I originally started writing this post before Christmas but then lost the near-completed version with the death of my laptop. However, I recently found some old backups and decided to finish it up and put it online for your enjoyment. Have fun!---BRSM.
Total Synthesis of (+)-Crotogoudin
As the name implies, crotogoudin is another natural product from the goldmine of bioactive compounds that is the Croton genus of flowering trees. Seeds of these plants have been used for hundreds of years to produce the famous croton oil, a violent emetic and purgative used in early medicine across the globe before anyone realised just how bad it really was. Now, the notorious extract is mostly used as a source of various natural products, a reproducible way of inducing pain and/or irritation in animal experiments and a case in point that things described as 100% natural can still be extremely bad for you. It also serves as the major source of the important natural product phorbol, and gave its name to crotonic and tiglic acid (and thus crotonaldehyde). Along with a number of other natural products isolated from this genus, crotogoudin displays promising cytotoxic activity, which, coupled with the rare 3,4-seco atisane skeleton, was probably one of the reasons that the Carreira group recently embarked on its total synthesis.
The group envisaged the use of a radical cyclisation as the key step to form the final ring in the natural product, the required radical generated from the reductive opening of a cyclopropyl ester as shown below. The precursor to this reaction could be prepared from the simpler chiral β-hydroxyketone, a building block that could be easily obtained in enantiopure form by enzymatic desymmetrisation of the corresponding meso-diketone. Although the use of enzymes to produce chiral starting materials is by no means a recent development, it remains a fairly uncommon sight in total synthesis, possibly because such reactions are limited to the preparation of a relatively small number of simple building blocks—desymmetrisation works best for diols, diesters and diketones, for example—and it’s not always easy to design efficient routes around these starting materials. Additionally, large amounts of substitution around these motifs is often not well tolerated as the enzyme’s active site is just not able to fit such unnatural substrates in; unlike new catalysts promising implausible substrate scope and generality, enzymes usually have evolved to be very fussy about what molecules they'll accept. Of course, with the advent of synthetic biology, it’s becoming increasingly possible to retool enzymes for our own purposes, and I think that this approach become a lot more popular over the next decade (especially in industry, where it’s more reasonable to spend huge sums of money to find a way of optimising a single step to perfection). Anyway, that’s probably the subject of another blog post, and—at least in the case of this synthesis—Nature's capabilities are adequate, and the reaction is a good fit for the route!
A funny thing happened the other day: I went onto the Sigma-Aldrich website to order some undecacyclo[10.8.0.0(2,11).0(3,6).0(4,9).0(5,8).0(7,10).0(13,16).0(14,19).0(15,18).0(17,20)]icosane, and was amused to notice a rather M. C. Escher-like rendering of the structure:
Looking for alternative suppliers on Chemspider, I noticed it too had depicted the molecule in quite a strange way (although interestingly their 3D view of the molecule is spot on):
I guess that both these structures were probably drawn by computers, so I decided to see how Chemdraw's name-to-structure function would deal with such a complicated case. I was certain that the name would either be rejected or that some kind of tortuous hydrocarbon Gordian knot would result, but to my surprise Chemdraw emerged as the clear winner in this bizarre and impromptu competition:
More serious posts soon!