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Platensimycin update

31 January 2009 - Total synthesis

Quick update on platensimycin total synthesis with two stragglers (see earlier post here). Matsuo et al. (DOI) create the tetracyclic core in a radical reaction akin the Barton-McCombie deoxygenation:

The synthesis of the precursor molecule is a thiol ene reaction with thiophenol.

Ghosh & Xi (DOI) obtain a similar looking derivative through an intramolecular Diels-Alder reaction:

Citalopram battle

28 January 2009 - News

Researchers from Dr. Reddy's Laboratories and Lundbeck have been exchanging letters in Organic Process Research & Development (OPRD) on the nicer details of citalopram production. This (racemic) antidepressant drug was invented 1989 by Lundbeck and after the patent expired in 2003, Dr. Reddy's went to the market with their own generic version while Lundbeck came up with the more potent (S)- enantiomer now called escitalopram. In these exchanges the Lundbeck scientists report on inconsistencies they found in a 2007 Dr. Reddy's article (Elati et al. DOI) regarding the synthesis of chiral citalopram. There is no clear winner yet although the editorial board and referees of OPRD should take some blame where they do not. Here is what happened.

Two elements in the 2007 article by Dr. Reddy's team that cause all the commotion are the chiral resolution by diastereomeric recrystallization of citalopram using (-)-di-p-toluoyltartaric acid (DPTTA) and the alkylation of an citalopram intermediate.

The Dr. reddy's team state at the onset that this chiral resolution method is not feasible on a plant-scale but nevertheless report a 18% yield with 98% of what is called chiral purity in the experimental section although the article itself does not discuss this result. The Lundbeck team asserts (DOI) that this method cannot work and spent some effort to repeat the results but without luck: the solubility of the racemate is simply too poor.

In their reply (DOI) the Dr. Reddy's team concede that their report did contain errors on three accounts: firstly the desired (S)-enantiomer is isolated not from the crystalline phase (the textbook scenario) but from the mother liquor, secondly not (-)-DPTTA is used but the other enantiomer (+)-DTTTA and lastly the filtrate is neutralized and the free base is extracted with toluene. On the other hand the team did report a corrected procedure and again did obtain enantiopure (S)-citalopram from racemic citalopram (11% percent yield , 96.4% chiral purity repeating the procedure twice).

In their reply to a reply (aptly called Response to the Comments by Elati et al. in Response to Our Article Examining One of Their Previous Articles) the Lundbeck team is still unconvinced (DOI). Again they repeat the resolution and this time obtain 76% enantiomeric excess with 7% yield in the second crystallisation. A third one (described by the Dr. Reddy's team) utterly fails.

The other topic of contention, the alkylation of the benzofuran intermediate by chloropropylamine is mentioned in the 2007 article but surprisingly only described in a patent (WO Patent 047274). The Lundbeck team questions the preparation of the amine as a free base which is known to rapidly polymerize to a polyamine and also question the use of a acetone / potassium tert-butoxide mixture which not only is known to react violently but is also known to yield only the aldol reaction product. In their reply The Dr. Reddy's team present their optimised procedure (6 Kg scale!) which involves adding the free base quickly to a benzofuran / DMSO (not acetone) / tBuOK mixture.

In an editoral(DOI) the OPRD concludes that the process is complete and that they trust our readers will gain a better understanding of a difficult situation and that we have illustrated a mechanism for handling similar disagreements that we may face in the future.. This blog is not so sure.

Why are the OPRD and its referees to blame: the reported chiral resolution of citalopram in the 2007 article should have been left out as it was unrelated to its main topic: the resolution of an intermediate. They further allowed the discussion to get out of control by having the Lundbeck team engage in lengthy discussion on patent literature. In addition they started a new round of criticism in their second reply, this time concerning the resolution of the primary amine intermediate. The referees also allowed the fuzzy unit of chiral purity to persist.

The discussion will probably resume in patent court.

Robert James Dancer, Heidi Lopez De Diego (2009). Response to the Comments by Elati et al. in Response to Our Article Examining One of Their Previous Articles Organic Process Research & Development, 13 (1), 38-43 DOI: 10.1021/op800252w

The methanol economy

22 January 2009 - Save the planet!

Introduced in 2003 but slow to infiltrate the mainstream, George Olah recently provided an update to his methanol economy (DOI). According to the Nobel Prize winner, methanol is an efficient energy carrier superior to hydrogen, a general feedstock for the chemical industry and on top of that methanol can save the climate from carbon dioxide induced global warming.

Methanol can easily compete with hydrogen (see hydrogen economy) as a transportation fuel. It is already mass-produced, its toxicity overrated (500mg per day intake is considered safe), has a favorably octane rating although the cetane number is lower. An even better candidate is demethyl ether (DME) which can be produced by MeOH dehydration.

