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Molecules that contain a stereogenic phosphorus atom are crucial to medicine, agrochemistry and catalysis. While methods are available for the selective construction of various chiral organophosphorus compounds, catalytic enantioselective approaches for their synthesis are far less common. Given the vastness of possible substituent combinations around a phosphorus atom, protocols for their preparation should also be divergent, providing facile access not only to one but to many classes of phosphorus compounds. Here we introduce a catalytic and enantioselective strategy for the preparation of an enantioenriched phosphorus(V) centre that can be diversified enantiospecifically to a wide range of biologically relevant phosphorus(V) compounds. The process, which involves an enantioselective nucleophilic substitution catalysed by a superbasic bifunctional iminophosphorane catalyst, can accommodate a wide range of carbon substituents at phosphorus. The resulting stable, yet versatile, synthetic intermediates can be combined with a multitude of medicinally relevant O-, N- and S-based nucleophiles.

Halide recognition by supramolecular receptors and coordination complexes in water is a long-standing challenge. In this work, we report chloride binding in water and in competing media by pre-organised binuclear kinetically inert lanthanide complexes, bridged by flexible –(CH2)2 – and –(CH2)3 – spacers, forming [Ln2(DO3A)2C-2] and [Ln2(DO3A)2C-3], respectively. These hydrophilic, neutral lanthanide coordination complexes are shown to bind chloride with apparent association constants of up to 105 M−1 in water and in buffered systems. Hydroxide bridging was observed in these complexes at basic pH, which was proven to be overcome by chloride. Thus, these lanthanide complexes show promise towards chloride recognition in biology and beyond. The results described here have clearly identified a new area of anion coordination chemistry that is ripe for detailed exploration.

Tetramates derived from phenylserines are obtained chemoselectively and diastereoselectively, and after derivatisation as their amides, in some cases exhibit excellent antibacterial activity against Gram-positive bacteria.

Cyclic porphyrin oligomers have been studied as models for photosynthetic light-harvesting antenna complexes and as potential receptors for supramolecular chemistry. Here, we report the synthesis of unprecedented β,β-directly linked cyclic zinc porphyrin oligomers, the trimer (CP3) and tetramer (CP4), by Yamamoto coupling of a 2,3-dibromoporphyrin precursor. Their three-dimensional structures were confirmed by nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry, and single-crystal X-ray diffraction analyses. The minimum-energy geometries of CP3 and CP4 have propeller and saddle shapes, respectively, as calculated using density functional theory. Their different geometries result in distinct photophysical and electrochemical properties. The smaller dihedral angles between the porphyrin units in CP3, compared with CP4, result in stronger π-conjugation, splitting the ultraviolet–vis absorption bands and shifting them to longer wavelengths. Analysis of the crystallographic bond lengths indicates that the central benzene ring of the CP3 is partially aromatic [harmonic oscillator model of aromaticity (HOMA) 0.52], whereas the central cyclooctatetraene ring of the CP4 is non-aromatic (HOMA –0.02). The saddle-shaped structure of CP4 makes it a ditopic receptor for fullerenes, with affinity constants of (1.1 ± 0.4) × 105 M–1 for C70 and (2.2 ± 0.1) × 104 M–1 for C60, respectively, in toluene solution at 298 K. The formation of a 1:2 complex with C60 is confirmed by NMR titration and single-crystal X-ray diffraction.

Application of a direct ring-closing approach which exploits an intramolecular aldol reaction with a ketene silyl acetal onto a remote imide function leading to the core skeleton of UCS1025A and B effectively provides access to small library of substituted analogues; of interest is their complete lack of antibacterial activity against MRSA (Gram+) and E. coli (Gram–) bacterial strains.

Molecular photoswitches operating in the red to near-IR region with controllable thermal relaxation rates are attractive components for photo-regulating biological processes. Herein, we report the synthesis of red-shifted azobenzenes functionalised with the heavier chalcogens and halogens that meet these requirements for biological application; namely fatigue-resistant photo-switching with red and near IR light and functional handles for further functionalisation for application. We report robust periodic trends for the chalcogen and halogen azobenzene series, and exploit intramolecular chalcogen bonding to tune and redshift the absorption maxima, supported by photo-physical measurements and solid-state structural analysis. Remarkably, the rate of the Z → E thermal isomerisation can be tuned over timescales spanning 107 s by judicious choice of chalcogen and halogen substituents.

