Sintesi di solfossidi e idantoine chirali, separazione dei loro enantiomeri in cromatografia liquida ad alta prestazione e studio dei meccanismi molecolari alla base della separazione enantiomerica

Responsabili di progetto

Alessandro Volonterio, Bezhan Chankvetadze

Accordo

GEORGIA - SRNSF - Shota Rustaveli National Science Foundation

Bando

CNR-SRNSF 2016-2017

Dipartimento

Scienze chimiche e tecnologie dei materiali

Area tematica

Scienze chimiche e tecnologie dei materiali

Stato del progetto

Nuovo

Proposta di ricerca

Separation of enantiomers of chiral racemic compounds belongs to one of the hot topics of contemporary chemistry from both practical and theoretical aspects. Practical importance of the problem is caused by the fact that many drugs, food additives, agrochemicals and chemical intermediates required for synthesis of high quality functional materials are chiral molecules. Separation of enantiomers of these chiral compounds is required for analytical, as well as for preparative purposes. Chiral recognition process is governed by non-covalent intermolecular forces which in many cases are very fine. At present, the nature and driving forces of non-covalent interactions are not understood as well as the driving forces for covalent interactions, although the former play important role not only in chemical processes but also in life biological systems. Thus, understanding the nature of forces involved in chiral recognition process is important not only for separation science but has more general significance.
In the past two decades, chromatographic enantioseparation, particularly direct separation of enantiomers by high-performance liquid chromatography (HPLC), have advanced markedly and this resolution procedure has become one of the most useful methods in many field dealing with drugs, natural products, agrochemicals, etc., not only for determining their enantiomeric purity, but also for obtaining enantiomerically pure chiral compounds in large scale. Indeed, the design and the development of a chiral stationary phase (CSP) capable of effective chiral recognition of a wide range of enantiomers is the key point of the chiral HPLC technique. Elucidation of the chiral discrimination mechanism on CSPs at a molecular level appears to be essential for further developments of more effective CSPs and, more in general, in this exciting area as a whole. In this context, the group of Prof Chankvetadze has contributed to this field by developing new kind of polysaccharide-based chiral selectors (CS) for high-performance liquid chromatographic HPLC separation of enantiomers which are commercialized by US, German and Japanese companies and used worldwide in academia and industry. In 2000 this group has reported extremely high value of enantioselectivity in HPLC separation of 2-(benzylsulfynyl)benzamide, a chiral sulfoxide, by using cellulose tris(3,5-dichlorophenylcarbammate) (CDCPC) as a CSP (Chankvetadze, B. et al. Chem. Lett. 2000, 1176-1177). This result is very interesting because, beyond demonstrating once again the efficiency of such CSP, enantiomerically pure sulfoxides are extremely interesting compounds not only as chiral auxiliaries in asymmetric reactions for the synthesis of compounds of biological importance, but also as bioactive compounds themselves. However, the molecular mechanisms responsible for this extremely high enantioselectivity could not be investigated complicating the further development of such CSP. The major reason for this was the fact that the chiral sulfoxides required for such studies are not commercially available. Since we have reported a methodology for the synthesis of these kinds of sulfoxides in a racemic form and their use as chiral auxiliaries for the synthesis of chiral alcohols, chlorides, tetralines, benzopyrans, and acetamides (Volonterio, A. et al. Tetrahedron Lett. 2005, 46, 8723-8726, and Tetrahedron 2011, 67, 5268-5281), in 2013 we have applied, with success, for a joint CNR-RGNSF grant. In these two years we have synthetized 17 new chiral sulfoxides and enantiomerically resolved using 18 polysaccharide-based chiral columns (most of which prepared for this project). The interesting results obtained has been presented in international conferences by 10 oral and poster presentations and three manuscripts will be submitted soon in peer-review international journals. However, even if most of the structural motifs and substituents responsible for the chiral recognition have been identified, in the frame of the new project further optimization of structure chiral sulfoxides will be addressed, as well as the relationships established between the structure of chiral sulfoxides and their enantiomer resolving ability with polysaccharide phenylcarbamates will be examined. Moreover, since the combination of the different know-hows of the groups has lead these interesting results in the separation of chiral sulfoxides, the same strategy will be applied to the enantiomeric separation of another class of very intriguing compounds, i.e. the hydantoin scaffold. Indeed, the hydantoin ring is present in many biologically active compounds and this heterocycle has been widely recognized as a privileged scaffold in medicinal chemistry. Recently, we have developed a new multicomponent domino process for the synthesis of libraries of differently substituted hydantoins and hydantoin conjugates (Volonterio, A. et al. J. Org. Chem. 2005, 70, 2161-2170 and Org. Biomol. Chem. 2012, 10, 9538-9555). Since the group of Prof. Chankvetadze has experience in the chiral separation of hydantoins (Chankvetadze, B. et al. J. Phar. Biomed. Anal. 2002, 27, 457-465) we would like to combine the different know-hows to better understand the nature of the non-covalent forces involved in chiral separation of such compounds.
Thus, in the frame of the present project Georgian and Italian groups will combine their expertise and efforts in chiral HPLC (Georgian Group) and synthesis of chiral sulfoxides and hydantoins (Italian Group) in order to deal with the global problem of understanding chiral recognition mechanisms in chemistry. We strongly believe that the information obtained within this project concerning the understanding of the chiral recognition at a molecular level will be very important for further developments of more effective CSPs and for the identification of new chiral racemic analytes to be efficiently submitted to enantiomeric separation through HPLC.

Obiettivi della ricerca

The overall goal of this Project will be the better understanding of the key recognition motifs for the excellent enantioselective separation capabilities of CDCPC-HPLC of racemic (alkylsulfinyl)benzamides and hydantoins in order to 1) even improve the performance of such columns, 2) identify new chiral racemic analytes to be submitted to enantioselective separation with HPLC, and 3) to identify new possible modifications of polysaccharides in order to obtain novel chiral selectors for HPLC. These goals will be pursued by the tight collaboration between the group of Prof. Chankvetadze with its experience on physical and analytical chemistry and the group of Prof. Volonterio with its expertise on synthetic organic chemistry. Taking in consideration the structural information obtained during the on-going joint project, a next generation of regioisomeric (alkylsulfinyl)benzamides with different substituents will be synthesized as racemate, characterized and submitted to chiral separation by HPLC. In the same time, the synthesis of a large library of differently substituted hydantoins will be performed by an innovative strategy and submitted to enantiomeric separation. An exhaustive analysis of the results obtained will enable us to better understand the key intermolecolar forces responsible for the high separation efficiency of such chiral selectors and to design novel effective polysaccharide-based materials for analytical and preparative scale separation of enantiomers.

Ultimo aggiornamento: 06/07/2025