Org Prep Daily

October 18, 2011

Trehalose!

Filed under: lit highlights — milkshake @ 12:07 am

A remarkable molecule:  Hygroscopic, edible, stable and pleasantly-tasting natural sugar. While keeping foodstuff moist and producing a desirable mouth-feel, trehalose also masks greasy rancid off-flavors like no other food additive. Trehalose inhibits lipid autooxidation by interacting with the C=C bonds of fatty acids. Trehalose has also a stabilizing effect on denaturation-prone proteins. It is an effective cryoprotectant and anti-desiccant for living cells.

Trehalose is widely used as food additive in Japan. (It got classified by FDA recently as ‘generally recognized safe’  so expect trehalose-immortalized pastry snacks at gas stations soon). Two protein-based drugs co-formulated with trehalose are already on the market.

I would like to direct you to a minireview from Dr. Higashiama, a research team leader at the trehalose manufacturer Hayashibara Co. Some important practical applications are discussed in detail:

“In this application, we examined the suppressive effect of trehalose on human body odor. The typical odor of a senior layer (odor from seniors) increases with age, especially 55 years or older. This odor contains unsaturated aldehydes such as 2-nonenal and 2-octenal. These aldehydes are produced by the degradation of unsaturated fatty acid (palmitoleic acid) in aged people’s skin. The subjects (55 years or older) were selected from our company. After a shower, their body was sprayed with a 2 % trehalose solution. They put on new underwear after the spray. Twenty hours later, the unsaturated aldehydes were sampled from the used underwear shown in this system using DNPH-column. The trapped aldehydes were eluted from this column and were analyzed by gas chromatography. The results showed a decrease of about 70 % in odor from seniors due to the action of trehalose (Fig. 7). This result indicates that trehalose has a suppressive effect on the formation of the odor released by the seniors’ bodies. The same results came out with the oxidation of fatty acid. Therefore, the application of trehalose for cosmetic fields is expected.”

T. Higashiama: Pure and Applied Chemistry 74, 1263–1269

(Fig. 8):

August 11, 2009

Dear ACS journal editors – please return from your vacation soon

Filed under: lab destruction, lit highlights — milkshake @ 1:14 am

dovolena credit: National Geographic ‘Photo of the day’

The spectacular “NaH catalytic” oxidation recently published in JACS has been thoroughly covered elsewhere. I would like to bring your attention to another jaw-dropping paper that just came out in Org Letters:

http://pubs.acs.org/doi/abs/10.1021/ol901250c

Acetophenones and 1-aryl-ethanols are oxidized to benzamides by heating the material with 3 – 4 equivs of iodine and ammonia in a pressure vessel. There is only a passing reference and footnote that “nitrogen triodide might form in the mix.”

In fact, NI3.NH3 readily precipitates upon mixing iodine with aqueous ammonia. (The products vary; a gradual iodine addition to a large excess of ammonia yields ammonium iodide and nitrogen.) Nitrogen triodide is a notoriously super-sensitive primary explosive. I spent some time hospitalized in eye clinic when I was ten years old – my corneas got burned with iodine and my eardrums ruptured because of playing with a spoonful of nitrogen triodide. (The window pane flew out and I was thrown to the ground by the blast;  it took me half a year to fully recover and this all was from few grams of dry material going poof, unconstrained). I cannot warn strongly enough against mixing iodine with ammonia in a pressure flask and then heating the stuff up!

The authors run these experiments on a 1 mmol scale and they give no details about the order of addition. Since the transformation is pretty useful – with a good substrate scope and it looks simple enough (its done in water) –  sooner or later some innocent person is bound to mix up a big batch in the wrong way – and as he screws on the the pressure vessel cap he is gonna blow himself up into a mauve cloud

April 22, 2009

blockbuster drugs

Filed under: industry life, lit highlights — milkshake @ 7:12 pm

I would like to direct the readers here to the excellent project-and-career story from Bruce Maryanoff in the most recent J. Med. Chem ASAP. It is very illuminating on how the drug discovery and development works, and it describes in some detail what a bright chemist can hope to achieve in this profession -with the necessary motivation and a decent employer (and tremendous amounts of luck).  

