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


Solve your deprotection problems… with TNT

A busy week in the lab trying to finish this damn natural product. More things at the weekend.

Update 30/07/11: Forgot to give a reference for the Hoffmann paper, which is Angew. Chem. Int. Ed., 1993, 32, 101-103. It's not a bad piece of work, and was for a time the shortest route, despite being entirely linear.

Johann Mulzer, one of my favourite chemists, wrote a review back in 1991 titled 'Erythromycin Synthesis—A Never-ending Story?'. It's well worth a read as these natural products have inspired an awesome body of work, and were an important benchmark in stereoselective natural product synthesis for many decades. Woodward, Stork, Corey, Danishefsky, Evans, Paterson, Reinhard Hoffmann, Mulzer, Carreira and most recently White have all worked on them, which is some recommendation.[1]

Anyway, I was reading Hoffmann's synthesis of (9S)-dihydroerythronolide A today when I encountered a most unusual set of conditions for deprotection. To set the problem in context, the (unstable) triply protected compound below had been obtained, and only three steps remained to the glorious completion of the target; selective cleavage of the cyclopentylidene acetal, macrolactonisation (assisted by the conformation limiting p-methoxybenzylidene acetals) and a final deprotection. The problem was that the cyclopentylidene acetal couldn't be removed without cleaving the other protecting groups, despite encouraging results obtained earlier in model studies. Not wanting to start again, a method to slow down hydrolysis of the p-methoxybenzylidene acetals was needed.

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(-)-strychnine, (+)-aspidospermidine + 4 others

Collective synthesis of natural products by means of organocascade catalysis

or, "The shortest reported routes so far to (-)-strychnine, (+)-aspidospermidine, (+)-vincadifformine, (-)-kopsanone, (-)-kopsinine and (-)-akuammicine."

MacMillan et al., Nature, 2011, 475, 183–188; [PDF] [SI] [GROUP]

DOI: 10.1038/nature10232

A couple of weeks ago the MacMillan group published a remarkable paper reporting the asymmetric synthesis of six natural products, from three different alkaloid families. I only noticed total syntheses coming out of the MacMillan lab two or three years ago, but now they're something I always find myself getting excited over, and this is no exception.

MacMillan contends at the start of the paper, and he's not the first, that given enough effort, money, and time it's now possible to make at least a few milligrams of almost any known natural product. Just look at Kishi's palytoxin synthesis, for example, or the ongoing Nicolaou efforts towards maitotoxin sporadically appearing in JACS. We all know that it's when you need to make large amounts of any complex molecule (even grams), that your troubles really begin. Another thing that takes a huge amount of effort using conventional chemistry is the preparation of libraries of natural products (and their analogues) for biological testing.

Obviously, Nature is much more better at the construction of complex molecules, thanks largely to its peerless enzyme catalysts and amazing use of cascade reactions. Another thing that makes Nature's approach very efficient is that it tends to produce a number of natural products from a single intermediate, giving rise to families of compounds. The broadest example I can think of is the use of IPP and DMAPP to produce the terpenoids, to which entire series of books have been dedicated, but there are also many smaller groups of natural products thought to share a common biosynthetic precursor. Chemists, on the other hand, traditionally just choose one or two targets, although we are getting a bit better at this, and 'general methods' for the synthesis of families of natural products are now not uncommon. While many different definitions of 'the ideal synthesis' and 'efficiency' have been offered, T. Hud. stated a few years back what he thought was the paragon of modern synthesis:

"The highest possible level of craft requires the synthesis of an entire class of natural products by a unified approach resembling, in principle, their biogenesis. All members of a specific class (as well as all of their possible diastereomers) should be attained in an enantiodivergent fashion as single entities"[1]

This latest work from MacMillan group is one of the few papers I can think of which comes close to this exacting standard. Here, perhaps inspired by Nature, the group accessed a number of quite different alkaloids (spanning three families), in what they call 'collective total synthesis'.

