Showing papers on "Bicyclic molecule published in 2013"

Rhodium-Catalyzed Conversion of Furans to Highly Functionalized Pyrroles

Abstract: The synthesis of highly functionalized pyrroles has been achieved by reaction of rhodium-stabilized imino-carbenes with furans. The reaction features an initial [3+2] annulation to form bicyclic hemiaminals, followed by ring opening to generate trisubstituted pyrroles.

Metal-free binding and coupling of carbon monoxide at a boron–boron triple bond

Abstract: Many metal-containing compounds, and some metal-free compounds, will bind carbon monoxide. However, only a handful of metal-containing compounds have been shown to induce the coupling of two or more CO molecules, potentially a method for use of CO as a one-carbon-atom building block for the synthesis of organic molecules. In this work, CO was added to a boron-boron triple bond at room temperature and atmospheric pressure, resulting in a compound into which four equivalent of CO are incorporated: a flat, bicyclic, bis(boralactone). By the controlled addition of one CO to the diboryne compound, an intermediate in the CO coupling reaction was isolated and structurally characterized. Electrochemical measurements confirm the strongly reducing nature of the diboryne compound.

Organocatalytic triazole formation, followed by oxidative aromatization: regioselective metal-free synthesis of benzotriazoles.

Abstract: Herein we report on our studies on the sequential one-pot combinations of amine-catalyzed multicomponent reactions (MCRs). We have developed the copper-free synthesis of functionalized bicyclic N-aryl-1,2,3-triazole and N-arylbenzotriazole products 4 and 5 from the simple unmodified starting materials through [3+2]-cycloaddition ([3+2]-CA) and oxidative aromatization reactions in one pot under amine catalysis. The sequential one-pot reaction proceeds in good yields with high selectivity by using pyrrolidine as the catalyst from the simple unmodified substrates of enones, aryl azides, and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). Furthermore, we have demonstrated the medicinal applications of products 4 and 5 through simple organic reactions.

Screening Bicyclic Peptide Libraries for Protein–Protein Interaction Inhibitors: Discovery of a Tumor Necrosis Factor-α Antagonist

Abstract: 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

Stress-Responsive Polymers Containing Cyclobutane Core Mechanophores: Reactivity and Mechanistic Insights

Abstract: A primary goal of covalent mechanochemistry is to develop polymer bound mechanophores that undergo constructive transformations in response to otherwise destructive forces. The [2 + 2] cycloreversion of cyclobutane mechanophores has emerged as a versatile framework to develop a wide range of stress-activated functionality. Herein, we report the development of a class of cyclobutane bearing bicyclo[4.2.0]octane mechanophores. Using carbodiimide polyesterification, these stress-responsive units were incorporated into high molecular weight polymers containing up to 700 mechanophores per polymer chain. Under exposure to the otherwise destructive elongational forces of pulsed ultrasound, these mechanophores unravel by ∼7 A per monomer unit to form α,β-unsaturated esters that react constructively via thiol-ene conjugate addition to form sulfide functionalized copolymers and cross-linked polymer networks. To probe the dynamics of the mechanochemical ring opening, a series of bicyclo[4.2.0]octane derivatives that varied in stereochemistry, substitution, and symmetry were synthesized and activated. Reactivity and product stereochemistry was analyzed by (1)H NMR, which allowed us to interrogate the mechanism of the mechanochemical [2 + 2] cycloreversion. These results support that the ring opening is not concerted but proceeds via a 1,4 diradical intermediate. The bicyclo[4.2.0]octanes hold promise as active functional groups in new classes of stress-responsive polymeric materials.

Rapid Access to Spirocyclic Oxindole Alkaloids: Application of the Asymmetric Palladium-Catalyzed [3+2] Trimethylenemethane Cycloaddition

Abstract: The marcfortines are complex secondary metabolites that show potent anthelmintic activity and are characterized by the presence of a bicyclo[2.2.2]diazaoctane fused to a spirooxindole. Herein, we report the synthesis of two members of this family. The synthesis of marcfortine B utilizes a carboxylative TMM cycloaddition to establish the spirocyclic core, followed by an intramolecular Michael addition and oxidative radical cyclization to access the strained bicyclic ring system. In addition, the first asymmetric synthesis of (−)-marcfortine C is described. The key step involves a cyano-substituted TMM cycloaddition, which proceeds in nearly quantitative yield with high diastereo- and enantioselectivity. The resulting chiral center was used to establish all remaining stereocenters in the natural product.

