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Radical-induced 1,2-metallate rearrangements of boronate complexes are an emerging and promising class of reactions that allow multiple new bonds to be formed in a single, tuneable reaction step. These reactions involve the addition of an alkyl radical, typically generated from an alkyl iodide under photochemical activation, to a boronate complex to produce an α-boryl radical intermediate. From this α-boryl radical, there are two plausible reaction pathways that can trigger the product forming 1,2-metallate rearrangement: iodine atom transfer (IAT) or single electron transfer (SET). Previous steady state techniques have struggled to differentiate these pathways. Here we apply state-of-the-art time-resolved infrared absorption spectroscopy to resolve all the steps in the reaction cycle, by mapping production and consumption of the reactive intermediates over picosecond to millisecond timescales. We apply this technique to a recently reported reaction involving the addition of an electron-deficient alkyl radical to the strained σ‑bond of a bicyclo[1.1.0]butyl boronate complex to form a cyclobutyl boronic ester. We show that the previously proposed SET mechanism does not adequately account for the observed spectral and kinetic data. Instead, we demonstrate that IAT is the preferred pathway for this reaction and is likely to be operative for other reactions of this type.

A gram-scale synthesis of iboxamycin, an antibiotic candidate bearing a fused bicyclic amino acid residue, is presented. A pivotal transformation in the route involves an intramolecular hydrosilylation-oxidation sequence to set the ring-fusion stereocenters of the bicyclic scaffold. Other notable features of the synthesis include a high-yielding, highly diastereoselective alkylation of a pseudoephenamine amide, a convergent sp3-sp2 Negishi coupling, and a one-pot transacetalization-reduction reaction to form the target compound's oxepane ring. Implementation of this synthetic strategy has provided ample quantities of iboxamycin to allow for its in vivo profiling in murine models of infection.

A new reductive strategy for the stereo- and regioselective synthesis of functionalized isoquinuclidines has been developed. Pivoting on the chemoselective iridium(I)-catalyzed reductive activation of β,γ-unsaturated δ-lactams, the efficiently produced reactive dienamine intermediates readily undergo [4 + 2] cycloaddition reactions with a wide range of dienophiles, resulting in the formation of bridged bicyclic amine products. This new synthetic approach was extended to aliphatic starting materials, resulting in the efficient formation of cyclohexenamine products, and readily applied as the key step in the shortest (five-step) total synthesis of vinca alkaloid catharanthine to date, proceeding via its elusive biosynthetic precursor, dehydrosecodine.

Among the ribosomally synthesized and post-translationally modified peptide (RiPP) natural products, “graspetides” (formerly known as microviridins) contain macrocyclic esters and amides that are formed by ATP-grasp ligase tailoring enzymes using the side chains of Asp/Glu as acceptors and Thr/Ser/Lys as donors. Graspetides exhibit diverse patterns of macrocylization and connectivities exemplified by microviridins, that have a caged tricyclic core, and thuringin and plesiocin that feature a “hairpin topology” with cross-strand ω-ester bonds. Here, we characterize chryseoviridin, a new type of multicore RiPP encoded by Chryseobacterium gregarium DS19109 (Phylum Bacteroidetes) and solve a 2.44 Å resolution crystal structure of a quaternary complex consisting of the ATP-grasp ligase CdnC bound to ADP, a conserved leader peptide and a peptide substrate. HRMS/MS analyses show that chryseoviridin contains four consecutive five- or six-residue macrocycles ending with a microviridin-like core. The crystal structure captures respective subunits of the CdnC homodimer in the apo or substrate-bound state revealing a large conformational change in the B-domain upon substrate binding. A docked model of ATP places the γ-phosphate group within 2.8 Å of the Asp acceptor residue. The orientation of the bound substrate is consistent with a model in which macrocyclization occurs in the N- to C-terminal direction for core peptides containing multiple Thr/Ser-to-Asp macrocycles. Using systematically varied sequences, we validate this model and identify two- or three-amino acid templating elements that flank the macrolactone and are required for enzyme activity in vitro. This work reveals the structural basis for ω-ester bond formation in RiPP biosynthesis.

Stable bridged azaozonides can be selectively assembled via a catalyst-free three-component condensation of 1,5-diketones, hydrogen peroxide, and an NH-group source such as aqueous ammonia or ammonium salts. This procedure is scalable and can produce gram quantities of bicyclic stereochemically rich heterocycles. The new azaozonides are thermally stable and can be stored at room temperature for several months without decomposition and for at least 1 year at -10 °C. The chemical stability of azaozonides was explored for their subsequent selective transformations including the first example of an aminoperoxide rearrangement that preserves the peroxide group. The amino group in aminoperoxides has remarkably low nucleophilicity and does not participate in the usual amine alkylation and acylation reactions. These observations and the 15 pKa units decrease in basicity in comparison with a typical dialkyl amine are attributed to the strong hyperconjugative nN→σ*C-O interaction with the two antiperiplanar C-O bonds. Due to the weakness of the complementary nO→σ*C-N donation from the peroxide oxygens (a consequence of "inverse α-effect"), this interaction depletes electron density from the NH moiety, protects it from oxidation, and makes it similar in properties to an amide.

