Unified Strategy to Prostaglandins: Chemoenzymatic Total Synthesis of Cloprostenol, Bimatoprost, PGF2α, Fluprostenol, and Travoprost Guided by Biocatalytic Retrosynthesis

Development of efficient and stereoselective synthesis of prostaglandins (PGs) is of utmost importance, owing to their valuable medicinal applications and unique chemical structures. We report here a unified synthesis of PGs cloprostenol, bimatoprost, PGF2α, fluprostenol, and travoprost from the readily available dichloro-containing bicyclic ketone 6a guided by biocatalytic retrosynthesis, in 11-12 steps with 2.9-6.5% overall yields. A Baeyer-Villiger monooxygenase (BVMO)-catalyzed stereoselective oxidation of 6a (99% ee), and a ketoreductase (KRED)-catalyzed diastereoselective reduction of enones 12 (87 : 13 to 99 : 1 dr) were utilized in combination for the first time to set the critical stereochemical configurations under mild conditions. Another key transformation was the copper (II)-catalyzed regioselective p-phenylbenzoylation of the secondary alcohol of diol 10 (3.8 : 1 rr). This study not only provides an alternative route to the highly stereoselective synthesis of PGs, but also showcases the usefulness and great potential of biocatalysis in construction of complex molecules.

Catalysis-Enabled Access to Cryptic Geldanamycin Oxides

Catalytic, selective modifications of natural products can be a fertile platform for unveiling not only new natural product analogs with altered biological activity, but also for revealing new reactivity and selectivity hierarchies for embedded functional groups in complex environments. Motivated by these intersecting aims, we report site and stereoselective oxidation reactions of geldanamycin facilitated by aspartyl-peptide catalysts. Through the isolation and characterization of four new geldanamycin oxides, we discovered a synergistic effect between lead peptide-based catalysts and geldanamycin, resulting in an unexpected reaction pathway. Curiously, it seems unlikely that our discoveries would not have been possible absent the outer sphere interactions intrinsic to both the catalyst and the natural product. The result is a set of new “meta” catalytic reactions that deliver both unknown and previously incompletely characterized geldanamycin analogs. Enabled by the catalytic, site-selective epoxidation of geldanamycin, biological assays were carried out to document the bioactivities of the new compounds.<div><br></div>

Catalysis-Enabled Access to Cryptic Geldanamycin Oxides

Catalytic, selective modifications of natural products can be a fertile platform for unveiling not only new natural product analogs with altered biological activity, but also for revealing new reactivity and selectivity hierarchies for embedded functional groups in complex environments. Motivated by these intersecting aims, we report site and stereoselective oxidation reactions of geldanamycin facilitated by aspartyl-peptide catalysts. Through the isolation and characterization of four new geldanamycin oxides, we discovered a synergistic effect between lead peptide-based catalysts and geldanamycin, resulting in an unexpected reaction pathway. Curiously, it seems unlikely that our discoveries would not have been possible absent the outer sphere interactions intrinsic to both the catalyst and the natural product. The result is a set of new “meta” catalytic reactions that deliver both unknown and previously incompletely characterized geldanamycin analogs. Enabled by the catalytic, site-selective epoxidation of geldanamycin, biological assays were carried out to document the bioactivities of the new compounds.<div><br></div>

Bioprocess Intensification Using Flow Reactors: Stereoselective Oxidation of Achiral 1,3-diols with Immobilized Acetobacter Aceti

Enantiomerically enriched 2-hydroxymethylalkanoic acids were prepared by oxidative desymmetrisation of achiral 1,3-diols using immobilized cells of Acetobacter aceti in water at 28 °C. The biotransformations were first performed in batch mode with cells immobilized in dry alginate, furnishing the desired products with high molar conversion and reaction times ranging from 2 to 6 h. The biocatalytic process was intensified using a multiphasic flow reactor, where a segmented gas–liquid flow regime was applied for achieving an efficient O2-liquid transfer; the continuous flow systems allowed for high yields and high biocatalyst productivity.

Chemoselective formal β-functionalization of substituted aliphatic amides enabled by a facile stereoselective oxidation event

A facile dehydrogenation event enables the functionalization of aliphatic amides at different positions in a one-pot fashion.