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Synthesis
DOI: 10.1055/a-2019-1532

Under mild irradiation conditions using violet light-emitting diodes, a catalytic amount of a thiolate of N-(4-mercaptophenyl)pivalamide promotes monoselective defluoroalkylation of trifluoroacetates with a variety of aliphatic alkenes in the presence of a formate salt. The reactions allow facile and low-cost synthesis of valuable α,α-difluoro substituted aliphatic carboxylate esters under mild conditions, and demonstrate the dual-functional role of arenethiolates in photocatalysis as both a strong photoreductant in a redox cycle and a hydrogen-atom-transfer catalyst.
[...]

Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

Synthesis
DOI: 10.1055/a-2022-2206

Bonding evolution theory has been used at the density functional theory level [ωB97X-D exchange-correlation functional, 6-311G(d,p) basis set, and solvent (toluene) effects with polarizable continuum model] to unravel the reaction mechanism of the intramolecular aza-Wittig reaction of 2-(acetylthio)phenyl isocyanate (1) catalyzed by 3-methyl-1-phenyl-2-phospholene 1-oxide (2) to form 2-methylbenzothiazole (3). The reaction involves four steps (transition states) corresponding to (1) the formation of a cycloadduct (O–C then P–N bonds), (2) a decarboxylation leading to the formation of an iminophosphorane, and (3) an intramolecular [2+2] cycloaddition (N–C then P–O bonds) followed by (4) a retro [2+2] cycloaddition (cleavage of the P–N then O–C bonds) to get the product and regenerate the catalyst. Step 1 is the rate-determining step with an activation Gibbs free enthalpy of 21 kcal mol–1 and it is favored with respect to a competitive pathway leading to the formation of another cycloadduct (P–C then O–N bonds). The whole reaction is exergonic with a Gibbs free energy decrease of 31 kcal mol–1, associated with the liberation of a CO2 molecule and the formation of the aromatic benzothiazole. Following the scale of Domingo, the successive steps of the reaction have a polar nature.
[...]

Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

Article in Thieme eJournals:
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Abstract

Substituted piperidine rings are a common motif in natural products and pharmaceutical drugs. The asymmetric synthesis of piperidines bearing multiple stereocentres remains a challenge, and current approaches often rely on lengthy reaction sequences and ‘chiral pool’ strategies. Herein, we report multi-enzymatic and chemo-enzymatic methods that allow the preparation of piperidines with three chirality centres in only two steps from achiral diketoester precursors. Stereocontrol is achieved by a highly enantioselective transamination leading to optically pure (ee >99%) enamine or imine intermediates, followed by diastereoselective reduction of these unsaturated N-heterocycles using either platinum(0)-catalysed flow hydrogenation or enzymatic imine reduction. In the latter case, coupling of the two biocatalytic reactions in a concurrent one-pot process is possible, thus reducing the synthetic sequence to a single biotransformation. In total, nine trisubstituted piperidines were prepared in high stereoisomeric purities (dr ≥98:2) and isolated yields of up to 73%. Lead-likeness analysis of five representative products using an open-source webtool suggests that these compounds possess considerable application potential as building blocks in drug discovery.

Abstract

The combination of gold(I) and enzyme catalysis has provided access to a series of nor(pseudo)ephedrine derivatives in a regio- and stereoselective manner. The approach involves developing IPrAuNTf₂-catalyzed hydration of 1-phenylprop-2-yn-1-yl acetate or N-(1-phenylprop-2-yn-1-yl)acetamide, followed by (dynamic) asymmetric biotransamination or bioreduction of the corresponding keto ester or keto amide intermediates. Enzyme actions were completely selective towards the modification of the methyl ketones in a highly stereoselective manner, allowing the synthesis of enantio- and diastereomerically enriched products using either racemic or optically active starting materials. Thus, a series of amino alcohol, diol, and diamine derivatives were produced from propargyl esters or amides (57 to 86% isolated yield), the biocatalyst of choice determining the (stereo)selectivity of the overall cascade process (70–99% diastereomeric excess and >98% enantiomeric excess), and providing access to nor(pseudo)ephedrine compounds in a straightforward manner.

Biased esterification of nucleosides with borate preferentially removes those reactants from biocatalytic equilibrium systems, with the resulting cyclic borate esters acting as reversible enzyme inhibitors. This effect can be used to manipulate glycosylation equilibria and facilitate biocatalytic access to nucleoside analogues.

Abstract

Biocatalytic nucleoside (trans-)glycosylations catalyzed by nucleoside phosphorylases have evolved into a practical and convenient approach to the preparation of modified nucleosides, which are important pharmaceuticals for the treatment of various cancers and viral infections. However, the obtained yields in these reactions are generally determined exclusively by the innate thermodynamic properties of the nucleosides involved, hampering the biocatalytic access to many sought-after target nucleosides. We herein report an additional means for reaction engineering of these systems. We show how apparent equilibrium shifts in phosphorolysis and glycosylation reactions can be effected through entropically driven, biased esterification of nucleosides and ribosyl phosphates with inorganic borate. Our multifaceted analysis further describes the kinetic implications of this in situ reactant esterification for a model phosphorylase.