The first and asymmetric total synthesis of 4β-acetoxyprobotryane-9β,15α-diol, containing a rare and highly strained trans-fused bicyclo[3.3.0]octane ring system, has been achieved. The synthetically challenging [6-5-5] tricyclic ring system in the final product was efficiently and diastereoselectively synthesized via an asymmetric rhodium-catalyzed [4 + 2] cycloaddition reaction, followed by a unique benzilic acid type rearrangement under very mild conditions. The seven contiguous stereocenters were installed efficiently and diastereoselectively.

Stimuli-responsive unimolecular chirality switching is a highly intriguing topic because the molecular structure as well as its function can be adjusted simultaneously by a switching process. Herein, a novel acid/base-tunable unimolecular chirality switching system based on a pillar[5]azacrown pseudo[1]catenane is reported. The bicyclic pillar[5]azacrown pseudo[1]catenane PN4 is synthesized through fusing an azacrown ring onto one repeating unit of a pillar[5]arene. Protonation and deprotonation can reversibly regulate the conformational transformations of PN4 between self-inclusion and self-exclusion structures, which results in the chiroptical inversions of the pseudo[1]catenane. NMR spectra, circular dichroism spectra, and single-crystal structures demonstrate these processes. This pseudo[1]catenane is a novel pillararene-based unimolecular chirality switching system driven by acid/base responsiveness and reveals a new perspective on the supramolecular chirality chemistry of macrocycles.

We provide spectroscopic and computational evidence for a substantial change in structure and gas phase reactivity of Al3O4+ upon Fe-substitution, which is correctly predicted by multireference (MR) wave function calculations. Al3O4+ exhibits a cone-like structure with a central trivalent O atom (C3v symmetry). The replacement of the Al- by an Fe atom leads to a planar bicyclic frame with a terminal Al-O•- radical site, accompanied by a change from the Fe+III/O-II to the Fe+II/O-I valence state. The gas phase vibrational spectrum of Al2FeO4+ is exclusively reproduced by the latter structure, which MR wave function calculations correctly identify as the most stable isomer. This isomer of Al2FeO4+ is predicted to be highly reactive with respect to C-H bond activation, very similar to Al8O12+ which also features the terminal Al-O•- radical site. Density functional theory, in contrast, predicts a less reactive Al3O4+-like "isomorphous substitution" structure of Al2FeO4+ to be the most stable one, except for functionals with very high admixture of Fock exchange (50%, BHLYP).

We report a concise, stereocontrolled synthesis of the neuro- toxic sesquiterpenoid, (–)-picrotoxinin (1, PXN). The brevity of the route owes to regio- and stereoselective formation of the [4.3.0] bicyclic core by incorporation of a symmetrizing geminal dimethyl group at C5. Dimethylation then enables selective C–O bond formation in multiple intermediates. A series of strong bond (C–C and C–H) cleavages convert the C5 gem-dimethyl group to the C15 lactone of PXN.

Isolable compounds that contain π bonding without an underlying σ-bond framework (π-type single bonding) remain scarce. Herein we report the synthesis and properties of 1,3-diiodotetrasilabicyclo[1.1.0]butane

Benzene exhibits a rich photochemistry which can provide access to complex molecular scaffolds that are difficult to access with reactions in the electronic ground state. While benzene is aromatic in its ground state, it is antiaromatic in its lowest ππ* excited states. Herein, we clarify to what extent relief of excited-state antiaromaticity (ESAA) triggers a fundamental benzene photoreaction: the photoinitiated nucleophilic addition of solvent to benzene in acidic media leading to substituted bicyclo[3.1.0]hex-2-enes. The reaction scope was probed experimentally, and it was found that silyl-substituted benzenes provide the most rapid access to bicyclo[3.1.0]hexene derivatives, formed as single isomers with three stereogenic centers in yields up to 75% in one step. Two major mechanism hypotheses, both involving ESAA relief, were explored through quantum chemical calculations and experiments. The first mechanism involves protonation of excited-state benzene and subsequent rearrangement to bicyclo[3.1.0]hexenium cation, trapped by a nucleophile, while the second involves photorearrangement of benzene to benzvalene followed by protonation and nucleophilic addition. Our studies reveal that the second mechanism is operative. We also clarify that similar ESAA relief leads to puckering of S1-state silabenzene and pyridinium ion, where the photorearrangement of the latter is of established synthetic utility. Finally, we identified causes for the limitations of the reaction, information that should be valuable in explorations of similar photoreactions. Taken together, we reveal how the ESAA in benzene and 6π-electron heterocycles trigger photochemical distortions that provide access to complex three-dimensional molecular scaffolds from simple reactants.

Oxidative transpositions of bicyclic cyclopentenones mediated by selenium dioxide (SeO2) are disclosed. Treatment of Pauson–Khand reaction (PKR) products with SeO2 in the presence or absence of wat...

The first enantioselective synthesis of (−)-cajanusine is presented. Key features of the route include a rapid synthesis of the [4.2.0] bicyclooctane core by an enantioselective isomerization/stereoselective [2+2]-cycloaddition strategy as well as prominent use of catalytic methods for bond construction. The evolution of the approach is also presented that highlights unexpected roadblocks and how novel solutions were developed.

