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17. The N-chloromethyl compound (0.96 g; 4 mmol) was dissolved in dry acetone
(20 mL), sodium iodide (0.66 g; 4.4 mmol) was added, and the reaction was
stirred at room temperature for 10 h. The precipitate was removed using a
silica gel column and eluting with methylene chloride. Evaporation of the
solvent left a residue which was dissolved in methylene chloride (10 mL). The
solution was treated with Z-Asp-CH2DCB (1.70 g; 4.4 mmol), followed by DBU
(0.66 g; 4.4 mmol), and the reaction mixture was stirred at room temperature
overnight. The solvent was removed, ethyl acetate (60 mL) was added and the
resulting solution was washed with 5% HCl (20 mL) and brine (20 mL). The
solution was dried, filtered and the solvent evaporated in vacuo, leaving a
crude product that was purified using flash chromatography (silica gel/ethyl
acetate/methylene chloride/hexanes) to give the desired product (0.59 g; 25%
yield), as a colorless oil. 1H NMR (CDCl3): d 0.88–0.98 (t, 3H), 1.25–1.56 (m, 2H),
1.68–2.00 (m, 2H), 2.82 (s, 3H), 2.90–3.20 (m, 2H), 3.80–3.88 (m, 1H), 4.71–
4.79 (m, 1H), 5.09–5.20 (m, 4H), 5.57–5.75 (m, 2H), 5.98–6.05 (t, 1H), 7.28–
7.40 (m, 8H). HRMS (ESI) calculated for C27H29Cl2N3O16SNa [M+Na]+ 680.0848,
found 680.0847.
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12. Nomenclature used is that of Schechter, I.; Berger, A. Biochem. Biophys. Res.
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correspond to the enzyme subsites on either side of the scissile bond. Each
18. Morris, G. M.; Huey, R.; Lindstrom, W.; Sanner, M. F.; Belew, R. K.; Goodsell, D.
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subsite accommodates
a
corresponding amino acid residue side chain
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20. Bode, W.; Wei, A.-Z.; Huber, R.; Meyer, E.; Travis, J.; Neumann, S. EMBO 1986, 5,
2453.
designated P1, P2, P3,. . ., Pn and P10, P20, P30,. . ., Pn0 of the substrate or
(inhibitor). S1 is the primary substrate specificity subsite, and P1–P10 is the
scissile bond..
13. Kuang, R.; Epp, J. B.; Ruan, S.; Chong, L. S.; Venkataraman, R.; Tu, J.; He, S.;
Truong, T. M.; Groutas, W. C. Bioorg. Med. Chem. 2000, 8, 1005.
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