Sintese formal do adoçante natural (-)-monatina

AUTOR(ES)
DATA DE PUBLICAÇÃO

2003

RESUMO

In this work we describe the asymmetric formal synthesis of (-)-monatin [(3-indolyl)-2-amino-4-carboxy-4-hydroxypentanoic acid), a powerful natural sweetener, isolated from roots of the african plant Schlerochiton ilicifolius. Monatin exhibit a sweet taste 1400 times more powerful than that of sucrose. (-)-Monatin bears two stereogenic centers, namely, 2S and 4S. The first asymmetric center (2S) came from the asymmetric starting material, S-pyroglutamic acid. The asymmetric quaternary center at C4 (S) has been prepared through a highly diastereoselective sequential oxidation and alkylation reactions of an enolate, induced by the asymmetric center at C2.Two synthetic strategies for the natural sweetener preparation have been studied in this work. In the first strategy, the quaternary asymmetric center would be prepared via [2+2] cycloaddition reaction between a kinetic enol ether and dichloroketene. The preparation of this enol ether would be secured from N-benzenesulphonamine-3-indoylpropanone, easily prepared from commercial 3-indoyl-acetic acid. Due to the lake of simmetry exhibited by methyl ketone it was necessary to establish a suitable experimental protocol in order to have a good control in the regioselectivity of the enolate formation. It is was necessary prepare selectively the kinetic enolate. Under kinetic conditions for enolate formation, it was possible to detect thermodynamic enolate as the only product. Several experimental modifications have been tested, unfortunately we were unable to obtain the kinetic enol ether as the major product. To circumvent theses problems, we have tried some alternatives methods to prepare kinetic enol ether. Thus, we decided to obtain the kinetic enol ether through an olefination reaction (Petasis and Tebbe reactions). Once a time we failed. Then we decided to test an alternative approach to achieve our goal. This alternative approach was based on the preparation of a pyroglutamate derivative bearing a hydroxyl group at C3. Then, the oxidation reaction was effected with dibenzyldicarbonate peroxide to provide 47 in a chemical yield of 50% and a high degree of diastereoselection (>90%). The trans relative stereochemistry of 47 was unambiguously determined through a nOe experiment. The formation of the quaternary center of monatin structure was secured via an alkylation reaction of an enolate, obtained from treatment of 47 with lithium hexamethyldisilylazide, with N-Boc-3-bromomethylindole to furnish 48 in 75% chemical yield. The high diastereoselectivity of this alkyklation reaction was determined by chiral HPLC (only one diastereoisomer detected). The relative stereochemistry of this diastereoisomer was determined by an nOe experiment. The lactam ring was opened by treatment of 48 with LiOH in a mixture of THF: water. Under this experimental condition it was possible to remove the Cbz protecting group to give 49, in a quantitative yield. The silyl group of 49 was removed and the free hydroxyl group was subsequentially oxizided with Jones reagent (0,003 M) in a acetonitrile at -15°C. Purification by silica gel column chromatography gave compound 50 in a chemical yield of 65%. In order to remove the Boc protective group of the indolic nitrogen, several methods have been tested. However, we are unable to adequately remove this protecting group. Finally, this work has permitted to establish a highly diastereoselective method for preparation of asymmetric quaternary center in a pyroglutamate derivative. N-Boc-Monatin, an advanced precursor for the total synthesis of Monatin, was synthetized in 12 steps with an overall yield of 16%.

ASSUNTO(S)

adoçantes - historia adoçantes naturais

ACESSO AO ARTIGO

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