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Phenol ester activated dipeptides that are reluctant to ring-close have been cyclised with the aid of sterically shielding metallo-porphyrins avoiding unwanted intermolecular reactions. The binding of ZnTPP to the dipyridine-functionalised activating phenolic ester was studied by NMR titrations and modelling. Staudinger-mediated cyclisations in the presence of ZnTPP increased the yield of the cyclic dipeptide from 16% to 40%.

Mechanically interlocked molecules are constituted of one or more molecular fragments held together or in a particular conformation by one or more mechanical bonds. These are enforced primarily by steric repulsion and allow the formation of knotted and chained architectures. The resulting unique translational and conformational properties are unlike those of any other chemical bond. Nevertheless, establishing a mechanical bond is a challenging endeavour and only a handful of synthetic methods have proven effective. Prior to the present work, our group investigated the use of covalent templates to force the “backfolding” macrocyclization of linear molecular fragments. Several inverted-spiro bismacrocycles could be isolated possessing a mechanical bond. Although effective in establishing the correct interlocked conformation, the templates proved impossible to cleave, thus never fully liberating the desired interlocked final product. In this work, the unexpected stability of the template linkages was investigated and successfully tackled, leading to the first [2]catenane obtained by backfolding macrocyclization using covalent templating. The approach was further improved with the introduction of an aminoacid template which required milder conditions to liberate the final interlocked species, as well as a lower degree of symmetry, giving rise to observable mechanical stereoisomers. This second approach lead to both a [2]catenane and a [2]rotaxane via a common late stage intermediate. A simpler terephthalate template was also explored in the preparation of a large number of rotaxanes by joining several different building blocks into a number of combinations. Mechanical chirality could also be introduced in this system.

The encounter complex, i.e. the pre-organized assembly consisting of a Lewis acid and a Lewis base, is a fundamental concept in frustrated Lewis pair (FLP) chemistry. However, this donor-acceptor complex is challenging to study due to its transient nature. Here, we present a combined theoretical and experimental investigation on the potential isolation of an encounter complex enabled by enhancement of London dispersion forces between a sterically encumbered Lewis acid and base pair. Guided by computational analyses, the FLP originating from the bulky triarylamine N(3,5-tBu2C6H3)3 and the novel triarylborane B(3,5-tBu2C6H3)3 was investigated, leading to the isolation of a 1:1 co-crystal of both FLP components.

Mechanically interlocked molecules (MiMs), such as catenanes and rotaxanes, exhibit unique properties due to the mechanical bond which unites their components. The translational and rotational freedom present in these compounds may be harnessed to create stimuli-responsive MiMs, which find potential application as artificial molecular machines. Mechanically interlocked structures such as lasso peptides have also been found in nature, making MiMs promising albeit elusive targets for drug discovery. Although the first syntheses of MiMs were based on covalent strategies, approaches based on non-covalent interactions rose to prominence thereafter and have remained dominant. Non-covalent strategies are generally short and efficient, but do require particular structural motifs which are difficult to alter. In a covalent approach, MiMs can be more easily modified while the components may have increased rotational and translational freedom. Both approaches have complementary merits and combining the unmatched efficiency of non-covalent approaches with the scope of covalent syntheses may open up vast opportunities. In this review, recent covalently templated syntheses of MiMs are discussed to show their complementarity and anticipate future developments in this field.1 Introduction2 Tetrahedral Templates2.1 A Carbonate Template for Non-Rusty Catenanes2.2 All-Benzene Catenanes on a Silicon Template2.3 Backfolding from Quaternary Carbon3 Planar Templates3.1 Rotaxanes Constructed in a Ring3.2 Hydrindacene as a Dynamic Covalent Template3.3 Templating on Tri- and Tetrasubstituted Benzenes4 Conclusion

Novel seven‐membered cyclic imine‐based 1,3‐P,N ligands were obtained by capturing a Beckmann nitrilium ion intermediate generated in situ from cyclohexanone with benzotriazole, and then displacing it by a secondary phosphane under triflic acid promotion. These “cycloiminophosphanes” possess flexible non‐isomerizable tetrahydroazepine rings with a high basicity; this sets them apart from previously reported iminophophanes. The donor strength of the ligands was investigated by using their P‐κ1‐ and P,N‐κ2‐tungsten(0) carbonyl complexes, by determining the IR frequency of the trans‐CO ligands. Complexes with [RhCp*Cl2]2 demonstrated the hemilability of the ligands, giving a dynamic equilibrium of κ1 and κ2 species; treatment with AgOTf gives full conversion to the κ2 complex. The potential for catalysis was shown in the RuII‐catalyzed, solvent‐free hydration of benzonitrile and the RuII‐ and IrI‐catalyzed transfer hydrogenation of cyclohexanone in isopropanol. Finally, to enable access to asymmetric catalysts, chiral cycloiminophosphanes were prepared from l‐menthone, as well as their P,N‐κ2‐RhIII and a P‐κ1‐RuII complexes., Complexes, chirality and catalysts: 1,3‐P,N hybrid ligands are broadly applied in cooperative catalysis, but show limited electronic variation. We report novel analogues with a high N‐basicity, based on 7‐membered cyclic imines. Their transition metal complexes demonstrated their donor strength (W), hemilabile coordination (Rh), and catalytic activity for nitrile hydration (Ru) and transfer hydrogenation (Ru, Ir). Chiral derivatives were also obtained, synthesized from l‐menthone.

