Synthetic Opportunities Research Articles

Asymmetric Synthesis of Seven‐Membered Lactams: Recent Advances and Future Perspectives

The optically active lactams represent an important structural motif and present in a wide range of natural products, biologically active compounds and drugs. Compared to the synthesis of chiral five‐ and six‐membered lactams, the asymmetric construction of seven‐membered lactams often presents a challenge due to their consequential entropic and enthalpic barriers. Over the past few decades, substantial efforts have been devoted to this field and chemists have developed various efficient strategies for the preparation of seven‐membered lactams. In this review, we will highlight the recent advances in enantioselective formation of seven‐membered lactams and the discussion will be logically divided into three parts according to the reaction mode. The aim of this review is to familiarize the Reader with new synthetic opportunities offered by these interesting methodologies.

2,3-Epoxyamide-alcohols in Domino Reactions: En Route to Molecular Diversity.

The synthesis of polycyclic γ- and δ-lactams bearing up to four contiguous fully controlled stereocenters is presented. For that purpose, we developed an original approach based on the use of 2,3-epoxyamides in domino reactions by taking advantage of the nucleophilic nitrogen atom and electrophilic epoxide. In reaction with enol ethers bearing gem bis-electrophiles on the double bond as Michael acceptors, four different reaction pathways were observed. They all started with a domino oxa-Michael/aza-Michael/epoxide opening sequence and depending on substrates engaged could be followed either by a lactonization or a hemiketalization/retro-aldol cascade. Thus, four original fully-substituted piperidine- or pyrrolidine-2-one scaffolds were selectively synthesized in good to high yields. Moreover, these polycyclic lactams were obtained in high stereo- and chemo-selectively highlighting the efficiency and molecular diversity offered by this new methodology that should offer various synthetic opportunities in the future.

Superfast Phase Transformation Driven by Dual Chemical Equilibrium Enabling Enhanced Electrochemical Energy Storage

AbstractPhase transformation engineering provides new synthetic opportunities and pathways toward functional materials with desirable phases and structures. However, current phase transformation processes are generally time‐consuming or low‐yielding due to the lack of favorable driving forces. Herein, a superfast and scalable phase transformation technique driven by dual chemical equilibrium is developed. Taking manganese hexacyanoferrate (MnHCF) as an example, precipitation–dissolution and oxidation‐reduction dual chemical equilibrium co‐drive the superfast phase transformation from cubic KMnFe(CN)6 (C‐MnHCF) to monoclinic K2MnFe(CN)6 (M‐MnHCF) and simultaneously oxidative polymerization of polypyrrole (PPy), enabling the formation of homogeneous M‐MnHCF/PPy hybrid materials. For electrochemical energy storage, the uniform hybridization of PPy improves the electrical conductivity, restrains the dissolution of Mn, and more importantly, promotes K+‐intercalation kinetics of the K‐intercalated MnHCF‐based cathodes with a K+/Na+ competing insertion/extraction mechanism. As a result, the M‐MnHCF/PPy hybrid cathode manifests enhanced structural integrity and charge‐transport capability and thus long‐term cyclic life (114.8 mAh g−1 after 200 cycles at 0.1 A g−1) and high rate performance (113.3 and 92.7 mAh g−1 at 0.5 and 1 A g−1, respectively).

Mechanistically Guided Materials Chemistry: Synthesis of Ternary Nitrides, CaZrN2 and CaHfN2.

