Generation of Mixed Anhydrides via Oxidative Fragmentation of Tertiary Cyclopropanols with Phenyliodine(III) Dicarboxylates.

Dzmitry M Zubrytski,Gábor Zoltán Elek,Dzmitry G Kananovich,Margus Lopp

doi:10.3390/molecules26010140

Abstract

Oxidative fragmentation of tertiary cyclopropanols with phenyliodine(III) dicarboxylates in aprotic solvents (dichloromethane, chloroform, toluene) produces mixed anhydrides. The fragmentation reaction is especially facile with phenyliodine(III) reagents bearing electron-withdrawing carboxylate ligands (trifluoroacetyl, 2,4,6-trichlorobenzoyl, 3-nitrobenzoyl), and affords 95−98% yields of the corresponding mixed anhydride products. The latter can be straightforwardly applied for the acylation of various nitrogen, oxygen and sulfur-centered nucleophiles (primary and secondary amines, hydroxylamines, primary alcohols, phenols, thiols). Intramolecular acylation yielding macrocyclic lactones can also be performed. The developed transformation has bolstered the synthetic utility of cyclopropanols as pluripotent intermediates in diversity-oriented synthesis of bioactive natural products and their synthetic congeners. For example, it was successfully applied for the last-stage modification of a cyclic peptide to produce a precursor of a known histone deacetylase inhibitor.

Highlights

Hydroxy-substituted cyclopropanes are widely used in organic synthesis as versatile C3 -building blocks [1,2,3,4,5], with a rapidly growing number of novel applications [6,7]
Taking into account that amide bond is frequently occurs in pharmaceuticals [44,45] and novel methods of amide synthesis currently attract a great deal of attention [46,47,48], one-pot preparation of amides from cyclopropanols was highly desired to bolster the performance of cyclopropanol moiety as pluripotent functionality suitable for the generation of bioactive molecular libraries
This achievement illustrates the suitability of the developed protocol for the synthesis of bioactive amides and was previously employed by us, along with several other ring-opening reactions, to generate a number of histone deacetylase (HDAC) inhibitors from the single cyclopropanol precursor according to diversity-oriented synthesis paradigm [39]

Summary

Introduction

Hydroxy-substituted cyclopropanes (cyclopropanols) are widely used in organic synthesis as versatile C3 -building blocks [1,2,3,4,5], with a rapidly growing number of novel applications [6,7]. The internal ring strain and the presence of electron-donating hydroxyl group facilitate ring-opening reactions of cyclopropanols under mild conditions, well tolerated by other functionalities. These reactions occur upon treatment with electrophilic reagents and proceed via homo- or heterolytic fission of the electron-rich carbon−carbon bonds adjacent to oxygen, affording β-functionalized ketones [20,21,22]. The reaction cascade results in a fast (typically, within few minutes) oxidative fragmentation of 1 via the cleavage of both carbon−carbon bonds adjacent to oxygen and produces carboxylic acid The fragmentation step requires anti-periplanar arrangement acid (or ester) and alkene.

Oxidative

Results and Discussion

REVIEW

Acylation

Methods

Conclusions