 5 (800 mg, 2.33 mmol), dissolved in 5 mL of DMF,
was added and the solution was stirred overnight. The solvent was
removed by an evaporator and the crude product was dissolved in
400 mL of ethyl acetate. The organic layer was extracted with
saturated NaHCO3 and NaCl solution and dried with Na2SO4, and
the solvent was removed by an evaporator. The crude product was
dissolved in 50 mL of dry THF. TBAF (8.5 mL, 1 M in THF) was
added and the solution was stirred for 2 h. An additional 6.5 mL
of 1 M TBAF in THF was added and the solution was stirred
overnight. The solvent was removed by an evaporator and the crude
product was dissolved in 400 mL of ethyl acetate. The organic layer
was extracted with water, saturated NaHCO3, and NaCl solution
and dried with Na2SO4, and the solvent was removed by an