Recent computational studies have predicted many new ternary nitrides, revealing synthetic opportunities in this underexplored phase space. However, synthesizing new ternary nitrides is difficult, in part because intermediate and product phases often have high cohesive energies that inhibit diffusion. Here, we report the synthesis of two new phases, calcium zirconium nitride (CaZrN2) and calcium hafnium nitride (CaHfN2), by solid state metathesis reactions between Ca3N2 and MCl4 (M = Zr, Hf). Although the reaction nominally proceeds to the target phases in a 1:1 ratio of the precursors via Ca3N2 + MCl4 → CaMN2 + 2 CaCl2, reactions prepared this way result in Ca-poor materials (CaxM2-xN2, x < 1). A small excess of Ca3N2 (ca. 20 mol %) is needed to yield stoichiometric CaMN2, as confirmed by high-resolution synchrotron powder X-ray diffraction. In situ synchrotron X-ray diffraction studies reveal that nominally stoichiometric reactions produce Zr3+ intermediates early in the reaction pathway, and the excess Ca3N2 is needed to reoxidize Zr3+ intermediates back to the Zr4+ oxidation state of CaZrN2. Analysis of computationally derived chemical potential diagrams rationalizes this synthetic approach and its contrast from the synthesis of MgZrN2. These findings additionally highlight the utility of in situ diffraction studies and computational thermochemistry to provide mechanistic guidance for synthesis.

Boosting Energy-Transfer Processes via Dispersion Interactions.

The generation of open-shell intermediates under mild conditions has opened broad synthetic opportunities during this century. However, these reactive species often require a case specific and tailored tuning of experimental parameters in order to efficiently convert substrates into products. We report a general approach that can overcome these ubiquitous limitations for several visible-light promoted energy-transfer processes. The use of either naphthalene (5-20 equiv.) or simple binaphthyl derivatives (10-30 mol %) greatly increases their efficiency, giving rise to a new strategy for catalysis. The trend is consistent among different media, photocatalysts, light sources and substrates, allowing one to improve existing methods, to more easily optimize conditions for new ones, and, moreover, to disclose otherwise inaccessible reaction pathways.

Organocatalytic enantioselective construction of Si-stereocenters: recent advances and perspectives.

Silicon-stereogenic chiral organosilanes have found increasing applications in synthetic chemistry, medicinal chemistry, and materials science. In this context, various asymmetric catalytic methods have been established for the diverse synthesis of silicon-stereogenic silanes. In particular, asymmetric organocatalysis is emerging as an important and complementary synthetic tool for the enantioselective construction of silicon-stereocenters, along with the rapid development of chiral-metal catalyzed protocols. Its advent provides a powerful platform to achieve functionalized silicon-stereogenic organosilanes with structural diversity, and should lead to great development in chiral organosilicon chemistry. In this Tutorial Review, we highlight these latest achievements from two aspects: desymmetrizations of prochiral tetraorganosilanes and dynamic kinetic asymmetric transformations of racemic organosilanes by employing five organocatalytic activation modes. The advantages, limitations and synthetic value of each protocol, as well as the synthetic opportunities still open for further exploration, are also discussed.

Novel applications of photobiocatalysts in chemical transformations.

Photocatalysis has proven to be an effective approach for the production of reactive intermediates under moderate reaction conditions. The possibility for the green synthesis of high-value compounds using the synergy of photocatalysis and biocatalysis, benefiting from the selectivity of enzymes and the reactivity of photocatalysts, has drawn growing interest. Mechanistic investigations, substrate analyses, and photobiocatalytic chemical transformations will all be incorporated in this review. We seek to shed light on upcoming synthetic opportunities in the field by precisely describing mechanistically unique techniques in photobiocatalytic chemistry.

(Invited) Delivering Electrons and Protons to the Substrate in Molecularly-Based Reductive Electrocatalysis