It is also an illuminating story on how the process does not work. For example, the currently most popular, target-driven rational-design-based approach can be pretty futile in CNS drug projects . The author also suggests that the management mantra about focusing on the discovery of the next “blockbuster drug” actually bankrupts the industry – financially and scientifically; his drug Topiramate (which has been making 2 billions a year for the company) would have not been discovered or developed under the management methods currently prevalent in the industry. Few things stand out: 1) It seems that having a blind luck and testing the compounds in a realistic animal model is more important than having a correct mechanistic understanding how the drug candidate actually works.  2) Few independent-minded individuals in their pharmacology and chemistry have made a good use of their lucky break. They stubbornly kept the research program going – even as their managers were lukewarm and would not support the compound development for a long time. It also goes to the credit of the management that allowed their researchers to pursue this as their hobby. The story shows that the progress in pharma research does not really happen by imposing some management-theory-derived reporting structure on the research department, by drafting the flowcharts and aligning the teams. For medchem research to succeed, the projects should be allowed to self-organize around the bright individuals rather than being planed out from top down, with red tape and micromanagement.

In this context it is entertaining to read rather disingenuous remarks made by the Merck chief strategy officer Merv Turner at the pharma management conference. He explained that they are currently sacking lots of people in research because  “Seventy-five cents of every dollar we spend on R&D goes to fund failure” and “the future results must come at a lower cost”.  

The actual drug discovery cost makes only few percent of the final drug development cost. By far the most expensive part is the clinical trials and namelly the late-stage clinical trials. What the Merck management poseurs do not tell in public is that it was the Merck top management decisions that cemented their company’s commitment to these “the next blockbuster” projects –  which eventually led to a string of stunningly expensive late-stage failures. When the top executives receive massive stock option bonuses, they become mercenaries of the stock prices. Their wishful thinking baloney percolates from top down through the management layers, etc.

There are many parallels between the state of pharma industry and the recent financial sector collapse, and it is always the executives who run their companies to the ground that are rewarding themselves most obscenely. Remember this whenever the pharma companies claim that the freedom to price their drugs is essential for the innovation.

_________________________________________________________

Update:  Here are additional two great articles from Bruce Maryanoff on the subject

August 2, 2008

This phosphine will get you fired

Filed under: lab destruction, lit highlights, mechanisms — milkshake @ 11:32 pm

Beautiful asymmetric transition metal-catalysed chemistry with phosphine ligands chiral on phosphorus dates back to Knowles and Mislow. But these P-stereogenic homochiral phosphines are usualy harder to make, so they were eventually supplanted by ligands with chirality on carbon. As a freshman I used to work for a young assistant prof in Prague - and since I was very interested in asymmetric synthesis, he suggested that I could do a thesis work with him on these ligands; We would put some chiral but racemic phosphine building block onto optically active binaphtyl piece derived from BINOL, and we would get BINAP-like ligands with both axial chirality and chirality on phosphorus. We would then try to separate the stereoisomers and see which one worked better in Rh and Ru-catalysed asym hydrogenations, and we would try to interconvert the stereoisomers to see how the kinetic vs thermodynamic induction control looks like, etc. (Chiral phosphines are conformationally labile on phosphorus above 100C whereas the 2,2′-disubst binaphtyl pieces are fairly stable and should not racemize).

This all happened more than 20 years ago and there is over-abundance of commercial chiral phosphines nowadays -  though as far as I know the doubly-chiral BINAP idea was never put into practice. The reason why we never managed to put it into practice was that we were inadequate - We did not realise that phosphines are so unstable. Unless in crystalline form or complexed to things like borane, alkyl phosphines oxidise rapidly in air (for example the used silica and eluent has to be deoxygenated)- and we had no glovebox; not even a vacuum/argon manifold line.

