Spontaneous enantiomer resolution

That such an approach was possible became parent with the work of Lehn and colleagues on Ni ternplated triple helicate complexes. It was fonnd that on crystallization, spontaneous partial resolution of A- and A-enantiomers rook place. Presumably due to cooperativ-itp inherent within such structures, these complexes racemized at much reduced rates, compared to related monomeric systems. The first true approach to kinetic locking, reported by Williams and colleagues, involved an... 

Cromakalim (137) is a potassium channel activator commonly used as an antihypertensive agent (107). The rationale for the design of cromakalim is based on P-blockers such as propranolol (115) and atenolol (123). Conformational restriction of the propanolamine side chain as observed in the cromakalim chroman nucleus provides compounds with desired antihypertensive activity free of the side effects commonly associated with P-blockers. Enantiomerically pure cromakalim is produced by resolution of the diastereomeric (T)-a-meth5lben2ylcarbamate derivatives. X-ray crystallographic analysis of this diastereomer provides the absolute stereochemistry of cromakalim. Biological activity resides primarily in the (—)-(33, 4R)-enantiomer [94535-50-9] (137) (108). In spontaneously hypertensive rats, the (—)-(33, 4R)-enantiomer, at dosages of 0.3 mg/kg, lowers the systoHc pressure 47%, whereas the (+)-(3R,43)-enantiomer only decreases the systoHc pressure by 14% at a dose of 3.0 mg/kg. 

It is well known that spontaneous resolution of a racemate may occur upon crystallization if a chiral molecule crystallizes as a conglomerate. With regard to sulphoxides, this phenomenon was observed for the first time in the case of methyl p-tolyl sulphoxide269. The optical rotation of a partially resolved sulphoxide (via /J-cyclodextrin inclusion complexes) was found to increase from [a]589 = + 11.5° (e.e. 8.1%) to [a]589 = +100.8 (e.e. 71.5%) after four fractional crystallizations from light petroleum ether. Later on, few optically active ketosulphoxides of low optical purity were converted into the pure enantiomers by fractional crystallization from ethyl ether-hexane270. This resolution by crystallization was also successful for racemic benzyl p-tolyl sulphoxide and t-butyl phenyl sulphoxide271. 

The first resolution of an octahedral complex into its enantiomers was achieved in 1911 by A. Werner, who got the Nobel Prize in 1913, with the complex [Co(ethylenediamine)(Cl)(NH3)] [10]. Obviously, resolution is to be considered only in the case of kinetically inert complexes whose enantiomers do not racemize quickly after separation. This is a very important remark since, as noted above, the interesting complexes are those containing exchangeable sites required for catalytic activity and thus more sensitive to racemization. We will not discuss here the very rare cases of spontaneous resolution during which a racemic mixture of complexes forms a conglomerate (the A and A enantiomers crystallize in separate crystals) [11,12]. 

Selenurane oxides are also one of the hypervalent selenium compounds. Recently, the enantiomers of chiral selenurane oxide 38 were isolated for the first time by enantioselective liquid chromatography of the racemate or by spontaneous resolution occurring during slow evaporation of its acetonitrile solution or slow crystallization from the same solvent.57 The absolute configurations of the enantiomers were determined by X-ray crystallographic analysis (Scheme 17). 

Figure 10 Spontaneous resolution of enantiomers below a critical point, shown diagrammatically in terms of the variation of chemical potential with mole fraction, near the critical point.

Tius and co-workers elegantly applied a variant of the Nazarov reaction to the preparation of cyclopentenone prostaglandins (Scheme 19.39) [46]. Moreover, it was demonstrated that the chirality of non-racemic allenes is transferred to an sp3-hybridized carbon atom. Preparation of allenic morpholinoamide 214 and resolution of the enantiomers by chiral HPLC provided (-)- and (+)-214. Compound (-)-214 was exposed to the vinyllithium species 215 to afford a presumed intermediate which was not observed but spontaneously cyclized to give (+)- and (—)-216 as a 5 1 mixture. Compound (+)-216 was obtained with an 84% transfer of chiral information and (-)-216 was obtained in 64% ee. The lower enantiomeric excess of (—)-216 indicates that some Z to E isomerization took place. This was validated by the conversion of 216 to 217, where the absolute configuration was established. The stereochemical outcome of this reaction has been explained by conrotatory cyclization of 218 in which the distal group on the allene rotates away from the alkene to give 216. 

