B.R.S.M. The road to Tet. Lett. Is paved with good intentions


(-)-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...

The Herzon synthesis starts from (R)-4-methylcyclohex-2-ene-1-one, a known compound, of which a number of syntheses have been reported. Here, the group opted to use the known preparation from inexpensive (+)-pulegone. Oddly, when referencing this paper, the group claim that the sequence to convert between the two is 4 steps, but as shown below it's clearly 6 steps (4 columns and a distillation, by way of purification). Still, it's fairly practical (at least on a research scale) and 20 grams of (+)-pulegone can be quickly converted into around 10 grams of (R)-4-methylcyclohex-2-ene-1-one without too much trouble. The route began with the diastereoselective 1,2-reduction of the enone using sodium borohydride, followed by ozonolysis of the isopropylidene group to give the α-hydroxyketone. This was then protected as the dioxolane by transketalisation, and the alcohol converted to the corresponding triflate. Elimination by heating in neat DBU, followed by a final deprotection with a little sulfuric acid gave the key building block in 42% overall yield.

Having made the starting material, the group set about its conversion to the natural product. Thus, lithium dimethylphenylsilylcuprate was added 1,4- to the enone, and the resulting enolate was trapped by alkylation with the dibromide shown. Unfortunately, the reaction had to be conducted in presence of a few equivalents of HMPA as a cosolvent, presumably because of trouble with the alkylation step.[2] That notwithstanding, the step works well, giving a single diastereomer by NMR and the group were able to conduct it on up to 4.5 gram batches. The product was then converted to the  α-cyanoketone by reaction of its lithium enolate with TsCN and a neat Pd-mediated α-arylation was then performed to close the final ring of the natural product. Highly optimised Wittig conditions were then used to convert the bridging ketone to the required olefin. Interestingly, a strong correlation was found between the concentration of the reaction (bizarrely conducted in ether) and the stereoselectity; at 1M a 1.1:1 mixture of E/Z isomers was obtained but at 0.01M a 5:1 mixture in favour of the desired E isomer was obtained. The group concludes that this result is consistent with a salt effect, and that it suggests that the desired E isomer is the kinetic product. Impressively, these three transformations (α-cyanation, arylation and Wittig olefination) could be telescoped together and therefore only required  one column between them to give the product in excellent yield over three steps.

Next the olefination product was treated with triflic acid followed by TBAF and hydrogen peroxide to effect Fleming-Tamao oxidative desilylation. The resulting alcohol was then dehydrated using the Burgess reagent in refluxing toluene, unsurprisingly forming the non-bridgehead alkene. The group then began the final sequence to convert the nitrile group into the amine found in the target compound. This began with hydration to the carboxamide using the rather difficult to draw (but surprisingly easy to make) platinum catalyst shown, a transformation I hadn't seen before.[3] Finally, this was converted via an iodine(III) mediated Hofmann rearrangement to the methyl carbamate, which was cleaved by methanolysis to the amine, completing the natural product.[4] Amazingly, all four transformations were accomplished with only a single purification step (at the end); a great example of an optimised and telescoped sequence in action. Even the sequence final step could be performed on greater than 1 gram scale, and over 3.5 grams of (-)-huperzine had been prepared at the time the paper was written. I'm not quite sure where to count the number of steps (and yield) from, but it's a big improvement on the previous state of the art, and for the first time delivers grams of the target compound for biological testing. Well done guys!

1. An enantioselective synthesis is desirable as (+)-huperzine is almost inactive against AChE, meaning you need twice as much racemic material to exert the same effect (and who knows what else the antipode does?). Kozikowski used Corey's classic (-)-8-phenylmenthol chiral auxilliary to achieve a stereoselective synthesis. Funnily enough, this auxiliary and Herzon's starting material are derived from (+)-pulegone, although the way the chirality is transferred to the rest of the molecule could hardly be more different.

2. HMPA is a bit of a carcinogen. I wonder if they ever tried DMPU, which is almost as good a lot of the time. I was made to distil HMPA as a masters student, and have used it a fair bit since so I'm not too uncomfortable with it. I even know where it comes in a proton NMR, but I still think twice about using it in a reaction. Conversely, I've heard of one organic research group who are banned by their supervisor from handling the stuff at all. We've got a chart of acceptable and unacceptable solvents for industry on the wall of our lab. It's not on there...

3. Just stir 5 parts dimethylphosphine oxide with 1 part tetrakis(triphenylphosphine)platinum(0) in toluene. Precipitate with ether. Filter. Dry. Full prep. and proposed mechanism in Journal of Molecular Catalysis A: Chemical, 2000, 160, 249–261.

4. Looks a bit like the last step in Garg's recent N-methylwelwitindolinone C isonitrile synthesis doesn't it? I don't think this goes via the free nitrene, though. The classic Hofmann is thought not to, anyway.


Comments (12) Trackbacks (0)
  1. “Having made the starting material…”? Hmmm, that reminds me of the compound that crystallized as an amorphous solid.

    That was an isopropylidene that was ozonized. (It seems rather inelegant to remove this then reattach an ethylidene later. How about olefin metathesis with propylene or is there any way to lop off one of the methyls instead? (or, for practical purposes, perhaps the isopropylidene homolog would be just as useful))
    Would you clarify Li dimethylphenylsilylcuprate vs. dimethylphenylsilyl Li + CuI?
    Attaching CN isn’t alkylation.
    The difficult to draw Pt hydration catalyst is a little easier to draw since it has one less H than shown.
    Dimethylphosphine oxide oxide?

