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Asymmetric Synthesis of Non-Proteinogenic Amino-Acids

#A-356


New Chiral Auxiliaries and Catalysts for the Asymmetric Synthesis of None-proteinogenic Alfa-Amino Acids

Tech Area / Field

  • CHE-SYN/Basic and Synthetic Chemistry/Chemistry
  • CHE-IND/Industrial Chemistry and Chemical Process Engineering/Chemistry
  • BIO-CHM/Biochemistry/Biotechnology
  • MED-OTH/Other/Medicine

Status
8 Project completed

Registration date
26.05.1999

Completion date
09.07.2004

Senior Project Manager
Endrullat B

Leading Institute
Yerevan State University, Armenia, Yerevan

Supporting institutes

  • INEOS (Organo-Element Compounds), Russia, Moscow

Project summary

The project objective is the development of a new generation of recoverable chiral auxiliaries and catalysts for the asymmetric synthesis of enantiomerically pure none-proteinogenic a-amino acids (AA), including those with quaternary carbon atoms and isotope-labeled AA (13С, 11С, 2Н, 15N) with particular emphasis on synthesis of heterocycle containing AA.

The area of asymmetric synthesis of none-proteinogenic AA is rapidly expanding with both stoichiometric and catalytic methods being elaborated [1 ]. Some of the leading organic chemists of the world are actively involved in the field as testified by the recent publications of Prof. E.Corey, a Nobel Prize Winner, [2] those of Prof. D.Seebach, [3] and Prof. H.Kagan [4]. The underlying reason for the growing interest in the development of the area is the great importance of unproteinogenic and labeled AA. For example, 11С labeled enantiomerically enriched proteinogenic АA are indispensable material used for positron emission tomography (PET) [5], whereas some none-proteinogenic AA are constituent of mutagenics, toxines, pyretroids, gerbicides, antibiotics, physyologically active peptides, and other pharmaceuticals. Among the variety of non-coden AA used to optimise the biological properties of bioactive peptides, for example, a-alkyl-a-AA have played a special role in the design peptides, irreversible enzymes inhibitors and toxines with special or enhanced properties [6]. Usually the number of those enantiomerically enriched AA available on the market is very limited and their prices are high. The synthetic chemists involved in R&D of new pharmaceuticals based partly or wholly on use of none-proteinogenic AA need cheap, convenient and ecologically friendly synthetic methods for their asymmetric production [6]. The routine chimico-enzymatic preparation efficient in the case of proteinogenic AA synthesis, may fail or become impractical for the production of enantiomerically pure none-proteinogenic AA [7, 8]. Thus the field represents a rare case of purely chemical methods of asymmetric synthesis becoming competitive relative to the biochemistry approach.

At present, there are several excellent general methods of asymmetric synthesis of AA, based on the use of chiral auxiliaries and kinetic control approach [1, 3, 9]. Unfortunately, most of the methods suffer such shortcomings as low temperatures of the reaction media, low concentrations of the reagents, difficulties of the chiral auxiliary recovery and often long reaction times. The scale up of the syntheses to 1 kg amount of the final product is either impossible or very difficult. On the other end of the scale, the syntheses of small amounts (<1 g) enantiomerically enriched 11C labeled AA become impractical because the synthetic protocol takes more time than the half-life period of the isotope (<1 hour).

We has been developing one of the best method of stoichiometric asymmetric synthesis of AA [10-18], which is currently being used by many chemical groups all over the world [1, 5, 10, 19]. The method has some advantages, including the simplicity of operation, ambient temperature of the reaction media, very high concentration of the reagents and the use of cheap bases. Other attractive features of the synthetic protocol are high rates of the alkylation reactions and the facile recovery of the AA and the chiral auxiliary, which are convenient for the synthesis of enantiomerically enriched 11C labeled AA with a short life period [5] and heterocycle containing AA for pharmacology and biotechnology [12-17]. Recently we have shown that mentioned method is convenient for large scale applications [20]. Unfortunately, optical purity of the AA obtained by this method, although in the range 85-92%, is not good enough especially for the synthesis of a-alkyl-AA.

One part of the project is designed to improve the performance of the technology by the modification of the chiral ligand in such a way as to make 98% enantiomeric purity of the resultant AA possible.

The second part of the project is dedicated to the development of a new type of asymmetric catalytic method of asymmetric synthesis of a-alkyl-AA [21].

As opposed to the stoichiometric asymmetric methods of AA synthesis, the catalytic versions are in their infancy. The asymmetric reductions of dehydro-AA represent the only exception [1, 9, 24]. Unfortunately, this approach can not be employed for the synthesis of a-alkyl-AA. Recently, a significant progress was achieved in the asymmetric C-alkylation of a derivative of glycine under phase transfer conditions [2]. The approach was based on the elaboration of an old family of phase transfer catalysts originated from chiral cinchona alkaloids. The catalysts suffer from their low range of stability, high cost and relative difficulties at modifications of their framework.

The objective of the second part of the project is to develop a new type of phase transfer catalysts based on chiral complexes of transition metals and to use them for catalytic asymmetric synthesis of a-alkyl-AA.

The project will meet the ISTC goals and objectives in the following ways:


· Providing weapons scientists and engineers in the CIS opportunities to redirect their talents to peaceful activities.
· Promoting integration of scientists of CIS states into the international scientific community.
· Supporting basic and applied research and technology development for peaceful purposes.
· Reinforcing the transition to market-based economies responsive to civil needs.


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The International Science and Technology Center (ISTC) is an intergovernmental organization connecting scientists from Kazakhstan, Armenia, Tajikistan, Kyrgyzstan, and Georgia with their peers and research organizations in the EU, Japan, Republic of Korea, Norway and the United States.

 

ISTC facilitates international science projects and assists the global scientific and business community to source and engage with CIS and Georgian institutes that develop or possess an excellence of scientific know-how.

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