Dornan, P. K.; Lee, D.; Grubbs, R. H. “Tandem Olefin Metathesis/Oxidative Cyclization: Synthesis of Tetrahydrofuran Diols from Simple Olefins.” J. Am. Chem. Soc. 2016, 138, 6372. DOI: 10.1021/jacs.6b02653
Here at ATM, we spend a lot of time talking about ruthenium-catalyzed metathesis transformations, but there are a whole lot of other reactions that ruthenium can mediate,1 from reductions2 and oxidations3 to C-H activation4 and photoredox catalysis.5 So, perhaps it’s no surprise that we often come across new ways to pair our favorite reaction with another ruthenium-catalyzed step to make interesting new products.6
The Grubbs group recently developed a tandem ruthenium-catalyzed metathesis/oxidative cyclization sequence that generates complexity in rapid order from mundane starting materials. In the opening examples, cyclooctadiene and acrylates are transformed into meso THF-diols containing four stereocenters with precise control of relative stereochemistry.
The excellent stereocontrol is possible because the oxidations each go through a stereospecific [3+2] cycloaddition with respect the relative outcome of each diol product, and the 2nd cycloaddition in the sequence is intramolecular and stereoselective in its facial approach.7 As long as the metathesis step forms the olefin in high E/Z selectivity, the sequence should lead to one diastereomer selectively. In the above example, the bisacrylate intermediate is formed as the E,E-isomer almost exclusively, and this isomer leads to only one diastereomer of the oxidative cyclization product.
If you make the starting materials just a little more complex, you can make chiral (albeit racemic) compounds with even more complexity built in. And, as predicted by the proposed mechanism, you can invert the relative stereochemistry at either diol by changing olefin geometry (either in the substrate as shown, or using a Z-selective catalyst for the metathesis step). Pretty slick.
Now, if you’re like me and spent 5+ years of your life trying to develop asymmetric reactions, this may leave you searching for a way to set absolute stereochemistry, not just relative. There are two that come to mind. First, you could try to control the absolute stereochemistry of the first dihydroxylation, for which there is precedent with chiral auxiliaries.8 But, if you’re like me and spent those 5+ years working on catalytic asymmetric reactions, the auxiliary approach won’t be satisfying. One catalytic approach would be enantioselective desymmetrization of a meso compound from the first set of examples. Enzymatic desymmetrizations of similar compounds are known,9 but one could also envision a chiral DMAP-catalyzed acylation that would do the trick.10 Perhaps someone interested in synthesizing one of the THF-containing natural products mentioned in the paper will go down this road. If so, we’ll be very interested to read about it!
 Ruthenium in Organic Synthesis; Murahashi, S.-I. ed.; Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim; 2004.
 Arockiam, P. B.; Bruneau, C.; Dixneuf, P. H. Chem. Rev. 2012, 112, 5879.
 Nam, Y. H; Snapper, M. L. “Ruthenium-Catalyzed Tandem Metathesis/Non-Metathesis Processes” in Handbook of Metathesis, Volume 2: Applications in Organic Synthesis; (Grubbs, R. H.; O’Leary, D. G eds.; Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim; 2015.
 Piccialli, V. Synthesis 2007, 2585.
 Lee, A. W. M.; Chan, W. H.; Yuen, W. H.; Xia, P. F.; Wong, W. Y. Tetrahedron Asym. 1999, 10, 1421.
 Candy, M.; Audran, G.; Bienayamé, H.; Bressy, C.; Pons, J.-M. Org. Lett., 2009, 11, 4950.
 Ruble, J. C.; Tweddell, J.; Fu, G. C. J. Org. Chem. 1998, 63, 2794.