B.R.S.M. To strive, to seek, to find and not to give a yield


Superlatives 2: The Gassiest Reaction of Them All?

Perhaps Organic and Biomolecular Chemistry isn't a journal well known for its reviews, however I recently enjoyed reading this rather unusual perspective by Jason Chen on "Gas Extrusion in Natural Products Total Synthesis". All the classics are there: the retro [4 + 1] cycloaddition of sulfolanes to generate dienes (and the related Ramberg–Bäcklund reaction), the Boger-style 1,2,4,5-tetrazine [4 + 2]-retro-[4 + 2] method for the synthesis of aromatic rings and many more unusual ways to lose nitrogen besides. There are also some much rarer reactions, including an example from Padwa's synthesis of stempeliopine where addition of carbon suboxide (O=C=C=C=O) to a thioamide is followed by a cascade that eventually spits out carbonyl sulfide (OCS). I bet that's a synthesis that makes you unpopular in the lab[1]

Probably the winner for the gassiest sequence described is from a Movassaghi paper that I remember from last year. Although the reaction hasn't actually been used to make a natural product yet, it looks like a useful way to access  hetero cyclotryptamine natural products, of which there are many. The idea is to synthesise an unsymmetrical sulfamide, where the two amines are connected to the two units to be linked. Oxidation of this with NCS then generated a thiadiaziridine dioxide in some bizarre Aza-Myers-Ramberg-Bäcklund-type reaction. This then lost sulfur dioxide as expected to give a diazene that was decomposed photolytically with loss of nitrogen to give a pair of radicals that recombined quickly. Amazingly this recombination occurred sufficiently to prevent the formation of homodimeric products. Neat reaction - I love the fact that the linker is completely traceless!

Gas extruding reactions are more important that might be imagined at first (especially for the construction of strained systems), and it's nice to see a review dedicated to them.



1. Carbon suboxide apparently smells (surprisingly?) awful . From an early review on its chemistry:

"The physical properties of carbon suboxide are of considerable interest.  It is a  gas  under ordinary conditions,  having  an unbearable odor like acrolein and mustard oil.  In  small amounts  it  acts as  a  lachrymator; in  high concentrations it attacks the eyes, nose  and breathing  organs, giving a  feeling of suffocation."

There are lots of ways to make it, some of which are more appealing than others. Padwa generates it from dibromomalonoyl dichloride and zinc in ether at room temperature, which sounds quite sensible. Unfortunately, the OCS by-product also smells pretty bad. It's a little known fact that pure carbon disulfide has a pleasant smell redolent of diethyl ether (according to the Merck index; I used to have a CS2 still and I never experienced this). The reason it's so unpleasant to work with are traces of OCS (and thiols) from its manufacture. According to Wolf and Amarego these can be removed by washing with aqueous KMnO4 solution, followed by mercury. Or not.


Filed under: Current Literature, Named reactions, Serious | 23,351 views | 5 comments 5 Comments

Superlatives 1: The Heaviest Catalyst Ever?

While browsing through the Advanced Synthesis and Catalysis Early View today, I noticed this paper on a new Rhodium catalyst for the asymmetric conjugate addition of boronic acids to enones in water. Pretty standard stuff... until you look at the catalyst structure. Now, I'm not particularly up on phosphine ligand design but I don't think that PEG and geranyl geranyl geranyl geranyl geranyl chains are a common thing to include. I mean, I've seen BINAP derivatives with some pretty big polyaromatic hydocarbon groups bolted on (e.g. anthracene and pyrene), but this is in a class of its own. In fact, I think that I can safely say that this is the largest catalyst for anything that I've ever seen. I guess the logic is that if you can't have the organic solvent in the flask you can just include it in the catalyst itself by larding it with hydrocarbon and polyether chains, and it does actually seem to work. A possible drawback of this approach is that the darn thing weighs more than maitotoxin and takes a total of twelve steps to make; all that just so we can have another way to add phenylboronic acid to cyclohexenone. I'm making a note of this for the next time someone calls my total synthesis project useless. Or am I being too harsh?

Filed under: Current Literature, Fun | 26,220 views | 7 comments 7 Comments

Alkaloid (-)-205B

Synthesis of Alkaloid (−)-205B via Stereoselective Reductive Cross-Coupling and Intramolecular [3 + 2] Cycloaddition

Micalizio et al., J. Am. Chem. Soc., 2012, ASAP [PDF][SI][GROUP]

DOI: 10.1021/ja306362m

Here’s a neat alkaloid synthesis published last week by Yang and Micalizio. An earlier JACS methodology paper from the group hinted at an interest in this target, so although this work isn't entirely out of the blue their final route contains a couple of quite unusual steps and is worth a quick look. I must say, the title of the paper is a little long for my taste, but you can't have everything.

Filed under: Current Literature, Total Synthesis | 21,849 views | 4 comments Continue reading

(+)-Prostaglandin PGF2a

Update 16-09-12: just found out that this has also been written about over at the greenchemblog. If you fancy an alternative take with more detail and less history, look over there!


Stereocontrolled organocatalytic synthesis of prostaglandin PGF2α in seven steps

Aggarwal et al., Nature, 2012 [PDF] [GROUP] [SI]

DOI: 10.1038/nature11411


I’ve heard it said a few times that if you can’t be the first to synthesise a natural product, then you should try and be the last; that is, you should aim to come up with the most elegant and efficient route you can now that the pressure’s off and there’s less of a rush. I think that some really popular molecules are still waiting for a ‘last’ synthesis (e.g. taxol), as even the best routes devised to date still seem ‘too long’ and are larded with too many oxidation level adjustments and protecting group juggling steps. Obviously synthetic organic chemistry – like any science – is constantly improving so the aim is to devise the best solution possible at the time, and to learn something along the way. A good synthesis is timeless.[1]

Filed under: BRSM Reviews, Current Literature, Total Synthesis | 42,342 views | 9 comments Continue reading