使用氯化镁除去三苯基氧膦
Mitsunobu反应是一种SN2反应，在三苯膦（PPh3）和偶氮二甲酸二乙酯（DEAD）作用下酸和醇缩合成酯的方法。当底物为仲醇的时候，与羟基相连的碳原子的构型会发生翻转。
文章中，用NaBH4还原酮得到11:1的cis构型和trans构型的醇。为了得到trans构型的氰基产物，通过Mitsunobu反应进行酯缩合，实现了构型翻转。
众所周知，反应中产生的副产物（byproduct）三苯基氧膦（TPPO）是一种很难除去的杂质。在小规模的应用方面，可以通过键合和生成水溶性的衍生物除去三苯基氧膦（TPPO）。但是，由于成本和实用性的限制，在大规模生产不能实现。
作者通过文献调研发现，金属卤代物能和三苯基氧膦（TPPO）形成络合物，尤其是氯化镁。当将氯化镁加入至该Mitsunobu反应液中，发现上清液中的三苯基氧膦（TPPO）含量降低了10-20%。为了更有效地除去三苯基氧膦（TPPO），作者认为溶剂起到关键的作用。在进行溶剂筛选的过程中发现，甲苯溶液能除去大于95%的三苯基氧膦（TPPO），而二氯甲烷只能除去约50%的三苯基氧膦（TPPO）。
作者怀疑造成的这个现象的原因有二：1.在二氯甲烷中有好的溶解性；2.络合物在二氯甲烷中分解。为了验证猜测，将用过量氯化镁处理三苯基氧膦（TPPO）后得到的二氯甲烷溶液进行浓缩，并用XRD、NMR和ICP等方法进行分析。
XRD证实形成了该络合物为一种独特的化合物，其衍射图谱与氯化镁和三苯基氧膦（TPPO）均不同。该络合物的1H NMR显示芳香族氢相对于TPPO参考物的位移略有下降，且磷和镁的ICP数据显示该络合物中三苯基氧膦（TPPO）与氯化镁的比值为1:1。
操作如下：
A mixture of alcohols 9, 14(∼50% solution in toluene, 200 g, 0.58 mol),2-chloro-4-hydroxynebzonitrile(84.5 g, 0.55 mol), and triphenylphosphine (175g, 0.67 mol) in toluene (700 mL) wascooled to 0−5 °C and diethylazadicarboxilate (DEAD, 40% solution in toluene, 300 g, 0.69 mol) was added at <25°C. The reaction mixture was thenheated to 25−30 °C until the reaction wascomplete (<5% s.m. by HPLC,typically 20 h). Then magnesium chloride(325 mesh powder, 130 g, 1.34 mol) was charged and the mixture was heated to 60 °C. The mixture wasdiluted with heptanes (700 mL) andheating was continued until TPPO concentration in the supernatant was reduced below 5% versus original value (typically 2 h). The mixture wascooled to ambient temperature and filtered to remove the solids. The filtercake was washed withtoluene−heptanes (700 mL) and the combined filtrate was concentratedin vacuo and chased with IPA to approximately 450mL volume. Themixture was diluted with IPA to approximately 600 mL volume and cooled to below 10°C. As product precipitation wasobserved the mixture was further diluted with 2:1 IPA−water (1.5 L) to precipitate theremaining product. The product was filtered, washed with IPA-water, and dried under vacuumat 50 °C to yield 15 (145 g, 81%). The material contains 4−5% of cis-isomer 15b.