Noteworthy Chemistry

February 2, 2009

Form bioactive compounds by enantioselective silylation of triols
Use Kepner–Tregoe decision analysis to compare synthetic routes
Coking on catalyst surface sustains olefin hydrogenation activity
pH mediates controlled release from peptide-based nanoparticles
Make a fuel cell without noble metal catalysts
Create ordered mesoporosity in zeolite catalysts
An allylborating reagent helps form functionalized β-amino alcohols

Form bioactive compounds by enantioselective silylation of triols. Polyoxygenated structures appear frequently in biologically active agents. Z. You, A. H. Hoveyda*, and M. L. Snapper* at Boston College (Chestnut Hill, MA) used a common amino acid–based catalyst (1) to mediate enantioselective silylations of

acyclic and cyclic triols with remarkable optical purity. Their study was designed to develop an efficient protocol for enantioselective total syntheses leading to the natural products cleroindicins D, F, and C.

The authors’ initial method used substrates such as meso acyclic 1,2,3-triols to yield monosilylated diols (e.g., 2) with >99:1 enantiomeric ratios (e.r.) and >98% ee in some cases. This method, however, is limited by its dependence on the size of the substituents on the acyclic triol substrates. (TBS is tert-butyldimethylsilyl; TES is triethylsilyl; DIPEA is N,N-diisopropylethylamine.)

The authors subsequently found that when they made monosilylated cyclic diols (e.g., 3), the product’s optical purity was independent of the size of the central alkyl group attached to the ring. In each variant of 3 they studied, they obtained the silylated diols in almost optically pure form (>99:<1 e.r., >98% ee). TBSCl was used with the acyclic substrates, but it was necessary to change to TESCl to obtain optimum optical purity for the cyclic substrates.

A version of the silylated cyclic diol was a key intermediate (4) in the authors’ new synthesis of cleroindicins D (5), F (6) and C (7), demonstrating the value of their method for preparing important bioactive compounds. These cleroindicins were originally isolated from Clerodendum indicum, a plant used in China to treat malaria and rheumatism. (Angew. Chem., Int. Ed. 2009, 48, 547–550; W. Jerry Patterson)

Use Kepner–Tregoe decision analysis to compare synthetic routes. In the first of a three-paper series, J. S. Parker, J. D. Moseley, and co-workers at AstraZeneca (Bristol, UK) describe the use of Kepner–Tregoe decision analysis as a tool for comparing synthetic routes. In the subsequent papers, they show actual applications of this method to some pyruvate dehydrogenase kinase inhibitors.

The first step is to define the intended result of the decision. This is followed by composing a list of the objectives or criteria that will influence the choice of route; the most important objectives probably were identified in the decision statement. The objectives are then categorized as “musts” or “wants”. Musts are mandatory objectives, such as safety requirements; all other objectives are wants.

The relative importance of the wants is defined via a weighting system. The most important want is scored 10, and the others are scored from 1 to 9. All possible routes are then evaluated against the musts, and some are rejected. The surviving routes are then scored against the wants. The best option scores 10, and the others score from 0 and 9. The scores are then multiplied by the weights and totaled to give an overall score for each route. The highest ranking route is the first candidate for development. (Org. Process Res. Dev. 2008, 12, 1041–1043, 1044–1059, 1060–1077; Will Watson)

Coking on catalyst surface sustains olefin hydrogenation activity. Coking (carbon deposition) on catalyst surfaces is one of the main causes of catalyst deactivation. However, M. Wilde, S. Schauermann, and coauthors at the University of Tokyo and the Fritz Haber Institute of the Max Planck Society (Berlin) report that coking is actually good for the catalytic hydrogenation of olefinic double bonds.

The traditional belief is that only surface hydrogen species are involved in hydrogenation reactions. But the authors found that olefin hydrogenations over palladium nanoparticles supported on Fe₃O₄/Pt(111) films or Al₂O₃/NiAl(110) substrates depend on the presence of weakly bound hydrogen that is absorbed within the palladium particle volume. They also found that a sub-monolayer covering of carbon significantly affects the depth of hydrogen distribution in the nanoparticles and promotes persistent hydrogenation activity. Promotion of sustained hydrogenation by the carbonaceous deposits is attributed to the facilitation of hydrogen diffusion from the surface to the bulk of the nanoparticles, which allows rapid replenishing of the volume-absorbed hydrogen atoms. (Angew. Chem., Int. Ed. 2008, 47, 9289–9293; George Xiu Song Zhao)

pH mediates controlled release from peptide-based nanoparticles. A. Chilkoti, R.L. Clark, and colleagues at Duke University (Durham, NC) evaluated electrospraying (see image) as a processing tool for developing peptidic nanoparticles for therapeutic delivery. They examined the role of glutamic acid–containing elastin-like polypeptide (ELP) molecular weight and concentration, electrospray voltage, and flow rate on the structure and size of the ELP nanoparticles.

For high molecular weight (70.2 kDa) ELP, a concentration of 0.01 w/v, and a flow rate of 0.05 mL/h, the authors determined that the structure of the ELP nanoparticles shifted from a mixture of particles and fibers to particles with fibrous tails as the electrospray voltage increased from 7 to 9 kV. At 0.1 mL/h, the predominantly fibrous morphology shifted to spherical particles with fibrous tails as the voltage increased. When the ELP molecular weight was lowered to 17.8 kDa (0.01 w/v, 0.05 mL/h), smooth, spherical nanoparticles with minimal tail structures appeared at voltages between 7 and 9 kV. More uniform, larger, and spherical ELP particles developed upon flow rate increase to 0.1 mL/h. The authors generated hollow ELP nanoparticles by lowering the ELP concentration to 0.005 w/v (0.05 mL/h, 17.68 kDa). Increasing the flow rate to 0.1 mL/h shifted the surface morphology of these ELP nanoparticles from smooth to collapsed.