Synthesis of ent-kaurane and beyerane diterpenoids by controlled fragmentations of overbred intermediates.

Abstract: In the first part of a two-phase pursuit of highly oxidized members of the ent-kaurane and beyerane diterpenoid families, steviol was identified as the ideal cyclase phase terminus. Accordingly, a synthesis of steviol has been developed. This synthesis features a polyene cyclization precursor designed to directly yield oxidation on the axial C19 methyl group. Construction of the necessary [3.2.1]bicyclic system found in the ent-kaurane skeleton was realized with two overbred intermediates. The resulting [3.2.1]bicyclic system undergoes Wagner–Meerwein rearrangement to yield the beyerane skeleton of isosteviol.

Bicyclic peptide ligands pulled out of cysteine-rich peptide libraries.

Abstract: 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.

Oligomeric compounds comprising bicyclic nucleotides and uses thereof

Abstract: The present invention provides oligomeric compounds. Certain such oligomeric compounds are useful for hybridizing to a complementary nucleic acid, including but not limited, to nucleic acids in a cell. In certain embodiments, hybridization results in modulation of the amount activity or expression of the target nucleic acid in a cell.

Highly enantioselective dearomatizing formal [3+3] cycloaddition reactions of N-acyliminopyridinium ylides with electrophilic enol carbene intermediates.

