Kauffman Goss S, Watson Paul S, Nugent William A
Process Research and Development Department, Bristol-Myers Squibb Company, P.O. Box 4000, Princeton, New Jersey 08543, USA.
J Org Chem. 2006 Nov 10;71(23):8975-7. doi: 10.1021/jo0616963.
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.
提出了一种对映选择性合成反式-2,4-二取代哌啶的策略，并将其应用于制备强效CCR3拮抗剂IS811。C2立体中心源自市售的(R)-环氧氯丙烷，而C4立体中心则通过α,β-不饱和内酯中间体的非对映选择性氢化引入。通过高效的分子内S(N)2胺化作用使原始立体中心发生构型翻转，得到IS811的哌啶核心。报道了一种改进的丙炔酸乙酯锂化方法。
