I. Gill, R. Patel / Bioorg. Med. Chem. Lett. 16 (2006) 705–709
709
Xing, L.; Tao, L.; Sitkoff, D. F.; Malley, M. F.; Gougou-
tas, J. Z.; Khanna, A.; Huang, Q.; Han, S.-P.; Parker, R.
A.; Hamann, L. G. J. Med. Chem. 2004, 47, 2587.
. Augeri, D. J.; Robl, J. A.; Betebenner, D. A.; Magnin, D.
R.; Khanna, A.; Robertson, J. G.; Simpkins, L. M.;
Taunk, P. C.; Huang, Q.; Han, S.-P.; Abboa-Offei, B.;
Wang, A.; Cap, M.; Xin, L.; Tao, L.; Tozzo, E.; Welzel,
G. E.; Egan, D. M.; Marcinkeviciene, J.; Chang, S. Y.;
Biller, S. A.; Kirby, M. S.; Parker, R. A.; Hamann, L. G.
J. Med. Chem. 2005, 48, 5025.
0. Kunishima, M.; Kawachi, C.; Hioki, K.; Terao, K.; Tani,
S. Tetrahedron 2001, 57, 1551.
1. Litjens, M. J. J.; Straathof, A. J. J.; Jongejan, J. A.;
Heijnen, J. J. Chem. Commun. 1999, 1255.
2. Prasad, A. K.; Husain, M.; Singh, B. K.; Gupta, R. K.;
Manchanda, V. K.; Olsen, C. E.; Parmar, V. S. Tetrahe-
dron Lett. 2005, 46, 4511.
3. Levinson, W. E.; Kuo, T. M.; Kurtzman, C. P. Enzyme
Microb. Technol. 2005, 37, 126.
containing 13.2 g, 54.8 mmol 1), ammonium carbamate
(5.4 g, 69 mmol, 2.5 mol equiv of ammonia), anhydrous
calcium chloride beads (6.6 g), and CALB powder (2.0 g,
15% w/w of ester input), then a 40 mL glass fiber thimble
containing 13 g Ascarite was placed in the neck of the flask,
the flask sealed, and the whole setup was shaken at
150 rpm, 50 ꢁC, 3 d. HPLC analysis indicated that 100%
conversion of ester had been achieved with the formation of
9
2
9
96% of amide and 4% of side products. The reaction
mixture was diluted with ethyl acetate (30 mL) and filtered
through a pad of silica gel 60 (10 g), and the filter cake was
washed with 1:1 toluene/ethyl acetate (2· 10 mL). Acetic
acid (0.5 mL) was added to the combined filtrates and the
solution was evaporated at 50 ꢁC to yield a viscous brown
liquid. This was diluted with ethyl acetate (30 mL), the
suspension was filtered through a pad of silica gel 60 (10 g),
and the pad was washed with ethyl acetate (1· 10 mL). The
filtrate was evaporated at 30 ꢁC to ca. 25 mL; the residue
was diluted with cyclohexane (ca. 75 mL), seeded with
crystalline amide, and the mixture was stirred at 100 rpm,
rt, 5 h, then at 100 rpm, 5 ꢁC, 22 h. The suspension was
filtered, and the cake was washed with 4:1 cyclohexane/
ethyl acetate (3· 10 mL), and then dried under vacuum at rt
to furnish the amide as off-white crystals, 9.42 g, 81% yield,
1
1
1
1
1
1
1
1
4. Gonz a´ lez-Sab ´ı n, J.; Gotor, V.; Rebolledo, F. Tetrahedron:
Asymmetry 2004, 15, 481.
