Self-assembly of dendritic dipeptides as a model of chiral selection in primitive biological systems.

Biological macromolecules are homochiral, composed of sequences of stereocenters possessing the same repeated absolute configuration. This chapter addresses the mechanism of homochiral selection in polypeptides. In particular, the relationship between the stereochemistry (L or D) of structurally distinct α-amino acids is explored. Through functionalization of Tyr-Xaa dipeptides with self-assembling dendrons, the effect of stereochemical sequence of the dipeptide on the thermodynamics of self-assembly and the resulting structural features can be quantified. The dendritic dipeptide approach effectively isolates the stereochemical information of the shortest sequence of stereochemical information possible in polypeptide, while simultaneously allowing for dendron driven tertiary and quaternary structure formation and subsequent transfer of chiral information from the dipeptide to the dendritic sheath. This approach elucidates a mechanism of selecting a homochiral relationship between dissimilar but neighboring α-amino acids through thermodynamic preference for homochirality in solution-phase and bulk supramolecular helical polymerization.

Ni(COD)2/PCy3 catalyzed cross-coupling of aryl and heteroaryl neopentylglycolboronates with aryl and heteroaryl mesylates and sulfamates in THF at room temperature.

Reaction conditions for the Ni(COD)(2)/PCy(3) catalyzed cross-coupling of aryl neopentylglycolboronates with aryl mesylates were developed. By using optimized reaction conditions, Ni(COD)(2)/PCy(3) was shown to be a versatile catalyst for the cross-coupling of a diversity of aryl neopentylglycolboronates with aryl and heteroaryl mesylates and sulfamates containing both electron-donating and electron-withdrawing substituents in their para, ortho, and meta positions in THF at room temperature. This Ni-catalyzed cross-coupling of aryl neopentylglycolboronates is also effective for the synthesis of heterobiaryls and biaryls containing electrophilic functionalities sensitive to organolithium and organomagnesium derivatives. In combination with the recently developed Ni-catalyzed neopentylglycolborylation, all Ni-catalyzed routes to functional biaryls and heterobiaryls are now easily accessible.

Self-assembly of dendronized perylene bisimides into complex helical columns.

The synthesis of perylene 3,4:9,10-tetracarboxylic acid bisimides (PBIs) dendronized with first-generation dendrons containing 0 to 4 methylenic units (m) between the imide group and the dendron, (3,4,5)12G1-m-PBI, is reported. Structural analysis of their self-organized arrays by DSC, X-ray diffraction, molecular modeling, and solid-state (1)H NMR was carried out on oriented samples with heating and cooling rates of 20 to 0.2 °C/min. At high temperature, (3,4,5)12G1-m-PBI self-assemble into 2D-hexagonal columnar phases with intracolumnar order. At low temperature, they form orthorhombic (m = 0, 2, 3, 4) and monoclinic (m = 1) columnar arrays with 3D periodicity. The orthorhombic phase has symmetry close to hexagonal. For m = 0, 2, 3, 4 ,they consist of tetramers as basic units. The tetramers contain a pair of two molecules arranged side by side and another pair in the next stratum of the column, turned upside-down and rotated around the column axis at different angles for different m. In contrast, for m = 1, there is only one molecule in each stratum, with a four-strata 2(1) helical repeat. All molecules face up in one column, and down in the second column, of the monoclinic cell. This allows close and extended π-stacking, unlike in the disruptive up-down alteration from the case of m = 0, 2, 3, 4. Most of the 3D structures were observed only by cooling at rates of 1 °C/min or less. This complex helical self-assembly is representative for other classes of dendronized PBIs investigated for organic electronics and solar cells.

Programming the supramolecular helical polymerization of dendritic dipeptides via the stereochemical information of the dipeptide.

