Synthesis of clasto-lactacystin beta-lactone and analogs thereof

Details Synthesis of clasto-lactacystin beta-lactone and analogs thereof Synthesis of clasto-lactacystin beta-lactone and analogs thereof

1998-08-14

2000-10-17

McKane, Joseph

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

548534, A01K 4336, C07D20728

Patent

active

061333085

ABSTRACT:
The present invention is directed to an improved synthesis of clasto-lactacystin-.beta.-lactone, and analogs thereof, that proceeds in fewer steps and in much greater overall yield than syntheses described in the prior art. The synthetic pathway relies upon a novel stereospecific synthesis of an oxazoline intermediate and a unique stereoselective addition of a formyl amide to the oxazoline. Also described are novel clasto-lactacystin-.beta.-lactones, and analogs thereof and their use as proteosome inhibitors.

REFERENCES:
patent: 5831068 (1998-11-01), Nair et al.
patent: 5942494 (1999-08-01), Ginsberg et al.
Corey et al., Total Synthesis of Lactacystin, J. Am. Chem. Soc., vol. 114 (26), Dec. 1992.
Choi, Dissertation, Department of Chemistry, Harvard University, Dec. 1995.
Chida, N. et al., "Total Synthesis of (+)-Lactacystin from D-Glucose," J. Chem. Soc., Chem. Commun. 7(7):793-794 (1995).
Corey, E.J. and G.A. Reichard, "Total Synthesis of Lactacystin," J. Am. Chem. Soc. 114(26):10677-10678 (1992).
Corey, E.J. and S. Choi, "An Enantioselective Synthesis of (6R)-Lactacystin," Tetrahedron Letters 34(44) :6969-6972 (1993).
Corey, E.J. and G.A. Reichard, "Synthesis of (6R,7S)-Lactacystin and 6-Deoxylactacystin from a common Intermediate," Tetrahedron Letters 34(44):6973-6976 (1993).
Corey, E.J. et al., "Studies on the Total Synthesis of Lactacystin, an Improved Aldol Coupling Reaction and a .beta.-Lactone Intermediate in Thiol Ester Formation," Tetrahedron Letters 34(44):6977-6980 (1993).
Dikshit, D.K. et al., "Self Reproduction of Chirality in Pyroglutamates: Reactions at .alpha.-Position with Electrophiles," Tetrahedron Letters 36(34):6131-6134 (1995).
Fenteany, G. et al., "A .beta.-lactone related to lactacystin induces neurite outgrowth in a neuroblastome cell line and inhibits cell cycle progression in an osteosarcoma cell line," Pro. Natl. Acad. Sci. USA 91:3358-3362 (1994).
Fenteany, G. et al., "Inhibition of Proteasome Activities and Subunit-Specific Amino-Terminal Threonine Modification by Lactacystin," Science 268:726-731 (1995).
Nagamitsu, T. et al., "Total Synthesis of (+)-Lactacystin," J. Am. Chem. Soc. 118:3584-3590 (Apr. 1996).
Nakagawa, A. et al., "Biosynthesis of Lactacystin. Orgin of the Carbons and Stereospecific NMR Assignment of the Two Diastereotopic Methyl Groups," Tetrahedron Letters 35(28):5009-5012 (1994).
Sunazuka, T. et al., "Total Synthesis of (+)-Lactacystin, the First Non-Protein Neurotrophic Factor," J. Am. Chem. Soc. 115:5302 (1993).
Uno, H. et al., "Total Synthesis of (+)-Lactacystin from (R)-Glutamate," J. Am. Chem. Soc. 116:2139-2140 (1994).
WPI Derwent Accession No. 96-485455, English language Abstract of WO 96/32105 (1996).
Choi, S., "Total Syntheses of (6R)-Lactacystin and .beta.-Lactone Derivatives,"in: Chapter 3, Dissertation, Department of Chemistry, Harvard University, (1995).
Shibata, K. et al., "Kinetic and Thermodynamic Control of L-Threonine Aldolase Catalyzed Reaction and Its Application to the Synthesis of Mycestericin D.," Tetrahedron Letters 37:2791-2794 (1996).
Wipf, P. and S. Venkatraman, "An Improved Protocol for Azole Synthesis with PEG-Supported Burgess Reagent," Tetrahedron Letters 37:4659-4662 (1996).

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