Browse > Article
http://dx.doi.org/10.5012/bkcs.2012.33.7.2213

From L-Ascorbic Acid to Protease Inhibitors: Practical Synthesis of Key Chiral Epoxide Intermediates for Aspartyl Proteases  

Chang, Sun-Ki (Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University)
So, Soon-Mog (Department of Chemistry, Seoul National University, College of Natural Sciences)
Lee, Sang-Min (Department of Chemistry, Seoul National University, College of Natural Sciences)
Kim, Min-Kyu (ST Pharm Co., Ltd. Shihwa Industrial Complex)
Seol, Kyoung-Mee (ST Pharm Co., Ltd. Shihwa Industrial Complex)
Kim, Sung-Min (ST Pharm Co., Ltd. Shihwa Industrial Complex)
Kang, Jae-Sung (ST Pharm Co., Ltd. Shihwa Industrial Complex)
Choo, Dong-Joon (Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University)
Lee, Jae-Yeol (Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University)
Kim, B.-Moon (Department of Chemistry, Seoul National University, College of Natural Sciences)
Publication Information
Bulletin of the Korean Chemical Society / v.33, no.7, 2012 , pp. 2213-2218 More about this Journal
Abstract
Efficient synthetic routes were developed to prepare a sizable amount (4-15 grams) of the chiral epoxides 4-6 as versatile intermediates for the synthesis of aspartyl protease inhibitors of therapeutic interest such as HIV protease and ${\beta}$-secretase. Oxidative cleavage of the C(2)-C(3) double bond of L-ascorbic acid followed by functional group manipulation led to the preparation of the epoxide 10, which was opened with an azide to yield a common aziridine intermediate 12. Through opening of the aziridine ring of 12 with either a carbon or a sulfur nucleophile, chiral epoxide precursors 4-6 could be prepared for various HIV protease inhibitors. Except for the final low melting epoxides 5 and 6, all intermediates were obtained as crystalline solids, thus the synthetic pathway can be easily applied to a large-scale synthesis of the chiral epoxides.
Keywords
L-Ascorbic acid; Protease inhibitors; Aziridine opening; HIV protease; Epoxide;
Citations & Related Records

Times Cited By Web Of Science : 0  (Related Records In Web of Science)
