Biocatalytic Dynamic Kinetic Resolution for the Synthesis of Atropisomeric Biaryl N‐Oxide Lewis Base Catalysts

Abstract

Atropisomeric biaryl pyridine and isoquinoline N-oxides were synthesized enantioselectively by dynamic kinetic resolution (DKR) of rapidly racemizing precursors exhibiting free bond rotation. The DKR was achieved by ketoreductase (KRED) catalyzed reduction of an aldehyde to form a configurationally stable atropisomeric alcohol, with the substantial increase in rotational barrier arising from the loss of a bonding interaction between the N-oxide and the aldehyde. Use of different KREDs allowed either the M or P enantiomer to be synthesized in excellent enantiopurity. The enantioenriched biaryl N-oxide compounds catalyze the asymmetric allylation of benzaldehyde derivatives with allyltrichlorosilane.

Lipase‐Catalyzed Dynamic Kinetic Resolution of C1‐ and C2‐Symmetric Racemic Axially Chiral 2,2′‐Dihydroxy‐1,1′‐biaryls

“…To the best of our knowledge, there is only one report from Bäckvall's group that uses this strategy on axially chiral compounds, in particular axially chiral allenes (Scheme B) . With this background in mind, we now report the first chemoenzymatic DKR of C 1 ‐ and C 2 ‐symmetric atropisomeric 2,2′‐dihydroxy‐1,1′‐biaryls that tend to racemize during oxidative biaryl coupling . Notably, racemization, which is a critical problem in the biaryl coupling strategy, is a favorable, and even crucial process in our present DKR (Scheme C).…”

Enantiodivergent Synthesis of Allenes by Point‐to‐Axial Chirality Transfer

“…To determine whether this elimination proceeded by a syn or an anti pathway,i tw as necessary to determine the absolute stereochemistry of allene 37.Asthis compound was an oil, we were unable to establish its absolute configuration by X-ray crystallographic analysis.W et herefore simulated the electronic circular dichroism spectrum (ECD) of (P)-37 at the CAM-B3LYP/6-311(d,p) level of theory. [17] Thes imulated ECD spectrum for (P)-37 was ag ood match for the experimental spectrum, enabling us to determine that both oxidative and alkylative elimination proceeded via a syn mechanism (Scheme 2a). This inversion of selectivity in the alkylative elimination of 36 and 32 is likely due to the fact that the conformation necessary for anti elimination results in significant A-1,3 strain between the tetravalent boron centre and the bulky phenyl substituent (Scheme 2b).…”

Enantiodivergent Synthesis of Allenes by Point‐to‐Axial Chirality Transfer

“…As this compound was an oil, we were unable to establish its absolute configuration by X‐ray crystallographic analysis. We therefore simulated the electronic circular dichroism spectrum (ECD) of ( P )‐ 37 at the CAM‐B3LYP/6–311(d,p) level of theory . The simulated ECD spectrum for ( P )‐ 37 was a good match for the experimental spectrum, enabling us to determine that both oxidative and alkylative elimination proceeded via a syn mechanism (Scheme a).…”