A tandem photo- and biocatalytic dynamic kinetic resolution of secondary alcohols and amines was achieved employing a commercially available lipase, Candida antarctica lipase B (CALB), and a ...heteroleptic copper complex. The process is an example of using copper-based photocatalysis to promote hydrogen atom transfer (HAT) processes employing thiyl radicals. Screening of 48 complexes and 5 disulfides identified Cu(dtbbpy)(DPEPhos)BF4 and (Ph3SiS)2 as an optimal catalyst system to promote the HAT process. The catalytic system represents a general system for radical-mediated racemization applicable to both aliphatic and aromatic alcohols and amines (18 examples, 60 → 97% yield, 76 → 99% ee).
Differentially substituted 1,2-amino alcohols are a prevalent motif in a variety of pharmaceutical and agrochemical molecules. Dynamic kinetic resolutions (DKRs) that involve the asymmetric reduction ...of α-amino ketones are attractive for preparing this motif; however, methods for racemizing the stereogenic α-carbon under mild conditions are underdeveloped. Here we report a chemoenzymatic DKR involving ketoreductases (KREDs), in which pyridoxal-5-phosphate (PLP) is used to catalyze racemization of the starting racemic α-aminoketone. This strategy enables access to a variety of 1,2-amino alcohols with high levels of diastereo- and enantioselectivity. Using commercially available KREDs, all four possible stereoisomers can be accessed, highlighting a benefit to this approach.
An unprecedent asymmetric catalytic benzilic amide rearrangement for the synthesis of α,α‐disubstituted piperazinones is reported. The reaction proceeds via a domino 4+1 imidazolidination/formal ...1,2‐nitrogen shift/1,2‐aryl or alkyl migration sequence, employing readily available vicinal tricarbonyl compounds and 1,2‐diamines as starting materials. This approach provides an efficient access to chiral C3‐disubsituted piperazin‐2‐ones with high enantiocontrol, which are exceedingly difficult to access from the existing synthetic methodologies. The observed enantioselectivity was proposed to be controlled by dynamic kinetic resolution in the 1,2‐aryl/alkyl migration step. The resulting densely functionalized products are versatile building blocks to bioactive natural products, drug molecules and their analogues.
The first examples of enantioselective benzilic amide rearrangement for the synthesis of chiral α,α‐disubstituted piperazinones have been developed. The reaction proceeds via a high ordered sequence of imidazolidination/formal 1,2‐aza shift/1,2‐aryl or alkyl migration. The observed enantioselectivity was proposed to be controlled by dynamic kinetic resolution in the 1,2‐aryl/alkyl migration step.
We have developed a synthetic strategy to access axially chiral biaryls through a dynamic-kinetic resolution-semipinacol rearrangement process. The axial chirality together with a sp3 quaternary ...carbon can be introduced in a single chemical operation. The products can be further ring-expanded to yield biologically relevant seven-membered dibenzolactams with inverted axial chirality.
Herein, we describe a chemoenzymatic synthesis of the bicyclic fragment of Darunavir. A ketoreductase was identified using metagenomic mining to catalyze a highly enantio- and diastereoselective ...dynamic kinetic resolution of a β-ketolactone. Subsequent lactone reduction with diisobutylaluminum hydride and phase transfer cyclization affords the bicyclic acetal fragment in 39% yield over four steps.
A ketone fluorination/reduction dynamic kinetic resolution (DKR) was developed for a third-generation synthesis of belzutifan. This new process replaced a precious metal catalyst with a ketoreductase ...(KRED) in the DKR. Achieving this one-pot reaction required several rounds of enzyme evolution that improved enzyme stability in the presence of acetonitrile and methanol. To maintain development progress and satisfy program timelines, process development around the reaction, workup, and isolation operations was performed in parallel with the enzyme evolution and required ongoing modification, as new variants were made available. Additionally, opportunities for improvements to product quality and process robustness were identified by resolving issues observed in piloting experiments.
β‐Branched noncanonical amino acids are valuable molecules in modern drug development efforts. However, they are still challenging to prepare due to the need to set multiple stereocenters in a ...stereoselective fashion, and contemporary methods for the synthesis of such compounds often rely on the use of rare‐transition‐metal catalysts with designer ligands. Herein, we report a highly diastereo‐ and enantioselective biocatalytic transamination method to prepare a broad range of aromatic β‐branched α‐amino acids. Mechanistic studies show that the transformation proceeds through dynamic kinetic resolution that is unique to the optimal enzyme. To highlight its utility and practicality, the biocatalytic reaction was applied to the synthesis of several sp3‐rich cyclic fragments and the first total synthesis of jomthonic acid A.
A transaminase‐based dynamic kinetic resolution was developed for the preparation of β‐branched aromatic α‐amino acids with high diastereo‐ and enantioselectivity. The reaction was facilitated by the use of a thermophilic enzyme that tolerates elevated temperatures and pH values and exhibits broad substrate promiscuity. The utility of the process was demonstrated in the total synthesis of jomthonic acid A (see scheme).
Kinetically fast racemization of chiral substrates through an achiral intermediate and enantioselective functionalization of one of the enantiomeric substrates forms the basis of the dynamic kinetic ...resolution (DKR) of centrally chiral molecules. We report herein DKR of inherently chiral macrocycles through enantioselective alkylation of one of the two rapidly interconverting conformers. Reaction of heteracalixaromatics with bromomethylarenes in the presence of a catalytic amount of Cinchonine-derived chiral phase transfer catalyst (PTC) affords inherently chiral O-alkylated products in 90%–99% yields with up to 95% enaniomeric excess. Density functional theory calculations indicate that a host–guest-like interaction between the macrocyclic substrate and catalyst effectively differentiates the reactivity of two enantiomers devoid of chiral elements.
An efficient RuPHOX−Ru catalyzed asymmetric cascade hydrogenation of 3‐substituted chromones has been achieved under mild reaction conditions, affording the corresponding chiral 3‐substituted ...chromanols in high yields with excellent enantio‐ and diastereoselectivities (up to 99 % yield, >99 % ee and >20 : 1 dr). Control reactions and deuterium labelling experiments revealed that a dynamic kinetic resolution process occurs during the subsequent hydrogenation of the C=O double bond, which is responsible for the high performance of the asymmetric cascade hydrogenation. The resulting products allow for several transformations and it was shown that the protocol provides a practical and alternative strategy for the synthesis of chiral 3‐substituted chromanols and their derivatives.
An efficient RuPHOX−Ru catalyzed asymmetric cascade hydrogenation of 3‐substituted chromones has been achieved under mild reaction conditions, affording the corresponding chiral 3‐substituted chromanols in high yields with excellent enantio‐ and diastereoselectivities. A dynamic kinetic resolution process occurs during the subsequent hydrogenation of the C=O double bond, which is responsible for the high performance of the asymmetric cascade hydrogenation.
Here we report the fluorination–dynamic kinetic resolution (DKR) process for the commercial supply of belzutifan (MK-6482). Key process safety and robustness issues in the Selectfluor fluorination ...reaction were identified and addressed on the basis of increased mechanistic understanding. Aggressive process optimization enabled a single-pot direct isolation process that allowed delivery of the fluorodiol product with low process mass intensity.
