Pharmaceutical Building Blocks Research Articles

Environmental impacts of drug products: The effect of the selection of production sites in the supply chain

The environmental impact of drug products is largely determined by activities beyond the direct control of pharmaceutical companies, such as outsourced production of pharmaceutical building blocks. Therefore, this study evaluates the environmental impacts of a prostate cancer drug packaged in one blister (declared unit), thereby analysing the whole value chain to gain insight into 1) the main contributors to the impact of drug product production and 2) the effect of the geographical location of production of solvents and pharmaceuticals. The carbon and resource footprints of the entire life cycle of the drug product are determined, using the IPCC GWP 100 and the Cumulative Exergy Extraction from the Natural Environment methods, respectively. Unlike many other studies, the impacts of building blocks, called intermediate pharmaceutical ingredients (IPIs), are modelled based on primary data, literature and similar processes. The carbon footprint per declared unit equals 34 kg CO2-eq, of which IPIs and active pharmaceutical ingredient (API) production account for 96 %. The resource footprint is 647 MJex/declared unit, with IPI and API production accounting for 93 %. The main impact contributors of these processes are solvents and electricity consumption. Four alternative scenarios for IPI and API production are developed to evaluate the geographical influence of different production locations of solvents and pharmaceuticals between Europe and China. European production of solvents and pharmaceuticals appears to have the lowest carbon and resource footprint. In contrast, Chinese production of solvents and pharmaceuticals increases the carbon footprint by 49 %, while the resource footprint increases by only 4 %, although the natural resource consumption shifts from abiotic renewable resources and nuclear energy to fossil fuels. The high contribution of IPI production and the influence of geography of the supply chain highlight the need for accurate data from external suppliers to fairly estimate the environmental footprint of drug products.

Crystal structure and enzyme engineering of the broad substrate spectrum l-amino acid oxidase 4 from the fungus Hebeloma cylindrosporum.

l-Amino acid oxidases (LAAOs) catalyze the oxidative deamination of l-amino acids to α-keto acids. Recombinant production of LAAOs with broad substrate spectrum remains a formidable challenge. We previously achieved this for the highly active and thermostable LAAO4 of Hebeloma cylindrosporum (HcLAAO4). Here, we crystallized a proteolytically truncated surface entropy reduction variant of HcLAAO4 and solved its structure in substrate-free form and in complex with diverse substrates. The ability to support the aliphatic portion of a substrate's side chain by an overall hydrophobic active site is responsible for the broad substrate spectrum of HcLAAO4, including l-amino acids with big aromatic, acidic and basic side chains. Based on the structural findings, we generated an E288H variant with increased activity toward pharmaceutical building blocks of high interest.

Kinetic Resolution Polymerization Enabled Chemical Synthesis of Perfectly Isotactic Polythioesters.

Isotactic polythioesters (PTEs) that are thioester analogs to natural polyhydroxyalkanoates (PHAs) have attracted growing attention due to their distinct properties. However, the development of chemically synthetic methods for preparing isotactic PTEs has long been an intricate endeavour. Herein, we report the successful synthesis of perfectly isotactic PTEs via stereocontrolled ring-opening polymerization. This binaphthalene-salen aluminium (SalBinam-Al) catalyst promoted a robust polymerization of rac-α-substituted-β-propiothiolactones (rac-BTL and rac-PTL) with highly kinetic resolution, affording perfectly isotactic P(BTL) and P(PTL) with Mn up to 276 kDa. Impressively, the isotactic P(BTL) formed a supramolecular stereocomplex with improved thermal property (Tm=204 °C). Ultimately, this kinetic resolution polymerization enabled the facile isolation of enantiopure (S)-BTL, which could efficiently convert to an important pharmaceutical building block (S)-2-benzyl-3-mercapto-propanoic acid. Isotactic P(PTL) served as a tough and ductile material comparable to the commercialized polyolefins. This synthetic system allowed to access of isotactic PTEs, establishing a powerful platform for the discovery of sustainable plastics.