An efficient organocatalytic method to synthetically versatile chiral triflones with two non-adjacent stereogenic centers was developed. The work uses, for the first time, α-aryl vinyl triflones as Michael acceptors in stereoselective catalysis. Control over the absolute configuration is achieved by a catalyst-controlled stereoselective C−C bond formation-protonation sequence.

Abstract

Trifluoromethylsulfones (triflones) are useful compounds for synthesis and beyond. Yet, methods to access chiral triflones are scarce. Here, we present a mild and efficient organocatalytic method for the stereoselective synthesis of chiral triflones using α-aryl vinyl triflones, building blocks previously unexplored in asymmetric synthesis. The peptide-catalyzed reaction gives rise to a broad range of γ-triflylaldehydes with two non-adjacent stereogenic centers in high yields and stereoselectivities. A catalyst-controlled stereoselective protonation following a C−C bond formation is key to control over the absolute and relative configuration. Straightforward derivatization of the products into, e.g., disubstituted δ-sultones, γ-lactones, and pyrrolidine heterocycles highlights the synthetic versatility of the products.

For the first time, a manganese-catalyzed three-component coupling of secondary alcohol, primary alcohol and methanol for the synthesis of β,β-methylated/alkylated alcohol with high chemoselectivity is presented.

Abstract

Herein, we report a manganese-catalyzed three-component coupling of secondary alcohols, primary alcohols and methanol for the synthesis of β,β-methylated/alkylated secondary alcohols. Using our method, a series of 1-arylethanol, benzyl alcohol derivatives, and methanol undergo sequential coupling efficiently to construct assembled alcohols with high chemoselectivity in moderate to good yields. Mechanistic studies suggest that the reaction proceeds via methylation of a benzylated secondary alcohol intermediate to generate the final product.

The synthesis of chiral cyclic amides has been achieved via cobalt-catalyzed asymmetric hydrogenation of the corresponding enamides with a high degree of enantioselectivity. This methodology extends the utilization of earth abundant metal catalysis in asymmetric synthesis.

Abstract

The enantioselective hydrogenation of cyclic enamides has been achieved using an earth-abundant cobalt-bisphosphine catalyst. Using CoCl₂/(S,S)-Ph-BPE, several trisubstituted carbocyclic enamides were reduced with high activity and excellent enantioselectivity (up to 99 %) to the corresponding saturated amides. The methodology can be extended to the synthesis of chiral amines by base hydrolysis of the hydrogenation products. Preliminary mechanistic investigations reveal the presence of a high spin cobalt (II) species in the catalytic cycle. We propose that the hydrogenation of the carbon-carbon double bond proceeds via a sigma-bond-metathesis pathway.

Biased esterification of nucleosides with borate preferentially removes those reactants from biocatalytic equilibrium systems, with the resulting cyclic borate esters acting as reversible enzyme inhibitors. This effect can be used to manipulate glycosylation equilibria and facilitate biocatalytic access to nucleoside analogues.

Abstract

Biocatalytic nucleoside (trans-)glycosylations catalyzed by nucleoside phosphorylases have evolved into a practical and convenient approach to the preparation of modified nucleosides, which are important pharmaceuticals for the treatment of various cancers and viral infections. However, the obtained yields in these reactions are generally determined exclusively by the innate thermodynamic properties of the nucleosides involved, hampering the biocatalytic access to many sought-after target nucleosides. We herein report an additional means for reaction engineering of these systems. We show how apparent equilibrium shifts in phosphorolysis and glycosylation reactions can be effected through entropically driven, biased esterification of nucleosides and ribosyl phosphates with inorganic borate. Our multifaceted analysis further describes the kinetic implications of this in situ reactant esterification for a model phosphorylase.

Synthesis
DOI: 10.1055/a-2019-1532

Under mild irradiation conditions using violet light-emitting diodes, a catalytic amount of a thiolate of N-(4-mercaptophenyl)pivalamide promotes monoselective defluoroalkylation of trifluoroacetates with a variety of aliphatic alkenes in the presence of a formate salt. The reactions allow facile and low-cost synthesis of valuable α,α-difluoro substituted aliphatic carboxylate esters under mild conditions, and demonstrate the dual-functional role of arenethiolates in photocatalysis as both a strong photoreductant in a redox cycle and a hydrogen-atom-transfer catalyst.
[...]

Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

Nature, Published online: 23 February 2023; doi:10.1038/d41586-023-00521-3