An asymmetric approach for the first total synthesis of (-)-rhodomollanol A, a highly oxidized diterpenoid, is described. The efficient synthetic strategy features three key transformations: (1) an oxidative dearomatization-induced (5 + 2) cycloaddition/pinacol-type 1,2-acyl migration cascade to build up the bicyclo[3.2.1]octane skeleton; (2) a retro-Dieckmann fragmentation/vinylogous Dieckmann cyclization cascade to assemble the bicyclo[3.3.0]octane subunit; and (3) a photo-Nazarov cyclization/intramolecular cycloetherification cascade to forge the 7-oxabicyclo[4.2.1]nonane core structure of the natural product.

A low-temperature, protecting-group-free oxidation of 2-substituted anilines has been developed to generate an electrophilic N-aryl nitrenoid intermediate that can engage in C-NAr bond formation to construct functionalized N-heterocycles. The exposure of 2-substituted anilines to PIFA and trifluoroacetic acid or 10 mol % Sc(OTf)3 triggers nitrenoid formation, followed by productive and selective C-NAr and C-C bond formation to yield spirocyclic- or bicyclic 3H-indoles or benzazepinones. Our experiments demonstrate the breadth of these oxidative processes, uncover underlying fundamental elements that control selectivity, and demonstrate how the distinct reactivity patterns embedded in N-aryl nitrenoid reactive intermediates can enable access to functionalized 3H-indoles or benzazepinones.

The oxadi-π-methane rearrangement of 2,4-cyclohexadienones to bicyclic ketones was found to proceed with high enantioselectivity (92-97% ee) in the presence of catalytic amounts of a chiral Lewis acid (15 examples, 52-80% yield). A notable feature of the transformation is the fact that it proceeds on the singlet hypersurface and that no triplet intermediates are involved. Rapid racemic background reactions were therefore avoided, and the catalyst loading could be kept low (10 mol %). Computational studies suggest that the enantioselectivity is determined within a Lewis acid bound singlet intermediate via a conical intersection. The utility of the method was demonstrated by a concise synthesis of the natural product trans-chrysanthemic acid.

The unusual reactivity of twisted amides has long been associated with the degree of amide distortion, though classical bridged bicyclic amides offer limited methods to further modify these parameters. Here, we report that the geometry and reactivity of a single twisted amide scaffold can be significantly modulated through remote substituent effects. Guided by calculated ground state geometries, a library of twisted amide derivatives was efficiently prepared through a divergent synthetic strategy. Kinetic and mechanistic investigations of these amides in the alkylation/halide-rebound ring-opening reaction with alkyl halides show a strong positive correlation between the electron donating ability of the substituent and distortion of the amide bond, leading to rates of nucleophilic substitution spanning nearly 2 orders of magnitude. The rate limiting step of the cascade sequence is found to be dependent on the nature of the substituent, and additional studies highlight the role of solvent polarity and halide ion on reaction pathway and efficiency.

Radical cascade cyclization reactions are highly attractive synthetic tools for the construction of polycyclic molecules in organic synthesis. While it has been successfully implemented in diastereoselective synthesis of natural products and other complex compounds, radical cascade cyclization faces a major challenge of controlling enantioselectivity. As the first application of metalloradical catalysis (MRC) for controlling enantioselectivity as well as diastereoselectivity in radical cascade cyclization, we herein report the development of a Co(II)-based catalytic system for asymmetric radical bicyclization of 1,6-enynes with diazo compounds. Through the fine-tuning of D(2)-symmetric chiral amidoporphyrins as the supporting ligands, the Co(II)-catalyzed radical cascade process, which proceeds in a single operation under mild conditions, enables asymmetric construction of multisubstituted cyclopropane-fused tetrahydrofurans bearing three contiguous stereogenic centers, including two all-carbon quaternary centers, in high yields with excellent stereoselectivities. Combined computational and experimental studies have shed light on the underlying stepwise radical mechanism for this new Co(II)-based cascade bicyclization that involves the relay of several Co-supported C-centered radical intermediates, including α-, β-, γ-, and ε-metalloalkyl radicals. The resulting enantioenriched cyclopropane-fused tetrahydrofurans that contain a trisubstituted vinyl group at the bridgehead, as showcased in several stereospecific transformations, may serve as useful intermediates for stereoselective organic synthesis. The successful demonstration of this new asymmetric radical process via Co(II)-MRC points out a potentially general approach for controlling enantioselectivity as well as diastereoselectivity in synthetically attractive radical cascade reactions.

Asymmetric allylic fluorination has proven to be a robust and efficient methodology with potential applications for the development of pharmaceuticals and practical synthesis for 18F-radiolabeling. A combined computational (dispersion-corrected DFT) and experimental approach was taken to interrogate the mechanism of the diene-ligated, iridium-catalyzed regio- and enantioselective allylic fluorination. Our group has shown that, in the presence of an iridium(I) catalyst and nucleophilic fluoride source (Et3N·3HF), allylic trichloroacetimidates undergo rapid fluoride substitution to generate allylic fluoride products with excellent levels of branched-to-linear ratios. Mechanistic studies reveal the crucial role of the trichloroacetimidate as a potent leaving group and ligand to enable conversion of racemic allylic trichloroacetimidates to the corresponding enantioenriched allylic fluorides, via a dynamic kinetic asymmetric transformation (DYKAT), in the presence of the chiral bicyclo[3.3.0]octadiene-ligated iridium catalyst.

