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The development of synthetic strategies for the preparation of bioisosteric compounds is a demanding undertaking in medicinal chemistry. Numerous strategies have been developed for the synthesis of bicyclo[1.1.1]pentanes (BCPs), bridge-substituted BCPs, and bicyclo[2.1.1]hexanes. However, progress on the synthesis of bicyclo[3.1.1]heptanes, which serve as meta-substituted arene bioisosteres, has not been previously explored. Herein, we disclose the first photoinduced [3σ + 2σ] cycloaddition for the synthesis of trisubstituted bicyclo[3.1.1]heptanes using bicyclo[1.1.0]butanes and cyclopropylamines. This transformation not only uses mild and operationally simple conditions but also provides unique meta-substituted arene bioisosteres. The applicability of this method is showcased by simple derivatization reactions.

Owing to its roles in human health and disease, the modification of nuclear, cytoplasmic, and mitochondrial proteins with O-linked N -acetylglucosamine residues (O-GlcNAc) has emerged as a topic of great interest. Despite the presence of O-GlcNAc on hundreds of proteins within cells, only two enzymes regulate this modification. One of these enzymes is O-GlcNAcase (OGA), a dimeric glycoside hydrolase that has a deep active site cleft in which diverse substrates are accommodated. Chemical tools to control OGA are emerging as essential resources for helping to decode the biochemical and cellular functions of the O-GlcNAc pathway. Here we describe rationally designed bicyclic thiazolidine inhibitors that exhibit superb selectivity and picomolar inhibition of human OGA. Structures of these inhibitors in complex with human OGA reveal the basis for their exceptional potency and show that they extend out of the enzyme active site cleft. Leveraging this structure, we create a high affinity chemoproteomic probe that enables simple one-step purification of endogenous OGA from brain and targeted proteomic mapping of its post-translational modifications. These data uncover a range of new modifications, including some that are less-known, such as O-ubiquitination and N-formylation. We expect that these inhibitors and chemoproteomics probes will prove useful as fundamental tools to decipher the mechanisms by which OGA is regulated and directed to its diverse cellular substrates. Moreover, the inhibitors and structures described here lay out a blueprint that will enable the creation of chemical probes and tools to interrogate OGA and other carbohydrate active enzymes.

Here we report the design of a superfast bioorthogonal ligation reactant pair comprising a sterically shielded, sulfonated tetrazole and bicyclo[6.1.0]non-4-yn-9-ylmethanol (BCN). The design involves placing a pair of water-soluble N -sulfonylpyrrole substituents at the C-phenyl ring of diphenyltetrazoles to favor the photoinduced cycloaddition reaction over the competing nucleophilic additions. First-principles computations provide vital insights into the origin of the tetrazole-BCN cycloaddition's superior kinetics compared to the tetrazole-spirohexene cycloaddition. The tetrazole-BCN cycloaddition also enabled rapid bioorthogonal labeling of glucagon receptors on live cells in as little as 15 s.

Amines containing bridged bicyclic carbon skeletons are desirable building blocks for medicinal chemistry. Herein, we report the conversion of bicyclo[1.1.1]pentan-1-amines to a wide range of polysubstituted bicyclo[3.1.1]heptan-1-amines through a photochemical, formal (4 + 2)-cycloaddition of an intermediate imine diradical. To our knowledge, this is the first reported method to convert the bicyclo[1.1.1]pentane skeleton to the bicyclo[3.1.1]heptane skeleton. Hydrolysis of the imine products gives complex, sp 3 -rich primary amine building blocks.

Expanding the repertoire of electrophiles with unique reactivity features would facilitate the development of covalent inhibitors with desirable reactivity profiles. We herein introduce bicyclo[1.1.0]butane (BCB) carboxylic amide as a new class of thiol-reactive electrophiles for selective and irreversible inhibition of targeted proteins. We first streamlined the synthetic routes to generate a variety of BCB amides. The strain-driven nucleophilic addition to BCB amides proceeded chemoselectively with cysteine thiols under neutral aqueous conditions, the rate of which was significantly slower than that of acrylamide. This reactivity profile of BCB amide was successfully exploited to develop covalent ligands targeting Bruton's tyrosine kinase (BTK). By tuning BCB amide reactivity and optimizing its disposition on the ligand, we obtained a selective covalent inhibitor of BTK. The in-gel activity-based protein profiling and mass spectrometry-based chemical proteomics revealed that the selected BCB amide had a higher target selectivity for BTK in human cells than did a Michael acceptor probe. Further chemical proteomic study revealed that BTK probes bearing different classes of electrophiles exhibited distinct off-target profiles. This result suggests that incorporation of BCB amide as a cysteine-directed electrophile could expand the capability to develop covalent inhibitors with the desired proteome reactivity profile.

