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Volume 85 Issue 32 | Web Exclusive
Issue Date: August 6, 2007

Cover Stories: Centering On Chirality

New Horizons Along Asymmetric Routes

Academic researchers describe new synthetic approaches at Chiral Chemistry meeting
Department: Business, Education
MAKING BONDS
Palladium-catalyzed asymmetric allylic alkylation using Trost's chiral ligand can generate a range of bond types.
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MAKING BONDS
Palladium-catalyzed asymmetric allylic alkylation using Trost's chiral ligand can generate a range of bond types.

THE PUSH-PULL RELATIONSHIP between academia and industry was evident at the Modern Synthetic Methods & Chiral USA meeting held by Scientific Update last month in Philadelphia. Pharmaceutical companies depend to a great extent on university researchers to come up with new reactions, and academics in turn get funded by industry. In asymmetric synthesis, the number of known reactions far exceeds the number industry has been able to implement practically in large-scale processes. This topic is explored in the Cover story of the Aug. 6 issue of C&EN.

"Industry thinks there's only one way of doing asymmetric synthesis, and that is by catalytic hydrogenation," Stanford University professor Barry M. Trost said good-naturedly after hearing the first few industrial presentations. "But asymmetric C–C bond formation can be very useful."

Trost then described the wealth of natural product syntheses his group has achieved via asymmetric allylic alkylations. He says he's excited about this class of reactions because, more so than other types of reactions such as hydrogenations and oxidations, this class offers many mechanisms for determining enantioselectivity.

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WASTE NOT
Krische's synthetic strategy reroutes intermediates of conventional hydrogenation reactions to form C—C bonds, leading to a new source of diverse products without forming by-products. A chiral ligand on the catalyst yields enantioenriched products (X = O or NR).
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WASTE NOT
Krische's synthetic strategy reroutes intermediates of conventional hydrogenation reactions to form C—C bonds, leading to a new source of diverse products without forming by-products. A chiral ligand on the catalyst yields enantioenriched products (X = O or NR).

The methodology's other power is the ability to form a large number of different bond types (C–O, C–N, C–S, C–P, C–C, C–H) using the same catalyst system, he told attendees. This ability distinguishes it from catalytic hydrogenation, which, according to the most traditional definition, makes only C–H bonds. Dowpharma has licensed Trost's catalysts, and the technology has found some limited use in pharmaceutical syntheses.

Recent work by Michael J. Krische, a chemistry professor at the University of Texas, Austin, may challenge the definition of catalytic hydrogenation or at least what to call reactions in which intermediates in hydrogenation processes are intercepted and rerouted to make C–C coupling products. Krische has called it "C–C bond-forming hydrogenations" or "hydrogen-mediated C–C bond formation."

In the atom-efficient, by-product-free reactions, unsaturated organic molecules, when exposed to hydrogen gas and a catalyst, are both hydrogenated and joined via a C–C bond to create a single, more complex product. His work has been recognized by a Presidential Green Chemistry Challenge Award (C&EN, July 9, page 35), as well as the Dowpharma Prize for Creativity in Chiral Chemistry, which was awarded at the meeting.

"Numerous possibilities emerge in how one can view molecules retrosynthetically," Krische told attendees, and he offered examples for the syntheses of drugs such as Merck's Vasotec and AstraZeneca's Zestril, both used to treat hypertension and heart failure, as well as pain relievers ibuprofen and naproxen. He also showed numerous examples in which the use of chiral ligands in transition-metal catalysts yields products in high enantiopurity.

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POLYMETHYL CHAIN
Burgess prepared deoxypolyketide structure 1 with diastereoselective hydrogenations using an iridium catalyst (2).
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POLYMETHYL CHAIN
Burgess prepared deoxypolyketide structure 1 with diastereoselective hydrogenations using an iridium catalyst (2).

Gold catalysts can also be used in enantioselective C–C, C–N, and C–O bond-forming reactions, F. Dean Toste, a chemistry professor at the University of California, Berkeley, reported at the meeting. Toste and coworkers have demonstrated the utility of chiral phosphine gold(I) catalysts in enantioselective cyclopropanation, hydroamination, cycloaddition, hydroalkoxylation and hydrocarboxylation reactions. Toste also described the use of chiral anions in enantioselective reactions, a concept that may have utility beyond gold-catalyzed reactions (C&EN, July 30, page 17). According to Toste, some of these reactions are being used by medicinal chemists.

Cambridge University professor Matthew J. Gaunt presented a range of catalytic approaches, including enantioselective organocatalysis using cinchona alkaloid-based catalysts. His research group has discovered asymmetric cyclopropanation reactions that exploit ammonium ylide catalytic intermediates, and more recently, they have explored enantioselective tandem and cascade processes for forming complex chiral molecules.

Taking another approach to catalysis, Kevin Burgess, chemistry professor at Texas A&M University, has developed iridium imadazolylidine-oxazoline complexes. These complexes are particularly useful in the asymmetric hydrogenation of largely unfunctionalized alkenes, which are more challenging substrates than functionalized alkenes.

Burgess offered a new approach using his catalysts for the enantio- and diastereoselective hydrogenation of dienes and polyenes. Through catalyst-controlled hydrogenations, two chiral centers can be formed simultaneously and with high diastereoselectivity. This approach enables access to deoxypolyketide chiral building blocks found in many natural products (Chem.—Eur. J., DOI: 10.1002/chem.200700390).

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SHORT CUT
One-pot process developed by Walsh generates enantioenriched diarylmethanols.
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SHORT CUT
One-pot process developed by Walsh generates enantioenriched diarylmethanols.

Enantioenriched diarylmethanols are useful intermediates in drug syntheses. To make them, chemistry professor Patrick J. Walsh and graduate student Jeung Gon Kim at the University of Pennsylvania developed a catalytic asymmetric addition that uses readily available aryl halides instead of expensive diarylzinc or aryl boron-containing reagents. They also telescoped the reaction to generate aryl zinc reagents in situ from aryl bromides to which they add aldehydes in the presence of a chiral amino alcohol catalyst (Angew. Chem., Int. Ed. 2006, 45, 4175).

On a related note, Walsh also presented new results on the direct asymmetric synthesis of (Z)-allylic alcohols. The method involves what Walsh and graduate student Luca Salvi described as the first general catalytic asymmetric addition of (Z)-vinyl groups to aldehydes. They showed that these substrates can be used in tandem addition/epoxidation reactions to provide epoxy alcohols with three contiguous stereocenters.

When asked about their colleagues in universities, many industry researchers expressed a similar sentiment: Cutting-edge academic research typically targets a complexity of transformations that aren't yet applied in industry, but ahead of the curve is exactly where the academics should be.

 
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