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Totally Synthetic by Paul H. Docherty, 20 December 2009

Total Synthesis of Isobongkrekic Acid


A Francais, A. Leyva, G. Etxebarria-Jardi, S. V. Ley, Org. Lett. 2010, 12, 340-343.

DOI: 10.1021/ol902676t

In a new attempt for the total synthesis of isobongkrekic acid, Lee focused on using the best methods available for each coupling. The retrosynthesis outlines that this paper is indeed rich in couplings. However, often more interesting is how the group made the coupling precursors, with a particular emphasis on installing vinyl iodides.

They started with the synthesis of a vinylstannane using a stereoselective Piers hydrostannylation published in a paper in JOC. But what was of more interest to me is a simple piece of convergence I haven’t read before - concommitant deprotection of a TBS ether and oxidation directly to the acid using Jones reagent. Very interesting!

For the first vinyl iodide synthesis, a a hydr-alumination of an acetylene in hexane in the presence of DiBAL-H gives after evaporation of the solvent a vinylalane - not a particularly nice species. This is then quenched by addition of iodine in dry THF, giving a high yield of E-vinyl iodide. However, one iodine isn’t enough here, so a gem-diiodide was formed by oxidising the alcohol to the aldehyde, and then adding hydrazine and iodine.

Ley refers the first coupling to as the Stille-Migita coupling. Using CuTC in Stille type couplings is something but I had always attributed to Liebeskind. A difference is that in most of the Liebeskind work, copper is the sole metal, whereas Ley uses a catalytic amount of palladium too. He also uses a phosphonate base, and explains it’s role as that of tin scavenger.

For the synthesis of another vinyl iodide, they used diethyl methyl malonate, a base and some iodoform. In the presence of an excess of base, single alkylation is followed by decarboxylation, saponification of the remaining ester and elimination to generate the vinyl iodide.

This fragment was reacted in a Suzuki coupling, quickly generating a diene and finally getting the group ready for an asymmetry propargylation. They opted for an indium mediated reaction using Singaram’s chemistry, which uses an ephedrine-like ligand to provide asymmetry. The reaction resulted in a very high yield, but also in a disappointing enantiomeric ratio. The group managed to improve the ratio by a non-enzymatic resolution with a commercially available planar-chiral DMAP-ferrocene catalyst developed by Greg Fu. You can find more information in a paper in Chem. Comm.

In the final Sonogashira coupling of a vinyl iodide, a standard palladium source and a common copper salt resulted in a rather neat yield of an enyne. However, what they desired was of course the E,Z-diene, so a reduction needed to be performed. Lindlar catalyst - the most obvious choice - failed, giving the group a bit of a headache. I’ll presume that a few sets of conditions were examined for this reduction, as they had success with an exotic copper/silver activated zinc reagent.

The reaction provided a very respectable yield of the desired trimethyl ester of the natural product, along with some of the undesired Bongkrekic Acid. Separation at this stage, followed by saponification gave the group a portion of each natural product, rounding-off a very interesting paper and an interesting total synthesis.