Kinetic Resolution Polymerization Enabled Chemical Synthesis of Perfectly Isotactic Polythioesters

AbstractIsotactic polythioesters (PTEs) that are thioester analogs to natural polyhydroxyalkanoates (PHAs) have attracted growing attention due to their distinct properties. However, the development of chemically synthetic methods for preparing isotactic PTEs has long been an intricate endeavour. Herein, we report the successful synthesis of perfectly isotactic PTEs via stereocontrolled ring‐opening polymerization. This binaphthalene‐salen aluminium (SalBinam‐Al) catalyst promoted a robust polymerization of rac‐α‐substituted‐β‐propiothiolactones (rac‐BTL and rac‐PTL) with highly kinetic resolution, affording perfectly isotactic P(BTL) and P(PTL) with Mn up to 276 kDa. Impressively, the isotactic P(BTL) formed a supramolecular stereocomplex with improved thermal property (Tm=204 °C). Ultimately, this kinetic resolution polymerization enabled the facile isolation of enantiopure (S)‐BTL, which could efficiently convert to an important pharmaceutical building block (S)‐2‐benzyl‐3‐mercapto‐propanoic acid. Isotactic P(PTL) served as a tough and ductile material comparable to the commercialized polyolefins. This synthetic system allowed to access of isotactic PTEs, establishing a powerful platform for the discovery of sustainable plastics.

Revealing protonation states and tracking substrate in serine hydroxymethyltransferase with room-temperature X-ray and neutron crystallography

Pyridoxal 5’-phosphate (PLP)-dependent enzymes utilize a vitamin B6-derived cofactor to perform a myriad of chemical transformations on amino acids and other small molecules. Some PLP-dependent enzymes, such as serine hydroxymethyltransferase (SHMT), are promising drug targets for the design of small-molecule antimicrobials and anticancer therapeutics, while others have been used to synthesize pharmaceutical building blocks. Understanding PLP-dependent catalysis and the reaction specificity is crucial to advance structure-assisted drug design and enzyme engineering. Here we report the direct determination of the protonation states in the active site of Thermus thermophilus SHMT (TthSHMT) in the internal aldimine state using room-temperature joint X-ray/neutron crystallography. Conserved active site architecture of the model enzyme TthSHMT and of human mitochondrial SHMT (hSHMT2) were compared by obtaining a room-temperature X-ray structure of hSHMT2, suggesting identical protonation states in the human enzyme. The amino acid substrate serine pathway through the TthSHMT active site cavity was tracked, revealing the peripheral and cationic binding sites that correspond to the pre-Michaelis and pseudo-Michaelis complexes, respectively. At the peripheral binding site, the substrate is bound in the zwitterionic form. By analyzing the observed protonation states, Glu53, but not His residues, is proposed as the general base catalyst, orchestrating the retro-aldol transformation of L-serine into glycine.

Immobilization of Lipase B from Candida antarctica on Magnetic Nanoparticles Enhances Its Selectivity in Kinetic Resolutions of Chiral Amines with Several Acylating Agents.

In lipase-catalyzed kinetic resolutions (KRs), the choice of immobilization support and acylating agents (AAs) is crucial. Lipase B from Candida antarctica immobilized onto magnetic nanoparticles (CaLB-MNPs) has been successfully used for diverse KRs of racemic compounds, but there is a lack of studies of the utilization of this potent biocatalyst in the KR of chiral amines, important pharmaceutical building blocks. Therefore, in this work, several racemic amines (heptane-2-amine, 1-methoxypropan-2-amine, 1-phenylethan-1-amine, and 4-phenylbutan-2-amine, (±)-1a-d, respectively) were studied in batch and continuous-flow mode utilizing different AAs, such as diisopropyl malonate 2A, isopropyl 2-cyanoacetate 2B, and isopropyl 2-ethoxyacetate 2C. The reactions performed with CaLB-MNPs were compared with Novozym 435 (N435) and the results in the literature. CaLB-MNPs were less active than N435, leading to lower conversion, but demonstrated a higher enantiomer selectivity, proving to be a good alternative to the commercial form. Compound 2C resulted in the best balance between conversion and enantiomer selectivity among the acylating agents. CaLB-MNPs proved to be efficient in the KR of chiral amines, having comparable or superior properties to other CaLB forms utilizing porous matrices for immobilization. An additional advantage of using CaLB-MNPs is that the purification and reuse processes are facilitated via magnetic retention/separation. In the continuous-flow mode, the usability and operational stability of CaLB-MNPs were reaffirmed, corroborating with previous studies, and the results overall improve our understanding of this potent biocatalyst and the convenient U-shape reactor used.

