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

Abstract

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 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.

Synthesis facilitates an understanding of the structural basis for translation inhibition by the lissoclimides

“…24,33 This stereochemically flexible strategy 35 would permit us to interrogate the importance of configuration of this part of the molecule via late-stage succinimide incorporation onto aldehyde-bearing decalin intermediates, as performed in our semi-synthesis work. These decalin cores would be produced by a cationic bicyclizations (Fig.…”

“…In a critical sequence, bromination stereoselectively provided a surprisingly robust allylic α-bromide, and aldehyde 26 was obtained after dioxolane cleavage. Application of our Evans-aldol-based succinimide introduction 24 delivered 28 . Finally, potassium-superoxide-mediated displacement 42 completed a total synthesis of hatQ ( 8 ).…”

“…2a). 24 This work permitted the preliminary evaluation of their activity against aggressive tumor cell lines (DU145 prostate and A2058 melanoma). In these assays, CL was the most potent of the four compounds, with sub-micromolar IC 50 values recorded against each cell line.…”

Applications of Nonenzymatic Catalysts to the Alteration of Natural Products

“…246 The chiral chloride-substituted C2 position in 295 is remote from the functionality of the molecule, making the installation of this group a challenge. However, treatment of 238 with N -chloroamide 296 under visible light irradiation revealed the desired chlorination product 297 in 82% yield.…”

“…( B ) This C2-equatorial selectivity is also observed for chlorination to yield 297 , which is further utilized in the total synthesis of 295 . 244,246 …”