Optically pure trans-1-benzyl-4-aminopiperidin-3-ols. Synthesis and absolute configuration

Abstract

Enantiomerically pure trans-(3R,4R)-4-aminopiperidin-3-ols, which are convenient precursors for making natural and synthetic aminohydroxylated piperidine alkaloid analogs, were efficiently synthesized through the reaction of enantiomerically pure (3R,4S)-3,4-epoxypiperidine with amines in the presence of LiClO 4 in CH 3 CN at room temperature. The absolute stereochemistry of the resultant amino alcohols was determined by the stereochemical correlation method and single-crystal X-ray analysis.

Regio - and stereoselective synthesis of the iminosugars – 4-substituted 1-benzylpiperidine-3,5-diols

“…We have previously developed a regio-and stereospecific synthesis of racemic and enantiopure trans-4amino-1-benzylpiperidin-3-ols 17,18 via nucleophilic ring opening of epoxide 7a under mild conditions with high yields in the presence of Lewis acid (lithium perchlorate, 1 equivalent). There is a general consensus that this outcome of the nucleophilic ring opening is promoted by the bidentate coordination of epoxide 7a organized to produce only 4-substituted regioisomer.…”

“…1-Benzyl-3,4-epoxypiperidines 7a-c and 1-benzyl-1,3,5,6-tetrahydropyridine-3-ols 8a-c were prepared according to the procedures described previously. 17,18 General method for preparation of 1-benzyl-4,5-epoxypiperidine-3-ols 9a-c. To a mixture of 46.7% water solution of hydrogen peroxide (0.34 g, 4.7 mmol) and anhydrous CH2Cl2 (5ml) was added at 0 o С and vigorous stirring a solution of (CF3CO)2O (3.08 g,14.5 mmol) in anhydrous CH2Cl2 (2ml). The stirring at the same temperature was continued 1.5 h. To thus obtained solution of CF3C(O)O2H (0.19 g, 1.0 mmol) prepared from 1-benzyl-1,2,3,6-tetrahydropyridine-3-ol (8a) (0.19 g, 1.0 mmol) and CF3CO2H in anhydrous CH2CL2 (3 ml) at 0 o С.…”

“…The key allyl alcohols 8a-c were produced by rearrangement of 1-benzyl-3,4-epoxy piperidines 7а-c under the influence of lithium diisopropylamide in THF at -70 o C under argon atmosphere. 18 Epoxidation of the allyl alcohol 8a generates a single compound with a mass molecular ion (m/z 205) corresponding to the epoxy alcohol 9a, which was isolated by column chromatography on silica gel with 63% yield. The epoxy alcohols 9b,c were produced with the 58-65% yields under similar conditions.…”

Microbial Transformation of Nitrogen Containing Heterocycles

“…Many hydroxylated piperidine alkaloids are potent inhibitors of glycosidases and related enzymes (Grishina et al 2011). 4-Hydroxypiperidines are present in many drugs, such as the antidiarrhoeal loperamide and the schizophrenia medications haloperidol and benztropine (McKay et al 2010).…”

Selection and Scale-Up Evaluation of an Alternative Route to (−)-(3R,4R)-1-Benzyl-4-(benzylamino)piperidin-3-ol

“…The final sequence considered ( Route D ) featured an alternative synthesis of the epoxide ( 18 ) used in Route C , albeit in racemic form ( 22 ) . After opening with BnNH 2 , (±)- 4 was produced in 50% yield (5 steps, unoptimized) from inexpensive and readily available benzyl chloride ( 19 ) and pyridine ( 20 ) .…”