Noteworthy Chemistry

March 14, 2011

Synthesize pentacyclic luotonin A in one pot. The alkaloid luotonin A (1) has useful cytotoxicity in vitro against the murine leukemia P-388 cell line with an IC50 of 6.3 μM. Whereas 1 is not potent enough for cancer chemotherapy, it may be a useful scaffold for more bioactive structures.

Y.-H. Chu and coauthors at National Chung Cheng University (Chiayi), Academia Sinica (Taipei), and Taipei Medical University (all in Taiwan) devised a self-directed, one-pot process that simultaneously forms the quinazoline and pyrroloquinoline cores in pentacyclic structure 1.

The synthesis uses commercially available, inexpensive isatoic anhydride (2) as the starting structure. Treating 2 with propargylamine (3) forms aminobenzamide 4 in situ. The subsequent ytterbium trifluoromethanesulfonate–mediated reaction with aniline and glyoxal triggers the reaction sequence that forms target structure 1 in 35% isolated yield.

The authors visualize this reaction cascade as a sequence consisting of imine formation, quinazolinone formation, an intramolecular aza-Diels–Alder reaction, dehydrogenation, and aromatization. They modified the synthesis by varying the substituents on the A ring of 1 (compounds 5 and 6) and expanding the C ring to form 7. The three modified structures are more potent inhibitors than parent compound 1 at a concentration of 5 μM, and they demonstrate the value of 1 as a starting point for other bioactive compounds.

The sequence that produces 1 features a one-pot route and an air- and water-stable catalyst. It does not require special reaction conditions such as harsh acids or bases, and isolation and purification of intermediates are unnecessary. (Org. Lett. 2011, 13, 920–923; W. Jerry Patterson)

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Molecular adsorption leads to supramolecular nanostructures. Forming molecular nanopatterns via selective trapping by surface nanotemplates is a promising route to ordered nanostructures with desired functionalities across macroscopic areas for nanodevice applications. Whereas many porous nanotemplates trap molecules in their geometrical voids, their nonporous counterparts have rarely been explored. Y. L. Huang, W. Chen*, and A. T. S. Wee* at the National University of Singapore created nonporous nanotemplates and demonstrated their usefulness for making supramolecular nanostructures.

The nanotemplates are hydrogen-bonded binary molecular networks of copper hexadecafluorophthalocyanine (CuF16Pc) with diindenoperylene or p-sexiphenyl. When a second layer of CuF16Pc molecules is deposited onto the nanotemplates, the molecules are adsorbed on the first layer via intermolecular π–π interactions, forming CuF16Pc molecular dots or chains.

The authors believe that this preferential adsorption on specific molecular sites of a binary molecular nanotemplate will be an ideal model for studying intermolecular interactions and kinetic growth processes on the atomic scale. (J. Am. Chem. Soc. 2011, 133, 820–825; Ben Zhong Tang)

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Use kinetics along with design of experiments for optimization. L. Massari, S. Bacchi, and co-workers at GlaxoSmithKline (Verona, Italy, and Stevenage, UK) describe the development and optimization of an SN2 substitution reaction between 3-chloropropylthiotriazole and an arylazabicyclo[3.1.0]hexane. In the initial design of experiments (DoE) studies, they investigated the effect of varying the levels of the two reactants and two reagents, KI and Et3N. In a second study, they added the effects of temperature and concentration. The DoE studies showed that the reaction conditions are not robust, but they did not identify better conditions within the ranges studied.

The authors then generated a kinetic model of the reaction with DynoChem software (DynoChem, Wilmington, DE). Simulation studies using DynoChem suggested that higher levels of Et3N would be beneficial, and this prediction was confirmed in practice—but without data on robustness. A DoE simulation of 86 experiments using a central composite design was carried out with the software. Finally, three lab runs confirmed the optimized conditions. (Org. Process Res. Dev. 2010, 14, 1364–1372; Will Watson)

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3,5,4’-Tri-O-acetylresveratrol protects against γ radiation. Ionization radiation (γ radiation) from radiotherapy or nuclear accidents is harmful and even fatal. No drugs are available to protect humans from this radiation. Because γ radiation generates superoxide radicals, antioxidants such as thiols have been tested to mitigate the effects of γ rays. The side effects of these compounds, however, make them unusable.

K. Koide, M. W. Epperly, and co-workers at the University of Pittsburgh investigated the use of resveratrol and its acetylated derivative 3,5,4’-tri-O-acetylresveratrol (1) to protect against γ radiation. Both compounds are natural products, but the hydroxyl groups in unacetylated resveratrol give it poor pharmacokinetic and bioavailability properties.

The authors measured radioprotective activity in vivo by intraperitoneally injecting mice with solutions of the compounds and then exposing them to radiation. They observed a significant survival rate of 80% when they used compound 1. They attribute the acetylated derivative’s activity to enhanced bioavailability provided by its ester groups. The combination of ethanol, water, and Cremophor EL (a nonionic surfactant) used to deliver 1 prevents ester group hydrolysis in vivo and results in a half-life of 48 min, which contributes to better distribution in animal tissues.