Cycloaddition reactions provide an expeditious route to construct ring systems in a highly convergent and stereoselective manner. For a typical cycloaddition reaction to occur, however, the installation of multiple reactive functional groups (π-bonds, leaving group, etc.) is required within the substrates, compromising the overall efficiency or scope of the cycloaddition reaction. Here, we report a palladium-catalyzed [3 + 2] reaction that utilizes twofold C(sp 3 )-H activation to generate the three-carbon unit for formal cycloaddition. The initial β-C(sp 3 )-H activation of aliphatic amide, followed by maleimide insertion, triggers a relayed, second C(sp 3 )-H activation to complete a formal [3 + 2] cycloaddition. The key to success was the use of weakly coordinating amide as the directing group, as previous studies have shown that Heck or alkylation pathways are preferred when stronger-coordinating directing groups are used with maleimide coupling partners. To promote the amide-directed C(sp 3 )-H activation step, the use of pyridine-3-sulfonic acid ligands is crucial. This method is compatible with a wide range of amide substrates, including lactams, which lead to spiro-bicyclic products. The [3 + 2] product is also shown to undergo a reductive desymmetrization process to access chiral cyclopentane bearing multiple stereocenters with excellent enantioselectivity.

We established a methodology for initiating cross-linking of antibodies selectively on the cell surface through intermolecular copper-free click reactions facilitated by increased effective concentrations of antibodies binding to target antigens. Upon cross-linking of tetrazine- and bicyclononyne-modified trastuzumab on the surface of HER2-overexpressing cells, increased antibody uptake and activation of intracellular signaling were observed. Our findings demonstrate that the cross-linking reaction can significantly alter the biophysical properties of proteins, activating their unique functionalities on targeted cells to realize an increased cargo delivery and synthetic manipulation of cellular signaling.

Synthesis of bridged scaffolds via Type II cyclization constitutes substantial challenges due to the intrinsic ring strain accumulated in reaction transition states. Catalytic enantioselective Type II-cyclization methods are even rarer. Here, we describe a detailed study of developing a Rh(I)-catalyzed enantioselective intramolecular Type II cyclization of alkynes via C-C activation of cyclobutanones. This method offers a rapid approach to access a wide range of functionalized [3.3.1]-bridged bicycles along with an exocyclic olefin and an all-carbon quaternary stereocenter. Excellent enantioselectivity has been achieved using a combination of cationic rhodium(I) and DTBM-segphos. Attributed to the redox neutral and strong acid/base-free reaction conditions, high chemoselectivity has also been observed. For the oxygen-tethered substrates, the reaction can proceed at room temperature. In addition, partial kinetic resolution has been achieved for substrates with existing stereocenters, forging interesting chiral tricyclic scaffolds. The methylalkyne-derived substrates gave unexpected dimeric structures in good yield with excellent enantioselectivity and complete diastereoselectivity. Furthermore, the bridged bicyclic products can be diversely functionalized through simple transformations. Finally, mechanistic studies reveal a surprising reaction pathway that involves forming a metal-stabilized anti -Bredt olefin intermediate.

The rhizobacterium Serratia plymuthica 4Rx13 releases a unique polymethylated hydrocarbon (C 16 H 26 ) with a bicyclo[3.2.1]octadiene skeleton called sodorifen. Sodorifen production depends on a gene cluster carrying a C-methyltransferase and a terpene cyclase along with two enzymes of the 2- C-methyl-d-erythritol 4-phosphate (MEP) pathway of isoprenoid biosynthesis. Comparative analysis of wild-type and mutant volatile organic compound profiles revealed a C-methyltransferase-dependent C 16 alcohol called pre-sodorifen, the production of which is upregulated in the terpene cyclase mutant. The monocyclic structure of this putative intermediate in sodorifen biosynthesis was identified by NMR spectroscopy. In vitro assays with the heterologously expressed S. plymuthica C-methyltransferase and terpene cyclase demonstrated that these enzymes act sequentially to convert farnesyl pyrophosphate (FPP) into sodorifen via a pre-sodorifen pyrophosphate intermediate, indicating that the S-adenosyl methionine (SAM)-dependent C-methyltransferase from S. plymuthica exhibits unprecedented cyclase activity. In vivo incorporation experiments with 13 C-labeled succinate, l-alanine, and l-methionine confirmed a MEP pathway to FPP via the canonical glyceraldehyde-3-phosphate and pyruvate, as well as its SAM-dependent methylation in pre-sodorifen and sodorifen biosynthesis. 13 C{ 1 H} NMR spectroscopy facilitated the localization of 13 C labels and provided detailed insights into the biosynthetic pathway from FPP via pre-sodorifen pyrophosphate to sodorifen.

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.

The development of a gold(III) catalyzed direct enantioconvergent 1,5-enyne cycloisomerization and kinetic resolution reaction is described. The transformation results in highly enantioenriched bicyclo[3.1.0]hexenes at all levels of conversion, with no racemization or symmetrization taking place during the course of the reaction, and simultaneously affords optically enriched 1,5-enynes. This report marks the first highly enantioselective transformation catalyzed by a well-defined cationic gold(III) catalyst and demonstrates the unique potential of gold(III) complexes in enantioselective catalysis.

The development of new antimalarial therapeutics is necessary to address the increasing resistance to current drugs. Bicyclic azetidines targeting Plasmodium falciparum phenylalanyl-tRNA synthetase comprise one promising new class of antimalarials, especially due to their activities against three stages of the parasite's life cycle, but a lengthy synthetic route to these compounds may affect the feasibility of delivering new therapeutic agents within the cost constraints of antimalarial drugs. Here, we report an efficient synthesis of antimalarial compound BRD3914 (EC 50 = 15 nM) that hinges on a Pd-catalyzed, directed C(sp 3 )-H arylation of azetidines at the C3 position. This newly developed protocol exhibits a broad substrate scope and provides access to valuable, stereochemically defined building blocks. BRD3914 was evaluated in P. falciparum-infected mice, providing a cure after four oral doses.

