Ying Weijiang, Herndon James W
Department of Chemistry and Biochemistry, New Mexico State University, MSC 3C, Las Cruces, NM 88003 USA.
European J Org Chem. 2013 May 1;2013(15). doi: 10.1002/ejoc.201300200.
The tylophorine alkaloid anticancer compounds antofine and cryptopleurine have been synthesized in optically active form. Both syntheses employ optically pure α-amino acids as the starting materials, require only seven steps from known 2-ethynylpyrrolidine or 2-ethynylpiperidine derivatives, and are free of protecting groups. Key steps include an alkyne hydration and a chromium carbene complex based net [5+5]-cycloaddition step. Alkyne hydration was accompanied by racemization of the resulting β-aminoketone under most of the conditions examined, and successful minimization of this side reaction was achieved through careful pH control and choice of metal additive. Final ring closure involves a Bischler-Napieralski reaction using a carbamate (antofine) or urea (cryptopleurine) precursor.
娃儿藤碱类抗癌化合物安托芬和隐肋娃儿藤碱已被合成出旋光活性形式。两种合成方法均采用光学纯的α-氨基酸作为起始原料，从已知的2-乙炔基吡咯烷或2-乙炔基哌啶衍生物出发仅需七步反应，且无需保护基团。关键步骤包括炔烃水合反应以及基于铬卡宾配合物的净[5+5]环加成反应。在大多数考察条件下，炔烃水合反应会伴随着所得β-氨基酮的外消旋化，通过仔细控制pH值和选择金属添加剂成功将该副反应降至最低。最终的环化反应涉及使用氨基甲酸酯（安托芬）或尿素（隐肋娃儿藤碱）前体的Bischler-Napieralski反应。