Oxidation coupling of terminal alkynes over CuPd bimetallic alloy enhanced by optimized charge transfer and alloy structure

Homocoupling of terminal alkynes is an effective approach for the synthesis of 1,3-diyne, which is an important building block for numerous fine chemicals and pharmaceuticals. However, this reaction frequently encounters difficulties in catalyst recovery, and requires the addition of base or organic ligands, limiting their practical applications. Herein, we developed an efficient and recyclable CuPd bimetallic nanoalloy catalyst, which exhibited superior activity and selectivity in the homocoupling of terminal alkynes under mild conditions without any additives. In contrast to the low activity of monometallic Cu or Pd catalysts, a full conversion with a 100% selectivity for 1,3-diyne was achieved on bimetallic Cu2Pd1-400 nanoalloy with an extremely high activity. The comprehensive characterizations clearly evidenced that the alloying Cu with Pd was found to perturb the Cu electronic structure, and the positively charged Cu on the step and edge sites of CuPd nanoalloy catalyzed the homocoupling reaction via Cu-acetylide intermediates, and the density functional theory calculations revealed that the desorption of 1,3-diyne on CuPd nanoalloy was the rate-determining step for the whole reaction. This work provides a viable strategy for the rational design and fabrication of other nanoalloy catalysts for the green synthesis related to terminal alkyne oxidation.

Structure-Activity Relationship Studies of 9-Alkylamino-1,2,3,4-tetrahydroacridines against Leishmania (Leishmania) infantum Promastigotes.

Leishmaniasis is one of the most neglected diseases in modern times, mainly affecting people from developing countries of the tropics, subtropics and the Mediterranean basin, with approximately 350 million people considered at risk of developing this disease. The incidence of human leishmaniasis has increased over the past decades due to failing prevention and therapeutic measures-there are no vaccines and chemotherapy, which is problematic. Acridine derivatives constitute an interesting group of nitrogen-containing heterocyclic compounds associated with numerous bioactivities, with emphasis to their antileishmanial potential. The present work builds on computational studies focusing on a specific enzyme of the parasite, S-adenosylmethionine decarboxylase (AdoMet DC), with several 1,2,3,4-tetrahydro-acridines emerging as potential inhibitors, evidencing this scaffold as a promising building block for novel antileishmanial pharmaceuticals. Thus, several 1,2,3,4-tetrahydroacridine derivatives have been synthesized, their activity against Leishmania (Leishmania) infantum promastigotes evaluated and a structure-activity relationship (SAR) study was developed based on the results obtained. Even though the majority of the 1,2,3,4-tetrahydroacridines evaluated presented high levels of toxicity, the structural information gathered in this work allowed its application with another scaffold (quinoline), leading to the obtention of N1,N12-bis(7-chloroquinolin-4-yl)dodecane-1,12-diamine (12) as a promising novel antileishmanial agent (IC50 = 0.60 ± 0.11 μM, EC50 = 11.69 ± 3.96 μM and TI = 19.48).

High yield production of 1,4-cyclohexanediol and 1,4-cyclohexanediamine from high molecular-weight lignin oil.

The complete utilization of all lignin depolymerization streams obtained from the reductive catalytic fractionation (RCF) of woody biomass into high-value-added compounds is a timely and challenging objective. Here, we present a catalytic methodology to transform beech lignin-derived dimers and oligomers (DO) into well-defined 1,4-cyclohexanediol and 1,4-cyclohexanediamine. The latter two compounds have vast industrial relevance as monomers for polymer synthesis as well as pharmaceutical building blocks. The proposed two-step catalytic sequence involves the use of the commercially available RANEY® Ni catalyst. Therefore, the first step involves the efficient defunctionalization of lignin-derived 2,6-dimethoxybenzoquinone (DMBQ) into 1,4-cyclohexanediol (14CHDO) in 86.5% molar yield, representing a 10.7 wt% yield calculated on a DO weight basis. The second step concerns the highly selective amination of 1,4-cyclohexanediol with ammonia to give 1,4-cyclohexanediamine (14CHDA) in near quantitative yield. The ability to use RANEY® Ni and ammonia in this process holds great potential for future industrial synthesis of 1,4-cyclohexanediamine from renewable resources.

