Noteworthy Chemistry

August 1, 2011

This total synthesis includes four consecutive reactions in one pot. The natural product isofregenedadiol (1) is a bicyclic diterpene isolated from the shrub Halimium viscosum. Although biological activity of 1 has not been reported, a series of related bioactive diterpenes known as labdanes exhibit a broad spectrum of antibacterial, antifungal, antiprotozoal, and anti-inflammatory activity.

D. S. Reddy and co-workers at Advinus Therapeutics (Pune, India) report the first total enantiospecific synthesis of 1 via an unusual one-pot quadruple reaction process that combines two metathesis reactions, a Diels–Alder cyclization, and an aromatization step.

The synthetic strategy for the key enyne precursor 5 is based on commercially available chiral lactone D-(–)-pantolactone (2), which is converted to known oxirane 3 with a primary alcohol protected as a p-methoxybenzyl ether (OPMB). The oxirane ring in 3 is regioselectively ring-opened with an allyl Grignard reagent to create a tert-butyldimethylsilyl (TBS) ether of newly formed secondary alcohol 4; Tf is trifluoromethanesulfonyl. Deprotection followed by Swern oxidation leads to an aldehyde (not isolated) that immediately forms enyne 5; DDQ is 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.

Structure 5 then undergoes this one-pot sequential process:

  1. Enyne ring-closing metathesis with the Grubbs II catalyst
  2. Cross metathesis (using the same catalyst) with alkene 6 prepared from (S)-(–)-citronellol
  3. Diels–Alder [4 + 2] cyclization with dienophile dimethylacetylenedicarboxylate (7) to form the cyclohexane ring in compound 8
  4. Oxidative aromatization to form the aromatic ring in 8 and complete the desired tetrahydronaphthalene scaffold

Reducing the ester groups in 8 gives first the corresponding diol, then dibromide 9 Benzyl group deprotection forms target structure 1. The authors confirmed the structure of 1 with single-crystal X-ray analysis and by comparing its spectral data with those of the authentic natural product. This example of a one-pot, quadruple synthetic sequence should be useful for making other complex bioactive compounds efficiently. (Org. Lett. 2011, 13, 3690–3693; W. Jerry Patterson)

Cyanide stimulates seed germination. Wildfires are widely recognized to promote seed germination by releasing bioactive substances such as karrikinolide (1) in smoke. G. Flematti and coauthors at the University of Western Australia (Crawley), Kings Park and Botanic Garden (West Perth, Australia), and Murdoch University (Australia) report the existence of another germination stimulant in smoke.

The authors observed that plant smoke that does not contain 1 stimulates the germination of kangaroo paw (Anigozanthos manglesii). Aqueous extracts of the bioactive constituents of the smoke are much more polar than 1. Workup of the extracts showed that 2,3-dihydroxypropanenitrile (glyceronitrile, 2) is the active compound.

The authors tested the effect of 2 on seeds of other plants, including the flowering plant Rhodocoma arida, which—like A. manglesii—responds poorly to karrikinolide. They confirmed germination activity and discovered that both enantiomers of 2 promote germination equally well. Cyanohydrins 36 and KCN solutions also stimulate germination, indicating that cyanohydrin hydrolysis produces cyanide ion, which is the active germination stimulant.

The authors found that the release of cyanide from cyanohydrins is spontaneous, not the result of enzymatic degradation; the mechanism of cyanide-stimulated germination, however, is not completely understood. This study may help scientists understand the evolutionary adaptation of plants to fire. (Nat. Commun. 2011, 2, 360 DOI: 10.1038/ncomms1356, JosÉ C. Barros)

Chain-growth polycyclotrimerization of triynes yields linear, not branched, modified polyphenylenes. Alkyne polycyclotrimerization generally produces polyphenylenes with hyperbranched structures because the cycloaddition reaction proceeds through the formation of nonlinear multisubstituted benzenes. S. Okamoto and co-workers at Kanagawa University (Yokohama) report the synthesis of linear polyphenylenes by an elegant molecular structure design that exploits the difference in reactivity between yne and diyne units of the triyne monomer.

The triple bond of the propargyl unit (red in the figure) selectively undergoes cycloaddition with the triple bonds of the diyne unit (blue) in triyne monomer 1 in the presence of a cobalt-complex catalyst. The polycyclotrimerization of 1 propagates by a chain-growth mechanism to give linear polyphenylene 2 with controllable molecular weight, narrow molecular weight distribution, and high yields.

The researchers also took advantage of large differences in monomer polymerizability to synthesize a block polyphenylene copolymer in one step instead of multiple steps from a mixture of two triyne monomers. (J. Am. Chem. Soc. 2011, 133, 9712–9715; Ben Zhong Tang)

Rearranging synthetic steps decreases environmental impact. The goal of J. Liu and co-workers at Johnson & Johnson Pharmaceutical Research and Development (San Diego) was to improve the synthesis of a transient receptor potential vanilloid inhibitor that contains a thiazolopyrimidine core. The process mass intensity (PMI) of the initial route was »1000, indicative of an adverse environmental impact (e.g., poor yields and excessive waste generation) if the process were scaled up.

