Radical mediated deoxygenation of inositol benzylidene acetals: conformational analysis, DFT calculations, and mechanism

doi:10.1016/j.carres.2012.01.001

Carbohydrate Research

Volume 351, 1 April 2012, Pages 26-34

https://doi.org/10.1016/j.carres.2012.01.001 Get rights and content

Abstract

Xanthates of 1,3-benzylidene acetal derivatives of myo- and neo-inositols undergo dideoxygenation under Barton-McCombie conditions, as a result of intramolecular abstraction of the benzylidene acetal hydrogen and subsequent cleavage of the acetal ring. Scrutiny of structure of these bicyclic inositol derivatives shows that although the conformation of the two rings can vary depending on the configuration of the inositol ring and the phase in which the molecules are present, both the xanthates lead to the formation of the same dideoxyinositol. DFT calculations on these molecular systems suggest that neo-inositol derivatives undergo conformational change prior to radical formation while myo-inositol derivatives undergo conformational change subsequent to radical formation, during the deoxygenation reaction. A low barrier for intramolecular hydrogen transfer supports the extreme facility of this deoxygenation reaction.

Graphical abstract

Highlights

► DFT calculations reveal relative stabilities of conformers of inositol 1,3-acetals. ► Relative stability of conformers provide insight into mechanism of deoxygenation. ► Deoxygenation of myo- and neo-xanthates proceeds through a common transition state.

Introduction

Cyclohexane polyols—tetrols, pentols, and hexols, collectively referred to as cyclitols form an important and interesting class among organic compounds due to their biological significance.1, 2, 3, 4, 5, 6, 7, 8 Naturally occurring cyclitols have been used as starting materials for the synthesis of natural products,9, 10, 11, 12, 13, 14, 15 scaffolds for the construction of metal ion complexing agents16, 17, 18 and the preparation of molecular crystals that possess unusual properties.19, 20, 21 Consequently, different synthetic approaches were developed for the preparation of cyclitols starting from benzene, quinic acid, carbohydrates, and naturally occurring inositols.22, 23, 24, 25, 26, 27, 28, 29, 30 Use of theoretical calculations to rationalize the relative reactivity of inositol hydroxyl groups have been attempted.31, 32, 33, 34, 35 However, reports on the conversion of inositols to other cyclitols via deoxygenation are scarce.36, 37, 38 Deoxygenation of alcohols via their xanthates is a versatile method for the removal of hydroxyl groups in small molecules.39, 40 We had previously reported⁴¹ a novel route to the synthesis of a deoxy as well as a dideoxy inositol from a single monoxanthate derivative of myo-inositol (Scheme 1). This reaction gave the same product irrespective of the configuration of the starting xanthate (myo- or neo-).

Deoxygenation of the epimeric (at the 1,3-benzylidene acetal carbon atom—shown as dark circle in Scheme 2) xanthates 7–9⁴² under similar radical deoxygenation conditions yielded the corresponding mono-deoxygenated derivatives exclusively since intramolecular (acetal) hydrogen abstraction is sterically forbidden in the C5-radicals produced from the xanthates 7–9. These results established that formation of the dideoxy myo-inositol derivative involved intramolecular hydrogen abstraction and subsequent cleavage of the 1,3-benzylidene acetal in the radical initially formed.

The xanthates 1 and 2 are derived from myo-inositol, while 3 is derived from neo-inositol; myo- and neo-xanthates vary in configuration at the carbon (C5, according to the numbering of the inositol ring) carrying the xanthate moiety. A comparison of the structure of the xanthates 1–3 and 7–9 shows that the relative conformation of the inositol and the acetal rings can vary among these bicyclic inositol derivatives. Such variations could have implications on the course and mechanism of these deoxygenation reactions. Although the conformations of the xanthates shown in Scheme 1 were established by X-ray crystallography, it does not imply that these are the reactive conformations nor minimum energy conformations nor does it imply that these conformations exist in solution, exclusively. In order to gain insight into these possibilities and the associated reaction mechanism, we have examined the conformation of the xanthates by DFT calculations and computed the geometry of the transition state for the intramolecular hydrogen transfer. Results of these investigations form the subject of the present article.

Section snippets

Results and discussion

Single crystal X-ray crystallographic data of the xanthates 1–3 showed that the conformation of the myo-xanthates 1⁴¹ and 2⁴² and the neo-xanthate 3 in their crystals are as shown in Scheme 1. NMR spectroscopy of the same compounds (Chart 1) revealed that solution state conformation of the myo-xanthates 1 and 2 is perhaps the same as that in their crystals but the neo-xanthate 3 does not maintain the same conformation in solution. Hence the possibility that these xanthates exist in more than

Conclusions

Analysis of the structure and conformation of inositol derived xanthates and the radicals generated from them under Barton–McCombie conditions reveal that myo-inositol derived xanthates and their neo-inositol analogs undergo deoxygenation by two different pathways. During this reaction, conformational changes occur in radicals derived from myo-inositol derivatives while conformational changes occur in neo-inositol derived xanthate prior to the formation of the radical. Although the difference

Computational details

All the density functional theory calculations were carried out using the Turbomole suite of programs.44, 45, 46 The strategy adopted for the geometry optimizations is as follows: for a given geometry, a conformational search was first done using Molecular Mechanics (MM+ force field) methods as implemented in the Hyperchem⁴⁷ software. The best five geometries obtained from the conformational analysis were then used as input structures for the DFT calculations. The conformation obtained with the

Acknowledgements

Bharat P. Gurale thanks CSIR, New Delhi, for the award of research fellowships. B.P.G. and K.V. acknowledge the Centre of Excellence in Scientific Computing (COESC), Pune, for providing computational facilities.

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Radical mediated deoxygenation of inositol benzylidene acetals: conformational analysis, DFT calculations, and mechanism

Abstract

Graphical abstract

Highlights

Introduction

Section snippets

Results and discussion

Conclusions

Computational details

Acknowledgements

Tetrahedron Lett.

Tetrahedron Lett.

Tetrahedron

Tetrahedron

Tetrahedron

Tetrahedron

Tetrahedron

Carbohydr. Res.

Tetrahedron

Tetrahedron

Chem. Phys. Lett.

J. Med. Chem.

Chem. Rev.

Nature

Mini-Rev. Med. Chem.

Chem. Rev.

Nat. Rev. Mol. Cell Biol.

Chem. Rev.

Chem. Commun.

J. Am. Chem. Soc.

Chem. Commun.

J. Org. Chem.

J. Org. Chem.

Chem. Soc. Rev.

Acta Crystallogr., Sect. B Acta

J. Indian Inst. Sci.