Many natural biomacromolecules are homochiral and are built from constituents possessing identical handedness. The construction of synthetic molecules, macromolecules, and supramolecular structures with tailored stereochemical sequences can detail the relationship between chirality and function and provide insight into the process that leads to the selection of handedness and amplification of chirality. Dendritic dipeptides, previously reported from our laboratory, self-assemble into helical porous columns and serve as fundamental mimics of natural porous helix-forming proteins and supramolecular polymers. Herein, the synthesis of all stereochemical permutations of a self-assembling dendritic dipeptide including homochiral, heterochiral, and differentially racemized variants is reported. A combination of CD/UV-vis spectroscopy in solution and in film, X-ray diffraction, and differential scanning calorimetry studies in solid state established the role of the stereochemistry of the dipeptide on the thermodynamics and mechanism of self-assembly. It was found that the highest degree of stereochemical purity, enantiopure homochiral dendritic dipeptides, exhibits the most thermodynamically favorable self-assembly process in solution corresponding to the greatest degree of helical order and intracolumnar crystallization in solid state. Reducing the stereochemical purity of the dendritic dipeptide through heterochirality or by partially or fully racemizing the dendritic dipeptide destructively interferes with the self-assembly process. All dendritic dipeptides were shown to coassemble into single columns regardless of their stereochemistry. Because these columns exhibit no deracemization, the thermodynamic advantage of enantiopurity and homochirality suggests a mechanism for stereochemical selection and chiral amplification.

Transfer, amplification, and inversion of helical chirality mediated by concerted interactions of C3-supramolecular dendrimers.

The synthesis, structural, and retrostructural analysis of two libraries containing 16 first and second generation C(3)-symmetric self-assembling dendrimers based on dendrons connected at their apex via trisesters and trisamides of 1,3,5-benzenetricarboxylic acid is reported. A combination of X-ray diffraction and CD/UV analysis methods demonstrated that their C(3)-symmetry modulates different degrees of packing on the periphery of supramolecular structures that are responsible for the formation of chiral helical supramolecular columns and spheres self-organizable in a diversity of three-dimensional (3D) columnar, tetragonal, and cubic lattices. Two of these periodic arrays, a 3D columnar hexagonal superlattice and a 3D columnar simple orthorhombic chiral lattice with P222(1) symmetry, are unprecedented for supramolecular dendrimers. A thermal-reversible inversion of chirality was discovered in helical supramolecular columns. This inversion is induced, on heating, by the change in symmetry from a 3D columnar simple orthorhombic chiral lattice to a 3D columnar hexagonal array and, on cooling, by the change in symmetry from a 2D hexagonal to a 2D centered rectangular lattice, both exhibiting intracolumnar order. A first-order transition from coupled columns with long helical pitch, to weakly or uncorrelated columns with short helical pitch that generates a molecular rotator, was also discovered. The torsion angles of the molecular rotator are proportional to the change in temperature, and this effect is amplified in the case of the C(3)-symmetric trisamide supramolecular dendrimers forming H-bonds along their column. The structural changes reported here can be used to design complex functions based on helical supramolecular dendrimers with different degree of packing on their periphery.

Zero-valent metals accelerate the neopentylglycolborylation of aryl halides catalyzed by NiCl2-based mixed-ligand systems.

The highly active mixed-ligand catalytic system NiCl2(dppp)/dppf combined with the reducing effect of zerovalent Zn and of other metals was used to demonstrate a method for the dramatic acceleration of the rate and for the enhancement of the yield of Ni-catalyzed neopentylglycolborylation of aryl halides. A diversity of electron-rich and electron-deficient aryl iodides, bromides, and chlorides were efficiently neopentylglycolborylated, typically in 1 h or less. This acceleration is particularly remarkable for the generally less reactive aryl bromides and chlorides and for all ortho-substituted aryl halides. By accelerating the rate of borylation and reducing its reaction time to complete conversion, pathways leading to protodeborylated or hydrodehalogenated side products have a reduced impact on the outcome of the overall reaction. Although Zn powder was the reducing agent of choice, compatibility of this technique with more readily recoverable Zn chips, as well as other metals such as Mn, Mg, Fe, Al, and Ca, has demonstrated the broad scope of this synthetic method.

Self-assembly of hybrid dendrons into doubly segregated supramolecular polyhedral columns and vesicles.

