Rhodium-Phosphoramidite Catalyzed Alkene Hydroacylation: Mechanism and Octaketide Natural Product Synthesis

Abstract

We describe a method that allows salicylaldehyde derivatives to be coupled with a wide range of unactivated alkenes at catalyst loadings as low as 2 mol %. A chiral phosphoramidite ligand and the precise stoichiometry of heterogeneous base are key for high catalytic activity and linear regioselectivity. This protocol was applied in the atom- and step-economical synthesis of eight biologically active octaketide natural products, including anticancer drug candidate cytosporone B. Mechanistic studies provide insight on parameters affecting decarbonylation, a side reaction that limits the turnover number for catalytic hydroacylation. Deuterium labeling studies show that branched hydride insertion is fully reversible, whereas linear hydride insertion is largely irreversible and turnover-limiting. We propose that ligand (R(a),R,R)-SIPHOS-PE effectively suppresses decarbonylation, and helps favor a turnover-limiting insertion, by lowering the barrier for reductive elimination in the linear-selective pathway. Together, these factors enable high reactivity and regioselectivity.

Synthesis and Biological Activity of Octaketides from the Cytosporone Family

“…Herein we report the synthesis of cytosporone B analogues that possess a wider range of functionality on the lipophilic acyl chain. We make use of an efficient alkene hydroacylation method previously developed in our laboratory, which provides access to the target structures in a mild and modular fashion. We report the biological activity of these compounds against a panel of in‐vitro assays that are relevant from a drug discovery perspective.…”

Traceless Chelation‐Controlled Rhodium‐Catalyzed Intermolecular Alkene and Alkyne Hydroacylation

“…An inherent feature of chelation‐controlled reactions is that the chelating group, which is necessarily present in the starting materials to ensure favourable reactivity, is also present in the product molecules. Derivatization of these controlling groups can provide opportunities for further functionalization of the products,4d, 5a, 10 but if an unadorned molecule is required, they represent a limitation of the strategy. Although a number of examples of successful non‐chelation‐controlled intermolecular hydroacylation reactions is known, they generally require specific substrate combinations or harsh reaction conditions 11.…”

Total Synthesis and Cytotoxic Activity of 5′‐Hydroxyzearalenone and 5′β‐Hydroxyzearalenone

“…The synthesis of benzoic acid derivative 8b was achieved in 10 steps from commercially available methyl 2‐(3,5‐dimethoxyphenyl)acetate ( 28 ) (Scheme ). Phenol 30 was prepared in two steps from 28 according to a procedure reported by Dong et al under slightly modified conditions . EOM ether 31 was formed by reprotection of the free phenol moieties of 30 with EOMCl.…”