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Cyanthiwigins B, F, and G

Total Syntheses of Cyanthiwigins B, F, and G

Stoltz et al., Chem. Eur. J., 2011, Early View; [PDF] [SI] [GROUP]

DOI: 10.1002/chem.201100425

I briefly contemplated not covering this, as I covered the Stoltz group conquest of liphagal last month,[1] and this uses the same palladium-catalysed enantioselective decarboxylative alkylation as the key asymmetry creating step. However, this is such a clever and powerful demonstration of the methodology that I couldn't help myself.[2] This time the targets are the cyanthiwigins, a family of marine diterpenoids with over 30 members, all sharing a highly conserved 5-6-7 tricyclic core. The few members isolated in sufficient quantity for testing, and the cyathanes in general, have demonstrated a range of biological activities so new routes to these compounds could be useful.

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Twitter, webhosting and domains

A couple of quick, non-chemical things. Firstly, I now have a Twitter account (@BRSM_blog, as @BRSM was taken), so if you're not into RSS or just hitting F5 every ten minutes I'll tweet something when I post things from now on. I promise there will be no non-chemical updates, rants, or boring stuff. Secondly, I'm contemplating moving the blog, and probably getting a more sensible domain sometime in the next few months. The hosting I currently have is pretty basic (no PHP5, which really limits what wordpress plugins I can use) and I'm pretty close to maxing out my meagre monthly bandwidth allowance even with a fairly small number of readers and a simple layout. I'm inclined to just get some better hosting and do everything myself, as that'd be nice and easy, and I could migrate the whole site pretty quickly, but I notice a lot of people are using wordpress.com for hosting. My main concern for wordpress.com is that I don't know how easy it'd be to migrate the site over, and I think you have to pay extra in order to stay ad free, which I really, really want to do. So, fellow bloggers, what are people doing? Who's good?

Also, I'm inclined to get a more sensible/memorable domain name while I'm at it, but brsm.com, .co.uk, .net, .org etc. are all taken. I can either get something silly like brsm.xxx, brsm.mobi or brsm.asia, or get something slightly different like brsmblog.com. That's pretty memorable, right?

Filed under: Ask the audience, Not Chemistry | 6,449 views | 4 comments 4 Comments


A second post this weekend - you guys are lucky the weather is awful here!

Total Synthesis of (+)-Omphadiol

Romo et al., Angew. Chem. Int. Ed., 2011, Early View; [PDF] [SI] [GROUP]

DOI: 10.1002/anie.201102289

Omphadiol is an africanane sesquiterpene isolated for the first time in 2000 from a basidiomycete. No-one knows what it does because of the small amounts isolated, but structurally similar sesqui- and diterpenes exhibit various biological activities including antiviral, anti-inflammatory and anti proliferative effects. It’s also got an interesting 5-7-3 ring system and 6 contiguous stereocentres around the ever popular trans-hydroazulene core. That notwithstanding, it took Daniel Romo and coworkers at Texas A&M University just 10 steps (and not a single protecting group) to prepare the natural product stereoselectively from (R)-carvone via a bicyclic b-lactone intermediate. 

Filed under: Current Literature, Serious, Total Synthesis | 10,106 views | 4 comments Continue reading

BIBS, the newest silicon protecting group

Note: I'm currently on holiday. I do have internet access, but drawing chemical structures on the netbook I've borrowed may just be too painful. I'll try and get some updates out ASAP.

Di-t-butylisobutylsilyl, Another Useful Protecting Group

Corey et al., Org. Lett., 2011, ASAP; [PDF] [SI] [GROUP]



I suspect that anybody who’s been engaged in synthetic chemistry for more than a year or two has probably used a silicon protecting group. I’ve used plenty, and they’re generally very useful, easy to put on and take off, and pretty robust under a lot of different conditions. One of the great things about these groups is the huge range available; from the labile TMS and TES, to the more robust (and useful) TBS and TBDPS, to the hardy TIPS.[1] At the extreme end of the scale an even tougher group is the tri-t-butylsilyl group, but that’s very hard to put on or take off, and the silylating reagent itself is a pain to make. This week Corey published an attempt to fill the niche for a group tougher than TIPS, but more useful than tri-t-butylsilyl, with the disclosure of the di-t-butylisobutylsilyl (BIBS) group.

