Totally Synthetic by Paul H. Docherty, 22 March 2009
Total Synthesis of Ciguatoxin
A. Hamajima, M. Isobe, Angew. Chem. Int. Ed. 2009, 48, 2941-2945.
A literature search reveals, this synthesis has been ongoing for years. And figuring out what was done, when, and how often takes hours. This seems to be a common issue for syntheses of marine polyethers, as Crimmin’s total synthesis of brevetoxin earlier this year also demonstrated. However, I’ve tried my best to figure a full retrosynthesis.
The key disconnection is down the middle of the F-ring, splitting it into two similar sized fragments. This is done about the F-G junction, so the G ring goes in at the same time, using an alkynylation to link them. Then the F ring was installed by Co-complex mediated displacement of an alcohol. The dissubstituted acetylene was oxidised by removal of the cobalt complex formed earlier. The G ring was then closed onto the resulting ketone, and the initial hemiketal reduced with Et3SiH in the presence of BF3.OEt2.
I must admire, I have no idea how the E ring was installed. One of the papers describes the synthesis of an E’FGH system, but the E’ ring described is a 6-membered analogue. And they buy it in. Moving on a bit, the D ring was created using the same approach mentioned earlier - alkynylation, Co-complex formation, followed by displacement of a propargyl alcohol. This brings the fragment back to a fused bispyran, and to more familiar strategies: An oxidative cyclisation formed the C ring as a hemiketal, with BF3.OEt2 / Et3SiH used to reduce again. This brings us back to the starting material, methyl-α-D-glucoside.
The other large fragment is a more lengthy synthesis due to its more complex nature featuring more medium rings. Formation of the H ring is done late-stage through a very interesting 1,4-addition. Prior to that, an asymmetric delivery of hydrogen to an exocyclic methylene on the I ring gave the methyl stereocenter, with formation of the ring done using Co complexes as before. For the union of the two quite unequally sized fragments, a Sonogashira coupling was used.
I’m not sure how they get to the terminal alkyne. They referenced a previous paper, but the actual steps used for the synthesis of the fragment are not featured.
The other fragment is far better documented, with a typical spiroketalisation used construct the L, M system, using a Sharpless dihdroxylation to install a glycol on the medium ring. That ring was build using the well-known Co complex approach, again unifying similar sized fragments with acetylene chemistry. However, the elaboration of the sugar derivatives shown at the end is far from efficient. Take the left-handside, a pyran evolved from a methyl α-D-glucopyranoside derivative: twenty one steps are required to get to its retrosynthetic parent. However, they start with 1.2 kg of the substrates…
Even though this total synthesis is enormously inefficient, it’s an epic feat.