B.R.S.M. Yield isn't everything


Top 5 Syntheses of July 2011

I'm going to try and make this a regular thing. Top 5 for May/June can be found here. Please stop by in the comments and point out any good ones I've missed (or rubbish the ones I've picked). As before, these aren't in any particular order, because that would be silly.

Total Synthesis of (-)-Histrionicotoxin

Fukuyama et al., Org. Lett., 2011, ASAP; [PDF] [SI] [GROUP]

DOI: 10.1021/ol2018032

Like the erythromycins from the previous post, the histrionicotoxin alkaloids have a rich and storied synthetic history (which you can get a flavour of in Rob Stockman's review in Nat. Prod. Rep., 2007, 24, 298-326). I'm often left a little unenthused by Fukuyama syntheses (a friend of mine described his tactics as 'the world war one approach to synthesis') but there's some interesting chemistry in this paper. The way in which chiral information is moved about the molecule is quite cool: asymmetry is first introduced by preparation of a chiral propargylic alcohol using the Noyori reduction, then transferred to a chiral silyl allene. This is then finally alkylated to generate an all carbon quaternary centre that allows a long sequence of reactions to be carried out under substrate control. There's also a retro-Brook rearrangement, an asymmetric propargylation and some dienyne metathesis to keep things interesting.

Collective synthesis of natural products by means of organocascade catalysis

MacMillan et al.Nature, 2011, 475, 183–188; [PDF] [SI] [GROUP]

DOI: 10.1038/nature10232

I covered this pretty recently. This is an excellent bit of work from the MacMillan group, containing within one paper six enantioselective syntheses of natural products spanning three different families. As you might expect from earlier work from the group the key asymmetry generating step is an organocatalytic cascade, which used to contruct the tetracycle shown above which is then developed into various alkaloids.


An Efficient Synthesis of (+)-Loline Alkaloids

D. Trauner et al.Nature Chemistry, 2011, 3, 543; [PDF][SI][GROUP]

DOI: 10.1038/nchem.1072

Okay, so it's not technically from July, but I wasn't aware of it when I did last month's top 5 (and I didn't cover it 'til July). Trauner's synthesis of the loline alkaloids is in many ways quite simple, but that's what's so good about it. The asymmetry originates from a Sharpless allylic epoxidation and the rest of the steps would easily be understood by many third or fourth year undergraduates. Not that these are easy targets; the previous record for enantioselective synthesis of (+)-loline was 20 steps (the Trauner group only needed half that) it's just that the synthesis is well thought out and well optimised.

Note: Amusingly, Tot. Syn. and I covered this the same weekend. Check out Paul's writeup  here.


Asymmetric Total Synthesis of a Pentacyclic Lycopodium Alkaloid: Huperzine-Q

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

DOI: 10.1002/anie.201103550

Another fawcettimine-type Lycopodium alkaloid synthesis (although the first of this particular compound) with plenty of good chemistry and a neat biomimetic aminal formation as the final step. The core of the natural product (highlighted) was obtained using a diastereoselective intramolecular Pauson-Khand as the key step. Nice work and only 19 steps (16% yield) - check it out!


Second-Generation Total Synthesis of Spirastrellolide F Methyl Ester: The Alkyne Route

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

DOI: 10.1002/anie.201103270

As I've said, I like second generation syntheses. It's often instructive to see the improvements that groups make with each generation, and watch the less desirable steps get replaced with more practical alternatives. When the Fürstner group achieved the first synthesis of this target back in 2009 a lot of the stereochemical details of the molecules were still unknown (particularly in the southern and western quadrants), which limited the group to a fragment based approach which was necessarily quite linear in places. Here, unfettered by the requirements of designing a flexible route to explore the unknown, the group were able to focus on just producing a good synthesis of this compound. One of the main differences in this route compared to the previous was the method of macrolactonisation. Whereas previously a quite conventional lactonisation-Suzuki sequence was used, here the group employed alkyne metathesis instead, and proceeded to use gold catalysis to develop this alkyne into the southern spirocyclic acetal instead of just reducing it out in the normal fashion. Great stuff.


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  1. Personally I liked Trauner’s syntheses of the (+) Loline the best. I found them to be the most elegant, practical, and amazingly short (8 steps in the streamlined version!!!)

    • It’s a great piece of work – I’ve heard the quote “any idiot can make something complicated but it takes a genius to make something simple” attributed to Einstein, but whoever said it was spot on. Wish I’d been on that project (and it’s not often I think that of syntheses I cover)!

      • Nah, don’t think you’d like to be in the loline team… What looks so simple on the paper was a huge effort in the lab – I have heard they always tried usual = complicated transformations first and just retracted on the simple steps = successful when convenient ideas failed… The guys were close to madness, rumors say!

  2. Am I the only one who just wants to add Grubb’s catalyst to (-)-Histrionicotoxin NOW to see what kind of metathesis products might pop out?

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