Despite the advances in the synthesis of mechanically interlocked molecules, a generally applicable approach to interlocked natural products, such as lasso peptides, is yet to be formulated. While amino acid sequences have been introduced into several rotaxanes, the key structural components have always been dictated by the method used for supramolecular preorganization. In this work, we report the use of an ester-functionalized, aromatic δ-amino acid as the central covalent templating unit in the synthesis of both a [2]catenane and a [2]rotaxane from the same multimacrocyclic intermediate. This represents a key step toward future synthetic peptide-based interlocked products.

Reversing the conventional site-selectivity of C−H activation processes provides new retrosynthetic disconnections to otherwise unreactive bonds. Here, we report a new catalytic system based on palladium/norbornene and an S,O-ligand for the meta-C−H arylation of aryl ethers that significantly outperforms previously reported systems. We demonstrate the unique ability of this system to employ alkoxyarene substrates bearing electron donating and withdrawing substituents. Additionally, ortho-substituted aryl ethers are well tolerated, overcoming the “ortho constraint”, which is the necessity to have a meta-substituent on the alkoxyarene to achieve high reaction efficiency, by enlisting novel norbornene mediators. Remarkably, for the first time the monoarylation of alkoxyarenes is achieved efficiently enabling the subsequent introduction of a second, different aryl coupling partner to rapidly furnish unsymmetrical terphenyls. Further insight into the reaction mechanism was achieved by isolation and characterization of some Pd-complexes—before and after meta C−H activation—prior to evaluation of their respective catalytic activities.

Mild and efficient macrocyclization of unprotected peptides featuring a backbone propargylic amide was accomplished by a new Au(I)-catalyzed reaction.

After earlier unsuccessful attempts, this work reports the application of covalent templating for the synthesis of mechanically interlocked molecules (MiMs) bearing no supramolecular recognition sites. Two linear strands were covalently connected in a perpendicular fashion by a central ketal linkage. After subsequent attachment of the first strand to a template via temporary benzylic linkages, the second was linked to the template in a backfolding macrocyclization. The resulting pseudo[1]rotaxane structure was successfully converted to a [2]catenane via a second macrocyclization and cleavage of the ketal and temporary linkages., A covalent template strategy for the synthesis of mechanically interlocked molecules has been successfully employed to give a [2]catenane. This approach results in a [2]catenane devoid of supramolecular recognition sites. An inverted spiro intermediate is formed due to the action of a covalent template, which enforces an otherwise unfavorable macrocyclization. The trapped thread could be clipped into a second macrocycle giving a precatenane and, upon cleavage of the covalent templating linkages, the [2]catenane architecture.

Persistency of chemicals in the environment is seen a pressing issue as it results in accumulation of chemicals over time. Persistent chemicals can be an asset in a well-functioning circular economy where products are more durable and can be reused or recycled. This objective can however not always be fulfilled as release of chemicals from products into the environment can be inherently coupled to their use. In these situations, chemicals should be designed for degradation. In this study, a systematic and computer-aided workflow was developed to facilitate the chemical redesign for reduced persistency. The approach includes elements of Essential Use, Alternatives Assessment and Green and Circular Chemistry and ties into goals recently formulated in the context of the EU Green Deal. The organophosphate chemical triisobutylphosphate (TiBP) was used as a case study for exploration of the approach, as its emission to the environment was expected to be inevitable when used as a flame retardant. Over 6.3 million alternative structures were created in silico and filtered based on QSAR outputs to remove potentially non-readily biodegradable structures. With a multi-criteria analysis based on predicted properties and synthesizability a top 500 of most desirable structures was identified. The target structure (di-n-butyl (2-hydroxyethyl) phosphate) was manually selected and synthesized. The approach can be expanded and further verified to reach its full potential in the mitigation of chemical pollution and to help enable a safe circular economy.

Frustrated Lewis pairs (FLPs) are well known for their ability to activate small molecules. Recent reports of radical formation within such systems indicate single‐electron transfer (SET) could play an important role in their chemistry. Herein, we investigate radical formation upon reacting FLP systems with dihydrogen, triphenyltin hydride, or tetrachloro‐1,4‐benzoquinone (TCQ) both experimentally and computationally to determine the nature of the single‐electron transfer (SET) events; that is, being direct SET to B(C6F5)3 or not. The reactions of H2 and Ph3SnH with archetypal P/B FLP systems do not proceed via a radical mechanism. In contrast, reaction with TCQ proceeds via SET, which is only feasible by Lewis acid coordination to the substrate. Furthermore, SET from the Lewis base to the Lewis acid–substrate adduct may be prevalent in other reported examples of radical FLP chemistry, which provides important design principles for radical main‐group chemistry., The radical reactivity of archetypal P/B frustrated Lewis pair (FLP) systems is probed through utilization of the light dependency of direct single‐electron transfer from the phosphine to the borane to determine that reactivity with H2 does not proceed via a radical pathway. For radical FLP reactions with carbonyl‐containing substrates, direct SET is excluded in favor of borane coordination to the carbonyl, after which SET occurs.

