The dynamic kinetic resolution of 6‐hydroxypyranones with enals or alkynals through an asymmetric redox esterification is catalyzed by a chiral N‐heterocyclic carbene. The resulting esters are ...obtained in good to high yields and with high levels of enantio‐ and diastereocontrol. The reaction products are further derivatized to obtain functionalized sugar derivatives and natural products.
Sweet products: The dynamic kinetic resolution of 6‐hydroxypyranones with enals or alkynals through an asymmetric redox esterification is catalyzed by a chiral N‐heterocyclic carbene (NHC). The resulting esters are obtained in good to high yields and with high levels of enantio‐ and diastereocontrol.
An efficient chiral 4-aryl-pyridine-N-oxide (ArPNO) nucleophilic organocatalyst was rationally designed, synthesized, and applied to the acylative dynamic kinetic resolution of azoles, aldehydes, and ...anhydride. The restriction of the pyridine’s C-4 position, where the dialkylamino group should be always present when using chiral pyridine-N-oxide as an acyl transfer catalyst, was overcome, thereby allowing structural diversity at this position. In the presence of 5 mol % 3,5-dimethylphenyl-derived ArPNO catalyst, the corresponding 2,5-disubstituted tetrazole hemiaminal esters were obtained in up to 93% yields, >20:1 rr, and 99% ee. Other N-heteroaromatics, including substituted pyrazole, imidazole, purine, benzimidazole, and benzotriazole, were also suitable substrates. Mechanistic studies by control experiments and density functional theory calculations indicated that an acyloxypyridinium cation was formed, and the nucleophilic substitution of azole hemiaminal with the acyloxypyridinium cation was the rate-determining step. Furthermore, the nucleophilic ability of oxygen in pyridine-N-oxide was higher than that of nitrogen in pyridine. This work provides an effective method for the utilization of the C-4 position of the pyridine ring, allowing the development of more varied chiral 4-substituted pyridine-N-oxides as efficient nucleophilic organocatalysts.
Enantiomerically pure chiral amines are valuable building blocks for the synthesis of pharmaceutical drugs and agrochemicals. Indeed it is estimated that currently 40 % of pharmaceuticals contain a ...chiral amine component in their structure. Chiral amines are also widely used as resolving agents for diastereomeric salt crystallization. One of the challenges of preparing chiral amines in enantiomerically pure form is the development of cost-effective and sustainable catalytic methods that are able to address the requirement for the entire range of primary, secondary and tertiary amines. In this review we highlight various biocatalytic strategies that have been developed, particularly those based upon asymmetric synthesis or their equivalent therefore (i.e. dynamic kinetic resolution, deracemisation) in which yields and enantiomeric excesses approaching 100 % can be attained. Particular attention is given to the use of monoamine oxidase (MAO-N) from
Aspergillus niger
which has been engineered by directed evolution to provide a tool-box of variants which can generate enantiomerically pure primary, secondary and tertiary amines. These MAO-N variants are combined with non-selective chemical reducing agents in deracemisation processes.
The radical‐mediated racemization has often hampered the production of optically pure 1,1′‐bi‐2‐naphthols (BINOLs) in transition‐metal‐catalyzed enantioselective oxidative couplings of 2‐naphthols. ...In their Communication on page 10278 ff., S. Akai et al. effectively use this undesired racemization and establish the first lipase/RU‐integrated dynamic kinetic resolution of racemic C1‐ and C2‐symmetric biaryl diols to afford homochiral biaryls in up to 98% yield and up to 98% ee.
Axially chiral architectures exist widely in natural products, biologically relevant molecules, chiral ligands and catalysts as well as functional materials. Therefore, catalytic asymmetric synthesis ...of atropisomers has become one of the most fast‐growing fields in the community of chemistry and rapid advances have occurred. Among different methods reported, the organocatalytic atroposelective dynamic kinetic resolution (DKR) involving ring manipulations stands out as a cutting‐edge technology to construct axial chirality from the point of atom/step economy. In this DKR strategy, the configurational lability of starting materials originates from chirally‐labile ring structure of cyclic substrates/intermediates or transient ring formation through noncovalent interactions from acyclic substrates. The two atropisomers of starting material are in equilibrium in the reaction medium, ensuring the constant transformation of the less reactive atropisomer into the more reactive one, and then to a single enantiopure product in the presence of an appropriate organocatalyst. This review summarizes recent advancements on this topic, including their scopes, limitations, mechanisms, applications and provides some insights into further developments.
A Z‐selective rhodium‐catalyzed hydrothiolation of 1,3‐disubstituted allenes and subsequent oxidation towards the corresponding allylic sulfones is described. Using the bidentate ...1,4‐bis(diphenylphosphino)butane (dppb) ligand, Z/E‐selectivities up to >99:1 were obtained. The highly atom‐economic desymmetrization reaction tolerates functionalized aromatic and aliphatic thiols. Additionally, a variety of symmetric internal allenes, as well as unsymmetrically disubstituted substrates were well tolerated, thus resulting in high regioselectivities. Starting from chiral but racemic 1,3‐disubstituted allenes a dynamic kinetic resolution (DKR) could be achieved by applying (S,S)‐Me‐DuPhos as the chiral ligand. The desired Z‐allylic sulfones were obtained in high yields and enantioselectivities up to 96 % ee.
Zelectivity: The title reaction permits the synthesis of valuable allylic thioethers and sulfones in excellent Z selectivity. By using unsymmetrically 1,3‐disubstituted allenes, good to high regioselectivities were obtained. Asymmetric hydrothiolation of racemic allenes with (S,S)‐Me‐DuPhos meets the criteria of a dynamic kinetic resolution. Me‐DuPhos=2′,5′,2′′,5′′‐tetramethyl‐1,2‐bis(phospholanyl)benzene.
A complementing Pd‐ and Rh‐catalyzed dynamic kinetic resolution (DKR) of racemic allenes leading to N‐allylated pyrazoles is described. Such compounds are of enormous interest in medicinal chemistry ...as certified drugs and potential drug candidates. The new methods feature high chemo‐, regio‐ and enantioselectivities aside from displaying a broad substrate scope and functional group compatibility. A mechanistic rational accounting for allene racemization and trans‐alkene selectivity is discussed.
A complementing Pd‐ and Rh‐catalyzed dynamic kinetic resolution (DKR) of racemic allenes leading to N‐allylated pyrazoles is described. Such compounds are of enormous interest in medicinal chemistry as drugs and drug candidates. The new methods feature high chemo‐, regio‐ and enantioselectivity displaying a broad substrate scope and functional group compatibility. A mechanistic rational explanation for allene racemization and trans‐alkene selectivity is discussed.
A dynamic kinetic resolution – asymmetric transfer hydrogenation (DKR‐ATH) methodology of α‐keto/enol‐lactams was developed. We also propose a possible catalytic mechanism evolving a transition state ...stabilized by η6‐arene CH−O interaction. The efficient approach can be applied to a wide range of substrates including non‐aryl ones which would be difficult to prepare by other asymmetric reduction methods.
We report an enzyme‐catalyzed dynamic kinetic resolution protocol for the one‐pot asymmetric synthesis of substituted purine derivatives. The controllable N‐9/N‐7 substitution, which posed formidable ...challenges in organic synthesis, could be accomplished by choosing different types of enzymes as catalysts. This method was proved scalable and was used to prepare a series of prodrugs of medicinally active acids. In addition, the recyclability test of the biocatalysts indicated the potential of this strategy for applications in the pharmaceutical industry.
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