The order of steps in the initial route was

  1. Conversion of a dichlorophenylacetic acid to its acid chloride
  2. Acylation of 5-amino-4,6-dichloropyrimidine with the acid chloride
  3. Thiazole ring formation with thiourea
  4. Replacement of a hydroxyl group on the pyrimidine ring with chlorine
  5. SNAr displacement of the chlorine atom by 4-trifluoromethylaniline

Carrying out the SNAr displacement first makes the subsequent acylation easier and gives a much better yield. Thiolation is carried out using thiourea, and cyclization with HCl in dimethylacetamide gives the final product with a PMI of only 118 before optimization. (Org. Process Res. Dev. 2011, 15, 382–388; Will Watson)

Correlated super-resolution imaging pinpoints SERS hotspots. Randomly aggregated silver colloids are one of the best substrates for surface-enhanced Raman scattering (SERS) studies. Although theoretical studies predict that the greatest electromagnetic field enhancements occur in junction regions between aggregated particles, experimental studies have lacked the ability to precisely locate the intensified Raman scatter from within a junction region to validate the predictions.

M. L. Weber and K. A. Willets* at the University of Texas at Austin report an example of correlated optical and structural studies of rhodamine 6G (R6G) adsorbed onto silver colloid aggregates. Their work validates the prediction that the most intense scattering occurs in junction regions. Using super-resolution optical imaging, the authors showed a spatial relationship between the SERS emission site and the intensity of that emission for individual R6G-labeled silver colloid aggregates (“A” images in the figure).

After optical analysis, the same SERS-active aggregates were imaged in a scanning electron microscope (SEM) for structural analysis (“B” images). By resizing the spatial intensity maps to match the scale of the SEM images, the two pieces of data can be overlaid, as shown in the “C” panels.

The authors found excellent agreement between the shape and gradient nature of the spatial intensity maps and the size and angular position of the junction regions in the aggregates, indicating that the most intense SERS occurs in junction regions. This work represents an important step toward developing robust SERS substrates through a better understanding of the influence of colloid shape and size and junction region morphology. (J. Phys. Chem. Lett. 2011, 2, 1766–1770; Gary A. Baker)

Here’s a new type of anion-exchange membrane for fuel cells. Fuel cells are a promising energy source and have the potential to reshape our power system. Many researchers in academia, industry, and government are working on making high-performance ion-exchange membranes that are reliable and inexpensive. A. Pucci and coauthors at the University of Pisa, Acta S.p.A. (Crespina), the CNR Institute of Nanoscience (Pisa), INSTM (Pisa), and Spin-Pet s.r.l. (Pisa, all in Italy) developed a new type of anion-exchange membrane with a grafted structure.

An ideal membrane should be chemically stable and have high ionic conductivity. The authors used a common synthetic rubber, the triblock copolymer polystyrene-b-polybutadiene-b-polystyrene (SBS), to form the membrane and quaternary ammonium units for the cationic sites.

To graft ammonium groups onto the polymer, the authors first treated the polybutadiene blocks with p-vinylbenzyl chloride via radical polymerization (1). The reaction of the chlorine functionality with the aliphatic diamine 1,4-diazabicyclo[2.2.2]octane (DABCO) adds the cationic side chain (2). Moderate cross-linking of the polymer chains also occurs (3).

The anion conductivity of the authors’ membranes is much greater than that of an industry standard. The membranes, however, swell, in water, and the cross-linking efficiency and membrane stability must be improved. (J. Polym. Sci. Part A: Polym. Chem. 2011, 49, 3437−3447; Sally Peng Li)

Synthesize 2-imidazolones in one pot. The 2-imidazolone scaffold is a key structural feature in pharmaceutically useful compounds such as human dopamine D4 receptor antagonists, enzyme inhibitors, and potential antitumor agents. D. S. Ermolat’ev, E. V. Van der Eycken, and coauthors at Leuven Catholic University (Belgium) and the University of Delhi (India) devised a synthetic strategy for 2-imidazolones based on Ag(I)-mediated cycloisomerization of secondary propargylamines (e.g., 1) with aryl isocyanates (2).

The process is carried out sequentially and efficiently in one pot. The method takes advantage of the ready availability of secondary propargylamines prepared by the authors’ recently reported coupling synthesis (Bariwal, J. B.; Ermolat’ev, D. S.; Van der Eycken, E. V. Chem.—Eur. J. 2010, 16, 3281–3284).

A key to the process is in situ acylation that leads to the formation of propargylic urea derivative 3. This provides a structure conducive to cycloisomerization to the target 2-imidazolone core 4 in yields as high as 94%.

A modification of the synthesis that uses fully substituted reactants produces tetrasubstituted 2-imidazolones, illustrated by structure 5, with yields as high as 72%. Typical yields, however, were only fair in a small library of 12 products. The four diverse substituents obtained by this degree of substitution provide a potentially useful route to biologically active 2-imidazolones. (J. Org. Chem. 2011, 76, 5867–5872; W. Jerry Patterson)

What do you think of Noteworthy Chemistry? Let us know.