Chemoselective ring closure of malonamides gives oxazolidine- or imidazolidine fused tetramates, some of which show antibacterial activity against Gram positive organism; these occupy a well-defined region of chemical space.

The use of benzylic and allylic alcohols in HFIP solvent together with Ti(OiPr)4 has been shown to trigger a highly stereoselective polyene cyclisation cascade. Three new carbon-carbon bonds are made during the process and complete stereocontrol of up to five new stereogenic centers is observed. The reaction is efficient, has high functional group tolerance and is atom-economic generating water as a stoichiometric by-product. A new polyene substrate-class is employed, and subsequent mechanistic studies indicate a stereoconvergent mechanism. The products of this reaction can be used to synthesize steroid-analogues in a single step.

Selective oxidation of ring C–H bonds is an attractive route to functionalized cyclic amines, which are versatile intermediates in drug synthesis and important fragment molecules in drug discovery. Here we report a combined substrate and enzyme engineering approach to achieve enantioselective functionalization of all unactivated C–H bonds of azepane, azocane, 7-azabicyclo[2.2.1]heptane and 8-azaspiro[4.5]decane by cytochrome P450BM3 (CYP102A1). Different N-modifying groups provide product diversity at high enantioselectivity (up to 99% e.e.) from a panel of just 48 variants of P450BM3. Substrate docking into molecular-dynamics-simulated structures of enzyme variants is shown to be useful for designing mutations to increase enantioselectivity by disfavouring binding poses leading to the unwanted enantiomer, and to increase enzymatic activity by disfavouring non-productive poses from ten or so variants per generation. The synthetic application of remote C–H activation within cyclic amines is exemplified by the synthesis of anisodamine via enantioselective hydroxylation of N-Boc-nortropinone.

Bicyclic lactams can be prepared from diethyl aminomalonate and substituted benzaldehydes by formation of a dimerised imidazolidine cycloadduct followed by a Dieckmann ring closure. The resulting N,N-heterocycles are metal-chelating but show no antibacterial activity.

Yndiamides (bis-N-substituted alkynes) are valuable precursors to azacycles. Here we report a cycloisomerization/1,2-sulfonyl migration of alkynyl-yndiamides to form tetrahydropyrrolopyrroles, unprecedented heterocyclic scaffolds that are relevant to medicinal chemistry. This functional group tolerant transformation can be achieved using Au(I) catalysis that proceeds at ambient temperature, and a thermally promoted process. The utility of the products is demonstrated by a range of reactions to functionalize the fused pyrrole core.

2-Difluoromethoxyestratriene derivatives were designed to improve potency and in vivo stability of the drug candidate 2-methoxyestradiol (2ME2). Compound evaluation in vitro against the proliferation of MCF-7 and MDA MB-231 breast cancer cells, as inhibitors of tubulin polymerisation and also steroid sulfatase (STS) both in cell lysates and in whole cells, showed promising activities. In antiproliferative assays 2-difluoromethoxyestradiol was less potent than 2ME2, but its sulfamates were often more potent than the corresponding nonfluorinated analogues. The fluorinated bis-sulfamate is a promising anti-proliferative agent in MCF-7 cells (GI50 0.28 µM) vs the known 2- methoxyestradiol-3,17-O,O-bissulfamate (STX140, GI50 0.52 µM), confirming the utility of our approach. Compounds were also evaluated in the NCI 60-cell line panel and the fluorinated bissulfamate displayed very good overall activities with a sub-micromolar average GI50. It was a very potent STS inhibitor in whole JEG-3 cells (IC50 3.7 nM) similar to STX140 (4.2 nM) and additionally interferes with tubulin assembly in vitro and colchicine binding to tubulin. An Xray study of 2-difluoromethoxy-3-benzyloxyestra-1,3,5(10)-trien-17- one examined conformational aspects of the fluorinated substituent. The known related derivative 2-difluoromethyl-3-sulfamoyloxyestrone was evaluated for STS inhibition in whole JEG-3 cells and showed an excellent IC50 of 55 pM.