In 1969 Calvin [64] proposed a scheme for autocatalytic symmetry breaking, which he called stereospecific autocatalysis . Calvin s mechanism has been validated experimentally in the context of the total spontaneous resolution during the crystallization of racemic mixtures. During crystallization, crystals of one enantiomer may spontaneously separate, leaving the other enantiomer in solution. If the possibility of the equilibration of the enantiomers in solution exists and if the enantiomer in solution can convert rapidly to the enantiomer that is crystallizing before crystallization is complete, then the entire racemate may deposit as a single enantiomer. At least half a dozen examples of Calvin s stereospecific autocatalysis involving such... 

These schemes have been frequently suggested [105-107] as possible mechanisms to achieve the chirally pure starting point for prebiotic molecular evolution toward our present homochiral biopolymers. Demonstrably successftd amplification mechanisms are the spontaneous resolution of enantiomeric mixtures under race-mizing conditions, [509 lattice-controlled solid-state asymmetric reactions, [108] and other autocatalytic processes. [103, 104] Other experimentally successful mechanisms that have been proposed for chirality amplification are those involving kinetic resolutions [109] enantioselective occlusions of enantiomers on opposite crystal faces, [110] and lyotropic liquid crystals. [Ill] These systems are interesting in themselves but are not of direct prebiotic relevance because of their limited scope and the specialized experimental conditions needed for their implementation. 

Dynamic kinetic resolution (DKR) is an extension to the kinetic resolution process, in which an enantioselective catalyst is usually used in tandem with a chemoselective catalyst. The chemoselective catalyst is used to racemize the starting material of the kinetic resolution process whilst leaving the product unchanged. As a consequence, the enantioselective catalyst is constantly supplied with fresh fast-reacting enantiomer so that the process can be driven to theoretical yields of up to 100 %. There are special cases where the starting material spontaneously racemizes under the reaction conditions and so a second catalyst is not required. 

As seen in Section 1.3.4.1 (synthesis of lotrafiban), the recycling of an unwanted enantiomer resulting from a kinetic resolution allows theoretical yields of up to 100% to be achieved, but it can also create a bottleneck in a production process. DKR, where a starting material undergoes racemization in situ, either spontaneously or through the action of a second catalyst, offers a more efficient approach. This technique has been applied, particularly in academia, to the preparation of a broad range of chiral building blocks, and a number of recent reviews are available. 

The simplest method relies on equilibration of the enantiomers in solution from which one of the enantiomers is obtained by spontaneous crystallization ( Spontaneous Resolution ). Al-... 

As described in the Introduction, Pasteur showed beautifully that racemic molecules resolve spontaneously into chiral forms when they crystallize. We call them conglomerates, in which molecules form condensates comprised of only one enantiomer. The condensation into conglomerates can now be observed not only in crystals but in monolayers, fibers, and supramolecules self-assembled in solution [35]. The researches became possible because of the development of microscopic observation techniques at the nanometer scale. However, in crystals we still do not know what kinds of molecules show spontaneous resolution. Hence, observation of chiral resolution in soft matter may provide important information on the general question. 

We have extended these studies to five /V-bcnzoylazolcs (imidazole, pyrazole, indole, benzimidazole and carbazole) [35] but this time centered on crystallography and solid state NMR. 9-Benzoylcarbazole (29) has a low barrier (29.7 kJ mol1) and shows spontaneous resolution (both axial enantiomers were separated by crystallization). Recently, /V-benzoylpyrazoles have been described as inhibitors of human neutrophil elastase [36],... 

In a racemic mixture, each crystal consists of molecules of the same chirality. Thus, a racemic mixture is an equimolar mixture of crystals of the (+) and (-)-forms. This occurs when each enantiomer has a greater affinity of molecules of the opposite chirality. This phenomenon is called a spontaneous resolution. The melting point of the ground mixture of these crystals is lower than that of the optically active component. In addition, the solubility of the racemic mixture is larger than that of the optically active forms (Figure 2). 

In general, however, the occurence of spontaneous resolution of racemate is rare. Moreover cases in which the crystals of the enantiomers have visually distinct hemihedral face are extremely rare. 

---