    • Thanks as always for taking the time to point out the mistakes! I quite like the phrase ‘having made the starting material…’; it shows that it’s not as easy as it looks. My favourite chemistry oxymoron is ‘intramolecular cyclisation’. Can a cyclisation be anything else?

      I guess you’re right about the isopropylidene – it does seem a bit silly – but I can’t think of a quick way to excise a methyl, let alone do it selectively. The ketone is also crucial for the cuprate addition-alkylation, cyanation, arylation etc., although I guess you could argue this strategy was built around it, and another could be devised for the alkene. Regarding the cuprate – I could have said dimethylphenylsilyllithium + CuI, that being what they put into the pot, but here they use two equivalents of PhMe2SiLi to CuI, premix them at -78 ºC, warm to 0 ºC then cool again to -78 ºC. The point of all that is to form the cuprate. Sometimes you can use catalytic copper, or just add everything together, but I’ve always had better results (less 1,2-addition) making the cuprate in this fashion.

      I’m a little irritated about that Pt catalyst as I gave up on drawing the darn thing and just cut it out of the paper, but it turned out that Herzon and friends were mistaken and I didn’t notice. Ah well, should have read it more carefully.

      • For intermolecular cyclizations see cyanolide A aglycone (June 16 Totally Synthetic) and the Diels-Alder reaction!
        Is the isomer of pulegone with the double bond in the side chain available? Ozonize that to an acetyl, reduce to alcohol, dehydrate to alkene and there you go. Well, in theory…
        Great explanation of the cuprate! I should have downloaded the SI…

      • It was warmed from -78 to -23 and back to -78 (and back to -23 after the dibromide was added).
        Also, the final series of steps had a yield of 56-70% & the desilylation step used TfOH with DCM.
        The Pt catalyst is right in the paper but wrong in the SI.
        Since the OMe actually has to be removed what about base hydrolysis of the nitrile?

        • Ah, I was just going from memory on the cuprate conditions; thanks. You’re right about the catalyst… and unfortunately I copied and pasted it out of the SI where it has that extra H. Regarding the nitrile – I guess you could probably hydrolyse the nitrile to the acid and convert the 2-methoxypyridine to the corresponding pyridone (by addition-elimination) in the same step with aqueous base, although you might need to be quite rough. I guess the potential downside of this is that the pyridine might not be compatible with the rearrangement you’d then need to do on the acid. I’d probably go Curtius, for which you’d need the acyl azide, which you’d either get via the acid chloride (not sure the pyridone would get on well with SOCl2 or ClCOCOCl…) or by treating the acid with DPPA (I have no idea what this’d do over at the pyridone… amides often seem to react with phosphorus reagents). I guess you’ve got the Schmidt and Lossen options as well, but no one wants to work with HN3 for the former, and the later would probably either need the acid chloride or an amide coupling. So the answer is, as usual, maybe.

  2. While perhaps slightly waistfull to ozonize the alkene and then run a wittig a few steps later, I particuarly enjoyed the play with reactivity displayed by this strategy. Very nice work, and good to see another great synthesis in Chemical Science. Also, wonderfully explained by BRSM.

  3. Hey, nice post. And thx for the pingback ;) i did not read the paper yet but did they try to hydrolyse the nitrile and throw some DPPA on it? seems to me much more convenient… nevertheless straightforward stuff

    • They don’t mention it, but I believe the hydrolysis of nitriles to acids is pretty hard to do; I had originally planned it as the last or penultimate step in the total synthesis I’m currently working on, but my boss advised me against it for that reason. I guess the problem here is that you can’t really use acid or base to help you out: acid will protonate the pyridine first, which will slow down the protonation and hydrolysis of the much less basic nitrile, and base will almost certainly displace the OMe group off the pyridine by addition-elimination. Although the hydration they use is at high temp at least it’s neutral. Regarding links – no problem, you write well and I don’t have time to cover half the things I’d like to here!

      • Heh….RE: hydrolysis of nitriles – I have a friend in his 5th year of PhD studies, and the only thing standing between him and thesis writing is a few of these reactions (to make sub’d serines, in the end). Yuck.

  4. Herzon and Myers used the same Pt-catalyst in their synthesis of the Stephacidin B for hydrolizing the nitrile-functionality to an amide when Herzon was a PhD student. Nice to see how people apply the lessons they have learned at school later on :)

  5. Hey BRSM, nice job explaining the sequence. the structure of the platinum catalyst as shown is right. For a look at the structure of the same catalyst, see page 5 of http://www.platinummetalsreview.com/pdf/pmr-v40-i4-169-174.pdf

    Moreover, hydrolysis of hindered nitriles is not an easy thing to do. That was the reason why the Pt-cat. nitrile hydrolysis was developed in the first place, and the amide (not the carboxylic acid) is the product.

    I think the structure of huperzine shown here still has the methyl group on the pyridine. It should be pyridone, which was revealed at the final step with TMSI.

    • Thanks! The structure I originally posted, which is the one from the paper, had an extra hydrogen on one of the phosphines, but I fixed it after gippgig pointed that out. I think I actually prefer the way it’s drawn in that PDF you link, but I’m not changing it now! Regarding that OMe – yeah, definitely shouldn’t be there in the natural product… Cheers!

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