Archetypal phosphine/borane frustrated Lewis pairs (FLPs) are famed for their ability to activate small molecules. The mechanism is generally believed to involve two‐electron processes. However, the detection of radical intermediates indicates that single‐electron transfer (SET) generating frustrated radical pairs could also play an important role. These highly reactive radical species typically have significantly higher energy than the FLP, which prompted this investigation into their formation. Herein, we provide evidence that the classical phosphine/borane combinations PMes3/B(C6F5)3 and PtBu3/B(C6F5)3 both form an electron donor–acceptor (charge‐transfer) complex that undergoes visible‐light‐induced SET to form the corresponding highly reactive radical‐ion pairs. Subsequently, we show that by tuning the properties of the Lewis acid/base pair, the energy required for SET can be reduced to become thermally accessible., Exciting FLPs! The radical‐ion pairs of the archetypal frustrated Lewis pair (FLP) systems PMes3/B(C6F5)3 and PtBu3/B(C6F5)3 can be accessed by visible‐light‐induced single‐electron transfer. Varying the FLP system shows this process is general for a range of donor–acceptor combinations and can be tuned to proceed thermally.

The reaction of the intramolecular frustrated Lewis pair (FLP) tBu2PCH2BPh2 with the amine-boranes NH3 center dot BH3 and Me2NH center dot BH3 leads to the formation of the corresponding FLP-H2 adducts as well as novel five-membered heterocycles that result from capturing the in situ formed amino-borane by a second equivalent of FLP. The sterically more demanding tBu2PCH2BMes2 does not form such a five-membered heterocycle when reacted with Me2NH•BH3 and its H2 adduct liberates dihydrogen at elevated temperatures, promoting the metal-free catalytic dehydrogenation of amine-boranes.

O- and S-heterocyclic carbenes (OHCs, SHCs) are shown experimentally and computationally to be stronger pi acceptors than NHCs and lack, of course, substituents at the heteroatoms. These different electronic and steric characteristics make OHCs and SHCs interesting ligands for coordination chemistry. Convenient synthetic routes are presented to access their iridium(I), iridium(III), and coinage-metal(I) (Cu, Ag, Au) complexes in good yields by means of dissociation of olefins, deprotonation of precursor salts, and transmetalation from a silver carbene complex Molecular structures and detailed bonding analyses of these complexes are presented.

Incorporation of 2,5-dihydroxyterephthalate as a covalent scaffold in the axis of a 30-membered all-carbon macrocycle provides access to a modular series of rotaxanes. Installment of tethered alkynes or azides onto the terephthalic phenolic hydroxyl functionalities, which are situated at opposite sides of the macrocycle, gives versatile prerotaxane building blocks. The corresponding [2]rotaxanes are obtained by introduction of bulky stoppering (“capping”) units at the tethers and subsequent cleavage of the covalent ring/thread ester linkages. Extension of this strategy via coupling of two prerotaxanes bearing complementary linker functionalities (i.e., azide and alkyne) and follow-up attachment of stopper groups provide efficient access to [n]rotaxanes. The applicability and modular nature of this novel approach were demonstrated by the synthesis of a series of [2]-, [3]-, and [4]rotaxanes. Furthermore, it is shown that the prerotaxanes allow late-stage functionalization of the ring fragment introducing further structural diversity.

Herein, we report a nondirected para-selective C−H alkynylation of aniline derivatives by a Pd/S,O-ligand-based catalyst. The reaction proceeds under mild conditions and is compatible with a variety of substituted anilines. The scalability and further derivatizations of the alkynylated products have been also demonstrated.

P-yramids: Tetrahedranes are highly strained molecules, and the all-carbon (CtBu)4 and all-phosphorus species P4 have been known for decades and centuries, respectively. Despite this, the mixed P/C tetrahedranes were unknown until recently when the syntheses of the phosphatetrahedranes P(CtBu)3 and P2(CtBu)2 were reported by the research groups of Cummins and Wolf.

Catalyst-controlled site selectivity in C-H functionalization reactions is a long-standing challenge. In this issue of Chem, Larrosa and co-workers employ a cyclometalated ruthenium catalyst (RuBnN) to reverse the conventional meta-selectivity to the unprecedented ortho-selectivity in the C(sp2)-H alkylation of arenes with secondary alkyl halides.

