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

Sims, Hunter S. and de Andrade Horn, Pedro and Isshiki, Ryota and Lim, Melissa and Xu, Yan and Grubbs, Robert H. and Dai, Mingji (2022) Catalysis-Enabled Concise and Stereoselective Total Synthesis of the Tricyclic Prostaglandin D₂ Metabolite Methyl Ester. Angewandte Chemie International Edition, 61 (5). Art. No. e202115633. ISSN 1433-7851. PMCID PMC8766936. doi:10.1002/anie.202115633. https://resolver.caltech.edu/CaltechAUTHORS:20211207-6355000

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Abstract

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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1002/anie.202115633DOIArticle
ORCID:
AuthorORCID
de Andrade Horn, Pedro0000-0001-5152-1998
Xu, Yan0000-0003-2808-7964
Grubbs, Robert H.0000-0002-0057-7817
Dai, Mingji0000-0001-7956-6426
Alternate Title:Catalysis-Enabled Concise and Stereoselective Total Synthesis of the Tricyclic Prostaglandin D2 Metabolite Methyl Ester
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.
Funders:
Funding AgencyGrant Number
NSFCHE-2102022
NIHCA023168
NIH Predoctoral FellowshipT32GM125620
NSFCHE-1625543
Subject Keywords:Carbonylation; Nickel catalysis; Olefin metathesis; Prostaglandins; Total synthesis
Issue or Number:5
PubMed Central ID:PMC8766936
DOI:10.1002/anie.202115633
Record Number:CaltechAUTHORS:20211207-6355000
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20211207-6355000
Official Citation:Catalysis-Enabled Concise and Stereoselective Total Synthesis of the Tricyclic Prostaglandin D₂ Metabolite Methyl Ester. H. S. Sims, P. de Andrade Horn, R. Isshiki, M. Lim, Y. Xu, R. H. Grubbs, M. Dai, Angew. Chem. Int. Ed. 2022, 61, e202115633; DOI: 10.1002/anie.202115633
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:112270
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:10 Dec 2021 22:43
Last Modified:21 Jan 2022 17:32

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