Abstract: Heterocyclic compounds are widely distributed in nature,[1] and their core structures are present in a vast array of pharmaceuticals.[2] Although extensive efforts have been concentrated on their syntheses,[3] including asymmetric catalytic processes,[4] the demand for greater structural diversity continues to be of intense interest.[5] In particular, there are increasing efforts for asymmetric syntheses of dihydropyridine, dihydroquinoline, dihydroisoquinoline and related heterocycles that are core structures in natural products and other bioactive molecules.[4a–4f] However, asymmetric syntheses of heterocyclic structures with more than one nitrogen-atom are rare. [6–8] The use of N-iminoquinolinium ylides for the asymmetric construction of dihydroquinoline derivatives by a [3+3]-cycloaddition with 1,1-cyclopropane diesters, originally reported by Charette for the non-asymmetric version, [7e] has recently been communicated. [4a] Good yields and high enantiocontrol were achieved in this kinetic resolution, but high catalyst loadings of nickel(II) perchlorate and the chiral In-Box ligand were required. We have been investigating the dirhodium-catalyzed 1,3-dipolar [3+3]-cycloaddition with enol-diazoacetates 1[9,10] whose metal enolcarbene intermediates, generated by dinitrogen extrusion, have electrophilic character at both the carbene and vinylogous positions with preferential reaction occurring at the vinylogous position (Scheme 1). Could these dipolar intermediates be effective for the asymmetric construction of dihydroquinoline derivatives with N-iminoquinolinium ylides? Prior efforts have shown that enolcarbene intermediates underwent [3+3]-cycloaddition reactions with nitrones to form 3,6-dihydro-1,2-oxazines (3) [9a] and with hydrazones to form tetrahydropyridazine derivatives (4), [9c] each by a stepwise process initiated by nucleophilic reaction at the vinylogous position that occurs with high enantiocontrol. Unlike cycloaddition reactions with nitrones and hydrazones, however, reactions with N-iminoquinolinium ylides afford a barrier to cycloaddition with the required dearomatization, and for this reason it is perhaps not surprising that cycloaddition reactions with N-iminopyridinium ylides have not yet been reported. We wish to report that N-iminopyridinium ylides undergo efficient and highly enantioselective [3+3]-cycloaddition reactions in chiral dirhodium-catalyzed reactions with enol diazoacetates. Scheme 1 Vinylogous dirhodium-enolcarbene formal [3+3]-cycloaddition reactions. Pyridine-N-aminidines 5a (N-acyliminopyridinium ylides) [4a,11] are stable but reactive dipolar species. Treatment of 5a with enoldiazoacetate 1a in the presence of a catalytic amount of rhodium(II) acetate in dichloromethane (DCM) at room temperature produced the dearomatized bicyclic tetrahydropyridazine derivative 6a (92% isolated yield) in one step (Eq 1). This transformation is a more direct and convenient way to the tetrahydropyridazine derivatives compared to previous two-step one-pot methodology from N-arylhydrazones and 1a, [9c] and the bicyclic tetrahydropyridazine products that are obtained (6) offer more functional diversity compared to 4. (1) Based on our previous studies, [9a,9c] Hashimoto’s dirhodium carboxylate catalysts were considered to have the reactivity and selectivity suitable for high enantioselectivity in the [3+3]-cycloaddition reaction; [12] however, although 100% conversion was obtained when the reaction was catalyzed by Rh2(S-PTA)4 in DCM, only 5% enantiomeric excess (ee) was detected (Table 1, entry 1). [13] Enantiomeric excess was increased to 45% by switching the solvent from DCM to methyl tert-butyl ether (TBME) or toluene with 71% and 100% conversion respectively (entries 2 and 3). Catalyst screening showed that increasing steric demand of the ligands on rhodium provided higher enantioselectivity (entries 3–8), which was opposite to previous results with reactions of enoldiazoacetates and nitrones[9a] or hydrazones[9c] (Scheme 1) in which the less sterically encumbered catalyst gave higher reactivity and selectivity. Further optimization with solvents (entries 9–12) gave 6a in up to 93% ee in chloroform but there was only 26% conversion (entry 12). The outcome having the highest conversion/yield and %ee was obtained when the reaction was catalyzed by Rh2(S-PTTL)4[14] in fluorobenzene at 0 °C with 85% isolated yield and 90% ee (entry 9). Similar results were obtained with Rh2(S-PTAD)4[15] in fluorobenzene or toluene, which was also used for exploration (entries 13 and 14). Table 1 Optimization of conditions for the enantioselective formal [3+3]-cycloadditon of enlodiazoacetate 1a with 5a.[a] A variety of enoldiazoacetates 1 were examined under the optimized reaction conditions. As shown in Table 2, except for benzyl enoldiazoacetate 1e (entry 5, 85% yield 77% ee), all of the TBS or TIPS protected enoldiazoacetates gave the corresponding bicyclic tetrahydropyridazines 6 in high yield with high to excellent enantioselectivity (entries 1–4 and 6–7, >75% yield, 90–95% ee). It is worth mentioning that enantioselectivity increased with increasing steric demand of the enoldiazoacetates 1 without affecting product yields. In our previously reported reactions of enoldiazoacetates with steric bulky hydrazones, the yields of the corresponding tetrahydropyridazine derivatives dropped dramatically with increasing steric demand. [9c] For the TIPS protected tert-butyl diazoacetate 1g, conditions A, C or D gave similar enantioselectivities (entries 7–9), while condition A offered higher yield. Table 2 Enantioselective formal [3+3]-cycloadditon of enlodiazoacetates 1 with 5a.[a] The reaction scope was extended to substituted N-acyliminopyridinium ylides, and these results are summarized in Table 3. The steric and electronic properties of the substituents on the phenyl group had slight influences on reactivity or selectivity (Table 3, entries 1–5), and the reaction could be carried out on a 1.0 mmol scale with 96% ee (entry 4). Notably, quinoline and isoquinoline derivatives were both well tolerated in this [3+3]-cycloaddition reaction and gave tricyclic tetrahydropyridazine derivatives in high yield with 97% ee and 96% ee respectively (entries 6 and 7). In addition, with a 3-methyl group introduced to the pyridinium ring, high regioselectivity (>19:1) was found (Scheme 2, 6o and 6o’),[16] and 95% ee was obtained for the major isomer, while up to 32% ee was determined for the minor one. These results indicated that during the ring closing step the dirhodium catalyst is still associated with the substrate, and this association determines the outcome between the two possible positions. [17] Scheme 2 Highly regioselective and enantioselective formal [3+3]-cycloadditon of enlodiazoacetate 1g with 5i. Table 3 Enantioselective formal [3+3]-cycloadditon of enlodiazoacetates 1g with 5.[a] The (S)-configuration of the generated chiral center in bicyclic tetrahydropyridazine derivatives was confirmed by single-crystal X-ray diffraction analysis of 6i, [18] and the configurations of other compounds were tentatively assigned by analogy (Figure 1), As is evident from this determination, the (S)-configured catalyst yields the (S)-configyred cycloaddition product. The generated bicyclic tetrahydropyridazine derivatives have multi-functional groups, including ester, ether, acyl, and diene generated by dearomatization of N-acyliminopyridinium ylide. A one-pot reaction with N-phenylmaleimide to give the polycyclic product 7 in 77% yield with 2:1 endo:exo selectivity, and enantiomeric excesses for both of the diastereoisomers were the same as that of 6g (Scheme 3). Figure 1 (S)-Configuration of 6i is produced with catalysis by Rh2(S-PTAD)4. Scheme 3 Sequential one-pot [3+3]-/[4+2]-cycloaddition reactions. In summary, we have developed a direct formal [3+3]-cycloaddtion that is a effective access to the bicyclic and tricyclic 1,2,3,6-tetrahydropyridazine derivatives starting from enoldiazoacetates and N-acyliminopyridinium ylide in good to high overall yields, high regioselectivities and excellent enantioselectivities that are controlled by catalysts and conditions. The sequence of reactions is triggered by Rh(II)-catalyzed dinitrogen extrusion followed by vinylogous addition with N-acyliminopyridinium ylide. Intramolecular asymmetric pyridinium ylide addition to the catalyst-activated vinyl ether functional group of 8 forms the [3+3]-cycloaddition product 6 (Scheme 4). And the generated 1,2,3,6-tetrahydropyridazine product can be transformed to polycyclic skeletons via [4+2]-cycloaddition without sacrifice the enantiomeric excess. Further expansion of the cycloaddition with electrophilic enolcarbene intermediates applied broadly is being pursued. Scheme 4 Proposed reaction pathway for the [3+3]-cycloaddition.