The authors also examined the release characteristics of ELP nanoparticle loaded with doxorubicin (Dox) by exploiting the pH-dependent inverse phase transition temperature of the ELP amino acid sequence. They suggest that the Dox release profile is governed by the solubility of ELP at various pH values and could provide new strategies for thermally governed controlled drug release An insoluble ELP coacervate phase forms at 37 °C and pH 2.5, permitting only ~70% Dox release. But ELP is soluble at pH 7.5, and gives >90% release within 15 min. (Biomacromolecules 2009, 10, 19–24; LaShanda Korley)

Make a fuel cell without noble metal catalysts. Polymer electrolyte fuel cells based on proton-exchange Nafion membranes can effectively separate the fuel (hydrogen) from the oxidant (oxygen), but they depend on expensive platinum catalysts because the membranes are strongly acidic. To avoid noble metal catalysts, an alkaline electrolyte must be used. L. Zhuang and co-workers at Wuhan University (China) developed an alkaline polymer electrolyte fuel cell (APEFC) that contains a quaternary ammonium polysulfone (QAPS) as a polymer electrolyte capable of hydroxyl transport.

QAPS is structurally similar to Nafion, thermally stable, and soluble in some organic solvents, so it is possible to cast it into membranes and to impregnate catalytic layers. It shows high ionic conductivity and good mechanical properties.

Because a nickel anode is not suitable for APEFCs, the authors performed a density functional theory (DFT) study of the system. The DFT calculations indicated that modifying the nickel with certain metal oxides might make it usable in APEFCs, and the authors designed a chromium-decorated nickel (CDN) anode. Their fuel cell consists of a QAPS membrane, a CDN anode, and a silver cathode. Oxygen is reduced at the cathode in presence of water to produce hydroxide ion, which transfers to the anode and reacts with hydrogen to produce H₂O and release electrical energy from the system. The maximum power density of the cell is 50 mW/cm², and it is stable for >100 h.

The authors note that in addition to providing noble metal–free fuel cells, this system can in principle use other sources of hydrogen (e.g., borohydrides) that are acid-sensitive. (Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 20611–20614; José C. Barros)

Create ordered mesoporosity in zeolite catalysts. Shaping microporous zeolites into 3-D ordered mesoporous structures is important for improving the performance of zeolite catalysts. M. Tsapatis and co-workers at the University of Minnesota (Minneapolis) report a promising method for making zeolite catalysts with mesopores.

The authors developed a four-step procedure:

Monodisperse colloidal silica spheres are used to form colloidal crystals via a self-assembly process.
The colloidal crystals are used as templates to make porous carbon.
The carbon is then used as a template for zeolite synthesis.
The carbon is removed to leave behind a hierarchical zeolite.

Transmission electron microscopy (TEM) and small-angle X-ray scattering (SAXS) data showed that the silica nanoparticles have a high degree of monodispersity. Scanning electron microscopy images, nitrogen adsorption, and SAXS data verified that the replicated porous carbon has a highly ordered mesoporous structure. TEM images showed that the replicated zeolite is faceted and isolatable. SAXS results showed that the replication process is conducted with high precision. Wide-angle X-ray scattering and small-angle electron diffraction patterns confirmed that the replicated zeolite is highly crystalline.

To demonstrate the tunability of the zeolite nanocrystal size, the authors synthesized 40- and 20-nm hierarchical zeolites. The high precision and reproducibility of the process make it a promising method for making other materials with similar structures. (Nat. Mater. 2008, 7, 984–991; George Xiu Song Zhao)

An allylborating reagent helps form functionalized β-amino alcohols with high optical purity. B. Soto-Cairoli and J. A. Soderquist* at the University of Puerto Rico (Rio Piedras) sought an efficient strategy for allylation of chiral α-amino aldehydes that would provide a simple entry to useful O-TIPS–protected β-amino alcohol derivatives. (TIPS is triisopropylsilyl.) They found that the innovative allylborane B-allyl-10-trimethylsilyl-9-borabicyclo[3.3.4]decane (1) is an ideal reagent for allylating optically pure α-amino aldehydes (2) and leads to a general method for the asymmetric synthesis of O-TIPS protected β-amino alcohols (3). The extremely selective 1 converts substrate 2 under mild conditions to a single isomeric amino alcohol in which the newly formed stereogenic center is determined solely by the enantiomer of 1 used for the reaction.

The authors developed an efficient protocol by using dry AcOH to effect the smooth migration of the TIPS group from the nitrogen atom to oxygen to give a series of products typified by 3. The products consistently formed with high enantiomeric purity (>99% ee) and >96% diastereomeric purity. They also used an N-Boc protected variant of 3 to demonstrate the practicality of this procedure, progressing in several steps to form two important leucine-based bioactive compounds, statine and epistatine.

The authors believe that completely predictable stereochemistries can be achieved in products represented by 3 simply by the appropriate choice of reactants 1 and 2. This method also reflects the powerful utility of silicon for organoborane conversions. (Org. Lett. 2009, 11, 401–404; W. Jerry Patterson)