B.R.S.M. Help! I'm trapped in a molecule factory!


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.

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(+/-)-Indoxamycin B

Total Synthesis and Stereochemical Reassignment of (±)-Indoxamycin B

Carreira et al., Angew. Chemie., 2012 Early View [PDF][SI][GROUP]

There haven’t been many total syntheses recently that I’ve really wanted to write about in the last month or two, but I quite enjoyed both the Carreira offerings that appeared in Angewandte last Friday. After realising that I didn’t have time to write about both, I decided on this one as it reminded me of some chemistry I’d done myself a while back.[1] I also enjoy it when total synthesis ends in reassignment, as it’s probably one of the more worthwhile outcomes of a synthetic campaign, and it makes a nice story.

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(+)-Daphmanidin E

Update 26/11/11: Link to newly available SI now added!

Update 30/10/11: Also, Tot. Syn. now has a post on this.

Update 29/10/11: Covered in more colours over at synthetic nature. Check it out!

Total Synthesis of (+)-Daphmanidin E [PDF][SI][GROUP]

Carreira et al., Angew. Chem., 2011, Early View

DOI: 10.1002/anie.201104681

Here's an interesting synthesis from a couple of weeks ago out of the Carreira lab - the first synthesis not only of daphmanidin E itself, but of any alkaloid of its family and skeleton. The daphmanidins constitute a recent addendum to the already fairly diverse class of alkaloids isolated from Daphniphyllaceae, with today's target only reported 5 years ago. Presumably, exciting features like "moderate vasorelaxant activity on rat aorta"[1] and that well nested central bicyclo[2.2.2]octane ring make them tempting targets...

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