To steer away from fossil fuels the primary sourcing for goods and chemicals, combining renewable electricity with sustainable feedstocks in an electrochemical strategy is a formidable synthetic opportunity. In that frame, we investigate how molecular electrocatalysis can foster electrosynthetic conversions, in particular for organics reductions.[1] Here, we will disclose that alkyne semihydrogenation, an important synthetic manifold, can be selectively electrocatalyzed by a simple molecular catalyst [Ni(bpy)3]2+, based on the earth-abundant metal nickel.[ 2 ] Our combined electrochemical, synthetic and computational investigations support that the catalytic cycle proceeds via the protonation of a nickelacyclopropene species and bypasses the need to generate a competent hydride.[3] As a proof-of-concept for molecular electrocatalytic alkyne semihydrogenation, this work opens a platform to develop original electrochemical routes for the hydrogenation/-functionalization of organics and small molecules.We will also discuss the use of Pickering emulsion that separates organic substrates and aqueous electrolytes in different phases for electrocatalytic hydrogenation at the interface. We developed a hybrid design based on carbon nanotube-supported Pd nanoparticles that places at the interface and acts both as emulsion stabilizer and electrocatalyst. The system electrohydrogenates styrene into ethylbenzene with high faradaic efficiency (95.0%) and Pd specific current density (–148.1 mA·cm–2). Our system combines good solubility of the substrates, high conductivity, facile product isolation and applies to the transformation of various alkenes. This strategy may thus provide original solutions to the ECH of substrates having low water-solubility.[4] References [1] N. Kaeffer, W. Leitner, JACS Au, 2022, 2, 1266.[2] M.-Y. Lee, C. Kahl, N. Kaeffer, W. Leitner, JACS Au, 2022, 2, 573.[3] G. Durin, M.-Y. Lee, T. Weyhermüller, N. Kaeffer, W. Leitner, ChemRxiv, 10.26434/chemrxiv-2023-whtfd.[4] C. Han, J. Zenner, J. Johny, N. Kaeffer, A. Bordet, W. Leitner, Nat. Catal., 2022 , 5, 1110.

Current State and Perspectives of Exfoliated Zeolites.

Zeolites are highly efficient industrial catalysts and sorbents with microporous framework structures. Approximately 10% of the frameworks, but eventually all in the long run, have produced both 3D crystals and 2D layers. The latter can be intercalated and expanded like all 2D materials but proved difficult to exfoliate directly into suspensions of monolayers in solution as precursors for unique synthetic opportunities. Successful exfoliations have been reported recently and are overviewed in this perspective article. The discussion highlights 3 primary challenges in this field, namely finding suitable 2D zeolite preparations that exfoliate directly in high yield, proving uniform layer thickness in solution and identifying applications to exploit the unique synthetic capabilities and properties of exfoliated zeolite monolayers. Four zeolites have been confirmed to exfoliate directly into monolayers: 3 with known structures-MWW, MFI, and RWR and one unknown, bifer with a unit cell close to ferrierite. The exfoliation into monolayers is confirmed by the combination of 5-6 characterization techniques including AFM, in situ and in-plane XRD, and microscopies. The promising areas of development are oriented films and membranes, intimately mixed zeolite phases, and hierarchical nanoscale composites with other active species like nanoparticles and clusters that are unfeasible by solid state processes.

The Q-Tube-Assisted Green Sustainable Synthesis of Fused Azines: New Synthetic Opportunities via Innovative Green Technology

An efficient, economical, and green, sustainable synthesis of fused azines using Mg-Al hydrotalcite under a high-pressure Q-Tube reactor has been developed. This reaction proceeds through the aza-Michael addition of α,β-unsaturated ketone with different aminoazoles. This method offered excellent yields in a short reaction time that economically saved energy in addition to the protocol showing the reuse of the catalyst seven times without losing its catalytic activity.

Visible Light and Triselenium Dicyanide (TSD): New Horizons in the Synthesis of Organic Selenocyanates.

Herein, we describe a new method for the synthesis of α-carbonyl selenocyanates by reacting triselenium dicyanide (TSD) and styrenes under blue light irradiation and O2 atmosphere. The reactions are triggered by the formation of Se-centered radical species, followed by the addition/oxidation of the styrene π-bond. α-Carbonyl selenocyanates and α-hydroxy selenocyanates were obtained in moderate to excellent yields from aryl- and alkyl-substituted alkenes, respectively. It was demonstrated that α-carbonyl selenocyanates could be used as a synthetic platform in a multicomponent reaction strategy to prepare 2-phenylimidazo[1,2-a]pyridine derivatives, which were evaluated for their photophysical properties. Overall, this new method provides a useful tool for synthesizing α-carbonyl selenocyanates, and demonstrates their potential for use in the synthesis of other compounds, thus giving new synthetic opportunities to construct organic selenocyanate compounds.

Photobiocatalytic Strategies for Organic Synthesis.