Molecular Evolution of an Aminotransferase Based on Substrate–Enzyme Binding Energy Analysis for Efficient Valienamine Synthesis

Valienamine is a valuable building block for active pharmaceuticals and agrochemicals because of its aminocyclitol structure and glucosidase inhibitory activity. Straightforward amino chiral center construction on valienone using a sugar aminotransferase (SAT) to produce valienamine achieved strict stereo-specificity; however, low transamination activity owing to an unfavorable binding conformation of the non-natural substrate valienone in the oversized substrate-binding pocket currently limits SAT-based valienamine production. Here, we employed a tailored combinatorial active-site saturation test/iterative saturation mutagenesis (CAST/ISM) strategy to engineer a recently identified SAT (RffA_Kpn) to optimize the binding of valienone in the large binding pocket and thus improve transamination activity. In silico analyses predicting mutation binding energies and assessing evolutionary conservation identified 9 of 62 contact residues positioned within 8 Å of the valienone–PMP external aldimine transition state as hotspots for destabilizing unfavorable binding. Four of these residues were subsequently confirmed to improve activity using site-directed saturation mutagenesis, and combinatorial mutations were prepared in further iterative cycles. The quadruple mutant M4 (K209W/Y321F/V318Q/K25W) displayed a 35.59-fold improvement in valienamine synthesis activity over wild-type RffA_Kpn and achieved 12.18% conversion toward valienone in 100 mg preparative-scale reaction. Our demonstration of asymmetric biosynthesis for a valuable chiral aminocyclitol illustrates how an evolution model can help engineer enzymes that handle small, non-natural substrates in oversized binding pockets.

Microbial Lipases and Their Potential in the Production of Pharmaceutical Building Blocks.

Processes involving lipases in obtaining active pharmaceutical ingredients (APIs) are crucial to increase the sustainability of the industry. Despite their lower production cost, microbial lipases are striking for their versatile catalyzing reactions beyond their physiological role. In the context of taking advantage of microbial lipases in reactions for the synthesis of API building blocks, this review focuses on: (i) the structural origins of the catalytic properties of microbial lipases, including the results of techniques such as single particle monitoring (SPT) and the description of its selectivity beyond the Kazlauskas rule as the “Mirror-Image Packing” or the “Key Region(s) rule influencing enantioselectivity” (KRIE); (ii) immobilization methods given the conferred operative advantages in industrial applications and their modulating capacity of lipase properties; and (iii) a comprehensive description of microbial lipases use as a conventional or promiscuous catalyst in key reactions in the organic synthesis (Knoevenagel condensation, Morita–Baylis–Hillman (MBH) reactions, Markovnikov additions, Baeyer–Villiger oxidation, racemization, among others). Finally, this review will also focus on a research perspective necessary to increase microbial lipases application development towards a greener industry.

Efficient methods for the synthesis of chiral 2-oxazolidinones as pharmaceutical building blocks.

Although the wide variety of heterocyclic compounds is common knowledge, chiral 2-oxazolidinones are recognized as some of the most important heterocycles in medicinal chemistry. Many important pharmaceutical molecules have been constructed based on the chiral 2-oxazolidinone backbone. Therefore, the development of even more efficient catalytic methods for the synthesis of chiral 2-oxazolidinones remains a very important pursuit in the field of synthetic organic chemistry. This review summarizes the coupling reactions of epoxides and isocyanates for the preparation of 2-oxazolidinones. Both metal catalysts and organocatalysts promote these reactions. Optically pure 2-oxazolidinones are prepared from optically pure epoxide substrates via these catalytic methods. A synthetic example of a commercially available pharmaceutical compound utilizing this method is also introduced.

Controlling Multiple Active Sites on Pd−CeO2 for Sequential C−C Cross‐coupling and Alcohol Oxidation in One Reaction System

AbstractCeria (CeO2)‐supported metal catalysts have been widely utilized for various single‐step chemical transformations. However, using such catalysts for a multistep organic reaction in one reaction system has rarely been achieved. Here, we investigate multiple active sites on Pd−CeO2 catalysts and optimize them for a multistep reaction of C−C cross‐coupling and alcohol oxidation. Atomic‐level imaging and spectroscopic studies reveal that metallic Pd0 and Pd−CeO2 interface are active sites on Pd−CeO2 for C−C cross‐coupling and oxidation, respectively. These active sites are controlled under the structural evolution of Pd−CeO2 during reductive heat‐treatments. Accordingly, we found that optimally reduced Pd−CeO2 catalysts containing ∼1.5 nm‐sized Pd nanoclusters with both sites in balance are ideal for multistep chemical transformations in one reaction system. Our strategy to design supported metal catalysts leads to one‐pot sequential synthetic protocols for pharmaceutical building blocks.

Rational Regulation of Reaction Specificity of Nitrilase for Efficient Biosynthesis of 2-Chloronicotinic Acid through a Single Site Mutation.

