Darko Kantoci

Dolastatins 24: synthesis of (–)-dolastatin 10. X-Ray molecular structure of N,N-dimethylvalyl-valyl-dolaisoleuine tert-butyl ester

Total synthesis of the extraordinary antineoplastic constituent, dolastatin 10, from the Indian Ocean mollusc Dolabella auricularia has been summarized. The final synthetic step involved diethyl cyanophosphonate-mediated coupling of Dov-Val-Dil with Dap-Doe. Improved syntheses of these important precursors has led to a very practical synthesis of natural dolastatin 10. Important details of the HPLC and high-field (500 MHz) NMR characterization techniques employed to confirm the purity of dolastatin 10 have been recorded.

Procedures for the Analyses of Dolastatins 10 and 15 by High Performance Liquid Chromatography

Abstract A series of HPLC procedures were evaluated for assessing the purity of dolastatin 10 (1) and dolastatin 15 (2) samples. Interestingly two readily interconvertible (ambient temperature) dolastatin 10 (1) conformers were detected using a potassium dihydrogen phosphate buffered solvent (methanol-water) with a C8 reversed-phase column. A solvent system composed of acetonitrile-2-propanol-water containing sodium 1-hexanesulfonate was found especially useful for evaluating the purity of dolastatin 10 and 15 specimens. Useful HPLC procedures were also found for detecting diastereomeric isomers in the key dolastatin 10 synthetic intermediate Boc-(S, R, R)-Dap-(S)-Doe using β-cyclodextrin in 3:2 methanol-water.

Efficient separation of dolaproine stereoisomers by optimization of a three component chromatographic solvent system

Abstract A solvent system composed of n-hexane-chloroform-acetone was selected (by TLC) for resolving a difficult to separate mixture of protected dolaproine stereoisomers. A set of points representing solvent ratios was generated by an application of statistical methods. From thin layer chromatography data semifinal solvent ratios were selected. By applying simplex optimization, the solvent ratio was found to be 32.3 : 53.4 : 14.3 respectively for the preceding solvent system.

Optimization of solvent mixture compositions for high speed countercurrent distribution

Abstract Seven solvents considered appropriate for use with relatively sensitive biosynthetic products undergoing separation by multilayer coil planet centrifuge high speed countercurrent distribution (HSCCD) have been evaluated in a new and systematic procedure for optimal solvent selection. the new method was illustrated by a complete HSCCD separation of five closely related dipeptides.

The dolastatins 25. Conformational isomerism of N-benzyloxycarbonl-N-methylisoleucinol and related substances

Conformational isomerism in a selection of N-Z-N-methylisoleucine derivatives was detected and investigated using variable temperature NMR spectroscopy. Thermodynamic values for the restricted rotation of conformational isomers were derived.