연도 인용수 순위
  • Reference
1 Tang, J. J. N.; Hong, L.; Ghosh, A. K. WO 01/00665, 2001.
2 Wei, C. C.; de Bernardo, S.; Tengi, J. P.; Borgese, J.; Weigele, M. J. Org. Chem. 1985, 50, 3462.   DOI
3 Merrer, Y. L.; Pelletier, C. G.; Dumas, J.; Depezay, J. C. Tetrahedron Lett. 1990, 31, 1003.   DOI
4 Kim, K. S.; Cho, I. H.; Ahn, Y. H.; Park, J. I. J. Chem. Soc. Perkin Trans. 1 1995, 1783.
5 Andre, C.; Bolte, J.; Demuynck, C. Tetrahedron: Asymm. 1998, 9, 1359.   DOI
6 Saito, S.; Yamashita, S.; Nishikawa, T.; Yokoyama, Y. Tetrahedron Lett. 1989, 30, 4153.   DOI
7 Saito, S.; Nishikawa, T.; Yokoyama, Y.; Moriwake, T. Tetrahedron Lett. 1990, 31, 221.   DOI
8 Kang, S. H.; Ryu, D. H. Bioorg. Med. Chem. Lett. 1995, 5, 2959.   DOI
9 Remuzon, P.; Dussy, C.; Jacquet, J. P.; Roty, P.; Bouzard, D. Tetrahedron: Asymm. 1996, 7, 1181.   DOI
10 Tang, J. N.; Koelsch, G.; Ghosh, A. K. WO 02/53594, 2002.
11 Kang, S. H.; Ryu, D. H. Bull. Korean Chem. Soc. 1996, 17, 219.
12 Kang, S. H.; Choi, H. W. Bull. Korean Chem. Soc. 1996, 17, 219.
13 Inaba, T.; Yamada, Y.; Abe, H.; Sagawa, S.; Cho, H. J. Org. Chem. 2000, 65, 1623.   DOI
14 John, V.; Tung, J.; Fang, L.; Mamo, S. S. WO 00/077030, 2000.
15 Hom, R.; Mamo, S.; Tung, J.; Gailunas, A.; John, V.; Fang, L. WO 01/070672, 2001.
16 Fang, L. Y.; Hom, R.; John, V.; Maillaird, M. WO 02/002505, 2002.
17 Schostarez, H.; Chrusciel, R. A.; Centko, R. S. WO 02/094768, 2002.
18 Fang, L. Y.; John, V. WO 02/002506, 2002.
19 Maillaird, M.; Hom, R.; Gailunas, A.; Jagodzinska, B.; Fang, L.Y.; John, V.; Freskos, J. N.; Pulley, S. R.; Beck, J. P.; TenBrink, R. E. WO 02/002512, 2002.
20 Beck, J. P.; Gailunas, A.; Hom, R.; Jagodzinska, B.; John, V.; Maillaird, M. WO 02/002520, 2002.
21 Freskos, J. N.; Aquino, J.; Brown, D. L.; Fang, L.; Fobian, Y. M.; Gailunas, A.; Guinn, A.; John, V.; Romero, A. G.; Tucker, J.; Tung, J.; Walker, D. WO 02/ 098849, 2002.
22 Pulley, S. R.; Beck, J. P.; TenBrink, R. E.; Jacobs, J. S. WO 02/100399, 2002.
23 Schostarez, H. J.; Chrusciel, R. A. WO 02/100818, 2002.
24 Maillaird, M.; Tucker, J. A. WO 02/ 100820, 2002.
25 Pulley, S. R.; Beck, J. P.; TenBrink, R. E. WO 02/100856, 2002.
26 John, V.; Hom, R.; Tucker, J. WO 03/ 002122, 2003.
27 Schostarez, H. J.; Chrusciel, R. A. WO 03/ 006013, 2003.
28 Schostarez, H. J.; Chrusciel, R. A. WO 03/ 006021, 2003.
29 Gailunas, A.; Hom, R.; John, V.; Maillard, M.; Chrusciel, R. A.; Fisher, J.; Jacobs, J.; Freskos, J. N.; Brown, D. L.; Fobian, Y. M. WO 03/006423, 2003.
30 Schostarez, J. H.; Chrusciel, R. A. WO 03/006453, 2003.
31 Gailunas, A.; Tucker, J. A.; John, V. WO 03/027068, 2003.
32 Fisher, J. F.; Jacobs, J. S.; Sherer, B. A. WO 03/029169, 2003.
33 Gurjar, M. K.; Devi, N. R. Tetrahedron: Asymm. 1994, 5, 755.   DOI
34 Kaldor, S. W.; Kalish, V. J.; Davies, J. F., II; Shetty, B. V.; Fritz, J. E.; Appelt, K.; Burgess, J. A.; Campanale, K. M.; Chirgadze, N. Y.; Clawson, D. K.; Dressman, B. A.; Hatch, S. D.; Khalil, D. A.; Kosa, M. B.; Lubbehusen, P. P.; Muesing, M. A.; Patick, A. K.; Reich, S. H.; Su, K. S.; Tatlock, J. H. J. Med. Chem. 1997, 40, 3979.   DOI
