Abstract

In the course of the development of calpain inhibitors, we report the synthesis of eight-membered cyclic pseudo dipeptides closely related to the known inhibitor SJA6017. The ring closure was effected by metathesis of the diallyl-substituted dipeptides 6 and 7. The formation of the dipeptides under kinetic control leads to the preferential formation of the unlike diastereomer 7 over the like diastereomer 6. The relative configuration of the diastereomers was determined by NMR and modeling studies of the related cyclic compounds 8 and 9 and their derivatives. The compounds proved not to inhibit calpain.

Keywords: Peptidomimetics; Molecular modeling; Metathesis; Cataract; Calpain

Abbreviations: Boc, tert-butyloxycarbonyl; DCM, dichloromethane; DIBAL, diisobutyl aluminium hydride; DIEA, diisopropyl ethyl amine; EtOAc, ethyl acetate; HATU, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetra-methyluronium hexafluorophosphate; HOBt, hydroxybenzotriazole; NMR, nuclear magnetic resonance; NOE, nuclear Overhauser enhancement; RMSD, root mean square deviation; TFA, trifluoroacetic acid

Article Outline

1. Introduction

2. Materials and methods

2.1. General

2.2. Synthesis

2.2.1. Synthesis of the 2-[2-tert-butoxycarbonylamino-pent-4-enoyl-(2,4-dimethoxy-benzyl)-amino]-pent-4-enoic acid methyl esters (6) (l) and (7) (u) [3]

2.2.2. Preparation of the (Z)-7-tert-butoxycarbonylamino-1-(2,4-dimethoxybenzyl)-8-oxo-1,2,3,6,7,8-hexahydro-azocine-2-carboxylic acid methyl esters (8) (l) and (9) (u) [3]

2.2.3. Preparation of l-(Z)-7-(4-fluorobenzenesulfonylamino)-8-oxo-1,2,3,6,7,8-hexahydro-azocine-2-carboxylic acid methyl ester (10)

2.2.4. Preparation of u-(Z)-7-(4-fluorobenzenesulfonylamino)-8-oxo-1,2,3,6,7,8-hexahydro-azocine-2-carboxylic acid methyl ester (11)

2.2.5. Preparation of l-7-(4-fluorobenzenesulfonylamino)-8-oxo-azocane-2-carboxylic acid methyl ester (12)

2.2.6. Preparation of u-7-(4-fluorobenzenesulfonylamino)-8-oxo-azocane-2-carboxylic acid methyl ester (13)

2.2.7. DIBAL reduction/sodium sulfate workup of 12 or 13

2.2.8. DIBAL reduction/acidic workup of 12 or 13

2.3. Computational methods

2.4. Testing of calpain inhibition

3. Results

3.1. Synthesis

3.2. NMR studies

3.3. Modeling

3.4. Testing of calpain inhibition

4. Discussion

5. Conclusion

Acknowledgements

References