B.R.S.M. All this happened, more or less.

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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10Jun/110

Iejimalide B

Note: I've never written a Tot. Syn. type post before, and it's come out a bit more detailed than I intended. I'll try and be a bit more brief next time...


Gram-Scale Total Synthesis of Iejimalide B

Fürstner et al., Chem. Eur. J., 2011, Early view; [PDF] [SI] [GROUP WEBSITE]

DOI: 10.1002/chem.201100178

Here's a nice modern synthesis from the Fürstner group; an impressive panoply of transition metal mediated reactions were used in this highly convergent synthesis of iejimalide B (although perhaps a little more tin than some people would be comfortable with...). I think the best way to show this is with a retrosynthesis:

Not happy with just the first total synthesis of the iejimalides (Tot. Syn. here) back in 2007 and prompted by encouraging biological results obtained using the material from the first campaign the Fürstner group set about developing a 'truly scalable' route to these compounds, a goal I'd say they'd accomplished admirably.  Apart the usual suspects (RCM, Stilles and a Heck) there's a few less common transformations which are worth a closer look.

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