All-cis Saturated 2,5-Diketopiperazines by a Diastereoselective Rhodium-Catalyzed Arene Hydrogenation

Abstract

The direct hydrogenation of aromatic systems is a compelling tool to access saturated carbo- and heterocycles, an omnipresent motif in natural products, pharmaceuticals, and agrochemicals. Although a variety of methods have been established for simple arenes, the selective hydrogenation of aromatic 2,5-diketopiperazines (2,5-DKPs) has not been explored. We herein report a modular approach to perform a highly diastereoselective arene hydrogenation of symmetric 2,5-DKPs catalyzed by a rhodium complex. Twenty-eight saturated pentacyclic 2,5-DKPs were obtained in high yields with exquisite diastereoselectivities, exhibiting the hydrogen atoms in an all-cis arrangement. The high tolerance toward functional groups and the compatibility with existing stereogenic centers are key features of the transformation.

cis-Selective Hydrogenation of Aryl Germanes: A Direct Approach to Access Saturated Carbo- and Heterocyclic Germanes

“…Herein, we describe the first comprehensive study for the direct preparation of diastereoselective saturated carbo-cyclic germanes including the unprecedented preparation of valuable saturated heterocyclic germanes via the additive-free hydrogenation of aryl germanes. Previously, the groups of Zeng et al, , Bullock et al, , Andersson et al, our group, ,− ,− and others − have reported novel catalytic arene hydrogenation reactions using rhodium and ruthenium metal-based catalytic systems. Intrigued by these reports, we examined the hydrogenation of aryl germanes employing various molecular complexes and heterogeneous metal species as catalysts.…”

Rhodium(CAAC)‐Catalyzed Arene Hydrogenation of Benzo‐Fused N‐Heterocycles to Saturated Building Blocks with an all‐cis Configuration

“…In all experiments, the reaction mixture was a homogeneous solution at the beginning, but a rhodium precipitate was formed under reductive conditions. Previous studies had revealed, that in situ formed small rhodium nanoparticles are the catalytically active species [8b,9g,12] . The nature of the active species was further validated through poisoning experiments [18] .…”

“…In previous work, we have shown that the known rhodium(I) (pre)catalyst 1 [6,7] with a cyclic (alkyl)(amino)carbene (CAAC) ligand [11] is superior for the selective hydrogenation of 2‐oxindoles, 3,4‐dihydroquinolones and aromatic 2,5‐diketopiperazines [8] . It was revealed by mechanistic studies, that the catalytically active rhodium species is not homogeneous but heterogeneous [8b,9g,12] . In order to demonstrate the potential of catalyst 1 for a broadly applicable arene hydrogenation, our present study commenced with optimization experiments [gas−liquid chromatography (GLC) analysis] and an evaluation of common commercially available heterogeneous hydrogenation catalysts.…”

“…Clearly, the rhodium (pre)catalyst 1 showed the highest selectivity, given that a rather labile substituent was retained at the arene core. The molecular sieves are likely required as support for the rhodium particles ( vide infra ) [8b] …”

Catalytic Asymmetric Syntheses of 2,5‐Diketopiperazine (DKP) Frameworks

“…For example, although the Ugi reaction has been widely used to smoothly construct DKP skeletons from chiral substrates, the development of its catalytic asymmetric version [25] is highly challenging. 2) Chiral units bearing quaternary carbon stereocentres provide long‐standing synthetic challenges [26] . 3) The enantioselectivities and diastereoselectivities of reactions involving nonsymmetric substrates need to be controlled.…”