Teaching Metathesis “Simple” Stereochemistry

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Science  20 Sep 2013:
Vol. 341, Issue 6152, 1229713
DOI: 10.1126/science.1229713

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Structured Abstract


Transition metal–catalyzed alkene metathesis has revolutionized organic synthesis during the last two decades, even though the commonly used catalysts do not provide kinetic control over the stereochemistry of the newly formed double bonds. It is of utmost importance to fix this shortcoming, because the olefin geometry not only determines the physical and chemical properties of the alkene products but is also innately linked to any biological activities that the olefins may have.


Recent progress in catalyst design led to the development of a first set of metal alkylidene complexes of ruthenium, molybdenum, and tungsten that allow a host of inter- and intramolecular alkene metathesis reactions to be performed with good to excellent levels of Z selectivity (see the figure). This marks a considerable advancement over prior art, even though inherently E-selective catalysts remain elusive. In the case of disubstituted olefins, this gap in coverage can be filled by a sequence of alkyne metathesis followed by stereoselective semi-reduction of the resulting acetylene derivatives, which provides highly selective access to either geometrical series. Because the required alkylidyne catalysts have also been greatly improved in terms of activity, functional group tolerance, and user-friendliness, this method constitutes a valuable preparative complement.

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Advances in catalyst design solve a long-standing stereochemical issue. Alkene metathesis was tremendously successful in the past despite lacking catalyst control over the geometry (E versus Z) of the newly formed double bond. Recently introduced molybdenum (left), tungsten, and ruthenium (center) alkylidenes partly fix this problem as they allow preparation of Z-alkenes with high selectivity. Alternatively, either geometrical series can be accessed by alkyne metathesis followed by semi-reduction, which also benefits from new catalysts (right) of much improved performance. R, generic substituent; TBDPS, tert-butyldiphenylsilyl; Mes, mesityl; Ph, phenyl.


It is expected that the new catalysts will be rapidly embraced by the synthetic community. Because the as-yet limited number of published case studies is very encouraging, it is reasonable to believe that more sophisticated applications to polyfunctionalized and/or industrially relevant targets will follow shortly. Such investigations will allow the selectivity and performance of the stereoselective metathesis catalysts to be scrutinized in great detail. In parallel, growing mechanistic insights into their mode of action will almost certainly be forthcoming that can then be translated into refined ligand design. The resulting feedback loops will likely result in the evolution of ever more selective and practical catalysts, the long-term impact of which on organic synthesis and materials science will surely be profound and lasting.

Pushing Metathesis Forward

It has been 8 years since the Nobel Prize in chemistry recognized the pioneers of olefin metathesis catalysis. Essentially, a means of shuffling the four carbons in a pair of double bonds, the transformation has enabled efficient synthesis of numerous complex organic compounds—particularly those incorporating large rings—and also underlies the ROMP (ring-opening metathesis polymerization) process for the preparation of specialty polymers. Analogous metathesis of (triple-bonded) alkynes has been applied as well. Fürstner (1357) reviews recent developments in the continuing optimization of this extraordinarily versatile reaction class. A long-standing deficiency has been the lack of stereoselectivity by the standard catalysts, precluding deliberate placement of substituents on the same (Z) or opposite (E) sides of the double-bond axis in the product, but recently introduced catalysts have shown promise in achieving high Z selectivity.


Applications of metal-catalyzed olefin metathesis reactions manifested dramatic growth during the late 20th and early 21st centuries, culminating in the 2005 Nobel Prize awarded to three of the pioneers. The standard catalysts developed during that time frame and their descendants have profoundly changed the mindset of the synthetic community, even though they do not provide a handle to control selectivity issues as fundamental as the E/Z geometry of the newly formed double bond. With yet another generation of catalysts in the making that are far superior in this regard, a new wave seems to be building up that is expected to have enormous impact, too. The current state of the art is critically assessed, as are possible alternatives such as the metathesis of triple bonds followed by stereoselective semi-reduction.

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