B.R.S.M. When all you have is a hammer everything looks like a nail


Woodward Wednesdays 2: Erythromycin A

Update 01/10/11 - It seems that I never actually gave the references for the original papers. The synthesis was actually published in three back-to-back JACS papers - the first is J. Am. Chem. Soc., 1981, 103, 3210, and you can read on from there. I also found the relevant synarchive page to be helpful when writing this.

I hadn't planned to cover this synthesis, Woodward's last, so early in this series, but as a review on the use of thiopyrans as templates in polypropionate syntheses was recently published in Chem. Commun. it seems timely to mention it now.[1] Woodward once said in a talk at CIBA in India that

"Much of the art of directed synthesis involves the design of ways to place constraints on molecular motion, with the aim of bringing about desired changes and suppressing others"

A popular way of doing this, as has been said before, is through the use of cyclic templates, a tactic used extensively by chemists of the Woodward and Corey eras. The ease with which desulfurisation can be accomplished using Raney Nickel makes thianes and thiopyans uniquely suitable as temporary rings which can be cleaved mildly and selectively later on.[2] This property made them the cornerstone of Woodward's approach to erythromycin A where they were used to set 8 of the 10 stereocentres found on the macrocyclic ring.[3]

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Cycloadditions are great

This is my attempt at answering Rachel Pepling’s call for posts for her blog carnival over at CENtral Science. The theme is 'Your favourite chemical reaction'.

Update: 23/09/11 - removed some of the more egregious grammatical errors.

It only took me a few seconds of thought to answer the question 'What's your favourite chemical reaction', far less than if I'd been asked about my favourite book, meal or album. It's the Diels-Alder cycloaddition, obviously. I reckon I've done well over a hundred of these by now (including three today), and those two names will certainly appear in the title of my PhD thesis. On social media websites I usually list my interests as rock climbing, mountain biking and cycloadditions.[1]

I guess what I like about this reaction, and why it's a mainstay of total synthesis, is that it's a fantastic way to generate stuctural complexity blindingly fast. It can set up to four stereocenters, and you can even take simple achiral precursors and introduce asymmetry catalytically. But, unlike a lot of reactions which are capable of such synthetic leaps forward, it's also generally very  predictable. One of my favourite parts of the history of this reaction is this quote from the seminal paper by Diels and Alder:

"We explicitly reserve for ourselves the application of the reaction developed by us to [natural products synthesis]"[2]

Nice try guys, but the 1300+ papers published in 2010 on this transformation seem to indicate that this request has been largely ignored by the synthetic community. And why not - it's an all round great reaction, probably the hammer and/or duct tape of the total synthesis toolbox. It's also nice that it's named for an advisor and his PhD student, because the people who actually do the chemistry often don't get the credit they deserve. However, despite all of these things I'm not actually going to write about the Diels-Alder reaction here. The reason is that it's just too well known - we even teach it to first year undergraduates. Everyone knows what it is, and how good it is, and I think this carnival is a great opportunity to dredge up some lesser known reactions and hopefully get people thinking about some chemistry that's new to them.

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On The Synthesis Of Ketones

A bit of a lack of exciting syntheses so far this week, so here's some methodology and random reflections and recollections.

I don't mind that we don't get told the whole truth as undergraduates, because most of us can't handle the truth (well, not all of it). I appreciate that trying to convey even the basic concepts of organic synthesis to a large room full of people of mixed abilities, attention spans and interest levels in a reasonable amount of time is hard. I realise that only a tiny percentage of students on any given organic chemistry course will ever pursue the subject to a level where the simplifications they're taught in their first few years cause them much trouble.

One of the earliest things I remember from undergraduate lectures on carbonyl chemistry is being told that Grignard reagents don't add to carboxylic acids, and that ketones (or tertiary alcohols) can't be made this way. The reason for this is simple - Grignards, like most nucleophilic organometallic reagents, are also strong bases so they deprotonate the acid and are then unable to attack the resulting anion. This property of carboxylic acids can be useful as it can be used to protect them from harm during a synthetic sequence (and is one of the reasons that carboxylic acids are just about the only carbonyl group to survive the Birch reduction).

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(+/-)-Chloranthalactone A

Total Synthesis of (±)-Chloranthalactone A

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

DOI: 10.1021/ol202190b

Despite being just 12 steps, Liu's synthesis of chloranthalactone A published last week is full of interesting chemistry including some pretty uncommon transformations. The compound itself shows some antifungal activity, and is also structurally very similar to the monomer unit of a number of related dimeric natural products which the Liu group are apparently interested in targeting. The compound also contains a trans-5/6 ring junction with an angular methyl group, which is not at all common in nature, given that such systems much prefer to be cis given half the chance.[1] This dangerously facile epimerisation meant that the group had to be very careful not to put any carbonyl groups near the ring junction at any point during the route, and lead to some creative chemistry.