A short enantioselective synthesis of 6-substituted cis-2,8-dioxabicyclo[3.3.0]octan-3-ones is described. The pivotal step is coupling of a tertiary radical generated directly from a tertiary alcohol with a 3-chloro-5-alkoxybutenolide. This strategy is applied toward scalable 14-15 step syntheses of three rearranged spongian diterpenoids: cheloviolenes A and B and dendrillolide C.

A compact and stable bicyclic bridged ketal was developed as a ligand for the asialoglycoprotein receptor (ASGPR). This compound showed excellent ligand efficiency, and the molecular details of binding were revealed by the first X-ray crystal structures of ligand-bound ASGPR. This analogue was used to make potent di- and trivalent binders of ASGPR. Extensive characterization of the function of these compounds showed rapid ASGPR-dependent cellular uptake in vitro and high levels of liver/plasma selectivity in vivo. Assessment of the biodistribution in rodents of a prototypical Alexa647-labeled trivalent conjugate showed selective hepatocyte targeting with no detectable distribution in nonparenchymal cells. This molecule also exhibited increased ASGPR-directed hepatocellular uptake and prolonged retention compared to a similar GalNAc derived trimer conjugate. Selective release in the liver of a passively permeable small-molecule cargo was achieved by retro-Diels-Alder cleavage of an oxanorbornadiene linkage, presumably upon encountering intracellular thiol. Therefore, the multicomponent construct described here represents a highly efficient delivery vehicle to hepatocytes.

Pantocin A (PA) is a member of the growing family of ribosomally encoded and post-translationally modified peptide natural products (RiPPs). PA is much smaller than most known RiPPs, a tripeptide with a tight bicyclic core that appears to be cleaved from the middle of a larger 30-residue precursor peptide. We show here that the enzyme PaaA catalyzes the double dehydration and decarboxylation of two glutamic acid residues in the 30-residue precursor PaaP. Further truncates of PaaP leader and follower peptide sequences demonstrate the different impacts of these two regions on PaaA-mediated tailoring and delineate an essential role for the follower sequence in the decarboxylation step. The crystal structure of apo PaaA is reported, allowing identification of structural features that set PaaA apart from other homologous enzymes that typically do not catalyze such extended post-translational chemistry. Together, these data reveal how additional chemistry can be extracted from a ubiquitous enzyme family toward ribosomally derived peptide natural product biosynthesis and suggest that more examples of such enzymes likely exist in untapped genomic space.

An efficient [4 + 3] cycloaddition reaction of D-A cyclopropanes with dienes has been successfully developed. The reaction proceeds well with various dienolsilyl ethers in the presence of Lewis acid, delivering a variety of cycloheptenes and [n,5,0]carbobicycles with excellent stereoselectivity. The asymmetric version of this reaction is also realized using a newly designed chiral Cy-TOX ligand, providing a new approach to access optically active cycloheptenes and [n,5,0]carbobicycles. Mechanisic study reveals that the reaction involves a stepwise pathway, which undergoes an unusual ring opening of five-membered [3 + 2] intermediate and sequential intramolecular cyclization to afford the thermodynamically stable [4 + 3] annulation product.

A self-assembled lyotropic liquid crystal (LLC) system exhibiting dynamic and reversible polymorphism was developed using the synthetic cyclic ethynylhelicene oligomers cyclobis[(M)-D-n] (n = 4 and 6), in which two oligomer moieties are connected by two flexible linkers. The cyclic molecular structure was designed to control aggregation properties ranging from the molecular level to the macroscopic level. The cyclic oligomer changed its structure between random coils and an intramolecular homo-double helix induced by temperature and solvents. In the presence of pseudoenantiomeric acyclic oligomers, cyclobis[(M)-D-4] formed trimolecular complexes with a total molecular weight of over 10 000 Da containing two intermolecular hetero-double helices. The trimolecular complex formation predominated over bimolecular complex formation. The trimolecular complex self-assembled at high concentrations and formed LLCs composed of anisotropically aligned fibers. The result is in contrast to acyclic systems, which form gels composed of randomly oriented fibers. The LLCs changed into turbid gels composed of randomly oriented bundles upon cooling, and the LLCs were regenerated by heating. This is a notable example of a self-assembled LLC system exhibiting dynamic and reversible polymorphism between two ordered structures in a closed system consisting of fully synthetic molecules.