In this work an approach for the synthesis of furanocembranoid natural products containing the C-7,8-diol moiety is disclosed. This culminated in the first total synthesis of the natural product molestin E, together with ent-sinulacembranolide A and ent-sinumaximol A as well as a thorough exploration of their chemistry. Late-stage ring-closure of the C-7,8-diols to the corresponding epoxides was also demonstrated. Key features of this synthetic strategy include a stereoselective Baylis-Hillman reaction, ring-closing metathesis and Shiina macrolactonisation. Chiral-pool materials were deployed to ensure the desired absolute stereochemistry which was confirmed by late-stage single crystal X-ray diffraction.

The total synthesis of (–)-γ-lycorane (10 steps) and synthesis of (±)- γ-lycorane (8 steps) was completed from cyclohexenone. A new two step hydrogen borrowing alkylation of an aziridinyl alcohol, coupled with a Ph* deprotection/cyclisation procedure was developed for de novo formation of the fused 6,5 heterocyclic ring. This work is one of the first examples of hydrogen borrowing C-C bond formation being used as a key step in a total synthesis project.

Tropane derivatives are extensively used in medicine, but catalytic asymmetric methods for their synthesis are underexplored. Here we report Rh-catalyzed asymmetric Suzuki-Miyaura type cross-coupling reactions between a racemic N-Bocnortropane-derived allylic chloride and (hetero-)aryl-boronic esters. The reaction proceeds via an unexpected kinetic resolution, and the resolved enantiopure allyl chloride can undergo highly enantiospecific reactions with N, O, and S-containing nucleophiles. The method was applied in a highly stereoselective formal synthesis of YZJ-1139(1), a potential insomnia treatment that recently completed Phase II clinical trials. Our report represents an asymmetric catalytic method for the synthesis of YZJ-1139(1) and related compounds.

Herein we disclose a mild protocol for the reductive functionalisation of quinolinium and isoquinolinium salts. The reaction proceeds under transition-metal-free conditions as well as under rhodium catalysis with very low catalyst loadings (0.01 mol %) and uses inexpensive formic acid as the terminal reductant. A wide range of electrophiles, including enones, imides, unsaturated esters and sulfones, β-nitro styrenes and aldehydes are intercepted by the in situ formed enamine species forming a large variety of substituted tetrahydro(iso)quinolines. Electrophiles are incorporated at the C-3 and C-4 position for quinolines and isoquinolines respectively, providing access to substitution patterns which are not favoured in electrophilic or nucleophilic aromatic substitution. Finally, this reactivity was exploited to facilitate three types of annulation reactions, giving rise to complex polycyclic products of a formal [3+3] or [4+2] cycloaddition.

A Ti(Oi-Pr)4 promoted 5 or 6-endo-trig cyclisation to make nitrogen heterocycles is presented. The utilisation of HFIP as a key solvent enables the stereoselective preparation of di- & tri-substituted pyrrolidines and piperidines while forming a new C-C bond at the same time. The process is triggered by a cationic intermediate generated from an allylic or benzylic alcohol and leads to the simultaneous generation of both a C-C and a C-N bond in a single step. Notably, either 2,3-trans or 2,3-cis substituted heterocycles can be obtained by using a nucleophilic amine bearing different substituents. Lastly, the stereoselective synthesis of enantiopure products was achieved by using readily available enantiopure acyclic starting materials.

Tropane derivatives are extensively used in medicine, but catalytic asymmetric methods for their synthesis are underexplored. Here, we report Rh-catalyzed asymmetric Suzuki-Miyaura-type cross-coupling reactions between a racemic

Polyyne polyrotaxanes, encapsulated cyclocarbon catenanes and other fascinating mechanically interlocked carbonrich architectures should become accessible if masked alkyne equivalents (MAEs) can be developed that are large enough to prevent unthreading of a macrocycle, and that can be cleanly unmasked under mild conditions. Here we report the synthesis of a new bulky MAE based on a t-butylbicyclo[4.3.1]decatriene. This MAE was used to synthesize a polyyne [2]rotaxane and a maskedpolyyne [3]rotaxane by Cadiot-Chodkiewicz coupling. Glaser cyclooligomerization of the [2]rotaxane gave masked cyclocarbon catenanes. The unmasking behavior of the catenanes and rotaxanes was tested by photolysis at a range of UV wavelengths. Photochemical unmasking did not proceed cleanly enough to prepare extended encapsulated polyyne polyrotaxanes. We highlight the scope and challenges involved with this approach to interlocked carbon-rich architectures.

