Glucopyranosylidene-Spiro-Thiazolinones: Synthetic Studies and Determination of Absolute Configuration by TDDFT-ECD Calculations.

Katalin Szabó,Sándor Kun,László Somsák,Tibor Kurtán,Attila Mándi

doi:10.3390/molecules22101760

Abstract

Reactions of O-peracylated C-(1-bromo-β-d-glucopyranosyl)formamides with thioamides furnished the corresponding glucopyranosylidene-spiro-thiazolin-4-one. While O-debenzoylations under a variety of conditions resulted in decomposition, during O-deacetylations the addition of MeOH to the thiazolinone moiety was observed, and with EtOH and water similar adducts were isolated or detected. The structure and stereochemistry of the new compounds were established by means of NMR and electronic circular dichroism (ECD) data supported by time-dependent density functional theory ECD (TDDFT-ECD) calculations. TDDFT-ECD calculations could efficiently distinguish the proposed epimeric products having different absolute configuration in the spiro heterocyclic ring.

Highlights

During the past two decades, several glucopyranosylidene-spiro heterocycles have emerged as potent inhibitors of glycogen phosphorylase (GP) [1,2,3,4,5]
Chart 1) was disclosed in the mid-nineties [17] followed by the more synthesized thiohydantoin counterpart (A, X = S) [18,19]. Both compounds were active as GP inhibitor (GPI) in the low micromolar concentration range
For the strong binding of compounds A to the enzyme, X-ray crystallography of the enzyme-inhibitor complexes revealed the importance of the H-bond donor β-NH, as well as that of the α-carbonyl groups highlighted in red [23,24]

Summary

Introduction

During the past two decades, several glucopyranosylidene-spiro heterocycles have emerged as potent inhibitors of glycogen phosphorylase (GP) [1,2,3,4,5]. Chart 1) was disclosed in the mid-nineties [17] followed by the more synthesized thiohydantoin counterpart (A, X = S) [18,19] Both compounds were active as GPIs in the low micromolar concentration range. An attempt was made to unify these properties by the study of compounds C [3] These derivatives proved rather weak inhibitors and this was attributed to the =N–C=O linker between the spirocycle and the aryl groups resulting in an unfavorable orientation of the latter for the binding. To circumvent this problem the synthesis of compounds D was envisaged, and the results of these studies are presented in this paper

Methods

Discussion

Conclusion