5. Jacobsen, E. E.; Hoff, B. H.; Moen, A. R.; Anthonsen, T.
J. Mol. Catal. B. 2003, 21, 55.
6. Slotema, W. F.; Sandoval, G.; Guieysse, D.; Straathof, A.
J. J.; Marty, A. Biotechnol. Bioeng. 2003, 82, 664.
7. Baldessari, A.; Mangone, C. P. J. Mol. Catal. B. 2001, 11,
1
98% potency, 99% AP (by HPLC), >99.9% ee. H NMR
(DMSO-d
6
, 25 ꢁC, 400 MHz) d 1.39 (s, 9H), 2.48 (m, 1H),
3
35.
2.94 (m, 1H), 4.37 (dd, 1H), 4.96 (m, 1H), 6.50 (br d, 1H),
6.96 (br d, 1H), 7.38 (m, 1H) ppm; C NMR (DMSO-d ,
6
1
3
1
1
8. Gotor, V. Bioorg. Med. Chem. 1999, 7, 2189.
9. Conde, S.; Lopez-Serrano, P.; Martinez, A. J. Mol. Catal.
B. 1999, 7, 299.
25 ꢁC, 125 MHz) d 28.7, 31.1, 58.1, 71.2, 111.7, 23.0, 152.2,
177.4 ppm.
2
0. Wegman, M. A.; Hacking, M. A. P. J.; Rops, J.; Pereira,
P.; van Rantwijk, F.; Sheldon, R. A. Tetrahedron:
Asymmetry 1999, 10, 1739.
29. Analytical methods: Samples for HPLC analysis were
diluted to 2 mM with methanol containing 1.0% acetic
acid, filtered (0.5 lm PTFE), and then analyzed on a
Shimadzu LC-10 system equipped with a Phenomenex
Synergi Max-RP (4 lm, 2· 50 mm) column. The column
was eluted with 10% to 100% B over 8 min, where A = 8:2
(v/v) water/methanol with 0.05% TFA and B = 8:2 (v/v)
acetonitrile/methanol with 0.05% TFA. The flow rate was
2
2
2
2
2
2
2
2
1. Garcia-Urdiales, E.; Rebolledo, F.; Gotor, V. Tetrahe-
dron: Asymmetry 1999, 10, 721.
2. Starmans, W. A. J.; Doppen, R. G.; Thijs, L.; Zwanan-
burg, B. Tetrahedron: Asymmetry 1998, 9, 429.
3. Hacking, M. A. P. J.; Wegman, M. A.; Rops, J.; van
Ranwijk, F.; Sheldon, R. A. J. Mol. Catal. B. 1998, 5, 155.
4. V o¨ rde, C.; H o¨ gberg, H.-E.; Hedenstr o¨ m, E. Tetrahedron:
Asymmetry 1996, 7, 1507.
5. Chamorro, C.; Gonz a´ lez-Mu n˜ iz, R.; Conde, S. Tetrahe-
dron: Asymmetry 1995, 6, 2343.
6. Garcia, M. J.; Rebolledo, F.; Gotor, V. Tetrahedron Lett.
993, 34, 6141.
7. Garcia, M. J.; Rebolledo, F.; Gotor, V. Tetrahedron 1994,
0, 6935.
8. Preparative scale ammonolysis of (5S)-4,5-dihydro-1H-
pyrrole-1,5-dicarboxylic acid (1): A 500 mL PTFE flask
was charged with process ester feed (72.4 g, ca. 60 mL,
À1
0.6 mL min , injection volume 5 lL, column temperature
30 ꢁC, and the detection wavelength 225 nm. The ester and
amide eluted at 6.9 and 2.0 min, respectively. Amide
enantiopurity was determined by chiral HPLC analysis on
a Shimadzu LC-10 system equipped with a Chiralpak AS-
H (5 lm, 4.6· 150 mm) column. The column was eluted
with 40% B over 30 min, where A = heptane and B = 1:1
(v/v) heptane/isopropanol. The flow rate was
1
À1
5
1.0 mL min , injection volume 20 lL, the column kept
at room temperature, and the detection wavelength
225 nm. The (R)- and (S)-amide enantiomers eluted at
7.2 and 15.6 min, respectively.