Strategy for the Enantioselective Synthesis of trans-2,4-Disubstituted Piperidines:  Application to the CCR3 Antagonist IS811

Abstract

A strategy for the enantioselective synthesis of trans-2,4-disubstituted piperidines is proposed and applied to the preparation of IS811, a potent CCR3 antagonist. The C2 stereocenter is derived from commercial (R)-epichlorohydrin, while the C4 stereocenter is installed via diastereoselective hydrogenation of an alpha,beta-unsaturated lactone intermediate. Inversion of the original stereocenter via an efficient intramolecular S(N)2 amination affords the piperidine core of IS811. An improved protocol for the lithiation of ethyl propiolate is reported.

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“…89 We were pleased to observe that this hypothesis was borne out and that 34l inhibited significantly fewer off-targets than 17 in a panel of approximately 40 receptors and enzymes known to be associated with toxicity in vivo. 99 Very importantly, 34l and other aryl-substituted compounds showed markedly improved tolerability in efficacy studies at higher doses compared to 17 and 30a. None of these aryl-substituted compounds tested significantly affected PXR activity at concentrations up to 10 μM.…”

“…The epoxide undergoes a Payne rearrangement to afford the epoxide 47 in an enantioselective manner. 99 The aniline 45 was added to this epoxide employing conditions similar to those of Albanese et al 100 Potassium carbonate together with tetrabutyl ammonium bromide makes the anion of the sulfonamide 45, effects the opening of the epoxide, and catalyzes the benzoxazine ring closure to prepare 48. Pd-mediated Suzuki reaction with (2,5difluorophenyl)boronic acid affords after hydrolysis with the strongly acidic mixture of concentrated HCl, sulfuric acid, and acetic acid, the benzoxazine 49 (the enantiomer of 37a).…”

“…Since this change decreases the possible locations of the pendant aryl ring, it was anticipated that it may increase the selectivity versus off-targets . We were pleased to observe that this hypothesis was borne out and that 34l inhibited significantly fewer off-targets than 17 in a panel of approximately 40 receptors and enzymes known to be associated with toxicity in vivo . Very importantly, 34l and other aryl-substituted compounds showed markedly improved tolerability in efficacy studies at higher doses compared to 17 and 30a .…”

“…Its coupling partner was the ( R )-2,2-dimethyl-3-(oxiran-2-yl)­propanenitrile 47 prepared from the addition of n -butyl lithium dropwise 2-methylpropanenitrile in the presence of ( R )-2-(chloromethyl)­oxirane 46 . The epoxide undergoes a Payne rearrangement to afford the epoxide 47 in an enantioselective manner . The aniline 45 was added to this epoxide employing conditions similar to those of Albanese et al Potassium carbonate together with tetrabutyl ammonium bromide makes the anion of the sulfonamide 45 , effects the opening of the epoxide, and catalyzes the benzoxazine ring closure to prepare 48 .…”