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


Maoecrystal V (Part 1: Thomson)

Enantioselective Total Synthesis of (−)-Maoecrystal V

Regan J. Thompson et al., J. Am. Chem. Soc. 2014, 136, 17750 [PDF] [SI] [GROUP]

DOI: 10.1021/ja5109694

0 minus 1Maoecrystal V—as the advanced nature of its final letter implies—is one of a great many unusual terpinoids from the Chinese flowing plant Isodon eriocalyx.[1] It possesses a rather intricate and complex structure, a fact illustrated by the two decades that passed between its (first) isolation in 1994 and the successful determination of its structure in 2004—a long period indeed with modern spectroscopic techniques. Its dense, cage-like structure proved a tough nut to crack and another 5 years passed before the deluge of synthetic publications for this target began in 2009. The first total synthesis, reported somewhat controversially by the Yang group the following year, has only seemingly intensified the attention that it has received.

0 - Structure

Maoecrystal V exhibits a heavily modified version of the more common ent-kaurene skeleton.

Interestingly, despite the hugely varied interests and specializations of the groups involved, all five of the successful total syntheses reported to date have constructed the molecule’s prominent bicyclo[2.2.2]octane ring system using the venerable Diels–Alder reaction (often in conjunction with the similarly tried-and-true tactic of oxidative dearomatization to establish the diene). That said, the number of Diels–Alder variants employed is impressive, and you could almost imagine giving a short lecture course on the reaction using nothing but examples from synthetic studies on maoecrystal V. I’ve tried to illustrate the variety below.

All 5 total syntheses to date have used a Diels–Alder reaction to form the molecule's fused bicyclo[2.2.2]octane ring system. The reaction has also featured prominently in approaches by Baran, Trauner, Nicolaou, Chen, Movin, Sorensen and others.[2]

All 5 total syntheses to date have used a Diels–Alder reaction to form the molecule's fused bicyclo[2.2.2]octane ring system. The reaction has also featured prominently in approaches by Baran, Trauner, Nicolaou, Chen, Movin, Sorensen and others.[2]

I’ve long wanted to write something about maocrystal V total synthesis, but I’ve always been too busy around the time that people have completed it to get a blog post out reasonably close to the event. Fortunately, two back-to-back syntheses from the Zakarian and Thomson groups were published in J. Am. Chem. Soc. earlier this month and I’ve now got plenty time to write about both of them, starting with that of the Thomson group in this post.

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Unnatural Products 3: Pentaprismane

For the last planned post in my Unnatural Products series, I’m going to write about Eaton’s 1981 synthesis of pentaprismane.[1] At the time, unnatural hydrocarbons were hot targets, and as the next largest prismane on the list this target was the subject of much research by groups around the world. Perhaps Eaton's biggest rivals were the groups of Paquette and Petit, and in fact all three had, at various times, synthesised hypostrophene as an intended precursor to the target.

Unfortunately, the ‘obvious’ [2 + 2] disconnection from pentaprismane turned out to be a dead end and the photochemical ring closure was unsuccessful. The 1970s and early 1980s saw the publication of a number of other similarly creative, but sadly ill-fated, approaches based on various ring contractions, and the compound gained a well-earned reputation for extraordinary synthetic inaccessibility.

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Taxol Time Again: What now, Phil?

Update 20-11-2011: Reference added and a couple of mistakes removed. Why can I never see those the first time?

Scalable Enantioselective Total Synthesis of Taxanes

Baran et al., Nature Chemistry, 2011, [PDF][SI][GROUP]


The taxanes are a large family of 350 or so natural products, of which the best known is taxol itself, a multibillion dollar anticancer drug with a rich and storied history, whose name and distinctive tetracyclic system are instantly recognisable to most organic chemists. Taxol itself has already been the subject of 7 epic total syntheses (see BRSM Reviews: Taxol In 10 Minutes if you need a quick reminder), all using conventional functional group lead approaches to bond formation. Nature's (and Phil's) approach is a bit different, though, as we'll see.

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Cycloadditions are great

This is my attempt at answering Rachel Pepling’s call for posts for her blog carnival over at CENtral Science. The theme is 'Your favourite chemical reaction'.

Update: 23/09/11 - removed some of the more egregious grammatical errors.

It only took me a few seconds of thought to answer the question 'What's your favourite chemical reaction', far less than if I'd been asked about my favourite book, meal or album. It's the Diels-Alder cycloaddition, obviously. I reckon I've done well over a hundred of these by now (including three today), and those two names will certainly appear in the title of my PhD thesis. On social media websites I usually list my interests as rock climbing, mountain biking and cycloadditions.[1]

I guess what I like about this reaction, and why it's a mainstay of total synthesis, is that it's a fantastic way to generate stuctural complexity blindingly fast. It can set up to four stereocenters, and you can even take simple achiral precursors and introduce asymmetry catalytically. But, unlike a lot of reactions which are capable of such synthetic leaps forward, it's also generally very  predictable. One of my favourite parts of the history of this reaction is this quote from the seminal paper by Diels and Alder:

"We explicitly reserve for ourselves the application of the reaction developed by us to [natural products synthesis]"[2]

Nice try guys, but the 1300+ papers published in 2010 on this transformation seem to indicate that this request has been largely ignored by the synthetic community. And why not - it's an all round great reaction, probably the hammer and/or duct tape of the total synthesis toolbox. It's also nice that it's named for an advisor and his PhD student, because the people who actually do the chemistry often don't get the credit they deserve. However, despite all of these things I'm not actually going to write about the Diels-Alder reaction here. The reason is that it's just too well known - we even teach it to first year undergraduates. Everyone knows what it is, and how good it is, and I think this carnival is a great opportunity to dredge up some lesser known reactions and hopefully get people thinking about some chemistry that's new to them.

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(-)-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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Solanoeclepin A

Total Synthesis of Solanoeclepin A

K. Tanino et al., Nature Chemistry, 2011, 3, 484–488; [PDF] [SI] [GROUP]

DOI: 10.1038/nchem.1044

Admittedly I don't check Nature Chemistry as often as I should, so I only noticed this truly epic synthesis of solanoeclepin A a few days ago. I remember being shocked by my first sight of the structure during a talk by Prof. Henk Hiemstra a couple of years back, especially that improbable looking DEF ring system. This synthesis is obviously a phenomenal technical achievement, and it must have been an incredibly demanding task, but at first glance there aren't too many sexy steps.[1] The abstract mentions 'addressing one of the critical food issues of the twenty-first century' and solving natural supply problems, goals towards which this synthesis could be the first step.[2]

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