Biocatalysis has revolutionized chemical synthesis, providing sustainable methods for preparing various organic molecules. In enzyme-mediated organic synthesis, most reactions involve molecules operating from their ground states. Over the past 25 years, there has been an increased interest in enzymatic processes that utilize electronically excited states accessed through photoexcitation. These photobiocatalytic processes involve a diverse array of reaction mechanisms that are complementary to one another. This comprehensive review will describe the state-of-the-art strategies in photobiocatalysis for organic synthesis until December 2022. Apart from reviewing the relevant literature, a central goal of this review is to delineate the mechanistic differences between the general strategies employed in the field. We will organize this review based on the relationship between the photochemical step and the enzymatic transformations. The review will include mechanistic studies, substrate scopes, and protein optimization strategies. By clearly defining mechanistically-distinct strategies in photobiocatalytic chemistry, we hope to illuminate future synthetic opportunities in the area.

Asymmetric Ion-Pairing in Stereoselective Vinyl Polymerization

Controlling polymer tacticity is a key consideration in macromolecular synthesis due to the impact of stereochemistry on a material’s thermomechanical and optical properties. Recently, inspired by work in small molecule catalysis, asymmetric ion-pairing has emerged as a valuable approach to control the stereochemistry of polymers made through chain growth polymerization of vinyl monomers. This Perspective outlines some of the challenges inherent to polymer stereocontrol as well as highlights recent catalyst development in the area of asymmetric ion-pairing that has enabled control of both the configuration and conformation of vinyl polymers. Several synthetic opportunities and mechanistic questions have been identified that will expand the impact of asymmetric ion-pairing in polymer synthesis.

Photochemistry Journey to Multielectron and Multiproton Chemical Transformation.

The odyssey of photochemistry is accompanied by the journey to manipulate "electrons" and "protons" in time, in space, and in energy. Over the past decades, single-electron (1e-) photochemical transformations have brought marvelous achievements. However, as each photon absorption typically generates only one exciton pair, it is exponentially challenging to accomplish multielectron and proton photochemical transformations. The multistep differences in thermodynamics and kinetics urgently require us to optimize light harvesting, expedite consecutive electron transfer, manipulate the interaction of catalysts with substrates, and coordinate proton transfer kinetics to furnish selective bond formations. Tandem catalysis enables orchestrating different photochemical events and catalytic transformations from subpicoseconds to seconds, which facilitates multielectron redox chemistries and brings consecutive, value-added reactivities. Joint efforts in molecular and material design, mechanistic understanding, and theoretical modeling will bring multielectron and proton synthetic opportunities for fuels, fertilizers, and chemicals with enhanced versatility, efficiency, selectivity, and scalability, thus taking better advantage of photons (i.e., sunlight) for our sustainable society.

Reactions with Geminal Diazides: Long Known, Full of Surprises, and New Opportunities

AbstractGeminal diazides are uncommon yet powerful tools in organic synthesis. The chemistry of this class of functional compounds is characterized by quite unusual reactivities, including fragmentations and degradations, along with known reactions of organic azides. This Short Review highlights the major reactivities of various structural units having geminal diazido moieties, and provides an overview on the synthetic opportunities of such compounds.1 Introduction2 Preparation of Geminal Diazides3 Reactivities of Geminal Diazides3.1 α,α-Diazido Carbonyls3.2 1,3-Diketones3.3 Diazidated β-Ketoesters3.4 Diazidated Malonates3.5 Diazidated Malonamides3.6 Miscellaneous Geminal Diazides4 Conclusion

Hybrid Improper Ferroelectricity: A Theoretical, Computational, and Synthetic Perspective

We review the theoretical, computational, and synthetic literature on hybrid improper ferroelectricity in layered perovskite oxides. Different ferroelectric mechanisms are described and compared, and their elucidation using theory and first-principles calculations is discussed. We also highlight the connections between crystal chemistry and the physical mechanisms of ferroelectricity. The experimental literature on hybrid improper ferroelectrics is surveyed, with a particular emphasis on cation-ordered double perovskites, Ruddlesden–Popper and Dion–Jacobson phases. We discuss preparative routes for synthesizing hybrid improper ferroelectrics in all three families and the conditions under which different phases can be stabilized. Finally, we survey some synthetic opportunities for expanding the family of hybrid improper ferroelectrics.

