Carbonyl-Olefin Metathesis.

This Review describes the development of strategies for carbonyl-olefin metathesis reactions relying on stepwise, stoichiometric, or catalytic approaches. A comprehensive overview of currently available methods is provided starting with Paternò-Büchi cycloadditions between carbonyls and alkenes, followed by fragmentation of the resulting oxetanes, metal alkylidene-mediated strategies, [3 + 2]-cycloaddition approaches with strained hydrazines as organocatalysts, Lewis acid-mediated and Lewis acid-catalyzed strategies relying on the formation of intermediate oxetanes, and protocols based on initial carbon-carbon bond formation between carbonyls and alkenes and subsequent Grob-fragmentations. The Review concludes with an overview of applications of these currently available methods for carbonyl-olefin metathesis in complex molecule synthesis. Over the past eight years, the field of carbonyl-olefin metathesis has grown significantly and expanded from stoichiometric reaction protocols to efficient catalytic strategies for ring-closing, ring-opening, and cross carbonyl-olefin metathesis. The aim of this Review is to capture the status quo of the field and is expected to contribute to further advancements in carbonyl-olefin metathesis in the coming years.

Photochemical Strategies Enable the Synthesis of Tunable Azetidine-Based Energetic Materials.

Despite their favorable properties, azetidines are often overlooked as lead compounds across multiple industries. This is often attributed to the challenging synthesis of densely functionalized azetidines in an efficient manner. In this work, we report the scalable synthesis and characterization of seven azetidines with varying regio- and stereochemistry and their application as novel azetidine-based energetic materials, enabled by the visible-light-mediated aza Paternò-Büchi reaction. The performance and stark differences in the physical properties of these new compounds make them excellent potential candidates as novel solid melt-castable explosive materials, as well as potential liquid propellant plasticizers. This work highlights the scalability and utility of the visible-light aza Paternò-Büchi reaction and demonstrates the impact of stereochemical considerations on the physical properties of azetidine-based energetics. Considering the versatility and efficiency of the presented synthetic strategies, we expect that this work will guide the development of new azetidine-based materials in the energetics space as well as other industries.

New strategies for the synthesis of 1- and 2-azetines and their applications as value-added building blocks.

Four-membered nitrogen-containing heterocycles are highly desirable functional groups with synthetic and biological applications. Unsaturated four-membered N-heterocycles, 1- and 2-azetines, are historically underexplored, but have recently been gaining interest due to the development of new synthetic methods to access these compounds, and to their potential as reactive intermediates. This review covers both the synthesis and applications of azetines, with a focus on synthetic methods to access azetines developed since 2018, and a comprehensive review of the reactivity and applications of azetines as starting materials or intermediates to access both other heterocycles and complex products.

Iron(III)-catalysed carbonyl-olefin metathesis.

The olefin metathesis reaction of two unsaturated substrates is one of the most powerful carbon-carbon-bond-forming reactions in organic chemistry. Specifically, the catalytic olefin metathesis reaction has led to profound developments in the synthesis of molecules relevant to the petroleum, materials, agricultural and pharmaceutical industries. These reactions are characterized by their use of discrete metal alkylidene catalysts that operate via a well-established mechanism. While the corresponding carbonyl-olefin metathesis reaction can also be used to construct carbon-carbon bonds, currently available methods are scarce and severely hampered by either harsh reaction conditions or the required use of stoichiometric transition metals as reagents. To date, no general protocol for catalytic carbonyl-olefin metathesis has been reported. Here we demonstrate a catalytic carbonyl-olefin ring-closing metathesis reaction that uses iron, an Earth-abundant and environmentally benign transition metal, as a catalyst. This transformation accommodates a variety of substrates and is distinguished by its operational simplicity, mild reaction conditions, high functional-group tolerance, and amenability to gram-scale synthesis. We anticipate that these characteristics, coupled with the efficiency of this reaction, will allow for further advances in areas that have historically been enhanced by olefin metathesis.

Total Synthesis of (+)-Cochlearol†B by an Approach Based on a Catellani Reaction and Visible-Light-Enabled [2+2] Cycloaddition.

A 14-step synthesis of (+)-cochlearol B is reported. This renoprotective meroterpenoid features a unique core structure containing a densely substituted cyclobutane ring with three stereocenters. Our strategy employed an organocatalytic Kabbe condensation in route to the key chromenyl triflate. A subsequent Catellani reaction incorporated the remaining carbon atoms featured in the skeleton of cochlearol B. An ensuing visible-light-mediated [2+2] photocycloaddition closed the cyclobutane and formed the central bicyclo[3.2.0]heptane core. Notably, careful design and tuning of the Catellani and photocycloaddition reactions proved crucial in overcoming undesired reactivity, including cyclopropanation reactions and [4+2] cycloadditions.

