SN2 reaction of 2-substituted 3-piperidinol mesylate with retention of configuration: application to the asymmetric synthesis of (2R,3S)-CP-99,994

Starting from protected (S)-3-hydroxyglutarimide 2a, the asymmetric synthesis of (2R,3S)-CP-99,994 8 was achieved. The crucial steps were a neighboring group participation leading to pyrrolidino-aziridinium intermediate 25 and the subsequent regioselective ring-opening reaction. In the case where neighboring group participation was not involved, only the eliminated product 15 was obtained.

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(5S,6R)-5-Hydroxyl-1-(4-methoxybenzyl)-6-phenyl-2-piperidinoneC19H21NO3[α]D20=+53.0 (c 1.0, CHCl3)Source of chirality:(S)-glutamic acidAbsolute configuration:(5S,6R)

(2R,3S)-3-Hydroxyl-1-(4-methoxybenzyl)-2-phenylpiperidineC19H23NO2[α]D20=-18.5 (c 1.0, CHCl3)Source of chirality:(S)-glutamic acidAbsolute configuration:(2R,3S)

(2R,3S)-3-[N-(2-Methoxybenzyl)-N-(2-nitrobenzenesulfonyl)]amino-1-(4-methoxybenzyl)-2-phenylpiperidineC33H35N3O6S[α]D20=-7.1 (c 1.0, CHCl3)Source of chirality:(S)-glutamic acidAbsolute configuration:(2R,3S)

(2R,3S)-3-[N-(2-Aminobenzenesulfonyl)-N-(2-methoxybenzyl)]amino-2-phenyl piperidineC25H29N3O3S[α]D20=+91.7 (c 0.2, CHCl3)Source of chirality:(S)-glutamic acidAbsolute configuration:(2R,3S)

(2R,3S)-3-(2-Methoxybenzyl)amino-2-phenylpiperidineC19H24N2O[α]D20=+73.4 (c 0.4, MeOH, dihydrochloride)Source of chirality:(S)-glutamic acidAbsolute configuration:(2R,3S)

(5S,6R)-5-Hydroxyl-1-(4-methoxybenzyl)-6-methyl-2-piperidinoneC14H19NO3[α]D20=+64.1 (c 1.6, CHCl3)Source of chirality:(S)-glutamic acidAbsolute configuration:(5S,6R)

(2R,3S)-3-Hydroxyl-1-(4-methoxybenzyl)-2-methylpiperidineC14H21NO2[α]D20=-32.7 (c 2.1, CHCl3)Source of chirality: (S)-glutamic acidAbsolute configuration: (2R,3S)

(2R,3S)-3-[N-(2-Methoxybenzyl)-N-(2-nitrobenzenesulfonyl)]amino-1-(4-methoxybenzyl)-2-methylpiperidineC28H33N3O6S[α]D20=-50.4 (c 1.4, CHCl3)Source of chirality: (S)-glutamic acidAbsolute configuration: (2R,3S)

(2R,3R)-3-[N-(2-Methoxybenzyl)-N-(2-nitrobenzenesulfonyl)]amino-1-(4-methoxybenzyl)-2-methylpiperidineC28H33N3O6S[α]D20=+10.2 (c 2.3, CHCl3)Source of chirality: (S)-glutamic acidAbsolute configuration: (2R,3R)