Noteworthy Chemistry

October 12, 2009

Hydroacylation reactions with unfunctionalized aldehydes
Relaxation modes of polyelectrolyte chains in salt-free dilute solutions
An organocatalytic synthesis of β-blockers
Particle size and shape effect on ruthenium/γ-alumina catalyst activity
Base-assisted polyimide chain growth with the silylation method
Control of assembly and rheology in multidomain peptides
Highly functionalized thiazoles: new tubulin polymerization inhibitors

Make unfunctionalized aldehydes highly reactive in hydroacylation reactions. The enantioselective reaction of alkenes with aldehydes is limited by the need for functionalized aldehydes. Many examples of these reactions also require intramolecular product formation.

Y. Shibata and K. Tanaka* at Tokyo University of Agriculture and Technology (Japan) have extended the scope of this synthesis. They report a successful strategy that combines unfunctionalized aldehydes and 1,1-disubstituted alkenes via a rhodium-catalyzed intermolecular method. A key to their success is the selection of a monoaromatic bisphosphine ligand QuinoxP (1) that leads to γ-ketoamide products (e.g., 2). The reaction features high yields and enantiomeric excesses and low catalyst loadings.

Various acrylamides serve as the 1,1-disubstituted alkene reactant. With only one exception, 15 variants of this reaction yielded almost optically pure products. The authors extended their technique to a trisubstituted alkene (3) with the ligand 1,2-bis(diphenylphosphino)benzene (dppb) to give a modest yield of hydroacylation product 4 with perfect diastereoselectivity and high enantioselectivity. This method demonstrates the successful entry of unsubstituted aldehydes into direct intermolecular hydroacylation reactions. (J. Am. Chem. Soc. 2009, 131, 12552–12553; W. Jerry Patterson)

What are the origins of the fast and slow modes in the relaxation processes of polyelectrolyte chains in salt-free dilute solutions? It is well known that salt-free polyelectrolyte solutions relax by fast and slow modes. The dynamics, however, are not well understood, and at times controversial mechanisms have been proposed. To understand the dynamics of the process in a salt-free polyelectrolyte solution, C. Wu and coauthors at the Shanghai Institute of Organic Chemistry, the University of Science and Technology of China (Hefei), and the Chinese University of Hong Kong (Shatin) designed and synthesized an amidine-containing copolymer.

The copolymer undergoes a neutral–charged–neutral transition when its solution in DMF with 0.5% water is alternatively bubbled with CO₂ and nitrogen gases. There is only one diffusive relaxation mode in the neutral state, but bubbling with CO₂ splits the single mode into fast and slow diffusive modes. Changing back to nitrogen eliminates the slow mode and brings the solution dynamics back to the neutral state.

The researchers attribute the fast mode to coupled diffusion that originates from a convective current generated by an induced electric field. The field is derived from the fluctuation of all charged species in the solution on a short time or length scale. The slow mode is not related to large objects, but to slowly moving scattering objects, which supports the authors’ assumption of retarded self-diffusion. (Macromolecules 2009, 42, 7146–7154; Ben Zhong Tang)

Here’s an organocatalytic synthesis of β-blockers. Organocatalytic asymmetric synthesis is an emerging

technique in organic synthesis that is mainly used to obtain chiral building blocks. Asymmetric β-aminoxylation of aldehydes catalyzed by proline enantiomers in low catalyst loadings gives enantiomerically enriched 1,2-diols. U. R. Kalkote and co-workers at the National Chemical Laboratory (Pune, India) used this strategy to synthesize 3-aryloxy-1,2-propanediol as part of the syntheses of the β-blockers (S)-propranolol and (S)-naftopidil.

Using α-naphthol and 3-bromopropanol as starting materials, the authors prepared alcohol 1 and oxidized it to aldehyde 2 using 2-iodoxybenzoic acid. The reaction of 2 with PhNO in the presence of 20 mol% L-proline, NaBH₄ reduction, and palladium-catalyzed hydrogenation led to chiral building block 3 in 78% yield and 98% optical purity. Epoxidizing 3 under Mitsunobu conditions (PPh₃ and diisopropyl azodicarboxylate) to give 4, epoxide opening with i-PrNH₂, and treatment with HCl gas provided (S)-propranolol hydrochloride (5) in an overall yield of 26% and >98% ee.

In a second synthesis, ring-opening epoxide 4 with 1-(2-methoxyphenyl)piperazine gave (S)-naftopidil (6) in 26% overall yield and >98% ee. This highly enantioselective, experimentally simple, environmentally friendly synthesis of β-blockers uses readily available starting materials. (Tetrahedron: Asymmetry 2009, 20, 1767–1770; José C. Barros)

Particle size and shape affect ruthenium/γ-alumina catalyst activity. Nanotechnology plays increasingly important roles in catalysis. Many studies have investigated the relationship between catalytic activity and particle morphology. D. G. Vlachos and coauthors at the University of Delaware (Newark) and Yeshiva University (New York City) prepared ruthenium nanoparticles with particle sizes ranging from 0.8 to 7.5 nm with γ-Al₂O₃ as the catalyst support, and they studied the catalyst’s behavior in the NH₃ decomposition reaction.

The researchers found that ruthenium particle shape changes with particle size from round for smaller particles to flat and elongated for larger particles. The turnover frequency (TOF) of NH₃ decomposition increased by almost 2 orders of magnitude when ruthenium particle size increased from 0.8 to 7.5 nm. The maximum TOF (based on total exposed Ru atoms) and number of active sites occurred at ~7 nm particle size for elongated nanoparticles.

