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Site-Selective Aliphatic C-H Chlorination Using N-Chloroamides Enables a Synthesis of Chlorolissoclimide

Methods for the practical, intermolecular functionalization of aliphatic C-H bonds remain a paramount goal of organic synthesis. Free radical alkane chlorination is an important industrial process for the production of small molecule chloroalkanes from simple hydrocarbons, yet applications to fine chemical synthesis are rare. Herein, we report a site-selective chlorination of aliphatic C-H bonds using readily available N-chloroamides and apply this transformation to a synthesis of chlorolissoclimide, a potently cytotoxic labdane diterpenoid. These reactions deliver alkyl chlorides in useful chemical yields with substrate as the limiting reagent. Notably, this approach tolerates substrate unsaturation that normally poses major challenges in chemoselective, aliphatic C-H functionalization. The sterically and electronically dictated site selectivities of the C-H chlorination are among the most selective alkane functionalizations known, providing a unique tool for chemical synthesis. The short synthesis of chlorolissoclimide features a high yielding, gram-scale radical C-H chlorination of sclareolide and a three-step/two-pot process for the introduction of the β-hydroxysuccinimide that is salient to all the lissoclimides and haterumaimides. Preliminary assays indicate that chlorolissoclimide and analogues are moderately active against aggressive melanoma and prostate cancer cell lines.

MECHANISMS OF FREE-RADICAL REACTIONS. XXIV. QUANTITATIVE DESCRIPTION OF THE POLAR EFFECTS OF SUBSTITUENTS ON THE KINETICS OF THE FREE-RADICAL CHLORINATION OF ALIPHATIC COMPOUNDS BY N-CHLOROPIPERIDINE

The free-radical chlorination of 1-substituted alkanes with electron-withdrawing substituents by N-chloropiperidine in trifluoroacetic acid was studied by the method of competing reactions, and the relative rate constants were obtained for all positions of the substrates.The data on the position selectivity can be described satisfactorily by means of an electrostatic model of the polar effect of the substituent, calculated according to the Kirkwood-Westheimer equation.The obtained characteristics of the electrostatic effect can be successfully applied to calculation of the substrate selectivity and the intermolecular relative rate constants for all the positions, beginning with the third.The Taft equation is unsuitable for description of the effect of substituents on the reaction rate.

Chlorination of Carboxylic Acid Derivatives. IX. Liquid Phase Chlorination of Aliphatic C2-C8 Alkyl Acetates. EI Mass Spectra of Monochlorinated Esters

A series of aliphatic alkyl acetates from ethyl to octyl acetate was chlorinated in the liquid phase in order to obtain monochlorinated products.The chlorination of esters was carried out with chlorine in the liquid phase in the absence and in the presence of benzene and with sulfuryl chloride in the presence of Bz2O2.The products were determined by gas-liquid chromatography and gas-liquid chromatography-mass spectrometry.Chlorination is appreciably deactivated at the 1-position, particularly with SO2Cl2, the deactivation at the 2-position being strongest with Cl2 in the presence of benzene.The amounts of 1-chloro and ω-chloro isomers constituted the greatest disparity between the chlorination methods.The most characteristic mass spectral fragment ions of the 35 chlorinated alkyl acetates are given.