B.R.S.M. To strive, to seek, to find and not to give a yield

9Oct/116

And Now For Something Completely Different 1: Progress In Strychnine Synthesis

Sorry things have been so quiet around here the last couple of weeks - I've been a bit uninspired, the start of term has been a bit hectic, and my boss has finally noticed that I haven't really made any progress in the last six months. Hopefully more things soon as I wrestle my life back under control.

A few weeks ago, as the result of a conversation in the lab, I thought it might be interesting to pick a popular molecule (i.e. something of which there have been numerous syntheses), and see how much better we've gotten at making it over time. After a bit of thought I settled on strychnine, and in order to not waste an excessive amount of my life, only took syntheses which produced a single enantiomer of the natural product. So, first let us look at how the number of steps (in the longest linear sequence) has varied over the years.

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21Aug/1119

Projects I’m glad I didn’t work on

Obviously this style of post is borrowed from Derek Lowe's Things I Won't Work With. I'm not the most original person, and this certainly isn't the most original blog.

Hopefully many of you will have now read Baran's axinellamine paper (my take here) - it's an impressive piece of work and worth a few minutes of your time. I've noticed that I keep having the same conversation about it with different people over the last day or two:

BRSM: Have you seen Baran's new axinellamine paper? It's the shit!

Chemist: Yeah, it's pretty cool, but you couldn't pay me to work on that project. Those guys must have spent a lot of time staring off the roof of the Scripps chemistry building.

BRSM: But he's so sexy!

Chemist: I have to go now, I, uh, have a TLC running...

Or variations on that theme. Anyway, I realised that actually: 1. I'm probably inclined to agree, and 2. I find myself thinking this quite a lot. As I told commenter gippgig yesterday, I saw Baran give a talk about this work back in 2009. I remember him describing the silver(ii) picolinate oxidation and saying they had to screen a massive number of oxidants to find this successful reagent. I think he described one of his students as having a 'black tar phase' of 6 months or so, where everything presumably kept degrading when they attempted to install that troublesome hydroxyl. Silver(ii) picolinate obviously wasn't high on the list  of things to try as they had to make it specially, and none of the references they give for its use are later than the early 1970s. Periods of faliure come to everyone who practises chemistry long enough, but when you're pushing the boundaries of what's known, as Baran was here, you can spend months in the lab going nowhere at all.

A couple of other syntheses from this year with similar heroic efforts at optimisation come to mind. I should say now that I think they're both fantastic, but I'm not sure I would have had the dedication and mental fortitude to see them through.

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25Jul/1110

(-)-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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