Hydrazone and Oxime Olefination via Ruthenium Alkylidenes.

We describe the development of an efficient method for the olefination of hydrazones and oximes. The key design approach that enables this transformation is tuning of the energy/polarity of C=N π-bonds by employing heteroatom functionalities (NR2 , OR). The resulting hydrazones or oximes facilitate olefination with ruthenium alkylidenes. Through this approach, we show that air-stable, commercially available ruthenium alkylidenes provide access to functionalized alkenes (20 examples) in ring-closing reactions with yields up to 88 %.

1- and 2-Azetines via Visible Light-Mediated [2 + 2]-Cycloadditions of Alkynes and Oximes.

Azetines, four-membered unsaturated nitrogen-containing heterocycles, hold great potential for drug design and development but remain underexplored due to challenges associated with their synthesis. We report an efficient, visible light-mediated approach toward 1- and 2-azetines relying on alkynes and the unique triplet state reactivity of oximes, specifically 2-isoxazolines. While 2-azetine products are accessible upon intermolecular [2 + 2]-cycloaddition via triplet energy transfer from a commercially available iridium photocatalyst, the selective formation of 1-azetines proceeds upon a second, consecutive, energy transfer process. Mechanistic studies are consistent with a stepwise reaction mechanism via N-O bond homolysis following the second energy transfer event to result in the formation of 1-azetine products. Characteristic for this method is its operational simplicity, mild conditions, and modular approach that allow for the synthesis of functionalized azetines and tetrahydrofurans (via in situ hydrolysis) from readily available precursors.

High-Throughput Approach toward the Development of a Mizoroki-Heck Reaction To Access Tricyclic Spirolactones.

The ent-kaurenes represent a class of naturally occurring diterpenes of biological importance. Several members of the ent-kaurenes contain a common, tricyclic spirolactone core as a key structural motif. This study details a concise approach toward the development of a Mizoroki-Heck reaction to access this spirolactone core. The strategy described herein was enabled in microscale high-throughput experiments to allow for the rapid identification and optimization of superior reaction conditions.

Total Syntheses of Herqulines B and C.

An approach for the syntheses of herqulines B and C is reported that takes advantage of an l-tyrosine-derived diketopiperazine, a mycocyclosin analogue, as a synthetic precursor. The strategy relies on a series of consecutive reductions to adjust the mycocyclosin oxidation state to that observed in the herquline class of natural products. The strained and distorted l-tyrosine-based biaryl system characteristic for mycocyclosin is selectively converted to the 1,4-diketone structural motif common to the herqulines via initial hypervalent iodine-mediated dearomatization and a subsequent directed Birch reduction, enabled by an intramolecular H-source. Additionally, the piperazine oxidation state is accessible via an iron-catalyzed reduction of a diketopiperazine intermediate.

Catalytic Carbonyl-Olefin Metathesis of Aliphatic Ketones: Iron(III) Homo-Dimers as Lewis Acidic Superelectrophiles.

Catalytic carbonyl-olefin metathesis reactions have recently been developed as a powerful tool for carbon-carbon bond formation. However, currently available synthetic protocols rely exclusively on aryl ketone substrates while the corresponding aliphatic analogs remain elusive. We herein report the development of Lewis acid-catalyzed carbonyl-olefin ring-closing metathesis reactions for aliphatic ketones. Mechanistic investigations are consistent with a distinct mode of activation relying on the in situ formation of a homobimetallic singly bridged iron(III)-dimer as the postulated active catalytic species. These "superelectrophiles" function as more powerful Lewis acid catalysts that form upon association of individual iron(III)-monomers. While this mode of Lewis acid activation has previously been postulated to exist, it has not yet been applied in a catalytic setting. The insights presented are expected to enable further advancement in Lewis acid catalysis by building upon the activation principle of "superelectrophiles" and to broaden the current scope of catalytic carbonyl-olefin metathesis reactions.

Beyond olefins: new metathesis directions for synthesis.

The olefin-olefin metathesis reaction has emerged as one of the most important carbon-carbon bond-forming reactions, as illustrated by its wide use in the synthesis of complex molecules, natural products and pharmaceuticals. The corresponding metathesis reaction between carbonyls and olefins or alkynes similarly allows for the formation of carbon-carbon bonds. Although these variants are far less developed and utilized in organic synthesis, they possess attractive qualities that have prompted chemists to incorporate and explore these modes of reactivity in complex molecule synthesis. This review highlights selected examples of carbonyl-olefin and carbonyl-alkyne metathesis reactions in organic synthesis, in particular in the total synthesis of natural products and complex molecules, and provides an overview of current advantages and limitations.

Functionalized Cyclopentanes via Sc(III)-Catalyzed Intramolecular Enolate Alkylation.

