C&EN Today - Wednesday, August 1, 2001 -
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Published on: 7/31/2001
Last Visited: 8/7/2001
Among them was P. Andrew Evans , a professor of chemistry at Indiana University , Bloomington.His group has been reexamining rhodium-catalyzed allylic substitutions.In particular , his goal has been to control the regioselectivity of allylic substitutions for unsymmetrical substrates.
Transition-metal-catalyzed allylic substitutions offer ways to construct new carbon-carbon and carbon-heteroatom bonds.The substitution increases molecular complexity because typically the incoming group , or nucleophile , is more complex than the leaving group.The reactions would be even more useful if the substitution could be perfect : That is , the nucleophile would go to the same exact location and bind in the same exact stereochemical orientation as the leaving group.
This type of control has not been generally forthcoming , Evans says.And allylic substitutions typically have been limited to symmetrical substrates.When the substrates are unsymmetrical , the reaction generates two different sites for substitution and the potential for the formation of regioisomers.Generally , what you want is attack on the more substituted site to create or retain a chiral center , Evans says.But that doesn't happen with the usual catalysts for allylic substitutions.
With those , the metal typically forms symmetrical , so-called 3-allyl complexes.However , interconversion of these complexes between two isomeric forms erodes the original regio- and stereochemical information held by the substrate.For this reason , allylic substitutions have been most useful with symmetrical substrates.
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In 1998 , Evans and graduate student Jade D. Nelson discovered that modifying the well-known Wilkinson catalyst makes allylic substitutions more discriminating than had been possible previously.They found that in situ exchange of the phenyl ligands in the Wilkinson catalyst--the rhodium complex [ ( C6H5 ) 3P ] 3RhCl--with triorganophosphites [ for example , trimethylphosphite or P ( OCH3 ) 3 ] produced a new catalyst.When this modified catalyst is used in alkylations of unsymmetrical allylic carbonates , the reaction has a marked selectivity for forming the more highly substituted product.That is , substitution occurs predominantly at the site of the leaving group and with that group's original stereochemistry.The reaction has memory , Evans says.It maintains the regio- and stereochemical information of the leaving group.
THE UNIQUE SELECTIVITY of the rhodium catalyst is presumably due to the electronic influence of the phosphites , Evans says.His studies suggest that the phosphite ligands cause the rhodium metal to bind to the allyl group in an unsymmetrical mode , creating a distorted rhodium-allyl complex that is stable under the reaction conditions.This complex may be described as a distorted -allyl or enyl ( + ) organorhodium intermediate.The ability to use this intermediate in synthesis has fascinated the Evans group since they discovered its unusual reactivity.
Although the exact nature of the bonding between rhodium and phosphite ligands is not entirely clear yet , it appears to prevent rapid isomerization of the rhodium-allyl complex.The complex does not isomerize relative to the rate of substitution , so that the memory of the original bond between the carbon and the leaving group is retained , Evans says.If the rate of isomerization is fast relative to substitution , the memory is either completely or partially lost..Enyl complexes of rhodium , as well as other metals , have been structurally characterized.However , the Evans lab is the first to use them as the basis of synthetic methods.
These reactions complement existing enantioselective reactions , Evans says.You may be doing a total asymmetric synthesis , and you have built this substitutable allyl in your system.Now , you can simply do the substitution with the triorganophosphite-modified rhodium catalyst and continue to build your molecule.You don't have to use a chiral catalyst every time..
Evans and graduate students Lawrence J. Kennedy , David K. Leahy , Nelson , and John E. Robinson , as well as postdoc Kristoffer K. Moffet , have very quickly exploited the unique reactivity of the triorganophosphite-modified rhodium catalyst.
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The fact that we can parlay these reactions with annulation reactions is extremely powerful for synthesis , Evans says.
Recently , for example , they have constructed bicyclic cyclopentenones by combining allylic substitution with the so-called Pauson-Khand annulation reaction.Previously , two different catalysts were required to do this.A palladium catalyst mediates addition of an alkyne to an allylic substrate.Then a rhodium catalyst mediates condensation of the enyne with carbon monoxide and ring formation.
INITIAL ATTEMPTS by Evans and Robinson to use the triorganophosphite-modified rhodium catalyst for a tandem process didn't work.
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The method developed by Evans and Robinson generates four carbon-carbon bonds and two asymmetric centers in one reaction using one catalyst [ J.
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The amount of diversity we could introduce this way is immense , Evans says.This reaction will be useful for people who want to do libraries..The two reactions are possible with only one catalyst because they have different temperature requirements.Allylic alkylation can proceed at low temperature , so it goes first.Jacking up the temperature then allows ring formation to occur.Ultimately , Evans and his group wish to incorporate these transformations into the synthesis of complex natural products.He says the new armory of synthetic transformations based on modified rhodium catalysts will allow convergent assembly of densely functionalized fragments under mild conditions.
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