Organic Chemistry Portal
Organic Chemistry Highlights

Monday, January 11, 2010
Douglass F. Taber
University of Delaware

Advances in Alkene Metathesis: The Hoveyda Synthesis of (+)-Quebrachamine

There are two major impediments to the scaling up of alkene metathesis, reducing the amount of the expensive Ru catalyst required, and minimizing residual Ru in the product. Robert H. Grubbs of Caltech developed (Org. Lett. 2009, 11, 1261. DOI: 10.1021/ol9000153) a family of silica-supported Ru complexes, exemplified by 1. At 0.75 mol % of 1, the rate of cyclization of 2 to 3 was maintained over eight cycles. The solution of product 3 showed < 5 ppb Ru. Hassan S. Bazzi and David E. Bergbreiter of the Texas A& M campuses in Qatar and College Station also reported (Org. Lett. 2009, 11, 665. DOI: 10.1021/ol802728t) a durable polymer-bound Ru metathesis catalyst that maintained its activity over many cycles.

Most metathesis catalysts are strongly E selective. Amir H. Hoveyda of Boston College designed (J. Am. Chem. Soc. 2009, 131, 3844. DOI: 10.1021/ja900097n) a chiral Mo catalyst that was both highly enantioselective and strongly Z selective, converting the prochiral 4 into the alkene 6.

Professor Hoveyda also took advantage (J. Am. Chem. Soc. 2009, 131, 8378. DOI: 10.1021/ja9030903) of the known propensity of Ru metathesis catalysts for H bonding, showing that metathesis of the prochiral cyclopropene 7 proceeded with remarkable diastereocontrol. This appears to be a generally useful protocol for assembling enantiomerically-pure alkylated quaternary stereogenic centers.

It is also possible to encapsulate the Ru catalyst. Ned B. Bowden of the University of Iowa pioneered the use of PDMS thimbles for this purpose. He has now shown (Org. Lett. 2009, 11, 33. DOI: 10.1021/ol8022215) that by subsequently adding AD-mix, cross metathesis can be followed directly by enantioselective dihydroxylation.

Ring-opening cross metathesis of an unsymmetrical alkene such as 13 could give two different products. Alberto Avenoza and Jesús H. Busto of the Universidad de La Rioja established (J. Org. Chem. 2009, 74, 1736. DOI: 10.1021/jo802399k) that by tuning the electronic nature of the participating alkene, either product can be obtained with high selectivity.

Metathesis can be used to close larger rings. Conformational effects are important. Motoo Tori of Tokushima Bunri University observed (Tetrahedron Lett. 2009, 50, 2225. DOI: 10.1016/j.tetlet.2009.02.163) that while 18 cyclized efficiently, the other three precursors that were diastereomeric on the cyclopentane ring did not undergo ring-closing metathesis.

To accomplish the enantioselective construction of the Aspidosperma alkaloid (+)-Quebrachamine 22, Professor Hoveyda envisioned (J. Am. Chem. Soc. 2009, 131, 943. DOI: 10.1021/ja8084934) the selective ring-closing metathesis of 20 to 21. The stereogenic-at-Mo complex he and his co-workers developed was also effective in other applications, including the ring-opening cross metathesis of 4.

D. F. Taber, Org. Chem. Highlights 2010, January 11.