B.R.S.M. The Battlefield Earth of organic chemistry blogs



I've not written all that many total synthesis posts this year, not for a dearth of interesting work, but more a lack of free time. I started writing this one about six months ago (!), and I guess most of you have probably seen this paper already, but I think it’s pretty cool so I decided it’d be worth finishing. Now featuring my new favourite piece of punctuation, the em dash!

Synthesis of (−)-Neothiobinupharidine

Ryan A. Shenvi et al., J. Am. Chem. Soc., 2013, 135, 1209 [PDF][SI][GROUP]

DOI: 10.1021/ja310778t


The first of the rather wacky looking nuphar alkaloids were actually isolated back in the 60s by Achmatowicz (of Achmatowicz reaction 'fame'), the family has now grown to a fair size, as you can see from the borrowed figure below. No-one paid them much attention for a while, as they weren't very bioactive, looked quite intimidating, and everyone was probably too busy psyching themselves up to make vernolepin anyway.[1] However, a recent report that they selectively kill off melanoma cells (via a mechanism that no-one’s worked out yet), combined with a pretty cool biosynthetic proposal by LaLonde, was enough for Shenvi to spend a little time working out a synthesis.

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Synthetic Biology versus Total Synthesis

From a series of paintings by David Cordes at Pacific University, Oregon.

I think most would agree that synthetic chemists can now make just about any non-protein/non-polysaccharide natural product if enough time, resources and manpower are brought to bear.[1] But that's not to say that the field is yet mature, or stagnating, as there still remain so many challenges to make our science more efficient, practical, and free from its current over-dependence on rare metals and petrochemical feedstocks. Recently, synthetic biology has started to emerge as a serious alternative to total synthesis when large amounts of complex natural products are required. Just think how many total synthesis papers start with a desultory line about 'the dearth of natural material', before recounting an arduous one- or two-yearlong quest to make a few more milligrams of the compound in question. Perhaps it sometimes makes more sense to try a different approach and ask 'can't we just improve the natural source?'. We synthetic chemists like to think we're special because we have the ability to make new compounds never seen in Nature, but with an increasing understanding of enzymes and the genes that encode for them, organisms can now be coaxed into producing compounds that have never been seen before. If you're interested in reading further debate over the future of the two fields then you should definitely read this short piece in Nature, in which champions of synthetic chemistry Phil Baran and Abraham Mendoza duke it out with Jay D. Keasling, a strong proponent of synthetic biology.

Reaction Vessels

From Nature, 492, 188.


1.  Of course, there still exists the question of 'should we?'. Aside from the importance of total synthesis in structural determination, and ignoring for the moment the oft quoted reason of solving supply problems, the other main justification offered by the practitioners of the art is the development of new methodology. I'd love to find a way to test this claim, but my feeling is that few generally useful reactions are discovered in long synthetic campaigns. Let me know in the comments if I'm wrong about this.

Filed under: Current Literature, Total Synthesis | 8,448 views | 8 comments 8 Comments

Mulvember 2: Echinopines A and B

Although there have been a couple of interesting syntheses this week, I'm still very busy so I'm going to write about another Mulzer synthesis from my talk. See my previous post for the background to this tribute.


Since their fairly recent isolation in 2008 the echinopine sesquiterpenes have proved quite popular targets for total synthesis. In fact, four rather different total syntheses have been reported since their unusual and compact molecular architectures first graced the literature. The first of these was that of Johann Mulzer, published just a year after their isolation, in which both natural products were synthesised in near enantiopure form (starting from cyclooctadiene!) and their absolute configurations were confirmed for the first time.[1]

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What’s Wrong With This Picture 1: Gibberellic Acid?

For people who say that inflation of yields is a new thing... think again. Corey's synthesis of gibberellic acid is otherwise really quite good.

Filed under: Literature, Total Synthesis, WWWTP | 7,219 views | 10 comments 10 Comments

Taxol Time Again: What now, Phil?

Update 20-11-2011: Reference added and a couple of mistakes removed. Why can I never see those the first time?

Scalable Enantioselective Total Synthesis of Taxanes

Baran et al., Nature Chemistry, 2011, [PDF][SI][GROUP]


The taxanes are a large family of 350 or so natural products, of which the best known is taxol itself, a multibillion dollar anticancer drug with a rich and storied history, whose name and distinctive tetracyclic system are instantly recognisable to most organic chemists. Taxol itself has already been the subject of 7 epic total syntheses (see BRSM Reviews: Taxol In 10 Minutes if you need a quick reminder), all using conventional functional group lead approaches to bond formation. Nature's (and Phil's) approach is a bit different, though, as we'll see.

Filed under: Current Literature, Total Synthesis | 11,171 views | 10 comments Continue reading