Through the use of model studies, an approach was conceived towards the synthesis of the taiwanschirin family of natural products. These are structurally complex compounds which represent highly challenging and biologically active targets for total synthesis. This work describes a successful synthesis of the complex taiwanschirin fused [8,6,5] core through a novel alkynylation reaction coupled with an intramolecular Heck reaction used to construct the 8-membered ring., Key enolate alkynylation and ring closing Heck reactions have been used to make the core of the taiwanschirin natural products.

Bicyclo[1.1.0]butanes (BCBs) are increasingly valued as intermediates in ‘strain release’ chemistry for the synthesis of substituted four membered rings and bicyclo[1.1.1]pentanes, with applications including bioconjugation processes. Variation of the BCB bridgehead substituents can be challenging due to the inherent strain of the bicyclic scaffold, often necessitating linear syntheses of specific BCB targets. Here we report the first palladium catalyzed cross-coupling on pre-formed BCBs which enables a ‘late stage’ diversification of the bridgehead position, and the conversion of the resultant products into a range of useful small ring building blocks.

The human 2‐oxoglutarate (2OG)‐dependent oxygenase aspartate/asparagine‐β‐hydroxylase (AspH) is a potential medicinal chemistry target for anticancer therapy. AspH is present on the cell surface of invasive cancer cells and accepts epidermal growth factor‐like domain (EGFD) substrates with a noncanonical (i. e., Cys 1–2, 3–4, 5–6) disulfide pattern. We report a concise synthesis of C‐3‐substituted derivatives of pyridine‐2,4‐dicarboxylic acid (2,4‐PDCA) as 2OG competitors for use in SAR studies on AspH inhibition. AspH inhibition was assayed by using a mass spectrometry‐based assay with a stable thioether analogue of a natural EGFD AspH substrate. Certain C‐3‐substituted 2,4‐PDCA derivatives were potent AspH inhibitors, manifesting selectivity over some, but not all, other tested human 2OG oxygenases. The results raise questions about the use of pyridine‐carboxylate‐related 2OG analogues as selective functional probes for specific 2OG oxygenases, and should aid in the development of AspH inhibitors suitable for in vivo use., Sights on a new target: A concise synthesis of C‐3‐substituted pyridine‐2,4‐dicarboxylic acid (2,4‐PDCA) derivatives is reported. The derivatives are potent inhibitors of the human 2‐oxoglutarate‐dependent oxygenase aspartate/asparagine‐β‐hydroxylase (AspH), which is a potential medicinal chemistry target for cancer therapy. This work constitutes a step towards the development of AspH inhibitors suitable for in vivo use.

A vinyl cyclopropane rearrangement embedded in an iridium‐catalyzed hydrogen borrowing reaction enabled the formation of substituted stereo‐defined cyclopentanes from Ph* methyl ketone and cyclopropyl alcohols. Mechanistic studies provide evidence for the ring‐expansion reaction being the result of a cascade based on oxidation of the cyclopropyl alcohols, followed by aldol condensation with the pentamethyl phenyl‐substituted ketone to form an enone containing the vinyl cyclopropane. Subsequent single electron transfer (SET) to this system initiates a rearrangement, and the catalytic cycle is completed by reduction of the new enone. This process allows for the efficient formation of diversely substituted cyclopentanes as well as the construction of complex bicyclic carbon skeletons containing up to four contiguous stereocentres, all with high diastereoselectivity., A vinyl cyclopropane/cyclopentene rearrangement process has been embedded in an iridium‐catalyzed hydrogen borrowing reaction, enabling the formation of substituted, stereo‐defined cyclopentanes containing up to four contiguous stereogenic centres—all from reaction of pentamethylphenyl (Ph*) methylketone and a variety of cyclopropyl alcohols.