The neurotransmitter metabolite 3,4-dihydroxy-phenylglycolaldehyde (dopegal) damages neurons and the myocardium by protein cross-linking, resulting in conglomerations and cell death. We investigated this process on a synthetic scale, leading to the discovery of an Amadori-type rearrangement of dopegal in the reaction with several amino acids and neuropeptides. This alkylation also occurs with neurotransmitters, suggesting an influence of dopegal on neurochemical processes. The rearrangement occurs readily under physiological conditions.

Herein, we report a highly selective C-H olefination of directing-group-free indolines (C5) and tetrahydroquinolines (C6) by Pd/S,O-ligand catalysis. In the presence of the S,O-ligand, a wide range of challenging indolines, tetrahydroquinolines, and olefins was efficiently olefinated under mild reaction conditions. The synthetic potential of this methodology was demonstrated by the efficient olefination of several indoline-based natural products.

Various international perspectives from selected regions where substantial work is being done on green and sustainable chemistry education emphasize a systems thinking framework. Common to most of the perspectives is the inclusion of more global paradigms involving economic, environmental, political, and social aspects as fundamental issues in the formerly merely technical and scientific discussions, as well as the development of laboratory experiences, training sessions, written materials, discussion meetings, and conferences. We include bird’s eye views from Europe (the Green Chemistry Centre of Excellence at the University of York, United Kingdom; the University of Cordoba, Spain; and the University of Amsterdam, The Netherlands), Latin America (the Universidad Nacional de Rosario, Argentina, and the Universidad Iberoamericana, Mexico), Africa (the University of Venda, South Africa), and Australia (Monash University).

Silicates with five organic groups are conformationally dynamic even with two bidentate ligands. Symmetry breaking by incorporating a single nitrogen or phosphorus atom provides insight into their dynamic behavior. N‐containing silicates with bidentate 2‐phenylpyridine, biphenyl, and a Me (8), Et (9) or Ph (10) ligand were studied comprehensively by NMR spectroscopy and DFT theory to reveal two isoenergetic conformers with a barrier of ca. 10 kcal mol–1. P‐containing silicate 14 with bidentate triphenylphosphane, biphenyl, and Me ligands is subject to multiple Berry pseudorotations, turnstile rotations, and conformational flexibility of the P‐center. The stability increased by masking the P‐center with a BH3 group (16). DFT and NMR modeling reveal two isoenergetic conformers for 16 with a barrier of ca. 19 kcal‧mol–1 for a complex interconversion pathway. This barrier bodes well for the design of configurationally stable chiral‐at‐metal transition metal catalysts.

Amine–boranes have gained a lot of attention due to their potential as hydrogen storage materials and their capacity to act as precursors for transfer hydrogenation. Therefore, a lot of effort has gone into the development of suitable transition‐ and main‐group metal catalysts for the dehydrogenation of amine–boranes. During the past decade, new systems started to emerge solely based on p‐block elements that promote the dehydrogenation of amine–boranes through hydrogen‐transfer reactions, polymerization initiation, and main‐group catalysis. In this review, we highlight the development of these p‐block based systems for stoichiometric and catalytic amine–borane dehydrogenation and discuss the underlying mechanisms.

Metal ligand cooperativity (MLC) and frustrated Lewis pair (FLP) chemistry both feature the cooperative action of a Lewis acidic and a Lewis basic site on a substrate. A lot of work has been carried out in the field of FLPs to prevent Lewis adduct formation, which often reduces the FLP reactivity. Parallels are drawn between the two systems by looking at their reactivity with CO2, and we explore the role of steric bulk in preventing dimer formation in MLC systems.

1,3-P,N-ligands provide the ideal spatial separation to facilitate homo and hetero metal-metal interactions to access multinuclear complexes. The rich chemistry of such complexes includes applications in coordination chemistry, metal-activation and (cooperative) catalysis. However, it has been especially the fruitful combination in photoluminescent P,N-coinage metal complexes which has renewed interest in these ligands. While the field classically focused on dinuclear species, now also coinage metal clusters have been studied for use in catalysis and photophysical applications. Reviewed are recent developments from 2009 to mid-2017.

1,3-P,N-ligands are prominent hybrid ligands which provide valuable mononuclear transition metal complexes, due to their varied bonding modes with an inherent usefulness in cooperative processes such as ligand-assisted substrate activation and both homogeneous and heterogeneous catalysis. Reviewed are recent developments in an expanding number of applications, including coordination chemistry, catalysis, and bio-inorganic applications.