The other reason was that I got fired from that lab soon after I started working on this project. Here is the story how it happened:

My adviser was a junior faculty, at a poor university - he shared the workspace with two other faculty members. The actual boss of the lab was an old and rather sardonic man. The old man became  noticebly grouchier during the year when I was working in their lab, especially after I had couple of fires and broke every valuable piece of glassware they had there; and soon everybody was calling me the Disaster-Master and “Bořivoj” – It translates as “the one who tears down the places”. Me and my young adviser made quite an enthusiastic team - we tried to synthesize optically active binaphtyl compounds on a grand scale. And when a 4-liter flask full of xylene refluxing on your bench ruptures into the heating mantle, people start taking notice…

There is a lovely one-pot procedure for turning triphenyl phosphine into PhePHMe: Sodium metal in liquid ammonia cleaves off phenyls from the phosphines in a controllable fashion. It goes like titration - while you feed the reaction mix with chunks of Na metal, the red color of Phe2PNa develops which then suddenly turns inky blue by the dissolved metal once you reach the equivalence point with 2 equivs of Na. Then you add tBuCl to selectively quench the formed sodium amide followed by MeI, to methylate the diphenyl phosphide anion, and the red color vanishes. Then you add more sodium until inky blue again, quench with solid NH4Cl, evaporate, then distill. The literature procedure has no comments on the smell of these things; I guess a man skilled in art is supposed to know. (We did not).

An inorganic chemistry colleague actually warned us about the phosphine stink - he advised us to make these compounds at night (and preferably in a student lab), to use baths of acidified permanganate or bleach or peroxide and decontaminate everything afterwards. It seemed  excessive to me but my boss borrowed keys from the teaching lab located at the distant end of a very long hallway, and we went to work there one Spring Sunday afternoon.

The reaction behaved beautifully - exactly as in literature procedure – the color transitions and all, and even the product distilled pure in a good yield in the end as a highly refractive clear, thin liquid. But the smell - right at the moment when we quenched (in a hood of course) we were pushed back by the solidity of the reek. I got to know many evil chemical smells over the years but nothing comes anywhere close. With the other stinkers, at least one can imagine what sort of unwashed, putrid, fishy, skunky, human-waste object those smells are related to. But I never encountered anything as nauseating or alien like PhePHMe: The memory is stil with me - the most sickly and sweetish smell of rancid gasoline combined with rotten water melons, with undertones of stale sweat, pig carcass, a hint of garlic, moldy oranges, russian-made aftershave and a cheap household air freshener…  its a whole package, and rather sweet one – like isonitriles or cyclopentadiene but magnified thousand times. A whiff of that thing and you feel that your nose just suffered a stroke and will hopefully die and peal off so that you never smell that thing again. Inconceivable - and it does not get any better when wearing off; quite opposite in fact – just like with butyric or isovaleric acid, the reek is developing a more alarming depth and complexity with the dilution.

Phosphines like to oxidise on air (unless in crystalline form) and those with H or small alkyls on P tend to catch on fire when neat. There was a flame-up when I took an adapter off after the vacuum distillation from a still warm flask - a bright flame jumped through, with a high-pitched bark and yet another wave of nauseating reek crashed over us…

Finally, we sealed the product into ampules as to keep it from oxidizing. We washed all the used glassware in permanganate and then in bleach - twice – and we put it on a cart and brought it back to our lab, happily tired after a long and productive Sunday. I remeber that before heading home - as I was putting the glassware on the drying rack above the sink - I noticed a shred of glass from a broken adaptor that remained in a joint of the distillation flask. (I panicked when the thing flamed on me and I broke it). So I dislodged that piece from the joint with tweezers and thew the shred into a glass waste bin next to the sink. It was late night and I did not give it much thought; I did not realise that the broken piece was stuck in the joint and the surface between the two did not get in contact with the bleach bath.

The next day we were both late, I made it to the lab at around 10:30a before my adviser arrived – and I noticed that all windows in the lab and hallway were open. Nothing too unusual on a warm late-spring day – except that our grouchy old colleague’s face was somewhat sallow. He even seemed pleased to see me, and he welcomed me calmly: ” Please sit down, Mr. Bořivoj. It is with enormous satisfaction for me to inform you that your long tenure in this lab just came to its abrupt end. My patience has been worn thin and through. I have been doing chemistry for forty years now and I have no desire to ever puke my guts out again in my own lab on Monday morning.”

I forgot to mention - this old man spent his career on making vinyl sulfur-and-selenium compounds. Forty years - and even he was impressed with our phosphine.