A reagent‐controlled stereodivergent carbocyclisation of aryl aldimine‐derived, photocatalytically generated, α‐amino radicals possessing adjacent conjugated alkenes, affording either bicyclic or tetracyclic products, is described. Under net reductive conditions using commercial Hantzsch ester, the α‐amino radical species underwent a single stereoselective cyclisation to give trans‐configured amino‐indane structures in good yield, whereas using a substituted Hantzsch ester as a milder reductant afforded cis‐fused tetracyclic tetrahydroquinoline frameworks, resulting from two consecutive radical cyclisations. Judicious choice of the reaction conditions allowed libraries of both single and dual cyclisation products to be synthesised with high selectivity, notable predictability, and good‐to‐excellent yields. Computational analysis employing DFT revealed the reaction pathway and mechanistic rationale behind this finely balanced yet readily controlled photocatalytic system., Through judicious choice of reductant, a switchable diastereodivergent cyclisation of a single alkene‐tethered imine, to either a trans‐fused amino‐indane or a cis‐fused tetracyclic tetrahydroquinoline structure, is herein described.

Bicyclic lactams may be prepared from serine or cysteine and 2-methylpropanal; the resulting S,N-heterocycles are more stable than the corresponding O,N-heterocycles but both are synthetic intermediates capable of further elaboration.

Laurefurenynes C–F are four natural products isolated from Laurencia species whose structures were originally determined on the basis of extensive nuclear magnetic resonance experiments. On the basis of a proposed biogenesis, involving a tricyclic oxonium ion as a key intermediate, we have reassigned the structures of these four natural products and synthesized the four reassigned structures using a biomimetic approach demonstrating that they are the actual structures of the natural products. In addition, we have developed a synthesis of the enantiomers of the natural products laurencin and deacetyllaurencin from the enantiomer of (E)-laurefucin using an unusual retrobiomimetic strategy. All of these syntheses have been enabled by the use of tricyclic oxonium ions as pivotal synthetic intermediates.

The synthesis of a boryl-substituted germanium(II) cation, [Ge{B(NDippCH)2 }(IPrMe)]+ , (Dipp=2,6-diisopropylphenyl) featuring a supporting N-heterocyclic carbene (NHC) donor, has been explored through chloride abstraction from the corresponding (boryl)(NHC)GeCl precursor. Crystallographic studies in the solid state and UV/Vis spectra in fluorobenzene solution show that this species dimerizes under such conditions to give [(IPrMe){(HCNDipp)2 B}Ge=Ge{B(NDippCH)2 }(IPrMe)]2+ (IPrMe = 1,3-diisopropyl-4,5-dimethylimidazolin-2-ylidene), which can be viewed as an imidazolium-functionalized digermene. The dimer is cleaved in the presence of donor solvents such as [D8 ]thf or [D5 ]pyridine, to give monomeric adducts of the type [Ge{B(NDippCH)2 }(IPrMe)(L)]+ . In the case of the thf adduct, the additional donor is shown to be sufficiently labile that it can act as a convenient in situ source of the monomeric complex [Ge{B(NDippCH)2 }(IPrMe)]+ for oxidative bond-activation chemistry. Thus, [Ge{B(NDippCH)2 }(IPrMe)(thf)]+ reacts with silanes and dihydrogen, leading to the formation of GeIV products, whereas the cleavage of the N-H bond in ammonia ultimately yields products containing C-H and B-N bonds. The facile reactivity observed in E-H bond activation is in line with the very small calculated HOMO-LUMO gap (132 kJ mol-1 ).

A highly convergent strategy for the synthesis of the natural product (−)‐rubriflordilactone B, and the proposed structure of (−)‐pseudo‐rubriflordilactone B, is described. Late stage coupling of diynes containing the respective natural product FG rings with a common AB ring aldehyde precedes rhodium‐catalyzed [2+2+2] alkyne cyclotrimerization to form the natural product skeleton, with the syntheses completed in just one further operation. This work resolves the uncertainty surrounding the identity of pseudo‐rubriflordilactone B and provides a robust platform for further synthetic and biological investigations., Rubri B or not Rubri B? A convergent late‐stage fragment coupling and rhodium‐catalyzed [2+2+2] alkyne cyclotrimerization strategy provides access to the natural product (−)‐rubriflordilactone B, and the proposed structure of (−)‐pseudo‐rubriflordilactone B. Thus, the uncertainty surrounding the identity of pseudo‐rubriflordilactone B is resolved, and a synthetic platform that offers broad scope for the exploration of this natural product family is established.

