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Synlett 2006(13): 2063-2066  
DOI: 10.1055/s-2006-948191
LETTER
© Georg Thieme Verlag Stuttgart · New York

Stereoselective Synthesis of the Epoxysuccinyl Peptide E-64c

Barry Lygo*, Stuart D. Gardiner, Daniel C. M. To
School of Chemistry, University of Nottingham, Nottingham, NG7 2RD, UK
e-Mail: B.Lygo@Nottingham.ac.uk;
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Publikationsverlauf

Received 6 June 2006
Publikationsdatum:
09. August 2006 (online)

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Abstract

A highly diastereoselective PTC epoxidation is employed in the synthesis of the potent cysteine protease inhibitor E-64c.

Key words

epoxysuccinates - asymmetric epoxidation - quaternary ammonium salts - phase-transfer catalysis

10

General Procedure for Asymmetric Epoxidation.
A mixture of 15% aq NaOCl (9.0 mmol) and 12 M aq KOH (1 mL) was added dropwise to a solution of enone (3.0 mmol) and the appropriate catalyst (0.15 mmol) in PhMe (70 ml). The resulting mixture was stirred vigorously (1000 rpm) at r.t. for 30 min, then a second portion of 15% aq NaOCl (9.0 mmol) was added and stirring continued for 4-16 h. Then, H2O (100 mL) was added and layers separated. The aqueous was extracted with EtOAc (2 × 100 mL) and the combined organics were dried (Na2SO4), then concentrated under reduced pressure. The residue was then purified by chromatography on silica gel.
Selected NMR Data.
Compound 9a: 1H NMR (400 MHz, CDCl3): δ = 7.99-7.95 (2 H, m, ArH), 7.64-7.46 (3 H, m, ArH), 6.60 (1 H, br d, J = 8.5 Hz, NH), 4.72-4.64 (1 H, m, NHCH), 4.27 (1 H, d, J = 2.0 Hz, NHCOCH), 3.78 (3 H, s, OMe), 3.72 (1 H, d, J = 2.0 Hz, ArCOCH), 1.78-1.58 [3 H, m, CH2, CH(CH3)2], 1.01 (3 H, d, J = 6.5 Hz, CH3), 0.99 (3 H, d, J = 6.5 Hz, CH3). 13C NMR (100 MHz, CDCl3): δ = 191.5 (C), 172.5 (C), 166.2 (C), 134.9 (C), 134.4 (CH), 129.0 (CH), 128.5 (CH), 56.2 (CH), 54.9 (CH), 52.5 (CH3), 50.4 (CH), 41.3 (CH2), 25.0 (CH), 22.7 (CH3), 22.0 (CH3).
Compound 10a: 1H NMR (400 MHz, CDCl3): δ = 7.99-7.95 (2 H, m, ArH), 7.64-7.46 (3 H, m, ArH), 6.50 (1 H, br d, J = 8.5 Hz, NH), 4.72-4.64 (1 H, m, NHCH), 4.41 (1 H, d, J = 2.0 Hz, NHCOCH), 3.78 (3 H, s, OMe), 3.73 (1 H, d, J = 2.0 Hz, ArCOCH), 1.78-1.58 [3 H, m, CH2, CH(CH3)2], 1.01 (3 H, d, J = 6.5 Hz, CH3), 0.99 (3 H, d, J = 6.5 Hz, CH3). 13C NMR (100 MHz, CDCl3): δ = 191.3 (C), 172.9 (C), 166.4 (C), 134.9 (C), 134.4 (CH), 129.0 (CH), 128.5 (CH), 55.8 (CH), 54.9 (CH), 52.5 (CH3), 50.2 (CH), 41.0 (CH2), 24.8 (CH), 22.8 (CH3), 21.7 (CH3).