Enzymes as catalysts in chemo-, regio- and stereoselective synthesis of organic compounds

Research Group

Head: Alicia Baldessari

Posdoc:

Luis E. Iglesias

PhD students:

Constanza P. Mangone

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Topics:

Chemoselective acylation of polyfunctional compounds

Chemoenzymatic synthesis of natural products derivatives

Enzymatic synthesis of substituted amides

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Chemoselective acylation of polyfunctional compounds

During the last years, synthetic processes using biological tools have been performed for the preparation of food additives, pharmaceuticals, and fine and commodity chemicals. These chemical reactions catalysed by enzymes, named biotransformations, are an emerging area of biotechnology. The recent discovery that some enzymes, such as lipases, are catalytically active in organic solvents has greatly expanded their use as biocatalysts. In this medium these enzymes show a new catalytic behavior. For example lipases catalyse esterification and transesterification reactions in organic media. This properties allow to prepare compounds which are difficult to obtain using chemical methods.

Using this approach various straight-chain hydroxyalkanethiols (HS(CH2)nOH with n: 2, 3, 4, 8 and 12) were chemospecifically acylated to O-acylesters through lipase-catalysed transesterifications in organic media. As the chain length of the ,-hydroxyalkanethiol increased, the reaction was limited to smaller acyl moieties. Products are known to be important molecular-weight controlling agent in chain polymerization.

Hydroxyalkanethiols with two hydroxyl groups exhibited regiospecificity or regioselectivity, depending on the nature of both the substrate and the lipase. We have been succesful in the selective acylation of thioglycerol which can be used as a precursor in the synthesis of low calorie fat mimetic compounds of interest in food industry, and of dithiotreitol and dithioeritritol which are used as protective agents for thiol group in biological systems.

Chemoenzymatic synthesis of natural products derivatives

Among the extensive field of natural compounds we are working on steroids and vitamin B6 derivatives.

Removal of protecting groups in steroids requires controlled reaction conditions in order to avoid modifications of other functional groups present in the molecule. Saponification is specially difficult and the conventional base catalysed reaction is not always successful. By studying the enzymatic deacetylation of pregnane, cholestane and androstane derivatives through lipase-catalysed alcoholysis we have observed the regioselective removal of the esters groups from several polyacetylated steroid compounds.

Some vitamin B6 derivatives, such as pyridoxine, show a polyhydroxylated system. This substrares are very appropriate to study regioselectivity, such in acylation reactions as in removal of acetyl groups. We have been succesful in obtaining, in a regioselective way, several products of mono- and diacylation.

Enzymatic synthesis of substituted amides

We have developed a procedure for the enzymatic one-pot preparation of substituted amides from caboxylic acids. Among the several compounds obtained through this approach, an intermediate of the synthesis of a drug used in treatment of benign prostatic hypertrophy was prepared.

The most relevant results obtained lately are described in the following publications:

. Regiospecific acylation of 2-mercaptoethanol by lipase-catalysed transesterification in organic solvents.

Alicia Baldessari, Luis E. Iglesias and Eduardo G. Gros, J. Chem. Res., 204 (1992).


. Regioselective acylation of 3-mercapto-1,2-propanodiol by lipase catalyzed transesterification.

Alicia Baldessari, Luis E. Iglesias and Eduardo G. Gros, J. Chem Res., 382 (1993).


. An improved procedure for chemospecific acylation of 2-mercaptoethanol by lipase-catalyzed transesterification.

Alicia Baldessari, Luis E. Iglesias and Eduardo G. Gros, Biotechnology Lett, 16, 479 (1994)


. Enzymatic deacetylation of steroids bearing labile functions.

Alicia Baldessari, Marta S. Maier and Eduardo G. Gros, Tetrahedron Lett., 36, 4349, (1995).


. Lipase-catalyzed chemospecific O-acylation of 3-mercaptopropanol and 4-mercaptobutanol.

Luis E. Iglesias, Alicia Baldessari and Eduardo G. Gros, Bioorg. & Med. Chem. Letters, 6, 853 (1996).


. Simple procedures for the preparation of a,w-hydroxyalkanethiols.

Luis E. Iglesias, Alicia Baldessari and Eduardo G. Gros, Org. Prep. & Proc. Int., 28, 319 (1996).


. Lipase catalysed regioselective deacetylation of androstane derivatives.

Alicia Baldessari, Andrea C. Bruttomesso and Eduardo G. Gros, Helv. Chim. Acta, 79, 999 (1996).


. Enzymatic procedure for one-pot preparation of substituted amides from carboxylic acids.

Alicia Baldessari and Eduardo G. Gros, P 9601 04756, 28-2-97, INPI, Argentina .