Nitrilase-catalyzed hydrolysis of 2-chloronicotinonitrile (2-CN) is a promising approach for the efficient synthesis of 2-chloronicotinic acid (2-CA). The development of nitrilase with ideal catalytic properties is crucial for the biosynthetic route with industrial potential. Herein, a nitrilase from Rhodococcus zopfii (RzNIT), which showed much higher hydration activity than hydrolysis activity, was designed for efficient hydrolysis of 2-CN. Two residues (N165 and W167) significantly affecting the reaction specificity were precisely identified. By tuning these two residues, a single mutation of W167G with abolished hydration activity and 20-fold improved hydrolysis activity was obtained. Molecular dynamics simulation and molecular docking revealed that the mutation generated a larger binding pocket, causing the substrate 2-CN to bind more deeply in the pocket and form a delocalized π bond between the residues W190 and Y196, which reduced the negative influence of steric hindrance and electron effect caused by chlorine substituent. With mutant W167G as biocatalyst, 100 mM 2-CN was exclusively converted into 2-CA within 16 h. The study provides useful guidance in nitrilase engineering for simultaneous improvement of reaction specificity and catalytic activity, which are highly desirable in value-added carboxylic acids production from nitriles hydrolysis. IMPORTANCE 2-CA is an important building block for agrochemicals and pharmaceuticals with a rapid increase in demand in recent years. It is currently manufactured from 3-cyanopyridine by chemical methods. However, during the final step of 2-CN hydrolysis under high temperature and strong alkaline conditions, the byproduct 2-CM was generated except for the target product, leading to low yield and tedious separation steps. Nitrilase-mediated hydrolysis is regarded as a promising alternative for 2-CA production, which proceeded under mild conditions. Nevertheless, nitrilase capable of efficient hydrolysis of 2-CN has not been reported because the enzymes showed either extremely low activity or surprisingly high hydration activity toward 2-CN. Herein, the reaction specificity of RzNIT was precisely tuned through a single site mutation. The mutant exhibited remarkably enhanced hydrolysis activity without the formation of byproducts, providing a robust biocatalyst for 2-CA biosynthesis with industrial potential.

Magnetic nanocomposite of crosslinked chitosan with 4,6-diacetylresorcinol for gold immobilization (Fe3O4@CS/DAR-Au) as a catalyst for an efficient one-pot synthesis of propargylamine

The magnetic DAR-chitosan was synthesized by condensation of magnetic chitosan [Fe3O4@CS] with freshly synthesized diacetylresorcinol (here calls DAR) as a cross-linking agent; the Schiff base precursor on the as-prepared magnetic DAR-chitosan polymer can be coordinated with Au (III) to give magnetic DAR chitosan-based Au (III) Schiff base complex (Fe3O4@CS/DAR-AuCl3). The structural properties of Fe3O4@CS/DAR-AuCl3 have been investigated by SEM, TEM, EDX, XRD, FT-IR and XPS (techniques) analysis. The XPS study proved the presence of Au species Schiff base complex as an ion and nanoparticles onto the magnetic DAR crosslinked chitosan. Subsequently, the synthesized Fe3O4@CS/DAR-AuCl3 used as sustainable catalysts in A3 coupling reactions leading to the synthesis of propargylamine, a pharmaceutical building blocks, under mild conditions in high yields of 80–92%. Furthermore, it was proved that the magnetic Fe3O4@CS/DAR-AuCl3 was easily recovered and reached 76% of the initial activity after 8 times, which revealed good reuse capacity.

Activated Hoveyda‐Grubbs Olefin Metathesis Catalysts Derived from a Large Scale Produced Pharmaceutical Intermediate – Sildenafil Aldehyde

AbstractTwo EWG‐activated Hoveyda‐Grubbs‐type ruthenium complexes (Sil‐II and Sil‐II’) were obtained, characterized, and screened in a set of olefin metathesis reactions. These catalysts were conveniently synthesized from a commercially available pharmaceutical building block – Sildenafil aldehyde – in two steps only. Stability and catalytic activity tests disclosed that the bulkier NHC‐ligand bearing catalyst Sil‐II’ is visibly more stable and productive than its smaller NHC‐analogue Sil‐II. Good application profile of catalyst Sil‐II’ was confirmed in a set of diverse metathesis reactions including ring‐closing metathesis (RCM) and cross‐metathesis (CM) of complex polyfunctional substrates of medicinal chemistry interest, including a challenging macrocyclization of the Pacritinib precursor. Compatibility of the new catalyst with various green solvents was checked and metathesis of Sildenafil and Tadalafil‐based substrates was successfully conducted in acetone. The mechanism of Sil‐II’ initiation has been investigated through kinetic experiments unveiling that the decrease of the steric hindrance of the chelating alkoxy moiety (from iPrO to EtO) favors the interchange initiation pathway over the typical dissociation pathway for other popular 2nd generation Hoveyda‐Grubbs catalysts.magnified image