The authors used a microkinetic model to describe the relationship between activity and catalyst size and shape and to estimate the fraction of active sites. Experimental and theoretical data suggest that the low catalyst activity measured for small nanoparticles is the result of particle size polydispersity. (J. Am. Chem. Soc. 2009, 131, 12230–12239; George Xiu Song Zhao)

Bases foster polyimide chain growth with the silylation method. Polyimides are synthetic resins with thermal stability, chemical resistance, and excellent mechanical properties. Polycondensation, the usual method for synthesizing polyimides, is problematic because the water produced can hydrolyze the starting anhydrides.

The “silylation method” generates more reactive silylated diamine reactants, but the polymers have low molecular weights. Adding pyridine favors polymer chain growth somewhat. A. E. Lozano and co-workers at the Institute of Polymer Science and Technology of the Spanish National Research Council (Madrid) studied the effect of various bases on the polymerization and made significant progress in synthesizing polyimides, especially from relatively inert diamine compounds.

4,4’-(Hexafluoroisopropylidene)dianiline (1) and 4,4’-diaminodiphenyl sulfone (2) are nucleophiles that have low reactivity. In silylated systems, neither reacts well with 3,3’,4,4’-(hexafluoroisopropylidene)diphthalic anhydride (3) to form high molecular weight polyimides. However, the authors show that adding base improves these reactions. In the presence of the silylating agent Me₃SiCl, bases 4–7 foster polymer chain growth significantly. The combination of 4 and 5 in a 10:1 ratio increases the polymer’s molecular weight to 3 times that obtained in a control experiment without the bases. (Macromolecules 2009, 42, 5892–5894; Sally Peng Li)

Control assembly and rheology in multidomain peptides by noncovalent and covalent interactions. L. Aulisa, H. Dong, and J. D. Hartgerink* at Rice University (Houston) have implemented a balanced design to produce multidomain peptides (MDPs) with controlled self-assembly behavior that can modulate mechanical response under physiological conditions. They developed MDPs (1 wt%) in β-sheet conformation with an ABA structure, in which the peripheral A block is the negatively charged polypeptide glutamic acid (E) that promotes electrostatic repulsion and can be noncovalently cross-linked by multivalent cations. The internal B block primarily incorporates the covalently cross-linked, hydrophilic, neutral amino acid serine (S), with or without cysteine (C) residues.

The authors observed that nanofiber length and structure were not affected by substituting positively charged lysine (K) for E in the A domain and that the differences in storage modulus were minimal before and after noncovalent cross-linking. However, longer and more highly entangled fibers with comparable fiber diameter (6 nm) formed when S replaced glutamine (Q) in the middle B domain, indicating significant differences in mechanical and rheological behavior (e.g., shear thinning and strength recovery). For example, substituting S for Q in negatively charged (E capped) MDPs in the presence of Mg²⁺ increased storage modulus from 99 to 482 MPa. MDPs that were partially modified with C in the B block had a dramatic increase in fiber length, entanglement structure, and storage modulus (101 to 6149 MPa) because of covalent cross-linking, which occurred via disulfide bridges formed under mild oxidative conditions. (Biomacromolecules 2009, 10, 2694–2698; LaShanda Korley)

Highly functionalized thiazoles represent a new class of tubulin polymerization inhibitors. Cancer cells can grow and metastasize via continuous mitotic division. Mitotic inhibitors prevent cancer growth by disrupting microtubule polymerization. The widely used anticancer drug paclitaxel is an example of a mitotic inhibitor.

R. Romagnoli, P. G. Baraldi, and coauthors at the University of Ferrara (Italy), the University of Padua (Italy), the Rega Institute for Medical Research (Leuven, Belgium), Cardiff University (UK), the University of Regensburg (Germany), and the National Institutes of Health (Frederick, MD) note that previously developed molecules such as 2-aminobenzophenone derivatives (e.g., 1) strongly inhibit cancer cell growth and tubulin polymerization and

arrest mitotic division. More recently, compounds such as 2 with a 2-arylaminothiazole nucleus were found to inhibit microtubule polymerization by interfering with the colchicine site of tubulin. Based on the structure–activity relationships of these compounds, the authors synthesized a new series of 2-arylamino-4-amino-5-aroylthiazole structures (3) in which the previously identified pharmacologically active sites (3-amino and 2-aroyl moieties) were “built” into the 4- and 5-positions of the new structures.

The synthesis of a series of 25 structures with substituents on the A or B ring in 3 was carried out using a simple one-pot, three-component reaction that combined phenyl isothiocyanates, α-bromoketones, and cyanamide in a 1:1:1 ratio, with in situ–generated NaOMe as the required base. This series was evaluated for its activity against a panel of five tumor cell lines, using the known antiproliferative compound combretastatin A-4 as a reference substance. The authors found that compound 4 had the highest overall cytostatic potency on the basis of IC₅₀ values. (IC₅₀ is the concentration required to inhibit tumor cell proliferation by 50%.) They also observed that electron-releasing groups (ERGs) on the A ring enhanced antiproliferative activity, whereas electron-withdrawing groups (EWGs) reduced such activity. Comparison of ERGs and EWGs on the B ring indicated that substituents with opposite electron effects showed similar potency. (J. Med. Chem. 2009, 52, 5551–5555; W. Jerry Patterson)