Bridged bicyclic metallacyclopentenes generated from the [4 + 2] cycloaddition of metallacyclopentadienes with alkenes have been proposed as reactive intermediates in the course of [2 + 2 + 2] annulation reactions. Recently a collection of alkoxide-directed Ti-mediated [2 + 2 + 2] annulation reactions have been discovered for the synthesis of densely functionalized hydrindanes, where the bridged bicyclic metallacyclopentenes from intramolecular [4 + 2] were treated as fleeting intermediates en route to cyclohexadiene products formed by formal cheletropic extrusion of Ti(Oi-Pr)2. In studies aimed at understanding the course of these organometallic cascade reactions it was later discovered that these bridged bicyclic intermediates can be trapped by various elimination processes. Here, we have realized metallacycle-mediated annulation reactions for the assembly of angularly substituted decalins--structural motifs that are ubiquitous in natural products and molecules of pharmaceutical relevance. In addition to defining the basic annulation reaction we have discovered a surprising stability associated with the complex organometallic intermediates generated in the course of this coupling process and document here the ability to control the fate of such species. Ligand-induced cheletropic extrusion of the titanium center delivers cyclohexadiene-containing products, while several distinct protonation events have been identified to realize polycyclic products that contain three new stereocenters (one of which is the angular quaternary center that is a hallmark of alkoxide-directed titanium-mediated [2 + 2 + 2] annulation reactions). Examples of this metallacycle-mediated annulation reaction are provided to demonstrate that a range of stereodefined fused bicyclo[4.4.0]decanes are accessible, including those that contain aromatic and aliphatic substituents, and an empirical model is presented to accompany the observations made.

We report the first experimental evidence for the generation of highly strained cis,trans-cycloheptadienones by electrocyclic ring opening of 4,5-fused cyclobutenamides. In the presence of AlCl3, the cyclobutenamides rearrange to [2.2.1]-bicyclic ketones; DFT calculations provide evidence for a mechanism involving torquoselective 4π-electrocyclic ring opening to a cis,trans-cycloheptadienone followed by a Nazarov-like recyclization and a 1,2-alkyl shift. Similarly, 4,6-fused cyclobutenamides undergo AlCl3-catalyzed rearrangements to [3.2.1]-bicyclic ketones through cis,trans-cyclooctadienone intermediates. The products can be further elaborated via facile cascade reactions to give complex tri- and tetracyclic molecules.

Aromatic hydrogenation is a challenging transformation typically requiring alkali or transition metal reagents and/or harsh conditions to facilitate the process. In sharp contrast, the aromatic heterocycle 2,4,6-tri-tert-butyl-1,3,5-triphosphabenzene is shown to be reduced under 4 atm of H2 to give [3.1.0]bicylo reduction products, with the structure of the major isomer being confirmed by X-ray crystallography. NMR studies show this reaction proceeds via a reversible 1,4-H2 addition to generate an intermediate species, which undergoes an irreversible suprafacial hydride shift concurrent with P-P bond formation to give the isolated products. Further, para-hydrogen experiments confirmed the addition of H2 to triphosphabenzene is a bimolecular process. Density functional theory (DFT) calculations show that facile distortion of the planar triphosphabenzene toward a boat-conformation provides a suprafacial combination of vacant acceptor and donor orbitals that permits this direct and uncatalyzed reduction of the aromatic molecule.

We have prepared two new diastereoisomeric 2-aza-5-phosphabicyclo[2.2.1]heptanes from naturally occurring trans-4-hydroxy-L-proline in six chemical operations. These syntheses are concise and highly efficient, with straightforward purification. When we used these chiral phosphines as catalysts for reactions of γ-substituted allenoates with imines, we obtained enantiomerically enriched pyrrolines in good yields with excellent enantioselectivities. These two diastereoisomeric phosphines functioned as pseudoenantiomers, providing their chiral pyrrolines with opposite absolute configurations.

Modulation of the complex reactivity of cyclohexenylidene malononitriles using diverse β-aryl-substituted enals and proper organocatalytic modalities resulted in divergent asymmetric reaction patterns to furnish angularly fused or bridged carbabicyclic frameworks. In particular, use of remotely enolizable dicyanodienes 1, under one-pot sequential amine/NHC catalysis, led to [3 + 2] cycloaddition to afford ε,δ-bonded spiro[4.5]decanone structures 5. Alternatively, modifying the standard amine catalysis by adding a suitable chemical stimulus (p-nitrophenol cocatalyst) switched the reactivity decidedly toward a domino [4 + 2] cycloaddition to afford γ',δ-bonded bicyclo[2.2.2]octane carbaldehydes 8. Products invariably formed in good yields, with rigorous chemo-, regio-, diastereo-, and enantiocontrol. Experimental evidence, including carbon isotope effects measured by (13)C NMR, were indicative of the rate (and stereochemistry) determining step of these transformations and suggested a stepwise mechanism for the [4 + 2] cycloadditive pathway.

Electrocyclic ring opening of 4,6-fused cyclobutenamides 1 under thermal conditions leads to cis,trans-cyclooctadienones 2-E,E as transient intermediates, en route to 5,5-bicyclic products 3. Theoretical calculations predict that 4,5-fused cyclobutenamides should likewise undergo thermal ring opening, giving cis,trans-cycloheptadienones, but in this case conversion to 5,4-bicyclic products is thermodynamically disfavored, and these cyclobutenamides instead rearrange to vinyl cyclopentenones.