Spiro- and bridged bicyclic structures are in demand for their sp3-rich frameworks that offer unique physiochemical properties and precisely positioned substituent groups. In order to rapidly access such molecules in a cross-coupling fashion we describe olefin amine (OLA) reagents for the transformation of aldehydes and ketones into all three topological types of bicyclic N-heterocycles: bridged, spiro-, and fused rings. The OLA reagents are easily prepared and allow the synthesis of complex molecular frameworks under operationally simple conditions that tolerate a wide array of functional groups. Investigations into the Mn or Fe promoted reaction pathway support a metal hydride hydrogen atom transfer (MH-HAT) to generate a C-centered radical that undergoes addition to an unactivated imine, leading to an N-centered radical. A catalytic cycle featuring regeneration of the metal catalyst by O2 and a second HAT to form the unprotected saturated N-heterocycle appears to be operative.

The first asymmetric total synthesis of the highly strained compound cerorubenic acid-III is reported. A type II intramolecular [5 + 2] cycloaddition allowed efficient and diastereoselective construction of the synthetically challenging bicyclo[4.4.1] ring system with a strained bridgehead (anti-Bredt) double bond in the final product. A unique transannular cyclization installed the vinylcyclopropane moiety with retention of the desired stereochemistry.

Two silylene molecules oxidatively react under formal [1 + 2 + 1]-cycloaddition to the C≡N bond of nitriles to yield 1-aza-2,4-disilabicyclo[1.1.0]butanes (L)(Cl)Si[μ-η1,2-NC(p-RC6H4)]Si(Cl)(L) (L = PhC(NtBu)2, R = CF3 (2), F (3), Cl (4), Br (5)). The strongly folded bicyclic SiCNSi cores in 2-5 feature inverted bridgehead carbon atoms and superelongated C-N bonds [1.745(12) to 1.801(2) A], exceeding the lengths of C-N single bonds in known silaaziridines by up to 23%. Detailed bonding analysis discloses C-N bonding interactions, sharing far-reaching similarities with the central C-C bond in [1.1.1]propellane.

Herein, we report that, by using chiral bicyclic bisborane catalysts, we have achieved the first highly regio-, diastereo-, and enantioselective direct asymmetric vinylogous Mannich reactions of acyclic α,β-unsaturated ketones. The strong Lewis acidity and steric bulk of the bisborane catalysts were essential for the observed high yields and selectivities.

Density functional theory was employed in order to elucidate the mechanism and factors that lead to the observed regioselectivity in the dialkylbiarylphosphine (Phos)/Pd-catalyzed C-C cleavage/cross-coupling of an N-fused bicyclo α-hydroxy-β-lactam, 1. We have identified that (a) a complex [(1)(Cs2CO3)]-PdL(PhBr) forms prior to a "base-mediated oxidative addition"; (b) Cs-carbonate (rather than a halide) deprotonates the alcohol substrate in the lowest energy pathway en route to Pd-alcoholate formation; (c) reactions using Phos ligands bearing OCF3 and OCF2H substituents on the "B"-ring are predicted to be selective toward proximal ring opening of 1; (d) steric repulsion between the bottom "B"-ring of the Phos ligand and the piperidine moiety of 1 controls the regioselectivity of the C-C cleavage followed by cross-coupling; and (e) the α- vs β-selective functionalization of the piperidine moiety in 1 is influenced by the bulkiness of the R2-substituent of the coupling partner. These studies will aid in the design of selective functionalizations of the piperidine moiety in 1.

Brasilane-type sesquiterpenes have been known for a long time, but their biosynthetic pathways and mechanisms remain elusive. Recently, two groups independently characterized a Trichoderma terpene cyclase that produces trichobrasilenol, a brasilane-type sesquiterpene, and a plausible biosynthetic pathway was proposed based on isotopic labeling experiments. In the proposed mechanism, the characteristic brasilane-type 5/6 bicyclic skeleton is synthesized from a 5/7/3 tricyclic intermediate via a complicated concerted reaction, including six chemical events of C-C σ bond metathesis and rearrangements, ring-contraction, π bond formation, and regioselective hydroxylation. However, our density functional theory (DFT) calculations do not support this mechanism. On the basis of DFT calculations, we propose a new pathway for trichobrasilenol biosynthesis, involving a multistep carbocation cascade in which cyclopropylcarbinyl cations in equilibrium with homoallyl cations play a pivotal role. This pathway and mechanism is in good agreement with previous biosynthetic studies on brasilane-type compounds and related terpenoids, including isotope-labeling experiments and byproducts analysis.

