Piperidines aminoalcohols

Treatment of the piperidine 74, obtainable from an aminonitrile such as 73, under N-methylation conditions leads to the dimethylamino derivative 75. The carbobenzoxy protecting group is then removed by catalytic hydrogenation. Reaction of the resulting secondary amine 76 with cyclohexene oxide leads to the alkylated trans aminoalcohol. There is thus obtained the anti-arrhythmic agent transcainide (77) [18]. 

In one example of this type of cyclization aminoalcohol, 288, which was obtained by conjugate addition of racemic 2-(2-hydroxyethyl)piperidine to allyl phenyl sulfone, was converted into the corresponding chloride and cyclized in the presence of LDA to give 289 as a single diastereomer (Scheme 63) <2003JOC9389>. In a related approach, the primary alcohol group was activated for a similar cyclization by transformation into a mesylate <20010L2957>. 

Amine/aminoalcohol Resin (22). A suspension of Merifield resin (5 g, 4.3 mmol Cl/g resin, 21.5 mmol) and morpholine (5.2 ml, 60 mmol) in DMF (35 ml) was treated with piperidin-3-yl-methanol (2.3 g, 20 mmol) at 65° for 6 h under a nitrogen atmosphere. Upon cooling to RT, the resin was filtered and washed with DMF, MeOH, Et3N, DMF, MeOH, Et3N, MeOH, DCM, MeOH, DCM, and EtOAc. The resulting amine/aminoalcohol resin was dried at 45° under vacuum overnight. 

Similarly, fV-BOC-aminoalcohols can be subjected to Mitsunobu reaction conditions to yield the piperidine structure 10 (Equation 26) <2004JOC2229>, which is an intermediate in the synthesis of galactohomonojirimycin (BOC = /-butoxycarbonyl). Cyclization of an iV-BOC derivative of an aminoalcohol mesylate was reported in the synthesis of enantiopure 3-hydroxy-4-phenylpiperidine derivatives starting from L-phenylglycine <2004TL987>. 

Ring formation by reaction of a A nucleophile on an electrophilic carbon atom continues to be a reliable route to piperidines. The examples shown in Scheme 54, 55 and 56 demonstrate recent applications of closure of nitrogen on an s -carbon atom. Treatment of an aminoalcohol 138 with PhjP/CBrii/TEA afforded the polyhydroxyindolizidine alkaloid precursor 139... 

Supported chiral bispidine-derived aminoalcohols were screened in the addition of diethylzinc to benzaldehyde [133]. These immobilized ligands were obtained in three steps from eompound 186 isolated from iV-Boc-piperidin-4-one (Scheme 79). The hydroxyl function of 186 was first linked onto ehloromethylated polystyrene to afford polymer 187. The carbamate was then removed under elassical conditions and reaction of the resulting polymer with chiral epoxides led to ehiial polymeric bispidine-derived aminoalcohols 188. 

A DFT study of the desymmetrization of a cyclic meio-anhydride, 5-norbornene-enr/o-l,2-dicarboxylic anhydride, by MeOH catalysed by a chiral )8-aminoalcohol, (l/ ,2/ )-2-(piperidin-l-yl)cyclohexanol, to form the corresponding chiral monomethyl ester showed that a general base mechanism in which the intermediate oxyanion is stabilized by the hydroxyl group of the catalyst is favoured over a nucleophilic mechanism. ... 

In the context of our studies on the use of aminoalcohol-derived lactams as building blocks for the enantioselective synthesis of substituted piperidines... 

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