Abstract
An efficient one-pot synthesis of novel β-amino acid derivatives containing a thiadiazole moiety was developed using a chiral squaramide cinchona alkaloid as organocatalyst. The reactions afforded chiral β-amino acid derivatives in moderate yields and with moderate to excellent enantioselectivities. The present study demonstrated for the first time the use of a Mannich reaction catalyzed by a chiral bifunctional organocatalyst for the one-pot synthesis of novel β-amino acid derivatives bearing a 1,3,4-thiadiazole moiety on nitrogen.
Highlights
ChemistrySeveral differentially substituted chiral derivatives of squaramides (SQ) have been synthesized and used as catalysts for asymmetric reactions [30,31,32,33,34]
Introduction βAmino acids are key structural components of peptides, peptidomimetics, and natural products [1,2].Stereochemically defined β-amino acids are synthesized and applied in drug development, molecular recognition, and bimolecular structure and functional studies [3,4,5,6,7]
Having established the ideal reaction conditions, we explored the synthetic scope of the reaction with different aldehydes and malonates as substrates
Summary
Several differentially substituted chiral derivatives of squaramides (SQ) have been synthesized and used as catalysts for asymmetric reactions [30,31,32,33,34]. The quinine catalyst Q-1 turned out to be a poor catalyst, affording a 37% yield and 11% ee, whereas the catalyst Q-2 performed slightly better, with 39% yield and 37% ee, respectively, when the reactions were carried out at 60 °C for 96 h (entry 1 and 2, Table 1). Since both Q-1 and Q-2 failed to achieve the desired high yield and enantioselectivity, we continued our search for a better catalyst and found that the cinchona alkaloid derivative (SQ) bearing both the hydrogen-bond donor squaramide and the hydrogen-bond acceptor tertiary amines delivered superior results. These speculated interactions in our proposed mechanism might be responsible for the observed stereochemical outcome of the reaction and the enhanced reaction rate
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