Angularly substituted trans-fused hydroindanes are now accessible by the direct and convergent union of trimethylsilyl (TMS)-alkynes with 4-hydroxy-1,6-enynes by a process that forges three C-C bonds, one C-H bond, and two new stereocenters. The annulation is proposed to proceed by initial formation of a Ti-alkyne complex (with a TMS-alkyne) followed by regioselective alkoxide-directed coupling with the enyne, stereoselective intramolecular cycloaddition, elimination of phenoxide, 1,3-metallotropic shift, and stereoselective protonation of the penultimate allylic organometallic intermediate. Several examples are given to demonstrate the compatibility of this reaction with substrates bearing aromatic and aliphatic substituents, and an empirical model is presented to accompany the stereochemical observations.

Protein sulfenic acids are formed by the reaction of biologically relevant reactive oxygen species with protein thiols. Sulfenic acid formation modulates the function of enzymes and transcription factors either directly or through the subsequent formation of protein disulfide bonds. Identifying the site, timing, and conditions of protein sulfenic acid formation remains crucial to understanding cellular redox regulation. Current methods for trapping and analyzing sulfenic acids involve the use of dimedone and other nucleophilic 1,3-dicarbonyl probes that form covalent adducts with cysteine-derived protein sulfenic acids. As a mechanistic alternative, the present study describes highly strained bicyclo[6.1.0]nonyne (BCN) derivatives as concerted traps of sulfenic acids. These strained cycloalkynes react efficiently with sulfenic acids in proteins and small molecules yielding stable alkenyl sulfoxide products at rates more than 100× greater than 1,3-dicarbonyl reagents enabling kinetic competition with physiological sulfur chemistry. Similar to the 1,3-dicarbonyl reagents, the BCN compounds distinguish the sulfenic acid oxoform from the thiol, disulfide, sulfinic acid, and S-nitrosated forms of cysteine while displaying an acceptable cell toxicity profile. The enhanced rates demonstrated by these strained alkynes identify them as new bioorthogonal probes that should facilitate the discovery of previously unknown sulfenic acid sites and their parent proteins.

The asymmetric total syntheses of the natural products (+)- and (-)-frondosin B and (+)-frondosin A are reported based on a diastereoselective cycloaddition between tetrabromocyclopropene and an annulated furan to provide a highly functionalized common building block. The bridged bicyclic intermediate could be stereo- and chemoselectively manipulated to produce the two structurally distinct members of the frondosins. Both syntheses feature regioselective palladium-coupling reactions and an unprecedented phosphine-mediated ether bridge cleavage. Surprisingly, the planned enantioselective synthesis of frondosin B led to the opposite epimer of the natural product, suggesting an unusual late stage stereoinversion at C8. Frondosin A, but not frondosin B, was shown to have selective antiproliferative activity against several B-cell lines.

Polyprenylated polycyclic acylphloroglucinols (PPAP) are a constantly growing class of natural products that exhibit a common bicyclo[3.3.1]nonatrione core and consist of currently more than 200 members. A subclassification among the various natural products of this class includes the position of the exocyclic acyl group, the prenylation grade of the core, and the relative configuration at C-7 within the core. About 10% of the reported structures, however, possess an additional chiral center at C-6. Herein we describe a straightforward access to guttiferone A and epi-guttiferone A, in which full control of stereoselectivity is achieved via conformational control, and a strict separation of framework decorating from framework constructing operations sets the stage for a short 13-step synthesis.

Members of the catechol diether class are highly potent non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs). The most active compounds yield EC50 values below 0.5 nM in assays using human T-cells infected by wild-type HIV-1. However, these compounds such as rilpivirine, the most recently FDA-approved NNRTI, bear a cyanovinylphenyl (CVP) group. This is an uncommon substructure in drugs that gives reactivity concerns. In the present work, computer simulations were used to design bicyclic replacements for the CVP group. The predicted viability of a 2-cyanoindolizinyl alternative was confirmed experimentally and provided compounds with 0.4 nM activity against the wild-type virus. The compounds also performed well with EC50 values of 10 nM against the challenging HIV-1 variant that contains the Lys103Asn/Tyr181Cys double mutation in the RT enzyme. Indolyl and benzofuranyl analogues were also investigated; the most potent compounds in these cases have EC50 values toward wild-type HIV-1 near 10 nM and high-nanomolar activities toward the double-variant. The structural expectations from the modeling were much enhanced by obtaining an X-ray crystal structure at 2.88 Å resolution for the complex of the parent 2-cyanoindolizine 10b and HIV-1 RT. The aqueous solubilities of the most potent indolizine analogues were also measured to be ~40 μg/mL, which is similar to that for the approved drug efavirenz and ~1000-fold greater than for rilpivirine.

Protein-protein interactions represent a new class of exciting but challenging drug targets, because their large, flat binding sites lack well-defined pockets for small molecules to bind. We report here a methodology for chemical synthesis and screening of large combinatorial libraries of bicyclic peptides displayed on rigid small-molecule scaffolds. With planar trimesic acid as the scaffold, the resulting bicyclic peptides are effective for binding to protein surfaces such as the interfaces of protein-protein interactions. Screening of a bicyclic peptide library against tumor necrosis factor-α (TNFα) identified a potent antagonist that inhibits the TNFα-TNFα receptor interaction and protects cells from TNFα-induced cell death. Bicyclic peptides of this type may provide a general solution for inhibition of protein-protein interactions.

