Escaping from Flatland: Stereoconvergent Synthesis of Three‐Dimensional Scaffolds via Ruthenium(II)‐Catalyzed Noyori–Ikariya Transfer Hydrogenation

Abstract

Noyori-Ikariya-type ruthenium(II)-catalysts for asymmetric transfer hydrogenation(ATH) have been known for 25 years and have proved asawell-behaved and userfriendly platform for the synthesis of chiral secondary alcohols. Ap rogress has been made in the past five years in understanding the asymmetric reduction of complex ketones, where up to four stereocenters can be controlled in as ingle chemical transformation. Intriguing multi-chiral molecular architecturesa re therefore available in few well understood and robusts ynthetic steps from commerciallya vailable buildingb locks and possessh andles for additional functionalization. The aim of this Review is to showcase the availability of three-dimensional scaffolds and homochiral lead-like compounds via ATHa nd inspiret heir direct use in drug discovery endeavors. Basic mechanistic insights are provided to demystifyt he stereo-chemical outcomes, as well as examples of diastereoselective transformationso fe nantiopure alcohols to give af eeling of how these rigid non-planar molecules can be further elaborated.

Access to enantioenriched molecules with diverse fluorinated tetrasubstituted stereocenters using hydroxy as a kinetic resolution auxiliary group

“…Furthermore, we have also considered the possibility of conducting the kinetic resolution of 1a′ through asymmetric reduction such as transfer hydrogenation. 16 As demonstrated in Scheme 3c, using classical Noyori–Ikariya type catalysts D 17 a and E 17 b , we found that the hydrogenation afforded a new diastereoisomer trans - 1a , which is very different from the products obtained using NaBH 4 reduction; secondarily, all attempts to achieve efficient kinetic resolution using D or E failed, and very low ee values of trans - 1a or recovered 1a′ were detected (Scheme 3c). All these results clearly demonstrate that the KRA* method is currently irreplaceable.…”

Asymmetric hydrogenation and transfer hydrogenation in the enantioselective synthesis of flavonoids

“…Consequently, modifications on the arene ligands allow a fine tuning of the enantiomeric excess, which can be favoured by tethered ligands in which the arene is covalently bound to the diamine, increasing the stability and turnover of the catalyst. 40,41…”

“…Furthermore, asymmetric hydrogenation (AH) 27–34 and asymmetric transfer hydrogenation (ATH) 35–44 have arisen as potent methodologies for the preparation of chiral compounds. As a result, they have been extensively explored in the synthesis of a variety of natural scaffolds and pharmaceutics.…”

“…45 Despite being periodically reviewed, AH/ATH has been mostly evaluated from a methodological point of view, instead of a total synthesis perspective. 46–50 Therefore, this review focuses on the recent applications of AH and ATH in the enantioselective synthesis of flavonoids, using this class of natural products as a theme to explore the advances, challenges, and opportunities in the field.…”

Straightforward Access to Enantioenriched cis-3-Fluoro-dihydroquinolin-4-ols Derivatives via Ru(II)-Catalyzed-Asymmetric Transfer Hydrogenation/Dynamic Kinetic Resolution

“…Asymmetric transfer hydrogenation (ATH) has been reported by Lassaletta and co-workers [ 5 ] as a method to access enantiomerically enriched fluoro-tetralol via a dynamic kinetic resolution (DKR) process ( Scheme 1 a). Following the premise of the fluorine need and the previous works in the laboratory including the ATH/DKR of 3-fluoro-chromanone derivatives [ 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 ] ( Scheme 1 b), we herein report an asymmetric transfer hydrogenation/dynamic kinetic resolution [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ] (ATH/DKR) of tert -butyl 3-fluoro-4-oxo-3,4-dihydroquinoline-1(2 H )-carboxylates into the corresponding enantioenriched cis -fluorohydrins ( Scheme 1 c).…”