Ortega N, Tang D.-TD, Urban S, Zhao D, Glorius F * Westfälische Wilhelms-Universität
Münster and Bayer Pharma AG, Wuppertal, Germany
Ruthenium–NHC-Catalyzed Asymmetric Hydrogenation of Indolizines: Access to Indolizidine
Alkaloids.
Angew. Chem. Int. Ed. 2013;
52: 9500-9503
Key words
asymmetric hydrogenation - heterocycles - indolizidine - N-heterocyclic carbenes -
ruthenium
Significance
The indolizidine motif, which is characterized by fused six- and five-membered rings
containing a bridgehead nitrogen atom, is widely distributed as a core structure in
bioactive alkaloids. The authors reported the direct asymmetric hydrogenation of the
challenging N-bridged heterocycles, represented by substituted indolizine and 1,2,3-triazolo[1,5-a]pyridine derivatives. High enantioselectivities and yields were achieved by the application
of a chiral ruthenium–NHC complex for the completely regioselective and asymmetric
hydrogenation. Additionally, access to indolizidine scaffolds is demonstrated by the
efficient synthesis of (−)-monomorine via hydrogenation of the remaining pyrrole ring
under Jefford’s conditions.
Comment
The high regioselectivity is explained by the unusual aromatic structure of the fused
N-bridged heterocycle, where the six-membered ring reacts more like a reactive diene
rather than a pyridine, furnishing partially hydrogenated products in high yields.
Interestingly, the chiral induction is influenced strongly by the substitution pattern
on the substrate. In the case of alkyl groups on the 3- and 5-position, high ee values
are observed. A similar trend was obtained for substrates substituted with aryl or
ester groups on the 2-position. Alkyl groups on the 6-, 7- and 8-position caused no
reaction or diminished enantioselectivies. The potential of the procedure was demonstrated
by the short two-step synthesis of an alkaloid in an overall yield of 98%.
