Phillips and Griggs. Org. Lett., 2008, ASAP. DOI: 10.1021/ol802041c.
I guess Andy Phillips has been a rather busy-boy – not many researchers get back-to-back articles in Tot. Syn.!Â However, both papers are definately worth writing about; his pyranicin synthesis showcases some rather neat methodology.Â From a biological perspective pyranicin is fairly interesting, as it exhibits the same nano-gram ED50 values against a variety of cancer cell-lines as the more complex acetogenins.Â 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 sticks with the tried and tested split-it-down-the-middle-and-stitch-the-halves-together-at-the-end style of fing, but it doesn’t half work well.Â The left hand fragment contains the titular pyran, built from a furan shown as the SM in the first scheme.Â Treatment of this racemic material with a bit of Sharpless (in the form of a kinetic resolution described by Sato) gave the enantiomerically pure hemiacetal product, in which the ring has been expanded by one.Â Technically, this is known as an Achmatowicz oxidation, but the reagents and conditions used seem to have modernised somewhat!
Reduction of this hemiacetal in situ with a bulky silane and some Lewis-acid resulted in the ether (a Kishi reduction for all you named reaction fans…), which was further reduced to the dihydropyranone, and then to the pyranol, fixing the last of the three stereocenteres on the ring.Â 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 and (later) Hoye. Carbonylative lactonization was induced by adding a bit of palladium catalyst in an atmosphere of carbonmonoxide, but the mechanism isn’t particularly simple.Â Loads of work was done on it by Stille back in the late 70’s – early 80’s, with this paper giving quite a bit of insight into the process.
Last-up is the coupling together of the two fragments; following a developing theme in this paper, it wasn’t done in any traditional method.Â Instead, Phillips turned to an alkyl-alkyl Suzuki coupling developed by Greg Fu, coupling a primary alkyl bromide with an alkyl borane (created by in situ hydroboration of a terminal olefin).Â This impressive and ambitious coupling worked rather well, using a fair-old lump of palladium catalyst, but otherwise mild conditions.Â Ace.
A deeply impressive little synthesis, I’m hoping that a full paper might follow sometime to elaborate on some of the chemistry used.Â Whilst I’m waiting on that, I’ll carry-on reading the references…