Over the past decades, organic chemists have focussed on developing new approaches to directed C–H functionalisations, where the site selectivity is steered by the presence of a directing group (DG). Nonetheless, in recent years, more and more non-directed strategies are being developed to circumvent the requisite directing group, making C–H functionalisations more generic. This short review focuses on the latest developments in palladium-catalysed non-directed C–H functionalisations of aromatic compounds.1 Introduction2 C–C Bond Formation2.1 C–H Arylation2.2 C–H Alkylation2.3 C–H Alkenylation2.4 C–H Carbonylation3 C–Heteroatom Bond Formation3.1 C–O Bond Formation3.2 C–N Bond Formation3.3 C–S Bond Formation4 Conclusion

We report the identification of high-affinity and selectivity integrin α5β1-binding bicyclic peptides via “designed random libraries”, that is, the screening of libraries comprising the universal integrin-binding sequence Arg-Gly-Asp (RGD) in the first loop in combination with a randomized sequence (XXX) in the second loop. Screening of first-generation libraries for α5β1-binding peptides yielded a triple-digit nanomolar bicyclic α5β1-binder (CT3RGDcT3AYGCT3, IC50 = 406 nM). Next-generation libraries were designed by partially varying the structure of the strongest first-generation lead inhibitor and screened for improved affinities and selectivities for this receptor. In this way, we identified three high-affinity α5β1-binders (CT3RGDcT3AYJCT3, J = D-Leu, IC50 = 90 nM; CT3RGDcT3AYaCT3, IC50 = 156 nM; CT3RGDcT3AWGCT3, IC50 = 173 nM), of which one even showed a higher α5β1-affinity than the 32 amino acid benchmark peptide knottin-RGD (IC50 = 114 nM). Affinity for α5β1-integrin was confirmed by SPFS analysis showing a Kd of 4.1 nM for Cy5-labeled RGD-bicycle CT3RGDcT3AYJCT3 (J = D-Leu) and a somewhat higher Kd (9.0 nM) for Cy5-labeled knottin-RGD. The α5β1-bicycles, for example, CT3RGDcT3AYJCT3 (J = D-Leu), showed excellent selectivities over αvβ5 (IC50 ratio α5β1/αvβ5 between 50 ratios α5β1/αvβ3 between 0.090 and 0.157). In vitro staining of adipose-derived stem cells with Cy5-labeled peptides using confocal microscopy revealed strong binding of the α5β1-selective bicycle CT3RGDcT3AWGCT3 to integrins in their natural environment, illustrating the high potential of these RGD bicycles as markers for α5β1-integrin expression.

Divergent total syntheses of 10 yaequinolone-related natural products have been achieved for the first time by latestage C-H olefination of 3,4-dioxygenated 4-aryl-5-hydroxyquinolin-2(1H)-ones, core structures of this family of natural products. A robust synthetic methodology to construct the core structures has been established, and the C-H olefination reaction has been carried out with synthetically useful yields and high levels of site-selectivity under mild reaction conditions in the presence of a Pd/S,O-ligand catalyst.

Frustrated Lewis pairs (FLPs) combine a Lewis acid, an electron pair acceptor, and a Lewis base, an electron-pair donor, to access unique chemistry. Steric encumbrance of both components is utilised to prevent classical Lewis adduct formation, which preserves the reactivity of both the Lewis acidic and Lewis basic moieties and allows for synergistic activation of a plethora of small molecules, most notably H2 and CO2. This reactivity has been successfully applied to achieve metal-free hydrogenation of a variety of substrates including imines, ketones, and alkenes. However, the exact mechanism by which FLP systems activate small molecules is still a topic of debate. Gaining mechanistic insight into the functioning of these systems is of great importance to further explore their unique chemistry and unlock their full potential as organocatalysts. In this PhD thesis entitled “Radicals and London dispersion in frustrated Lewis pair chemistry” two highly important aspects that influence the mechanism and reactivity of FLP systems have been discussed: radical formation, and London dispersion forces. Firstly, a combination of experimental and computational analysis is used to demonstrate the different conditions under which radical formation within FLP systems occurs. Next, the influence of London dispersion on chemical transformation is examined, focusing on the formation of van der Waals complexes within FLP systems and effect this has on FLP reactivity.

Cyclic and multicyclic peptides are ubiquitous in Nature. They show interesting biological activities as for example antibacterial agents. Due to their constrained nature, they show improvements compared to their linear counterparts, such as higher metabolic stabilities, specificities and oral availabilities. Several methods have been developed to synthesize monocyclic peptides. Methods to further constrain peptides to bicyclic peptides have even found application in high-throughput library-based synthesis methods, such as phage display. While these advances have shown the importance of constraining a peptide to increase activity, there is still room for improvement. Adding peptide cycles, yielding tricyclic, or even higher multicycles, is a challenging objective where the current methodologies may fall short. In this thesis, the scaffold-assisted synthesis of tri-, tetra-, and pentacyclic peptides is described, using the sequential combination of CLiPS and oxime ligation as orthogonal ligation techniques. The CLiPS reaction is a well-known constraining technology, whereby nucleophilic cysteine thiolates react with scaffold-bound arylmethyl bromide electrophiles. Oxime ligation is a click-type reaction between an electrophilic aldehyde or ketone and a nucleophilic aminooxy group, forming an oxime linkage that can exhibit E/Z isomerism. There are two possible strategies to combine CLiPS with oxime ligation. In the first, the scaffold bears all electrophiles, while the peptides bear all nucleophiles. In the second strategy, the oxime groups are reversed, meaning that both the peptides and scaffolds contain both nucleophilic and electrophilic groups. Within this framework, our aim was to develop a one-pot procedure, to access isomerically pure multicyclic peptides.

