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


Two Reactions of Hydrazones

I thought I'd quickly share with you a couple of useful transformations involving hydrazones that I read about recently. The first one I found yesterday, reading George Majetich's perovskone full paper in Gilbert Stork's special issue of Tetrahedron. Although it's not the most atom economic thing ever, it struck me as quite a neat, if somewhat oldschool, way to transfer chirality. The second reaction is from Rawal's recent total synthesis of the weltwitindolinones, which I blogged about in detail here, and which I actually saw Rawal himself talk about on Tuesday at Bristol. The reason I've brought it up again is that when I wrote my last post commenter MadForIt asked about the mechanism of this transformation, which at the time I didn't know and didn't get round to looking up. By chance I found out the mechanism a few weeks later (completely by accident) but never got round to posting it up. Rawal's talk reminded me of this, but it didn't seem worth burying the answer in the archives so I thought I'd make a new post out of it here.

So, before I give you some possible answers, have a think about how you might do these and then read on for more information.

Filed under: Literature, Named reactions | 23,180 views | 9 comments Continue reading

The Splenda Effect and Chlorosulfolipids

Acknowledgement: I took the term 'Splenda Effect' from Carreira's talk at the Bristol Synthesis Meeting on Tuesday. It's a useful term to describe the low reactivity of alkyl halides near electron withdrawing groups. This post is mostly sourced from that, wikipedia and the Nature paper cited below.

Anyone eat any primary alkyl chlorides today? My dad had a few spoons in his morning coffee but that's not unusual. I only found out at the start of the week that sucralose, the main ingredient in Splenda and other sweetners, actually contains not one BUT TWO primary alkyl chlorides.[1] That makes it rather indigestable and also about 600 times sweeter than the starting material. In fact, as it contains fewer than 5 calories per serving the FDA allow it to be sold as 'zero calorie'. Because anything below five is basically zero.[2]

But why bring that up? Well, in considering synthetic approaches to the chlorosulfolipids Carreira asked the obvious question, 'can't we just start from a polyol and do a bunch of halogenations?'

"The result of initial synthetic efforts involving model systems led us to conclude that construction of such systems would have to take into account the unique behaviour and properties of a polychlorinated backbone with electron-withdrawing groups. As a relevant benchmark, sucralose, the key ingredient of Splenda, incorporates two 1° and one 2° chlorides on a disaccharide core and is sufficiently stable and safe to be widely used as an artificial sweetener. In a similar fashion, in preliminary investigations we observed that displacement reactions of activated alcohol derivatives to furnish the corresponding alkyl chlorides proved unworkable when the carbinol bears two methine substituents with electron-withdrawing groups, such as chlorides. Additionally, we noted that α- and β-chlorinated aldehydes are fleeting intermediates, which undergo enolization, hydration or elimination too rapidly. Thus, we sought to implement strategic approaches that would circumvent these limitations in crafting a synthesis route to chlorosulpholipid 5." - Carreira in Nature, 2009, 457, 573

The route the group actually used was interesting, and worth a minute's consideration. It's from three years ago, but I didn't have a blog back then so I'll quickly cover it now.

Filed under: Current Literature, Total Synthesis | 20,765 views | 5 comments Continue reading

Woodward Wednesday 4: And All That Could Have Been

Woodward was a member of the highly elite few; organic chemists who won Nobel prizes not for a specific reaction, discovery, or work with a particular element but for simple mastery of organic chemistry - theory, synthesis, methodology, structural determination, biochemistry - the list goes on. The elegant citation for his prize summed this up nicely:

"Professor Woodward's research work covers vast and various fields in Organic Chemistry. A leading feature is that the problems have been extremely difficult and that they have been solved with brilliant mastery. He has attacked them with a maximum of theoretical knowledge, a never-failing practical judgement and, not least, a genial intuition. He has, in a conspicuous way, widened the limits for what is practically possible."

I'd be very surprised if we see a Nobel Prize award to a synthetic organic chemist any time soon. The total synthesis/general organic crowd never seem very high up Paul's lists. As we saw in the very first post in this series, Woodward interestingly didn't use the opportunity given him to lecture on the work that actually won him the prize, instead choosing to speak on his entirely new and unpublished work on cephalosporin C. I think Woodward entirely deserved his Nobel prize, which he gained through an unbelievable pertinacity where chemical problems and puzzles were concerned, as well as the willingness to take on daunting challenges. Woodward's chemical legacy was enviable and it's telling that no conversation or book on classic synthesis can fail to cover such masterpieces as his work on reserpine, strychnine, chlorophyll and B12. That aside, I've heard numerous chemists talk about his contributions to other Nobel Prize winning work, so I thought it might be interesting to write a post on this.

Filed under: Literature, Woodward Wednesdays | 51,076 views | 13 comments Continue reading

Unnatural Products 4: Tetrahedrane

“Why does the tetrahedrane molecule fascinate the organic chemist? Is it the aesthetic appeal of the topology of the tetrahedron or the hope that the unusual bonding properties of this molecule could lead to otherwise inaccessible knowledge of general importance, or is it indeed the synthetic challenge of the highly reactive - if at all capable of existence - tetrahedrane, together with the sporting ambition to reach the goal first?” – Maier, 1988

This bonus Unnatural Products post was written by guest blogger Ckellz from New Reactions, who has worked on far more strained systems than most of us ever will. If anyone else fancies writing a post, get in touch. Enjoy! --BRSM.

When I first found out that BRSM was doing a series on unusual and platonic hydrocarbons, I immediately became really excited and nostalgic. I spent a good part of my undergraduate research career working on strained systems (which culminated in the synthesis of a highly strained bicyclobutane bearing a CF3 group). During my time in Dr. Tilley's lab tetrahedrane 4 often came up as a topic of discussion (Dr. Tilley's goal is ultimately the synthesis of this elusive molecule) and how we thought it was a very interesting molecule that might actually be quite stable. So when I was reading the posts about cubane, I commented that I had a good deal of knowledge about its smaller C4 cousin. The next morning I received a very nice e-mail from BRSM asking me to do a guest post about tetrahedrane and I jumped at the opportunity!

Filed under: Literature, Total Synthesis | 81,408 views | 14 comments Continue reading