Solid-phase Synthesis of [4.4] Spirocyclic Oximes

Here we present a protocol to demonstrate an efficient method for the synthesis of spirocyclic heterocycles. The five-step process utilizes solid-phase synthesis and regenerating Michael linker strategies. Generally difficult to synthesize, we present a customizable method for the synthesis of spirocyclic molecules otherwise inaccessible to other modern approaches.

Transcript

This solid-phase organic synthetic technique may find applications in the construction of a combinatorial library, while synthesis of het spirocyclic heterocycles, which can be tested for anti-cancer activities using bioassays. Though this method can be used for the synthesis of spirocyclic compounds, it can also be applied to other small molecules, such as isoxazolines and isoxazoles. To begin the synthesis, add to a 25 millileter solid-phase reaction vessel one gram of REM resin, 20 millileters of dimethylformamide, and 2.4 milliliters of furfurylamine.

Cap the vessel and agitate it for 24 hours on a shaker at room temperature to load the resin with furfurylamine. Then drain the furfurylamine bearing resin and agitate it for about three minutes in five milliliters of DMF to wash it. After that, wash the resin four times, alternating between five milliliters of dichloromethane to swell the resin, and five milliliters of methanol to contract the resin.

Then thoroughly dry the resin with compressed air, which usually takes about 30 minutes. Next, in a well ventilated fume hood, add 1.48 milliliters of triethylamine, 10 milliliters of anhydrous toluene, and 637 grams of beta nitrostyrene to the dry furfurylamine bearing resin. Add one milliliter of trimethylsilyl chloride to the reaction mixture.

And leave the vessel open until the mixture has finished releasing hydrochloride gas. Then cap the vessel and agitate the mixture for 48 hours at room temperature to form the isoxazole intermediate. After that, add five milliliters of methanol to quench the reaction.

Shake the mixture for three minutes, and then let it soak for two minutes. Then drain the resin and wash it four times, alternating between five milliliters of DCM, and five milliliters of methanol. Thoroughly dry the washed resin with compressed air.

Next, add one milliliter of anhydrous tetrahydrofuran to the dry resin. Then add 1.24 milliliters of a one molar solution of tetra-n-butylammonium flouride in the THF and agitate the mixture at room temperature for 12 hours to open the isoxazole ring. Afterward, strain the resin and wash it with five milliliters of THF, followed by four washes alternating between five milliliters of DCM and five milliliters of methanol.

Dry the resin thoroughly with compressed air. Next, add five milliliters of DMF to the resin, followed by one milliliter of one-bromooctane. Agitate the mixture for 24 hours at room temperature to form the quaternary amine.

Then drain the resin and wash it with five milliliters of DMF. Wash the resin four more times, alternating between DCM and methanol, and dry with compressed air. Next, add three milliliters of DCM to the dry resin, followed by 1.5 milliliters of TEA.

Agitate the mixture for 24 hours to cleave the spirocyclic oxime from the polymer support. Then, collect the crude product in a vial or flask. Wash the resin four times, alternating between DCM and methanol, and collect the washes in the product vial.

Remove volatiles from the product mixture on a rotary evaporator. Then, triturate the crude product with 5 milliliters of boiling methanol, and carefully remove the liquid. Wash the resin twice with five milliliter portions of DCM and dry it with compressed air for reuse in subsequent experiments.

Spirocyclic oximes with various substituents were synthesized with excellent stereoselectivity. The overall yield indicates an average of 80 to 88%yield for each synthetic step. The reaction progress up through the isoxazole ring opening can be monitored by IR spectroscopy.

Generally, individuals new to this method struggle with selecting the appropriate polymer support linker. It is essential for the linker to be robust to all reaction conditions during the synthesis. While attempting this procedure, remember to wash and dry the resin before the next reaction step.

Leftover reagents from the previous step will complicate the overall synthesis and will affect the yield and purity of the spirocyclic product.

Read Article

Journal (Chemistry)

Journal (Chemistry)

Solid-phase Synthesis of [4.4] Spirocyclic Oximes

Chapters

Transcript

Related Videos

Get cutting-edge science videos from JoVE sent straight to your inbox every month.

Your free access has ended.