Discovery, Synthetic Methodology, and Biological Evaluation for Antiphotoaging Activity of Bicyclic[1,2,3]triazoles: In Vitro and in Vivo Studies

Abstract: Novel bicyclic[1,2,3]triazoles (4, 7, 11, 15) have been synthesized using a one-pot metal free strategy with high structural diversity as photoprotective agents, and their effect on UVA-induced senescence in human dermal fibroblast cells (FB) and the associated mechanism are delineated. 11d plus UVA can induce a decrease in reactive oxygen species (ROS) production and senescence-associated β-galactosidase (SA-β-gal) activity but an increase in adenosine triphosphate (ATP) synthesis and mitochondrial membrane potential (ΔΨmt). The mRNA levels of six senescence-associated genes, matrix metalloproteinase-1 (MMP-1), was decreased, while elastin, procollagen I type I, fibronectin, COL1α1, and tissue inhibitor of metalloproteinase-1 (TIMP-1) were increased. 11d plus UVA also decreased MMP-1 and increased TIMP-1 protein levels. Additionally, the thickness of the murine dorsal skin and epidermis, by UVA, was decreased by topical 11d treatment. Our results indicate that bicyclic[1,2,3]triazoles protect UVA-induced...

Mechanistic insights from the binding of substrate and carbocation intermediate analogues to aristolochene synthase.

Abstract: Aristolochene synthase, a metal-dependent sesquiterpene cyclase from Aspergillus terreus, catalyzes the ionization-dependent cyclization of farnesyl diphosphate (FPP) to form the bicyclic eremophilane (+)-aristolochene with perfect structural and stereochemical precision. Here, we report the X-ray crystal structure of aristolochene synthase complexed with three Mg2+ ions and the unreactive substrate analogue farnesyl-S-thiolodiphosphate (FSPP), showing that the substrate diphosphate group is anchored by metal coordination and hydrogen bond interactions identical to those previously observed in the complex with three Mg2+ ions and inorganic pyrophosphate (PPi). Moreover, the binding conformation of FSPP directly mimics that expected for productively bound FPP, with the exception of the precise alignment of the C–S bond with regard to the C10–C11 π system that would be required for C1–C10 bond formation in the first step of catalysis. We also report crystal structures of aristolochene synthase complexed with Mg2+3-PPi and ammonium or iminium analogues of bicyclic carbocation intermediates proposed for the natural cyclization cascade. Various binding orientations are observed for these bicyclic analogues, and these orientations appear to be driven by favorable electrostatic interactions between the positively charged ammonium group of the analogue and the negatively charged PPi anion. Surprisingly, the active site is sufficiently flexible to accommodate analogues with partially or completely incorrect stereochemistry. Although this permissiveness in binding is unanticipated, based on the stereochemical precision of catalysis that leads exclusively to the (+)-aristolochene stereoisomer, it suggests the ability of the active site to enable controlled reorientation of intermediates during the cyclization cascade. Taken together, these structures illuminate important aspects of the catalytic mechanism.