35 Ghosh, A. K.; McKee, S. P.; Lee, H. Y.; Thompson, W. J. Chem. Commun. 1993, 273.
36 Parkes, K. E. B.; Bushnell, D. J.; Cracjeff, P. H.; Dunsdon, S. J. Freeman, A. C.; Gunn, M. P.; Popkins, R. A.; Lambert, R. W.; Thomas, G. J. J. Org. Chem. 1994, 59, 3656.   DOI
37 Beaulieu, P. L.; Wernic, D. J. Org. Chem. 1996, 61, 3635.   DOI
38 Shibata, N.; Katoh, T.; Terashima, S. Tetrahedron Lett. 1997, 38, 619.   DOI
39 Beaulieu, P. L.; Lavallee, P.; Abraham, A.; Anderson, P. C.; Boucher, C.; Bousquet, Y.; Duceppe, J. S.; Gillard, J.; Gorys, V.; Grand-Maître, C.; Grenier, L.; Guindon, Y.; Guse, I.; Plamondon, L.; Soucy, F.; Valois, S.; Wernic, D.; Yoakim, C. J. Org. Chem. 1997, 62, 3440.   DOI
40 Rieger, D. L. J. Org. Chem. 1997, 62, 8546.   DOI
41 Ghosh, A. K.; Fidanz, S. J. Org. Chem. 1998, 63, 6146.   DOI
42 Corey, E. J.; Zhang, F. Y. Angew. Chem. Int. Ed. 1999, 38, 1931.   DOI
43 Inaba, T.; Yamada, Y.; Abe, H.; Sagawa, S.; Cho, H. J. Org. Chem. 2000, 65, 1623.   DOI
44 Zook, S. E.; Busse, J. K.; Borer, B. C. Tetrahdron Lett. 2000, 41, 7017.   DOI
45 Tamamura, H.; Hori, T.; Otaka, A.; Fujii, N. J. Chem. Soc., Perkin Trans. 1 2002, 577.
46 Mimoto, T.; Imai, J.; Kisanuki, S.; Enomoto, H.; Hattori, N.; Akaji, K.; Kiso, Y. Kynostatin. Chem. Pharm. Bull. 1992, 40, 2251.   DOI
47 Kim, B. M.; Bae, S. J.; So, S. M.; Yoo, H. T.; Chang, S. K.; Lee, J. H.; Kang, J. S. Org. Lett. 2001, 3, 2349.   DOI
48 Sham, H. L.; Kempf, D. J.; Molla, A.; Marsh, K. C.; Kumar, G. N.; Chen, C. M.; Kati, W.; Stewart, K.; Lal, R.; Hsu, A.; Betebenner, D.; Korneyeva, M.; Vasavanonda, S.; McDonald, E.; Saldivar, A.; Wideburg, N.; Chen, X.; Niu, P.; Park, C.; Jayanti, V.; Grabowski, B.; Granneman, G. R.; Sun, E.; Japour, A. J.; Norbeck, D. W. Antimicrob. Agents Chemother. 1998, 42, 3218.
49 Thaisrivongs, S.; Skulnick, H. I.; Turner, S. R.; Strohbach, J. W.; Tommasi, R. A.; Johnson, P. D.; Aristo, P. A.; Judge, T. M.; Gammill, R. B.; Morris, J. K.; Romaines, K. A.; Chrusciel, R. A.; Hinshaw, R. R.; Chong, K.-T.; Tarpley, W. G.; Poppe, S. M.; Slade, D. E.; Lynn, J. C.; Hog, M.-M.; Tomich, P. K.; Seest, E. P.; Dolak, L. A.; Howe, W. J.; Howard, G. M.; Schwende, F. J.; Toth, L. N.; Padbury, G. E.; Wilson, G. J.; Shiou, L.; Zipp, G. L.; Wilkinson, K. F.; Rush, B. D.; Ruwart, M. J.; Koeplinger, K. A.; Zhao, Z.; Cole, S.; Zaya, R. M.; Kakuk, T. J.; Janakiraman, M. N.; Watenpaugh, K. D. J. Med. Chem. 1996, 39, 4349.   DOI
