Natural Product Synthesis using Grubbs Metathesis Lasubine II

Natural Product Synthesis Using Grubb Metathesis Lasubine II, Ingenol, and Ophirin B 

Practitioners of total synthesis have been pushing the limits of Grubbs metathesis. Siegfried Blechert of the Technisches Universitat, Berlin, envisioned (Tetrahedron 2004, 60, 9629) that Grubbs metathesis of 1 could open the cyclopentene, to give a new Ru alkylidene that could condense with a styrene such as 2. In practice, this transformation worked well, yielding 3. Deprotection, intramolecular Michael addition and reduction then gave (-)-lasubine II4, 

There are times that it is important to run the Grubbs reaction undsT equilibrating conditions. In the course of a synthesis of ophirin B 12, Michael Crimmins of the University of North Carolina observed (J. Am. Chem. Soc. 2004, 126, 10264) that metathesis of 8 under the usual conditions gave mainly the undesired cyclic dimer. At elevated temperature, the dimer re-entered the equilibrium, leading to the desired 9 as the major (15 1) product. The oxonene ring system of 10 then directed the intramolecular Diels-Alder cycloaddition, leading to 12. 

The synthesis started with levoglucosenone 4, available by the pyrolysis of cellulose, e.g. old newspapers. Bromination-dehydrobromination gave the enantiomerically-pure Diels-Alder dienophile 5, which was combined with isoprene to give predominantly the crystalline adduct 1. Hydrolysis and acetylation led to 6, which was carried on to the geometrically-defined allylic alcohol 7 via reduction with Zn-Cu couple. Ovemian rearrangement of 7 proceeded with high facial control, to give 8. 

The next stage of the synthesis was ring oxygenation, to convert 8 into 13. The key to this tr ansformation was the observation that the amide oxygen of 8 participated in the solvolysis of the allylic bromide, setting, after hydrolysis, the new secondary stereocenter of 9. Hydroxyl-directed epoxidation gave 10, which was rearranged with Ti(0-i-C,H,) to 11. After some experimentation, it was found that the derived dione 12 could be reduced to the desired cis diol 13 with LiBr and LiAlH(0-t-CjH,),followed by NaBH /CeCl,. 

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Natural Product Synthesis using Grubbs Metathesis Lasubine II, 134... 

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