The synthesis, crystallization, single crystal X-ray structure, and solid state dynamics of molecular rotor 3 provided with a high symmetry order and relatively cylindrical bicyclo[2.2.2]octane (BCO) rotator linked to mestranol fragments were investigated in this work. By use of solid state (13)C NMR, three rotating fragments were identified within the molecule: the BCO, the C19 methoxy and the C18 methyl groups. To determine the dynamics of the BCO group in crystals of 3 by variable temperature (1)H spin-lattice relaxation (VT (1)H T1), we determined the (1)H T1 contributions from the methoxy group C19 by carrying out measurements with the methoxy-deuterated isotopologue rotor 3-d6. The contributions from the quaternary methyl group C18 were estimated by considering the differences between the VT (1)H T1 of mestranol 8 and methoxy-deuterated mestranol 8-d3. From these studies it was determined that the BCO rotator in 3 has an activation energy of only 1.15 kcal mol(-1), with a barrier for site exchange that is smaller than those of methyl (E(a) = 1.35 kcal mol(-1)) and methoxy groups (E(a) = 1.92 kcal mol(-1)), despite their smaller moments of inertia and surface areas.

The rod-like molecule bis((4-(4-pyridyl)ethynyl)bicyclo[2.2.2]oct-1-yl)buta-1,3-diyne, 1, contains two 1,4-bis(ethynyl)bicyclo[2.2.2]octane (BCO) chiral rotators linked by a diyne fragment and self-assembles in a one-dimensional, monoclinic C2/c centrosymmetric structure where two equilibrium positions with large occupancy imbalance (88% versus 12%) are identified on a single rotor site. Combining variable-temperature (70-300 K) proton spin-lattice relaxation, (1)H T1(-1), at two different (1)H Larmor frequencies (55 and 210 MHz) and DFT calculations of rotational barriers, we were able to assign two types of Brownian rotators with different activation energies, 1.85 and 6.1 kcal mol(-1), to the two (1)H spin-lattice relaxation processes on the single rotor site. On the basis of DFT calculations, the low-energy process has been assigned to adjacent rotors in a well-correlated synchronous motion, whereas the high-energy process is the manifestation of an abrupt change in their kinematics once two blades of adjacent rotors are seen to rub together. Although crystals of 1 should be second harmonic inactive, a large second-order optical response is recorded when the electric field oscillates in a direction parallel to the unique rotor axle director. We conclude that conformational mutations by torsional interconversion of the three blades of the BCO units break space-inversion symmetry in sequences of mutamers in dynamic equilibrium in the crystal in domains at a mesoscopic scale comparable with the wavelength of light used. A control experiment was performed with a crystalline film of a similar tetrayne molecule, 1,4-bis(3-((trimethylsilyl)ethynyl)bicyclo[1.1.1]pent-1-yl)buta-1,3-diyne, whose bicyclopentane units can rotate but are achiral and produce no second-order optical response.

Bicyclic peptide ligands were found to have good binding affinity and target specificity. However, the method applied to generate bicyclic ligands based on phage-peptide alkylation is technically complex and limits its application to specialized laboratories. Herein, we report a method that involves a simpler and more robust procedure that additionally allows screening of structurally more diverse bicyclic peptide libraries. In brief, phage-encoded combinatorial peptide libraries of the format X(m)CX(n)CX(o)CX(p) are oxidized to connect two pairs of cysteines (C). This allows the generation of 3 × (m + n + o + p) different peptide topologies because the fourth cysteine can appear in any of the (m + n + o + p) randomized amino acid positions (X). Panning of such libraries enriched strongly peptides with four cysteines and yielded tight binders to protein targets. X-ray structure analysis revealed an important structural role of the disulfide bridges. In summary, the presented approach offers facile access to bicyclic peptide ligands with good binding affinities.

Acid treatment of densely substituted 2-silyl-1,2-dihydropyridines provides a new and convenient entry to reactive azomethine ylides that can (1) be protonated and reduced with high stereoselectivity to give piperidines, (2) participate in [3 + 2] dipolar cycloaddition to give tropanes, and (3) undergo a Nazarov-like 6-π electrocyclization that upon reduction give 2-azabicyclo[3.1.0] systems.

A modular, 18-step total synthesis of hyperforin is described. The natural product was quickly accessed using latent symmetry elements, whereby a group-selective, Lewis acid-catalyzed epoxide-opening cascade cyclization was used to furnish the bicyclo[3.3.1]nonane core and set two key quaternary stereocenters.

A rhodium-catalyzed dehydrogenation protocol for the conversion of 3,5-diarylcyclopentenones to the corresponding 2,4-diarylcyclopentadienones has been developed. With this protocol, analogues of the cytotoxic agent chamaecypanone C have been synthesized via Diels-Alder cycloaddition between the cyclopentadienones and in situ-generated o-quinols. Biological evaluation of these analogues revealed a compound with higher activity as a microtubule inhibitor and cytotoxic agent in comparison with the parent structure.

