Homogeneous palladium-catalyzed enantioselective hydrogenation of 5-methylenhydantoin for the synthesis of L-Valine

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Highlights

  • The enantioselective hydrogenation of 5-methylenhydantoin can lead to L-Valine.

  • A palladium catalyst allowed the asymmetric hydrogenation of 5-methylenhydantoin.

  • Hydrolysis of the corresponding hydrogenated product afforded L-Valine.

  • A partial racemization was observed upon hydrolysis and recovery of L-Valine.

Abstract

In this article, we present the development of a synthetic methodology based on homogeneous catalysis for the preparation of enantioenriched L-Valine aminoacid. The enantioselective hydrogenation of 5-methylenhydantoin has been developed through broad screenings of chiral ligands, metal precursors and reaction conditions including scale-up experiments and recyclability studies. A palladium catalyzed asymmetric hydrogenation of 5-methylenhydantoin afforded the corresponding hydrogenated product in a 70% enantiomeric excess using a substrate/catalyst ratio of 500/1. A partial racemization was observed upon hydrolysis and recovery of L-Valine.

Introduction

Chiral amino acids are key molecules in the pharmaceutical, food, cosmetic and agricultural industries [1] Due to increasing costs and sustainability issues, the feedstuff industry has gradually developed reduced protein diets for animals. Such strategy has led to a growing demand of L-Valine which is implied in several vital functions in animals [2]. Indeed, the use of L-Valine in reduced protein diets has been shown to increase the feed conversion and therefore the animal body weight while reducing water consumption and nitrogen waste excretions. Among hydantoins, which are saturated heterocycles comprising 2 lactam functions, 5-substituted hydantoins can be found in a wide range of natural and synthetic chemicals of biological and pharmaceutical interests. More particularly, the simple and low cost 5-substituted hydantoins have been useful intermediates in the synthesis of aminoacids [3]. Though the asymmetric hydrogenation of 5-ylidenhydantoins allows a direct access to enantioenriched aminoacids, it has scarcely been studied [4]. In this article , we present the development of a synthetic methodology based on homogeneous catalysis for the preparation of enantioenriched L-Valine 3 based on a catalyzed asymmetric hydrogenation of 5-methylenhydantoin 1 [5] into 2 [6] and a subsequent hydrolysis (Scheme 1).

Section snippets

Results and discussion

Due to solubility issues (Table S1), the asymmetric hydrogenation of 5-methylenehydantoin 1 was studied in CH3OH, i-PrOH and 1,4-dioxane. At first, we screened various privileged catalysts based on iridium, cobalt and nickel but did not observe any significant conversion and enantioselectivity (Scheme S1). Afterwards, we tried rhodium based catalysts combining [Rh(COD)2]BF4 precursor and specific ligands like BIBOP [7], UREAphos and METAMORPhos bifunctional phosphoramidites [8] or Zhaophos [9],

Conclusion

We developed a synthetic methodology for the preparation of enantioenriched L-Valine 3 based on a catalyzed asymmetric hydrogenation of 5-methylenhydantoin 1 and a subsequent hydrolysis. Selected palladium homogeneous catalysts based on chiral diphosphine ligands were the single effective species allowing the hydrogenation of 5-methylenhydantoin in high yields and good enantioselectivities. Though L-Valine was obtained through hydrolysis of the hydrogenated product, a significant racemization

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

This research was first funded by ADISSEO France SAS. The CNRS, the Chevreul Institute (FR 2638), the Ministère de l'Enseignement Supérieur et de la Recherche, the Région Hauts-de-France and the FEDER are acknowledged for supporting and funding partially this work. Mrs C. Delabre (UCCS) is thanked for GC and GC–MS analyses and some HPLC separations.

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