Synthesis of Meso‐Substituted Subphthalocyanine–Subporphyrin Hybrids: Boron Subtribenzodiazaporphyrins

The first syntheses of hybrid structures that lie between SubPhthalocyanines and SubPorphyrins are reported. The versatile, single-step synthetic protocol uses a preformed aminoisoindolene to provide the bridging methine unit and its substituent, while trialkoxyborates simultaneously act as Lewis acid/template and provider of the apical substituent. Selection of each component therefore allows controlled formation of diverse, differentially functionalised systems. The new hybrids are isolated as robust, pure materials that display intense absorption and emission in the mid-visible region. They are further characterised in solution and solid state by variable temperature NMR spectroscopy and X-ray crystallography respectivel

Oligomerization Route to Py-Im Polyamide Macrocycles

Cyclic eight-ring pyrrole−imidazole polyamides are sequence-specific DNA-binding small molecules that are cell permeable and can regulate endogenous gene expression. Syntheses of cyclic polyamides have been achieved by solid-phase and solution-phase methods. A rapid solution-phase oligomerization approach to eight-ring symmetrical cyclic polyamides yields 12- and 16-membered macrocycles as well. A preference for DNA binding by the 8- and 16-membered oligomers was observed over the 12-ring macrocycle, which we attributed to a conformational constraint not present in the smaller and larger systems

On the prevalence of bridged macrocyclic pyrroloindolines formed in regiodivergent alkylations of tryptophan.

A Friedel-Crafts alkylation is described that efficiently transforms tryptophan-containing peptides into macrocycles of varying ring connectivity. Factors are surveyed that influence the distribution of regioisomers, with a focus on indole C3-alkylations leading to bridged endo-pyrroloindolines. We probe the stability and stereochemistry of these pyrroloindolines, study their rearrangement to C2-linked indolic macrocycles, and demonstrate a scalable, stereoselective synthesis of this compound class. Placing the macrocyclization in sequence with further template-initiated annulation leads to extraordinary polycyclic products and further demonstrates the potential for this chemistry to drive novel peptidomimetic lead discovery programs

Cyclic pyrrole-imidazole polyamides targeted to the androgen response element

Hairpin pyrrole−imidazole (Py-Im) polyamides are a class of cell-permeable DNA-binding small molecules that can disrupt transcription factor−DNA binding and regulate endogenous gene expression. The covalent linkage of antiparallel Py-Im ring pairs with an γ-amino acid turn unit affords the classical hairpin Py-Im polyamide structure. Closing the hairpin with a second turn unit yields a cyclic polyamide, a lesser-studied architecture mainly attributable to synthetic inaccessibility. We have applied our methodology for solution-phase polyamide synthesis to cyclic polyamides with an improved high-yield cyclization step. Cyclic 8-ring Py-Im polyamides 1−3 target the DNA sequence 5′-WGWWCW-3′, which corresponds to the androgen response element (ARE) bound by the androgen receptor transcription factor to modulate gene expression. We find that cyclic Py-Im polyamides 1−3 bind DNA with exceptionally high affinities and regulate the expression of AR target genes in cell culture studies, from which we infer that the cycle is cell permeable

Convergent diversity-oriented side-chain macrocyclization scan for unprotected polypeptides

Here we describe a general synthetic platform for side-chain macrocyclization of an unprotected peptide library based on the S[subscript N]Ar reaction between cysteine thiolates and a new generation of highly reactive perfluoroaromatic small molecule linkers. This strategy enabled us to simultaneously “scan” two cysteine residues positioned from i, i + 1 to i, i + 14 sites in a polypeptide, producing 98 macrocyclic products from reactions of 14 peptides with 7 linkers. A complementary reverse strategy was developed; cysteine residues within the polypeptide were first modified with non-bridging perfluoroaryl moieties and then commercially available dithiol linkers were used for macrocyclization. The highly convergent, site-independent, and modular nature of these two strategies coupled with the unique chemoselectivity of a S[subscript N]Ar transformation allows for the rapid diversity-oriented synthesis of hybrid macrocyclic peptide libraries with varied chemical and structural complexities.National Institutes of Health (U.S.) (GM101762)National Institutes of Health (U.S.) (GM046059)MIT Faculty Start-up FundSontag Foundation (Distinguished Scientist Award)Deshpande Center for Technological InnovationMassachusetts Institute of Technology (Charles E. Reed Faculty Initiative Fund)Damon Runyon Cancer Research Foundatio