Catalytic production of anilines by nitro-compounds hydrogenation over highly recyclable platinum nanoparticles supported on halloysite nanotubes

Pt-nanoparticles supported on halloysite-nanotubes (HNTs) were selectively deposited onto the inner (Pt(IN)/HNT) or outer (Pt(OUT)/HNT) surface of the support to evaluate their operational stability on the cleaner and efficient hydrogenation of nitro compounds to produce their corresponding anilines. The formation of Pt0-aggregates on the inner or outer surfaces was observed, with mean particles sizes of 2.4–2.9 nm. The catalysts were evaluated using ethanol as solvent and nitrobenzene as a model substrate at a temperature of 298 K, under 1 bar of H2 pressure. The Pt(IN)/HNT catalyst showed better catalytic performance than Pt(OUT)/HNT, which was mainly attributed to the confinement effect of the Pt-nanoparticles inside the HNTs. However, the operational stability showed that Pt(OUT)/HNT retained its catalytic performance after 15 cycles, while the Pt(IN)/HNT catalyst suffered deactivation after the 5th cycle. The best catalytic system showed a moderate-to-high efficiency in the efficient hydrogenation of 7 nitro compounds used to produce their corresponding anilines, which are important pharmaceutical building blocks.

C(sp3)-H methylation enabled by peroxide photosensitization and Ni-mediated radical coupling.

The "magic methyl" effect describes the change in potency, selectivity, and/or metabolic stability of a drug candidate associated with addition of a single methyl group. We report a synthetic method that enables direct methylation of C(sp3)-H bonds in diverse drug-like molecules and pharmaceutical building blocks. Visible light-initiated triplet energy transfer promotes homolysis of the O-O bond in di-tert-butyl or dicumyl peroxide under mild conditions. The resulting alkoxyl radicals undergo divergent reactivity, either hydrogen-atom transfer from a substrate C-H bond or generation of a methyl radical via β-methyl scission. The relative rates of these steps may be tuned by varying the reaction conditions or peroxide substituents to optimize the yield of methylated product arising from nickel-mediated cross-coupling of substrate and methyl radicals.

Cell-free in vitro reduction of carboxylates to aldehydes: With crude enzyme preparations to a key pharmaceutical building block.

The scarcity of practical methods for aldehyde synthesis in chemistry necessitates the development of mild, selective procedures. Carboxylic acid reductases catalyze aldehyde formation from stable carboxylic acid precursors in an aqueous solution. Carboxylic acid reductases were employed to catalyze aldehyde formation in a cell-free system with activation energy and reducing equivalents provided through auxiliary proteins for ATP and NADPH recycling. In situ product removal was used to suppress over-reduction due to background enzyme activities, and an N-protected 4-formyl-piperidine pharma synthon was prepared in 61% isolated yield. This is the first report of preparative aldehyde synthesis with carboxylic acid reductases employing crude, commercially available enzyme preparations.

Front Cover Picture: Zinc‐Catalyzed Asymmetric Hydrosilylation of Cyclic Imines: Synthesis of Chiral 2‐Aryl‐Substituted Pyrrolidines as Pharmaceutical Building Blocks (5/2021)

The front cover picture illustrates the application of Zn-complex as a key catalyst for enantioselective hydrosilylation of cyclic imines. As the replacement of platinum-group metals is currently an interesting challenge in catalysis, a promising alternative in asymmetric hydrosilylation, is to use environmentally benign and easily accessible chiral Zn-based catalysts. I. Węglarz, K. Michalak and J. Mlynarski show that in situ generated zinc-ProPhenol complex with silane affords pharmaceutically relevant enantioenriched 2-aryl-substituted pyrrolidines in high yields and with excellent enantioselectivities (up to 99% ee). Details can be found in the communication by Jacek Mlynarski and co-workers (I. Węglarz, K. Michalak, J. Mlynarski, Adv. Synth. Catal. 2021, 363, 1317–1321; DOI: 10.1002/adsc.202001043).