The aim of this thesis was to develop novel and efficient methodologies to functionalize amine containing compounds. We have adopted different tactics to functionalize different amine substrates. In Chapter 2 , the combination of a monodentate directing group, triflyl protected amine, with pyridine- or quinoline-based external ligand to promote Pd-catalyzed γ-C(sp3)–H acetoxylation of aliphatic amines is described. Chapter 3 describes the non-directed highly para-selective olefination reaction of indolines and tetrahydroquinolines by using Pd/S,O-ligand catalysis under mild reaction conditions. This transformation shows broad substrate scope regarding indolines, tetrahydroquinolines and olefins. This chapter also contains examples for late-stage selective functionalization of complex molecules. In Chapter 4 , the methodology described in Chapter 3 is applied for the divergent total synthesis of yaequinolone related natural products. To achieve this goal, a reliable synthetic sequence for the preparation of 3,4-dioxygenated 5-hydroxy-4-aryl-quinolin-2(1H)-ones, which are the core structures of this family of natural products, is described. Then, by performing para-selective late-stage olefination on these core structures, we successfully realized the total synthesis of 11 yaequinolone related natural products.

In this paper, we highlight the synthesis of a variety of primary phosphine‐boranes (RPH2⋅BH3) from the corresponding dichlorophosphines, simply by using Li[BH4] as reductant and provider of the BH3 protecting group. The method offers facile access not only to alkyl‐ and arylphosphine‐boranes, but also to aminophosphine‐boranes (R2NPH2⋅BH3) that are convenient building blocks but without the protecting BH3 moiety thermally labile and notoriously difficult to handle. The borane‐protected primary phosphines can be doubly deprotonated using n‐butyllithium to provide soluble phosphanediides Li2[RP⋅BH3] of which the phenyl‐derivative Li2[PhP⋅BH3] was structurally characterized in the solid state., A range of differently substituted primary phosphine‐boranes (RPH2⋅BH3) are now accessible that as unprotected phosphines difficult to handle or even unstable. In particular, the synthesis of the aminophosphane‐boranes (R2NPH2⋅BH3) offers new opportunities to use as versatile building blocks in the syntheses of organophosphorus compounds.

Salt metathesis of 1‐methyl‐2,4,6‐triphenylphosphacyclohexadienyl lithium and chlorobis(pentafluorophenyl)borane affords a 1‐phospha‐7‐bora‐norbornadiene derivative 2. The C≡N triple bonds of nitriles insert into the P−B bond of 2 with concomitant C−B bond cleavage, whereas the C≡C bonds of phenylacetylenes react with 2 to form λ4‐phosphabarrelenes. Even though 2 must formally be regarded as a classical Lewis adduct, the C≡N and C≡C activation processes observed (and the mild conditions under which they occur) are reminiscent of the reactivity of frustrated Lewis pairs. Indeed, NMR and computational studies give insight into the mechanism of the reactions and reveal the labile nature of the phosphorus–boron bond in 2, which is also suggested by detailed NMR spectroscopic studies on this compound. Nitrile insertion is thus preceded by ring opening of the bicycle of 2 through P−B bond splitting with a low energy barrier. By contrast, the reaction with alkynes involves formation of a reactive zwitterionic methylphosphininium borate intermediate, which readily undergoes alkyne 1,4‐addition., Just like an FLP: A hetero‐norbornadiene incorporating phosphorus and boron atoms is accessible by a facile salt metathesis procedure. Although this compound represents a classical Lewis acid–base adduct, its reactivity is reminiscent of frustrated Lewis pairs. Reactions with nitriles and alkynes afford unusual insertion and 1,4‐addition products. In both cases, reversible P−B bond dissociation is of key mechanistic significance.

The common para regioselectivity in Pictet-Spengler reactions with dopamine derivatives is redirected to the ortho position by a simple change of solvents. In combination with a chiral auxiliary on nitrogen, this ortho-selective Pictet-Spengler produced the 1-benzyltetrahydroisoquinoline alkaloids ( S)-crassifoline and ( S)-norcrassifoline and the bioactive 1,2-dioxygenated tetrahydroprotoberberine alkaloids ( S)-govaniadine, ( S)-caseamine, and ( S)-clarkeanidine with high enantiopurity. Ortho/para ratios up to 89:19 and diastereomeric ratios up to 85:15 were obtained during formation of the B-ring. The general applicability of this solvent-directed regioselectivity was demonstrated with a second Pictet-Spengler reaction as required for C-ring formation of caseamine (o/p = 14:86 in trifluoroethanol) and clarkeanidine (o/p = 86:14 in toluene).

