Volume 86 Issue 26 | p. 11 | News of The Week
Issue Date: June 30, 2008

Constructing Cyanthiwigin F

Enantioselective double alkylation is key to engineering marine natural product's chiral core
Department: Science & Technology
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Synthetic Strategy
Stoltz and Enquist's synthesis of (–)-cyanthiwigin F starts with diallyl succinate, which self-condenses into a diastereomeric mix of the bis(β-ketoester) intermediate. A double catalytic enantioselective alkylation then establishes two quaternary chiral centers, with the desired R,R isomer as the major product.
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Synthetic Strategy
Stoltz and Enquist's synthesis of (–)-cyanthiwigin F starts with diallyl succinate, which self-condenses into a diastereomeric mix of the bis(β-ketoester) intermediate. A double catalytic enantioselective alkylation then establishes two quaternary chiral centers, with the desired R,R isomer as the major product.

IN JUST NINE chemical transformations, researchers at Caltech have managed to synthesize the marine diterpenoid (–)-cyanthiwigin F (Nature 2008, 453, 1228). Their synthetic strategy, which establishes the molecule's two quaternary chiral centers in one step, could be used to access the 29 other cyanthiwigin natural products, the authors note. Although this class of compounds has shown promising biological activity, only two other cyanthiwigins have been made to date.

With only 20 carbon atoms, cyanthiwigin F may not seem like a particularly tough target, but the four stereocenters buried within the molecule's central six-membered ring pose a challenge, particularly the two all-carbon quaternary chiral centers. The compound also has few functional-group "handles" to latch onto for synthetic machinations, notes graduate student John A. Enquist, who completed the synthesis along with chemistry professor Brian M. Stoltz.

Enquist and Stoltz decided to tackle the quaternary stereocenters in the early stages of their synthetic scheme through a protocol previously developed in their lab. The methodology uses a chiral palladium catalyst to mediate the asymmetric alkylation of cyclic ketone enolates. Enquist and Stoltz reasoned they could make the catalyst do double duty and generate both quaternary chiral centers in a single step.

"We knew what configuration to expect for a single enantioselective transformation," Enquist says. "We were hoping that we could then extend that to the other side of the molecule."

The process is stereoablative—the starting compound's stereochemistry is destroyed in the chemical transformation. So even though they started with a bis(β-ketoester) that was a mix of R,R; S,S; and meso configurations, the double alkylation generated the desired R,R diketone in a 4.4:1 ratio over the meso diketone. Virtually none of the S,S diketone was produced.

The synthesis' other highlights include a Claisen-Diekmann cyclization to knit the bis(β-ketoester) from diallyl succinate starting material, ring-closing metathesis and cross-metathesis reactions done in tandem, and a thiol-mediated radical cyclization. Of the scheme's nine steps, four generate more than one C–C bond in a single transformation.

"By any standards, the synthesis is a classic with a magnificently orchestrated functionalization of the key intermediate," comments Andrew J. Phillips, a chemistry professor at the University of Colorado, Boulder.

Pier Giorgio Cozzi, a chemistry professor at Italy's University of Bologna, calls the work a "stunning accomplishment," adding that the critical one-pot multiple asymmetric alkylation strategy could be extended to generate quaternary chiral centers in multicomponent, domino, and cascade reactions.

 
Chemical & Engineering News
ISSN 0009-2347
Copyright © American Chemical Society

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