Fragment-based discovery of new highly substituted 1H-pyrrolo[2,3-b]- and 3H-imidazolo[4,5-b]-pyridines as focal adhesion kinase inhibitors.

Abstract: Focal adhesion kinase (FAK) is considered as an attractive target for oncology, and small-molecule inhibitors are reported to be in clinical testing. In a surface plasmon resonance (SPR)-mediated fragment screening campaign, we discovered bicyclic scaffolds like 1H-pyrazolo[3,4-d]pyrimidines binding to the hinge region of FAK. By an accelerated knowledge-based fragment growing approach, essential pharmacophores were added. The establishment of highly substituted unprecedented 1H-pyrrolo[2,3-b]pyridine derivatizations provided compounds with submicromolar cellular FAK inhibition potential. The combination of substituents on the bicyclic templates and the nature of the core structure itself have a significant impact on the compounds FAK selectivity. Structural analysis revealed that the appropriately substituted pyrrolo[2,3-b]pyridine induced a rare helical DFG-loop conformation. The discovered synthetic route to introduce three different substituents independently paves the way for versatile applications o...

Desymmetrization of meso-2,5-diallylpyrrolidinyl ureas through asymmetric palladium-catalyzed carboamination: Stereocontrolled synthesis of bicyclic ureas

Abstract: Catalytic asymmetric desymmetrization reactions are powerful and efficient tools for the synthesis of chiral molecules.[i] These transformations convert simple achiral substrates into complex enantioenriched products through the differentiation of two enantiotopic groups, and can generate complex structures bearing multiple stereocenters in a highly controlled fashion. As such, the development of asymmetric desymmetrization reactions that allow for the construction of important structural motifs is of considerable utility. Tricyclic guanidines are an interesting class of compounds that could potentially be accessed via catalytic asymmetric desymmetrization reactions (Figure 1). These scaffolds are displayed in a wide variety of biologically active natural products,[ii] including the batzelladine alkaloids[iii] (e.g. batzelladine K, 1),[iiic] the merobatzelladine alkaloids (e.g., merobatzelladine B, 2),[iv] and the crambescidin alkaloids[v] (e.g., crambescidin 359, 3).[vb] Many synthetic routes to these compounds involve the generation of a fused-bicyclic urea or guanidine derivative (e.g., 4), which is then transformed to the tricyclic guanidine in subsequent steps.[vi,vii,viii] As such, development of a concise asymmetric synthesis of 4 could provide access to a broad array of interesting alkaloids. Figure 1 Bioactive guanidine alkaloids prepared from bicyclic urea precursors We recently reported an asymmetric synthesis of the tricyclic guanidine natural product (+)-merobatzelladine B (2), which featured a new strategy for the construction of bicyclic ureas and polycyclic guanidines via Pd-catalyzed carboamination reactions of enantiomerically enriched 2-allylpyrrolidine-1-carboxamide derivatives 5 (Scheme 1).[viii] These reactions provided bicyclic urea products 6 in good yield with excellent diastereoselectivity, but control of absolute stereochemistry required the chiral-auxiliary mediated introduction of the C2 stereocenter during the fairly lengthy asymmetric synthesis of 5 (7–9 steps).[ix] Scheme 1 Synthesis of bicyclic ureas via Pd-catalyzed asymmetric desymmetrization A potentially more attractive route to enantiomerically enriched bicyclic ureas and related bi- and tricyclic guanidines would involve the asymmetric Pd-catalyzed desymmetrization of meso-2,5-diallylpyrrolidnyl urea 7. This approach would allow for facile introduction of different R1-substituents, and the alkene present in product 8 provides a convenient handle for further elaboration to tricyclic guanidine products or more highly substituted urea derivatives. In addition, the meso substrate 7 can be prepared in only four steps. Our preliminary studies in this area are described in this communication. These transformations represent the first examples of asymmetric desymmetrizations of bis-alkene substrates in intermolecular Pd-catalyzed alkene carboamination reactions, and also the first examples of six-membered ring formation in an asymmetric Pd-catalyzed alkene carboamination.[x,xi,xii] In initial experiments we elected to employ a catalyst composed of Pd2(dba)3/(S)-Siphos-PE[xiii] for desymmetrization reactions of 7, as we previously illustrated this complex provides good results in related asymmetric carboamination reactions of simple N-allyl urea derivatives.