Totally Synthetic by Paul H. Docherty, 13 October 2008
Total Synthesis of Pyranicin
N. D. Griggs, A. J. Phillips, Org. Lett. 2008, 10, 4955-4957.
Andy Phillips' total synthesis of pyranicin showcases some rather neat methodology. From a biological perspective pyranicin is fairly interesting, as it exhibits the same nanogram ED50 values against a variety of cancer cell-lines as the more complex acetogenins. Phillips suggests that it was this activity, along with inhibition of electron transport, that prompted their synthetic efforts.
From a retrosynthetic point of view, Phillips tried to split the molecules into halves. The left hand fragment contains the titular pyran, built from a furan shown as the starting material in the first scheme. Sharpless asymmetric kinetic resolution reported by Sato gave the enantiomerically pure hemiacetal product, in which the ring has been expanded. Technically, this is known as an Achmatowicz oxidation, but the reagents and conditions used seem to have been modernised!
Kishi reduction of this hemiacetal in situ with a bulky silane and some Lewis-acid resulted in an ether, which was further reduced to the dihydropyranone, and then to the pyranol, fixing the last of the three stereocenteres on the ring. Nice work!
Moving on to the other fragment, an interesting chiral butenolide fragment had to be built, and Phillips went for an interesting procedure developed by Stille in the late 70’s - early 80’s and then by Hoye. Carbonylative lactonization was induced by adding a palladium catalyst in an atmosphere of carbon monoxide, but the mechanism isn’t particularly simple. This paper provides an insight.
The last step is the coupling of the two fragments; which wasn’t done using any traditional method. Instead, Phillips turned to an alkyl-alkyl Suzuki coupling developed by Greg Fu, coupling a primary alkyl bromide with an alkyl borane, that was created by in situ hydroboration of a terminal olefin. This impressive and ambitious palladium catalyst coupling worked rather well under mild conditions.
A very impressive total synthesis, I’m hoping that a full paper might follow sometime to elaborate on some of the chemistry used.