Methanol can be used to make a lot of other chemical products. In the methanol to olefin (MTO) process, DME is dehydrated once more, this time to ethylene using for instance the zeolite ZSM-5.

Methanol is linked to global warming remediation because carbon dioxide be converted to methanol by reaction with hydrogen. Capturing CO2 is an ongoing research effort in itself and recently summarized in the New Scientist (here). The proposed methods involve passing air through sodium hydroxide or calcium oxide either in solution or solid which will capture carbon dioxide to form sodium or calcium carbonate. When the scrubber is saturated it is heated to release concentrated carbon dioxide whilst regenerating the oxide.

Carbon dioxide sequestration (the second step) is generally supposed to involve underground storage for example in disused gasfields but Olah at least won't hear of it: earthquakes or other ground movements could result in devastating CO2 release. His solution is conversion to methanol and he directs our attention to Carbon recycling International that is as we speak building a CO2 to MeOH plant (4.5 million liters p.a.) with hydrogen generated from water via hydrothermal energy. Another company Mitsui Chemicals has started a pilot facility with hydrogen production based on solar energy. As an alternative to water splitting, hydrogen can also be produced in the so-called Carnol cycle from methane with as only by-product carbon soot.

This methanol economy holds the promise of chemical industry generating healthy global warming profits with carbon-neutral cars whizzing by, which must come as a disappointment to those who use the global warming threat as a pretext for the reversal of civilisation. So be it.

Lets blow things up (responsibly)

7 January 2009 - Energetic materials

Nowadays the politically correct term for an explosive is an energetic material and if you thought the world already has too many kinds of explosives available in quantities too high, please be informed that at least from the organic chemists point of view research into it is very much alive. Just a few examples from the recent literature.

Researchers at the University of Idaho go for high density salts as density is proportional to detonation velocity and proportional to the power of two of the detonation pressure (Huang et al. 2008 DOI). Citing Carnelley's rule they argue high density equals molecules with high symmetry. Another contributor to density is the presence of hydrogen bonds. For their ultimate target (a cousin of TNT) they reacted chloranil with sodium nitrite in water to a nitroanilate and then replaced the sodium cations by simple amine cations such as ammonium or tetrazolium .

That ions high in nitrogen content contribute favorably to the heat of formation is a notion also advocated by a group of researchers at LMU (Energetic Materials Research). They (Klapötke et al. 2008 DOI) recently investigated picric acid (a well known explosive and a phenol!) pimped up with tetrazolium counterions. The researchers are happy to report that tetrazolium picrates are less sensitive than TNT and also release larger amounts of environmentally friendly nitrogen gas with less carbon soot residue.

Equally concerned with eco friendly explosives (...) are researchers from the State Key Laboratory of Explosion Science and Technology at the Beijing Institute of Technology who used diaminotetrazole (DAT, 84% N!) as ligand for cadmium in the novel explosive (Cd(DAT)6)(ClO4)2 (CUI et al. DOI). The publication reports that sensitivity tests reveal that the title compound has sensitive nature but also that Cd is one kind of toxic heavy metal and perchlorate may be a possible teratogen which may limit the utilization of the title compound as energetic materials to some extent.

Finally, researchers at the Los Alamos National Laboratory (High Explosives Science and Technology) recently came up with a novel explosive that can be melt-casted below 100°C. Melt casting is another desirable property, one shared with commercially available 3,3,1-trinitroazetidine (TNAZ). The compound (one related to PETN) was stumbled upon when a Kaplan-Shechter reaction misbehaved.

In step one (a coupling reaction) only the sodium persulfate remains as a Kaplan-Shechter reagent.

Easiest alkene hydration ever

5 January 2009 - News

The laboratory of Guy Bertrand has synthesised a new variety of fulvalenes, the compounds characterized as cyclic polyenes yet not aromatic and exhibiting cross-conjugation (Kinjo et al. DOI). Although the new compound is stable at ambient temperature and even melts without complaining at 130°C owing in part to a hydrocarbon kinetic shield, oxygen is toxic and the central alkene group is found to react spontaneous with water: the easiest alkene hydration ever.

Remarkably the compound (as the cis and trans isomer) is synthesized from tetrachlorocyclopropene in good yield in four reaction steps (each as old as chemistry) but without any serious intermediate workup/purification steps. It can almost be mass-produced. Step one is a double Friedel-Crafts reaction first with bulky triisopropyl benzene (Tip) and next with less-bulky mesitylene (mes) forming 3. Phosgene reinstates the chlorine groups and Wurtz type reaction with magnesium clenches the deal.

The triafulvalene skeleton is almost planar, the central alkene is found to be extremely short and in UV/VIS the absorption present in ethylene at 171 nm is now redshifted to 502 nm.