Difunctionalization reactions of C-C σ bonds have the potential to streamline access to molecules that would otherwise be difficult to prepare. However, the development of such reactions is challenging because C-C σ bonds are typically unreactive. Exploiting the high ring-strain energy of polycyclic carbocycles is a common strategy to weaken and facilitate the reaction of C-C σ bonds, but there are limited examples of highly strained C-C σ bonds being used in difunctionalization reactions. We demonstrate that highly strained bicyclo[1.1.0]butyl boronate complexes (strain energy: ca. 65 kcal/mol), which were prepared by reacting boronic esters with bicyclo[1.1.0]butyl lithium, react with electrophiles to achieve the diastereoselective difunctionalization of the strained central CC -bond of the bicyclo[1.1.0]butyl unit. The reaction shows broad substrate scope, with a range of different electrophiles and boronic esters being successfully employed to form a diverse set of 1,1,3-trisubstituted cyclobutanes (>50 examples) with high diastereoselectivity. The high diastereoselectivity observed has been rationalized based on a combination of experimental data and DFT calculations, which suggests that separate concerted and stepwise reaction mechanisms are operating depending upon the migrating substituent and electrophile used.

Herein, we describe a stereodivergent route to (±)-batzelladine D (2), (+)-batzelladine D (2), (−)-batzelladine D (2), and a series of stereochemical analogues and explore their antimicrobial activity for the first time. The concise synthetic approach enables access to the natural products in a sequence of 8–12 steps from readily available building blocks. Highlights of the synthetic strategy include gram-scale preparation of a late stage intermediate, pinpoint stereocontrol around the tricyclic skeleton, and a modular strategy that enables analogue generation. A key bicyclic β-lactam intermediate not only serves as the key controlling element for pyrrolidine stereochemistry but also serves as a preactivated coupling partner to install the ester side chain. The stereocontrolled synthesis allowed for the investigation of the antimicrobial activity of batzelladine D, demonstrating promising activity that is more potent for non-natural stereoisomers.

A stereoselective synthesis of the ribosome-binding antitumor antibiotic (-)-bactobolin A is reported. The presented approach makes effective use of (-)-quinic acid as a chiral pool starting material and substrate stereocontrol to establish the five contiguous stereocenters of (-)-bactobolin A. The key steps of the synthesis include a stereoselective vinylogous aldol reaction to introduce the unusual dichloromethyl substituent, a completely diastereoselective rhodium(II)-catalyzed C-H amination reaction to set the configuration of the axial amine, and an intramolecular alkoxycarbonylation to build the bicyclic lactone framework. The developed synthetic route was used to prepare 90 mg of (-)-bactobolin A trifluoroacetate in 10% overall yield.

Abiespiroside A (1), beshanzuenone C (2), and beshanzuenone D (3) belong to the Abies sesquiterpenoid family. Beshanzuenones C (2) and D (3) are isolated from the critically endangered Chinese fir tree species Abies beshanzuensis and demonstrated weak inhibiting activity against protein tyrosine phosphatase 1B (PTP1B). We describe herein the first total syntheses of these Abies sesquiterpenoids relying on the sustainable and inexpensive chiral pool molecule (+)-carvone. The syntheses feature a palladium-catalyzed hydrocarbonylative lactonization to install the 6,6-fused bicyclic ring system and a Dreiding-Schmidt reaction to build the oxaspirolactone moiety of these target molecules. Our chemical total syntheses of these Abies sesquiterpenoids have enabled (i) the validation of beshanzuenone C’s weak PTP1B inhibiting potency, (ii) identification of new synthetic analogs with promising and selective protein tyrosine phosphatase SHP2 inhibiting potency, and (iii) preparation of azide-tagged probe molecules for target identification via a chemoproteomic approach. The latter has resulted in the identification and evaluation of DNA polymerase epsilon subunit 3 (POLE3) as one of the novel cellular targets of these Abies sesquiterpenoids and their analogs. More importantly, via POLE3 inactivation by probe molecule 29 and knockdown experiment, we further demonstrated that targeting POLE3 with small molecules may be a novel strategy for chemosensitization to DNA damaging drugs such as etoposide in cancer.

We present here a library of protein mimetic bicyclic peptides. These nanosized structures exhibit rigid backbones and spatially diversifiable side chains. They present modular amino acids on all three linkages, providing access to a true 3D diversifiable chemical space. These peptides are synthesized through a Cu-catalyzed click reaction and a Ru-catalyzed ring-closing metathesis reaction. Their bicyclic topology can be reduced to a linear one, using Edman degradation and Pd-catalyzed deallylation reactions. The linearization approaches allow de novo sequencing through mass spectrometry methods. We demonstrate the function of a particular peptide that was identified through a high throughput screening against the E363-R378 epitope on the intrinsically disordered c-Myc oncoprotein. Intracellular delivery of this peptide could interfere with the c-Myc-mediated transcription and inhibit proliferation in a human glioblastoma cell line.

Linear silanes are efficient molecular wires due to strong σ-conjugation in the transoid conformation; however, the structure-function relationship for the conformational dependence of the single-molecule conductance of silanes remains untested. Here we report the syntheses, electrical measurements, and theoretical characterization of four series of functionalized cyclic and bicyclic silanes including a cyclotetrasilane, a cyclopentasilane, a bicyclo[2.2.1]heptasilane, and a bicyclo[2.2.2]octasilane, which are all extended by linear silicon linkers of varying length. We find an unusual variation of the single-molecule conductance among the four series at each linker length. We determine the relative conductance of the (bi)cyclic silicon structures by using the common length dependence of the four series rather than comparing the conductance at a single length. In contrast with the cyclic π-conjugated molecules, the conductance of σ-conjugated (bi)cyclic silanes is dominated by a single path through the molecule and is controlled by the dihedral angles along this path. This strong sensitivity to molecular conformation dictates the single-molecule conductance of σ-conjugated silanes and allows for systematic control of the conductance through molecular design.