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Eaton’s other reagents

On Friday, I found myself discussing the use of Eaton's reagent with a coworker. Many people know it as a handy alternative to polyphosphoric acid (PPA) for acylations, Friedel-Crafts reactions and the like. It's even endorsed by Milkshake. A simple 7.7 wt% solution of phosphorus pentoxide in methanesulfonic acid, it's not as viscid, viscous or  unpleasant to work up as PPA.[1] And it's commercially available. But neither my coworker, nor many other people I know, are aware of Eaton's other contributions to the synthetic world. He's still an emeritus professor at the University of Chicago, and you can read about his interests on his website, but what he's most famous for, unbeknownst to many younger chemists, is his synthesis of the cubanes.

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Schindilactone A

Here's an impressive total synthesis of schindilactone A by Tang, Chen, Yang,[1] and 14 coworkers. At 29 steps in the longest linear sequence that's comfortably fewer than two per author. Still, the route is entirely linear and it's a fairly heroic effort, as we'll see.

Work began sometime ago as the group published syntheses of the ABC (Org. Lett., 2006, 8, 107) and FGH (Org. Lett., 2005, 7,885) fragments of the slightly more complex micrandilactone A some time ago. Apparently that unique, ketal spanned, 7-8 carbocyclic system in the middle took some time to work out. I'll cover the older work on those fragments as well, as it shows the origins of some of the key steps in the schindilactone A total synthesis.

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Chemistry By Design

Update: I'm an idiot. Link fixed. That's what I get for copying and pasting from an email

I've just been made aware of this awesome project by Jón Njarðarson's group at the University of Arizona. You might already be aware of their excellent poster on the 200 best selling drugs (free to download and print!). Their newest gift to the synthetic community is a website which allows you to browse a number (>200) of inspiring syntheses and then test yourself on them. Aside from the obvious use of this, people without access to the literature at the moment, or people looking for good syntheses to prepare problem sessions on will probably find it a useful resource. The amount of effort that's gone into this is staggering (I certainly don't envy whoever entered all 54 steps of Steve Ley's epic azadirachin synthesis). I'll let Jón explain:

Dear Fellow Organic Chemists,


In a few weeks this project will also be available as a free APP for i-phones and i-pads.

With the help of my students we have added more than 200 total syntheses to the site, representing more than 100 different PI's and covering more than 40 years of publications. We plan to continue to add to the site, but we would like to encourage everyone to submit a synthesis they would like to see featured on our site. Instructions to do so can be found on the website.

Please share this link with everyone. I am convinced your students, post-docs, colleagues and many others will enjoy. This website should be a great supplement to graduate synthetic courses and advanced undergraduate courses.  Make sure to check out the QUIZ mode, which operates like a serial flashcard that allows you to test your synthetic knowledge (you can browse through each sequence in many different ways).

I hope you enjoy.

Best regards,


Tell the (synthetic) world!

Filed under: Uncategorized | 5,912 views | 1 comment 1 Comment

(+)-Loline Alkaloids

2330 - update: Just noticed the Tot. Syn. writeup. Check it out for an alternative discussion! Funny that this work's two weeks old, yet we both write about it today!

An Efficient Synthesis of (+)-Loline Alkaloids

D. Trauner et al., Nature Chemistry, 2011, 3, 543 [PDF][SI][GROUP]

DOI: 10.1038/nchem.1072

I just noticed this very efficient enantioselective synthesis of a trio of the loline pyrrolizidine alkaloids reported by Trauner and coworkers back in June. Although loline has been known for more than a century, prior to this work only one enantioselective synthesis had been reported, and at 20 steps in length - that's well over two synthetic operations per carbon atom - it's as good an example as any to illustrate the point that size isn't always what makes a target challenging. Trauner, with characteristic German efficiency, took only 9 steps to reach loline through clever use of some simple and largely well established chemistry. Reading this paper reminds me of one of the most important axioms for designing anything (syntheses, websites, software, machinery...): that a thing should only be as complicated as it needs to be - and no more.

Filed under: Current Literature, Total Synthesis | 5,956 views | 3 comments Continue reading