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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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August 12, 2009

Sulfoxides: A Sneaking Affection

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Posted by Derek

Let us now praise sulfur. Well, some kinds of sulfur, anyway. The +2 oxidation state (earlier typo fixed, aargh) is a bit hard to handle, what with all those angry-skunk, burnt-tire overtones. But move up the ladder to +4, and you've got some possibilities.

Those do not include the hideous thioacetone, but bring some oxygen into the picture and you get a sulfoxide. And these guys I like, probably because one of the best compounds I've made in my career had one as a prominent feature.

Not every medicinal chemist shares my enthusiasm, that's for sure. Sulfoxides have a reputation for being potentially metabolically unstable - and they can go either way, being oxidized up to sulfones or reduced back to the parent sulfide. (I believe the former is more common, and is the clearance mechanism for DMSO, among other members of the tribe). But there are some out there in the market, chief among them esomeprazole (Nexium). Then there's armodafinil (Nuvigil), Cephalon's follow-up to Provigil, like Nexium another single-enantiomer-of-a-racemate drug.

But sulfoxides aren't just for extending your patent life and raking in the money. They can make a big difference in activity. The group has a strange character to it, because that oxygen atom is about as close to a naked O-minus as you're going to find. And the tetrahedral geometry of the sulfur means that this electronegative group is held is a very specific orientation relative to the other parts of your molecule. Like a nitrile, a sulfoxide is sui generis: there's nothing else that will do what it does.

And they're chiral. That can either be a bug or a feature, depending on your project and on your view of the world. If your target protein recognizes that chirality, it's probably really going to recognize it, because of that strong character. But that chirality is yet another reason that people avoid the sulfoxide, because that means chiral synthesis, which is a pain. All sorts of methods have shown up - chiral oxidation of sulfides, displacement with inversion at the sulfoxide sulfur - but there's no good general solution. The existence of the commercial drugs shows that this problem can be overcome, but there's no use denying that it's a problem.

All these problems can, at times, blend together. I was told some years ago about a Merck clinical compound that had a chiral sulfoxide. When they checked for metabolites, they found what looked like unchanged drug substance coming back out. A closer look, though showed that this was actually the enantiomer of the starting drug! What happened, as I heard it, was that the sulfoxide was first getting reduced, then oxidized back up to the opposite sulfoxide, when then passed out unchanged. Eating your starting material and collecting your own urine has yet to catch on as a sulfoxide inversion method, though. . .

Comments (18) + TrackBacks (0) | Category: Life in the Drug Labs


1. Yossarian on August 12, 2009 8:52 AM writes...

+1 oxidation state ?

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2. opsomath on August 12, 2009 8:59 AM writes...

I was given to understand that DMSO was oxidized to the sulfone (methyl sulfonyl methane). A brief inspection of the toxicity reveals that all three of the series (sulfide, sulfoxide, sulfone) are extremely nontoxic, with a LD50 for the sulfide of 3-4 g/kg oral, So, no help there. Anyone know for sure?

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3. Anon on August 12, 2009 9:21 AM writes...

Metabolism doesn't imply toxicity!

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4. retread on August 12, 2009 9:39 AM writes...

Probably some dumb questions -- but -- Why is the sulfoxide chiral at all? Why doesn't it invert through the S atom (like tertiary amines with 3 different groups attached) ? Also does anyone know why in R-S-S-R', the R and R' are at 90 degrees to each other? Just getting back into the swim of organic chemistry. Thanks

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5. fluorous on August 12, 2009 9:55 AM writes...

The combination of sulfur with fluorine is also pretty interesting, those RSF4R` and RSF5-type combounds. Seems that they are stable enough to incoorporate into bioactive molecules

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6. Chemjobber on August 12, 2009 10:02 AM writes...

Isn't there some old organic teaching experiment that requires you to eat the compound at bedtime and collect your urine in the morning to extract the (esterified?) product?

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7. JR on August 12, 2009 10:22 AM writes...

Indeed. I did that experiment. If I remember correctly, you ingest sodium benzoate (a common food preservative) and isolate its glycine amide conjugate, hippuric acid from your urine the following morning. After eating ~10g of sodium benzoate I can't stand the taste of some commercial iced teas.

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8. Hap on August 12, 2009 10:27 AM writes...

The lone pair is fixed in space (per se), so it acts like a fourth substituent, and renders the atom to which it's attached chiral. Amines simply invert really fast, so even when they're chiral, the enantiomers aren't isolable at meaningful temperatures. [Aziridines, however, don't invert rapidly and so can form separable stereoisomers in some cases - March (4th ed., p. 99) - also bridgehead nitrogen atoms where inversion is impossible (p.100).] Phosphines generally invert more slowly, generally only on heating, so they can be resolved and kept at ambient temperature (such as DIPAMP, the ligand used in hydrogenations to prepare L-DOPA). Sulfoxides have inversion barriers closer to those of phosphines than amines. I don't know why the inversion rates differ so much, though.

