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The highly strained and reactive 2H-azirines have been extensively studied for various synthetic purposes, such as ring expansion reactions, 1,2 cycloaddition reactions,2,3 and preparation o f functionalized amines3 and substituted aziridines.1 ~3 The applicability o f these small-ring heterocycles is strongly deter mined by the nature of the substituents.2,3 2tf-Azirine 2-car boxylic acids and esters are of particular interest as they form an entrée to e.g. nonprotein amino acids.4 Moreover, azirinom ycin5 (1, R = M e, R' = H), disydazirine6,7 (1, R = trans-n-C n iib C H^C H , R/ = M e), and antazirine7 (1, R = trans-

The possibility of solid solution behavior of diastereomeric salts, containing multiple resolving agents of the same family (Dutch Resolution), is predicted by molecular modeling. Super-cells containing different ratios of resolving agents in the diastereomeric salt are constructed and optimized, and their lattice energy is computed. The energy difference between these "simulated solid solutions" and the native structures is related in an understandable fashion to the probability of solid solution formation. This procedure is applied to a family of diastereomeric salts of ephedrine and cyclic phosphoric acids, for which the ternary diagrams have been determined experimentally at 25 degrees C in ethanol. Good agreement between experimental and computational results indicates that this relatively simple and fast method could predict the stable character of solid solution behavior in binary systems.

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New resolving bases for ibuprofen 1 and mandelic acid 2 were studied and qualified by their binary phase diagrams of the corresponding salts. It was shown that analysis of the binary phase diagrams gives a good prediction for a resolution process. A comparison of resolving bases revealed that (S)-phenylglycinol (S)-7 is the best resolving base for ibuprofen 1. By the same procedure, various resolving bases for mandelic acid 2 were studied. The known resolving base (S)-MBA 9 was found to be the best for this acid.

Resolution of enantiomers through selective crystallisation of diastereomeric inclusion compounds can extend the scope of traditional racemate resolution beyond salt forming compounds. To assess the practical value of this approach the literature was carefully screened and promising results were checked. Also an extensive range of new inclusion hosts suitable for resolution processes, derived from simple hydroxyand amino acids were prepared and tested. Several techniques, including the Dutch Resolution approach utilizing mixtures of resolving agents, were applied. Over 70 potential resolving agents were tested in combinations with 34 racemates (over 100 racemates if literature results are included). Reproducibility of literature results was found to be problematic. Also the number of successful new resolutions found was very limited: only two efficient resolutions out of 1200 combinations of racemate and resolving agent tested in over 10.000 experiments! Crystal studies of representative combi-

Engineering cysteines at specific sites in antibodies to create well-defined ADCs for the treatment of cancer is a promising approach to increase the therapeutic index and helps to streamline the manufacturing process. Here, we report the development of an in silico screening procedure to select for optimal sites in an antibody to which a hydrophobic linker−drug can be conjugated. Sites were identified inside the cavity that is naturally present in the Fab part of the antibody. Conjugating a linker−drug to these sites demonstrated the ability of the antibody to shield the hydrophobic character of the linker−drug while resulting ADCs maintained their cytotoxic potency in vitro. Comparison of site-specific ADCs versus randomly conjugated ADCs in an in vivo xenograft model revealed improved efficacy and exposure. We also report a selective reducing agent that is able to reduce the engineered cysteines while leaving the interchain disulfides in the oxidized state. This enables us to manufacture site-specific ADCs without introducing impurities associated with the conventional reduction/oxidation procedure for site-specific conjugation.

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