A tetrabenzotriazaporphyrin based organic thin film transistor: Comparison with a device of the phthalocyanine analogue

The characteristics of bottom-gate bottom-contact organic thin film field-effect transistors (OTFTs) with 70 nm thick films of solution processed non-peripherally octahexyl-substituted nickel tetrabenzo triazaporphyrin (6NiTBTAP) molecules as active layers on silicon substrates are experimentally studied and the results are compared with the similary configured transistors using the corresponding nickel phthalocyanine (6NiPc) compound. 6NiTBTAP transistors are found to exhibit improved performance over 6NiPc transistors in terms of greater saturation hole mobility, two orders of magnitude higher on/off ratio and lower threshold voltage. This enhanced performance of 6NiTBTAP OTFTs over 6NiPc devices is attributed to improved surface morphology and large grain size of the active 6NiTBTAP film

Macrocyclization Reactions: The Importance of Conformational, Configurational, and Template-Induced Preorganization

The success of a given macrocyclization reaction involves a very delicate balance of many different factors. First, a proper understanding of the basic thermodynamic and kinetic concepts underlying these processes is essential in defining the strategies to obtain the targeted cyclic structures and the experimental elements to be optimized. essential element for achieving high yields in a macrocyclization process is the appropriate selection of the disconnection site. This defines the reaction used for the key step, which will clearly affect the overall process, but also delineates the nature and structure of the immediate linear precursor. The presence of structural elements, including configurational elements, able to induce a favorable folding of this linear precursor in such a way that both reactive ends approach with the proper orientation provides significant enhancements in macrocyclizations. The use of templates of very different natures is a versatile strategy to overcome the limitations of the other macrocyclization strategies. The use of templates has allowed the preparation of a variety of macrocyclic structures in better yields and usually in shorter reaction times, and often allows easier purification protocols.Financial support of the Spanish Ministry of Science and Innovation (CTQ2012-38543-C03) and Generalitat Valenciana (PROMETEO/2012/020) is acknowledged. V.M.-C. thanks the Spanish Ministry of Science and Education for a predoctoral fellowship (FPU AP2007-02562) and Generalitat Valenciana for a VALi+d postdoctoral fellowship (APOSTD/2013/041). M.D.P. thanks the Spanish Ministry of Education for a postdoctoral fellowship and UGC India for a Startup Grant

Macrocyclization by Nickel-Catalyzed, Ester-Promoted, Epoxide-Alkyne Reductive Coupling: Total Synthesis of (−)-Gloeosporone

Ringing the changes: The total synthesis of the title compound centers around a novel strategy that employs a nickel(0)–phosphine complex and triethyl borane in an efficient closure of a 14-membered ring through C--C bond formation (see scheme; cod=cyclooctadiene). The synthesis was accomplished in 10 steps and in approximately 9 % overall yield.National Institute of General Medical Sciences (U.S.) (GM-72566)National Science Foundation (U.S.) (CHE-9809061)National Science Foundation (U.S.) (DBI-9729592)National Institutes of Health (U.S.) (1S10RR13866-01

Synthesis of a Molecular Charm Bracelet via Click Cyclization and Olefin Metathesis Clipping

We describe the synthesis of a polycatenated cyclic polymer, a structure that resembles a molecular charm bracelet. Ruthenium-catalyzed ring-opening metathesis polymerization of an aminocontaining cyclic olefin monomer in the presence of a chain transfer agent generated an α,ω-diazide functionalized polyamine. Cyclization of the resulting linear polyamine using pseudo-high-dilution coppercatalyzed click cyclization produced a cyclic polymer in 19% yield. The click reaction was then further employed to remove linear contaminants from the cyclic polymer using azide- and alkyne-functionalized scavenging resins, and the purified cyclic polymer product was characterized by gel permeation chromatography, ^1H NMR spectroscopy, and IR spectroscopy. Polymer hydrogenation and conversion to the corresponding polyammonium species enabled coordination and interlocking of diolefin polyether fragments around the cyclic polymer backbone using ruthenium-catalyzed ring-closing olefin metathesis to afford a molecular charm bracelet structure. This charm bracelet complex was characterized by ^1H NMR spectroscopy, and the catenated nature of the small rings was confirmed using two-dimensional diffusion-ordered NMR spectroscopy