Abstract 2801: Detection of biallelic loss of DNA repair genes in formalin-fixed, paraffin embedded (FFPE) tumor samples using a novel tumor-only sequencing panel with error correction

Abstract Background: Loss-of-function (LOF) mutations in DNA damage response (DDR) tumor suppressor genes are compensated for by functional redundancies, exposing synthetic lethal (SL) interactions and opportunities for targeted therapy. Patient selection for SL-based therapy may be improved by assessment of gene-specific loss of heterozygosity (LOH) and biallelic LOF, neither of which is routinely reported by existing targeted sequencing panels. The Synthetic Lethal Interactions for Precision Diagnostics (SNiPDx) targeted sequencing panel features a novel bioinformatic analysis pipeline that enables accurate genome-wide determination of allele-specific copy number, estimation of tumor ploidy and purity, and detection of single nucleotide and indel variants in target genes focused on DDR pathways, all from tumor-only samples. Here we describe the development and accuracy of SNiPDx for detection of LOH and bi-allelic LOF genetic alterations in FFPE samples. Methods: Genomic DNA (&amp;gt;50 ng) was extracted from FFPE samples of multiple solid tumor types (n = 43). Next-generation sequencing was performed on anchored multiplex PCR libraries, constructed using probes that incorporate unique molecular identifiers and span 26 genes and 5,000 genome-wide common germline single-nucleotide polymorphisms (SNPs). Unmatched non-tumor samples (n = 24) were used to generate a reference baseline dataset. The FACETS algorithm, optimized to account for differential DNA fragmentation across samples, was used to assess copy number imbalance in heterozygous SNPs and to quantify tumor purity. Allele fractions at each heterozygous SNP were used to estimate allelic imbalances across chromosomal regions. A reference dataset was derived from matched FFPE tumor samples by whole genome sequencing (WGS) and analysis of sequence data using 3 complementary algorithms. Allele-specific copy number analysis and tumor purity estimation from SNiPDx and WGS data were compared. Results: Copy number was evaluable in 605 genes from 24 matched tumor samples that passed quality control filters. Median sequencing depth across samples by SNiPDx and WGS were 1346x and 18.6x, respectively. LOH detection by SNiPDx was reproducible (100%) across 170 genes from 7 samples sequenced and analyzed in duplicate. A strong correlation was observed between sample purity estimates by WGS and SNiPDx (Pearson’s r = 0.81, p &amp;lt; 0.001). Compared with WGS-derived calls, the sensitivity and specificity of LOH detection by SNiPDx were 95% and 90%, respectively, rising to 97% and 91% in regions with LOH agreement by all 3 WGS algorithms, and to 99% and 97% in diploid regions with no subclonal alterations. b The SNiPDx panel is a novel clinical test for biallelic loss in FFPE tumor-only samples with high accuracy as validated through concordance with a WGS-derived dataset. Citation Format: Dominik Glodzik, Pier Selencia, Ryan Rogge, Ian M. Silverman, Michael Zinda, Maria Koehler, Robert D. Daber, Verity Johnson, Jorge S. Reis-Filho, Victoria Rimkunas. Detection of biallelic loss of DNA repair genes in formalin-fixed, paraffin embedded (FFPE) tumor samples using a novel tumor-only sequencing panel with error correction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2801.

Chemodivergent Csp3─F bond functionalization and cross-electrophile alkyl-alkyl coupling with alkyl fluorides.

