Artificial model for cystathionine β-synthase: construction of a catalytic cycle with a pyridoxal model compound having an ionophore function

Abstract

Catalytic transformation of serine-O-carbonate to S-aryl cysteine derivatives was successfully achieved in the presence of Li⁺ by the use of a pyridoxal model compound having an ionophore function, which is the first example mimicking cystathionine β-synthase, artificially.

Introduction

Pyridoxal 5′-phosphate (PLP, 1) and pyridoxamine 5′-phosphate (PMP, 2) are important coenzymes related with the biosynthetic and metabolic reactions of α-amino acids. A number of reactions mediated by these coenzymes are known.¹ β-Replacement reaction of the serine hydroxyl group with a nucleophile is one such reaction mediated by pyridoxal, and is a biologically important reaction for biosynthesis of amino acids. Tryptophan synthase and cystathionine β-synthase are typical examples, in which the nucleophiles are indole and homocysteine, respectively (Figure 2). In order to clarify the mechanisms of the biological reactions, and from the viewpoint of synthetic organic chemistry, a number of studies mimicking the biological reactions mediated by a pyridoxal–pyridoxamine system have been conducted.² In fact, pyridoxal model studies mimicking tryptophan synthase have also been reported,³ but, to the best of our knowledge, that mimicking cystathionine β-synthase has not. Cystathionine β-synthase is a biologically important enzyme, working as a homocysteine scavenger,⁴ deficiency of which causes homocystinuria, and is known to be related with cardiovascular diseases, neural tube defects and Altzheimer's disease.⁵ Cystathionine β-synthase is known to require two co-factors, pyridoxal and heme. Although the role of pyridoxal is apparent, that of heme has not been clarified, but it may be a regulatory role.⁶

In previous papers, we reported a novel type of pyridoxal model compound having an ionophore side-chain at the C-3 hydroxyl group, which had not been modified in previous model compounds, and its application to the synthesis of α,α-dialkyl amino esters by the α-alkylation.7., 8. In these studies, it was found that aldimine, prepared from 3 and an amino ester, can capture Li⁺ specifically as shown in Figure 1, and, as a consequence, the α-hydrogen is activated.⁷ This interesting feature of 3 was expected to be of use for other reactions mediated by PLP (1). As the β-replacement reaction appears to be useful for the synthesis of various β-modified amino acids by employing various kinds of nucleophiles, we, at first, applied our model compound 3 to the β-replacement reaction employing thiols as a nucleophile, and successfully achieved the reaction under catalytic conditions. Herein we describe details of the results.⁹