Inspired by the commercially available azoimidazolium dyes (e.g., Basic Red 51) that can be obtained from aryldiazonium salts and N‐heterocyclic carbenes, we developed the synthesis of a unique set of arylazophosphonium salts. A range of colours were obtained by applying readily tuneable phosphine donor ligands and para‐substituted aryldiazonium salts as nitrogen‐based Lewis acids. With cyclic voltammetry, a general procedure was designed to establish whether the reaction between a Lewis acid and a Lewis base occurs by single‐electron transfer or electron‐pair transfer.

Treatment of the preorganized frustrated Lewis pairs (FLPs) tBu2PCH2BPh2 (1) and o‐Ph2P(C6H4)BCat (Cat=catechol) (4) with 2‐methyloxirane, 2‐phenyloxirane and 2‐(trifluoromethyl)oxirane resulted in epoxide ring‐opening to yield the six‐ and seven‐membered heterocycles 2 a–c and 5 a–c, respectively. These zwitterionic products were characterized spectroscopically, and compounds 2 a, 2 b, 5 a and 5 c were structurally characterized by single‐crystal X‐ray structure analyses. Based on computational and kinetic studies, the mechanism of these reactions was found to proceed via activation of the epoxide by the Lewis acidic borane moiety followed by nucleophilic attack of the phosphine of a second FLP molecule. The resulting chain‐like intermediates afford the final cyclic products by ring‐closure and concurrent release of the second equivalent of FLP that behaves as catalyst in this reaction.

Syntheses, properties, and reactivity of N-heterocyclic carbene-phosphinidene adducts are reviewed. These adducts, formally built by combining a phosphinidene with a carbene, are characterized by high nucleophilicity at the phosphorus atom. The main types of reactivity these adducts exhibit are: Lewis-base reactivity towards main group and organic compounds as well as transition-metal complexes, substitution reactions at the phosphorus atom with main group compounds and transition-metal complexes, and phosphinidene transfer reactions resulting in C-P bond cleavage. These differ substantially from the classic phosphaalkenes.

An efficient cross‐dehydrogenative coupling of o‐xylene under neat conditions, which brings important industrial benefits towards the synthesis of a monomer used in polyimide resins, is reported. The catalyst based on the combination of Pd/N ligand/carboxylate=1:1:2 does not require a Cu cocatalyst and proceeds at 11 bar of O2 pressure. Evaluation of the deuterium kinetic isotope effect (KIE) provides evidence for three different rate‐determining steps, which depend on the reaction conditions (medium, temperature). Under the reported neat conditions, the dissociation of a carboxylate‐bridged dimer to generate a more reactive monometallic Pd species is proposed to be the rate‐limiting step.

In this work, we explored the coordination properties of the geminal phosphinoborane tBu2PCH2BPh2 (2) toward different gold(I) precursors. The reaction of 2 with an equimolar amount of the sulfur-based complex (Me2S)AuCl resulted in displacement of the SMe2 ligand and formation of linear phosphine gold(I) chloride 3. Using an excess of ligand 2, bisligated complex 4 was formed and showed dynamic behavior at room temperature. Changing the gold(I) metal precursor to the phosphorus-based complex, (Ph3P)AuCl impacted the coordination behavior of ligand 2. Namely, the reaction of ligand 2 with (Ph3P)AuCl led to the heterolytic cleavage of the gold–chloride bond, which is favored over PPh3 ligand displacement. To the best of our knowledge, 2 is the first example of a P/B-ambiphilic ligand capable of cleaving the gold–chloride bond. The coordination chemistry of 2 was further analyzed by density functional theory calculations.

The synthesis of thymosin-α1, an acetylated 28 amino acid long therapeutic peptide, via conventional chemical methods is exceptionally challenging. The enzymatic coupling of unprotected peptide segments in water offers great potential for a more efficient synthesis of peptides that are difficult to synthesize. Based on the design of a highly engineered peptide ligase, we developed a fully convergent chemo-enzymatic peptide synthesis (CEPS) process for the production of thymosin-α1via a 14-mer + 14-mer segment condensation strategy. Using structure-inspired enzyme engineering, the thiol-subtilisin variant peptiligase was tailored to recognize the respective 14-mer thymosin-α1 segments in order to create a clearly improved biocatalyst, termed thymoligase. Thymoligase catalyzes peptide bond formation between both segments with a very high efficiency (>94% yield) and is expected to be well applicable to many other ligations in which residues with similar characteristics (e.g. Arg and Glu) are present in the respective positions P1 and P1′. The crystal structure of thymoligase was determined and shown to be in good agreement with the model used for the engineering studies. The combination of the solid phase peptide synthesis (SPPS) of the 14-mer segments and their thymoligase-catalyzed ligation on a gram scale resulted in a significantly increased, two-fold higher overall yield (55%) of thymosin-α1 compared to those typical of existing industrial processes.

Guest Editors Dietrich Gudat, Andreas Orthaber, Chris Slootweg, and Rainer Streubel report the increasing importance of phosphorus chemistry in Europe and beyond, summarizing the contributions in this special issue in honor of the 70th and 80th birthdays of Professors Koop Lammertsma and Edgar Niecke.