June 7, 2008

Strange bits from Schlosser

Filed under: lit highlights, mechanisms, procedures — milkshake @ 3:10 am

2,5-dihalopyridines lithiate with LDA into the 4 postion quite nicely. With 5-CF3-2-halopyridines the lithiation goes all over and separating the isomers is pain; a colleague found that with LDA in Et2O he can improve the selectivity up to 3:1- which was sufficient for his purposes - so it appears the regioselectivity of lithiation and the isomerisation of the lithiated species is sensitive to the media effect. Now it turns out Schlosser group published a lithiation procedure that uses iPr2NCO2Li – “a carbonated LDA” - together with LDA and LiBr – and with these additives all of sudden the lithiation becomes almost completely 4-selective for the 5-CF3 substrates. We needed the material so the trick came handy - yet I don’t pretend to understand what is actually happening here. And those mysterious isomerisations…

Anyway, if you ever consider this carbamate as a modifier for your lithiations, I found a more practical protocol: rather than spooning out a fairly hygroscopic solid lithium salt from a flask and into the LDA solution as described in the publication, I have been preparing and evaporating the reagent into the flask used for the next lithiation step and then transfering the LDA solution to this solid – in that way I was able to run the lithiations on a 250 mmol scale. (Keeping things dry takes more effort here in Florida).

August 26, 2007

One phosphine to rule them all

Filed under: lit highlights — milkshake @ 10:20 am

sauronphos.gif

Buchwald et al: Angew Chem Int Ed Eng 45(39) 6523-7 (2006) DOI 10.1002/anie.200601612

Buchwald group developed a number of biphenyl-based phosphine ligands useful for Pd(0)-catalyzed arylations. Descendants from BINAP, these ligands form 1:1 complexes with Pd(0) that are particularly active catalysts, allowing arylations with both poor electrophiles (unactivated aryl chlorides) and lazy nucleophiles (such as heterocycles with very acidic NH).

The reason why the bulky monodentate electrone rich 2-biphenyl phosphines are good is that they make Pd(0) more nucleophilic – which helps the Pd insertion into Ar-X - while the bulk promotes the fast migration/dissociation rates in the intermeditate complexes and the formation of PdL2 is supressed. [Even a very sterically hindered PdL complex is coordinationally less saturated and hence more reactive than a PdL2 complex with a less bulky ligand. PdL4 is worse still]. The pi-electrons of the second benzene ring donate to Pd and the ring shielding prevents PdL2 from happening.

One of the problems with aryl-based phosphines has been cyclometallation, the palladacycles (such as Hermann catalyst) are good for high temperature Heck reactions but are quite inert below their decomposition temperature. In this case the cyclometallation is prevented by the ortho isopropyl groups.

There are other good phosphine ligands useful for difficult arylations: Xanphos (1), tert-Bu3P (2) and Josiphos (3). The great advantage of Buchwald phosphine ligands is that they are perfectly air stable, highly crystalline solids, easy to make and the produced catalysts are pretty active and robust.

This newest ligand with isopropyls on the ring and tert-butyls on the phosphine is reported to be very good for arylation of poorly reactive N-nucleophiles, with Pd2(dba)3 as a Pd source and NaOtBu in toluene (at 80C) or Cs2CO3 in dioxane (at 100C) . And some functional groups can be even left unprotected, such as primary amide and phenol, without interfering with the arylation process.

I have tried this ligand with my substrates and aryl bromindes and nearly everything that I did worked on the first try with 2-5% of Pd loadings and NaOtBu in toluene at 80C. The only exception was arylation using aryl iodide, as an electrophile – I suspect that the generated iodide anion complexed to Pd and prevented the catalyst from turning over. But all my aryl bromides worked beautifully.

The ligand is available from Aldrich, 638080-5G, and it is not too cheap ($161/5g) – so it would be worth making your own ligand for large-scale experiments. The phosphine can be made in a one-pot reaction from commercial reactants.

Note 1: Cheap, but often needs high temperature and a high-boiling solvent like o-dichlorobenzene. Best to be used 1:1 with Pd(0) since Pd(xanphos)2 is inert
Note 2: Expensive. The free tBu3P is super air-sensitive and should be handled only in glove box – it likes to smolder on air. Use the air-stable tetrafluoroborate salt (tert-Bu3PH) BF4 instead, 2:1 with Pd(0)
Note 3: Josiphos is a chiral ligand, very expensive

Older Posts »

The Shocking Blue Green Theme. Blog at WordPress.com.

Follow

Get every new post delivered to your Inbox.

Join 137 other followers