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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.

DOI: 10.1021/ol802041c

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.

Selected Comments

14 October, 2008 at 6:36, antiaromatic says:
The sp3-sp3 coupling is nice. I wonder if they tried using the iodide instead of the bromide.
14 October, 2008 at 12:14, Tot. Syn. says:
If you read the linked Fu paper, you’ll see that he finds that alkyl bromides are better partners for the coupling, as the reaction temperature can be lowered. I guess that alkyl bromides are also a little less likely to eliminate, which would always be a concern when using primary alkyl halides with beta-protons.
14 October, 2008 at 18:30, milkshake says:
Sometimes Pd(0) -catalysed coupling reactions work better with bromides: iodides do have much faster insertion rates but the produced iodide anion complexes to Pd rather strongly and saturating the coordination sites with iodide slows down the turnover – especially when bulky phosphine ligands are used or when the substrate itself is strongly coordinating. This iodide inhibition is a problem one can counteract it by adding stoechiometric Ag or Tl salt.
In my hands, for Buchwald-Hartwig N-arylations and Suzukis, the Buchwalds bulky biphenyl ligands are best suited for aryl bromides (and chlorides), and the old fashioned tetrakis or Xanthphos in THF as a solvent works better for iodides.