50 Lam, P. Y. S.; Ru, Y.; Jadhav, P. K.; Aldrich, P. E.; DeLucca, G. V.; Eyerma, C. J.; Chang, C.-H.; Emmett, G.; Holler, E. R.; Daneker, W. F.; Li, L.; Confalone, P. N.; McHugh, R. J.; Han, Q.; Li, R.; Markwalder, J. A.; Seitz, S. P.; Sharpe, T. R.; Bacheler, L. T.; Rayner, M. M.; Klabe, R. M.; Shum, L.; Winsloe, D. L.; Kornhauser, D. M.; Jackson, D. A.; Erickson-Viitanen, S.; Hodge, C. N. J. Med. Chem. 1996, 39, 3514.   DOI
51 Bold, G.; Fassler, A.; Capraro, H.-G.; Cozens, R.; Klimkait Lazdins, J.; Mestan, J.; Poncioni, B.; Rosel, J.; Stover, D.; Tintelnot-Blomley, M.; Acemoglu, F.; Beck, W.; Boss, E.; Eschbach, M.; Hurlimann, T.; Masso, E.; Roussel, S.; Ucci-Stoll, K.; Wyss, D.; Lang, M. J. Med. Chem. 1998, 41, 3387.   DOI
52 Roberts, N. A.; Martin, J. A.; Kinchington, D.; Broadhurst, A. V.; Craig, J. C.; Duncan, I. B.; Galphin, S. A.; Handa, B. K.; Krohn, A.; Lambert, R. W.; Merrett, J. H.; Mills, J. S.; Parkes, K. E. B.; Redshaw, S.; Ritchie, A. J.; Taylor, D. L.; Thomas, G. J.; Machin, P. J. Science 1990, 248, 358.   DOI
53 Kim, E. E.; Baker, C. T.; Dwyer, M. D.; Murcko, M. A.; Rao, B. G.; Tung, R. D.; Navia, M. A. J. Am. Chem. Soc. 1995, 117, 1181.   DOI
54 Tomasselli, A. G.; Heinrikson, R. L. Biochim. Biophys. Acta 2000, 189.
55 Meek, T. D. J. Enz. Inhib 1992, 5, 65.
56 Wlodwer, A.; Erickson, J. W. Annu. Rev. Biochem. 1993, 543.
57 Martin, J. A. Antiviral Research 1992, 17, 265.   DOI
58 Czarnocki, Z.; Mieczkowski, J. B.; Ziolkowski, M. Tetrahedron: Asymm. 1996, 7, 2711.   DOI
59 Le Merrer, Y.; Gravier-Pelletier, C.; Gerrouache, M.; Jean-Claude Depezay, J. Tetrahedron Lett. 1998, 39, 385.   DOI
60 Thopate, S. R.; Kulkarni, M. G.; Puranik, V. G. Angew. Chem. Int. Ed. 2000, 39, 4573.   DOI
61 Bond, S.; Perlmutter, P. Tetrahedron 2002, 58, 1779.   DOI
62 Wroblewski, A. E.; Gowacka, I. E. Tetrahedron: Asymm. 2002, 13, 989.   DOI
63 Paquette, L. A.; Chang, J.; Liu, Z. J. Org. Chem. 2004, 69, 6441.   DOI
64 Ishikawa, T.; Ishii, H.; Shimizu, K.; Nakao, H.; Jin Urano, J.; Kudo, T.; Saito, S. J. Org. Chem. 2004, 69, 8133.   DOI
65 Dorsey, D. D.; Levi, R. B.; McDaniel, S. L.; Vacca, J. P.; Guare, J. P.; Darke, P. L.; Zugay, J. A.; Emini, E. A.; Schleif, W. A.; Quintero, J. C.; Lin, J. I.-W.; Holloway, M. K.; Fitzgerald, P. M. D.; Azel, M. G.; Ostovic, D.; Anderson, P. S.; Hu, J. R. J. Med. Chem. 1994, 34, 3443.
66 Kempf, D. J.; Marsh, K. C.; Denissen, J. F.; McDonald, E.; Vasavanoda, S.; Flentge, C. A.; Green, B. E.; Fino, L.; Park, C. H.; Kong, X.-P.; Wideburg, N. E.; Saldivar, A.; Ruiz, L.; Kati, W. M.; Sham, H.; Robin, T.; Srewart, K. D.; Hsu, A.; Plattner, J. J.; Leonard, J. M.; Norbeck, D. W. Proc. Natl. Acad. Sci.: U.S.A. 1995, 92, 2484.   DOI
67 Huff, J. R. J. Med. Chem. 1991, 34, 2305.   DOI
68 Flexner, C. New Eng. J. Med. 1998, 338, 1281-1292.   DOI