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Totally Synthetic by Paul H. Docherty, 11 February 2007

Total Synthesis of Laureatin & Isolaureatin


H. Kim, H. Lee, D. Lee, S. Kom, D. Kim, J. Am. Chem. Soc. 2007, 129, 2269-2274.

DOI: 10.1021/ja068346i

Continuing their fascination with natural products derived from the Laurencia family (not an uncommon fascination!), Deukjoon Kim’s group (the same team that brought you this post) has completed two more related structures, each with that eight-member ring, often found in the family. They base most of the work on an advanced intermediate, created in their total synthesis of Laurencin (seven steps, 35% yield), containing that eight-membered ether ring, set for functionalisation.

The first step was halogenation, inverting the free hydroxyl; this isn’t an easy transformation, as the secondary hydroxyls on a ring tend to be quite hindered. However, using trioctyl phosphine under the conditions shown, they got a great yield - conditions they used to even more success later in the synthesis. Osmylation then returned the last common intermediate in good yield.

Oxolane and oxetane formation then diverged the route; however, some complication occured when differentiating the hydroxyls. In the first case, treatment of the diol with base unexpectedly delivered the five member ring. Formation of a stannylene intermediate helped to differentiate the hydroxyls. With the protection complete, treatment with base then returned the oxetane in good yield.

In the case of Isolaureatin, the conformation of the medium ring meant that inversion of the hydroxyl using the same halogenation conditions as before didn’t occur. However, they used this steric preference to their benefit by creating a vinyl bromide via formation of the vinyl triflate (the “Wulff protocol”). Then delivery of diimide from the accessible face allows overall inversion.

Alkylation of the amide returned the ketone, at which point they epimerised the adjacent centre using the unfavorable electrostatic repulsion between the oxygen lone pairs to deliver a d.r. of 4:1 in their favour. The ketone was then reduced by L-Selectride with good distereocontrol. The sidechain was then tranformed into a terminal alkene to allow an interesting cross metathesis, using Lee’s protocol to return the desired enyne. Simple deprotection of the terminal alkyne then retuned the natural product.

They then turned to the total synthesis of Laureatin, using a similar strategy. Inversion of the freed hydroxyl using the conditions show before worked well this time, and alkylation of the amide was also effective. However, epimerisation didn’t go so well…!

Reordering the steps was quite effective (alkylation with ethyl grignard, epimeriation and then halogenation), allowing completion of the target using similar chemistry. A great read!