Stereoselectivities of the dihydroxylations of cis-bicyclo[3.3.0]octene intermediates for a projected total synthesis of chromodorolide A have been explored experimentally. The reaction occurs unexpectedly on the apparently more hindered (concave) face; this result has been explained through computational studies using B3LYP and B3LYP-D3 methods. Torsional effects are largely responsible for the stereoselectivity encountered in the chromodorolide A synthesis. Many literature examples have been reported on related cases. QM calculations show that the stereoselectivities of dihydroxylations of fused cyclopentenes are influenced by the conformational rigidity or flexibility of the substrate. Torsional, electrostatic, and steric effects can all influence stereoselectivity, and the rigidity or flexibility of conformations of reactants provides a predictive guide to stereoselectivity.

Force-induced transformations of polymer-bound functionalities have the potential to produce a rich array of stress-responsive behavior. One area of particular interest is the activation of non-scissile mechanophores in which latent reactivity can be unveiled that, under the appropriate conditions, could lead to constructive bond formation in materials exposed to typically destructive stress. Here, the mechanical activation of a bicyclo[3.2.0]heptane (BCH) mechanophore is demonstrated via selective labeling of bis-enone products. BCH ring-opening produces large local elongation (>4 Å) and products that are reactive to conjugate additions under mild conditions. Subsequent photocyclization regenerates the initial BCH functionality, providing switchable structure and reactivity along the polymer backbone in response to stress and visible light.

Fused-ring and bridged-ring tetrahydrofuran scaffolds are found in a number of natural products and biologically active compounds. A new copper-catalyzed intramolecular carboetherification of alkenes for the synthesis of bicyclic tetrahydrofurans is reported herein. The reaction involves Cu-catalyzed intramolecular addition of alcohols to unactivated alkenes and subsequent aryl C-H functionalization provides the C-C bond. Mechanistic studies indicate a primary carbon radical intermediate is involved and radical addition to the aryl ring is the likely C-C bond-forming mechanism. Preliminary catalytic enantioselective reactions are promising (up to 75% ee) and provide evidence that copper is involved in the alkene addition step, likely through a cis-oxycupration mechanism. Catalytic enantioselective alkene carboetherification reactions are rare and future development of this new method into a highly enantioselective process is promising. During the course of the mechanistic studies a protocol for alkene hydroetherification was also developed.

A new Cu-catalyzed asymmetric [3 + 3] cycloaddition of propargyl esters with cyclic enamines is reported. With a combination of Cu(OAc)(2)·H(2)O and a chiral tridentate ferrocenyl-P,N,N ligand as the catalyst, perfect endo selectivities (endo/exo > 98/2) and excellent enantioselectivities (up to 98% ee) for endo cycloadducts were achieved under mild conditions. This method provides a simple and efficient approach for the synthesis of optically active bicyclo[n.3.1] frameworks.

A novel oxygen-atom-transfer process enables the catalytic [2 + 2 + 1] synthesis of bicyclic furans from α,ω-diynes with DMSO. [CpRu(AN)(3)]PF(6) catalyzed the transfer oxygenative cyclization of diynes with aryl terminal groups, while those of diynes with alkyl terminal groups were effectively promoted by the corresponding Cp* complex. A mechanism for bicyclic furan formation via a ruthenacyclopentatriene was proposed on the basis of both experimental and theoretical studies.

A highly enantioselective Rh(I)-catalyzed intramolecular [3 + 2] cycloaddition of 1-yne-VCPs to bicyclo[3.3.0] compounds with an all-carbon chiral quaternary stereocenter at the bridgehead carbon was developed. DFT calculations of the energy surface of the catalytic cycle (complexation, cyclopropane cleavage, alkyne insertion, and reductive elimination) of the asymmetric [3 + 2] cycloaddition reaction indicated that the rate- and stereo-determining step is the alkyne-insertion step. Analysis of the alkyne-insertion transition states revealed that the serious steric repulsion between the substituents in the alkyne moiety of the substrates and the rigid H(8)-BINAP backbone is responsible for not generating the disfavored [3 + 2] cycloadducts., (© 2011 American Chemical Society)

The synthesis and direct comparison of the chemical reactivity of the two highly oxidized bicyclic lactone fragments found in rearranged spongian diterpenes (8-substituted 6-acetoxy-2,7-dioxabicyclo[3.2.1]octan-3-one and 6-substituted 7-acetoxy-2,8-dioxabicyclo[3.3.0]octan-3-one) are reported. Details of the first synthesis of the 6-acetoxy-2,7-dioxabicyclo[3.2.1]octan-3-one ring system, including an examination of several possibilities for the key bridging cyclization reaction, are described. In addition, the first synthesis of 7-acetoxy-2,8-dioxabicyclo[3.3.0]octanones containing quaternary carbon substituents at C6 is disclosed. Aspects of the chemical reactivity and Golgi-modifying properties of these bicyclic lactone analogs of rearranged spongian diterpenes are also reported. Under both acidic and basic conditions, 8-substituted 2,7-dioxabicyclo[3.2.1]octanones are converted to 6-substituted-2,8-dioxabicyclo[3.3.0]octanones. Moreover, these dioxabicyclic lactones react with primary amines and lysine side chains of lysozyme to form substituted pyrroles, a conjugation that could be responsible for the unique biological properties of these compounds. These studies demonstrate that acetoxylation adjacent to the lactone carbonyl group, in either the bridged or fused series, is required to produce fragmented Golgi membranes in the pericentriolar region that is characteristic of macfarlandin E.