The authors ascribe resveratrol and its acetylated derivative’s mechanism of action to radical scavenging, but they do not exclude other mechanisms. Because 3,5,4’-tri-O-acetylresveratrol is easy to prepare from resveratrol and does not have side effects, it has the potential for mass oral delivery for radioprotection, and it is a lead compound for developing new radioprotective agents. (ACS Med. Chem. Lett. 2011, 2, Article ASAP DOI: 10.1021/ml100159p, José C. Barros)

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Polyimide aerogels make good insulators. H. Gui, M. A. B. Meador, and colleagues at Ohio Aerospace Institute (Cleveland), NASA Glenn Research Center (Cleveland), and the National Polymer Innovation Center (Akron, all in OH) explored the synthesis and characterization of aerogels derived from polyhedral oligomeric silsesquioxane cross-linked polyimides for insulating applications. Specifically, they used octa(aminophenyl) silsesquioxane and an oligomeric polyimide synthesized from 3,3’4,4’-biphenyltetracarboxylic dianhydride and bisaniline-p-xylidene to form opaque, yellow mesoporous gels with minimal shrinkage.

Depending on the length of the oligomer (n = 10, 15, 20, or 25), the gelation time ranged from 30 min to 1 h; the 25-unit oligomer had the longest time. The porosity (~90%) and Brunauer−Emmett−Teller surface area (~250 m2/g) remained relatively constant regardless of oligomer length. Length, however, influenced the pore size distribution: Longer polyimide oligomers gave narrower distributions.

The microstructure of these highly thermally stable polyimide aerogels consisted of entangled fibers with 15–50 nm diam. The compressive modulus decreased from ~5.3 to ~1.7 MPa as the polyimide oligomer length increased from 10 to 25 units. Flexible aerogel films (n = 25) were also prepared; they had a thermal conductivity of 14.4 mW/(m·K) at ambient temperature and pressure. (ACS Appl. Mater. Interfaces 2011, 3, 546–552; LaShanda Korley)

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Compensate for volume contraction during cross-linking. When polymers are cross-linked, their volume often shrinks, and this can affect the physical properties of the resulting materials. Significant shrinkage during cross-linking may lead to structural collapse and mechanical loss. Few methods are available to suppress this shrinkage effect.

S. Lin-Gibson and coauthors at the National Institute of Standards and Technology (Gaithersburg, MD) propose a method to control shrinking by generating pores during cross-linking.

The authors used 1,3-acetonedicarboxylic acid (ADCA, 1) to form pores during cross-linking. Their polymer matrix was an oligomer of ethoxylated bisphenol A dimethacrylate (2), which has two reactive double bonds. Methacryloyloxyethyl succinate (3) was used as an additive to enhance the solubility of ADCA in the bulk oligomer.

In the presence of photoinitiator phenylbis(2,4,6-trimethylbenzoyl)phosphine oxide (4), UV radiation induces the oligomer units to couple covalently. The released heat decomposes ADCA and liberates CO2 gas, which is trapped in the 3-D polymer network. The volume contraction caused by chemical reactions is minimized by gas diffusion. Neither the mechanical strength nor the elasticity of the final polymeric material decreases. (Adv. Mater. 2011, 23, 409–413; Sally Peng Li)

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Use a chiral template to prepare pyrrolidines stereoselectively. Optically pure pyrrolidine derivatives are often used to synthesize bioactive molecules. These compounds demonstrate a wide spectrum of activity as antibacterial, antifungal, and cytotoxic agents.

X.-W. Liu and co-workers at Nanyang Technological University (Singapore) describe the efficient use of carbohydrates as chiral auxiliaries in a [3 + 2] cycloaddition of carbohydrate-based allenes and imines that leads to the formation of the pyrrolidine ring.

A key feature of this process is the use of a tert-butyldimethylsilyl (TBS) ether–protected carbohydrate auxiliary, which provides high diastereoselectivity and prevents aggregation during the formation of the lithiated allene intermediate. In a typical procedure, allene 1 is treated with LiCl, then n-BuLi, to form a strong nucleophile for cycloaddition to imine 2; Ts is p-toluenesulfonyl. This reaction is mediated by a silver catalyst to form the desired pyrrolidine derivative 3 in high yields and up to 95% diastereoselectivity. The range of substituents on the imine reactant makes this technique flexible.

The chiral auxiliary is easily removed and recovered by using Danishefsky’s method (Halcomb, R. L., et al. J. Am. Chem. Soc. 1995, 117, 5720–5749). This step generates free pyrrolidine 4 in almost optically pure form and high yield.

The authors demonstrated the potential utility of the pyrrolidine derivative for subsequent syntheses by its simple, mild NaBH4 reduction to the corresponding alcohol. This conversion is carried out with almost complete preservation of diastereoselectivity. (Org. Lett. 2011, 13, 1072–1075; W. Jerry Patterson)

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