B.R.S.M. When all you have is a hammer everything looks like a nail

28Jun/111

Top Five Syntheses of May/June 2011

Here's an idea for a feature I've not seen anywhere else that I thought I'd try. It wasn't easy to choose, and my tastes in chemistry may be different to yours. These are not in any kind of order, because that would be silly. Please point out any nice work I've missed in the comments!


KCN's first dithiodiketopiperazine

Total Synthesis of Epicoccin G [PDF][SI][GROUP]

DOI: 10.1021/ja2032635

K. C. Nicolaou et al.J. Am. Chem. Soc., 2011, 133, 8150–8153

I was contemplating doing a full write up of this when I started blogging at the start of this month, but I'm not sure I'll get round to it now, unless it's a quiet few weeks or people really want to see one (let me know!). KC chooses a fantastically non-obvious disconnection for this molecule; the two g-hydroxycyclohexanones are actually derived from two molecules of tyrosine using a neat oxidative dearomatisation procedure developed by Wipf, followed by dimerisation. These spend most of the route masked as the 1,3-cyclohexadienes only to be revealed in the penultimate step by a [4 + 2] with singlet oxygen, followed by a Kornblum - DeLaMare rearrangement. How often do you see those?

Garg's aspidophylline A synthesis

N. Garg et al., J. Am. Chem. Soc., 2011, 133, 8877–8879 [PDF][SI][GROUP]

Total Synthesis of (±)-Aspidophylline A

DOI: 10.1021/ja203227q

Judicious application of some old school reactions, starting with a classic Diels-Alder reaction with maleic anhydride as the dienophile, and later employing an interrupted Fischer indole synthesis as its key step. Covered by Paul over at Tot. Syn.

 

Big Phil's full paper on cortistatin A

Scalable Synthesis of Cortistatin A and Related Structures [PDF][SI][GROUP]

P. Baran et al., J. Am. Chem. Soc., 2011, 133, 8014–8027

DOI: 10.1021/ja202103e

The past 3 years have generated an incredible body of work on the cortistatins, with total syntheses by Baran (Tot. Syn.), Nicolaou (Tot. Syn.), Shair and Myers, and more 'formal total synthesis' (e.g. Hirama), 'studies towards' and 'core structure of' papers than you can shake a stick at. It's easy to look at a Baran synthesis and think 'woah, how do they come up with this stuff?'. I like this paper because it goes some way to explaining the numerous unsuccessful approaches the group tried in achieving their impressive final route. Some people seem to think that big name chemists just pull these awesome syntheses out of the air, and this is a great reminder that there's still no real substitute for hard work in synthetic organic chemistry. I don't ever remember seeing so much chemistry that doesn't work in a JACS paper. There's also a lot of good background on steroids and semisynthesis, and plenty of exciting transformations. I learnt several things from reading this.

 

Stoltz's liphagal synthesis

The Catalytic Enantioselective Total Synthesis of (+)-Liphagal

B. M. Stoltz et al., Angew. Chem. Int. Ed., 2011, Early View; [PDF] [SI] [GROUP]

DOI: 10.1002/anie.20110184

I covered this when it came out. Lots of interesting chemistry in this - Stoltz's own palladium mediated enantioselective decarboxylative alkylation, a photochemical [2 + 2], an alkoxide cyclisation onto an aryne, Pd mediated a-arylation of a ketone, Wacker oxidation, thermal ring expansion and nitrosonium tetrafluoroborate used as a hydride abstractor... all this and more in 19 steps!

 

Fürster's metal-heavy 2nd generation synthesis of iejimalide B

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

This was my first post on this blog. Could you make a gram of that? Shame about all the tin! Lots of attention for this target with an earlier 'practical' 2nd generation synthesis reported back in April by Paul Helquist and coworkers, who managed an unbelievable 19.5% yield over their 15 step longest linear sequence. In their own words this "paves the way for efficient preparation of analogues for drug development efforts", although as far as I can tell they haven't pushed much material through the route yet. I really enjoy reading 2nd+ generation syntheses and comparing them to the originals as it's usually pretty instructive in how to optimise a sequence and cut out undesirable steps.

 

Honorable mentions

1. Ready's Total Synthesis of Isofregenedadiol for its delicious one-pottedness

2. Curran's Short Total Synthesis of (±)-Meloscin for having his name written all over it.

I just look at the key step and think back to his classic Hirsutene synthesis from '85, a brilliant piece of work born of "(1) an established interest in polyquinane* chemistry, (2) an on-off fascination with radical chemistry, and (3) a strong desire to earn tenure".[1] The first two clearly still influence his work more than a quarter of a century later.

 

Okay, so those are the syntheses that have particularly impressed me this month. Anything else good I should know about?

 

*well, it's got two five membered rings...

[1] According to his personal recollection in 'The Way of Synthesis', page 418

 

 

 

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