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9. Anonymous on August 12, 2009 11:23 AM writes...

Rather then eating the chiral sulfoxide and then collecting your urine, you could just go to an enzyme company and buy a library of isolated enzyme powders that will do this series of transformations.

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10. ig on August 12, 2009 1:58 PM writes...

That chiral Merck sulphoxide was the intermediate enterohepatically generated from the sulphide of Sulindac (Clinoril). This brilliant discovery was made by Bruce Witzel from TY Shen's Inflammation group in the 70's. Bruce Witzel, a BS chemist, was one of the most productive and imaginative Med Chemists that graced this profession. He blew away most of the Ph.D. chemists that worked at Merck.

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11. ZY on August 12, 2009 2:36 PM writes...

I am very glad to see your post about sulfoxide, which seems to be a neglected field in chemistry. I am not working on drug discovery, but my current work involves methionine sulfoxide in proteins. There seems no chemical reaction that will allow the identification of sulfoxide in proteins easily. Of course, there are quite some reactions reported involving organic sulfoxide, but those conditions are very difficult to apply to the protein system. I just wish there's a good chemical probe available to detect sulfoxide in protein.

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12. CMCguy on August 12, 2009 3:51 PM writes...

After enduring weeks of PK/ADME discussions I have heard enough about various body fluids and excretions thank you. Makes me what to go hug a Rot Vap or open some solvent bottles. Always realized there are indeed different strokes for different folks with many biologists/biochemist/MDs doing stuff that makes me literally cringe while they find synthetic chemistry incomprehensible.

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13. Curious Wavefunction on August 12, 2009 4:32 PM writes...

Retread, I believe that the 90 degrees dihedral in disulfides arises from the minimization of the repulsion between the 3p-pi electron lone pairs on the sulfurs (which would be maximum at 0 and 180 degrees). But I probably must dig up my copy of Pauling to refresh my memory.

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14. retread on August 12, 2009 6:06 PM writes...

Hap and Ashutosh -- thanks

A few biologic relevancies about one particular sulfoxide: e.g. that of methionine -- one of the 20 amino acids making up proteins.

Methionine sulfoxide is formed on proteins all the time by the action of superoxide radical anion, hydrogen peroxide, hydroxyl radical and hypochlorite ion (OCl-) on the sulfur atom. An enzyme found in all organisms (peptide methionine sulfoxide reductase) reforms methionine [ Proc. Natl. Acad. Sci. vol. 93 pp. 2095 - 2099 '96 ]. The enzyme is highly expressed in neurons (which may be why they last as long as you do, OR maybe that's why you last as long as they do).

[ Proc. Natl. Acad. Sci. vol. 99 pp. 2748 - 2753 '02 ] Peptide methionine sulfoxide reductase enzyme activity decreases with age in rats, and in Alzheimer brain. This paper shows that overexpression of the enzyme markedly extends the lifespan of Drosophila (the fruitfly). Mice with REDUCED activity of the enzyme have a 40% shorter lifespan. So this all fits nicely with the oxidant theory of aging, and with the use of antioxidants to prolong life -- sadly, they don't appear to do much in the clinical trials of which I'm aware.

The enzyme overexpressing fruitflies sustain high physical and reproductive activities much longer. Many mutations extending the lifespan of model organisms lower their physical activity and reproductive capacity.

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15. Diyne on August 13, 2009 5:36 AM writes...

I wonder how sulfinamides fair in vivo? I'm thinking along the lines of Ellman's t-butyl sulfinamide. How does the configurational stability compare to sulfoxides? Do they get oxidized in vivo?

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16. cookingwithsolvents on August 13, 2009 9:32 AM writes...

The ~90 degree dihedral in RSSR is because s and p don't mix as easily as you go down the periodic table and the p orbitals get used for bonding. The inversion at phosphines and R(R')SO is also slow because the TS requires mixing of S and P orbitals.

The ease with which C, N, and O s and p orbitals mix is actually pretty special.

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17. RTW on August 14, 2009 8:09 AM writes...

Ah the Sulfoxide. Involved in my favorite named reaction. The Pummerer Reaction, or rearangement.

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18. artemis on August 14, 2009 11:38 AM writes...

The the SF5 moiety is certainly interesting, being a chunky electronegative group and as far as I know- metabolically inert as an aryl substituent. It isnt used however, as its an absolute shit to introduce into compounds: cleavage of aryl disulfides over silver oxide at 200C under a stream of F2 gas isnt compatible with many functional groups. Also, any further ring elaboration means dealing a strong meta-director, so any compounds made with SF5 are going to look quite similar-almost any indole made with it will be a 5-SF5 indole etc....

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