In this work, we present the synthesis of (hereafter referred to as 4β ), a synthetic carbocyclic analogue designed to resist metabolic degradation while retaining high EP4 binding affinity. The synthesis focuses on the stereocontrolled installation of the 15(S)-hydroxyl group—a critical pharmacophore for receptor activation—and the replacement of the labile carboxylic acid with a stable heterocyclic bioisostere. 2. Results and Discussion 2.1. Retrosynthetic Analysis The target molecule 4β consists of a cyclopentane core bearing three distinct side chains. Retrosynthetically, the molecule was disconnected into three key fragments: a protected cyclopentene core ( A ), an upper side-chain boronic ester ( B ), and a lower side-chain vinyl iodide ( C ). This disconnection strategy allows for the late-stage introduction of the $\omega$-chain, facilitating rapid analogue generation. 2.2. Synthesis of the Cyclopentane Core Synthesis commenced with commercially available cyclopentadiene. A Diels-Alder reaction followed by oxidative cleavage provided the racemic cyclopentenone intermediate. Enzymatic resolution utilizing lipase PS-30 yielded the enantiomerically pure intermediate 1 . Download- Fblite-video-3.mp4 -3.06 Mb- Page
Stereoselective Synthesis and Biological Evaluation of a Novel Carbocyclic EP4 Receptor Agonist: “Compound 4β” Video Title- Jills Mohan - Keerthana Mohan Show...
Step 2: Stereoselective Reduction. To a solution of ketone (2.0 g, 4.2 mmol) in dry THF (50 mL) at -78 °C was added L-Selectride (1.0 M in THF, 5.0 mL, 5.0 mmol) dropwise. The reaction was stirred for 2 h at -78 °C. The reaction was quenched with NaOH solution and H₂O₂, warmed to room temperature, and extracted with EtOAc. The organic layer was dried over Na₂SO₄ and concentrated. The diastereomers were separated via flash chromatography to isolate the desired 4β isomer.
EP4 Agonist, Prostaglandin Analogue, Stereoselective Synthesis, Bone Healing, Palladium Catalysis. 1. Introduction Prostaglandin E2 (PGE2) is a major cyclooxygenase metabolite of arachidonic acid, exerting diverse physiological effects via four distinct G-protein coupled receptors: EP1, EP2, EP3, and EP4. Among these, the EP4 receptor has garnered significant pharmaceutical interest due to its role in stimulating bone formation and repair, as well as its gastroprotective properties. Unlike non-steroidal anti-inflammatory drugs (NSAIDs), which block prostaglandin synthesis and can inhibit bone healing, selective EP4 agonists have shown the potential to accelerate fracture repair without the systemic toxicity associated with PGE2.
However, the clinical translation of early EP4 agonists has been hindered by chemical instability, particularly the rapid enzymatic oxidation of the 15-hydroxyl group by 15-hydroxyprostaglandin dehydrogenase (15-PGDH). To overcome this, the design of "synthetic EP4" analogues often focuses on modifying the upper $\omega$-chain and stabilizing the lower $\alpha$-chain via carbocyclic or heteroatom substitutions.
Step 3: Hydrolysis. To a solution of the ester (1.0 g, 2.0 mmol) in MeOH/THF/H₂O (1:1:1, 30 mL) was added LiOH·H₂O (168 mg, 4.0 mmol). The reaction was stirred at 25 °C for 4 h. The solvent was removed under reduced pressure, and the residue was purified by reverse-phase HPLC to yield the title compound as a white solid.