Chiral, non-racemic piperidines are found in natural products such as alkaloids and are important building blocks for the construction of prescription drugs. Stoichiometric chiral ammonia equivalents such as R-tert-butanesulfinamide developed by Ellman provide access to enantiopure R or S N-sulfinyl imines. A series of ortho, meta, and para substituted benzaldehydes were treated with R-tert-butanesulfinamide and tri-isopropyl borate to afford homochiral imines in high yield without need for further purification. Allylation with stoichiometric powder indium metal and allyl bromide in tetrahydrofuran or N,N-dimethylforamide at 70 degrees C afforded homoallylic amines in high yield and high diastereoselectivity. Based on Ellman’s cyclic transition state model and prior work by Yus, allylation occurs from the si face to give the S diastereomer at the benzylic carbon. The amine free base was isolated after deprotection of the N-sulfinyl chiral auxiliary under acidic conditions with 4 molar HCl in dioxane. Treatment of the homoallylic amine with phthalic anhydride furnished the phthalimide that was reduced sodium borohydride to the aminal. Under acidic conditions the aminal underwent intramolecular cyclization to afford the isoindolone. The structure was fully elucidated using two-dimensional nuclear magnetic resonance experiments such as HSQC, HMBC, and NOESY. We are examining a series of benzaldehyde and aliphatic derived chiral imines to prepare enantioenriched homoallylic amines to carry through this sequence. These piperidine ring derivatives are a common heterocyclic structure found in numerous alkaloid natural products and some FDA approved drugs.

The use of chiral, non-racemic homoallylic amines as building blocks for piperidine synthesis

255th National Meeting (2018)

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