The reactivity of the geminal phosphinoborane tBu2PCH2BPh2 towards terminal alkynes, nitriles and nitrilium salts is investigated. Terminal alkynes react via C–H bond splitting (deprotonation) resulting in the formation of phosphonium borates. In contrast, both nitriles and nitrilium salts undergo addition reactions resulting in the formation of five-membered heterocycles. All compounds were characterized by multinuclear NMR spectroscopy, and single-crystal X-ray structure determinations. Insight into the reaction mechanisms was gained by DFT calculations.

Research on chlorine-free conversions of P4 into organophosphorus compounds (OPCs) has a long track record, but methods that allow desirable, direct P−C bond formations have only recently emerged. These include the use of metal organyls, carbenes, carboradicals, and photochemical approaches. The versatile product scope enables the preparation of both industrially relevant organophosphorus compounds, as well as a broad range of intriguing new compound classes. Herein we provide a concise overview of recent breakthroughs and outline the acquired fundamental insights to aid future developments.

Phosphinidenes [R-P] are convenient P1 building blocks for the synthesis of a plethora of organophosphorus compounds. Thus far, transition-metal-complexed phosphinidenes have been used for their singlet ground-state reactivity to promote selective addition and insertion reactions. One disadvantage of this approach is that after transfer of the P1 moiety to the substrate, a challenging demetallation step is required to provide the free phosphine. We report a simple method that enables the Lewis acid promoted transfer of phenylphosphinidene, [PhP], from NHC=PPh adducts (NHC=N-heterocyclic carbene) to various substrates to produce directly uncoordinated phosphorus heterocycles that are difficult to obtain otherwise.

Strategies for the efficient synthesis of peptide macrocycles have been a long-standing goal. In this paper, we demonstrate the use of the peptide ligase termed omniligase-1 as a versatile and broadly applicable enzymatic tool for peptide cyclization. Several head-to-tail (multi) cyclic peptides have been synthesized, including the cyclotide MCoTI-II. Cyclization and oxidative folding of the cyclotide MCoTI-II were efficiently performed in a one-pot reaction on a 1-gram scale. The native cyclotide was isolated and the correct disulfide bonding pattern was confirmed by NMR structure determination. Furthermore, compatibility of chemo-enzymatic peptide synthesis (CEPS) using omniligase-1 with methods such as chemical ligation of peptides onto scaffolds (CLIPS) was successfully demonstrated by synthesizing a kinase-inhibitor derived tricyclic peptide. Our studies indicate that the minimal ring size for omniligase-1 mediated cyclization is 11 amino acids, whereas the cyclization of peptides longer than 12 amino acids proceeds with remarkable efficiency. In addition, several macrocycles containing non-peptidicbackbones (e.g., polyethylene glycol), isopeptide bonds (amino acid sidechain attachment) as well as d-amino acids could be efficiently cyclized.

The development of selective functionalization strategies of white phosphorus (P4) is important to avoid the current chlorinated intermediates. The use of transition metals (TMs) could lead to catalytic procedures, but these are severely hampered by the high reactivity and unpredictable nature of the tetrahedron. Herein, we report selective first steps by reacting P4 with a metal anion [Cp*Fe(CO)2]− (Cp*=C5(CH3)5), which, in the presence of bulky Lewis acids (LA; B(C6F5)3 or BPh3), leads to unique TM‐substituted LA‐stabilized bicyclo[1.1.0]tetraphosphabutanide anions [Cp*Fe(CO)2(η1‐P4⋅LA)]−. Their P‐nucleophilic site can be subsequently protonated to afford the transient LA‐free neutral butterflies exo,endo‐ and exo,exo‐Cp*Fe‐ (CO)2(η1‐P4H), allowing controllable stepwise metalate‐mediated functionalization of P4.

While the current supramolecular syntheses of [2]rotaxanes are generally efficient, the final product always retains the functional groups required for non-covalent preorganization. A short and high-yielding covalent-template-assisted approach is reported for the synthesis of a [2]rotaxane. A terephthalic acid template core preorganizes the covalently connected ring precursor fragments to induce a clipping-type cyclization over the thread moiety. Cleavage of the temporary ester bonds that connect the ring and thread fragments liberates the [2]rotaxane.

Highly stable iminophosphanes, obtained from alkylating nitriles and reaction of the resulting nitrilium ions with secondary phosphanes, were explored as tunable P-monodentate and 1,3-P,N bidentate ligands in rhodium complexes. X-ray crystal structures are reported for both k1 and k2 complexes with the counterion in one of them being an unusual anionic coordination polymer of silver triflate. The iminophosphane-based ruthenium(II)-catalyzed hydration of benzonitrile in 1,2-dimethoxyethane (180 degrees C, 3 h) and water (100 degrees C, 24 h) and under solvent free conditions (180 degrees C, 3 h) results in all cases in the selective formation of benzamide with yields of up to 96%, thereby outperforming by far the reactions in which the common 2-pyridyldiphenylphosphane is used as the 1,3-P,N ligand.