Welcome to the new version of CaltechAUTHORS. Login is currently restricted to library staff. If you notice any issues, please email coda@library.caltech.edu
Published January 26, 2022 | Accepted Version + Supplemental Material
Journal Article Open

Catalysis-Enabled Concise and Stereoselective Total Synthesis of the Tricyclic Prostaglandin D₂ Metabolite Methyl Ester


A concise and stereoselective total synthesis of the clinically relevant tricyclic prostaglandin D₂ metabolite (tricyclic-PGDM) methyl ester in racemic form was accomplished in eight steps from a readily available known cyclopentene-diol derivative. The synthesis features a nickel-catalyzed Ueno–Stork-type dicarbofunctionalization to generate two consecutive stereocenters, a palladium-catalyzed carbonylative spirolactonization to build the core oxaspirolactone, and a Z-selective cross-metathesis to introduce the (Z)-3-butenoate side chain, a group challenging to introduce through traditional Wittig protocols and troublesome for the two previous total syntheses. A general Z-selective cross-metathesis protocol to construct (Z)-β,γ-unsaturated esters was also developed that has broad functional group tolerance and high stereoselectivity. Additionally, our synthesis already accumulated 75 mg of valuable material for an ¹⁸O-tricyclic-PGDM-based assay used in clinical settings for inflammation.

Additional Information

© 2021 Wiley-VCH. Issue Online: 18 January 2022; Version of Record online: 14 December 2021; Accepted manuscript online: 06 December 2021; Manuscript received: 16 November 2021. This work was supported by NSF 2102022. The NIH CA023168 is acknowledged for supporting shared NMR resources to Purdue Center for Cancer Research. H.S. gratefully acknowledges support from the Purdue Drug Discovery Training Program (NIH T32GM125620). The XRD data was collected on a new single-crystal X-ray diffractometer supported by the NSF through the Major Research Instrumentation Program under Grant No. CHE 1625543. The authors declare no conflicts of interest. Data Availability Statement: The data that support the findings of this study are available in the Supporting Information of this article.

Attached Files

Accepted Version - anie.202115633.pdf

Accepted Version - nihms-1763138.pdf

Supplemental Material - anie202115633-sup-0001-15.cif

Supplemental Material - anie202115633-sup-0001-misc_information.pdf


Files (10.2 MB)
Name Size Download all
1.2 MB Preview Download
7.1 MB Preview Download
421.6 kB Download
1.5 MB Preview Download

Additional details

August 22, 2023
October 23, 2023