Asymmetric Hydrogenation of 2,4-Dioxo Esters: Selective Synthesis of 2-Hydroxy-4-oxo Esters and Direct Access to Chiral 2-Hydroxy-4-butyrolactones

Abstract

2,4‐Dioxoesters 1a–c are selectively converted into optically active 2‐hydroxy‐4‐oxoesters 2a–c by hydrogenation with chiral rhodium‐aminophosphane‐phosphinite catalysts (82–88% ee) or ruthenium‐bisphosphane catalysts (52–67% ee). Direct one‐pot hydrogenation of 2,4‐dioxoesters 1a–c to 2‐hydroxy‐4‐butyrolactones 4a–c proceeds in high yields; catalytic activities, chemo‐, dia‐, and enantioselectivities are strongly dependant upon the nature of the substrate and the catalyst.

Facile Synthesis of Enantiopure 4‐Substituted 2‐Hydroxy‐4‐ butyrolactones using a Robust Fusarium Lactonase

“…We used 1 H NMR and NOE experiments to assign the relative configuration (Figure 4). 6,17 In cis lactones H‐2 exhibits a dd peak with coupling constants of ∼8.1 Hz ( J 2,3′ ) and ∼11.1 Hz ( J 2,3 ) while H‐4 also shows a dd peak with coupling constants of ∼5.1 Hz ( J 4,3′ ) and ∼11.1 Hz ( J 4,3 ) 18,19. The 1 H NMR spectra of trans lactones show the proton signal at the 2‐position as a dd peak with the same coupling constants of ∼7.8 Hz ( J 2,3 and J 2,3′ ) while the proton signal at the 4‐position is a dd peak with the coupling constants of ∼4.5 Hz and ∼7.5 Hz.…”

“…4‐Substituted 2‐hydroxy‐4‐butyrolactones comprise a vast family of compounds with great importance. As chiral building blocks, they have been widely used in the pharmaceutical industry for the production of ACE inhibitors1a such as Enalapril, Cilazapril, Benazepril etc. They are also used in the synthesis of natural products with antitumor or cytotoxic activities, including Apoptolidin,1b Epothilones,1c Salicylihal‐amides1d and Bengazoles 1e.…”

“…Due to the great interest in their four stereoisomers, different strategies to make these chiral lactones have been developed. These include: a) chiral pool synthesis, using glucose,1d malic acid,1c xylose3 and so on; b) chiral auxiliaries, such as hydrazine SAEP4 and c) asymmetric catalysis, including enzymatic5 and non‐enzymatic routes 6. However, strategies a and b share common problems, such as expensive starting materials or auxiliaries and complicated synthetic routes 4,7.…”

“…In addition, only one substrate, 4‐phenyl‐2,4‐diketobutyric acid, was studied in this method. Carpentier et al6 reported asymmetric hydrogenation of readily available ethyl 2,4‐diketo acids using a series of metal/ligand systems. The efficiency and selectivity of the catalysts were highly dependent on the substrate structures and only two [(2 R ,4 R )‐ and (2 R ,4 S )‐lactones] of the four stereoisomers of 4‐substituted 2‐hydroxy‐4‐butyrolactones could be prepared.…”

Diastereoselective Hydrogenation

“…Reduction of b,d-diketo esters using various atropisomeric diphosphine ligands afforded generally the anti-3,5-dihydroxy products in moderate to good diastereoselectivity, and in high enantioselectivity (Table 21.16) [101][102][103][104]. This suggests that stereocontrol in the hydrogenation of diketo esters is, in general, very similar to that found in the hydrogenation of diketones with Ru-binap (vide infra) [105,106].…”