Macrocyclic peptides are capable of binding to flat protein surfaces such as the interfaces of protein–protein interactions with antibody-like affinity and specificity, but generally lack cell permeability in order to access intracellular targets. In this work, we designed and synthesized a large combinatorial library of cell-permeable bicyclic peptides, in which the first ring consisted of randomized peptide sequences for potential binding to a target of interest, while the second ring featured a family of different cell-penetrating motifs, for both cell penetration and target binding. The library was screened against the IκB kinase α/β (IKKα/β)-binding domain of NF-κB essential modulator (NEMO), resulting in the discovery of several cell-permeable bicyclic peptides, which inhibited the NEMO-IKKβ interaction with low μM IC50 values. Further optimization of one of the hits led to a relatively potent and cell-permeable NEMO inhibitor (IC50 = 1.0 μM), which selectively inhibited canonical NF-κB signaling in mammalian cells and the proliferation of cisplatin-resistant ovarian cancer cells. The inhibitor provides a useful tool for investigating the biological functions of NEMO/NF-κB and a potential lead for further development of a novel class of anti-inflammatory and anticancer drugs.

A 10-step synthesis of the C25 steroid natural product cyclocitrinol from inexpensive, commercially available pregnenolone is reported. This synthesis features a biomimetic cascade rearrangement to efficiently construct the challenging bicyclo[4.4.1] A/B ring system, which enabled a gram-scale synthesis of the bicyclo[4.4.1] enone intermediate 18 in only nine steps. This work also provides experimental support for the biosynthetic origin of cyclocitrinol.

Septedine (2) is a hetidine type C20-diterpenoid alkaloid bearing an oxygenated heptacyclic scaffold. We have accomplished the first and asymmetric total synthesis of 2 and its 7-deoxy analogue 3. A functionalized tricyclic intermediate was prepared with excellent enantiopurity by using Carreira polyene cyclization. An unusual anionic Diels–Alder reaction was responsible for the construction of the bicyclo[2.2.2]octane. The α-methyl ketone was furnished by iridium-catalyzed allylic alcohol isomerization. Sanford Csp3–H oxidation was exploited to install the secondary hydroxy group of 2. The oxazolidinopiperidine was assembled by selective reductive amination and spontaneous N,O-ketalization at a final stage.

α-Amanitin is an extremely toxic bicyclic octapeptide isolated from the death-cap mushroom, Amanita phalloides. As a potent inhibitor of RNA polymerase II, α-amanitin is toxic to eukaryotic cells. Recent interest in α-amanitin arises from its promise as a payload for antibody-drug conjugates. For over 60 years, A. phalloides has been the only source of α-amanitin. Here we report a synthesis of α-amanitin, which surmounts the key challenges for installing the 6-hydroxy-tryptathionine sulfoxide bridge, enantioselective synthesis of (2 S,3 R,4 R)-4,5-dihydroxy-isoleucine, and diastereoselective sulfoxidation.

2,5-Disilylsubstituted germole dianions 1 react with hafnocene dichloride to give hafnocene-based bicyclo[2.1.1]hexene germylenes 3. Their formation proceeds via hafnocene-germylene complexes 2 that were identified by NMR and UV spectroscopy. Germylenes 3 are stabilized by homoconjugation between the empty 4p(Ge) orbital and the π-bond of the innercyclic C2═C3 double bond. This interaction can be understood as σ2, π-coordination of the butadiene part to the dicoordinated germanium atom that leaves the 16e– hafnocene moiety electronically unsaturated. We demonstrate that this new class of germylenes might serve as ligand to a variety of low-valent transition-metal complexes. The structure of the germylene ligand in complexes with Fe(0), Ni(0), and Au(I) and in reaction products with N-heterocyclic carbenes showed an intriguing structural flexibility that allows to accommodate different electronic situations at the ligating germanium atom. The origin of this structural adaptability is the interplay between ...

The enantioselective desymmetrization of carboxylic acids by chiral Brønsted base catalysis is reported, leading to bridged bicyclic lactones with up to 94% ee. Crystallographic analysis of a substrate-catalyst complex suggests an origin of stereocontrol, reminiscent of functional Brønsted bases in biological settings, and enabled reaction optimization. The products contain an all-carbon quaternary stereocenter, and can be derivatized to functionalized cyclopentanes.

Three-dimensional, small-ring scaffolds are very important in modern drug discovery to expand the available drug-like chemical space and to optimize drug candidates. Among them, bicyclo[1.1.1]pentane (BCP) is regarded as a high-value bioisostere for a phenyl ring or tert-butyl group; it provides an option to generate drug-like molecules with good passive permeability, high aqueous solubility, and improved metabolic stability, though the lack of methodology to functionalize BCP remains a significant challenge. Here we present an efficient method, developed with the aid of density functional theory calculations, for the synthesis of multifunctionalized BCP derivatives by means of a radical multicomponent carboamination of [1.1.1]propellane. This reaction features mild conditions, one-pot operation, and gram-scale synthetic capability, and opens up a unique and highly efficient route for the synthesis of multifunctionalized BCP derivatives, including synthetically useful 3-substituted BCP-amines.

