Title

Acylation of trans-2-substituted cyclohexanols: The impact of substituent variation on the pyridine-induced reversal of diastereoselectivity

Poster Number

1

Lead Author Affiliation

Chemistry

Introduction

Diastereoselectivity in chemical reactions can arise from differences in activation energies associated with the reactants, if the process is kinetically controlled. Such selectivity is influenced by a number of factors, such as solvent polarity or temperature and examples for the complete reversal of diastereoselectivity. However, in some cases even achiral additives are known to influence the stereochemical course of reactions. In previous studies in our laboratory, we have demonstrated the capability of pyridine and other amine-based catalysts to reverse the diastereoselectivity of an acylation of racemic trans-1,2-substituted cyclohexanols with racemic acyl chloride and observed a catalyst-load dependence of the diastereoselectivity, as well as solvent dependence.

Purpose

We will report on our continued investigation of the pyridine-induced changes in diastereoselectivity of the acylation of racemic trans-1,2-substituted cyclohexanols with racemic acyl chloride, presenting new results on the reason for the previously observed catalyst-load dependence. In addition, the influence of the trans-2-substituents on the stereochemical outcome of the acylation reaction will be discussed in more detail.

Method

The acylation reactions of interest were optimized toward increased yield and different auxiliary bases were screened. A small library of trans-2-substituted cyclohexanols was synthesized and screened together with different acyl chlorides. The diastereoselectivity was determined on the crude reaction mixture using nuclear magnetic resonance (NMR) spectroscopy. Compounds were characterized via 1D + 2D-NMR and high resolution mass spectrometry after purification with column chromatography.

Results

Improved reaction conditions were established that allowed the use of catalytic amounts of pyridine together with an auxiliary base. The screening of a small library of trans-2-substituted cyclohexanols revealed effects of substitution patterns on the stereoselectivity of the reaction, with modifications leading to bulk near the reactive center giving higher diastereomeric ratios up to 15:1.

Significance

Today, there is a large demand for efficient stereospecific and stereoselective synthetic methods in both pharmaceutical research and manufacturing. Such selectivity is influenced by a number of factors, such as solvent polarity or temperature and others. Understanding the mechanism of the reversal of diastereoselectivity in this particular system of an acylation of racemic trans-2-substituted cyclohexanols with racemic acyl chloride will allow for chemical modification on the substrates in a deliberate manner. As a result, improved acylation reagents may lead to new and improved stereoselective acylation methods. These could potentially be applied to the efficient separation of racemic acyl chlorides, an underappreciated part of the synthetic organic chemistry literature.

Location

DeRosa University Center, Stockton campus, University of the Pacific

Format

Poster Presentation

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Acylation of trans-2-substituted cyclohexanols: The impact of substituent variation on the pyridine-induced reversal of diastereoselectivity

DeRosa University Center, Stockton campus, University of the Pacific

Diastereoselectivity in chemical reactions can arise from differences in activation energies associated with the reactants, if the process is kinetically controlled. Such selectivity is influenced by a number of factors, such as solvent polarity or temperature and examples for the complete reversal of diastereoselectivity. However, in some cases even achiral additives are known to influence the stereochemical course of reactions. In previous studies in our laboratory, we have demonstrated the capability of pyridine and other amine-based catalysts to reverse the diastereoselectivity of an acylation of racemic trans-1,2-substituted cyclohexanols with racemic acyl chloride and observed a catalyst-load dependence of the diastereoselectivity, as well as solvent dependence.