The root microbiota is critical for agricultural yield, with growth-promoting bacteria able to solubilise phosphate, produce plant growth hormones, antagonise pathogens and fix N2. Plants control the microorganisms in their immediate environment and this is at least in part through direct selection, the immune system, and interactions with other microorganisms. Considering the importance of the root microbiota for crop yields it is attractive to artificially regulate this environment to optimise agricultural productivity. Towards this aim we express a synthetic pathway for the production of the rhizopine scyllo-inosamine in plants. We demonstrate the production of this bacterial derived signal in both Medicago truncatula and barley and show its perception by rhizosphere bacteria, containing bioluminescent and fluorescent biosensors. This study lays the groundwork for synthetic signalling networks between plants and bacteria, allowing the targeted regulation of bacterial gene expression in the rhizosphere for delivery of useful functions to plants., The root microbiota is critical for promoting crop yield. Here, the authors create a synthetic pathway for the production of the rhizopine scyllo-inosamine in Medicago truncatula and barley, and show its perception by rhizosphere bacteria for targeted regulation of bacterial gene expression.

Compounds containing one or more stereogenic phosphorous atoms in the P(V) oxidation state are important to chemistry, biology and medicine. These include marketed antiviral drugs such as Tenofovir alafenamide and Remdesivir, an effective treatment for Ebola which has also recently been approved for use against SARS-CoV-2 in the US. Existing approaches for the stereoselective synthesis of P-stereogenic centers, while elegant, remain mostly diastereoselective, with catalytic enantioselective approaches remaining limited in application. Accordingly, conceptually novel, broad-scope, catalytic strategies for the efficient stereoselective synthesis of diverse stereogenic P(V) containing compounds remain essential. To this end, we describe a novel enantioselective two-stage strategy, exploiting the first catalytic and highly enantioselective desymmetrisation of phosphonate esters. Pivoting on the stereocontrolled, sequential nucleophilic substitution of enantiotopic leaving groups from readily accessible pro-chiral P(V) precursors, a bifunctional iminophosphorane (BIMP) superbase catalyst was found to be essential in delivering reactive desymmetrised intermediates capable of downstream enantiospecific substitution. This uniquely modular, catalytic platform allows broad-scope, stereoselective access to a diverse library of chiral P(V) compounds including those with O, N and S-linkages.

Compounds containing one or more stereogenic phosphorous atoms in the P(V) oxidation state are important to chemistry, biology and medicine. These include marketed antiviral drugs such as Tenofovir alafenamide and Remdesivir, an effective treatment for Ebola which has also recently been approved for use against SARS-CoV-2 in the US. Existing approaches for the stereoselective synthesis of P-stereogenic centers, while elegant, remain mostly diastereoselective, with catalytic enantioselective approaches being limited in application. Accordingly, conceptually novel, broad-scope, catalytic strategies for the efficient stereoselective synthesis of diverse stereogenic P(V) containing compounds remain essential. To this end, we describe a novel enantioselective two-stage strategy, exploiting a catalytic and highly enantioselective desymmetrisation of phosphonate esters. Pivoting on the first stereocontrolled, sequential nucleophilic substitution of enantiotopic leaving groups from readily accessible pro-chiral P(V) precursors, a bifunctional iminophosphorane (BIMP) superbase catalyst was found to be essential in delivering reactive desymmetrised intermediates capable of downstream enantiospecific substitution. This uniquely modular, catalytic platform allows broad-scope, stereoselective access to a diverse library of chiral P(V) compounds including those with O, N and S-linkages.

CREBBP (CBP/KAT3A) and its paralogue EP300 (KAT3B) are lysine acetyltransferases (KATs) that are essential for human development. They each comprise 10 domains through which they interact with >400 proteins, making them important transcriptional co-activators and key nodes in the human protein-protein interactome. The bromodomains of CREBBP and EP300 enable the binding of acetylated lysine residues from histones and a number of other important proteins, including p53, p73, E2F, and GATA1. Here, we report a work to develop a high-affinity, small-molecule ligand for the CREBBP and EP300 bromodomains [(-)-OXFBD05] that shows >100-fold selectivity over a representative member of the BET bromodomains, BRD4(1). Cellular studies using this ligand demonstrate that the inhibition of the CREBBP/EP300 bromodomain in HCT116 colon cancer cells results in lowered levels of c-Myc and a reduction in H3K18 and H3K27 acetylation. In hypoxia (