An efficient enantioselective protocol has been reported to build highly oxygenated and densely substituted bicyclo[m.n.1] skeletons through intramolecular asymmetric α-arylative desymmetrization of 1,3-diketones. Employing Pd catalyst and FOXAP ligand, various bicyclo[m.n.1] skeleton with different size can be accessed with high enantio- and diastereoselectivities. Utilizing the present method as a key step, formal asymmetric total synthesis of the (-)-parvifoline has been demonstrated.

Stereodivergent asymmetric catalysis is an important technology that can allow efficient access to various stereoisomers of a given product with multiple stereocenters from the same set of starting materials, but its application to the synthesis of a highly strained cyclopropane compound has remained unexplored to date. We report here the first diastereodivergent enantioselective synthesis of bicyclic aminocyclopropanes by lanthanum-catalyzed asymmetric carboamination/annulation of cyclopropenes with aminoalkenes. This protocol features 100% atom efficiency, good yield (up to 90%), and high chemo- (up to >20:1) and stereoselectivity (up to >20:1 dr and 99% ee), constituting a unique route for the efficient synthesis of two different diastereoisomers of a given chiral bicyclic aminocyclopropane compound.

Bicyclo[3.3.1]nonane (BCN) polycations were synthesized by the reaction of the bivalent electrophile thiabicyclo[3.3.1]nonane dinitrate with a series of simple bis(pyridine) nucleophiles. Oligomers of moderate chain length were formed in a modular approach that tolerated the inclusion of functionalized and variable-length linkers between the pyridine units. Post-polymerization modification via copper-catalyzed azide-alkyne cyloaddition was enabled by the inclusion of terminal alkyne groups in these monomers. Most of the resulting polymers, new members of the polyionene class, inhibited the growth of bacteria at the μg/mL level and killed static bacterial cells at polymer concentrations of tens of ng/mL, with moderate to good selectivity with respect to lysis of red blood cells. While resistance to the BCN polymers was developed only very slowly over multiple passages, a degradable version of the polycation was observed to make E. coli cells more susceptible to other quaternary ammonium based antimicrobials. Solid substrates (glass and crystalline silicon) covalently functionalized with a representative BCN polycation were also able to repetitively kill bacteria in solution at high rates and with cleaning by simple sonication between exposures.

The preparation of a series of four analogues of the aminoglycoside antibiotics neomycin and paromomycin is described in which ring I, involved in critical binding interactions with the ribosomal target, is replaced by an apramycin-like dioxabicyclo[4.4.0]octane system. The effect of this modification is to lock the hydroxymethyl side chain of the neomycin or paromomycin ring I, as part of the dioxabicyclooctane ring, into either the gauche-gauche or the gauche-trans conformation (respectively axial or equatorial to the bicyclic system). The antiribosomal activity of these compounds is investigated with cell-free translation assays using both bacterial ribosomes and recombinant hybrid ribosomes carrying eukaryotic decoding A site cassettes. Compounds substituted with an equatorial hydroxyl or amino group in the newly formed ring are considerably more active than their axial diastereomers, lending strong support to crystallographically-derived models of aminoglycoside-ribosome interactions. One such bicyclic compound carrying an equatorial hydroxyl group has activity equal to that of the parent, yet displays better ribosomal selectivity, predictive of an enhanced therapeutic index. A paromomycin analog lacking the hydroxymethyl ring I side chain is considerably less active than the parent. Antibacterial activity against model Gram negative and Gram positive bacteria is reported, for selected compounds, as is activity against ESKAPE pathogens and recombinant bacteria carrying specific resistance determinants. Analogues with a bicyclic ring I carrying equatorial amino or hydroxyl groups mimicking the bound side chains of neomycin and paromomcyin, respectively, show excellent activity and, by virtue of their novel structure, retain this activity in strains that are insensitive to the parent compounds.

Cobalt(II)-based metalloradical catalysis has been successfully applied to radical bicyclization of allyl azidoformates to construct aziridine/oxazolidinone-fused bicyclic structures. The Co(II) complex of D2-symmetric chiral amidoporphyrin 3,5-DitBu-QingPhyrin has been identified as an effective metalloradical catalyst for the intramolecular radical aziridination of this type of carbonyl azides, allowing for high-yielding formation of synthetically useful chiral [3.1.0]-bicyclic aziridines with high diastereo- and enantioselectivity.

A straightforward strategy allows for the synthesis of storable bicyclic (alkyl)(amino)carbenes (BICAACs), which feature enhanced σ-donating and π-accepting properties compared to monocyclic (alkyl)(amino)carbenes (CAACs). Due to the bicyclo[2.2.2]octane skeleton, the steric environment around the carbene center is different from that of CAACs and similar to that observed in classical N-heterocyclic carbenes. The different electronic properties of BICAACs as compared to CAACs allow for ligand exchange reactions not only at a metal center, but also at main group elements.

