Week one solution for the Mega Chemist Challenge

Well done to Shaun Pollock and Richard Collins, the solution is indeed Kurt Alder. Alder is arguably one of the most famous synthetic organic chemists of all time owing to the reaction developed alongside his mentor and PhD supervisor Otto Diels. The Diels-Alder [4+2] cycloaddition (or diene reaction) is known by all who have studied organic chemistry, and becomes beloved by those with a penchant for total synthesis (in particular one Professor Samuel Danishefsky). Alder is also know for his extensive studies and development of the hydro-allyl addition or Alder (ene) reaction.

Here I have linked to some of the seminal work of Alder in both the Diels-Alder and the Alder-ene reaction, though unfortunately these are all written in German and currently my translation skills on a scale of 1-10 come in around 0. Should anyone be aware of translations online or be capable and willing to undertake such a challenge themselves I would love to hear from you.

Cause of the “azo ester” reaction

Addition of “diene” hydrocarbons

Addition of azodicarboxylic esters to aldehydes 

Substitution processes in the allyl position

A full biography of Alder can be found here via nobelprize.org

Finally, I want to try to finish each solution to the Mega Chemist Challenge with some relevant chemistry that I love (or at least have read in my own exploration of the author).  For week one I can not help but talk about Corey’s beautiful  use of the Diels-Alder reaction in his 1969 synthesis of prostaglandins F2α and E2.  Those of you whom have read this before can once again revel in its magnificence and the warm feeling of inspiration that it imbibes into you; and those of you fortunate to read it for the first time, read it again and take note!

My fascination with Corey’s prostaglandin synthesis is that on not only the first, but for a considerable number of glances after, a Diels-Alder disconnection is not apparent. We have a fully saturated five membered ring and two double bonds which scream Wittig/HWE type disconnections, but not a six membered ring in sight, nor a reconnection to form one.

Taking extreme liberties and stepping into the mind of the forefather of retrosynthesis, I hypothesise that after the obvious double bond disconnections Corey arrived somewhere in the region of 1, with the three contiguous chiral centres installed (scheme 1). Even here though, it still takes beautiful vision to see that these three centres can be installed in a single step using a Diels-Alder reaction.

Corey skillfully envisioned the cycloaddition of 5-methoxymethyl-1,3-cyclopentadiene and 2-chloro-acrylonitrile to give a mixture of bridged bicycles which were readily converted into a single product 2 with the three stereocenters installed.  Subsequent Bayer-Villager oxidation, followed by saponification and in situ iodo-lactonisation to give 3, all proceed exceedingly well and without contemporary purification techniques (scheme 2).

As a (young) synthetic chemist this paper impresses not only with respect to the chemistry, but what can be achieved with what many may now regard as frightful working conditions; we should all take note and maybe not reach for the columns so readily. Lines must be drawn though, and should I be informed that I was only allowed a 60Hz NMR spectrometer for the rest of the week, I must be honest, I would probably just go for a pint and not come back!

p.s. Any advice on making ChemDraw look good on WordPress would be very welcome.

 

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6 thoughts on “Week one solution for the Mega Chemist Challenge

  1. I love the idea of the Mega Chemist Challenge! Regarding schemes in wordpress, there are some tips on the Totally Synthetic FAQ, but here’s what I do (which is simpler and still looks good). For examples, see things I’ve posted in the last few months:

    1. Use Chemdraw 10 or 11
    2. Increase line thickness to 0.04 cm
    3. Draw things
    4. Save as pngs
    5. Convert said pngs to jpgs as pngs don’t seem to work well with WordPress. This is easily automated with photoshop if you have a lot of schemes.
    6. Find a mistake and bang head on keyboard.

  2. Addendum:
    Personally, I wouldn’t advise drawing arrows in 0.04 cm thickness; they just look too chunky. You’ll find a style you like over time.

  3. Pingback: Mega Chemist 3 – Solution | Mega Chemist Challenge

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