Aerobic reactions of CoX (X = OAc, Cl) or Co(ClO) with (S,S)-1,2-diphenylethylenediamine [(S,S)-dpen] in CHOH, followed by HCl or HClO additions, give the diastereomeric lipophobic salts Λ-[Co((S,S)-dpen)]3Cl [Λ-(S,S)-13Cl] or Δ-(S,S)-13ClO (60-65%) with high degrees of selectivity. Anion metatheses (room temperature) and equilibrations (charcoal, CHOH, 70 °C) show that the former is more stable than Δ-(S,S)-13Cl, and the latter is more stable than Λ-(S,S)-13ClO. Additional anion metatheses lead to large families of lipophilic salts Λ- and Δ-(S,S)-12XX' [X/X' = Cl/BAr [BAr = B(3,5-CH(CF))], PF/BAr, BF/BAr, PhBF/BAr, Cl/BAr [BAr = B(CF)], BAr/BAr, BAr/BAr, BF/BF, PF/PF]. Mixed salts of the formula Λ- and Δ-[Co((S,S)-NHCHArCHArNH)]2ClBAr are similarly prepared (Ar = 4-CHn-Bu, 4-CHCl, 4-CHCF, 4-CHOCH, α-naphthyl, β-naphthyl, 2-CHOBn). The diastereotopic NHH' protons exhibit different H NMR signals; one shifts far downfield when X/X' = Cl/BAr (δ ca. 8.0 vs 4.0 ppm). This is believed to arise from hydrogen bonding between the two Cl anions and the two C faces of the D-symmetric trication, each of which feature three synperiplanar NH groups. When all of the anions are poor hydrogen-bond acceptors (e.g., BAr, BF, ClO), equilibria favor Δ diastereomers.

The enantiopure salt Δ-[Co((S,S)-dpen)3](3+)2Cl(-)B(C6F5)4(-) is an effective hydrogen bond donor catalyst for additions of 1,3-dicarbonyl compounds to di-tert-butyl azodicarboxylate in the presence of N-methylmorpholine (1.0:1.0:0.10) in CH3CN at 0 °C, as illustrated with educts derived from five- or six-membered ring ketones (99-88% yields, >99-91% ee) and cycloheptanone (94%, 72% ee) as well as 2-cyanocyclopentanone (92%, 45% ee) and an acyclic system (98%, >99% ee).

Polymorphism in drugs and bioactive molecules is not uncommon, and it has remained as one of the critical issues in drug development processes. While improving physicochemical properties of bioactive molecules has been a prime focus of the pharmaceutical chemists, not much efforts have been put toward the improvement of their potency via polymorphic modifications. Here, we consider five cases of 5-arylidene-2-aminothiazolidinones derivatives, the known anticancer agents, and discover eights polymorphs in three out of the five cases. We perform systematic crystallization experiments and detailed crystal structure analysis of the eight polymorphs and two compounds, estimate both their energetic and thermal stabilities, and compare their solid state properties. We also compare in-solution properties, e.g., equilibrium solubility, intrinsic dissolution rate, and phase stability, of three polymorphs of one of the cases. Further, we study the extent of inhibition imposed by those eight polymorphs and seven bulk and crystal forms of the compounds on the proliferation of MCF7 breast cancer cells and also the extent of their binding to the isozyme γ-enolase. Furthermore, we perform MD simulations on the eight polymorphs and one compound to estimate and compare their binding affinity with γ-enolase. Our experimental and MD simulation analyses in general emphasize the importance of polymorphism in improving the biological potency of individual molecules.

The enantiopure and diastereopure salts Λor Δ-[Co((S,S)-dpen) 3 ] 3+ 2Cl − BAr f − (Λ-or Δ-(S,S)-1 3+ 2Cl − BAr f − ; dpen/BAr f = 1,2-diphenylethylenediamine/B(3,5-C 6 H 3 (CF 3 ) 2 ) 4 ) and Λ-(S,S)-1 3+ 3Cl − are treated with salts of the enantiopure chiral monoanions (A − ) or dianions (A 2− ) 3-bromocamphor-8sulfonate (camphSO 3 − ), 1,1′-binaphthyl-2,2′-diyl phosphate (and three 3,3′-disubstituted derivatives), a related biphenanthryl species, tartrate, and Sb 2 (tart′− , and Λ-(S,S)-1 3+ 3A − are isolated as hydrates and characterized by NMR and microanalyses. In the presence of tertiary amines, many of these are highly enantioselective catalysts for additions of 1,3-dicarbonyl compounds to trans-β-nitrostyrene and di-tert-butylazodicarboxylate. The ee values for diastereomeric salts can exhibit significant differences (avg/high/median Δ %ee = 10/63/6; matched/mismatched effect), and in a few cases, they are better than those obtained with Λor Δ-(S,S)-1 3+ 2Cl − BAr f − . The crystal structure of Δ-(S,S)-1 3+ 2(1S)-camphSO 3 − BAr f − shows that the two sulfonate moieties hydrogen-bond to opposite (idealized) C 3 -symmetric faces of the trication, with a separate oxygen atom associated with each of the three synperiplanar NH groups.

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