B.R.S.M. Yield isn't everything


‘No Added Metals’ Is The New ‘Metal Free’

Base image from http://mrsec.wisc.edu/Edetc/nanolab/photonic/index.html

Did anyone else see that paper on Thursday in Chem. Comm. titled "Use of Dimethyl Carbonate as a Solvent Greatly Enhances the Biaryl Coupling of Aryl Iodides and Organoboron Reagents without Adding Any Transition Metal Catalysts", and think "here we go again"?[1] I immediately though it kind of appropriate that Chem. Soc. Rev. very recently published a history of transition metal contaminants in catalysis (DOI: 10.1039/C2CS15249E). However, on reading the Chem. Comm. paper, it seems the authors were very careful both to check all their reagents, and not make any grand claims. Not surprising, really, given the numerous examples of misunderstanding of such results in the literature. Even the title is cautious, saying 'without adding any transition metal catalysts', quite a step down from the bold claims of 'transition metal free' reactions seen in the literature of a decade or so ago.


Welwitindolinones Redux

Perhaps not unexpectedly, given last year's exciting breakthrough syntheses, more synthetic work on the weltwitindolinones appeared in the literature last week, so I think an update is in order. As a reminder, the first synthesis of a bridged bicyclic member of this family came in March last year when Rawal reported a neat racemic route to N-methylwelwitindolinone D isonitrile, emerging as the winner of a 15 year race between plenty of well known synthetic chemists. This was rapidly followed by Garg, who published an excellent synthesis of (-)-N-methylwelwitindolinone C isothiocyanate in August, which I covered here.

Well, two more back to back JACS papers,[1] one each from Rawal and Garg have just appeared, and I'll summarise both here. Garg's describes improvements to the key step in his previously reported route to (-)-N-methylwelwitindolinone C isothiocyanate, along with the synthesis of (-)-N-methylwelwitindolinone C isonitrile and a couple of the so-called 'oxidised welwitindolinones'. Rawal's contains an asymmetric version of his previous racemic route, allowing access to (-)-N-methylwelwitindolinone C isothiocyanate/isonitrile, along with one of the 'oxidised welwitindolinones'. As Rawal’s has the most new chemistry of the two we'll look at that first.

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Sunday Evening Maths 1: ovatoxin-a

Among other things in JACS last week (such as more exciting welwitindolinone stuff from Rawal and Garg), I noticed this enormous (and enormously toxic) palytoxin-type natural product (DOI: 10.1021/ja210784u). Although I'm not particularly excited as a synthetic chemist, and I don't understand the biology, I do like compounds like this because they're so silly.

Structural elucidation was a bit tricky as the group only got 700 μg of compound. They say that as a result they 'could not afford any reliable 13C spectrum', by which they presumably mean they couldn't afford the 6 months of NMR time it'd probably take to get a good one, or that the one they got resembled the black forest prior to the industrial revolution. That's 0.26 μmol for you.

Regarding stereochemistry, there are some 4,611,686,018,427,387,904 possible diastereomers for this behemoth, which sounds like a quite a lot. Thankfully, comparison with palytoxin allowed assignment of 28 of the 62 stereocentres, meaning that actually only 17,179,869,184 diastereomers are left. That's not bad, as they've straight away ruled out 99.999999996275% of the possible structures, without setting foot in the lab. Depending how precise you're being, that's all of them. The fairly hefty molecular weight of 2648.13 means that if someone made 1 mmol of each that'd be 45,441 tonnes of material. To put this is perspective, may I remind you that this is approximately the same weight of tomatoes exported by New Zealand every year (to 2 significant figures). The authors conclude:

"Eventually, the availability of pure OVTX-a, which is by far the main toxin produced by O. cf. ovata, heralds the potential of characterizing the risks it poses to humans as well as of establishing the tolerable daily intake for seafood consumers."

However, as  the 'mouse lethality assessment' found that:

"one to 3 min after injection, mice started wriggling and all died within 30 min with paralyzed limbs. These preliminary studies on OVTX-a’s toxicity led us to conclude that the toxin mouse lethality lies below 7.0 μg/kg."

I think I might play it safe and have none.


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Holiday Reading 1: Perspectives and Humble Beginnings

Thanks to DrFreddy and Young Padawan for providing the inspiration for this post! Happy New Year!

I have always enjoyed learning about the history of reactions and strategies; for me the who and when are often as interesting as the what as they put the chemistry in context, and often make things a bit easier to remember because they help with the big picture. Plus, we all like to have stories about famous chemists to tell when we get together over coffee (or beer).

Late last year an interesting discussion took place over at Synthetic Remarks, sparked by the autobiographical piece published by Stork in the Tetrahedron issue celebrating his 90th birthday.[1] The article itself is well worth a read for some interesting anecdotes interspersed with a little chemistry. I particulary enjoyed Stork's offhand description of his marriage:

"My progress in the lab was only moderately affected by getting married to Winifred Stewart, the same young woman that I had met at St. Petersburgh Junior College some years before. As I recall, I asked one of my lab partners to watch over a reaction while I went to meet my future wife in the office of the justice of the peace who was to marry us"

Well, I guess you don't get that good by wasting time on your personal life! I also liked the story of his and Woodward's recruitment as promoters for the journal Tetrahedron at its launch:

"...one event I remember was the launching of Tetrahedron. Captain Maxwell, as the editor of the journal in question was known, had invited in April 1957, a number of guests in a townhouse in downtown New York to mark that event. During the celebrations, Maxwell placed a bet with some of the guests, namely Bob Woodward, Bill Doering, Carl Djerassi, and myself that the circulation of Tetrahedron ‘will not exceed 2499 copies’ by April 24, 1961. The bet, which was witnessed by Sir Robert Robinson, was for 100 gold guineas. This was a clever bet, because Maxwell would essentially get four salesmen for his new journal in exchange for a relatively small amount of money. Time passed, and one day I received a phone call from Woodward who said ‘you know, we won the bet’. I did not know, but I eventually got a call from Maxwell who suggested I meet him in a townhouse downtown where, after some champagne, he gave me a copy of a letter from a bank in Basel stating that 100 gold sovereigns (the bet had been changed to sovereigns by mutual agreement) was waiting for me in the branch of the Swiss bank in New York. I went there, carrying a French newspaper that I thought would give me some appearance of respectability, and was introduced to a vice president who did, in fact, hand me a small bag containing 100 gold sovereigns. This, after many years, is worth quite a bit. In 2011, at the time of this writing, 100 gold sovereigns equal in excess of $30,000!"

There are also a number of the infamous 'car stories' for which Stork is quite well known.[2]

Following DrFreddy's post, commenter Young Padawan asked if anyone knew of  any other such pieces on the lives of famous chemists and a list was created:

Steve Ley:

Tetrahedron, 2010, 66, 6270-6292. (DOI: 10.1016/j.tet.2010.05.049)

Larry Overman:

Tetrahedron, 2009, 65, 6432-6446. (DOI: 10.1016/j.tet.2009.05.067)

Robert Grubbs:

Tetrahedron, 2004, 60, 7117-7140. (DOI: 10.1016/j.tet.2004.05.124)

K. C. Nicolaou:

Tetrahedron, 2003, 59, 6683-6738. (DOI: 10.1016/S0040-4020(03)00943-8)

David Evans:

Tetrahedron, 1999, 55, 8589-8608. (DOI: 10.1016/S0040-4020(99)00436-6)

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