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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.

Total Syntheses of (-)-Palau’amine, (-)-Axinellamines, and (-)-Massadines

1. Scalable, Stereocontrolled Total Syntheses of (±)-Axinellamines A and B

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

DOI: 10.1021/ja206191g

2. Enantioselective Total Syntheses of (-)-Palau’amine, (-)-Axinellamines, and (-)-Massadines

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

DOI: 10.1021/ja2047232

Are Baran syntheses a bit hyped? Yes! Is this an outstanding piece of work at the cutting edge of modern organic chemistry. Definitely! When I covered the first of these papers a couple of weeks ago I pointed out that Baran already had managed the first synthesis of these compounds way back in 2008. What this first paper contains is a new (shorter and more efficient) route to a (racemic) precursor used for all of the above natural products, and while the main thrust of the paper was the fact that this allows access to gram quantities of the axinellamines, it also significantly improves access to the others. Although I never got round to covering the second paper, it's again worth noting that Baran already reported routes to the massadines (also in 2008) and to palau'amine (in 2009). When Tot. Syn. covered the first palau'amine synthesis Paul remarked

"Now that’s a damn nice piece of work.  But I’m eagerly waiting for the full paper, which I’m sure will put this synthesis in context, as then we’ll have a better idea of what didn’t work.  That is perhaps the legacy of palau’amine – confounded logic, and ultimately the triumph of human endeavour."

Well, that moment is here! Although I doubt we'd even want to know the whole story (the paper references no fewer than 28 PhD theses at various institutions), it's great to have a recap of the early developments in the assignments of the structures themselves and a detailed description of the routes themselves (and the methodologies they inspired). Synthetic chemists often tell people that total synthesis is great because (when done correctly) it's not just a named reaction-fest and forces the development of new methodology. This campaign has given us plenty!


Total Synthesis of (–)-N-Methylwelwitindolinone C Isothiocyanate

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

DOI: 10.1021/ja206538k

As I said when I covered this, I wouldn't have tipped Garg to get to this target first, with all the big names that had already published in the field, but as they say, predictions are hard, especially about the future. One of my favourite stories to come out of the ACS Denver conference was that of Wood's congratulatory present to Garg and coworkers, which just looks so beautiful:

Photo by J. L. Wood via cenblog.org

The synthesis itself was very interesting, with some great chemistry, including regioselective indolyne formation and ensuing intramolecular enolate cyclisation, an exciting new method for making vinyl chlorides, and an intramolecular nitrene C-H insertion to functionalise the tricky bridgehead position where the isothiocyanate was to be installed.


Total Synthesis of Echinopines A and B: Exploiting a Bioinspired Late-Stage Intramolecular Cyclopropanation

D. Y.-K. Chen et al., Org. Lett., 2011, ASAP; [PDF][SI][GROUP]

DOI: 10.1021/ol202053m

Although there seems to be trouble brewing over in the comments at Tot. Syn. regarding the apparent copy-and-pasting of spectra from earlier papers, I'm still very impressed with this bioinspired route (and David Chen's third paper on the molecule). The late stage (compared to the earlier approaches) cyclopropanation is particularly satisfying but there a number of tasty steps including a beautiful palladium mediated cycloisomerisation-intramolecular Diels-Alder sequence. From the 'old-school' drawer of the total synthesis toolbox the group also manage a Henry-Nef sequence and also a late stage Eschenmoser fragmentation (and when was the last time you saw one of those in a total synthesis?). Although this route initially borrows heavily from the group's earlier unfinished formal total synthesis I think the concluding steps are interesting enough to make up for it!


A Concise Total Synthesis of (–)-Maoecrystal Z

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

DOI: 10.1021/ja2073356

This was on my 'to blog' list at the weekend, but I decided to write about the history of the Boc group first, and now it's been Tot. Syn.'d I won't bother with my own post. If you're wondering why you haven't much heard of Sarah, it might just be because she only finished her PhD with John Wood 5 years ago (back in 2006). Since then she managed a quick postdoc with Eric Jacobsen and now has a group of 15 people at Caltech. Wow! The synthesis itself is plenty interesting and well worth a read, using a clever diastereoselective double reductive cyclisation of a dialdehyde with samarium(ii) iodide as the key step to form two of the four rings.




Comments (7) Trackbacks (0)
  1. I think the axinellamines are reversed. (You’ve used 2 drawings of the structure, one flipped over relative to the other, which should switch alpha to beta & vice versa. You switched versions without changing the designations.)

  2. @ Baran´s work: I miss the gram quantities of the natural products in the Supp Inf. Only see tiny amounts isolated.

    • Industrial chemist – Yeah, the SI doesn’t seem to reflect the claim (in the axinellamines paper, scheme 1) that ‘all 12 steps were conducted on gram scale’. As you said in your comment on my axinellamines post, I think the often mediocre yields make the paper seem a bit more honest. Looking at the route, I think they could make a few grams if they wanted, without too much effort (that’s large scale to a lot of us…). Whether they ever did all the steps on the scales they claimed, I don’t think we’ll ever know.

      gippgig – You’re right as usual. I copied the structure from part of an older scheme, and the caption from another part. They do indeed not match up. Fixed now.

      • 892 mg of A + 221 mg of B = 1.113 g axinellamines. “gram scale” seems a reasonable description. That’s a tiny amount by industrial standards but a large quantity from a research perspective.

        I recommend drawing all structures in the same orientation whenever possible. Besides reducing the opportunity for errors it makes it much easier to follow what’s going on.

  3. Apparently “gram scale” doesn’t necessarily mean you actually make a gram at a time. Here’s another recent example, where repeat syntheses of 0.67g at a time is described as multigram. I guess 0.67 is technically a multiple…


  4. The baran SI shows all reactions for axinellamine done on a gram scale, am I missing something or did you guys download a different file? perhaps you are confusing the full paper of the old approach with the communication.

    • Before the final hydrogenation-amide formation the alpha- and beta- compounds are separated by HPLC. 921 mg of the beta- compound gives 892 mg A and 344 mg of the alpha- compound gives 221 mg of B. If you take gram scale at its literal ‘done on one or more grams’ meaning, then this step isn’t (especially not for axB). I really couldn’t care less, as I like this paper a lot and I don’t think it’d be significantly better if they’d put an additional 79mg of the alpha- compound into the flask for that final step. I guess it’s a gram-scale/multigram in the sense that you could quite easily make a few grams over a number of runs if you wanted. I still think that this remains an exceptionally practical synthesis for such complex compounds (at least by academic standards).

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