Synthetic methods for 3-azabicyclo[3.1.0]hex-2-enes and 4-carbonylpyrroles have been developed that use copper-mediated/catalyzed reactions of N-allyl/propargyl enamine carboxylates under an O(2) atmosphere and involve intramolecular cyclopropanation and carbooxygenation, respectively. These methodologies take advantage of orthogonal modes of chemical reactivity of readily available N-allyl/propargyl enamine carboxylates; the complementary pathways can be accessed by slight modification of the reaction conditions.

Four diastereomeric series of N-alkylated [6+5] bicyclic isoureas having hydroxyl substituents mimicking glucose hydroxyl groups have been synthesized as potential β-glucocerebrosidase (GCase) inhibitors with the aim of developing pharmacological chaperones for enzyme deficiency in Gaucher disease (GD). The bicyclic compounds differ either by the configuration of the ring fusion carbon atoms or by the nature of the N-alkyl substituents. When assayed for effects on GCase activity, the isoureas displayed selective inhibition of GCase with low micromolar to nanomolar IC(50)'s in isolated enzyme experiments. One of the series of isoureas, a family having a specific cis ring fusion, exhibited strong inhibition of recombinant GCase activity with K(i) values in the 2-42 nM range. In addition, the [6+5] bicyclic guanidine derivatives with a substitution pattern analogous to the most active isoureas were also found to be potent inhibitors of GCase with K(i) values between 3 and 10 nM. Interestingly, the active bicyclic isoureas and guanidines also behaved as GCase inhibitors in wild-type human fibroblasts at nanomolar concentrations. The potential of these compounds as pharmaceutical chaperones was determined by analyzing their capacity for increasing GCase activity in GD lymphoblasts derived from N370S and L444P variants, two of the most prevalent Gaucher mutations. Six compounds were selected from the different bicyclic isoureas and guanidines obtained that increased GCase activity by 40-110% in N370S and 10-50% in L444P cells at low micromolar to nanomolar concentrations following a 3 day incubation. These results describe a promising series of potent GCase ligands having the cellular properties required for pharmacological chaperones., (© 2011 American Chemical Society)

We report a highly stereoselective Au-catalyzed synthesis of 9-oxabicyclo[3.3.1]nona-4,7-dienes from diverse 1-oxo-4-oxy-5-ynes. Formation of these highly strained anti-Bredt oxacycles implies the workability of an unprecedented 1,4-dipole of s-trans-methylene(vinyl)oxonium. This work reveals the feasibility of a formal [4 + 2] cycloaddition on an s-trans-heterodiene framework.

Kinetically controlled hydroboration of allenes 8 and 14a-d with the readily accessible Soderquist borane 7, which is generated in situ from borohydride 6, constitutes a convenient and preparatively useful method for synthesis of (Z)-gamma-(substituted)allylboranes 9 and 15a-d. These allylboranes undergo highly diastereo- (> or = 90: 10) and enantioselective (typically 89-96% e.e.) allylboration reactions with representative aldehydes to give syn-beta-functionalized homoallylic alcohols.

A Mn(III)-mediated divergent synthesis of substituted pyridines and 2-azabicyclo[3.3.1]non-2-en-1-ol derivatives was exploited using readily available vinyl azides and cyclopropanols with a wide range of substituents. In short, the reactions of vinyl azides with monocyclic cyclopropanol provided pyridines in the presence of Mn(acac)(3) (1.7 equiv), whereas those with bicyclic cyclopropanols led to the formation of 2-azabicyclo[3.3.1]non-2-en-1-ol derivatives using a catalytic amount of Mn(acac)(3). These reactions may be initiated by a radical addition of beta-keto radicals, generated by the one-electron oxidation of cyclopropanols, to vinyl azides to give iminyl radicals, which would cyclize with the intramolecular carbonyl groups. In addition, versatile transformations of 2-azabicyclo[3.3.1]non-2-en-1-ol to 2-azabicyclo[3.3.1]nonane or -non-2-nen frameworks were developed.

Using epoxy enol triethylsilanes as oxyallyl cation precursors, [4 + 3] cycloadditions with various dienes occur under catalysis by silyl triflates and acids in good yields. The intramolecular [4 + 3] cycloaddition proceeds under mild conditions and generate hydroxylated cycloadducts with high diastereoselectivity and yields. Enantiomerically pure epoxy enol silanes have been shown to give excellent yields of the optically pure cycloadduct bearing multiple stereocenters.

A concise enantioselective synthesis of the fungal metabolite ent-malbrancheamide B was accomplished through the union of a C-prenylated proline derivative and a substituted indole pyruvic acid SEM enol ether, followed by a cationic double cyclization as the key step.

A significant improvement in the generality and reactivity of MBH-type reactions is made possible by anion catalysis and a 1,3-Brook rearrangement. In this new reaction, both aliphatic and aromatic aldehydes are rapidly added to silylallenes, leading to gamma-carbinol allenoates at low temperatures. The utility of these reaction products is demonstrated by a fast-tracked synthesis of a [3.2.1] bisoxa bicycle that makes up the framework of many biologically active natural products, including vitisinol D, an antithrombotic agent.