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Top 5 Syntheses of August 2011

Okay, you know how this works by now - here, in no particular order, are my five favourite synthesis from August(ish). If I do this every month and this blog keeps going for a bit then this should be a useful resource for preparing problem sessions or just reminiscing. Also, I'd love to hear about good things I've missed!


Concise Total Synthesis and Stereochemical Revision of (+)-Naseseazines A and B: Regioselective Arylative Dimerization of Diketopiperazine Alkaloids

M. Movassaghi et al.J. Am. Chem. Soc, 2011, ASAP; [PDF][SI][GROUP]

DOI: 10.1021/ja206743v

Movassaghi seems to publish indole alkaloid syntheses at such a fantastic rate that it's easy to see them in the JACS ASAP and dismiss them as 'another Movassaghi paper'. We shouldn't, though, as I've never failed to learn something from reading one, and the amount of new reactions being generated is amazing. A recent cool example is the diazene based heterodimerisation of cyclotryptamines the group published last month, a new methodology designed to compliment their previously reported Co-mediated homodimerisation of similar compounds (seen, for example, in their excellent 2009 Science paper on the synthesis of (+)-11,11'-dideoxyverticillin A). Anyway, the new reaction in this paper, which allows rapid access to the two targets above, is a Friedel-Crafts-type arylation of various π-nucleophiles using C-3 halogenated hexahydropyrroloindoles as the electrophiles (activated with AgSbF6). Although this transformation was developed with the naseseazines in mind, an interesting discovery was made along the way. The group found that where poor C-6/C-7 selectivity was obtained in the arylation of indoles that the site of attack could be directed by the inclusion of a trifluoroborate substituent in the indole being arylated. This effect turned out to be quite general, and could be used to overturn the expected reactivity of a number of systems including anisole and thiophene. Overall, access to either naseseazine took only 9 steps, with excellent diastereoselectivity in the key C-C bond forming step.

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Woodward Wednesdays 1.5: A Brief History Of Boc

It hasn't escaped my notice that today is not Wednesday, but this is just a follow up post, and you know what they say about gift horses and looking...

As we saw in the inaugural Woodward Wednesday post last week, the second step in Woodward's 1965  synthesis of cephalosporin C was the Boc protection of an amino acid derivative. Having chosen cysteine as the starting material, and performed the known reaction with acetone, the next transformation that the group needed to carry out was this was this:

What I wasn't aware of when I wrote that post was that one of the authors on the Woodward paper, Helmut Vorbrüggen, actually went on to publish a paper on the difficulties of this step and the group's eventual solution more than 40 years later (Synthesis, 2008, 3739-3740). It turns out that the nearby gem-dimethyl group made this protection unexpectedly challenging, and Vorbrüggen provides a good insight into the difficulties Boc protection used to entail, as well as the thought processes that lead to the final choice of reagents.

Normally, when I want to make a carbamate, I reach for the corresponding chloroformate (ROCOCl) or maybe the carbonate, but it turns out that neither is very useful for the introduction of Boc groups. BocCl is woefully unstable and decomposes rapidly if you handle it roughly, by, say, storing it in the fridge or showing it traces of air or water. Conversely, (t-BuO)2CO isn't so much unreactive as inert, remaining unchanged even under quite vigorous conditions such as heating to 150 ºC in concentrated sodium hydroxide solution, which greatly limits its synthetic usefulness. A few papers describing the use of the relatively stable yet reactive BocF also exist, but the main drawback of this reagent is the difficulty associated with its production.[1]

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(-)-huperzine A

Update 02/09: just realised that Fukuyama's 2009 synthesis of (-)-huperzine was covered over at synthetic nature last year and the compound itself has a wikipedia page. Also, I notice that HMPA is mentioned in the paper. Whoops.


A Robust and Scalable Synthesis Of the Potent Neuroprotective Agent (-)-Huperzine A

S. Herzon et al., Chem. Sci., 2011, Advance Article; [PDF][SI][GROUP]

DOI: 10.1039/c1sc00455g

There's been a quite a lot of interest in this little natural product already, as it's known to be a potent and selective reversible inhibitor of acetylcholine esterase (AChE), with an impressive Ki of 23 nM. Apparently, recent studies have established that this property makes the compound a possible counter to organophosphate chemical weapons, such as the 'nerve gases' sarin and VX, which work by covalently modifying AChE (I, for one, am so glad I wasn't in that clinical trial). There's also some evidence it may be useful in slowing the progression of neurodegenerative diseases. However, the problem is (as usual) the difficulty of getting useful amounts of the darn thing for further studies - in this case the compound comes from a painfully slow growing chinese herb, with an isolation yield of just 0.011%. If my readership is what I anticipate then I expect you're all thinking, "that sounds like a job for total synthesis!", and you'd be right. The best asymmetric synthesis of (-)-huperzine reported prior to this work was that of Kozikowski and coworkers, published way back in 1991, standing at 16 steps with an overall yield of around 2.8%.[1] This new route by Herzon and coworkers manages a significant improvement on both counts, despite actually using the same chiral building block to introduce asymmetry...

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