We report herein the intramolecular α-tert-alkylation of unsaturated ß-ketoesters which gives rise to highly functionalized cyclopentanes. This strategy is characterized by its operational simplicity, mild reaction conditions and the use of scandium(III) triflate as a Lewis acid catalyst. Of interest, cyclopentanes bearing heterocycles, sites for post reaction functionalization and spirocyclic architectures are accessible with this strategy.

Polycyclic Aromatic Hydrocarbons via Iron(III)-Catalyzed Carbonyl-Olefin Metathesis.

Polycyclic aromatic hydrocarbons are important structural motifs in organic chemistry, pharmaceutical chemistry, and materials science. The development of a new synthetic strategy toward these compounds is described based on the design principle of iron(III)-catalyzed carbonyl-olefin metathesis reactions. This approach is characterized by its operational simplicity, high functional group compatibility, and regioselectivity while relying on FeCl3 as an environmentally benign, earth-abundant metal catalyst. Experimental evidence for oxetanes as reactive intermediates in the catalytic carbonyl-olefin ring-closing metathesis has been obtained.

Mechanistic Investigations of the Iron(III)-Catalyzed Carbonyl-Olefin Metathesis Reaction.

Iron(III)-catalyzed carbonyl-olefin ring-closing metathesis represents a new approach toward the assembly of molecules traditionally generated by olefin-olefin metathesis or olefination. Herein, we report detailed synthetic, spectroscopic, kinetic, and computational studies to determine the mechanistic features imparted by iron(III), substrate, and temperature to the catalytic cycle. These data are consistent with an iron(III)-mediated asynchronous, concerted [2+2]-cycloaddition to form an intermediate oxetane as the turnover-limiting step. Fragmentation of the oxetane via Lewis acid-activation results in the formation of five- and six-membered unsaturated carbocycles.

Enantioselective Aza-Sakurai Cyclizations: Dual Role of Thiourea as H-Bond Donor and Lewis Base.

An enantioselective, catalytic aza-Sakurai cyclization of chlorolactams has been developed as an efficient entry into indolizidine and quinolizidine frameworks. Structure-enantioselectivity relationship studies and mechanistic analysis point to a dual role of the catalyst wherein the thiourea moiety of the catalyst is engaged in both anion binding and Lewis base activation of a substrate.

Access to the aeruginosin serine protease inhibitors through the nucleophilic opening of an oxabicyclo[2.2.1]heptane: total synthesis of microcin SF608.

Serine proteases play key roles in many biological processes and are associated with several human diseases such as thrombosis or cancer. During the search for selective inhibitors of serine proteases, a family of linear peptides named the aeruginosins was discovered in marine cyanobacteria. We herein report an entry route into the synthetically challenging core fragment of these natural products. Starting from the common oxabicyclic building block 11, we accessed the octahydroindole core of the aeruginosins, exemplified by the total synthesis of microcin SF608 (2). Key to the synthetic strategy is a highly efficient nucleophilic opening of an oxabicyclo[2.2.1]heptane producing the hydroindole motif of microcin SF608. Moreover, during the synthetic efforts we have observed an unusual regioselective epoxide reduction. Detailed experimental studies of this reaction led us to propose a mechanistic rationale involving intramolecular hydrogen atom delivery by a carbamate NH group to control the regioselectivity of the homolytic epoxide cleavage.

Visible light-mediated aza Paternò-Büchi reaction of acyclic oximes and alkenes to azetidines.

The aza Paternò-Büchi reaction is a [2+2]-cycloaddition reaction between imines and alkenes that produces azetidines, four-membered nitrogen-containing heterocycles. Currently, successful examples rely primarily on either intramolecular variants or cyclic imine equivalents. To unlock the full synthetic potential of aza Paternò-Büchi reactions, it is essential to extend the reaction to acyclic imine equivalents. Here, we report that matching of the frontier molecular orbital energies of alkenes with those of acyclic oximes enables visible light-mediated aza Paternò-Büchi reactions through triplet energy transfer catalysis. The utility of this reaction is further showcased in the synthesis of epi-penaresidin B. Density functional theory computations reveal that a competition between the desired [2+2]-cycloaddition and alkene dimerization determines the success of the reaction. Frontier orbital energy matching between the reactive components lowers transition-state energy (ΔGǂ) values and ultimately promotes reactivity.

Intramolecular, Visible-Light-Mediated Aza Paternò-Büchi Reactions of Unactivated Alkenes.

Azetidines are of particular interest in medicinal chemistry for their favorable properties, including increased resistance to oxidative metabolism and lower lipophilicity. The recent development of [2 + 2] reactions has significantly expanded the limited repertoire of methods for azetidine synthesis, but access to more complex architectures still requires further development. Herein, we report a visible-light-enabled intramolecular [2 + 2] cycloaddition of unactivated alkenes that proved previously unreactive to access tricyclic azetidines with 3D complex structures and high levels of saturation.