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