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

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 ¹⁸ O-tricyclic-PGDM-based assay used in clinical settings for inflammation.

Keywords: Carbonylation; Nickel catalysis; Olefin metathesis; Prostaglandins; Total synthesis.

Figure 1.

Clinical use of tricyclic-PGDM methyl ester and its synthesis

Figure 2.

Carbonylative spirolactonization and retrosynthetic analysis.

Scheme 1.

Total synthesis of tricyclic-PGDM methyl ester (3). TBS = tert-butyldimethylsilyl, NIS = N-iodosuccinimide, DCM = dichloromethane, TBAF = tetrabutylammonium fluoride, DMAP = 4-(dimethylamino)pyridine, DIPEA = N,N-diisopropylethylamine, AIBN = 2,2’-azobis(2-methylpropionitrile), THF = tetrahydrofuran, DCE = 1,2-dichloroethane, DDQ = 2,3-dichloro-5,6-dicyano-p-benzoquinone, KHMDS = potassium bis(trimethylsilyl)amide.