Bicyclo[1.1.0]butanes (BCBs) are increasingly valued as intermediates in ‘strain release’ chemistry for the synthesis of substituted four membered rings and bicyclo[1.1.1]pentanes, with applications including bioconjugation processes. Variation of the BCB bridgehead substituents can be challenging due to the inherent strain of the bicyclic scaffold, often necessitating linear syntheses of specific BCB targets. Here we report the first palladium catalyzed cross-coupling on pre-formed BCBs which enables a ‘late stage’ diversification of the bridgehead position, and the conversion of the resultant products into a range of useful small ring building blocks., Bicyclo[1.1.0]butanes (BCBs) are valuable precursors to four-membered rings and bicyclo[1.1.1]pentanes, and useful bioconjugation agents. We describe a versatile approach to access 1,3-disubstituted BCBs, which are otherwise challenging to prepare.

Laurefurenynes C–F are four natural products isolated from Laurencia species whose structures were originally determined on the basis of extensive nuclear magnetic resonance experiments. On the basis of a proposed biogenesis, involving a tricyclic oxonium ion as a key intermediate, we have reassigned the structures of these four natural products and synthesized the four reassigned structures using a biomimetic approach demonstrating that they are the actual structures of the natural products. In addition, we have developed a synthesis of the enantiomers of the natural products laurencin and deacetyllaurencin from the enantiomer of (E)-laurefucin using an unusual retrobiomimetic strategy. All of these syntheses have been enabled by the use of tricyclic oxonium ions as pivotal synthetic intermediates., The synthesis and structural reassignment of laurefurenynes C–F has been achieved, with the new structures fitting with a proposed biosynthesis. Also reported is the synthesis of ent-laurencin and ent-deacetyllaurencin via a retrobiomimetic approach.

An efficient synthesis of enantioenriched hydroquinazoline cores via a novel bifunctional iminophosphorane squaramide catalyzed intramolecular aza-Michael reaction of urea-linked α,β-unsaturated esters is described. The methodology exhibits a high degree of functional group tolerance around the forming hydroquinazoline aryl core and wide structural variance on the nucleophilic N atom of the urea moiety. Excellent yields (up to 99%) and high enantioselectivities (up to 97 : 3 er) using both aromatic and less acidic aliphatic ureas were realized. The potential industrial applicability of the transformation was demonstrated in a 20 mmol scale-up experiment using an adjusted catalyst loading of 2 mol%. The origin of enantioselectivity and reactivity enhancement provided by the squaramide motif has been uncovered computationally using density functional theory (DFT) calculations, combined with the activation strain model (ASM) and energy decomposition analysis (EDA)., The activation of both aromatic and aliphatic ureas as N-centered nucleophiles in intramolecular Michael addition reactions to α,β-unsaturated esters was achieved under bifunctional iminophosphorane squaramide superbase catalysis.

The alkylation of a variety of ketones using 1° or 2° alcohols under hydrogen borrowing catalysis is described. Initial research focused on the α-alkylation of cyclopropyl ketones with higher 1° alcohols (i.e. larger than MeOH), leading to the formation of α-branched products. Our search for additional substrates with which to explore this chemistry led us to discover that di-ortho-substituted aryl ketones were also privileged scaffolds, with Ph∗ (C6Me5) ketones being the optimal choice. Further investigations revealed that this motif was crucial for alkylation with 2° alcohols forming β-branched products, which also provided an opportunity to study diastereoselective and intramolecular hydrogen borrowing processes.

An efficient synthesis of enantioenriched hydroquinazoline cores via a novel bifunctional iminophosphorane squaramide catalyzed intramolecular aza-Michael addition of urealinked α,β-unsaturated esters is described. The methodology exhibits a high degree of functional group tolerance around the forming hydroquinazoline aryl core and wide structural variance on the nucleophilic N atom of the urea moiety. Excellent yields (up to 99%) and high enantioselectivities (up to 97:3 e.r.) using both aromatic and less acidic aliphatic ureas were realized. The potential industrial applicability of the transformation was demonstrated in a 20 mmol scale-up experiment using an adjusted catalyst loading of 2 mol%. The origin of enantioselectivity and reactivity enhancement provided by the squaramide motif has been uncovered computationally using density functional theory (DFT) calculations, combined activation strain model (ASM) and energy decomposition analysis (EDA).