The synthesis and structural analysis of supramolecular dendrimers self-assembled from 3 libraries containing 20 first-generation hybrid dendrons are reported. Combinations of benzyl ether, naphthyl methyl ether, and biphenyl methyl ether repeat units with different alkyl carboxylates at the apex of the dendron decreased its molecular solid angle to values that led to the discovery of a new mechanism of self-assembly. This new self-assembly mechanism generated a diversity of unprecedented supramolecular assemblies, including hollow and nonhollow singly or doubly segregated supramolecular columns and vesicles exhibiting polyhedral shapes. The polyhedral shape of the self-organized supramolecular dendrimers was demonstrated to be an intrinsic characteristic of all the doubly segregated structures. The self-assembly mechanism elucidated here provides access to new strategies that will be used to fabricate complex supramolecular organizations.

Neopentylglycolborylation of ortho-substituted aryl halides catalyzed by NiCl(2)-based mixed-ligand systems.

NiCl(2)-based mixed-ligand systems were shown to be very effective catalysts for the neopentylglycolborylation of aryl iodides, bromides, and chlorides bearing electron-rich and electron-deficient ortho-substituents. Although NiCl(2)-based single-ligand catalytic systems were able to mediate neopentylglycolborylation of selected substrates, they were not as effective for all substrates, highlighting the value of the mixed-ligand concept. Optimization of the Ni(II)-catalyzed neopentylglycolborylation of 2-iodoanisole and methyl 2-iodobenzoate demonstrated that, while the role of ligand and coligand in the conversion of Ni(II) precatalyst to Ni(0) active catalyst cannot be ignored, a mixed-ligand complex is likely present throughout the catalytic cycle. In addition, protodeborylation and hydrodehalogenation were demonstrated to be the predominant side reactions of Ni(II)-catalyzed borylation of ortho-substituted aryl halides containing the electron-deficient carboxylate substituents. Ni(II) complexes in the presence of H(2)O and Ni(0) are responsible for the catalysis of these side reactions.

Self-assembly of Janus dendrimers into uniform dendrimersomes and other complex architectures.

Self-assembled nanostructures obtained from natural and synthetic amphiphiles serve as mimics of biological membranes and enable the delivery of drugs, proteins, genes, and imaging agents. Yet the precise molecular arrangements demanded by these functions are difficult to achieve. Libraries of amphiphilic Janus dendrimers, prepared by facile coupling of tailored hydrophilic and hydrophobic branched segments, have been screened by cryogenic transmission electron microscopy, revealing a rich palette of morphologies in water, including vesicles, denoted dendrimersomes, cubosomes, disks, tubular vesicles, and helical ribbons. Dendrimersomes marry the stability and mechanical strength obtainable from polymersomes with the biological function of stabilized phospholipid liposomes, plus superior uniformity of size, ease of formation, and chemical functionalization. This modular synthesis strategy provides access to systematic tuning of molecular structure and of self-assembled architecture.

Neopentylglycolborylation of aryl mesylates and tosylates catalyzed by Ni-based mixed-ligand systems activated with Zn.

The mixed-ligand system NiCl(2)(dppp)/dppf is shown to be an effective catalyst for the neopentylglycolborylation of ortho-, meta-, and para-substituted electron-rich and electron-deficient aryl mesylates and tosylates. The addition of Zn powder as a reductant dramatically increases the reaction yield and reduces the reaction time by more than an order of magnitude, providing complete conversion in 1-3 h.

Predicting the structure of supramolecular dendrimers via the analysis of libraries of AB3 and constitutional isomeric AB2 biphenylpropyl ether self-assembling dendrons.