The widespread use of fluorinated organic compounds in the health, agrochemical, and materials sciences is sustained by a steadily growing pool of commercially available fine chemicals. The synthetic utility of the increasingly ubiquitous Csp3─F bond, however, remains to be fully exploited, which is often a difficult task because of its paramount stability and chemical inertness. Here, we demonstrate chemodivergent activation of monofluoroalkyl compounds toward either nucleophilic or electrophilic intermediates. This is accomplished under conditions that are compatible with several reaction types and many functional groups, which drastically widens the current scope of organofluorine chemistry and sets the stage for carbon-carbon and carbon-heteroatom bond formations, stereoselective construction of bisoxindole alkaloid scaffolds via in situ Umpolung, and cross-electrophilic coupling methodology. The selective generation of either nucleophilic or electrophilic species and the possibility of doing so simultaneously or, alternatively, switching molecular polarity enable previously unidentified synthetic opportunities that recognize alkyl fluorides as chemodivergent building blocks.

Recent advances in gold-complex and chiral organocatalyst cooperative catalysis for asymmetric alkyne functionalization

Homogeneous gold catalysis has demonstrated the preponderant capability of realizing a broad range of synthetically versatile alkyne functionalization over the last two decades. Though catalytic asymmetric alkyne transformation has focused on the principle of using gold catalysts either associated with chiral phosphine ligand or combined with chiral counterion, a variety of breakthroughs have been reported with the application of gold-complex and chiral organocatalyst cooperative catalysis strategy, which could enable the challenging transformations that cannot be realized by mono-catalysis with excellent stereoselectivity. This review will cover two general protocols in this field, including relay catalysis and synergistic catalysis, with emphasis on the detailed cooperative catalysts models to illustrate the roles of the two catalysts and highlight the potential synthetic opportunities offered by asymmetric cooperative catalysis.

Genomic classification of clinically advanced pancreatic ductal adenocarcinoma (PDAC) based on methylthioadenosine phosphorylase (MTAP) genomic loss (MTAP loss).

604 Background: MTAP loss is represented across a wide variety of cancer types including PDAC and is an emerging target for synthetic lethality-based cancer therapies. Preclinically, MTAP loss leads to the accumulation of 2-methylthioadenosine, reduced protein arginine N-methyltransferase 5 (PRMT5) methylation activity and increased vulnerability to targeting of the methionine adenosyltransferase IIα (MAT2A)/ PRMT5 axis. In addition, 9p21 loss, homozygous co-deletion of MTAP/CDKN2A or homozygous deletion of either gene have been associated with an immunologically “cold” tumor microenvironment, primary resistance to anti PD(L)1 immunotherapy (IO) and poor prognosis phenotype (Han G, Nat Commun 2021). We investigated concurrent mutations and immune biomarkers in clinical PDAC samples with MTAP-loss versus -intact status. Methods: From a series of 177705 consecutive cases, we performed comprehensive genomic profiling on 9423 cases of PDAC using an FDA-approved assay (F1CDx) to evaluate all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by immunohistochemistry (Dako 22C3). Furthermore, we correlated pertinent findings within a database of 16558 cases of clinically advanced cancer with MTAP loss. Results: 2003 (21.3%) of 9423 PDAC demonstrated MTAP-loss. Similar gender, age and number of GA per tumor were observed between MTAP-loss and -intact groups. Frequencies of TP53, CDKN2A/B, SMAD4, PTEN and ARID1A were significantly higher in MTAP-loss PDAC. However, previously-described biomarkers of IO efficacy (MSI, TMB, CD274 amplification and PD-L1 expression) and resistance ( STK11, KEAP1 and MDM2) were infrequent and similar in both groups. The frequencies of other potentially targetable GA including BRCA1/2, ATM, KRAS G12C, ERBB2, BRAF, FGFR1, NF1 and PIK3CA were also infrequent and similar in both groups of PDAC patients. Amongst a database of 16558 cases of clinically advanced cancer with MTAP loss, 1538 (9.3%) featured co-alterations in MTAP and SMAD4. 52% of the MTAP/SMAD4 co-altered cases were PDAC. Conclusions: MTAP loss is associated with a distinctive concurrent genomic profile in PDAC and represents a potential new synthetic lethality-based opportunity for treatment with PRMT5 and MAT2A inhibitors. Furthermore, MTAP loss may represent an independent negative predictive biomarker for immune checkpoint inhibition in PDAC.[Table: see text]