Resolution

Resolution was achieved by crystallization of the dibenzoyltartrate salts. Reaction of racemic Tröger's Base (TB) with (-)-dibenzoyl tartaric acid (0.5 equivalent) in a 5/1 chloroform/methanol mixture led to the formation of salt from which (+)-TB could be obtained after basic treatment. The (+)-TB obtained showed = +4650 (c 9 10^-3, EtOH-H₂ O 95-5). The nmr analysis indicated an enantiomeric excess close to 80 %. The resolution performed with (+)-dibenzoyl tartaric acid similarly gave (-)-BT. The circular dichroism spectra of both enantiomers are shown below.

The 7R,17R configuration was assigned to the (-)-BT enantiomer based on its circular dichroism spectrum (exciton mechanism). (Coll. with A. Collet and C. Andraud, Ecole Nationale Supérieure de Lyon).

Circular Dichroism

pK-racemisation

The pKa values were measured by pHmetric titration and compared to the half-molecule 3-aminoacridine.

 

This is a good indication that the two acridine nuclei are protonated in this pH range. This is confirmed by the pH dependence of the UV/Vis absorption spectra.

Major changes of the spectrum occur around pH 6, with the lowest-energy band being shifted from 390 at pH > 8 to 457 nm in acidic solution. Such variation is attributed to the protonation of the acridine ring nitrogens.

 

From these data, it can be assumed that in the pH range 2-10, the nitrogens of the methano diazocine unit are not protonated. This result is of major importance for the racemization properties of the heterocyclic Tröger's Base analogue.

Dibenzo-methanodiazocine (such as the Tröger's Base itself) racemizes readily in acidic medium. Comparatively, (+)-TB and (-)-TB do not racemize in the same conditions. The postulated mechanism for racemization of a Tröger's Base implies protonation of one nitrogen of the methano diazocine unit, opening of the bridge and reclosure. This mechanism is considerably slowed down for the heterocyclic Tröger's Base analogue due to the presence of the two basic aminoacridines. As protonation of the aminoacridines occurs on the ring nitrogens, the electron withdrawing effect of the acridinium lowers the pKa of the diazocine nitrogens so that they are not protonated in the 2-9 pH range

	[Summary]	[Introduction]	[Synthesis]	[Interaction...]	[Enantioselective...]	[Conclusion]