Saunders J, Showell G A, Baker R, Freedman S B, Hill D, McKnight A, Newberry N, Salamone J D, Hirshfield J, Springer J P
J Med Chem. 1987 Jun;30(6):969-75. doi: 10.1021/jm00389a003.
The four separated isomers of the muscarinic agonist 1, previously known as AF30, have been synthesized by a route that has allowed the absolute stereochemistry of each isomer to be assigned. With the chirality of (-)-camphanic acid known, X-ray analysis of the more crystalline intermediate diastereomeric camphanate 5A allowed the absolute stereochemistry at the quinuclidine chiral center to be determined. Each diastereomer was separately transformed into the spirodioxolane with concomitant introduction of the second chiral center. Chromatographic separation followed by a second crystal structure determination revealed the absolute stereochemistry of all four isomers of 1. Detailed biological evaluation of each isomer indicated that while the 3(R),2'(S) isomer was the most active in binding studies, it was the 3(R),2'(R) isomer that displayed the largest functional selectivity between ganglion (M-1 site) and heart (M-2 site). With the same internal chiral standard, the absolute configuration of the more active enantiomer of 3 was shown to be S, confirming earlier literature reports.
毒蕈碱激动剂1（以前称为AF30）的四种分离异构体已通过一种方法合成，该方法能够确定每种异构体的绝对立体化学结构。已知（-）-樟脑酸的手性，对结晶性更强的非对映体樟脑酸酯5A进行X射线分析，从而确定了奎宁环手性中心的绝对立体化学结构。每个非对映体分别转化为螺二氧戊环，同时引入第二个手性中心。通过色谱分离并进行第二次晶体结构测定，揭示了1的所有四种异构体的绝对立体化学结构。对每种异构体的详细生物学评估表明，虽然3（R），2'（S）异构体在结合研究中活性最高，但显示出神经节（M-1位点）和心脏（M-2位点）之间最大功能选择性的是3（R），2'（R）异构体。使用相同的内部手性标准，3的活性更高的对映体的绝对构型显示为S，这证实了早期文献报道。