[xiv,xv] We decided to first optimize the structure of the urea N-aryl group, as prior studies in our lab suggested this group may have a significant influence on the level of asymmetric induction.[xiv] Thus, we explored the coupling of Z-1-bromobutene[xvi] with ureas 7 bearing different N-aryl substituents. As shown in Table 1, the use of electron-poor p-cyanophenyl or p-nitrophenyl N-aryl groups resulted in the formation of products 8 with the highest levels of both diastereoselectivity and enantioselectivity. However, these electron-poor substrates were transformed in modest chemical yield due to competing cleavage of the urea moiety (entries 5–6). Use of the electron-rich p-methoxyphenyl group led to improved yields but with lower levels of stereocontrol. After some exploration we found that a substrate bearing a p-chlorophenyl group was transformed to the desired product with both good chemical yield and stereoselectivity (entry 3).[xvii] Table 1 N-Aryl group effects.[a] As shown in Table 2, the asymmetric desymmetrization reactions of 7c are effective with a number of different alkenyl and aryl bromide electrophiles. The main side products generated in these reactions were cis-2,5-diallylpyrrolidine (resulting from competing urea cleavage) and an unsaturated bicyclic urea that is generated by competing β-hydride elimination of an intermediate alkylpalladium complex.[xviii] In the reaction of 7c with E-1-bromohexene a regioisomeric side product bearing a 2-hex-1-enyl group was also generated.[xix] Table 2 Reaction Scope.[a] The best enantioselectivities were obtained when either alkenyl bromides, electron-rich aryl bromides, or electron-neutral aryl bromides were employed as substrates. Diastereoselectivities were generally higher with the alkenyl electrophiles than with aryl electrophiles. Use of sterically hindered aryl bromides (entries 14–15) or electron-poor aryl bromides (entries 9, 11, and 13) led to lower diastereo- and enantioselectivities. Selectivities improved when NaOMe was used in place of NaOtBu in reactions of electron-poor aryl bromides (entries 10 and 12), although yields decreased in these cases. To further demonstrate the utility of the asymmetric desymmetrization reactions, we examined the deprotection of 8c and the conversion of 8c to tricyclic guanidine derivatives. As shown in equation 1, cleavage of the N-p-chlorophenyl group can be accomplished via Pd-catalyzed N-arylation with acetamide[xx, xxi] followed by oxidation of the resulting N-aryl amide with ceric ammonium nitrate. This sequence afforded 9 in 65% yield over two steps. (1) The conversion of 8c to tricyclic guanidine 12 was carried out as shown in Scheme 2. Treatment of 8c with POCl3 followed by NH3 provided bicyclic guanidine 10 in 78% yield. Wacker oxidation of 10 afforded hemiaminal 11, which was then transformed to tricyclic product 12 in 70% yield with 5:1 dr via reductive amination with NaBH3CN.[xxii] Overall, the synthesis of 12, which is structurally related to the batzelladine and merobatzelladine alkaloids, was accomplished in 5 steps and 41% yield from meso-2,5-diallylpyrrolidinyl urea 7c. In addition, this is the first example of a Wacker oxidation/ring-closure sequence to generate a tricyclic guanidine.[xxiii,xxiv] Scheme 2 Conversion of 8c to a tricyclic guanidine derivative Finally, 8c was converted to tricyclic guanidine 16, which is an unnatural stereoisomer of batzelladine k,[xxv,xxvi] as shown in Scheme 3. To avoid problems with base-mediated epimerization of the C4 stereocenter, the Pd-catalyzed N-arylation with acetamide was carried out prior to Wacker oxidation of the alkene. This two-step sequence provided 13 in 65% yield. Reduction of the alkene followed by CAN deprotection generated urea 14, which was converted to guanidine aminal 15 by O-methylation and treatment with ammonia.[xxvii] The reduction of 15 proceeded with modest diastereoselectivity (3:1 dr), but upon purification 9-epi-batzelladine k was isolated as a single stereoisomer in 48% yield over three steps from 14. Scheme 3 Conversion of 8c to 9-epi-batzelladine K. In conclusion we have developed a concise route to enantiomerically enriched bicyclic ureas via Pd-catalyzed desymmetrizing carboamination reactions of meso-diallylpyrroldinyl ureas. These transformations effect formation of both a C–N and a C–C bond, and provide products bearing three stereocenters with good levels of diasteroselectivity and enantioselectivity. These reactions illustrate the potential utility of asymmetric Pd-catalyzed alkene carboamination for desymmetrization processes and provide synthetically valuable products in a straightforward manner. Further exploration of enantioselective Pd-catalyzed alkene difunctionalization reactions are currently underway.

