Totally Synthetic by Paul H. Docherty, 22 January 2007
Total Synthesis of Intricatetraol
Y. Morimoto, T. Okita, M. Takaishi, T. Tanaka, Angew. Chem. Int. Ed. 2007, 46, 1132-1135
Somewhat similar in structure to silvaticin, described here back in October, intricatetraol is an interesting C2 symmetric bis-THF. This feature lead to a somewhat unsurprising disconnection along the axis of symmetry, to reveal a dimerisation metathesis and reduction strategy. As dull as that might be, the rest of the synthesis was a whole lot more exciting, if based predominately on epoxidation/opening. However, it’s quite the master class, so lets look at the epoxidation strategy at a whole. As you can see, the SM is trans,trans-farnesyl acetate, which might actually be the biological starting material too.
So, how are they planning to make all those epoxides? Quite easily, really:
The “left-most” epoxide isn’t actually made from a Sharpless epoxidation; they actually do a dihydroxylation, and then selectively mesylate and displace to leave the desired epoxide. With the epoxides in place, the next step was THF formation:
A very impressive use of the Payne rearrangement, and a fairly impressive yield. However, they still had one more epoxide to make, which as I said before, was generated by selective mesylation of the less hindered secondary alcohol, and then treatment with base. With the epoxide in hand, it was time to halogenate several times; however, this is way less than trivial. In the end, they used a rather exotic source of bromide, and were able to open the epoxide in their favour. However, what happens next to put in the chlorine is a bit special.
Finishing the synthesis from here was a matter of a couple of steps, and completed a rather nice synthesis and a great paper.