The synthesis of 4'-hydroxy-4-biphenylpropionic, 3',4'-dihydroxy-4-biphenylpropionic, 3',5'-dihydroxy-4-biphenylpropionic, and 3',4',5'-trihydroxy-4-biphenylpropionic methyl esters via three efficient and modular strategies including one based on Ni-catalyzed borylation and sequential cross-coupling is reported. These building blocks were employed in a convergent iterative approach to the synthesis of one library of 3,4,5-trisubstituted and two libraries of constitutional isomeric 3,4- and 3,5-disubstituted biphenylpropyl ether dendrons. Structural and retrostructural analysis of supramolecular dendrimers revealed that biphenylpropyl ether dendrons self-assemble and self-organize into the same periodic lattices and quasi-periodic arrays observed in previously reported libraries, but with larger dimensions, different mechanisms of self-assembly, and improved solubility, thermal, acidic, and oxidative stability. The different mechanisms of self-assembly led to the discovery of two new supramolecular structures. The first represents a new banana-like lamellar crystal with a four layer repeat. The second is a giant vesicular sphere self-assembled from 770 dendrons that exhibits an ultrahigh molar mass of 1.73 x 10(6) g/mol. Thus, the enhanced size of the self-assembled structures constructed from biphenylpropyl ether dendrons permitted for the first time discrimination of various molecular mechanisms of spherical self-assembly and elaborated a continuum between small filled spheres and very large hollow spheres that is dictated by the primary structure of the dendron. The comparative analysis of libraries of biphenylpropyl ether dendrons with the previously reported libraries of benzyl-, phenylpropyl-, and biphenyl-4-methyl ether dendrons demonstrated biomimetic self-assembly wherein the primary structure of the dendron and to a lesser extent the structure of its repeat unit determines the supramolecular tertiary structure. A "nanoperiodic table" of self-assembling dendrons and supramolecular dendrimers that allows the prediction of the general features of tertiary structures from primary structures was elaborated.

Neopentylglycolborylation of aryl chlorides catalyzed by the mixed ligand system NiCl2(dppp)/dppf.

The mixed ligand system 10 mol % NiCl(2)(dppp) with 5 mol % dppf was discovered to be an extremely efficient catalyst for the neopentylglycolborylation of a diversity of electron-rich and electron-deficient aryl chlorides. Optimization showed that 5 mol % catalyst with 10% dppf was even more efficient. These results highlight the complexity of the relationship between catalyst and coligand in Ni catalysis and the benefit of combinations of mixed ligand in catalyst design.

Elucidating the structure of the Pm3n cubic phase of supramolecular dendrimers through the modification of their aliphatic to aromatic volume ratio.

The synthesis, and structural and retrostructural analysis of a library of second-generation conical dendrons that self-assemble into spherical supramolecular dendrimers is reported. This library consists of amphiphilic dendrons with n-alkyl groups containing from 4 to 16 carbon atoms. The dendrons containing 6 to 16 carbon atoms in their n-alkyl groups self-assemble into spherical supramolecular dendrimers that self-organize in a Pm3n cubic lattice. The structural and retrostructural analysis of the Pm3n lattices generated from the supramolecular dendrimers demonstrated that the volume of the aromatic core of the spherical dendrimers is not dependent on the number of carbon atoms from their alkyl groups. This result facilitated the calculation of the average values of the absolute electron density of the aliphatic and aromatic domains of the spherical supramolecular dendrimers. The relative intensity of the higher order diffraction peaks of the Pm3n lattice increases as the volume of the aliphatic part of the sphere mediated by the number of carbon atoms in the n-alkyl groups decreases. This study demonstrates the maximum increase of the relative intensity of the higher order diffraction peaks of the Pm3n lattice generated from non-hollow supramolecular dendrimers.

Two-step, one-pot Ni-catalyzed neopentylglycolborylation and complementary Pd/Ni-catalyzed cross-coupling with aryl halides, mesylates, and tosylates.

Two-step, one-pot neopentylglycolborylation of aryl iodides and bromides catalyzed by NiCl2(dppe) and NiCl2(dppp) is reported. Electron-rich and electron-deficient aryl neopentylglycolboronates were efficiently cross-coupled with aryl iodides, bromides, chlorides, mesylates, and tosylates by exploiting complementary Pd/Ni and Ni/Ni catalysis. The borylation route was further extended to a three-step, one-pot synthesis of biaryls via in situ Ni-catalyzed borylation and Pd-mediated cross-coupling.

Sequential Ni-catalyzed borylation and cross-coupling of aryl halides via in situ prepared neopentylglycolborane.

A procedure for NiCl(2)(dppp)-catalyzed pinacolborylation and neopentylglycolborylation that utilizes in situ prepared inexpensive pinacolborane and neopentylglycolborane is reported. The scope of this reaction was demonstrated with a variety of aryl bromides and iodides. The resulting aryl neopentylglycolboronic esters undergo a NiCl(2)(dppe)-catalyzed cross-coupling with aryl halides, resulting in an extremely efficient and cost-effective method for the synthesis of functional biaryls, dendritic building blocks, and other complex architectures.