Rhodium(III)-Catalyzed C-H Activation Mediated Synthesis of Isoquinolones from Amides and Cyclopropenes.

Abstract: We have developed a synthesis of 4-substituted isoquinolones from the rhodium(III)-catalyzed, C–H activation mediated coupling of O-pivaloyl benzhydroxamic acids and 3,3-disubstituted cyclopropenes. Experiments suggest the formation of a [4.1.0] bicyclic system, which can open under acidic conditions to generate the desired isoquinolone.

Enantioselective β-Boration of Acyclic Enones by a [2.2]Paracyclophane-Based N-Heterocyclic Carbene Copper(I) Catalyst

Abstract: A new planar and centrally chiral bicyclic 1,2,4-triazolium salt has been synthesized from [2.2]paracyclophane and phenylglycinol. The N-heterocyclic carbene (NHC) copper(I) complex generated in situ by the reaction of the triazolium salt and Cu2O was an efficient catalyst for the asymmetric β-boration of acyclic enones, producing β-boryl ketones in high yields and enantioselectivities.

Oxidative Cyclization Reactions: Controlling the Course of a Radical Cation‐Derived Reaction with the Use of a Second Nucleophile

Abstract: The oxidative generation of reactive radical cation intermediates can serve as a powerful tool for the construction of new ring systems.[1,2] For example, substrates with electronrich olefins can be oxidized to generate radical cations that trigger cyclizations with a variety of electron-rich groups.[3] Enol ethers, vinylsulfides, ketene derivatives, electron-rich aryl rings, and styrenes have all been oxidized to form radical cations, whereas enol ethers, allyl and vinylsilanes, aryl rings, styrenes, alcohols, amides, sulfonamides, and amines have all been used to trap the radical cation. The reactions have led to the synthesis of fused and bicyclic ring skeletons and are often compatible with the formation of tetrasubstituted carbons. In addition, they have served to help us gain a better understanding of radical cation intermediates.[4]

Free-radical-mediated [2 + 2 + 1] cycloaddition of acetylenes, amidines, and CO leading to five-membered α,β-unsaturated lactams.

Abstract: A free-radical-mediated [2 + 2 + 1] cycloaddition reaction comprising acetylenes, amidines, and CO was achieved by radical chain reaction to give five-membered α,β-unsaturated lactams in good yields. Both acyclic and cyclic amidines reacted with a variety of terminal acetylenes to afford monocyclic, bicyclic, and tricyclic lactams. We propose that vinyl radical carbonylation and nucleophilic addition of the amidine onto the resulting α-ketenyl radical give stable intermediates that are ready to undergo five-membered ring closure with elimination of tin radical.

Solid-state modification of PBT with cyclic acetalized galactitol and D-mannitol: Influence of composition and chemical microstructure on thermal properties

Abstract: Two bicyclic carbohydrate-based diols, 2,3:4,5-di-O-methylene-galactitol (Galx) or 2,4:3,5-di-O-methylene-d-mannitol (Manx), were introduced into the backbone of poly(butylene terephthalate) using ...