Elsevier

Tetrahedron

Volume 59, Issue 26, 23 June 2003, Pages 4873-4879
Tetrahedron

Artificial model for cystathionine β-synthase: efficient β-replacement reaction with thiols employing a novel pyridoxal model compound having an imidazole function

https://doi.org/10.1016/S0040-4020(03)00666-5Get rights and content

Abstract

As a second-generation pyridoxal model compound for cystathionine β-synthase, we designed a novel model compound having an ionophore function and an imidazole function, application of which to the β-replacement reaction with various thiols smoothly took place to give S-substituted cysteines. Peptides having a serine-O-carbonate residue at the N-terminal position were also converted to the corresponding peptides having an S-substituted cysteine residue under the catalytic conditions of the novel pyridoxal model compound.

Introduction

A β-replacement reaction of the serine hydroxyl group with a nucleophile catalyzed by pyridoxal plays an important role in a biological system.1 Although this reaction system is expected to be of great use for the synthesis of various unnatural amino acids by artificial mimicking, only a limited number of examples mimicking tryptophane synthase, in which the nucleophile is indole, have been reported.2 In a preceding paper, we have described catalytic transformation of serine-O-carbonate 3 into S-substituted cysteines 4 employing pyridoxal model compound 1 (Fig. 1), which is the first example mimicking cystathionine β-synthase as shown in Figure 2.3 However, there still remains a problem in that compound 1 is a good catalyst for the reaction with aryl thiols, but is less effective for that with alkane thiols. In order to extend the reaction system to a general method, it is necessary to solve this problem. For the purpose, we designed a novel second-generation model compound of pyridoxal derivative 1.

As, in general, alkane thiols are more nucleophilic than aromatic thiols because of the electron-donating property of an alkyl group, the phenomenum appears to be strange. This result could indicate that, as aromatic thiols are less nucleophilic but are more acidic than alkane thiols, the formation of thiolate from thiol and/or the protonation procedure to an enolate species might be important to finish the reaction. In order to overcome this problem, we designed model compounds 2 which have an imidazole function. Introduction of the imidazole function was expected to introduce activation of the elimination of the carbonate moiety of 5 (Step 1) as well as activation of the 1,4-addition of alkane thiols to 6 (Step 2) as shown in Fig. 3. Taking into account the distance between the imidazole moiety and the reaction site, two model compounds 2a and 2b having different methylene lengths were designed.

On the other hand, we previously described regio- and stereoselective α-alkylation of peptides at the N-terminal position, employing a pyridoxal derivative.4 This is a unique and useful method to synthesize peptides including unnatural amino acids without preparing the corresponding unnatural amino acids,5 and would be of great use for construction of an unnatural peptide library.6 Accordingly, we utilized the novel model compounds 2 to β-replacement reaction of peptides having a serine-O-carbonate residue at the N-terminal position as well. In this paper, we would like to describe the synthesis of pyridoxal model compounds 2 and their ability for β-replacement reaction of serine-O-carbonate derivatives including peptides with thiols.7

Section snippets

Results and discussion

Synthesis of the model compounds 2 was achieved as shown in Scheme 1. Alcohol 88 was protected with a tert-butyldiphenylsilyl (TBDPS) group to give 9, the acetonide group of which was removed by acidic treatment, affording diol 10. Oxidation of 10 with MnO2 afforded aldehyde 11, which was protected as dimethyl acetal 12. An ethoxyethyl goup was introduced to 12, affording 13. In order to couple with an imidazole moiety, the silyl group of 13 was removed under conventional fluoride treatment to

General

Melting points (mps) were taken on a Yanagimoto micro-melting point apparatus and are uncorrected. Infrared spectra were measured on a JASCO FT/IR-200 Fourier-transfer infrared spectrometer. 1H NMR spectra were measured on a JEOL EX-270 (270 MHz) spectrometer and tetramethylsilane (TMS) was used as an internal standard. 13C NMR spectra were measured on the same instrument (67.8 MHz) with CDCl3 as an internal standard (77.0 ppm). Low and High resolution mass spectra (EI-MS and HR-MS) were

Acknowledgements

A part of this work was supported by SUNBOR Grant.

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