A bicyclic olefin was discovered as a cocatalyst in a Cp*Rh(III)-catalyzed C-H bond amidation proceeding by an intramolecular amide transfer in N-phenoxyacetamide derivatives. Combining experimental and theoretical studies, we propose that the olefin promotes a Rh(III) intermediate to undergo oxidative addition into the O-N bond to form a Rh(V) nitrenoid species and subsequently direct the nitrenoid to add to the ortho position. The amide directing group plays a dual role as a cleavable coordinating moiety as well as an essential coupling partner for the C-H amidation. This methodology was successfully applied to the late-stage diversification of natural products and a marketed drug under mild conditions.

A grand challenge that crosses synthetic chemistry and biology is the scalable production of functional analogues of biomacromolecules. We have focused our attention on the use of deoxynucleoside building blocks bearing non-natural bases to develop a synthetic methodology that allows for the construction of high molecular weight deoxynucleotide polymers. Our six-membered cyclic phosphoester ring-opening polymerization strategy is demonstrated, herein, by an initial preparation of novel polyphosphoesters, comprised of butenyl-functionalized deoxyribonucleoside repeat units, connected via 3′,5′-backbone linkages. A thymidine-derived bicyclic monomer, 3′,5′-cyclic 3-(3-butenyl) thymidine ethylphosphate, was synthesized in two steps directly from thymidine, via butenylation and diastereoselective cyclization promoted by N,N-dimethyl-4-aminopyridine. Computational modeling of the six-membered 3′,5′-cyclic phosphoester ring derived from deoxyribose indicated strain energies at least 5.4 kcal/mol higher than tho...

Cyclic peptides are drawing wide attention as potential medium-sized modulators of biomolecular interactions with large binding surfaces. Simple but effective peptide cyclization methods are needed to construct cyclic peptide libraries by both peptide and nonpeptide chemists. Herein, we report a highly chemoselective and operation-simple method directly cyclizing unprotected peptides, in which ortho-phthalaldehyde (OPA) is found to react with the lysine/N-terminus and cysteine within one unprotected peptide sequence effectively to form the isoindole-bridged cyclic peptides. This reaction is carried out in the aqueous buffer and features tolerance of diverse functionalities, rapid and clean transformation, and operational simplicity. In addition, OPA peptide cyclization can also be combined with native chemical ligation-mediated cyclization to generate bicyclic peptides. Furthermore, the OPA peptide cyclization product can further react with the N-maleimide moiety in a one-pot manner to introduce additional functional motifs, like a fluorophore probe, biomolecules (e.g., glycan, peptide, or DNA). This OPA-cyclization method extends the toolbox for integrating postcyclization modification and bioconjugation into peptide cyclization with an all-in-one manner strategy.

A reversible polymer modification involving structural changes of the polymer chains was accomplished for the copolymer of CO2 and butadiene. The bicyclic structures were opened by hydrolysis and aminolysis reactions of the lactone moiety. For the hydrolysis product, the ring-closing of the ring-opened product was achieved by simply heating without any reagents or solvents. Nuclear magnetic resonance and matrix assisted laser desorption/ionization time-of-flight analyses and size-exclusion chromatography measurement of the polymer before ring-opening and after ring-closure suggested the retention of the polymer structure as well as the molecular weight and polydispersity during the reversible processes, proving that the modification can be performed without significant macroscopic changes of the polymer structure.

An Ir/spiro[4,4]-1,6-nonadiene-based phosphine-oxazoline ligand (SpinPHOX) complex-catalyzed double asymmetric hydrogenation of 3,6-dialkylidene-1,4-dimethylpiperazine-2,5-diones has been developed, providing efficient and practical access to a wide variety of chiral 3,6-disubstituted-2,5-diketopiperazines in high yields with exclusive cis-diastereo- and excellent enantioselectivities (>99% de, up to 98% ee). The synthetic utilities of the protocol have been demonstrated in a gram scale synthesis of 6a and efficient construction of chiral products 8, 14, and 17 as well as a 2-butenyl-bridged bicyclic diketopiperazine 10 and hydroxydiketopiperazine 11. With an analogous achiral Ir catalyst, the hydrogenation of enantiopure monohydrogenated intermediate 7a gave cis-6a as the only product, indicating that the second-step hydrogenation of the titled transformation is a chiral substrate controlled process. The reaction profile study for asymmetric hydrogenation (AH) of 5a revealed that the concentration of the monohydrogenation intermediate 7a remained at a low level (

Structurally complex and bioactive ent-kaurane diterpenoids have well-characterized biological functions and have drawn widespread attention from chemists for many decades. However, construction of highly oxidized forms of such diterpenoids still presents considerable challenges to synthetic chemists. Herein, we report the first total syntheses of C19 oxygenated spiro-lactone ent-kauranoids, including longirabdiol, longirabdolactone, and effusin. A concise synthesis of the common intermediate used for all three syntheses was enabled via three free-radical-based reactions: (1) a newly devised tandem decarboxylative cyclization/alkenylation sequence that forges the cis-19, 6-lactone concomitantly with vicinal alkenylation, (2) a Ni-catalyzed decarboxylative Giese reaction that constructs C10 quaternary center stereoselectively, and (3) a vinyl radical cyclization that generates a rigid bicyclo[3.2.1]octane. A series of late-stage oxidations from the common intermediate then provided each of the natural products in turn. Further biological evaluation of these synthetic natural products reveals broad anticancer activities.