In recent years, extensive efforts have been made to expand the chemical structure space that can be accessed by organic synthesis. Therefore the development of new chemo- and diastereoselective hydrogenation protocols is of great value to the synthetic community. A rhodium-complex bearing a cyclic (alkyl)(amino)carbene (CAAC) ligand was found to serve as a potent (pre)catalyst for the arene hydrogenation of benzene derivatives and aromatic heterocycles. In the presence of the rhodium complex Cy(CAAC)Rh(cod)Cl 1, the benzene ring of 2-oxindoles and 3,4-dihydroquinol-2-ones was transformed into a saturated cyclohexane ring by hydrogenation. This catalytic system generates the corresponding alicyclic products in high isolated yields. The two rings were exclusively linked in a cis-fashion. The stereoselectivity of the process was found to be high in relation to both the external substituent Y within the saturated part of the heterocyclic ring and substituent X on the benzene ring. An array of hexahydroindolin-2(3H)-ones and octahydro-2(1H)-quinolinones were obtained with the major diastereoisomer exhibiting the hydrogen atoms in an all-cis arrangement. Up to three stereogenic centers are formed in a single operation with a predictable outcome. Subsequent transformations of the alicyclic products yielded the congeners without compromising the integrity of the stereogenic centers. Hydrogenation of aromatics is an important strategic transformation for the direct preparation of saturated carbo- and heterocycles. Inspired by the wide scope of the 2-oxindole and 3,4-dihydroquinolone hydrogenations, we turned our attention to the arene hydrogenation of amino acid derived heterocycles. Given the large number of bioactive molecules containing such frameworks, we anticipated that this method could find many applications in total synthesis. Thus, we have embarked on the total synthesis of a saturated pentacyclic natural product, with encouraging preliminary results.

All-cis arrangement: Rhodium-catalyzed diastereoselective arene hydrogenation reactions to saturated heterocycles

ACS Spring 2022

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